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Purpose: The purpose of this study was to assess the predictive capability of HER2DX assay following (neo)adjuvant trastuzumab-pertuzumab (HP)-based therapy in HER2-positive (HER2+) early breast cancer., Experimental Design: HER2DX was analyzed in baseline pretreatment tumors from the PHERGain trial. Patients with stage I-IIIA HER2+ early breast cancer were randomized to group A [docetaxel, carboplatin, and HP (TCHP)] and group B (HP ± endocrine therapy). PET response was evaluated after two cycles. Group A received TCHP for six cycles regardless of PET response. Group B continued with HP ± endocrine therapy for six cycles (PET responders) or with TCHP for six cycles (PET nonresponders). The primary objective of this retrospective study was to associate the HER2DX pathologic complete response (pCR) score with pCR. The secondary objective was the association of the HER2DX risk score with 3-year invasive disease-free survival (iDFS)., Results: HER2DX was performed on 292 (82.0%) tumors. The overall pCR rate was 38.0%, with pCR rates of 56.4% in group A and 33.8% in group B. In multivariable analysis including treatment and clinicopathologic factors, the HER2DX pCR score (continuous variable) significantly correlated with pCR [OR, 1.29; 95% confidence interval (CI), 1.10-1.54; P < 0.001]. HER2DX-defined pCR-high, -med, and -low groups exhibited pCR rates of 50.4%, 35.8%, and 23.2%, respectively (pCR-high vs. pCR-low OR, 3.27; 95% CI, 1.54-7.09; P < 0.001). In patients with residual disease, the HER2DX high-risk group demonstrated numerically worse 3-year iDFS than the low-risk group (89.8% vs. 100%; HR, 2.70; 95% CI, 0.60-12.18; P = 0.197)., Conclusions: HER2DX predicts pCR in the context of neoadjuvant HP-based therapy, regardless of chemotherapy addition, and might identify patients at higher risk of recurrence among patients with residual disease., (©2024 The Authors; Published by the American Association for Cancer Research.)

Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest. All authors contributed equally to this work.

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).)

Background: Early-stage triple-negative breast cancer (TNBC) displays clinical and biological diversity. From a biological standpoint, immune infiltration plays a crucial role in TNBC prognosis. Currently, there is a lack of genomic tools aiding in treatment decisions for TNBC. This study aims to assess the effectiveness of a B-cell/immunoglobulin signature (IGG) alone, or in combination with tumor burden, in predicting prognosis and treatment response in patients with TNBC., Methods: Genomic and clinical data were retrieved from 7 cohorts: SCAN-B (N = 874), BrighTNess (n = 482), CALGB-40603 (n = 389), METABRIC (n = 267), TCGA (n = 118), GSE58812 (n = 107), GSE21653 (n = 67). IGG and a risk score integrating IGG with tumor/nodal staging (IGG-Clin) were assessed for event-free survival (EFS) and overall survival (OS) in each cohort. Random effects model was used to derive pooled effect sizes. Association of IGG with pathological complete response (pCR) was assessed in CALGB-40603 and BrighTNess. Immune significance of IGG was estimated through CIBERSORTx and EcoTyper., Findings: IGG was associated with improved EFS (pooled HR = 0.77, [95% CI = 0.70-0.85], I 2  = 18%) and OS (pooled HR = 0.79, [0.73-0.85], I 2  = 0%) across cohorts, and was predictive of pCR in CALGB-40603 (OR 1.25, [1.10-1.50]) and BrighTNess (OR 1.57 [1.25-1.98]). IGG-Clin was predictive of recurrence (pooled HR = 2.11, [1.75-2.55], I 2  = 0%) and death (pooled HR = 1.99, 95% [0.84-4.73], I 2  = 79%) across cohorts. IGG was associated with adaptive immune response at CIBERSORTx and EcoTyper analysis., Interpretation: IGG is linked to improved prognosis and pCR in early-stage TNBC. The integration of IGG alongside tumor and nodal staging holds promise as an approach to identify patients benefitting from intensified or de-intensified treatments., Funding: This study received funding from: Associació Beca Marta Santamaria, European Union's Horizon 2020 research and innovation and Marie Skłodowska-Curie Actions programs, Fundación FERO, Fundación CRIS contra el cáncer, Agència de Gestó d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Fundación Contigo, Asociación Cáncer de Mama Metastásico IV, Breast Cancer Research Foundation, RESCUER, Fundación científica AECC and FSEOM., Competing Interests: Declaration of interests B. Conte reports speaker fees from Veracyte and payment for educational events from Medsite and Novartis. A. Prat reports consulting fees from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc and Lilly, lecture fees from Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies and Daiichi Sankyo; patents filed PCT/EP2016/080056, PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369; stockholder and consultant of Reveal Genomics, SL; and institutional financial interests from Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, Medica Scientia Innovation Research, SL, Celgene, Astellas and Pfizer. F. Schettini has declared consulting fees from Pfizer, honoraria for lectures from Novartis, Gilead and Daiichy Sankyo, and travel expenses from Novartis and Daiichy Sankyo. O. Martínez-Sáez has declared institutional grants from Roche; personal consulting fees from Roche and Reveal Genomics; honoraria for presentations by Daiichi Sankyo, Pierre Fabre, and Reveal Genomics; and travel expenses by Gilead, Pierre Fabre, Novartis, and MSD. A. Vivancos has declared institutional grants from Bristol Meyers Squibb, Incyte, and Roche; personal consulting fees from Bayer, Bristol Meyers Squibb (BMS); Guardant, Incyte, and Roche; and personal stock options from Reveal Genomics. F. Brasó-Maristany has patents filed: PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369. J. Parker as declared individual and institutional royalties from Veracyte–Prosigna, consulting fees from Bristol Meyers Squibb, Reveal Genomics, and GeneCentric, and holds a patent for breast cancer subtyping. Additionally, he has an equity interest in Reveal Genomics. M. Vidal has declared honoraria for presentations from Novartis, Roche, Pfizer, and Daichii, and travel expenses from Roche and Pfizer. Additionally, she has participated on a Data Safety Monitoring Board or Advisory Board for Novartis and Roche. C. Perou has declared consulting fees and personal stock options from Reveal Genomics. T. Pascual has declared consulting fees from Novartis; honoraria from Novartis, Astra-zeneca, Veracyte, and Argenetics. I. Garcia-Fructuoso has declared honoraria for presentations from Novartis, Daiichi Sankyo, Esteve, GSK; and travel expenses from Novartis, Gilead, Daiichi Sankyo, Lilly, and BMS. L. Paré has declared contract from Reveal Genomics, a HER2DX patent filed (PCT/EP2022/086493), and the TNBCDX patent filed (EP23382703.9). M. Marín-Aguilera has declared contract from Reveal Genomics. P. Villagrasa has declared contract and personal stock options from Reveal Genomics, the HER2DX patent filed (PCT/EP2022/086493), and the DNADX patent filed (EP22382387.3). G. Villacampa has received a speaker's fee from Merck Sharp & Dohme, Pfizer, GlaxoSmithKline and Pierre Fabrer, and received consultant fees from Reveal Genomics. C. Falato is currently employed in AstraZeneca. The remaining authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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: HER2DX, a multianalyte genomic test, has been clinically validated to predict breast cancer recurrence risk (relapse risk score), the probability of achieving pathological complete response post-neoadjuvant therapy (pCR likelihood score), and individual ERBB2 messenger RNA (mRNA) expression levels in patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This study delves into the comprehensive analysis of HER2DX's analytical performance., Materials and Methods: Precision and reproducibility of HER2DX risk, pCR, and ERBB2 mRNA scores were assessed within and between laboratories using formalin-fixed paraffin-embedded (FFPE) tumor tissues and purified RNA. Robustness was appraised by analyzing the impact of tumor cell content and protocol variations including different instruments, reagent lots, and different RNA extraction kits. Variability was evaluated across intratumor biopsies and genomic platforms [RNA sequencing (RNAseq) versus nCounter], and according to protocol variations., Results: Precision analysis of 10 FFPE tumor samples yielded a maximal standard error of 0.94 across HER2DX scores (1-99 scale). High reproducibility of HER2DX scores across 29 FFPE tumors and 20 RNAs between laboratories was evident (correlation coefficients >0.98). The probability of identifying score differences >5 units was ≤5.2%. No significant variability emerged based on platform instruments, reagent lots, RNA extraction kits, or TagSet thaw/freeze cycles. Moreover, HER2DX displayed robustness at low tumor cell content (10%). Intratumor variability across 212 biopsies (106 tumors) was <4.0%. Concordance between HER2DX scores from 30 RNAs on RNAseq and nCounter platforms exceeded 90.0% (Cohen's κ coefficients >0.80)., Conclusions: The HER2DX assay is highly reproducible and robust for the quantification of recurrence risk, pCR likelihood, and ERBB2 mRNA expression in early-stage HER2-positive breast cancer., Competing Interests: Disclosure MMA is an employee at Reveal Genomics; GV has received a speaker’s fee from MSD, Pfizer, GSK, and Pierre Fabrer, has held an advisory role with AstraZeneca, and received consultant fees from Reveal Genomics; FBM has a HER2DX patent application EP21383165; PG is an employee at Reveal Genomics; OMS has declared travel expenses and consulting fees from Roche and Reveal, and speaker fees from Eisai, Daiichi, and Novartis; KP serves on the Scientific Advisory Board of Novartis, Ideaya Biosciences, and Scorpion Therapeutics, holds equity options in Scorpion Therapeutics and Ideaya Biosciences, and receives sponsored research funding from Novartis through DFCI; and has patents on S100A7 antibody and BET inhibitor resistance held by DFCI; JM is an employee at Reveal Genomics; WB is an employee at Reveal Genomics; CMP is an equity stockholder and consultant of BioClassifier LLC, and for Reveal Genomics, is also listed as an inventor on patent applications for the Breast PAM50 assay; PVG is one of the stockholders of Reveal Genomics; AP reports advisory and consulting fees from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc, and Lilly, lecture fees from Roche, Pfizer, Novartis, Amgen, BMS, and Daiichi Sankyo, institutional financial interests from Novartis, Roche, and Pfizer, stockholder and consultant of Reveal Genomics, SL; AP is also listed as an inventor on patent applications for the HER2DX assay; JSP is an equity stockholder and consultant for Reveal Genomics and is also listed as an inventor on patent applications for the Breast PAM50 assay; LP is listed as an inventor on HER2DX patent PCT/EP2021/070788 and is an employee at Reveal Genomics. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.)

Background: The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status., Materials and Methods: Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status., Results: HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk., Conclusions: HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Importance: Biomarkers to guide the use of pertuzumab in the treatment of early-stage ERBB2 (formerly HER2)-positive breast cancer beyond simple ERBB2 status are needed., Objective: To determine if use of the HER2DX genomic assay (Reveal Genomics) in pretreatment baseline tissue samples of patients with ERBB2-positive breast cancer is associated with response to neoadjuvant trastuzumab-based chemotherapy with or without pertuzumab., Design, Setting, and Participants: This is a retrospective diagnostic/prognostic analysis of a multicenter academic observational study in Spain performed during 2018 to 2022 (GOM-HGUGM-2018-05). In addition, a combined analysis with 2 previously reported trials of neoadjuvant cohorts with results from the assay (DAPHNe and I-SPY2) was performed. All patients had stage I to III ERBB2-positive breast cancer, signed informed consent, and had available formalin-fixed paraffin-embedded tumor specimens obtained prior to starting therapy., Exposures: Patients received intravenous trastuzumab, 8 mg/kg, loading dose, followed by 6 mg/kg every 3 weeks in combination with intravenous docetaxel, 75 mg/m2, every 3 weeks and intravenous carboplatin area under the curve of 6 every 3 weeks for 6 cycles, or this regimen plus intravenous pertuzumab, 840 mg, loading dose, followed by an intravenous 420-mg dose every 3 weeks for 6 cycles., Main Outcome and Measures: Association of baseline assay-reported pathologic complete response (pCR) score with pCR in the breast and axilla, as well as association of baseline assay-reported pCR score with response to pertuzumab., Results: The assay was evaluated in 155 patients with ERBB2-positive breast cancer (mean [range] age, 50.3 [26-78] years). Clinical T1 to T2 and node-positive disease was present in 113 (72.9%) and 99 (63.9%) patients, respectively, and 105 (67.7%) tumors were hormone receptor positive. The overall pCR rate was 57.4% (95% CI, 49.2%-65.2%). The proportion of patients in the assay-reported pCR-low, pCR-medium, and pCR-high groups was 53 (34.2%), 54 (34.8%), and 48 (31.0%), respectively. In the multivariable analysis, the assay-reported pCR score (as a continuous variable from 0-100) showed a statistically significant association with pCR (odds ratio [OR] per 10-unit increase, 1.43; 95% CI, 1.22-1.70; P < .001). The pCR rates in the assay-reported pCR-high and pCR-low groups were 75.0% and 28.3%, respectively (OR, 7.85; 95% CI, 2.67-24.91; P < .001). In the combined analysis (n = 282), an increase in pCR rate due to pertuzumab was found in the assay-reported pCR-high tumors (OR, 5.36; 95% CI, 1.89-15.20; P < .001) but not in the assay-reported pCR-low tumors (OR, 0.86; 95% CI, 0.30-2.46; P = .77). A statistically significant interaction between the assay-reported pCR score and the effect of pertuzumab in pCR was observed., Conclusions and Relevance: This diagnostic/prognostic study demonstrated that the genomic assay predicted pCR following neoadjuvant trastuzumab-based chemotherapy with or without pertuzumab. This assay could guide therapeutic decisions regarding the use of neoadjuvant pertuzumab.

Importance: Patients with early-stage ERBB2 (formerly HER2)-positive breast cancer (ERBB2+ BC) who experience a pathologic complete response (pCR) after receiving neoadjuvant therapy have favorable survival outcomes. Predicting the likelihood of pCR may help optimize neoadjuvant therapy., Objective: To test the ability of the HER2DX assay to predict the likelihood of pCR in patients with early-stage ERBB2+ BC who are receiving deescalated neoadjuvant therapy., Design, Setting, and Participants: In this diagnostic/prognostic study, the HER2DX assay was administered on pretreatment tumor biopsy samples from patients enrolled in the single-arm, multicenter, prospective phase 2 DAPHNe clinical trial who had newly diagnosed stage II to III ERBB2+ BC that was treated with neoadjuvant paclitaxel weekly for 12 weeks plus trastuzumab and pertuzumab every 3 weeks for 4 cycles., Interventions and Exposures: The HER2DX assay is a classifier derived from gene expression and limited clinical features that provides 2 independent scores to predict prognosis and likelihood of pCR in patients with early-stage ERBB2+ BC. The assay was administered on baseline tumor samples from 80 of 97 patients (82.5%) in the DAPHNe trial., Main Outcomes and Measures: The primary aim was to test the ability of the HER2DX pCR likelihood score (as a continuous variable from 0-100) to predict pCR (ypT0/isN0)., Results: Of 80 participants, 79 (98.8%) were women and there were 4 African American (5.0%), 6 Asian (7.5%), 4 Hispanic (5.0%), and 66 White individuals (82.5%); the mean (range) age was 50.3 (26.0-78.0) years. The HER2DX pCR score was significantly associated with pCR (odds ratio, 1.05; 95% CI, 1.03-1.08; P < .001). The pCR rates in the HER2DX high, medium, and low pCR score groups were 92.6%, 63.6%, and 29.0%, respectively (high vs low odds ratio, 30.6; P < .001). The HER2DX pCR score was significantly associated with pCR independently of hormone receptor status, ERBB2 immunohistochemistry score, HER2DX ERBB2 expression score, and prediction analysis of microarray 50 ERBB2-enriched subtype. The correlation between the HER2DX pCR score and prognostic risk score was weak (Pearson coefficient, -0.12). Performance of the risk score could not be assessed due to lack of recurrence events., Conclusions and Relevance: The results of this diagnostic/prognostic study suggest that the HER2DX pCR score assay could predict pCR following treatment with deescalated neoadjuvant paclitaxel with trastuzumab and pertuzumab in patients with early-stage ERBB2+ BC. The HER2DX pCR score might guide therapeutic decisions by identifying patients who are candidates for deescalated or escalated approaches.

In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P < .001). ERBB2 mRNA was statistically significantly associated with better progression-free survival (P = .002) and overall survival (OS; P = .02). These findings were independent of HER2 immunohistochemistry (IHC) levels, hormone receptor, age, brain metastasis, and line of therapy. The HER2DX risk score (P = .04) and immunoglobulin signature (P = .04) were statistically significantly associated with overall survival since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ breast cancer., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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: We aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis., Methods: In this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (≤3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m 2 ) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual., Findings: Between Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1-11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3-94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3-98·3), 10-year overall survival was 94·3% (95% CI 91·8-96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6-100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00-1·52]; p=0·047) and recurrence-free interval (1·45 [1·09-1·93]; p=0·011)., Interpretation: Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population., Funding: Genentech., Competing Interests: Declaration of interests SMT has received grant support (paid to institution) from AstraZeneca, Merck, Nektar, Novartis, Pfizer, Genentech (Roche), Gilead, Exelixis, BMS, Eisai, NanoString, Cyclacel, Sanofi, Seagen, and Eli Lilly; and has received consulting or advisory board fees (paid to self) from AstraZeneca, Eli Lilly, Merck, Novartis, Pfizer, Genentech (Roche), Gilead, BMS, Eisai, Sanofi, SeaGen, Daiichi-Sankyo, Athenex, OncoPep, Kyowa Kirin Pharma, CytomX, Certara, Mersana Therapeutics, Ellipses Pharma, 4D Pharma, OncoSec, Infinity Therapeutics, BeyondSpring Pharma, OncXerna, Zymeworks, Zentalis, ARC Therapeutics, Reveal Genomics, Blueprint Medicines, Myovant, Umoja Biopharma, Stemline (Menarini), and Artios Biopharma. PT has received consulting or advisory board fees from AstraZeneca, Daiichi-Sankyo, and Lilly and has received payment or honoraria for educational events from AstraZeneca and Daiichi-Sankyo. NT has received honoraria for a Clinical Research Workshop at the San Antonio Breast Cancer Symposium. LP is an employee of Reveal Genomics and has a patent (EP 20 382 679.7—in vitro method for the prognosis of patients suffering from HER2-positive breast cancer). GV has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from MSD, GSK, Pierre Fabre, and Pfizer and has participated on a data safety monitoring board or advisory board for AstraZeneca. CTD has received research funding from Genentech (Roche) and Puma and has received consulting fees from Daiichi-Sankyo, Novartis, Pfizer, Gilead, Seagen, and Genentech (Roche). DAY has received funding (paid to institution) for the present manuscript from Dana-Farber Cancer Institute; grant support (paid to institution) from Ambrx, Amgen, BIOMARIN, Biothera Pharmaceuticals, Clovis Pharma, Dana-Farber Cancer Institute, Lilly, Genentech (Roche), G1 Therapeutics, Gilead Sciences, Incyte, Innocrin Pharmaceuticals, Macrogenics, MedImmune, Medivation, Merck, Merrimack Pharmaceuticals, Nektar Therapeutics, Novartis, the National Surgical Adjuvant Breast and Bowel Project, Pfizer, and Polyphor; and has received consulting fees (paid to institution) from AstraZeneca, Athenex, bioTheranostics, G1 Therapeutics, Gilead Sciences, Immunomedics, Merck, Novartis, Pfizer, and Sanofi-Aventis. PKM has received support (paid to institution) for the present manuscript from Genentech; has participated on a data safety monitoring board for Genentech (Roche); has stock or stock options in Veracyte; and was a full-time employee of Veracyte at time of manuscript submission. KSA has received funding (paid to institution) for the present manuscript from Dana-Farber Cancer Institute for data management support. HSR has received grant funding (paid to UC Regents only) from Ambrx, Astellas Pharma, AstraZeneca, Daiichi-Sankyo, Genentech (Roche), Gilead Sciences, GSK, Lilly, Merck & Co, Novartis Pharmaceuticals, OBI Pharma, Pfizer, Pionyr Immunotherapeutics, Seattle Genetics, Sermonix Pharmaceuticals, Taiho Oncology, and Veru; has received consulting fees from Puma, Napo Pharmaceuticals, and Blueprint; and has received support for attending meetings and travel from Merck, AstraZeneca, and Gilead. MJE has reported a PAM50 Bioinformatics for Prosigna royalty-bearing license to Veracyte; and and has been an employee of AstraZeneca since March 7, 2022 (AstraZeneca had no role in this study and the author's involvement in this study preceded his employment with AstraZeneca). LAC has received research funding (paid to institution) from Syndax, Novartis, NanoString Technologies, Seattle Genetics, Veracyte, and AstraZeneca and declares participation in uncompensated consulting activities for Eisai (to self), Sanofi (to self), Lilly (to self), Seagen (to self), Novartis (to institution), G1 Therapeutics (to institution), Genentech (Roche; to institution), GSK (to institution), AstraZeneca (to institution), and Daiichi-Sankyo (to institution). RBS has received consulting fees from AstraZeneca, Libbs, Daiichi-Sankyo, Eli Lilly, Pfizer, Novartis, MSD, and Roche; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or education events from AstraZeneca, Libbs, Daiichi-Sankyo, Eli Lilly, Pfizer, Novartis, MSD, and Roche; has received support for attending meetings and travel from Daiichi-Sankyo, Eli Lilly, MSD, and Roche; has participated on a data safety monitoring board or advisory board for AstraZeneca, Daiichi-Sankyo, and Roche; and is a member of the Clinical Research Committee of the Brazilian Society of Clinical Oncology. JGTZ has stock or stock options in Loncar Cancer Immunotherapy ETF, iShares Genomics Immunology and Healthcare ETF, iShares Biotechnology ETF, SPDR S&P Biotech ETF, Adaptive Biotechnologies, 2seventy bio, and bluebird bio. NW has received grant support from AstraZeneca; has received consulting fees from Relay Therapeutics, Flare Therapeutics, Eli Lilly, and Section 32; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Genentech; and has stock or stock options in Relay Therapeutics and Flare Therapeutics. AHP has received royalties from UpToDate. AGW has received grant support (paid to institution) from Macrogenics, Genentech, and Merck and has received consulting fees (paid to self) from AstraZeneca. CAH is Chief Executive Officer at the American Society of Clinical Oncology, which pays 100% of the author's personal annual earned income. IEK has received support for the present manuscript from Genentech (Roche); has received grant support from Macrogenics and Pfizer; has received consulting fees from Daiichi-Sankyo, Macrogenics, Roche, Seagen, and AstraZeneca; and has participated on a data safety monitoring board or advisory board for Novartis, Merck, Daiichi-Sankyo, Macrogenics, Roche, Seagen, and AstraZeneca. AP has received funding for the present manuscript from Reveal Genomics; has received grants (paid to institution) from Roche, Daiichi-Sankyo, and Reveal Genomics; has received royalties or licenses from Reveal Genomics (paid to institution); has received consulting fees (paid to self) from Roche, Novartis, Daiicki-Sankyo, and AstraZeneca; has patents licensed to Reveal Genomics: HER2DX, ERBB2, and DNADX genomic tools; and has stock or stock options in Reveal Genomics and Oncolytics Biotech. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Background: HER2DX is a prognostic and predictive assay in early-stage HER2-positive breast cancer based on clinical features and the expression of 4 gene signatures (immune, proliferation, luminal differentiation and HER2 amplicon), including ERBB2 mRNA levels. Here, we evaluated the ability of HER2DX to predict efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HER2-positive/hormone receptor-positive breast cancer., Methods: HER2DX was evaluated on pre-treatment tumour samples from the PerELISA phase II study focused on postmenopausal patients with operable HER2-positive/hormone receptor-positive breast cancer. Patients received 2-weeks of letrozole, and then underwent a re-biopsy for Ki67 evaluation. Patients with endocrine therapy sensitive disease (ESD) (i.e., >20.0% Ki67 relative reduction at week 2) continued letrozole and 5 cycles of trastuzumab and pertuzumab. Primary aim was to test the ability of HER2DX risk-score, HER2DX pCR score and HER2DX ERBB2 mRNA score (as continuous variables and group categories) to predict pathological complete response (pCR) in patients with ESD. Logistic regression and receiver...operator curve (ROC) analysis assessed associations of HER2DX scores with pCR and ESD., Findings: HER2DX was evaluated in 55 patients (86.0%) enrolled in PerELISA and 40 patients (73.0%) had ESD. The pCR rate in patients with ESD was 22.5% (9/40). In this group, HER2DX pCR score and HER2DX ERBB2 mRNA score were significantly associated with pCR (p.ß=.ß0.008 and p.ß=.ß0.003, univariate logistic regression model; area under ROC [AUC].ß=.ß0.803 and 0.896). The pCR rate in low, medium, and high HER2DX pCR score groups was 7.7% (2/26), 46.2% (6/13) and 100.0% (1/1), respectively. The pCR rate in low, medium, and high HER2DX ERBB2 score groups was 0.0% (0/12), 7.7% (1/13) and 53.3% (8/15), respectively. HER2DX pCR score was also significantly associated with Ki-67 response following 2-weeks of letrozole (p.ß=.ß0.002, univariate logistic regression model; AUC.ß=.ß0.775). The rate of ESD in low, medium, and high HER2DX pCR score groups was 89.7% (26/29), 65.0% (13/20) and 16.7% (1/6), respectively., Interpretation: HER2DX predicts response following neoadjuvant letrozole in combination with dual HER2 blockade with trastuzumab and pertuzumab in early-stage HER2-positive/hormone receptor-positive breast cancer., Funding: This study received funding from Reveal Genomics., Competing Interests: Declaration of interests Dr. Perou, Dr. Prat, Dr. Vivancos, Dr. Villagrasa, and Dr. Parker are equity stockholders of Reveal Genomics; Dr. Perou, Dr. Prat, Dr. Vivancos, and Dr. Parker are also consultants of Reveal Genomics. Dr. Prat reports grants from Reveal Genomics, during the conduct of the study; other from Reveal Genomics, personal fees from Roche, grants and personal fees from AstraZeneca, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Novartis, personal fees from Foundation Medicine, personal fees from Oncolytics Biotech, outside the submitted work; In addition, Dr. Prat has a patent HER2DX licensed to Reveal Genomics, and a patent WO 2018/103834 licensed to Reveal Genomics. Dr. Par.. is an employee of Reveal Genomics and has a patent HER2DX licensed to Reveal Genomics. Dr. Mar.ín-Aguilera is an employee of Reveal Genomics. Dr. Dieci reports personal fees from Astrazeneca, Daiichi Sankyo, Gilead, Eli Lilly, MSD, Exact Sciences, Novartis, Pfizer, Seagen, outside the submitted work; In addition, Dr. Dieci has a patent HER2DX pending to Reveal Genomics. Dr. Griguolo reports personal fees from Eli Lilly, Amgen, Novartis, Pfizer, Daiichi Sankyo, Gileas outside the submitted work. Dr. Guarneri reports personal fees from Eli Lilly, Novartis, MSD, GSK, Gilead, Exact Science, Merck Serno, Sanofi, Pfizer, Amgen, Eisai outside the submitted work; In addition, Dr. Guarneri has a patent HER2DX licensed to Reveal Genomics. Dr. Miglietta reports consulting fees from Gilead outside the submitted work. Dr. Villagrasa reports other from Reveal Genomics, personal fees from Nanostring, outside the submitted work; In addition, Dr. Villagrasa has a patent HER2DX pending. Dr. Conte reports personal fees from Roche, personal fees from Novartis, personal fees from Daiichi Sankyo, personal fees from Astrazeneca, personal fees from Eli-lilly, outside the submitted work; In addition, Dr. Conte has a patent HER2DX pending licensed to Reveal Genomics. Dr. Bras..-Maristany has a patent HER2DX pending licensed to Reveal Genomics. Dr. Vivancos reports personal fees from Bayer, personal fees from Bristol Meyers Squibb, personal fees from Guardant Health, personal fees from Merck, personal fees from Novartis, personal fees from Roche, personal fees from Incyte, outside the submitted work; In addition, Dr. Vivancos has a patent WO2015145388A3 licensed. Dr. Perou are equity stockholders of Bioclassifier LLC and Drs. Perou and Parker have a patent on PAM50 subtype assays; other from Reveal Genomics, outside the submitted work. All the other authors do not report conflicts of interest. No authors have been paid to write this article., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

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.)

Competing Interests: Competing interests: None.

Competing Interests: Conflict of interestThe authors have no conflicts of interest to disclose.

Objetive: To review and discuss the current evidence of the use of metformin as a therapeutic tool in frequent skin diseases., Design: Original article. Qualitative research. Narrative review., Location: Aragon and Murcia, Spain., Participants: Resident Physicians. Dermatology and Primary Health Care., Method: A narrative review has been carried out using the PubMed bibliographic database, being the search date the 27th of January of 2022., Results: Metformin has proven to be effective in the treatment of inflammatory skin diseases such as acne, hidradenitis suppurativa, psoriasis and allergic contact dermatitis. It has also shown antitumor properties regarding basal cell carcinoma, squamous cell carcinoma and melanoma. Additionally, beneficial effects of adjuvant treatment with metformin have been described in patients with basal cell carcinoma receiving photodynamic therapy. In patients with endocrinology-related dermatosis such as hirsutism, acanthosis nigricans and eruptive xanthomas, treatment with metformin has demonstrated therapeutic effectiveness. Topical treatment with metformin has also been useful in the treatment of melasma. Finally, it has been proposed as a drug with anti-aging and wound-healing promoting properties. Severe adverse effects have not been observed for any of the previously described indications, being this a well-tolerated treatment., Conclusions: Metformin is an effective and safe adjuvant in the therapeutic scheme of various inflammatory dermatoses, skin neoplasms, endocrinology-related dermatosis, melasma, skin aging and wound healing processes., (Copyright © 2022 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial., Experimental Design: In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by MRI. We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. One hundred and twenty-five baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points., Results: Tumors with genomic/protein alterations in PIK3CA/AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated AKT (pAKT) levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a downregulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment., Conclusions: We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Both clinical and genomic data independently predict survival and treatment response in early-stage HER2-positive breast cancer. Here we present the development and validation of a new HER2DX risk score, and a new HER2DX pathological complete response (pCR) score, both based on a 27-gene expression plus clinical feature-based classifier., Methods: HER2DX is a supervised learning algorithm incorporating tumour size, nodal staging, and 4 gene expression signatures tracking immune infiltration, tumour cell proliferation, luminal differentiation, and the expression of the HER2 amplicon, into a single score. 434 HER2-positive tumours from the Short-HER trial were used to train a prognostic risk model; 268 cases from an independent cohort were used to verify the accuracy of the HER2DX risk score. In addition, 116 cases treated with neoadjuvant anti-HER2-based chemotherapy were used to train a predictive model of pathological complete response (pCR); two independent cohorts of 91 and 67 cases were used to verify the accuracy of the HER2DX pCR likelihood score. Five publicly available independent datasets with >1,000 patients with early-stage HER2-positive disease were also analysed., Findings: In Short-HER, HER2DX variables were associated with good risk outcomes (i.e., immune, and luminal) and poor risk outcomes (i.e., proliferation, and tumour and nodal staging). In an independent cohort, continuous HER2DX risk score was significantly associated with disease-free survival (DFS) (p=0·002); the 5-year DFS in the low-risk group was 97·4% (94·4-100·0%). For the neoadjuvant pCR predictor training cohort, HER2DX variables were associated with pCR (i.e., immune, proliferation and HER2 amplicon) and non-pCR (i.e., luminal, and tumour and nodal staging). In both independent test set cohorts, continuous HER2DX pCR likelihood score was significantly associated with pCR (p<0·0001). A weak negative correlation was found between the HER2DX risk score versus the pCR score (correlation coefficient -0·19)., Interpretation: The two HER2DX tests provide accurate estimates of the risk of recurrence, and the likelihood to achieve a pCR, in early-stage HER2-positive breast cancer., Funding: This study received funding from Reveal Genomics, IDIBAPS and the University of Padova., Competing Interests: Declaration of Competing Interest Dr. Perou, Dr. Prat, Dr. Vivancos, Dr. Villagrasa, and Dr. Parker are equity stockholders of Reveal Genomics; Dr. Perou, Dr. Prat, Dr. Vivancos, and Dr. Parker are also consultants of Reveal Genomics. Dr. Prat reports grants from Reveal Genomics, during the conduct of the study; other from Reveal Genomics, personal fees from Roche, grants and personal fees from AstraZeneca, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Novartis, personal fees from Foundation Medicine, personal fees from Oncolytics Biotech, outside the submitted work; In addition, Dr. Prat has a patent HER2DX licensed to Reveal Genomics, and a patent WO 2018/103834 licensed to Reveal Genomics. Dr. Paré has a patent HER2DX licensed to Reveal Genomics. Dr. Cortés reports grants and personal fees from Roche, personal fees from Celgene, personal fees from Cellestia, grants and personal fees from AstraZeneca, personal fees from Seattle Genetics, personal fees from Daiichi Sankyo, personal fees from Erytech, personal fees from Athenex, personal fees from Polyphor, personal fees from Lilly, personal fees from Merck Sharp&Dohme, personal fees from GSK, personal fees from Leuko, personal fees from Bioasis, personal fees from Clovis Oncology, personal fees from Boehringer Ingelheim, personal fees from Ellipses, personal fees from Hibercell, personal fees from BioInvent, personal fees from Gemoab, personal fees from Gilead, personal fees from Menarini, personal fees from Zymeworks, grants from Guardant health, grants from Pfizer, grants from Puma, non-financial support from Medsir, outside the submitted work; In addition, Dr. Cortés has a patent WO 2018/103834 licensed to Reveal Genomics. Dr. Dieci reports personal fees from Eli Lilly, MSD, Exact Sciences, Novartis, Pfizer, Seagen, outside the submitted work; In addition, Dr. Dieci has a patent HER2DX licensed to Reveal Genomics. Dr. Griguolo reports personal fees from Eli Lilly, Amgen, Novartis, Pfizer, Daiichi Sankyo, outside the submitted work; Dr. Guarneri reports personal fees from Eli Lilly, Roche, Novartis, MSD, GSK, Gilead, outside the submitted work; In addition, Dr. Guarneri has a patent HER2DX licensed to Reveal Genomics. Dr. Llombart-Cussac reports grants and personal fees from Roche, grants and personal fees from Daiichi Sankyo, personal fees from Pfizer, personal fees from Novartis, personal fees from Lilly, personal fees from MSD, personal fees from Agendia, from Exact Sciences, non-financial support from AstraZeneca, personal fees from Gilead, other from MedSir, outside the submitted work; In addition, Dr. Llombart-Cussac has a patent WO 2018/103834 licensed to Reveal Genomics. Dr. Villagrasa reports other from Reveal Genomics, personal fees from Nanostring, outside the submitted work; In addition, Dr. Villagrasa has a patent HER2DX pending. Dr. Conte reports personal fees from Roche, personal fees from Novartis, personal fees from Daiichi Sankyo, personal fees from Astrazeneca, personal fees from Elililly, outside the submitted work; In addition, Dr. Conte has a patent HER2DX pending. Dr. Brasó-Maristany has a patent New HER2DX assay licensed to Reveal Genomics. Dr. Vivancos reports personal fees from Bayer, personal fees from Bristol Meyers Squibb, personal fees from Guardant Health, personal fees from Merck, personal fees from Novartis, personal fees from Roche, personal fees from Incyte, outside the submitted work; In addition, Dr. Vivancos has a patent WO2015145388A3 licensed. Dr. Perou reports grants from Reveal Genomics, during the conduct of the study; other from Reveal Genomics, outside the submitted work. No authors have been paid to write this article., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Eribulin prolongs overall survival in patients with pre-treated advanced breast cancer. However, no biomarker exists to prospectively select patients who will benefit the most from this drug. SOLTI-1007-NeoEribulin is a phase II, open-label, two-cohort, exploratory pharmacogenomic study in patients with clinical stage I-II HER2-negative breast cancer receiving neoadjuvant eribulin monotherapy treatment. Primary objective was to explore the association of baseline tumor gene expression with pathological complete response in the breast (pCR B ) at surgery. Key secondary objectives were pCR B rates in all patients and according to HR status, gene expression changes during treatment and safety. One-hundred one hormonal receptor-positive (HR + ) and seventy-three triple-negative breast cancer (TNBC) patients were recruited. The pCR B rates were 6.4% in all patients, 4.9% in HR + disease and 8.2% in TNBC. The TNBC cohort was interrupted due to a progression disease rate of 30.1%. The pCR B rates differed according to intrinsic subtypes: 28.6% in HER2-enriched, 11.1% in Normal-like, 7.9% in Luminal B, 5.9% in Basal-like and 0% in Luminal A (HER2-enriched vs. others odds ratio = 7.05, 95% CI 1.80-42.14; p-value = 0.032). Intrinsic subtype changes at surgery occurred in 33.3% of cases, mostly (49.0%) Luminal B converting to Luminal A or Basal-like converting to Normal-like. Baseline tumor-infiltrating lymphocytes (TILs) were significantly associated with pCR. Eribulin showed a good safety profile with a low response and pCR B rates. Patients with HER2-negative disease with a HER2-enriched profile may benefit the most from eribulin. In addition, significant biological activity of eribulin is observed in Luminal B and Basal-like subtypes., (© 2021. The Author(s).)

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 microbiological diagnosis of skin lesions related to COVID-19 is not well known., Objective: Perform a microbiological diagnosis in COVID19-related cutaneous manifestations., Methods: A cross-sectional study was performed with 64 patients with cutaneous manifestations associated with COVID-19 who underwent serological and nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2., Results: Out of the 64 patients, 6 patients had positive RT-PCR, with all of them developing SARS-CoV-2 IgG and 4 of them had positive IgM + IgA. Of the 58 patients with negative RT-PCR, 8 cases had positive IgM + IgA and only one of them had IgG seroconversion. Therefore, the infection was demonstrated in 7 cases (10.9%) and was doubtful in 7 other cases (10.9%) who presented negative RT-PCR and presence of IgA + IgM without subsequent seroconversion of IgG. Fifty patients (78.1%) had negative serological tests. The most frequent cutaneous pattern was pseudo-chilblain (48.4%) followed by maculo-papular pattern (26.6%), urticarial lesions (10.9%), vesicular eruptions (6.3%) and livedoid pattern (4.7%). The maculo-papular pattern showed the highest positivity in RT-PCR (3 cases; 17.6%) and serologies (4 cases; 23.5%). Skin lesions developed after the systemic symptoms in most patients (19 cases; 61.3%)., Conclusions: Microbiological confirmation tests may not be an effective diagnostic technique for COVID-related cutaneous manifestations or that attributed lesions are not related to COVID-19. Confounding factors such as adverse drug reaction, serological cross-reactions with other viruses, the low production of antibodies in asymptomatic or mild forms of COVID-19 or its rapid disappearance, increase diagnostic uncertainty., (© 2021 Wiley Periodicals LLC.)

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.)

The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R 2  = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R 2  = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.

Purpose: We do not yet have validated biomarkers to predict response and outcome within hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer. The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ breast cancer., Experimental Design: Intrinsic subtype and clinicopathologic data were obtained from seven studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores [CES-C (chemo-sensitive), CES-U (uncertain), and CES-E (endocrine-sensitive)]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS)., Results: A total of 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U, and CES-E were identified in 60%, 23%, and 17% of the patients, respectively. High CES (i.e., CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted OR = 0.42; P = 0.016). A total of 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted HR, 0.174; P = 0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS HR of CES was 0.160 ( P = 0.012)., Conclusions: In HER2+/HR+ breast cancer, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics., (©2021 American Association for Cancer Research.)

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.)

Despite their recognised role in HER2-positive (HER2+) breast cancer (BC), the composition, localisation and functional orientation of immune cells within tumour microenvironment, as well as its dynamics during anti-HER2 treatment, is largely unknown. We here investigate changes in tumour-immune contexture, as assessed by stromal tumour-infiltrating lymphocytes (sTILs) and by multiplexed spatial cellular phenotyping, during treatment with lapatinib-trastuzumab in HER2+ BC patients (PAMELA trial). Moreover, we evaluate the relationship of tumour-immune contexture with hormone receptor status, intrinsic subtype and immune-related gene expression. sTIL levels increase after 2 weeks of HER2 blockade in HR-negative disease and HER2-enriched subtype. This is linked to a concomitant increase in cell density of all four immune subpopulations (CD3 + , CD4 + , CD8 + , Foxp3 + ). Moreover, immune contexture analysis showed that immune cells spatially interacting with tumour cells have the strongest association with response to anti-HER2 treatment. Subsequently, sTILs consistently decrease at the surgery in patients achieving pathologic complete response, whereas most residual tumours at surgery remain inflamed, possibly reflecting a progressive loss of function of T cells. Understanding the features of the resulting tumour immunosuppressive microenvironment has crucial implications for the design of new strategies to de-escalate or escalate systemic therapy in early-stage HER2+ BC.

Circulating tumor DNA (ctDNA) levels may predict response to anticancer drugs, including CDK4/6 inhibitors and endocrine therapy combinations (CDK4/6i+ET); however, critical questions remain unanswered such as which assay or statistical method to use. Here, we obtained paired plasma samples at baseline and week 4 in 45 consecutive patients with advanced breast cancer treated with CDK4/6i+ET. ctDNA was detected in 96% of cases using the 74-gene Guardant360 assay. A variant allele fraction ratio (VAFR) was calculated for each of the 79 detected mutations between both timepoints. Mean of all VAFRs (mVAFR) was computed for each patient. In our dataset, mVAFR was significantly associated with progression-free survival (PFS). Baseline VAF, on-treatment VAF or absolute changes in VAF were not associated with PFS, nor were CA-15.3 levels at baseline, week 4 or the CA-15.3 ratio. These findings demonstrate that ctDNA dynamics using a standardized multi-gene panel and a unique methodological approach predicts treatment outcome. Clinical trials in patients with an unfavorable ctDNA response are needed.

Novel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression.

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.)