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Objective: This systematic review aims to evaluate the proactive or real-time assessment of patient reported outcomes in studies involving patients with ovarian cancer undergoing systemic therapy., Methods: PubMed, Embase, and Cochrane databases were searched (from database inception until February 2022), and prospective ovarian cancer studies (experimental or observational) that incorporated patient reported outcomes, including quality of life, were included. The primary objective was to assess the ratio of studies incorporating real-time use of patient reported outcomes among those studies performing patient reported outcomes. A secondary objective was to describe the patient reported outcome reporting. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 checklist was followed. Descriptive statistics were used., Results: 3071 articles were screened, with 117 included in the final analysis. Studies were published between 1990 and 2022, and consisted of 35 735 patients (median 140 patients per study; interquartile range 58-415). Median time from patient enrollment initiation to study publication was 7 years (range 1-15). Most studies were experimental/clinical trials (n=93, 79%) followed by observational (n=23, 20%). Therapeutic strategies were assessed in 98% (91/93) of experimental studies, most frequently chemotherapy (n=53, 58%), followed by antiangiogenics or poly-ADP ribose polymerase (PARP) inhibitors (n=8, 9%, each). Patient reported outcomes were the primary endpoint in 7.5% (7/93) and 83% (19/23) of experimental and observational studies, respectively. The ratio of real-time patient reported outcomes assessment/evaluation was 0.9% (1/117)., Conclusions: Completion of patient reported outcome questionnaires involves time and effort for patients with ovarian cancer. Responses to these questionnaires were only assessed in real time in <1% of analyzed studies. Efforts should be made to incorporate proactive assessment of patient reported outcomes to optimize patient care and safety., Competing Interests: Competing interests: AM received honoraria from AstraZeneca, Clovis, GSK, MSD, PharmaMar. SL is principal investigator or co-investigator of different clinical trials with agents from AstraZeneca, Merck, Roche, GSK, Regeneron, Repare Therapeutics, Clovis. LK received honoraria from Eisai, Novartis, GSK. PT reports a consulting or advisory role with AstraZeneca, Daiichi-Sankyo, Adamed, Novartis and Seagen. Speakers’ bureaus for Pfizer, Novartis, Lilly, AstraZeneca, Daiichi-Sankyo, Esteve, Gilead, Reveal Genomics and Seagen. Travel grants from Pfizer, Novartis, AstraZeneca and Gilead. DV received honoraria from Abbie, Agios, Amgen, Astellas, BMS/Celgene, Gebro, Grifols, Janssen, Jazz Pharmaceuticals, Kite/Gilead, MSD, Novartis, Pfizer, Sanofi, Servier, Sobi and Takeda. AMO declared uncompensated consulting or advisory role in AstraZeneca and GSK. He has uncompensated relationships with AstraZeneca and Clovis and research funding from AstraZeneca, GSK. SL declared consulting fees from AstraZeneca, GSK, Merck, Eisai, Shattuck laboratories, Repare and Seagen. The remaining authors declare no other competing interests., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Imlunestrant is an oral SERD with favorable safety and preliminary efficacy in patients with ABC. PD biomarker data can optimize drug dosing; herein is the PD data from the EMBER-2 study., Methods: Postmenopausal women with untreated, operable ER-positive, HER2-negative EBC were randomized to 400mg vs 800mg of imlunestrant daily for ~2 weeks before surgery. A single arm testing 200mg daily was later accrued. PD biomarker changes (ER, PR, Ki-67 by IHC, and mRNA expression of ER-related genes) were evaluated in paired tumor samples (pre-/ post-treatment). Safety and PK were also assessed., Results: Among evaluable paired samples (n=75), PD profiles demonstrated consistent ER targeting between 400 and 800mg doses with less toxicity at the 400mg dose. Although inducing the lowest rate of CCCA, PD and PK results were similar for the 200mg dose., Conclusion: EMBER-2 combined with existing phase 1 data has identified 400mg as the optimal imlunestrant dose.

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2 + ) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2 + mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 + mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 ., (© 2024. The Author(s).)

Purpose: This study aimed to investigate the current therapeutic management of patients with early-stage HER2-positive (HER2+) breast cancer in Spain, while also exploring the perceptions surrounding HER2DX in terms of its credibility, clinical relevance, and impact on therapeutic decision-making. Understanding these aspects is crucial for optimizing treatment strategies and enhancing patient outcomes in the context of HER2+ breast cancer., Methods: An online questionnaire was conducted by an independent third-party between April and May 2022 across 70 medical oncologists highly specialized in breast cancer management in Spain. The survey included 37 questions regarding treatment decision making in HER2+ early breast cancer., Results: The management of patients with HER2+ early breast cancer exhibited a high degree of heterogeneity. Among the interviewed oncologists, 53% would recommend upfront surgery for node negative tumors measuring 1 cm or less. Interestingly, 69% and 56% of interviewers were open to deescalate the duration of adjuvant trastuzumab in pT1a and pT1b N0 tumors, respectively. Certain clinicopathological characteristics, such as high grade, high Ki-67, and young age, influenced the decision to prescribe neoadjuvant treatment for patients with clinical stage 1 disease. In cases where neoadjuvant treatment was prescribed for cT1-2 N0 tumors, there was a wide variation in the choice of chemotherapeutic and anti-HER2 regimens. Regarding the use of adjuvant trastuzumab emtansine (T-DM1) in patients with residual disease after neoadjuvant therapy, there was diversity in practice, and a common concern emerged that T-DM1 might be overtreating some patients. HER2DX, as a diagnostic tool, was deemed trustworthy, and the reported scores were considered clinically useful. However, 86% of interviewees believed that a prospective trial was necessary before fully integrating the test into routine clinical practice., Conclusion: In the context of early-stage HER2+ breast cancer in Spain, a notable diversity in therapeutic approaches was observed. The majority of interviewed medical oncologists acknowledged HER2DX as a clinically valuable test for specific patients, in line with the 2022 SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer. To facilitate the full integration of HER2DX into clinical guidelines, conducting prospective studies to further validate its efficacy and utility was recommended., (© 2024. The Author(s).)

Introduction: Advancements in monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates (ADCs) have notably enhanced outcomes for metastatic HER2-positive breast cancer patients. Despite the expanding treatment options and clinical complexities, determining the optimal sequence of HER2-targeted therapies remains partly uncertain, influenced by various factors., Methods: To refine HER2-positive metastatic breast cancer management, particularly regarding tucatinib's position, a Steering Committee of leading oncologists in breast cancer care devised a panel of statements via a Delphi approach, focusing on five key topics: general clinical management, therapeutic approaches for patients with HER2-positive breast cancer and brain metastases, treatment sequence, and tucatinib's safety and efficacy., Results: A total of 29 statements were deliberated, with strong consensus achieved for most. However, no consensus emerged regarding the management of brain progression alongside stable extracranial disease: 48 % advocated for switching to tucatinib, while 53 % favored a stereotactic brain radiotherapy (SBRT) approach if feasible., Conclusion: The unanimous consensus attained in this Delphi panel, particularly regarding tucatinib's efficacy and safety, underscores oncologists' recognition of its clinical significance based on existing trial data. These findings align closely with current literature, shedding light on areas necessitating further investigation, not thoroughly explored in prior studies. Moreover, the results underscore the scarcity of data on managing brain progression alongside stable extracranial disease, emphasizing the imperative for dedicated research to address these gaps and yield definitive insights., Competing Interests: Declaration of competing interest PC: Consulting or Advisory Role: Daiichi Sankyo/Lilly, Reveal Genomics, Gilead Sciences; Speakers' Bureau: Roche/Genentech, Novartis, AstraZeneca, Lilly, BMS; Research Funding: Merck KGaA (Inst); Patents, Royalties, Other Intellectual Property: HER2Dx patent; Expert Testimony: AstraZeneca. EC: reports consulting fees from Novartis, Lilly, Pfizer, Roche, AstraZeneca, and Daiichi Sankyo; speaker's bureau from Lilly, Pfizer, AstraZeneca, and Daiichi Sankyo; and travel and accommodations from Pfizer and Roche. GC: received honoraria for speaker's engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, MSD; Honoraria for providing consultancy: Roche, Seattle Genetics, NanoString; Honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medi-cine, Samsung, Celltrion, Mylan; Honoraria for writing engagement: Novartis, BMS; Honoraria for participation in Ellipsis Scientific Affairs Group; Institutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, MedI- mmune MDL: advisory boards, activities as a speaker, travel grants, consultancy: Eli Lilly, Novartis, Seagen, Takeda, Roche, Daiichi Sankyo, Tomalab, Gilead, Genetic, Menarini, Sophos, AstraZeneca, Pfizer, Sanofi, Ipsen, Pierre Fabre, GSK. AG: research funding to the Institution: AstraZeneca, Pfizer, Janssen, Roche, MSD, Daichii-Sankyo, GSK/Tesaro, HiFiBio, Merck, Boehringer-Ingelheim, Exelixis, Bayer, Incyte, Bayer, Aileron; travel, accommodation, expenses: Gentili. LDM: advisory role for Agendia, Amgen, AstraZeneca, Collage SpA, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Havas Life, Pfizer, Pierre Fabre, Roche, Seagen Int, Stemline Menarini and Uvet; personal fees as an invited speaker for Accademia Nazionale Medicina, Andromeda E20, Aristea, Delphi international, Editree, Eli Lilly, Ipsen, Meeting SrL, MSD, Novartis, Over Srl, Prex Srl, Symposia and Vyvamed Srl; personal fees for writing engagements for Edizioni Minerva Medica, Pensiero Scientifico Editore and Roche; personal consultancy fees from Eli Lilly, Gilead, Kardo Srl and Sharing Progress in Cancer Care (SPCC)—Switzerland; personal fees for author slide kits from Forum service and Think2it; personal fees for interviews from Infomedica Srl and Think2it; institutional funding as a local PI from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Novartis, Novella Clinical, Roche and Seagen; institutional funding as a national coordinating PI from Roche; institutional research grant from Pfizer; and non-remunerated product samples from FoundationOne. AG: received advisory role from AstraZeneca, Daiichi, Eisai, Lilly, Novartis, Pfizer, Roche, Seagen, Gilead, Teva, and Gentili; lecture honoraria from Novartis, Pfizer, Gilead, Roche, Eisai, Seagen, Teva, and Gentili; and research support from Roche, Eisai, Gilead, and Pharmanutra AL: Research support: Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp&Dhome, Gilead, Daiichi Sankyo; Consulting/advisor: Lilly, Roche, Pfizer, Novartis; Speaker's Bureaus: Lilly, Astrazeneca, Merck Sharp&Dhome, Pfizer, Novartis; Travel support: Roche, Pfizer, Astrazeneca, Merck Sharp&Dhome. MM: Honoraria: Roche/Genentech, Lilly, Pfizer, Novartis, Pierre Fabre, Seagen; Consulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi-Sankyo; Speakers' Bureau: Lilly/ImClone, Lilly/ImClone, Roche/Genentech, Pierre Fabre; Research Funding: Novartis (Inst), Roche (Inst), Puma Biotechnology (Inst); Travel, Accommodations, Expenses: Daiichi-Sankyo; Other Relationship: Roche, Novartis. FPo: advisory board from AstraZeneca; speaking honoraria and travel grants from Eli Lilly, Novartis, Seagen, Daichii Sankyo, and Gilead. AP: reports grants and personal fees from NanoString Technologies, Veracyte, Novartis, AstraZeneca, DaiichiSankyo, and Roche; in addition, A. Prat has a patent for DNADX pending. FPu: reports honoraria for advisory boards, activities as a speaker, travel grants, research grants from Amgen - Astrazeneca - Daiichi Sankyo - Celgene - Eisai - Eli Lilly- Exact Sciences- Gilead - Ipsen – Menarini- MSD - Novartis - Pierre Fabre - Pfizer - Roche - Seagen - Takeda – Viatris; Research funding from Astrazeneca – Eisai – Roche. CS: consultancy or advisory role for AstraZeneca, Ax's Consulting, Byondis, Daiichi Sankyo, Eisai, Exact Sciences, Exeter, F. Hoffmann-La Roche Ltd., International Society for the Study and Exchange of evidence from Clinical research And Medical experience (ISSECAM), Medical Statistics Consulting, MediTech, Merck Sharp and Dohme Corp, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche, Sanofi, Seagen, Zymeworks, and research funding from Aragon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Byondis, CytomX, Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Genentech, German Breast Group Forchungs, GlaxoSmithKline, Immunomedics, Innoup, International Breast Cancer Study Group (IBCSG), Lilly, Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merck Sharp and Dohme Corp, Merus, Millennium, Novartis, Pfizer, Piqur, Puma, Roche, Sanofi, Seagen, Synthon, and Zenith., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation., Patients and Methods: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed., Results: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median t max was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases., Conclusions: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298)., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Retrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT., Methods: This prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels., Results: From Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy., Conclusions: Neither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy., Clinical Trial Registry: ClinicalTrials.gov Identifier: NCT01733628., (© 2024. The Author(s).)

Purpose: Everolimus in combination with endocrine therapy (ET) was formerly approved as 2nd-line therapy in HR(+)/HER2(-) advanced breast cancer (aBC) patients (pts) progressing during or after a non-steroidal aromatase inhibitor (NSAI). Since this approval, the treatment landscape of aBC has changed dramatically, particularly with the arrival of CDK 4-6 inhibitors. Endocrine monotherapy after progression to CDK4/6 inhibitors has shown a limited progression-free survival (PFS), below 3 months. Evidence of the efficacy of everolimus plus ET after CDK4/6 inhibitors is scarce., Methods: A retrospective observational study of patients with aBC treated with everolimus and ET beyond CDK4/6-i progression compiled from February 2015 to December 2022 in 4 Spanish hospitals was performed. Clinical and demographic data were collected from medical records. The main objective was to estimate the median progression-free survival (mPFS). Everolimus adverse events (AE) were registered. Quantitative variables were summarized with medians; qualitative variables with proportions and the Kaplan-Meier method were used for survival estimates., Results: One hundred sixty-one patients received everolimus plus ET (exemestane: 96, fulvestrant: 54, tamoxifen: 10, unknown: 1) after progressing on a CDK4/6 inhibitor. The median follow-up time was 15 months (interquartile range: 1-56 months). The median age at diagnosis was 49 years (range: 35-90 years). The estimated mPFS was 6.0 months (95%CI 5.3-7.8 months). PFS was longer in patients with previous CDK4/6 inhibitor therapy lasting for > 18 months (8.7 months, 95%CI 6.6-11.3 months), in patients w/o visceral metastases (8.0 months, 95%CI 5.8-10.5 months), and chemotherapy-naïve in the metastatic setting (7.2 months, 95%CI 5.9-8.4 months)., Conclusion: This retrospective analysis cohort of everolimus plus ET in mBC patients previously treated with a CDK4/6 inhibitor suggests a longer estimated mPFS when compared with the mPFS with ET monotherapy obtained from current randomized clinical data. Everolimus plus ET may be considered as a valid control arm in novel clinical trial designs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft  models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer., (© 2024. The Author(s).)

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that targets human epidermal growth factor receptor 2 (HER2) and has shown promising results in the treatment of advanced/metastatic breast cancer. The objective of this report is to provide guidance on the prophylaxis, monitoring, and management of adverse events (AEs) in patients with breast cancer treated with T-DXd, and to emphasize that proper management of AEs is needed to optimize the effectiveness of T-DXd treatment and reduce the number of discontinuations. The article covers various aspects of T-DXd treatment, including its clinical efficacy, safety profile, and dosing considerations, and provides practical recommendations for managing AEs, such as nausea/vomiting, interstitial lung disease, and hematologic toxicity. Although there are still many knowledge gaps about the cause and incidence of AEs in real-world patients, this document may serve as a valuable resource for clinicians who are involved in the care of breast cancer patients receiving T-DXd treatment., (© 2024. The Author(s).)

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/ PIK3CA -mutated advanced breast cancer (ABC)., Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively., Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P  < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P  = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2)., Interpretation: In HR+/HER2-/ PIK3CA -mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia., Funding: Novartis Pharmaceuticals., Competing Interests: ALC reports research support from Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, and Daichii-Sanyo; a consulting or advisory role with Lilly, Roche, Pfizer, and Novartis. Speakers’ bureaus for Lilly, AstraZeneca, Merck Sharp & Dohme; travel support from Roche, Pfizer, AstraZeneca; and stock or other ownership in MEDSIR and Initia-Research. JMPG reports a consulting or advisory role with Lilly, Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics; and employment at MEDSIR. MRB reports research support and participating in an advisory board of Novartis. PT reports a consulting or advisory role with AstraZeneca, Daiichi-Sankyo, Novartis and Seagen. Speakers’ bureaus for Pfizer, Novartis, Lilly, AstraZeneca, Daiichi-Sankyo and Seagen. IB reports grants and research support to the Institution: AstraZeneca, Lilly, Pfizer and Roche; honoraria and advisor colaboration: AstraZeneca, Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre-Fabre, Bristol-Myers Squibb, Daiichi Sankyo, Grünenthal, Seagen and Veracyte and support for attending meetings and/or travel: AstraZeneca, Roche, Novartis, Pfizer, Lilly, Pierre-Fabre, Bristol-Myers Squibb and Daiichi Sankyo. BR reports travel support from Roche and Lilly. AFO reports travel support from Novartis. CS reports research support, consulting or advisory role from Genentech, AstraZeneca, Aragon Pharmaceuticals, Bayer Pharma, Byondis, Boehringer Ingelheim, Bristol-Myers Squibb, Cytomx Therapeutics, Daiichi Sankyo, F. Hoffmann-La Roche, Eisai, Genomic Health, GlaxoSmithKline, Innoup Farma, Eli Lilly, Macrogenics, Menarini Ricerche, Merck Sharp & Dohme, Merus, Millennium Pharmaceuticals, Novartis, Pfizer, Pierre Fabre, PintPharma, Puma Biotechnology, Sanofi, Seattle Genetics, Zymeworks. JPL reports honoraria from Seagen, Novartis, Pfizer, AstraZeneca/Daiichi Sankyo, Eli Lilly, Roche; and a consulting or advisory role with Seagen, Novartis, AstraZeneca/Daiichi Sankyo, Roche. EL reports honoraria from Ipsen, MSD, Pfizer, AstraZeneca/Daiichi Sankyo and Roche. EG reports honoraria from Roche/Genentech, Pfizer, Novartis, AstraZeneca, Seagen; a consulting or advisory role with AstraZeneca, Seagen, PharmaMar, Gilead Sciences; and speakers’ bureaus for Pfizer, Novartis, Roche. SGS reports honoraria for speaking from Novartis and GSK; Advisory role from Lilly, Seagen and Astra Zeneca; and travel expenses from Clovis and Pfizer outside the submitted work. EC reports consultancy and speakers’ bureaus for Novartis, Pfizer, Roche, Lilly, Celgene; and personal fees from Novartis, Pfizer, Roche, Lilly, Celgene, during the conduct of the study. JFC reports honoraria from Roche, AstraZeneca, Teva, Celgene, Pfizer, GSK, Novartis; and a consulting or advisory role with Roche, AstraZeneca, Pfizer, GSK, Novartis. MSC reports advisory Board of MEDSIR, Optimapharm; Speaker's Bureau in MEDSIR, Optimapharm; and Funding from MEDSIR, Optimapharm, FGP has taken part in advisory panels for Sanofi and Novo Nordisk; has received research support from Sanofi, Novo Nordisk, Boehringer Ingelheim Pharmaceuticals and Lilly; and has acted as a speaker for Sanofi, Novo Nordisk, Boehringer Ingelheim Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Co. and Lilly. JC reports research support from ARIAD, Astrazeneca, Baxalta GMBH/Servier Affaires, Bayer, Eisai, Guardanth health, Merck Sharp & Dohme, Pfizer, Puma, Queen Mary University of London, Roche, Piqur; honoraria from Novartis, Eisai, Celgene, Pfizer, Roche, Samsung, Eli Lilly, Merck Sharp & Dohme Daiichi Sankyo; a consulting or advisory role with Celgene, Cellestia Biotech, AstraZeneca, Roche, Seattle Genetics, Daiichi Sankyo, ERYTECH Pharma, Polyphor, Athenex, Lilly, SERVIER, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Clovis Oncology, Bioasis, Boehringer Ingelheim, Ellipses Pharma, HiberCell, Bioinven, GEMoaB, Gilead Sciences, Menarini, Zymeworks, Reveal Genomics; stock or other ownership in Leuko, MEDSIR, Nektar; and travel support from Roche, Pfizer, Eisai, Novartis, Daiichi Sankyo. AU, EMD, SB, BB, MGC, PCC, AL, JLAR report no competing interests. JMPG, GM, PG, DAL, and MSC are employed by MEDSIR., (© 2024 Published by Elsevier Ltd.)

In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p < 0.001), whereas the opposite was observed with tumor cellularity (p = 0.002). Gene expression signatures (GES) associated with antigen-presenting cells (APCs) and innate immune system activity showed increased expression post-chemotherapy but decreased expression post-ribociclib. Interferon-associated GES had decreased expression with CCCA and increased expression with non-CCCA. Our findings suggest that while both treatment strategies decreased proliferation, the depth and the patterns over time differed by treatment arm. Immunologically, ribociclib was associated with downregulated GES associated with APCs and the innate immune system in Luminal B tumors, contrary to existing preclinical data. Further studies are needed to understand the effect of CDK4/6 inhibition on the tumor cells and microenvironment, an effect which may vary according to tumor subtypes., (© 2024. The Author(s).)

Background: The HER2DX risk-score has undergone rigorous validation in prior investigations involving patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer. In this study, we present the outcomes of the HER2DX risk-score within the most recent release of the Sweden Cancerome Analysis Network-Breast (SCAN-B) HER2+ cohort. This updated examination benefits from a larger patient sample, an extended follow-up duration, and detailed treatment information., Materials and Methods: Clinical and RNAseq data from the SCAN-B dataset were retrieved from Gene Expression Omnibus (GSE81538). Among the 6600 patients, 819 had HER2+ breast cancer, with 757 individuals with research-based HER2DX risk-scores and corresponding survival outcomes. The HER2DX risk-score was evaluated (i) as a continuous variable and (ii) using predefined cut-offs. The primary endpoint for this study was overall survival (OS). The Kaplan-Meier method and Cox models were used to estimate OS and a multistate model with four states was fitted to better characterize patients' follow-up., Results: The median follow-up time was 7.5 years (n = 757). The most common systemic therapy was chemotherapy with trastuzumab (82.0%) and most tumors were classified as T1-T2 (97.1%). The HER2DX risk-score as a continuous variable was significantly associated with OS after adjustment for clinical variables and treatment regimen [hazard ratios (HR) per 10-unit increment = 1.31, 95% confidence interval (CI) 1.13-1.51, P < 0.001] as well as within predefined risk groups (high versus low; HR = 2.57, 95% CI 1.36-4.85, P < 0.001). Patients classified as HER2DX high-risk also had higher risk of (i) breast cancer recurrence and (ii) death without previous recurrence. Within the subgroup of HER2+ T1N0 tumors (n = 297), those classified as high-risk demonstrated inferior OS compared to low-risk tumors (7-year OS 77.8% versus 96.8%, P < 0.001). The HER2DX mRNA ERBB2 score was associated with clinical HER2 status (area under the receiver operating characteristic curve = 0.91)., Conclusions: In patients with early-stage HER2+ breast cancer, HER2DX risk-score provides prognostic information beyond clinicopathological variables, including treatment regimen with or without trastuzumab., Competing Interests: Role of the funder In addition to financial support, the funders actively contributed to various aspects of the research, including study design, data collection, analysis, interpretation, and report writing. Disclosure GV has received a speaker’s fee from MSD, Pfizer, GSK, and Pierre Fabre; has held an advisory role with AstraZeneca; and received consultant fees from Reveal Genomics. TP has received honoraria for speaker activities from AstraZeneca, Pfizer, Novartis, Veracyte, and Argenetics, and has held an advisory role with Novartis. FBM has a patent application (EP21383165). LP is listed as an inventor on patent PCT/EP2021/070788. OMS has declared travel expenses and consulting fees from Roche and Reveal, and speaker fees from Eisai, Daiichi-Sankyo, and Novartis. JC has ownership interests in MedSIR, Nektar, and Leuko; has held consulting or advisory roles in Celgene, Cellestia Biotech, AstraZeneca, Roche, Seattle Genetics, Daiichi-Sankyo, ERYTECH Pharma, Polyphor, Athenex, Lilly, Servier, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Clovis Oncology, Bioasis, Boehringer Ingelheim, Ellipses Pharma, HiberCell, Bioinvent, GEMoaB, Gilead Sciences, Menarini, Zymeworks, and Reveal Genomics; has received research funding from ARIAD, AstraZeneca, Baxalta, Bayer, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, Puma Biotechnology, Queen Mary University of London, Roche, and Piqur; has patents, royalties, or other intellectual property from pharmaceutical combinations of a Pi3k Inhibitor and a microtubule destabilizing agent (Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A, Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés. US 2019/ 0338368 A1); and has received travel expenses from Roche, Pfizer, Eisai, Novartis, Daiichi-Sankyo, and Gilead Sciences. EC has received honoraria for advisory roles from Pfizer, AstraZeneca, Daiichi-Sankyo, Roche, Novartis, Lilly, and MSD; and has received a speaker’s fee from Roche and Lilly. MM reports research grants from Puma; consulting/advisory fees from Roche, Novartis, AstraZeneca, Daiichi-Sankyo, Seagen, Lilly, and Sanofi; speakers’ honoraria from Seagen, Lilly, AstraZeneca, Pfizer, Daiichi-Sankyo, and Roche; a leadership or fiduciary role as Chairman, GEICAM and as a member of the Board of Directors for TRIO. PC reports speakers’ bureaus with AstraZeneca, GlaxoSmithKline, Novartis, and Roche; travel, accommodation, and expenses from Celgene, GlaxoSmithKline, and Novartis; and research funding from Merck Serono, Novartis, and Roche. LAC reports participation on a Data Safety Monitoring Board or Advisory Board of Sanofi Aventis, Novartis, Genentech/Roche, GSK, AstraZeneca/Daiichi-Sankyo, and Aptitude Health; and has a spouse serving on the board of Falcon Therapeutics and spouse involvement in a neural stem cell therapy patent. NH received consulting fees from Pierre Fabre and Roche. AV has the DNADX patent filed (EP22382387.3). GC served as consultant or advisor for Roche, Lilly, and Bristol-Myers Squibb; served on the speaker’s bureau for Roche, Pfizer, and Lilly; received travel funding from Pfizer and Roche; and received honoraria from Roche, Pfizer, Lilly, Novartis, and Seagen, all outside the submitted work. PV is one of the stockholders of Reveal Genomics, and also reports personal fees from NanoString. JSP is an equity stockholder and consultant for Reveal Genomics and is listed as an inventor on patent applications for the Breast PAM50 assay. CMP is an equity stockholder and consultant of BioClassifier LLC and Reveal Genomics, and is listed as an inventor on patent applications for the Breast PAM50 assay. AP reports advisory and consulting fees from Roche, Pfizer, Novartis, Amgen, Bristol-Myers Squibb, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc, and Lilly; lecture fees from Roche, Pfizer, Novartis, Amgen, Bristol-Myers Squibb, NanoString Technologies, and Daiichi-Sankyo; institutional financial interests from Boehringer, Novartis, Roche, NanoString, Sysmex Europa GmbH, Medica Scientia Innovation Research, SL, Celgene, Astellas, and Pfizer; is a stockholder and consultant of Reveal Genomics and SL; and is listed as an inventor on patent applications for the HER2DX assay. SMT reports consulting or advisory roles for Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol-Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi-Sankyo, Gilead, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Sumitovant Biopharma, Zetagen, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Biopharma, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, and Hengrui USA; research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol-Myers Squibb, Eisai, AstraZeneca, Gilead, NanoString Technologies, Seattle Genetics, and OncoPep; and travel support from Eli Lilly, Sanofi, Gilead, and Pfizer. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Breast cancer incidence has increased in the last two decades and, simultaneously, survival has improved due to earlier detection and improved treatment options. Despite this improvement, locoregional recurrences and distant metastases occur in up to 10 and 30% of women diagnosed with early breast cancer, respectively. Around 70% of breast cancers are hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), and associated with a persistent risk of relapse up to 20 years after diagnosis/initial treatment. We conducted a narrative review by combining PubMed searches with our clinical experience to describe patient characteristics, biomarkers, and genomic profiling tools available to clinicians for the identification of patients with HR+, HER2- early breast cancer at high risk of recurrence and to provide recommendations to classify patients into recurrence risk categories. National and international treatment guidelines are also summarised. Accurate assessment of the risk of recurrence in these patients is crucial as the predicted risk guides treatment decisions; imprecise estimations can result in over- or undertreatment, with either scenario having negative consequences for patients. Multiple prognostic tools and factors are recommended for early breast cancer, and no single test provides accurate prognosis in isolation. Since no single test can provide accurate prognosis in isolation, a combination of tools should be used. Risk thresholds are important to guide optimised and balanced therapeutic decisions in HR+, HER2- early breast cancer. However, prognostic assessment should be performed on a case-by-case basis, making patient-specific prognostic approaches essential to avoid over- or undertreatment., Competing Interests: Conflict of Interest Professor Fasching: Personal fees from Novartis, grants from BioNTech, personal fees from Pfizer, personal fees from Daiichi Sankyo, personal fees from AstraZeneca, personal fees from Eisai, personal fees from Merck Sharp & Dohme, grants from Cepheid, personal fees from Lilly, personal fees from Pierre Fabre, personal fees from Seattle Genetics, personal fees from Roche, personal fees from Hexal. Professor Kreipe: Personal fees for participation in advisory boards from Roche Pharma, Exact Sciences, Novartis, Lilly, and AstraZeneca. Professor Del Mastro: Personal fees from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly and Co, Exact Sciences, Gilead Sciences, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, and Seagen outside the submitted work. Professor Ciruelos: Consulting Fees (e.g. advisory boards); Pfizer, Daiichi Sankyo, Novartis, MSD, AstraZeneca, Roche, Lilly. Fees for non-CME services received directly from commercial interest or their agents (e.g. speakersʼ bureaux); Roche, Eli Lilly and Company. Professor G. Freyer: Pfizer, Eli Lilly and Company, AstraZeneca, Novartis. Agnieszka Korfel, Nadia Chouaki, Clemens Stoffregen, and Francisco Sapunar are employees of Eli Lilly and Company. Professor Cameron: Consulting or Advisory Role: Eli Lilly and Company, Novartis, Research Triangle Institute RTI Health Solutions, Daiichi Sankyo, Merck Sharp & Dohme, Prima BioMed, Zymeworks, Eisai, Puma Biotechnology, Pfizer, Oncolytics, Roche, Samsung Bioepis, Seattle Genetics, Synthon, Clarity Pharmaceuticals, Zymeworks, Sanofi; Research Funding: Roche, AstraZeneca, Novartis., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background: Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2-) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables., Methods: In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2- locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov, NCT03901339., Findings: At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12·5-month (IQR 6·4-18·8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14·4 months [95% CI 13·0-15·7] vs 11·2 months [10·1-12·7]; hazard ratio [HR] 0·79, 95% CI 0·65-0·96; p=0·020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1·63 [95% CI 1·03-2·56]; p=0·035), as was time to deterioration of global health status and quality of life (median 4·3 months vs 3·0 months; HR 0·75 [0·61-0·92]; p=0·0059) and fatigue (median 2·2 months vs 1·4 months; HR 0·73 [0·60-0·89]; p=0·0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment., Interpretation: Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3·2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2- metastatic breast cancer., Funding: Gilead Sciences., Competing Interests: Declaration of interests HSR reports honoraria from Puma Biotechnology, Mylan, and Samsung Bioepis, and institutional research funding from Macrogenics, OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Odonate Therapeutics, Daiichi Sankyo, Seattle Genetics, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, and Ayala Pharmaceuticals. AB reports institutional research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health and Menarini, Immunomedics and Gilead Sciences, Daiichi Sankyo, and AstraZeneca, and Eli Lilly, and consulting fees from Pfizer, Novartis, Genentech, Merck, Radius Health and Menarini, Immunomedics and Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, Phillips, Eli Lilly, and Foundation Medicine. FM reports institutional research funding from Roche, Novartis, AstraZeneca, GSK and Tesaro, MED, Clovis, Vaccibody, Gilead Sciences, and Eisai; consulting fees from AstraZeneca, GSK and Tesaro, Pfizer, Eisai, Gilead Sciences, Vaccibody, and GenomicHealth; honoraria from AstraZeneca, Clovis, GSK and Tesaro, Eli Lilly, Novartis, Pfizer, Roche, Myriad Genetics, PharmaMar, Eisai, MSD, Immunomedics and Gilead Sciences, Pierre-Fabre, Agendia, Genomic Health, and Seattle Genetics; support for meeting attendance and travel from Pfizer, Roche, and AstraZeneca; and participation on a data safety monitoring board or advisory board for Palleos and Amgen. JC reports institutional research funding from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta, Servier Affaires, Bayer Healthcare, Eisai, F Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma Biotechnology, and Queen Mary University of London; consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck, Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, GEMoaB, Gilead Sciences, Menarini, Zymeworks, Reveal Genomics, and Expres2ion Biotechnologies; honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck, Sharp & Dohme, and Daiichi Sankyo; travel and accommodations from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, and Gilead Sciences; stock ownership from MedSIR and Nektar Pharmaceuticals; and several patents. PS reports institutional research funding from Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, and Medivation; consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Eisai, and Celgene; and spouse's employment at Roche. DL reports honoraria from AstraZeneca, Novartis, MSD, Lilly, Amgen, Eisai, and Gilead Sciences; consulting fees from Roche, AstraZeneca, Pfizer, Novartis, MSD, Immunomedics, Pharma4D, Daiichi Sankyo, Lilly, Amgen, and Eisai; and travel and accommodations from Roche, AstraZeneca, Pfizer, Novartis, MSD, Gilead Sciences, and Amgen. OT reports institutional research funding from Bristol Myers Squibb and MSD; honoraria from Roche, Pfizer, Novartis-Sandoz, Lilly, MSD, AstraZeneca, Pierre Fabre, Seagen, Daiichi Sankyo, Gilead Sciences, Eisai, and Stemline; travel and accommodations from Roche, Pfizer, Novartis-Sandoz, Lilly, MSD, AstraZeneca, Seagen, Daiichi Sankyo, and Gilead Sciences; and participation on a data safety monitoring board or advisory board for Roche, Pfizer, Novartis-Sandoz, Lilly, MSD, AstraZeneca, Seagen, and Daiichi Sankyo. EC reports consulting fees from Novartis, Lilly, Pfizer, Roche, AstraZeneca, and Daiichi Sankyo; speaker's bureau from Lilly, Pfizer, AstraZeneca, and Daiichi Sankyo; and travel and accommodations from Pfizer and Roche. KLJ reports consulting fees from Novartis, Pfizer, Bristol Myers Squibb, Jounce Therapeutics, Taiho Oncology, Genentech, Synthon, AbbVie, Eisai, AstraZeneca, Blueprint Medicine, Daiichi Sankyo, Sun Pharma Advanced Research Company, Gilead Sciences, Seattle Genetics, and Lilly Pharmaceuticals and Loxo Oncology; and institutional research funding from Novartis, Clovis Oncology, Genentech, AstraZeneca, ADC Therapeutics, Novita Pharmaceuticals, Debio Pharmaceuticals, Pfizer, Lilly Pharmaceuticals and Loxo Oncology, Zymeworks, Immunomedics and Gilead Sciences, Puma Biotechnology, and Merck Pharmaceuticals. RD, TV, HW, MM, and OKY report employment by and stock ownership in Gilead Sciences. WV reports previous employment by and stock ownership in Genentech and employment by Gilead Sciences. SMT reports institutional research funding from Gilead Sciences, AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech and Roche, Exelixis, Bristol Myers Squibb, Eisai, Nanostring, Cyclacel, Sanofi, Odonate, and Seagen; consulting fees from AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech and Roche, Gilead Sciences, Bristol Myers Squibb, Eisai, Nanostring, Sanofi, Odonate, Seagen, Daiichi Sankyo, Athenex, CytomX, Blueprint Medicines, Zentalis, Zymeworks, Ellipses Pharma, 4D Pharma, OncoSec, Infinity Therapeutics, BeyondSpring Pharma, OncXerna, Reveal Genomics, ARC Therapeutics, Kyowa Kirin Pharma, G1 Therapeutics, Silverback Therapeutics, Certara, Mersana Therapeutics, and OncoPep; and honoraria from Chugai, Genentech and Roche, Eisai, Gilead Sciences, AstraZeneca, and Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: HER2-low has emerged as a new predictive biomarker in metastatic breast cancer. However, its prognostic value in early-stage carcinomas needs to be revisited. We aimed to evaluate the association of HER2-low carcinomas with PAM50 risk groups combined with clinicopathological variables in early breast cancer., Methods: We conducted a retrospective analysis of 332 patients with early-stage breast cancer that underwent PAM50 signature analysis between 2015 and 2021at Hospital Universitario 12 de Octubre (Madrid, Spain). Clinical and pathological variables were collected from medical records. After adjusting for potential confounders, we estimated Odds Ratio (OR) and 95% confidence interval for high-risk PAM50 subgroup, comparing HER2-low versus HER2-zero carcinomas by multivariable logistic regression. P values below 0.05 were deemed statistically significant., Results: 192 (57%) patients were classified as HER2-low carcinomas. Median follow-up was 34 months. Adjusted OR for high-risk PAM50 when comparing HER2-low versus HER2-zero carcinomas was 1.31 (95% CI: 0.75-2.30, p = 0.33). The multivariable model detected significant associations for Ki-67% (≥20% vs. <20%: OR = 4.03, 95% CI: 2.15-7.56, p < 0.001), T staging category (T2/T3 vs. T1: OR = 3.44, 95% CI: 1.96-6.04, p < 0.001), progesterone receptor (PR ≥ 20% vs. <20%: OR = 0.44, 95% CI: 0.23-0.83, p = 0.01), nodal staging category (N+ vs. N0: OR = 3.8, 95% CI: 1.89-7.62, p < 0.001) and histological grade (grade 2 vs. 1: OR = 2.41, 95% CI: 1.01-5.73, p = 0.04; grade 3 vs 1: OR = 5.40, 95%CI: 1.98-14.60, p = 0.001)., Conclusions: In this early-stage breast cancer cohort, HER2-low was not associated with a high-risk PAM50 compared to HER2-zero carcinomas. Ki-67 ≥ 20%, T2/T3, histological grade 2/3, N+ and PR<20% were significantly associated to a high-risk PAM50., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Breast cancer is the leading cause of cancer in women in Spain and its annual incidence is rapidly increasing. Thanks to the screening programs in place, nearly 90% of breast cancer cases are detected in early and potentially curable stages, despite the COVID-19 pandemic possibly having impacted these numbers (not yet quantified). In recent years, locoregional and systemic therapies are increasingly being directed by new diagnostic tools that have improved the balance between toxicity and clinical benefit. New therapeutic strategies, such as immunotherapy, targeted drugs, and antibody-drug conjugates have also improved outcomes in some patient subgroups. This clinical practice guideline is based on a systematic review of relevant studies and on the consensus of experts from GEICAM, SOLTI, and SEOM., (© 2023. The Author(s).)

A hallmark of many malignant tumors is dedifferentiated (immature) cells bearing slight or no resemblance to the normal cells from which the cancer originated. Tumor dedifferentiated cells exhibit a higher capacity to survive to chemo and radiotherapies and have the ability to incite tumor relapse. Inducing cancer cell differentiation would abolish their self-renewal and invasive capacity and could be combined with the current standard of care, especially in poorly differentiated and aggressive tumors (with worst prognosis). However, differentiation therapy is still in its early stages and the intrinsic complexity of solid tumor heterogeneity demands innovative approaches in order to be efficiently translated into the clinic. We demonstrate here that microRNA 203, a potent driver of differentiation in pluripotent stem cells (ESCs and iPSCs), promotes the differentiation of mammary gland tumor cells. Combining mouse in vivo approaches and both mouse and human-derived tridimensional organoid cultures, we report that miR-203 influences the self-renewal capacity, plasticity and differentiation potential of breast cancer cells and prevents tumor cell growth in vivo. Our work sheds light on differentiation-based antitumor therapies and offers miR-203 as a promising tool for directly confronting the tumor-maintaining and regeneration capability of cancer cells., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (HER3)-directed antibody-drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score [= -0.8 × tumor cellularity (in %)  +  1.3  × tumor-infiltrating lymphocytes (TILs) (in %)], and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer., Patients and Methods: Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score., Results: Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, -3.8 to 12.7; P = 0.003). Among patients assessable for clinical response (n = 62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease., Conclusions: A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In hormone receptor-positive (HoR+) breast cancer (BC), gene expression analysis identifies luminal A (LumA), luminal B (LumB), human epidermal growth factor receptor 2 (HER2)-enriched (HER2-E), basal-like (BL) intrinsic subtypes and a normal-like group. This classification has an established prognostic value in early-stage HoR+ BC. Here, we carried out a trial-level meta-analysis to determine the prognostic ability of subtypes in metastatic BC (MBC)., Materials and Methods: We systematically reviewed all the available prospective phase II/III trials in HoR+ MBC where subtype was assessed. The primary endpoint was progression-free survival (PFS)/time to progression (TTP) of the LumA subtype compared to non-LumA. Secondary endpoints were PFS/TTP of each individual subtype, according to treatment, menopausal and HER2 status and overall survival (OS). The random-effect model was applied, and heterogeneity assessed through Cochran's Q and I 2 . Threshold for significance was set at P < 0.05. The study was registered in PROSPERO (ID: CRD42021255769)., Results: Seven studies were included (2536 patients). Non-LumA represented 55.2% and was associated with worse PFS/TTP than LumA [hazard ratio (HR) 1.77, P < 0.001, I 2  = 61%], independently of clinical HER2 status [P subgroup difference (P sub ) = 0.16], systemic treatment (P sub  = 0.96) and menopausal status (P sub  = 0.12). Non-LumA tumors also showed worse OS (HR 2.00, P < 0.001, I 2  = 65%), with significantly different outcomes for LumB (PFS/TTP HR 1.46; OS HR 1.41), HER2-E (PFS/TTP HR 2.39; OS HR 2.08) and BL (PFS/TTP HR 2.67; OS HR 3.26), separately (PFS/TTP P sub  = 0.01; OS P sub  = 0.005). Sensitivity analyses supported the main result. No publication bias was observed., Conclusions: In HoR+ MBC, non-LumA disease is associated with poorer PFS/TTP and OS than LumA, independently of HER2, treatment and menopausal status. Future trials in HoR+ MBC should consider this clinically relevant biological classification., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Metastatic breast cancer (mBC) causes nearly all BC-related deaths. Next-generation sequencing (NGS) technologies allow for the application of personalized medicine using targeted therapies that could improve patients' outcomes. However, NGS is not routinely used in the clinical practice and its cost induces access-inequity among patients. We hypothesized that promoting active patient participation in the management of their disease offering access to NGS testing and to the subsequent medical interpretation and recommendations provided by a multidisciplinary molecular advisory board (MAB) could contribute to progressively overcome this challenge. We designed HOPE (SOLTI-1903) breast cancer trial, a study where patients voluntarily lead their inclusion through a digital tool (DT). The main objectives of HOPE study are to empower mBC patients, gather real-world data on the use of molecular information in the management of mBC and to generate evidence to assess the clinical utility for healthcare systems., Trial Design: After self-registration through the DT, the study team validates eligibility criteria and assists patients with mBC in the subsequent steps. Patients get access to the information sheet and sign the informed consent form through an advanced digital signature. Afterwards, they provide the most recent (preferably) metastatic archival tumor sample for DNA-sequencing and a blood sample obtained at the time of disease progression for ctDNA analysis. Paired results are reviewed by the MAB, considering patient's medical history. The MAB provides a further interpretation of molecular results and potential treatment recommendations, including ongoing clinical trials and further (germline) genetic testing. Participants self-document their treatment and disease evolution for the next 2 years. Patients are encouraged to involve their physicians in the study. HOPE also includes a patient empowerment program with educational workshops and videos about mBC and precision medicine in oncology. The primary endpoint of the study was to describe the feasibility of a patient-centric precision oncology program in mBC patients when a comprehensive genomic profile is available to decide on a subsequent line of treatment., Clinical Trial Registration: www.soltihope.com, identifier NCT04497285., Competing Interests: ElS reports having obtained travel/accommodation paid by Gilead and Daiichi Sankyo and honoraria from Novartis. JC reports personal fees from NOVARTIS and Pfizer. Mafalda Oliveira reports financial relationships with AstraZeneca, Guardant Health, Roche, MSD, Pfizer, SeaGen, iTEOS, Eisai, Novartis, Relay Therapeutics and Gilead. PT reports honoraria and consulting fees from AstraZeneca, Daiichi-Sankyo, Novartis, Seagen, Pfizer and Lilly and travel and accommodation paid by AstraZeneca and Pfizer. MV reports honoraria and consulting fees from Roche, Novartis and Daiichi Sankyo- AstraZeneca. MaM reports honoraries received from Lilly and Prosenestar; and research agreements with Pfizer, Lilly, Prosenestar, PharmaMar and Circle Pharma. JG reports grants and personal fees from Novartis, grants and personal fees from Pfizer, grants, and personal fees from Roche, outside the submitted work. CS has served as consultant, participated in advisory boards or received travel grants from AstraZeneca, AX’s Consulting, Byondis BV, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann - La Roche Ltd, Exact Sciences, Exeter Pharma, Genomic Health, Merck, Sharp and Dhome España S.A., Novartis, Odonate Therapeutics, Pfizer, Philips Healthwork, Pierre Fabre, Pint Pharma, prIME Oncology, Puma Biotechnology, Seagen, Synthon, Sanofi Aventis and Zymeworks. SP reports advisor/consultant role for AstraZeneca, Daiichi-Sankyo, Eisai, Pfizer, SeaGen, Polyphor, Roche, Gebro Pharma, Pierre Fabre, and conference travel and accommodation paid by Gilead and Pfizer. RL reports grants and personal fees from Roche, grants and personal fees from Merck, personal fees from AstraZeneca, personal fees from Bayer, personal fees, and non-financial support from BMS, personal fees from Pharmamar, personal fees from Leo, personal fees and non-financial support from Novartis, outside the submitted work. MiM has declared advisor role or consulting from Novartis, Pfizer, Lilly, Gilead, PiereFabre and MSD; research funding from Pfizer and travel expences from Pfizer and Gilead. JB reports personal fees from Astra Zeneca and Pfizer. MoM declares the following competing interests: expert testimony honoraria from Novartis, Roche, and Eisai; advisory board honoraria from Pierre Fabre, and Seagen; and conference travel grants from Roche, Pfizer, Gilead and Lilly. IB reports honoraria and consulting fees from AstraZeneca, Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre-Fabre, Bristol-Myers Squibb, Daiichi Sankyo, Grünenthal, Seagen and Veracyte; and grant/Research Support to the Institution from AstraZeneca, Lilly and Roche and travel and accommodation paid by Roche, Lilly and Pierre-Fabre, outside the submitted work. VB reports consultant or Advisory Role fees from Puma Biotechnology; Ideaya Biosciences; Loxo Therapeutics, CytomX Therapeutics; Guidepoint; Oncoart, Lilly; Janssen; personal fees Nanobiotix NANORAY-312/and Honoraria from Eli Lilly; MSD; SOLTI; TACTICS; Getthi; Gedefo. Travel/inscription/accommodation: Bayer ESMO GI and Institutional financial support for clinical trials from: Abbvie; ACEO; Adaptaimmune; Amcure; AMGEN; Amunix, AstraZeneca; Bycicle; BMS Cytomx; GSK; Genentech/Roche; Genmab; Incyte; Ipsen; Janssen; Kura; Lilly; Loxo; Nektar; Macrogenics; Menarini; Merck; Merus; Nanobiotix; Novartis; Pfizer; PharmaMar; Principia; PUMA; Ryvu; Ribbon; Sanofi; Taiho; Tesaro; BeiGene; Transgene; Takeda; Incyte; Innovio; MSD; PsiOxus; Seattle Genetics; Mersana; Daiichi; Nektar; Astellas; ORCA; Boston Therapeutics; Dynavax; DebioPharm; Boehringer Ingelheim; Regeneron; Rigontec; Millennium; Seagen; Synthon; Spectrum; Urogen; Zenith. EC reports personal fees from Roche, Lilly, Novartis, Pfizer, during the conduct of the study. EG reports advisory or consultant role from Roche, AstraZeneca, Seattle Genetics, Gilead, Pfizer and Eisai and travel grants from Pfizer, AstraZeneca and Roche. RS-B reports personal honoraria from Novartis, AstraZeneca, MSD Oncology, Lilly Oncology, Glaxo Smith Kline, Clovis, and Seagen. SC reports advisory or consultant role from Pfizer, Daiichi Sankyo, and Seagen and travel grants from Pfizer and AstraZeneca. MH reports consulting fees from AstraZeneca. AlP has declared personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo, travel, accommodations, and expenses paid by Daiichi Sankyo, research funding from Nanostring Technologies, Roche and Novartis, consulting/advisory role for Nanostring Technologies, Roche, Novartis, Pfizer, Oncolytics Biotech, Amgen, Lilly, MSD, PUMA and Daiichi Sankyo, Inc. outside the submitted work. AC reports honoraria and consulting fees from Pfizer, Novartis, and AstraZeneca. TP reports having received Fees for Non-CME Services Received Directly from Commercial Interest or their Agents e.g., speakers’ bureaus from AstraZeneca, Consulting Fees e.g., advisory boards from Novartis, and Fees for Non-CME Services Received Directly from Commercial Interest or their Agents e.g., speakers’ bureaus from Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Olivera-Salguero, Seguí, Cejalvo, Oliveira, Tolosa, Vidal, Malumbres, Gavilá, Saura, Pernas, López, Margelí, Balmaña, Muñoz, Blancas, Boni, Ciruelos, Galve, Perelló, Sánchez-Bayona, de la Cruz, de la Hoya, Galván, Sanfeliu, Gonzalez-Farre, Sirenko, Blanch-Torras, Canes, Masanas, Olmos, Forns, Prat, Casas and Pascual.)

Liquid biopsy has proven valuable in identifying individual genetic alterations; however, the ability of plasma ctDNA to capture complex tumor phenotypes with clinical value is unknown. To address this question, we have performed 0.5X shallow whole-genome sequencing in plasma from 459 patients with metastatic breast cancer, including 245 patients treated with endocrine therapy and a CDK4/6 inhibitor (ET + CDK4/6i) from 2 independent cohorts. We demonstrate that machine learning multi-gene signatures, obtained from ctDNA, identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to what is accomplished using direct tumor tissue DNA or RNA profiling. More importantly, 4 DNA-based subtypes, and a ctDNA-based genomic signature tracking retinoblastoma loss-of-heterozygosity, are significantly associated with poor response and survival outcome following ET + CDK4/6i, independently of plasma tumor fraction. Our approach opens opportunities for the discovery of additional multi-feature genomic predictors coming from ctDNA in breast cancer and other cancer-types., (© 2023. The Author(s).)

Background: Very young premenopausal women diagnosed with hormone receptor-positive, HER2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained., Patients and Methods: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the SOFT clinical trial to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1,276 patients (deep targeted sequencing, N=1258; whole-exome sequencing in a young-age, case-control subsample, N=82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI), and overall survival (OS)., Results: Younger women (<40 years, N=359) compared with older women (≥40 years, N=917) had significantly higher frequencies of mutations in GATA3 (19%vs16%) and CN-amplifications (47%vs26%), but significantly lower frequencies of mutations in PIK3CA (32%vs47%), CDH1 (3%vs9%), and MAP3K1 (7%vs12%). Additionally, significantly higher frequencies of features suggestive of HRD (27%vs21%), and a higher proportion of PIK3CA mutations with concurrent CN-amplifications (23%vs11%).Genomic features suggestive of HRD, PIK3CA mutations with CN-amplifications, and CN-amplifications associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% ≥40 years. Poor prognostic features (N=584[46%]) vs none (N=692[54%]) had an 8-year DRFI of 84%vs94% and OS of 88%vs96%. Younger women (<40) had the poorest outcomes: 8-year DRFI 74%vs85% and OS of 80%vs93% respectively., Conclusion: These results provide insights into genomic alterations that are enriched in young women with HR+HER2-EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Purpose: Hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) endocrine-resistant metastatic breast cancer is treated with sequential single-agent chemotherapy with poor outcomes. Sacituzumab govitecan (SG) is a first-in-class antibody-drug conjugate with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer., Methods: In this global, randomized, phase III study, SG was compared with physician's choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR+/HER2- locally recurrent inoperable or metastatic breast cancer. The primary end point was progression-free survival (PFS) by blinded independent central review., Results: Patients were randomly assigned to receive SG (n = 272) or chemotherapy (n = 271). The median age was 56 years, 95% had visceral metastases, and 99% had a prior cyclin-dependent kinase 4/6 inhibitor, with three median lines of chemotherapy for advanced disease. Primary end point was met with a 34% reduction in risk of progression or death (hazard ratio, 0.66 [95% CI, 0.53 to 0.83; P = .0003]). The median PFS was 5.5 months (95% CI, 4.2 to 7.0) with SG and 4.0 months (95% CI, 3.1 to 4.4) with chemotherapy; the PFS at 6 and 12 months was 46% (95% CI, 39 to 53) v 30% (95% CI, 24 to 37) and 21% (95% CI, 15 to 28) v 7% (95% CI, 3 to 14), respectively. Median overall survival (first planned interim analysis) was not yet mature (hazard ratio, 0.84; P = .14). Key grade ≥ 3 treatment-related adverse events (SG v chemotherapy) were neutropenia (51% v 38%) and diarrhea (9% v 1%)., Conclusion: SG demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2- advanced breast cancer and limited treatment options., Competing Interests: Hope S. RugoHonoraria: Puma Biotechnology, Mylan, Samsung Bioepis, Chugai Pharma, Blueprint Medicines, Napo PharmaceuticalsResearch Funding: OBI Pharma (Inst), Pfizer (Inst), Novartis (Inst), Lilly (Inst), Genentech (Inst), Merck (Inst), Odonate Therapeutics (Inst), Daiichi Sankyo (Inst), Sermonix Pharmaceuticals (Inst), AstraZeneca (Inst), Gilead Sciences (Inst), Ayala Pharmaceuticals (Inst), Astellas Pharma (Inst), Seattle Genetics (Inst), MacroGenics (Inst), Boehringer Ingelheim (Inst), Polyphor (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/summary Aditya BardiaConsulting or Advisory Role: Novartis (Inst), Genentech, Pfizer, Spectrum Pharmaceuticals, BioTheranostics, Merck, Radius Health (Inst), Immunomedics (Inst), Genentech/Roche (Inst), Pfizer (Inst), Innocrin Pharma (Inst), Sanofi, Puma Biotechnology, Daiichi Sankyo/AstraZeneca, Foundation Medicine, Philips HealthcareResearch Funding: Genentech (Inst), Novartis (Inst), Pfizer (Inst), Merck (Inst), Sanofi (Inst), Radius Health (Inst), Immunomedics (Inst), AstraZeneca/Daiichi Sankyo (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/523675 Frederik MarméHonoraria: Roche/Genentech, Novartis, Pfizer, AstraZeneca, Tesaro, Clovis Oncology, Eisai, Celgene, Genomic Health, PharmaMar, Amgen, MSD Oncology, Immunomedics (Inst), Settle Genetics, Myriad Genetics, Pierre Fabre, GlaxoSmithKline, AGENDIA, Lilly, Gilead SciencesConsulting or Advisory Role: AstraZeneca (Inst), Tesaro, Pfizer, Roche (Inst), Genomic Health, CureVac, Amgen, Vaccibody (Inst), Immunomedics (Inst), Eisai, GlaxoSmithKline, Gilead SciencesResearch Funding: Roche/Genentech (Inst), Novartis (Inst), AstraZeneca (Inst), Tesaro (Inst), Clovis Oncology (Inst), MSD Oncology (Inst), Vaccibody (Inst), Gilead Sciences (Inst), GlaxoSmithKline (Inst)Travel, Accommodations, Expenses: Roche, Pfizer, AstraZeneca Javier CortesStock and Other Ownership Interests: MedSIR, Nektar, Leuko (I)Honoraria: Novartis, Eisai, Celgene, Pfizer, Roche, Samsung, Lilly, Merck Sharp & Dohme, Daiichi SankyoConsulting or Advisory Role: Celgene, Cellestia Biotech, AstraZeneca, Roche, Settle Genetics, Daiichi Sankyo, ERYTECH Pharma, Polyphor, Athenex, Lilly, Servier, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Clovis Oncology, Bioasis, Boehringer Ingelheim, Ellipses Pharma, HiberCell, BioInvent, GEMoaB, Gilead Sciences, Menarini, Zymeworks, Reveal GenomicsResearch Funding: ARIAD (Inst), AstraZeneca (Inst), Baxalta (Inst), Bayer (Inst), Eisai (Inst), Guardant Health (Inst), Merck Sharp & Dohme (Inst), Pfizer (Inst), Puma Biotechnology (Inst), Queen Mary University of London (Inst), Roche (Inst), Piqur (Inst)Patents, Royalties, Other Intellectual Property: Pharmaceuticals Combinations of A Pi3k Inhibitor and a Microtubule Destabilizing Agent. Javier Cortes Castan, Alejandro Piris Gimenez, Violeta Srra Elizalde. WO 2014/199294 A, Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy, Aleix Prat, Antonio Llombart, Javier Cortes, US 2019/0338368 A1Travel, Accommodations, Expenses: Roche, Pfizer, Eisai, Novartis, Daiichi Sankyo, Gilead Sciences Peter SchmidEmployment: Roche (I)Honoraria: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma Biotechnology, Roche, Eisai, CelgeneConsulting or Advisory Role: Genentech/Roche (I), AstraZeneca, Merck, Boehringer Ingelheim, Bayer, Pfizer, Novartis, Eisai, Celgene, Puma BiotechnologyResearch Funding: AstraZeneca (Inst), Astellas Pharma (Inst), OncoGenex (Inst), Genetech (Inst), Novartis (Inst), Roche (Inst), Medivation Delphine LoiratHonoraria: MSD, Gilead Sciences, AstraZeneca, LillyConsulting or Advisory Role: Roche, MSD Oncology, AstraZeneca, Novartis, Pfizer, Immunomedics, Gilead Sciences, 4D Pharma, LillyTravel, Accommodations, Expenses: Roche, AstraZeneca, MSD, Pfizer, Gilead Sciences Olivier TrédanConsulting or Advisory Role: Roche, Pfizer, Lilly, AstraZeneca, MSD Oncology, Daiichi Sankyo Europe GmbH, Eisai Europe, Sandoz-Novartis, Seattle Genetics, Pierre Fabre, Gilead SciencesResearch Funding: Roche (Inst), Bristol Myers Squibb (Inst), MSD Oncology (Inst), AstraZeneca (Inst), Novartis (Inst), Bayer (Inst),Travel, Accommodations, Expenses: Roche, Novartis, Pfizer, Lilly, AstraZeneca, MSD Oncology Eva CiruelosConsulting or Advisory Role: Roche, Pfizer, AstraZeneca, Novartis, Lilly, MSD Oncology, Daiichi Sankyo/AstraZenecaSpeakers' Bureau: Lilly, Roche, Pfizer, Daiichi Sankyo/AstraZeneca, NovartisTravel, Accommodations, Expenses: Roche, Pfizer Komal L. JhaveriConsulting or Advisory Role: Novartis, Pfizer, AstraZeneca, Jounce Therapeutics, Synthon, IntelliSphere, Bristol Myers Squibb, Genentech, AbbVie, Lilly, Blueprint Medicines, Seattle Genetics, Daiichi Sankyo, Biotheranostics, Sun Pharma Advanced Research Company, Taiho Oncology, Sanofi, Gilead SciencesResearch Funding: Novartis (Inst), Genentech (Inst), Debiopharm Group (Inst), ADC Therapeutics (Inst), Pfizer (Inst), Novita Pharmaceuticals (Inst), Clovis Oncology (Inst), Lilly (Inst), Zymeworks (Inst), Immunomedics (Inst), Puma Biotechnology (Inst), VelosBio/Merck (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Taiho Pharmaceutical, Jounce Therapeutics, Pfizer, AstraZeneca, IntelliSphere, Lilly, Gilead Sciences Rosemary DelaneyEmployment: Gilead SciencesStock and Other Ownership Interests: Immunomedics (I), Gilead Sciences Olivia FuEmployment: Gilead SciencesStock and Other Ownership Interests: Gilead SciencesTravel, Accommodations, Expenses: Gilead Sciences Lanjia LinEmployment: Gilead SciencesStock and Other Ownership Interests: Gilead SciencesTravel, Accommodations, Expenses: Gilead Sciences Wendy VerretEmployment: Roche/Genentech, Gilead Sciences Sara M. TolaneyThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech, Eisai, Sanofi, Bristol Myers Squibb, Paxman, Seattle Genetics, Odonate Therapeutics, G1 Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Immunomedics/Gilead, Mersana, Certara Inc, 4D Pharma, Ellipses Pharma, OncoSec, Chugai Pharma, BeyondSpring Pharmaceuticals, OncXerna Therapeutics, Infinity Pharmaceuticals, Zymeworks, Zentalis, BluePrint Medicines, Reveal GenomicsResearch Funding: Genentech/Roche (Inst), Merck (Inst), Exelixis (Inst), Pfizer (Inst), Lilly (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Eisai (Inst), AstraZeneca (Inst), NanoString Technologies (Inst), Cyclacel (Inst), Nektar (Inst), Immunomedics (Inst), Odonate Therapeutics (Inst), Sanofi (Inst), Settle Genetics (Inst)No other potential conflicts of interest were reported.

Introduction: In the phase II CORALLEEN trial, patients with PAM50 luminal B early breast cancer (EBC) were randomised to neoadjuvant ribociclib plus letrozole (R + L) or chemotherapy based on anthracyclines and taxanes. Results from the primary efficacy analysis showed a similar proportion of patients with response at surgery in both groups. How health-related quality of life (HRQoL) outcomes with R + L compare with chemotherapy in EBC setting is still unknown. Here, we report the results of the HRQoL analysis from the CORALLEEN study., Methods: A total of 106 women were randomised 1:1 to receive neoadjuvant R + L (n = 52) or chemotherapy (n = 54). Patient-reported outcomes were assessed using two questionnaires: EORTC QLQ-C30 and EORTC QLQ-BR23. Change from baseline in the global health status, functional, and symptom scales was analysed using linear mixed-effect models, and between-treatment differences were estimated along with 95% confidence interval (95% CI)., Results: At baseline, the overall questionnaire available rate was 94.3%, and patient-reported outcomes were similar between treatment groups. At the end of the study treatment (24 weeks), patients receiving R + L showed better global health status scores with a between-treatment difference of 17.7 points (95% CI 9.2-26.2; p-value &lt;0.001). The R + L group also presented numerically better outcomes in all functional and symptom scales. The larger between-treatment differences in symptom severity were found in fatigue (-28.9; 95% CI -38.5 to -19.3), appetite loss (-23; 95% CI -34.9 to -11.2) and systematic therapy side-effects (-11.4; 95% CI -18.3 to -4.6)., Conclusions: Neoadjuvant R + L was associated with better HRQoL outcomes compared with chemotherapy in patients with luminal B EBC., Registration Identification: ClinicalTrials.gov Identifier: NCT03248427., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G. Villacampa: Consulting Fees (e.g. advisory boards); AstraZeneca. Other (speakers' bureaus); MSD, GSK and Pierre Fabre. C. Falato: Contracted Research; Fellowship from the Swedish Society for Medical Research. L. Paré: Receipt of Intellectual Property Rights/Patent Holder; HER2DX filing. C. Hernando: None declared. M. Arumí: Other; Roche, Eisai, MSD. C. Saura: Consulting Fees (e.g. advisory boards); Astrazeneca, Daiichi Sankyo, Exact Sciences, MSD, Philips, Pierre-Fabre, Puma Biotechnology, Roche, SeaGen, Zymeworks. Other (Consultant); Astrazeneca, AX'S Consulting sprl, Byondis B.V, Eisai, Exeter Pharma, Roche, MediTech, Novartis, Pfizer, Pierre Fabre, PintPharma and SeaGen. G. Gomez Melis: None declared. M. Muñoz: Consulting Fees (e.g. advisory boards); Pierre Fabre. Other; Eisai, Lilly, Novartis, Pfizer, Roche. M. Gil-Gil: Consulting Fees (e.g. advisory boards); AstraZeneca, Agendia. Other; Pfizer, Roche, Novartis, Pierre-Faber, Daiichi-Sankyo, Eisai. Y. Izarzugaza: Consulting Fees (e.g. advisory boards); Novartis. Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); Novartis, Pfizer. N. Ferrer: None declared. J. Najera-Zuloaga: None declared. A. Montaño: None declared. E. Ciruelos: Consulting Fees (e.g. advisory boards); Pfizer, Daiichi Sankyo, Novartis, MSD, AstraZeneca, Roche, Lilly. Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); Roche, Lilly. S. González-Santiago: Consulting Fees (e.g. advisory boards); Roche, Lilly, MSD, Pharmamar, Clovis, Pfizer. Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); Novartis, GSK, MSD, Pfizer. P. Villagrasa: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); Summit NS ESMO 2019 speaker. Other; Oncolytics. J. Gavilá: Consulting Fees (e.g. advisory boards); Lilly, AstraZeneca, Novartis, Pfizer, Roche. Other; AstraZeneca, Lilly, Novartis, Pfizer, Roche. A. Prat: Salary; Pfizer, Roche, Lilly, Amgen, Novartis, MSD Oncology, Daiichi Sankyo, Guardant Health. Receipt of Intellectual Property Rights/Patent Holder; PCT/EP2016/080056: HER2 AS A PREDICTOR OF RESPONSE TO DUAL HER2 BLOCKADE IN THE ABSENCE OF CYTOTOXIC THERAPY, WO/2018/096191. Chemoendocrine score (CES) Based on PAM50 for breast cancer with positive hormone receptors with an intermediate risk of recurrence, METHODS FOR BREAST CANCER TREATMENT AND PREDICTION OF THERAPEUTIC RESPONSE (US 63/023785), HER2DX filing. Consulting Fees (e.g. advisory boards); Amgen, Novartis, Bristol-Myers Squibb, PUMA, Daiichi Sankyo, Astrazeneca, Roche, Pfizer, Boehringer, Oncolytics Biotech, Abbvie, NanoString Technologies. Contracted Research; Roche, Novartis, Incyte, Puma Biotechnology. Ownership Interest (stock, stock options, or other ownership interest excluding diversified mutual funds); Reveal Genomics. Other; Oncolytics, Daiichi Sankyo, Peptomyc SL. T. Pascual: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); AstraZeneca, Pfizer. Consulting Fees (e.g. advisory boards); Novartis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Primary systemic treatment (PST) downsizes the tumor and improves pathological response. The aim of this study is to analyze the feasibility and tolerance of primary concurrent radio−chemotherapy (PCRT) in breast cancer patients. Patients with localized TN/HER2+ tumors were enrolled in this prospective study. Radiation was delivered concomitantly during the first 3 weeks of chemotherapy, and it was based on a 15 fractions scheme, 40.5 Gy/2.7 Gy per fraction to whole breast and nodal levels I-IV. Chemotherapy (CT) was based on Pertuzumab−Trastuzumab−Paclitaxel followed by anthracyclines in HER2+ and CBDCA-Paclitaxel followed by anthracyclines in TN breast cancers patients. A total of 58 patients were enrolled; 25 patients (43%) were TN and 33 patients HER2+ (57%). With a median follow-up of 24.2 months, 56 patients completed PCRT and surgery. A total of 35 patients (87.5%) achieved >90% loss of invasive carcinoma cells in the surgical specimen. The 70.8% and the 53.1% of patients with TN and HER-2+ subtype, respectively, achieved complete pathological response (pCR). This is the first study of concurrent neoadjuvant treatment in breast cancer in which three strategies were applied simultaneously: fractionation of RT (radiotherapy) in 15 sessions, adjustment of CT to tumor phenotype and local planning by PET. The pCR rates are encouraging.

Background: High-risk triple-negative breast cancers (TNBCs) are characterized by poor prognosis, rapid progression to metastatic stage and onset of resistance to chemotherapy, thus representing an area in need of new therapeutic approaches. Programmed death-ligand 1 (PD-L1) expression is an adaptive mechanism of tumour resistance to tumour-infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, available data support the concept that blockade of PD-L1/programmed cell death protein 1 checkpoint may improve efficacy of classical chemotherapy., Patients and Methods: Two hundred and eighty patients with TNBC were enrolled in this multicentre study (NCT002620280) and randomized to neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m 2 intravenously (i.v.) on days 1 and 8, without (n = 142) or with (n = 138) atezolizumab 1200 mg i.v. on day 1. Both regimens were given q3 weeks for eight cycles before surgery followed by four cycles of an adjuvant anthracycline regimen. The primary aim of the study was to compare event-free survival (EFS), and an important secondary aim was the rate of pathological complete response (pCR defined as the absence of invasive cells in breast and lymph nodes). The primary population for all efficacy endpoints is the intention-to-treat (ITT) population., Results: The ITT analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab [44.4%: odds ratio (OR) 1.18; 95% confidence interval 0.74-1.89; P = 0.48]. Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminase abnormalities with atezolizumab., Conclusions: The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the rate of pCR in women with TNBC. In multivariate analysis, the presence of PD-L1 expression was the most significant factor influencing the rate of pCR (OR 2.08). Continuing follow-up for the EFS is ongoing, and molecular studies are under way., Competing Interests: Role of the funder The sponsor of the study is Fondazione Michelangelo, a non-profit organization, who collaborated in the study design. Fondazione Michelangelo had no primary roles in the collection, analysis or interpretation of the data. Hoffman-La Roche, Ltd, and Celgene, had no role in the study design, or in the interpretation of the data or in writing the report. Disclosure LG has received consulting fees from Novartis and Odonate Therapeutics; honoraria for lecture from Roche; support for attending meetings from Pfizer; is co-inventor of ‘European patent Application N. 12195182.6 and 12196177.5 titled PDL-1 expression in anti-HER2 therapy’—Roche—Issued (no compensation provided); has served on Advisory Boards for Astra Zeneca, Celgene, Genentech, Merk Sharp & Dohme, Roche, Pfizer and Sanofi Aventis; and is Chair of the Breast Cancer Research Committee of Fondazione Michelangelo. CSH has received research grants for his institution from Daiichi Sankyo, Astra Zeneca, EirGenix, Eli Lilly, MSD, OBI Pharma, Pfizer, Roche and Novartis; honoraria for speakers’ bureaus from Amgen, Astra Zeneca, Pfizer, Roche and Novartis; support for attending meetings from Astra Zeneca, Pfizer and Roche; and has served on Advisory Boards for Amgen, Astra Zeneca, Eli Lilly, Pfizer, Roche and Novartis. DE has received consulting fees from Astra Zeneca, Daichii Sankyo, Gilead, Novartis, MSD, Roche, Pfizer and Seagen; honoraria for lectures from Amgen, AstraZeneca, Daichii Sankyo, Novartis, MSD, Roche and Pfizer; and support for attending meetings from Pfizer and Roche. BB has received honoraria for speaker bureaus from MDS, Roche, Novartis, Pfizer, Palex, Astra Zeneca and Lilly; and has served on Advisory Boards for MSD, Roche and Daichii Sankyo. CZ has received grants from Eisai, Pharmamar, Eli Lilly, Celgene, MSD, GSK, Amgen and Daichii Sankyo and for him and his institution from Roche, Novartis, Astra Zeneca, Pfizer, Tesaro, Pierre Fabre, Ist. Gentili, Teva and Seagen; support for attending meetings from Roche, Novartis, Pfizer, Pharmamar, Tesaro, Pierre Fabre, Ist. Gentili and Celgene; has served on Advisory Boards for Roche, Eisai, Novartis, Astrazeneca, Pfizer, Pharmamar, Amgen, Tesaro, QuintilesIMS, Eli Lilly, Celgene, MSD, GSK and Daichii Sankyo; and has received other financial and non-financial interests from Roche, Novartis, Astra Zeneca, Pfizer, Amgen, Tesaro, QuintilesIMS, MSD, GSK and Daichii Sankyo. MT has received research grants from Roche and Exact Sciences; consulting fees from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche and Seagen; honoraria for speakers’ bureaus from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Seagen and VIfor; support for attending meetings from Amgen, AstraZeneca, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Hexal, I-Med-Institute, Lilly, MSD, Novartis, Pfizer, pfm Medical and Roche; has served on Advisory Board for Roche; is Chair of Board of Directors AWOgyn; and has received other services from Celgene. AA has received consulting fees from Daichii Sankyo, Roche, Pfizer and Bayer Spain; payment for expert testimony from Pfizer; has served on Advisory Boards for Lilly and Gilead; and has received other services from GSK. GB has received consulting fee from Roche, AstraZeneca, Novartis, MSD, Sanofi, Daiichi Sankyo and Exact Science; honoraria for speakers’ bureaus from Roche, Pfizer, AstraZeneca, Lilly, Novartis, Neopharm Israel, MSD, Chugai, Daiichi Sankyo, EISAI and Exact Science; support for attending meetings from Roche, Pfizer and AstraZeneca; and has served on Advisory Board for Roche, Pfizer, Daiichi Sankyo, Lilly, MSD, Novartis, AstraZeneca, Genomic Health, EISAI, Gilead and Seagen. EMC has received consulting fee from Roche, Lilly, Astra Zeneca, Daiichi Sankyo, Novartis, Pfizer and MSD; honoraria for speakers’ bureaus from Lilly and Roche; and support for attending meetings from Pfizer and Roche. RG has received consulting fees from Celgene, Novartis, Roche, BMS, Takeda, Abbvie, Astra Zeneca, Jaanssen, MSD, Merk, Gilead, Daiichi Sankyo and Sanofi; support for attending meetings from Roche, Amgen, Janssen, Astra Zeneca, Novartis, MSD, Celgene, Gilead, BMS, Abbvie and Daiichi Sankyo; has served on Advisory Boards for Celgene, Novartis, Roche, BMS, Takeda, Abbvie, Astra Zeneca, Jaanssen, MSD, Merk, Gilead, Daiichi Sankyo and Sanofi; and has received other financial or non-financial interests from Celgene, Roche, Merk, Takeda, Astra Zeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead and Daiichi Sankyo. MC has received research grant from Roche. CK has received grants from Mater Foundation and HRB Grant/Hospital Co investment and from Irish Cancer Society; honoraria for educational events from Exact Sciences, Astra Zeneca and Daiichi Sanyko; support for attending meetings from Roche; and has participated in Steering Committees for PALLAS trial, PenelopeB trial and Destiny Breast 11. LDM has received honoraria for speakers’ bureaus from Roche, Novartis, Eli Lilly, MDS, Pfizer, Ipsen and from Novartis for her institution; support for attending meetings from Roche, Pfizer and Celgene; and has served on Advisory Boards for Roche, Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sanyko and Seagen. GV has received grants from Roche/Genentech and Astra Zeneca for his institution; consulting fees from Roche/Genentech, Astra Zeneca, MDS Oncology and Daiichi Sanyko; honoraria for lectures from Roche/Genentech, Astra Zeneca and Daiichi Sanyko; support for attending meetings from Roche/Genentech; and has served on Advisory Boards for Roche/Genentech, Astra Zeneca, Pfizer, MDS Oncology and Novartis. All other authors have declared no conflicts of interest. Data sharing Qualified researchers can address requests to the datasets generated during and/or analysed during the current study to the corresponding author or to segreteria@fondazionemichelangelo.org and the request will be examined by the members of the Protocol Steering Committee., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Aims: To evaluate echocardiographic and biomarker changes during chemotherapy, assess their ability to early detect and predict cardiotoxicity and to define the best time for their evaluation., Methods and Results: Seventy-two women with breast cancer (52 ± 9.8 years) treated with anthracyclines (26 also with trastuzumab), were evaluated for 14 months (6 echocardiograms/12 laboratory tests). We analysed: high-sensitivity cardiac troponin T, NT-proBNP, global longitudinal strain (GLS), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF). Cardiotoxicity was defined as a reduction in LVEF>10% compared with baseline with LVEF<53%. High-sensitivity troponin T levels rose gradually reaching a maximum peak at 96 ± 13 days after starting chemotherapy (P < 0.001) and 62.5% of patients presented increased values during treatment. NT-proBNP augmented after each anthracycline cycle (mean pre-cycle levels of 72 ± 68 pg/mL and post-cycle levels of 260 ± 187 pg/mL; P < 0.0001). Cardiotoxicity was detected in 9.7% of patients (mean onset at 5.2 months). In the group with cardiotoxicity, the LVESV was higher compared with those without cardiotoxicity (40 mL vs. 29.5 mL; P = 0.045) at 1 month post-anthracycline treatment and the decline in GLS was more pronounced (-17.6% vs. -21.4%; P = 0.03). Trastuzumab did not alter serum biomarkers, but it was associated with an increase in LVESV and LVEDV (P < 0.05). While baseline LVEF was an independent predictor of later cardiotoxicity (P = 0.039), LVESV and GLS resulted to be early detectors of cardiotoxicity [odds ratio = 1.12 (1.02-1.24), odds ratio = 0.66 (0.44-0.92), P < 0.05] at 1 month post-anthracycline treatment. Neither high-sensitivity troponin T nor NT-proBNP was capable of predicting subsequent cardiotoxicity., Conclusions: One month after completion of anthracycline treatment is the optimal time to detect cardiotoxicity by means of imaging parameters (LVESV and GSL) and to determine maximal troponin rise. Baseline LVEF was a predictor of later cardiotoxicity. Trastuzumab therapy does not affect troponin values hence imaging techniques are recommended to detect trastuzumab-induced cardiotoxicity., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: The addition of immune checkpoint inhibitors (ICI) to chemotherapy (CT) has been one of the main clinical research endeavors over the last few years in patients with metastatic triple-negative breast cancer (TNBC). Recent randomized controlled trials (RCTs) have presented heterogeneous results that have elicited discussion in the oncology community. Here we conducted a systematic review and meta-analysis to evaluate this strategy., Material and Methods: A systematic literature review was conducted to identify RCTs that evaluated the combination of ICI plus CT versus CT alone in untreated metastatic TNBC. Random effects models were used to estimate pooled hazard ratios (HR) and odds ratios with 95% confidence intervals (95 %CI)., Results: A total of three RCTs including 2,400 patients with TNBC met the eligibility criteria. Patients with PD-L1-positive tumors had a significantly better PFS with the addition of ICI (HR = 0.67; 95 %CI: 0.58-0.79) and a trend towards better OS (HR = 0.79; 95 %CI: 0.60-1.03), while no benefit was observed in patients with PD-L1-negative tumors. In the PD-L1-positive subgroup, no relevant differences were found according to taxane agent used, ECOG performance status or number of metastatic sites. However, CT naïve patients obtained a larger benefit with ICI (PFS HR = 0.53) than patients previously treated with CT in neoadjuvant/adjuvant setting (PFS HR = 0.81). The most frequent immune-related adverse events in patients receiving ICI were hypothyroidism (16%) and hyperthyroidism (4.9%)., Conclusions: ICI plus CT improves PFS and OS in PD-L1-positive population. A greater benefit in CT naïve patients was observed for the PD-L1-positive population while no difference was observed between taxane regimes used., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In advanced breast cancer, biomarker identification and patient selection using a metastatic tumor biopsy is becoming more necessary. However, the biology of metastasis according to the organ site is largely unknown. Here, we evaluated the expression of 771 genes in 184 metastatic samples across 11 organs, including liver, lung, brain, and bone, and made the following observations. First, all PAM50 molecular intrinsic subtypes were represented across organs and within immunohistochemistry-based groups. Second, HER2-low disease was identified across all organ sites, including bone, and HER2 expression significantly correlated with ERBB2 expression. Third, the majority of expression variation was explained by intrinsic subtype and not organ of metastasis. Fourth, subtypes and individual subtype-related genes/signatures were significantly associated with overall survival. Fifth, we identified 74 genes whose expression was organ-specific and subtype-independent. Finally, immune profiles were found more expressed in lung compared to brain or liver metastasis. Our results suggest that relevant tumor biology can be captured in metastatic tissues across a variety of organ sites; however, unique biological features according to organ site were also identified and future studies should explore their implications in diagnostic and therapeutic interventions., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: The SOLTI-1301 AGATA study aimed to assess the feasibility of a multi-institutional molecular screening program to better characterize the genomic landscape of advanced breast cancer (ABC) and to facilitate patient access to matched-targeted therapies in Spain., Methods: DNA sequencing of 74 cancer-related genes was performed using FFPE tumor samples in three different laboratories with three different gene panels. A multidisciplinary advisory board prospectively recommended potential targeted treatments. The primary objective was to determine the success of matching somatic DNA alteration to an experimental drug/drug class., Results: Between September 2014 and July 2017, 305 patients with ABC from 10 institutions were enrolled. Tumor sequencing was successful in 260 (85.3%) patients. Median age was 54 (29-80); most tumors were hormone receptor-positive/HER2-negative (74%), followed by triple-negative (14.5%) and HER2-positive (11.5%). Ninety-seven (37%) tumor samples analyzed proceeded from metastatic sites. Somatic mutations were identified in 163 (62.7%) patients, mostly in PIK3CA (34%), TP53 (22%), AKT1 (5%), ESR1 (3%), and ERBB2 (3%) genes. Significant enrichment of AKT1 mutation was observed in metastatic versus primary samples (9% vs. 2%; p=0.01). Genome-driven cancer therapy was recommended in 45% (n=116) of successfully screened patients, 11% (n=13) of whom finally received it. Among these patients, 46.2% had a PFS of ≥6 months on matched therapy., Conclusions: AGATA is the first nationwide molecular screening program carried out in Spain and we proved that implementing molecular data in the management of ABC is feasible. Although these results are promising, only 11% of the patients with genome-driven cancer therapy received it., Competing Interests: SP reports advisor/consultant role for AstraZeneca, Daiichi-Sankyo, Polyphor, Novartis, SeattleGenetics, Pierre Fabre, Eisai, and Roche. Advisory role of A.P. for Nanostring Technologies, Pierre Fabre, Roche, Pfizer, Novartis, BMS and Roche. MO reports Grant/Research Support (to the Institution) from AstraZeneca, Philips Healthcare, Genentech, Roche, Novartis, Immunomedics, Seattle Genetics, GSK, Boehringer-Ingelheim, PUMA Biotechnology, and Zenith Epigenetics; personal fees from Roche, Seattle Genetics, and Novartis; consultant role for Roche/Genentech, GSK, PUMA Biotechnology, AstraZeneca, and Seattle Genetics; and travel Grants from Roche, Pierre-Fabre, Novartis, and Eisai. APr has declared personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo, travel, accommodations, and expenses paid by Daiichi Sankyo, research funding from Nanostring Technologies, Roche and Novartis, consulting/advisory role for Nanostring Technologies, Roche, Novartis, Pfizer, Oncolytics Biotech, Amgen, Lilly, MSD, PUMA and Daiichi Sankyo, Inc. EC reports personal fees from Pfizer and non-financial support from Pfizer during the conduct of the study; personal fees from Roche, personal fees from Lilly, personal fees from Astra Zeneca, personal fees from Novartis, and personal fees from MSD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pernas, Villagrasa, Vivancos, Scaltriti, Rodón, Burgués, Nuciforo, Canes, Paré, Dueñas, Vidal, Cejalvo, Perelló, Llommbard-Cussac, Dorca, Montaño, Pascual, Oliveira, Ribas, Rapado, Prat and Ciruelos.)

Background: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes., Patients and Methods: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively., Results: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs. -2.1 for capecitabine (95% confidence interval [CI], 1.4-8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale., Conclusion: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated., Trial Registration Number: NCT02028507 (ClinTrials.gov)., Eudract Study Number: 2013-003170-27., Competing Interests: Conflict of interest statement Z.K. has participated in advisory boards of and received speaker fees or travel support from Pfizer, Roche, AstraZeneca and Novartis. M.G-G.- has received honoraria from Pfizer and Eisai and has participated in advisory boards of Genentech and Daiichi Sankyo. He has received travel support from Pfizer, Novartis, Daiichi Sankyo, Roche and Kern. M.R.B. has received speaker fees and advisory grants from Pfizer, Novartis and Lilly. E.Ca., who has a stock and other ownership interests from Lilly, has received travel and accommodation support from Roche, and her husband, who has participated in consulting and advisory board activities with Bristol Myers Squibb, Novartis, Celgene, Roche Pharma, Janssen, Amgen, Incyte, AbbVie and Pfizer, has received travel and accommodation support from Celgene, Novartis and Bristol Myers Squibb. His institution has received research funding from Celgene, Janssen, Bristol Myers Squibb, Novartis, Roche/Genentech, Amgen, Pfizer and AbbVie. GEICAM has received research funding from Roche/Genentech, Bristol Myers Squibb, Novartis, Pfizer, Celgene, AstraZeneca, Merck Sharp & Dohme, Pierre Fabre and Takeda. E.Ci. has received advisory board honoraria from Lilly, Novartis, MSD, AstraZeneca, Pfizer and Roche and speakers' honoraria from Roche, Lilly and Pfizer, and she has received travel and congress assistance support from Pfizer and Roche. M.Mu. has received travel and congress assistance support from Roche, Novartis, Pfizer and Eisai. B.B. has received advisory board honoraria from Roche, Novartis and MSD and speakers' honoraria from Roche, Novartis, MSD, Pfizer and Pierre Fabre, and she has received travel and congress assistance support from Pfizer. M.Marg. has received advisory board fees from Roche, Novartis, Pfizer and Eisai. Her institution, ICO-Badalona. B-ARGO (Badalona Applied Research Group in Oncology) Hospital Universitari Germans Trias i Pujol, Badalona, has received research funding from Roche, Pfizer, Novartis, Lilly, AstraZeneca, Eisai and Kern, and she has received travel and congress assistance support from Roche. A.A. has received advisory board fees from Bayer, Spain. E.A. has received advisory board fees from Roche, Novartis, Pfizer, Lilly, Bristol Myers Squibb, Genomic Health and Nanostring. He has received travel support from Celgene. His institution, Hospitales Regional y Virgen de la Victoria, Málaga, has received research funding from Roche, Pfizer, Sysmex, Merck Sharp & Dohme and Nanostring. J.d.l.H-R. has received speaker's honoraria from AstraZeneca, Pfizer, Novartis and Lilly. M.R. has received honoraria from Novartis, Roche and Pfizer. I.M.A-L. has received consulting or advisory board honoraria from AstraZeneca, Pfizer, Novartis, Palex and Roche; speakers' honoraria from AstraZeneca, Pfizer, Novartis, Roche and Eisai; travel and congress assistance support from AstraZeneca, Pfizer, Roche and Eisai and research funding from Pfizer, Novartis, AstraZeneca and Roche. E.G-Y. has received honoraria and travel support and has participated in advisory boards for Pfizer, Roche, Novartis and Eli Lilly. S.G-S. has received consulting or advisory board honoraria from Pfizer, MSD, GSK and Roche and speakers' honoraria from AstraZeneca, Pfizer and Novartis. C.A.R. has received consulting or advisory board honoraria from AstraZeneca, Pfizer, Novartis, SeaGen, DaiiChi Sankyo and Roche and speakers' honoraria from MSD, Pfizer, Novartis, Roche, Nanostring, Amgen and Eisai. S.S. has received consulting or advisory board or speakers' honoraria from Roche, Eisai, Daiichi Sankyo, AstraZeneca, MSD and Genomic Health. M.C. is employed by Pfizer and has the company's stock options. X.H. is employed by Pfizer and has the company's stock options. C.Z. has received consulting fees and speaker's honoraria from Roche, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, FibroGen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Eli Lilly and Athenex. His institution, Central European Cancer Center, Wiener Privatklinik Hospital, has received fees from Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, AstraZeneca and Merck KGaA. M.Mart. has received consulting fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology and Pfizer; speakers' honoraria from AstraZeneca, Amgen, Roche/Genentech, Novartis, Daiichi Sankyo and Pfizer and contracted research fees from Roche, Novartis and PUMA. All remaining authors have declared no conflicts of interest. A complete list of the PEARL trial collaborators is provided in the Supplementary Appendix., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting., Patients and Methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors., Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months)., Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design., Competing Interests: Disclosure DM has received honoraria for advisory boards from Roche/Genentech, Genomic Health and Eisai, and has been an invited speaker for Roche/Genentech and Genomic Health. EC has received consultancy fees from Roche, Lilly, Novartis and Pfizer, and has received honoraria for speaker engagements from Celgene, Roche, Novartis and Pfizer. AS has received honoraria for scientific talks from Roche, Celgene, AstraZeneca, Pfizer and Novartis, and travel support from Roche and Celgene. FP reports consultant/advisory roles for Amgen, AstraZeneca, Daichii-Sankyo, Eli Lilly, Ipsen, MSD, Novartis, Pierre Fabre, Pfizer and Roche, and research funding from AstraZeneca, Eisai and Roche. TP-Y has received honoraria for advisory boards and lectures from F. Hoffmann-La Roche, Pfizer, Neopharm, MSD, AstraZeneca, Janssen, Teva, Screen Cell, Medison, AbbVie and Takeda, and has received travel support from F. Hoffmann-La Roche, Bristol-Myers Squibb, AstraZeneca and Janssen. MC reports participation in advisory boards for AstraZeneca, Novartis, AbbVie, Sanofi, Pfizer, Sandoz, ACCORD and Lilly GT1 group, consultancy roles for Pierre Fabre Oncology, Sanofi, Novartis, Servier and Sanofi, speaker bureau/expert testimony for Novartis and travel/accommodation/expenses from Pfizer, Novartis, Roche and AstraZeneca. IB and his institution have received an investigator fee from Roche for the PERUSE study. ZN has received travel/accommodation/expenses from Roche. HE reports advisory/consultancy roles for Roche, MSD, Pfizer, Astellas and Merck and speaker bureau/expert testimony for Novartis and Amgen. SP-S has received honoraria for consultancy and speaker engagements from Roche, Novartis, Pfizer, AstraZeneca, Nanostring and Teva. AW reports personal fees from Roche, NAPP, Amgen, MSD, Novartis, Pfizer, AstraZeneca, Pierre Fabre, ACCORD, Athenex, Gerson Lehmann Group, Coleman Expert Network Group and Guidepoint global; he also reports personal fees and other from Lilly and Daichii-Sankyo (all outside the submitted work) and employment with AstraZeneca after completion of this work. J-LM is employed by IQVIA, a clinical research organisation contracted by F. Hoffmann-La Roche. PT is an employee of Genentech and holds shares in F. Hoffmann-La Roche Ltd. YdT, CP-M, VR and DK are employees and shareholders of F. Hoffmann-La Roche Ltd. TB has received research funding from AstraZeneca, Novartis and Pfizer, and has acted as a consultant for and received travel grants from AstraZeneca, Roche, Novartis and Pfizer., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: CompLEEment-1 is a phase 3b trial in an expanded patient population with hormone receptor-positive (HR +), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC), the largest current trial of cyclin-dependent kinase 4 and 6 inhibitors in ABC., Methods: Patients treated with ≤ 1 line of prior chemotherapy and no prior endocrine therapy for ABC received ribociclib 600 mg/day (3-weeks-on/1-week-off) plus letrozole 2.5 mg/day and additionally monthly goserelin/leuprolide in men and pre-/perimenopausal women. Eligibility criteria allowed inclusion of patients with stable CNS metastases and an Eastern Cooperative Oncology Group performance status of 2. Primary objectives were safety and tolerability, and secondary objectives were efficacy and quality of life (QoL)., Results: Overall, 3,246 patients were evaluated (median follow-up 25.4 months). Rates of all-grade and grade ≥ 3 treatment-related adverse events (AEs) were 95.2% and 67.5%, respectively. Treatment-related discontinuations due to all grade and grade ≥ 3 AEs occurred in 12.9% and 7.3% of patients, respectively. Rates of all-grade AEs of special interest (AESI) were as follows: neutropenia (74.5%), increased alanine aminotransferase (16.2%), increased aspartate aminotransferase (14.1%), and QTcF prolongation (6.7%); corresponding values for grade ≥ 3 AESI were 57.2%, 7.7%, 5.7%, and 1.0%, respectively. Median time to progression was 27.1 months (95% confidence interval, 25.7 to not reached). Patient QoL was maintained during treatment., Conclusion: Safety and efficacy data in this expanded population were consistent with the MONALEESA-2 and MONALEESA-7 trials and support the use of ribociclib plus letrozole in the first-line setting for patients with HR + , HER2- ABC., Trial Registration: linicalTrials.gov NCT02941926., (© 2021. The Author(s).)

The use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has proven to be a successful strategy in the treatment of advanced hormone receptor-positive (HR + ) and human epidermal growth factor receptor 2-negative (HER2 - ) breast cancer (BC), leading to a strong interest in their possible role in the treatment of early luminal BC. In this review we collect the most relevant and recent information on the use of CDK4/6i for the treatment of early BC in the neoadjuvant and adjuvant settings. Specifically, we evaluate the results of the large phase 3 adjuvant trials recently released, which have yielded apparently divergent results. We also examine the relevance of biomarkers as response predictive factors for CDI4/6i, the combination between radiotherapy and CDK4/6i, and provide a critical discussion on the evidence that we have so far and future directions of the role of these drugs in the treatment of early BC., Competing Interests: Declaration of competing interest MGG reports consulting fees and honoraria from Pfizer, Agendia, and Kern; advisory roles for AstraZeneca and Daiichi-Sankyo; travel grants from Pfizer, Roche, Novartis, and Kern. EA reports advisory roles for Roche, Novartis, Pfizer, Eli Lilly, BMS, AstraZeneca, Genomic Health, and Nanostring; travel grants from Celgene; research grants from Roche, Pfizer, Sysmex, MSD, and Nanostring. JG reports consulting fees and honoraria from Novartis, Pfizer, AstraZeneca and Daiichi-Sankyo; advisory roles for Novartis, Pfizer, Eli Lilly and AstraZeneca. JdlH-R reports consulting fees and honoraria from Pfizer, Novartis, and Agendia; advisory roles for AstraZeneca, Daiichi-Sankyo, Pfizer, Novartis and Roche; travel grants from Astra Zeneca, Pfizer, Roche and Novartis. EC reports consulting fees from Pfizer, Eli Lilly, Roche, Novartis, AstraZeneca and MSD; participating as a speaker for Roche, Pfizer and Eli Lilly; travel grants from Roche and Pfizer. PT reports personal fees from AstraZeneca and honoraria for participation in advisory boards from Amgen, AstraZeneca, MSD, Roche, Pfizer and Eisai. DC is an employee of and may own stock in Pfizer Inc. AL-C reports owing stock, patents and intellectual property with MedSIR; consultant for AstraZeneca, Daiichi-Sanyo, MSD, Novartis, Pfizer, Roche and Eli Lilly; research funding from Eisai, Daiichi-Sanyo, Roche, Pfizer, Eli Lilly, MSD, Genomic-Health, Agendia and Pierre Fabre; travel grants from Roche, Pfizer and Eli Lilly; providing expert testimony for AstraZeneca., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The CAPRICE trial was designed to specifically evaluate neoadjuvant pegylated liposomal doxorubicin (PLD) in elderly patients or in those with other cardiovascular risk factors in whom conventional doxorubicin was contraindicated. The primary analysis of the study showed a pathological complete response (pCR) of 32% and no significant decreases in LVEF during chemotherapy. Here, we report important secondary study objectives: 5-year cardiac safety, disease-free survival (DFS), overall survival (OS) and breast cancer specific survival (BCSS)., Methods: In this multicentre, single-arm, phase II trial, elderly patients or those prone to cardiotoxicity and high risk stage II-IIIB breast cancer received PLD (35 mg/m 2 ) plus cyclophosphamide (600 mg/m 2 ) every 4 weeks for 4 cycles, followed by paclitaxel for 12 weeks as neoadjuvant chemotherapy (NAC). Left ventricular ejection fraction (LVEF) monitorization, electrocardiograms and cardiac questionnaires were performed at baseline, during treatment and at 9, 16, 28 and 40 weeks thereafter. The primary endpoint was pCR and 5-year cardiac safety, DFS, BCSS and OS were also analyzed., Results: Between Oct 2007, and Jun 2010, 50 eligible patients were included. Median age was 73 (35-84) years, 84% were older than 65; 64% of patients suffered from hypertension, and 10% had prior cardiac disease. Most of tumors (88%) were triple negative. No significant decreases in LVEF were observed. The mean baseline LVEF was 66.6% (52-86) and after a median follow-up of 5 years, mean LVEF was 66 (54.5-73). For intention to treat population, 5-year DFS was 50% (95% CI 40.2-68.1) and 5-year OS was 56% (95%CI 41.2-68.4). There were 8 non-cancer related deaths, achieving a 5 years BCSS of 67.74% (CI 95%:54.31%- 81.18%)., Conclusion: At 5-year follow-up, this PLD-based NAC regimen continued to be cardiac-safe and effective in a population of very high-risk breast cancer patients. This scheme should be considered as an option in elderly patients or in those with other risks of developing cardiotoxicity., Trial Registration Number: ClinicalTrials.gov reference NCT00563953., Competing Interests: MG-G declares consulting/advisory fees from Pfizer, Daiichi-Sankyo, Novartis and Roche. MB declares consulting/advisory fees from Pfizer, Novartis and Lilly. SM declares consulting/advisory fees from Pfizer, Roche and Lilly. AB declares consulting/advisory fees from Pfizer, Roche, Bristol Muers Squibb, Astra-Zeneca and Lilly. CS declares consulting/advisory fees from Pfizer, Roche, Macrogenics, Piqur therapeutics, Puma, Synthon and Novartis. EG-M declares consulting/advisory fees from Roche; Astra-Zeneca, Clovis, Pharmamr, Celgene and Novartis. EC declares consulting/advisory fees from Puma, Pfizer, Roche, Astra-Zeneca, Celgene, Daiichi-Sankyo, Eisai, Genomyc Health, Novartis Pierre Fabre and Synthon. SP declares consulting/advisory fees from Astra-Zeneca, Daiichi-Sankyo, Novartis, Polyphor, Roche, and Seattle Genetics; and travel/accommodation grants from Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gil-Gil, Bellet, Bergamino, Morales, Barnadas, Manso, Saura, Fernández-Ortega, Garcia-Martinez, Martinez-Jañez, Melé, Villagrasa, Celiz, Perez Martin, Ciruelos and Pernas.)

Background: Chemotherapy efficacy in early-stage hormone receptor-positive (HR+) breast cancer (BC) according to menopausal status needs a biological explanation., Methods: We compared early-stage HR+ BC biological features before and after (neo)adjuvant chemotherapy or endocrine therapy (ET), and assessed oestrogen receptor (ER) pathway activity in both pre- and post-menopausal patients. The nCounter platform was used to detect gene expression levels., Findings: In 106 post-menopausal patients with HR+/HER2-negative BC randomized to neoadjuvant chemotherapy or ET (letrozole+ribociclib), a total of 19 oestrogen-regulated genes, including progesterone receptor (PGR), were found downregulated in the ET-based arm-only. We confirmed this finding in an independent dataset of 20 letrozole-treated post-menopausal patients and found, conversely, an up-regulation of the same signature in HR+/HER2-negative MCF7 cell line treated with estradiol. PGR was found down-regulated by 2 weeks of ET+anti-HER2 therapy in pre-/post-menopausal patients with HR+/HER2-positive (HER2+) BC, while anti-HER2 therapy alone increased PGR expression in HR-negative/HER2+ BC. In 88 pre- and post-menopausal patients with newly diagnosed HR+/HER2-negative BC treated with chemotherapy, the 19 oestrogen-regulated genes were found significantly downregulated only in pre-menopausal patients. In progesterone receptor (PR)+/HER2-negative BC treated with neoadjuvant chemotherapy (n=40), tumours became PR-negative in 69.2% of pre-menopausal patients and 14.8% of post-menopausal patients (p=0.001). Finally, a mean decrease in PGR levels was only observed in pre-menopausal patients undergoing anti-HER2-based multi-agent chemotherapy., Interpretation: Chemotherapy reduces the expression of ER-regulated genes in pre-menopausal women suffering from hormone-dependent BC by supressing ovarian function. Further studies should test the value of chemotherapy in this patient population when ovarian function is suppressed by other methods., Funding: Instituto de Salud Carlos III, Breast Cancer Now, the Breast Cancer Research Foundation, the American Association for Cancer Research, Fundació La Marató TV3, the European Union's Horizon 2020 Research and Innovation Programme, Pas a Pas, Save the Mama, Fundación Científica Asociación Española Contra el Cáncer, PhD4MDgrant of "Departament de Salut", exp SLT008/18/00122, Fundación SEOM and ESMO. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s)., Competing Interests: Declaration of Competing Interest Dr. Prat reports grants and personal fees from Pfizer, grants and personal fees from Lilly, personal fees from Nanostring tecnologies, grants and personal fees from Amgen, grants from Roche, personal fees from Oncolytics Biotech, personal fees from Daiichi Sankyo, personal fees from PUMA, personal fees from BMS, from Daiichi Sankyo, outside the submitted work. Dr. Perou reports personal fees from Bioclassifier LLC, outside the submitted work; in addition, Dr. Perou has a U.S. Patent No. 12,995,459 with royalties paid. Dr. Saura reports personal fees from AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, Puma, Roche Farma, Sanofi-Aventis, SeaGen, and Zymeworks outside the submitted work. Dr. Ciruelos reports personal fees from Roche, Pfizer, Lilly, Novartis, Astra-Zeneca/Daiichy Sankio and from MSD outside the submitted work. Dr. Gavilá reports grants from Novartis, Pfizer, Astra-Zeneca and Lilly, outside the submitted work. Dr. Soberino reports grants and personal fees from MSD, grants from Sanofi and personal fees from Roche outside the submitted work. Dr. Carey reports uncompensed relationship with Sanofi, G1 Therapeutics, Genentech/Roche, AstraZeneca/Daiichi Sankyo, Apitude Health and Exact Sciences; in addition Dr. Carey declared that Companies who have provided research funds to her institution in the past 1–2 years were Syndax, Immunomedics, Novartis, Nanostring technologies, Abbvie, Seattle Genetics and Veracyte, outside the submitted work. Dr Bellett declares advisory board participation for Lilly, Pfizer and Novartis, as well as travel expenses from Pfizer, outside the submitted work. Dr. Muñoz reports expert testimony for Eisai, Novartis and Roche, advisory board for Pierre Fabre and travel grants from Lilly, Pfizer and Roche, outside the submitted work. Dr. Oliveira reports grants from Pfizer, grants, personal fees and non-financial support from Roche, grants and personal fees from Genentech, grants, personal fees and non-financial support from Novartis, grants and personal fees from Seattle Genetics, grants and personal fees from Astra-Zeneca, grants and personal fees from PUMA Biotechnolgy, grants from Immunomedics, grants from Boehringer-Ingelheim, non-financial support from Eisai, Grunenthal, GP Pharma and Pierre Fabre, outside the submitted work. Dr. Pernas reports personal fees and non-financial support from Novartis, personal fees from AstraZeneca, Daiichi-Sankyo, Polyphor, Seattle Genetics, Eisai, Roche and Pierre-Fabre, outside the submitted work. Dr. Cortes reports personal fees and travel expenses from Pfizer, personal fees from Lilly, Servier, Athenex, personal fees and travel expenses and advisory/honoraria from Roche, personal fees from Polyphor, personal fees and travel expenses from Daiichi Sankyo, Novartis and Eisai, personal fees from MSD, GSK, Astra-Zeneca, Celgene, Cellestia, Biothera, Merus, Seattle Genetics, Erytech, Leuko, Bioasis, Clovis Oncology, Boerhinger-Ingelheim, Samsung Bioepis, and stocks from MedSIR, outside the submitted work. The other authors have nothing to declare., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Preclinical data support a key role for the human epidermal growth factor receptor 3 (HER3) pathway in hormone receptor (HR)-positive breast cancer. Recently, new HER3 directed antibody drug conjugates have shown activity in breast cancer. Given the need to better understand the molecular biology, tumor microenvironment, and mechanisms of drug resistance in breast cancer, we designed this window-of-opportunity study with the HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402). Trial Design: Based on these data, a prospective, multicenter, single-arm, window-of-opportunity study was designed to evaluate the biological effect of patritumab deruxtecan in the treatment of naïve patients with HR-positive/HER2-negative early breast cancer whose primary tumors are ≥1 cm by ultrasound evaluation. Patients will be enrolled in four cohorts according to the mRNA-based ERBB3 expression by central assessment. The primary endpoint is a CelTIL score after one single dose. A translational research plan is also included to provide biological information and to evaluate secondary and exploratory objectives of the study. Trial Registration Number: EudraCT 2019-004964-23; NCT number: NCT04610528., Competing Interests: SE and PF are employed by Daiichi Sankyo, Inc. AP has declared personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly, and Daiichi Sankyo, travel, accommodations, and expenses paid by Daiichi Sankyo, research funding from Nanostring Technologies, Roche, and Novartis, and consulting/advisory role for Nanostring Technologies, Roche, Novartis, Pfizer, Oncolytics Biotech, Amgen, Lilly, MSD, PUMA, and Daiichi Sankyo, Inc. outside the submitted work. MO reports honoraria and consulting fees from Roche/Genentech, GSK, PUMA Biotechnology, AstraZeneca, Seattle Genetics, and Novartis; travel and accommodation paid by Roche, Pierre-Fabre, Novartis, GP Pharma, Grünenthal, and Eisai; and grant/Research Support (to the Institution) from AstraZeneca, Philips Healthcare, Genentech, Roche, Novartis, Immunomedics, Seattle Genetics, GSK, Boehringer-Ingelheim, PUMA Biotechnology, and Zenith Epigenetics outside the submitted work. EC reports personal fees from Roche, personal fees from Lilly, personal fees from Novartis, and personal fees from Pfizer, during the conduct of the study. SP reports an advisor/consultant role for AstraZeneca, Daiichi-Sankyo, Polyphor, and Roche, and travel and accommodation paid by Novartis. JC reports an advisor/consultant role for Roche, Novartis, Pfyzer, Pharmamar, Lilly, Eisai, and Amgen, and travel and accommodation by Novartis and Pharmamar. FS-B has declared personal honoraria from Pfizer, Novartis, Roche, and Daiichi Sankyo. PV has received honoraria as a Speaker from Nanostring. MM has declared an advisor role or consulting from Novartis, Pfizer, and Roche; research funding from Roche, Eisai, and AstraZeneca; and travel expenses from Roche. OM-S reports an advisor role from Roche; honoraria as a speaker from Eisai; and travel expenses from Novartis. GV reports receiving honoraria for speaker activities from MSD and an advisory role from AstraZeneca. CS has served as a consultant, participated in advisory boards, or received travel grants from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann—La Roche Ltd., Genomic Health, Merck, Sharp and Dhome España S.A., Novartis, Odonate Therapeutics, Pfizer, Philips Healthwork, Pierre Fabre, prIME Oncology, Puma, Synthon, and Sanofi Aventis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pascual, Oliveira, Ciruelos, Bellet Ezquerra, Saura, Gavilá, Pernas, Muñoz, Vidal, Margelí Vila, Cejalvo, González-Farré, Espinosa-Bravo, Cruz, Salvador-Bofill, Guerra, Luna Barrera, Arumi de Dios, Esker, Fan, Martínez-Sáez, Villacampa, Paré, Ferrero-Cafiero, Villagrasa and Prat.)

Background: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A., Methods: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755., Findings: Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported., Interpretation: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor., Funding: Novartis Pharmaceuticals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial., Patients and Methods: PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA., Results: From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85)., Conclusions: There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life., Competing Interests: Disclosure MM has received consulting fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, and Pfizer; speakers' honoraria from AstraZeneca, Amgen, Roche/Genentech, Novartis, Daiichi-Sankyo, and Pfizer; contracted research fees from Roche, Novartis, and PUMA. CZ has received consulting fees and speaker’s honoraria from Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Eli Lilly, and Athenex. His institution, Central European Cancer Center, Wiener Privatklinik Hospital, has received fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, AstraZeneca, and Merck KGaA. MRB has received speaker fees and advisory grants from Pfizer, Novartis, and Lilly. EC, who has a stock and other ownership interests from Lilly, has received travel and accommodation support from Roche, and her husband who has participated in consulting and advisory board activities with Bristol-Myers Squibb, Novartis, Celgene, Roche Pharma, Janssen, Amgen, Incyte, Abbvie, and Pfizer, has received travel and accommodation support from Celgene, Novartis, and Bristol-Myers Squibb. His institution has received research funding from Celgene, Janssen, Bristol-Myers Squibb, Novartis, Celgene, Roche/Genentech, Amgen, Pfizer, and Abbvie. GEICAM has received research funding from Roche/Genentech, Bristol-Myers Squibb, Novartis, Pfizer, Celgene, AstraZeneca, Merck Sharp & Dohme, Pierre Fabre, and Takeda. NT has received advisory board honoraria from AstraZeneca, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Bicycle Therapeutics, Taiho, Zeno Pharmaceuticals, and Repare Therapeutics and research funding from AstraZeneca, Bio-Rad, Pfizer, Roche/Genentech, Clovis, Merck Sharp & Dohme, and Guardant Health. MM has received travel and congress assistance support from Roche, Novartis, Pfizer, and Eisai. BB has received advisory board honoraria from Genentech, Novartis, Merck Sharpe and Dohme, speakers’ honoraria from Genentech, Eisai and she has received travel and congress assistance support from Pfizer. MM has received advisory board fees from Roche, Novartis, Pfizer, and Eisai. Her institution, Hospital Universitari Germans Trias i Pujol, Badalona, has received funding research from Roche, Pfizer, Novartis, Lilly, AstraZeneca, Eisai, and Kern. AA has received advisory board fees from Bayer, Spain. EA has received advisory board fees from Roche, Novartis, Pfizer, Lilly, Bristol-Myers Squibb, Genomic Health, and Nanostring. He has received travel support from Celgene. His institution, Hospitales Regional y Virgen de la Victoria, Málaga, has received funding research from Roche, Pfizer, Sysmex, Merck Sharp & Dohme, and Nanostring. EG-Y has received honoraria, travel support, and has participated in advisory boards for Pfizer, Roche, Novartis, and Eli Lilly. ÁG-Z has received investigational fees and travel support from Pfizer. JdelaH has received honoraria from AstrazZeneca, Pfizer, Novartis, Roche, and Agendia. MR has received honoraria from Novartis, Roche, and Pfizer. IÁ has received consulting or advisory board honoraria from AstraZeneca, Pfizer, Novartis, and Roche; speakers’ honoraria from AstraZeneca, Pfizer, Novartis, Roche, and Eisai; travel and congress assistance support from AstraZeneca, Pfizer, Roche, and Eisai. CH has a stock from Pfizer and AstraZeneca, she was an employee of Pfizer during the study, and is an employee of AstraZeneca currently, where she holds a stock. MK has Pfizer stock and was an employee of Pfizer during the study. MC is employed by Pfizer and has the company’s stock options. XH is employed by Pfizer and has the company’s stock options. JAG-S has consultancy/speaker fees from Novartis, Celgene, Eli Lilly, Eisai, and AstraZeneca. He received travel support from Novartis, Roche, and Pfizer. His institution, Hospital Clínico Universitario San Carlos, received research funding from AstraZeneca. MG-G has received honoraria from Pfizer and Eisai and has participated in advisory boards of Genentech and Daiichi-Sankyo. He has received travel support from Pfizer, Novartis, Daiichi-Sankyo, Roche, and Kern. All remaining authors have declared no conflicts of interest. A complete list of the PEARL trial collaborators is provided in the Supplementary Appendix., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: The COVID-19 pandemic has affected healthcare systems globally, leading to reorganization of medical activities. We performed an international survey aimed to investigate the medium- and long-term impact on oncology units., Materials and Methods: An 82-item survey was distributed from June 17 to July 14, 2020 among medical oncologists worldwide., Results: One hundred nine medical oncologists from 18 countries in Europe (n = 93), United States (n = 5), and Latin America (n = 11) answered the survey. A systematic tracing of COVID-19-positive patients was continued in the postacute phase by 77.1% of the centers; 64.2% of the respondents participated in a local registry and 56% in international or national registries of infected patients. Treatment adaptations were introduced, and surgery was the most affected modality being delayed or canceled in more than 10% of patients in 34% of the centers, whereas early cessation of palliative treatment was reported in 32.1% of the centers; 64.2% of respondents reported paying attention to avoid undertreatments. The use of telemedicine has been largely increased. Similarly, virtual tools are increasingly used particularly for medical education and international or national or multidisciplinary meetings. 60.6% of the participants reduced clinical activity, and 28.4% compensated by increasing their research activity. Significant reduction of clinical trial activities is expected in 37% of centers this year. The well-being of healthcare staff would not recover by the end of the year according to 18% of the participants., Conclusion: The COVID-19 outbreak has had a major impact on oncologic activity, which will persist in the future, irrespective of geographical areas.

Background: Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2- ABC., Patients and Methods: Men and postmenopausal women with HR+, HER2- ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan-Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien-Fleming efficacy boundary of P ≤ 0.0161., Results: In the PIK3CA-mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up., Conclusions: Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2- ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. CLINICALTRIALS., Gov Id: NCT02437318., Competing Interests: Disclosure FA reports research grants, paid to the institution, from Novartis, AstraZeneca, Pfizer, Eli Lilly, Daiichi Sankyo, and Roche. EMC reports honoraria from Novartis, Pfizer, Eli Lilly, Roche, and AstraZeneca; consulting and paid speakers' bureaus for Novartis, Pfizer, Eli Lilly, and Roche; and travel support from Roche and Pfizer. DJ reports personal fees from Novartis, Genentech, Eisai, Ipsen, EMD Serono, Syros, Relay Therapeutics, MapKure, Vibliome, and Petra Pharma; grant from Novartis; and research grants to institution from Genentech, Eisai, EMD Serono, Takeda, Amgen, Celgene, Placon Therapeutics, Syros, Petra Pharma, InventisBio, and Infinity Pharmaceuticals. SL reports grants and other (honoraria for lectures and ad boards) from AbbVie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche, and Daiichi Sankyo; other (honoraria for lectures and ad boards) from Seattle Genetics, PriME/Medscape, Eli Lilly, Samsung, Eirgenix, BMS, Puma, and MSD; personal fees from Chugai; grants from Teva, Vifor, and Immunomedics, outside the submitted work and paid to her institution; and patent EP14153692.0 pending. MC reports grants and non-financial support from Novartis; grants and personal fees from Roche; grants from Tessaro; personal fees from AstraZeneca and Pfizer; and other support from Servier, Eli Lilly, Sanofi, and Accord. IAM reports consulting fees from Novartis, Genentech, Eli Lilly, AstraZeneca, GlaxoSmithKline, Immunomedics, MacroGenics, Seattle Genetics, AbbVie, and Puma; and research funding to institution from Novartis, Genentech, AbbVie, Puma, Immunomedics, Polyphor, and Pfizer. GR reports consulting fees from Novartis, Lilly, and Pfizer, speaker fee from Novartis, Pfizer, Roche, Swixx, Lilly, and Amgen. TY reports grants and honoraria from Chugai, Kyowa Kirin, and Nippon Kayaku; and honoraria from Eisai, Novartis, Taiho, AstraZeneca, Pfizer Japan, Eli Lilly, and Daiichi Sankyo. BK reports speaker's fees from Novartis, Roche, AstraZeneca, Pfizer, and AbbVie. Y-SL reports clinical trial grants, consultation fees, and speaker fees from Novartis; consultation fees from Pfizer and Boehringer Ingelheim; and contracted research grants from Roche, Pfizer, GlaxoSmithKline, and Merck, Sharp & Dohme. KI reports grants to institution from Novartis during the conduct of the study; grants to institution and personal fees from Pfizer, Chugai, and Eli Lilly; and grants to institution from Daiichi Sankyo, PAREXEL/Puma Biotechnology, MSD, AstraZeneca, and Sanofi, outside the submitted work. MT reports personal fees from AstraZeneca, Eisai, Eli Lilly, Novartis, and Pfizer; and grants from Chugai, Eisai, Nippon Kayaku, and Taiho. FG is employed by and owns stock in Novartis Pharmaceuticals Corporation. DM is employed by and owns stock in Novartis Pharma AG. MK is employed by and owns stock in Novartis Pharmaceuticals Corporation. MM is employed by and owns stock in Novartis Pharmaceuticals Corporation. PFC reports speakers' bureau for Roche/Genentech, Novartis, and AstraZeneca; research funding to institution from Roche, Novartis, and Merck Serono; and travel, accommodations, and expenses from Novartis, Celgene, and AstraZeneca. HI reports honoraria from Daiichi Sankyo, Chugai/Roche, AstraZeneca, Pfizer, Eli Lilly, Novartis, Taiho, and Eisai; consulting or advisory role for Daiichi Sankyo, Chugai/Roche, AstraZeneca, Eli Lilly, Pfizer, Novartis, Kyowa Hakko Kirin, AbbVie, and Odonate; uncompensated member of the steering committee for the SOLAR-1 trial; and member of the steering committee of DS-8201 registration study. HSR reports research funding paid to institution from Pfizer, Merck, Novartis, Eli Lilly, Genentech, OBI, Odonate, Sermonix, Daiichi Sankyo, Eisai, Seattle Genetics, MacroGenics and Immunomedics; travel, accommodations, and expenses from Daiichi Sankyo, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and MacroGenics; one-time consulting for Samsung; and advisory boards for Puma. ZP has declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Predicting prognosis in HR + /HER2 - metastatic breast cancer (MBC) might be clinically useful; however, no validated prognostic biomarkers exist in this setting to date., Patients and Methods: In phase III, EGF30008 trial, 484 patients with HER2 - MBC who received letrozole and placebo or lapatinib were selected. PAM50 data, ECOG performance status, visceral disease, number of metastasis, biopsy type, and age were evaluated. A progression-free survival (PFS) Cox model was evaluated. The final model (PAM50MET) with a prespecified cutoff was validated in patients ( n = 261) with HR + /HER2 - advanced breast cancer (aBC) from BOLERO-2 (phase III trial that evaluated exemestane and placebo or everolimus)., Results: In EGF30008, prognostic models with PAM50 plus clinical variables yielded higher C-index values versus models with only PAM50 or clinical variables. The PAM50MET model combined 21 variables: 2 PAM50 subtypes, basal signature, 14 genes, and 4 clinical variables. In EGF30008, the optimized cutoff was associated with PFS [HR = 0.37; 95% confidence interval (CI), 0.29-0.47; P < 0.0001] and overall survival (OS; HR = 0.37; 95% CI, 0.27-0.51; P < 0.0001). The median (months; 95% CI) PFS and OS were 22.24 (19.0-24.9) and not reached in PAM50MET-low versus 9.13 (8.15-11.0) and 33.0 (28.0-40.0) in PAM50MET-high groups, respectively. In BOLERO-2, the PAM50MET-low was associated with better PFS (HR = 0.72; 95% CI, 0.53-0.96; P = 0.028) and OS (HR = 0.51; 95% CI, 0.35-0.69; P < 0.0001). The median (months) (95% CI) PFS and OS were 6.93 (5.57-11.0) and 36.9 (33.4-NA) in PAM50MET-low versus 5.23 (4.2-6.8) and 23.5 (20.2-28.3) in PAM50MET-high groups, respectively., Conclusions: PAM50MET is prognostic in HR + /HER2 - MBC, and further evaluation might help identify candidates for endocrine therapy only or novel therapies., (©2020 American Association for Cancer Research.)

Purpose: To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer., Patients and Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes., Results: Seventy-one patients were recruited ( n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1-2 and 3-4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3-4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003)., Conclusions: Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population., (©2020 American Association for Cancer Research.)

Background: Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer., Methods: This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies., Results: Fifty patients were enrolled. Median number of cycles was 2 (range 1-10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6-2.3). Median OS was 11.2 months (95% CI 6.2-25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease., Conclusions: Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer., Trial Registration: NCT01790932 . Registered on 13 February 2013; NCT01629615 . Registered on 27 June 2012.

The addition of CDK4 and 6 inhibitors (abemaciclib, palbociclib or ribociclib) to endocrine therapy, as first-line treatment or following progression after initial endocrine therapy, significantly increased progression-free survival, objective response rates and in some trials overall survival, compared with endocrine therapy alone in HR+ and HER2- breast metastatic breast cancer. These CDK4 and 6 inhibitors are now approved in this context and have become a new standard of care. A hypothesis-generating exploratory analysis suggested that the addition of abemaciclib to endocrine therapy showed the largest effects in subgroups of women with indicators of poor prognosis, although these data require confirmation. This review provides updated clinical trial data for all three drugs in metastatic breast cancer, focusing on abemaciclib, the most recently approved agent.

Purpose: Neoadjuvant clinical trials with dual HER2 blockade with pertuzumab and trastuzumab plus chemotherapy demonstrated high rates of pathological complete response (pCR) in HER2-positive early breast cancer (BC). We investigated whether the benefit on pCR seen in clinical trials is confirmed in a real-world setting., Methods: Multicenter, retrospective study in patients with HER2-positive early BC receiving neoadjuvant treatment with pertuzumab and trastuzumab in routine clinical practice (n = 243). The primary endpoint was total pCR (tpCR) (ypT0/is ypN0)., Results: A total of 243 evaluable patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes in 74.1% of patients, with single-agent taxane in 11.1% of patients and with platinum-based chemotherapy (CT) in 14.4% of patients. The tpCR rate was 66.4%:71% with anthracyclines and taxanes, 59.3% with single-agent taxane, and 48.6% with platinum-based combinations. The tpCR rate was higher among patients with hormone receptor (HR)-negative tumors (80.9%) vs HR-positive tumors (55.4%) (p < 0.001). A pCR in the breast (ypT0/is) was achieved in 67.6% of patients. Of 143 patients who showed radiological complete response (rCR) (62%), 112 (78.3%) patients also achieved tpCR. Assessment of rCR by magnetic resonance imaging (MRI) showed the highest negative predictive value (NPV) for predicting tpCR (83.5%). Breast-conserving surgery was performed in 58.7% of patients. Grade 3 and grade 4 toxicities were reported in 33 (18.2%) and 12 (6.6%) patients, respectively. No toxicity leading to death was reported., Conclusions: This real-world analysis shows that neoadjuvant pertuzumab, trastuzumab, and chemotherapy achieve comparable or even higher rates of tpCR than those seen in clinical trials. The pCR benefit is higher in HR-negative tumors. The assessment of rCR by MRI showed the highest ability for predicting pCR. In addition, this neoadjuvant strategy confers an acceptable safety profile.