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Neuropsychiatric manifestations can be a serious complication of systemic lupus erythematosus, affecting nearly 56% of these patients. Frequently, acceptable clinical outcome is observed in neurolupus with immunosuppressive therapy. Different metabolites identified with MR spectroscopy may be associated with modifications in the natural history of this disease, specifically in the central nervous system. We report a case of neurolupus with progressive neurologic impairment despite aggressive immunosuppressive treatment. We describe clinical features, laboratory and MRI results, as well as characteristic findings on MR spectroscopy. Serial MRI identified atrophy of the left temporal lobe. MR spectroscopy showed an increase of myo-inositol/creatine ratio intensity, accompanied by a decrease of N-acetylaspartate/creatine ratio in both parietal white and gray matter. During follow-up, the patient developed progressive cognitive deficiency despite the intensification of therapy. Neurolupus manifestations are common and immunosuppressive treatment often avoids severe complications. Characteristic findings on MR spectroscopy may be useful for clinicians to determine poor prognosis and resistance to therapy. [ABSTRACT FROM PUBLISHER]

Neoadjuvant chemoimmunotherapy (NACIT) has been shown to improve pathologic complete response (pCR) rates and survival outcomes in stage II-III triple-negative breast cancer (TNBC). Promising pCR rate improvements have also been documented for selected patients with estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC). However, one size does not fit all and predicting which patients will benefit from NACIT remains challenging. Accurate predictions would be useful to minimize immune-related toxicity, which can be severe, irreversible, and potentially impact fertility and quality of life, and to identify patients in need of alternative treatments. This review aims to capitalize on the existing translational and clinical evidence on predictors of treatment response in patients with early-stage BC treated with neoadjuvant chemotherapy (NACT) and NACIT. It summarizes evidence suggesting that NACT/NACIT effectiveness may correlate with pre-treatment tumor characteristics, including mutational profiles, ER expression and signaling, immune cell presence and spatial organization, specific gene signatures, and the levels of proliferating versus quiescent cancer cells. However, the predominantly qualitative and descriptive nature of many studies highlights the challenges in integrating various potential response determinants into a validated, comprehensive, and multimodal predictive model. The potential of novel multi-modal approaches, such as those based on artificial intelligence, to overcome current challenges remains unclear, as these tools are not free from bias and shortcut learning. Despite these limitations, the rapid evolution of these technologies, coupled with further efforts in basic and translational research, holds promise for improving treatment outcome predictions in early HER2- BC., Competing Interests: Declaration of competing interest CCo reports travel/accommodations (to scientific meeting) from Veracyte, past support by the IEO-Monzino Foundation (2023), and is supported by Fondazione Gianni Bonadonna (FGB) and Associazione Italiana per la Ricerca contro il Cancro (AIRC) (2024-2026). All the competing interests were outside the submitted work. BBK, BK, TR, FC, LP and SKK have no potential conflicts of interest to disclose. GB reports fees for advisory boards, travel grants, consultancy: Seagen, Eli Lilly, Novartis, Pfizer, Roche, AstraZeneca, MSD, Daiichi Sankyio, Eisai, Gilead, Exact Science, Stemline, Agendia. All the competing interests were outside the submitted work. CCr reports personal fees for consulting, advisory role and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead and Pfizer. All the competing interests were outside the submitted work. GC reports the following 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 Medicine, 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, Medimmune. All the competing interests were outside the submitted work. ACG-C reports research funding (to the Institution) from AstraZeneca, Daiichi-Sankyo, Merck, Gilead Sciences, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Biovica International AB, and Foundation Medicine; and travel/accommodations (to scientific meeting) from Roche/Genentech. AGW institutional research support from Reveal Genomics, Genentech, Macrogenics, and Merck and personal fees from AstraZeneca outside the submitted work. EAM reports service on scientific advisory boards for Astra Zeneca, Exact Sciences, Roche/Genentech, and Merck; steering committee service for BMS, Lilly, and Roche/Genentech; and institutional research support from Roche/Genentech, Gilead, as well as research funding from Susan Komen for the Cure and participation as a member of the American Society of Clinical Oncology board of directors outside the submitted work. SMT reports a consulting or advisory role 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, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Biopharma, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, and Hengrui USA; reports institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, NanoString Technologies, Seattle Genetics, and OncoPep, and receives travel support from Eli Lilly, Sanofi, Gilead, and Pfizer. All the competing interests were outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The impact of human epidermal growth factor receptor 2 (HER2) expression determined by immunohistochemistry (IHC) on outcomes in early-stage triple-negative breast cancer (eTNBC) is unclear. Using a large, multi-institutional cohort, we evaluated outcomes by HER2 IHC status in patients with eTNBC who received neoadjuvant therapy (NAT)., Patients and Methods: Patients with stage I-III TNBC who received NAT and underwent surgery from January 2016 to June 2019 were identified from three databases. HER2 expression was defined as low (IHC1+ or 2+/FISH not amplified) or HER2 IHC score 0 by local testing at diagnosis. Pathological complete response (pCR) rates were compared using logistic regression adjusted for multiple factors. Survival outcomes were estimated using Kaplan-Meier and Cox proportional hazards models., Results: Among 977 consecutive patients, 388 (39.7%) had HER2-low and 589 (60.3%) had HER2 IHC score 0 tumors. Median age at eTNBC diagnosis was 50.3 years (range 21.0-83.4 years). At baseline, clinical nodal positivity rate was significantly higher in HER2-low (55.0%) versus HER2 IHC score 0 tumors (46.6%) (P = 0.011); pCR rates were similar (32.0% versus 32.6%; adjusted P = 0.924). At a median follow-up of 3.5 years, recurrence-free survival (RFS) did not vary significantly between HER2-low versus HER2 IHC score 0 among patients with pCR (adjusted P = 0.368) or residual disease (RD) after NAT (adjusted P = 0.573). Distant RFS and overall survival (OS) did not differ by HER2 category for patients with pCR [distant RFS (DRFS), adjusted P = 0.509; OS, adjusted P = 0.514] or RD (DRFS, adjusted P = 0.812; OS, P = 0.285). Discordance of tumor HER2 status was seen in 31.1% of HER2 IHC score 0 cases, with HER2 expression observed post-treatment; 34.8% of HER2-low cases showed discordance, with absent HER2 expression in RD., Conclusions: In this large cohort of patients with eTNBC treated with NAT, HER2-low status was not associated with pCR or survival after adjusting for clinical factors. The discordance in HER2 IHC pre- and post-NAT likely reflects challenges in HER2 quantification and heterogeneity., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence 1 . The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived 1,2 . Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN 3-6 . However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors 7 . Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit., Competing Interests: Competing interests: K.C. is an advisor at Genentech and serves on the scientific advisory board of Erasca. S.M.T. has consulting or advisory roles at Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, Odonate Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Chugai Pharma, Ellipses Pharma, Infinity, 4D Pharma, OncoSec Medical, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics and ARC Therapeutics; and received institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Odonate Therapeutics, Sanofi and Seattle Genetics. P.K.S. is a co-founder and member of the BOD of Glencoe Software, member of the BOD for Applied Biomath, member of the scientific advisory board for RareCyte, NanoString and Montai Health, holds equity in Glencoe, Applied Biomath and RareCyte, consults for Merck, and has received research funding to the institution from Novartis and Merck in the past 5 years. A.C.G.-C. has grant/research funding to institution from Gilead Sciences, AstraZeneca, Daiichi-Sankyo, Merck, Zenith Epigenetics, Bristol-Myers Squibb, Novartis, Foundation Medicine and Biovica; serves as a consultant and member of the scientific advisory board for AstraZeneca, Daiichi-Sankyo and Novartis; has received honoraria from AstraZeneca and Daiichi-Sankyo; and has other financial or materials support from Roche/Genentech, Gilead Sciences, AstraZeneca, Novartis and Merck. K.H. is a consultant for and a co-founder of Dania Therapeutics Aps and a scientific advisor for Hannibal Health Innovation. S.R.V.K. is a founder and consultant at Faeth Therapeutics and Transomic Technologies. D.A.B. is a consultant for N of One/QIAGEN and Tango Therapeutics; is a founder and shareholder in Xsphera Biosciences; has received honoraria from Merck, H3 Biomedicine/Esai, EMD Serono, Gilead Sciences, Abbvie and Madalon Consulting; and has received research grants from BMS, Takeda, Novartis, Gilead and Lilly. The other authors declare no competing interests., (© 2024. The Author(s).)

For patients with metastatic triple-negative breast cancer (TNBC), treatment with pembrolizumab is dependent on the accurate determination of programmed death ligand 1 (PD-L1) expression using immunohistochemistry (IHC). This study evaluated the interobserver concordance in assessing PD-L1 expression on TNBC samples using the commercial 22C3 IHC assay and an in-house assay based on the E1L3N antibody. Concordance between the 22C3 and the E1L3N IHC assays was evaluated on TNBC samples read by a commercial laboratory and a Brigham and Women's Hospital breast pathologist (BWH reader). Each slide was given a PD-L1 combined positive score (CPS) and was considered PD-L1 positive or negative based on the CPS cutoff of 10. Interobserver concordance for the assays was also evaluated on a subset of samples between 2 and 3 independent readers. On 71 samples, 2 independent readers (1 BWH reader and commercial laboratory) using E1L3N and 22C3, respectively, reached agreement on PD-L1 status (positive/negative) on 64 samples (90.1%). Using 22C3, 2 independent readers reached agreement on PD-L1 status on 30 of 36 samples (83.3%), and 3 independent readers reached agreement on 16 of 27 samples (59.3%). Using E1L3N, 2 BWH readers reached agreement on PD-L1 status on 18 of 27 samples (66.7%). Three BWH readers reached an agreement on 2 of 12 of the most challenging samples (16.7%). In conclusion, concordance between E1L3N and 22C3 testing using CPS for PD-L1 in metastatic TNBC was >90%. However, certain cases were challenging to agree upon using current threshold criteria, highlighting the need for more standardized evidence-based methods to assess PD-L1 expression., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Therapeutic advances in breast cancer have significantly improved outcomes in recent decades. In the early setting, there has been a gradual shift from adjuvant-only to neoadjuvant strategies, with a growing focus on customizing post-neoadjuvant treatments through escalation and de-escalation based on pathologic response. At the same time, the transition from a pre-genomic to a post-genomic era, utilizing specific assays in the adjuvant setting and targeted sequencing in the advanced stage, has deepened our understanding of disease biology and aided in identifying molecular markers associated with treatment benefit. Finally, the introduction of new drug classes such as antibody-drug conjugates, and the incorporation in the (neo)adjuvant setting of therapies previously investigated in the advanced stage, like immunotherapy and CDK4-6 inhibitors, poses new challenges in treatment sequencing.

Introduction: We have previously found that HER2 expression is dynamic, and can change from the primary breast tumor to matched recurrences. With this work, we aimed to assess the dynamics of HER2 during neoadjuvant treatment.(NAT)., Methods: We reviewed HER2 expression in pre- and post-treatment samples from consecutive patients with early-stage breast cancer that received NAT and underwent surgery at Dana-Farber Brigham Cancer Center between 01/2016-08/2022. The primary outcome was evolution of HER2 expression from pre- to post-NAT specimens in patients with residual disease., Results: Among 1613 patients receiving NAT, 1080 had residual disease at surgery. A total of 319 patients (29.5%) experienced a change in HER2 expression (HER2 0 vs. HER2-low vs. HER2-positive) from the pre-treatment sample to residual disease, with roughly equal distribution between decreased (50.5%) and increased HER2 expression (49.5%). Similar rates of change in HER2 expression were observed with anthracycline-based (31.8%) or taxane/platinum-based regimens (32.4%). Patients with HER2-0 or HER2-low tumors at diagnosis were likelier to experience a change in HER2 expression post-NAT compared to HER2-positive (32.3% vs. 21.3%, p < 0.001). Changes in HER2 expression post-NAT were prognostic among patients with HER2-positive tumors at diagnosis (3-year recurrence-free survival for change vs. no change: 71.6% vs. 89.6%, p = 0.006) but not among those with HER2-negative tumors at diagnosis (3-year recurrence-free survival for change vs. no change: 79.3% vs. 81.1%, p = 0.31)., Conclusions: Nearly 30% of patients with early-stage breast cancer showed a change in HER2 expression after NAT. Changes in HER2 expression post-NAT were only prognostic in the setting of HER2-positive tumors becoming HER2-negative at surgery., Competing Interests: Declaration of Competing Interest PT served as advisor/consultant for AstraZeneca, Daiichi-Sankyo, Gilead, Genentech, Roche, Eli Lilly. TAK reports speaker honoraria and compensated service on the scientific Advisory Board of Exact Sciences. EAM reports compensated service on scientific advisory boards for Astra Zeneca, BioNTech, Exact sciences (formerly Genomic Health), Merck, Moderna, and Roche/Genentech; uncompensated service on steering committees for Bristol Myers Squibb, Lilly, and Roche/Genentech; speakers honoraria and travel support from Merck Sharp & Dohme; and institutional research support from Roche/Genentech (via SU2C grant) and Gilead. EAM also reports research funding from Susan Komen for the Cure, for which she serves as a Scientific Advisor, and uncompensated participation as a member of the American Society of Clinical Oncology Board of Directors. NUL reports consulting honoraria from Puma, Seattle Genetics, Daiichi-Sankyo, AstraZeneca, Olema Pharmaceuticals, Janssen, Blueprint Medicines, Stemline/Menarini, Artera Inc., and Eisai; institutional research funding from Genentech (and Zion Pharmaceutical as part of GNE), Pfizer, Merck, Seattle Genetics (now Pfizer), Olema Pharmaceuticals, and AstraZeneca; royalties from UptoDate (book); and travel support from Olema Pharmaceuticals. SMT has served as an advisor/consultant to 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, Suvitovant Biopharma, Zetagen, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Biopharma, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, and Hengrui USA; has received institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, NanoString Technologies, Seattle Genetics, and OncoPep; and has received travel support from Eli Lilly, Sanofi, Gilead, and Pfizer. GC reports honoraria for speaker's engagements at Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, Bristol Myers Squibb, and MSD; honoraria for providing consultancy to Roche, Seattle Genetics, and NanoString; honoraria for participating on the Advisory Boards of Roche, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, and Mylan; honoraria for writing engagements for Novartis and Bristol Myers Squibb; honoraria for participation in the Ellipsis Scientific Affairs Group; and institutional research funding for conducting phase I and II clinical trials for Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, Bristol Myers Squibb, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, and Medimmune. ACGC reports research funding (to institution) from AstraZeneca, Daiichi-Sankyo, Merck, Gilead Sciences, and Zenith Epigenetics; and travel accommodations from Roche/Genentech. The remaining authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Sacituzumab govitecan (SG), a novel antibody-drug conjugate (ADC) targeting TROP2, is approved for pre-treated metastatic triple-negative breast cancer (mTNBC). We conducted an investigator-initiated clinical trial evaluating neoadjuvant (NA) SG (NCT04230109), and report primary results., Patients and Methods: Participants with early-stage TNBC received NA SG for four cycles. The primary objective was to assess pathological complete response (pCR) rate in breast and lymph nodes (ypT0/isN0) to SG. Secondary objectives included overall response rate (ORR), safety, event-free survival (EFS), and predictive biomarkers. A response-guided approach was utilized, and subsequent systemic therapy decisions were at the discretion of the treating physician., Results: From July 2020 to August 2021, 50 participants were enrolled (median age = 48.5 years; 13 clinical stage I disease, 26 stage II, 11 stage III). Forty-nine (98%) completed four cycles of SG. Overall, the pCR rate with SG alone was 30% [n = 15, 95% confidence interval (CI) 18% to 45%]. The ORR per RECIST V1.1 after SG alone was 64% (n = 32/50, 95% CI 77% to 98%). Higher Ki-67 and tumor-infiltrating lymphocytes (TILs) were predictive of pCR to SG (P = 0.007 for Ki-67 and 0.002 for TILs), while baseline TROP2 expression was not (P = 0.440). Common adverse events were nausea (82%), fatigue (76%), alopecia (76%), neutropenia (44%), and rash (48%). With a median follow-up time of 18.9 months (95% CI 16.3-21.9 months), the 2-year EFS for all participants was 95%. Among participants with a pCR with SG (n = 15), the 2-year EFS was 100%., Conclusions: In the first NA trial with an ADC in localized TNBC, SG demonstrated single-agent efficacy and feasibility of response-guided escalation/de-escalation. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed., Competing Interests: Disclosure LMS: consulting or advisory role—Avrobio; Novartis; Puma Biotechnology; research funding—Merck (Inst); Philips Healthcare (Inst). SMT: consulting or advisory role—4D Pharma, AstraZeneca, Athenex, BeyondSpring Pharmaceuticals, Blueprint Medicines, Bristol-Myers Squibb, Certara Inc., Chugai Pharma, CytomX Therapeutics, Daiichi Sankyo, Eisai, Ellipses Pharma, G1 Therapeutics, Genentech, Immunomedics/Gilead, Infinity Pharmaceuticals, Kyowa Hakko Kirin, Lilly, Merck, Mersana, NanoString Technologies, Nektar, Novartis, Odonate Therapeutics, OncoPep, OncoSec, OncXerna Therapeutics, Paxman, Pfizer, Puma Biotechnology, Reveal Genomics, Samsung Bioepis, Sanofi, Seagen, Zentalis, Zymeworks; research funding—AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Cyclacel (Inst), Eisai (Inst), Exelixis (Inst), Genentech/Roche (Inst), Immunomedics (Inst), Lilly (Inst), Merck (Inst), NanoString Technologies (Inst), Nektar (Inst), Novartis (Inst), Odonate Therapeutics (Inst), Pfizer (Inst), Sanofi (Inst), Seagen (Inst). LT: consulting or advisory role—Galera Therapeutics; research funding—Candel Therapeutics (Inst); AC: consulting or advisory role—Advance Medical, Applied Genetic Technologies Corporation (I), Beam Therapeutics (I), Biogen (I), Blue Cross Blue Shield Association (I), Crico, Editas Medicine (I), GenSight Biologics (I), Harvard Medical School, infiniteMD (I), Sanofi (I), Vedere Bio (I), WAVE Life Sciences (I). TM: consulting or advisory role—Outcomes4Me. ACG-C: research funding—AstraZeneca/MedImmune (Inst), Gilead Sciences (Inst), Merck (Inst). FL: consulting or advisory role—AmerisourceBergen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo/Astra Zeneca, OncoSec; research funding—AstraZeneca/Daiichi Sankyo (Inst), Bristol-Myers Squibb, CytomX Therapeutics (Inst), Immunomedics (Inst), Inivata (Inst). BM: consulting or advisory role—MOTUS (I); research funding—Puma Biotechnology (Inst); SJI: employment—Merus (I); consulting or advisory role—Novartis, Paxman, Puma Biotechnology, Seagen; research funding—Abbvie (Inst), AstraZeneca/MedImmune (Inst), Genentech (Inst), Merck (Inst), OncoPep (Inst), Outcomes4Me (Inst). NT: consulting or advisory role—AstraZeneca; research funding—AstraZeneca (Inst); EAM: honoraria—Physicans' Education Resource; consulting or advisory role—Exact Sciences, Merck, Roche, Roche/Genentech; research funding—GlaxoSmithKline; (OPTIONAL) uncompensated relationships—Bristol-Myers Squibb; Lilly. AB: consulting or advisory role—bioTheranostics, Daiichi Sankyo/AstraZeneca, Foundation Medicine, Genentech, Genentech/Roche (Inst), Immunomedics, Immunomedics (Inst), Innocrin Pharma (Inst), Merck, Novartis, Novartis (Inst), Pfizer, Pfizer (Inst), Philips Healthcare, Puma Biotechnology, Radius Health;, Radius Health (Inst), Sanofi, Spectrum Pharmaceuticals; research funding—AstraZeneca/Daiichi Sankyo (Inst), Genentech (Inst), Immunomedics (Inst), Merck (Inst), Novartis (Inst), Pfizer (Inst), Radius Health (Inst), Sanofi (Inst). All other authors have declared no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

The molecular underpinnings of HER2-low and HER2-0 (IHC 0) breast tumors remain poorly defined. Using genomic findings from 1039 patients with HER2-negative metastatic breast cancer undergoing next-generation sequencing from 7/2013-12/2020, we compare results between HER2-low (n = 487, 47%) and HER2-0 tumors (n = 552, 53%). A significantly higher number of ERBB2 alleles (median copy count: 2.05) are observed among HER2-low tumors compared to HER2-0 (median copy count: 1.79; P = 2.36e-6), with HER2-0 tumors harboring a higher rate of ERBB2 hemideletions (31.1% vs. 14.5%). No other genomic alteration reaches significance after accounting for multiple hypothesis testing, and no significant differences in tumor mutational burden are observed between HER2-low and HER2-0 tumors (median: 7.26 mutations/megabase vs. 7.60 mutations/megabase, p = 0.24). Here, we show that the genomic landscape of HER2-low and HER2-0 tumors does not differ significantly, apart from a higher ERBB2 copy count among HER2-low tumors, and a higher rate of ERBB2 hemideletions in HER2-0 tumors., (© 2023. The Author(s).)

Immune checkpoint inhibition combined with chemotherapy is currently approved as first-line treatment for patients with advanced PD-L1-positive triple-negative breast cancer (TNBC). However, a significant proportion of metastatic TNBC is PD-L1-negative and, in this population, chemotherapy alone largely remains the standard-of-care and novel therapeutic strategies are needed to improve clinical outcomes. Here, we describe a triple combination of anti-PD-L1 immune checkpoint blockade, epigenetic modulation thorough bromodomain and extra-terminal (BET) bromodomain inhibition (BBDI), and chemotherapy with paclitaxel that effectively inhibits both primary and metastatic tumor growth in two different syngeneic murine models of TNBC. Detailed cellular and molecular profiling of tumors from single and combination treatment arms revealed increased T- and B-cell infiltration and macrophage reprogramming from MHCIIlow to a MHCIIhigh phenotype in mice treated with triple combination. Triple combination also had a major impact on gene expression and chromatin profiles shifting cells to a more immunogenic and senescent state. Our results provide strong preclinical evidence to justify clinical testing of BBDI, paclitaxel, and immune checkpoint blockade combination., (©2023 The Authors; Published by the American Association for Cancer Research.)

In the OlympiA study, 1 year of adjuvant olaparib significantly extended invasive disease-free survival and overall survival. The benefit was consistent across subgroups, and this regimen is now recommended after chemotherapy for germline BRCA1/2 mutation (gBRCA1/2m) carriers with high-risk, HER2-negative early breast cancer. However, the integration of olaparib in the landscape of agents currently available in the post(neo)adjuvant setting-ie, pembrolizumab, abemaciclib, and capecitabine-is challenging, as there are no data suggesting how to select, sequence, and/or combine these therapeutic approaches. Furthermore, it is unclear how to best identify additional patients who could benefit from adjuvant olaparib beyond the original OlympiA criteria. Since it is unlikely that new clinical trials will answer these questions, recommendations for clinical practice can be made through indirect evidence. In this article, we review available data that could help guide treatment decisions for gBRCA1/2m carriers with high-risk, early-stage breast cancer., (© The Author(s) 2023. Published by Oxford University Press.)

Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer that presents as de novo metastatic disease in 20-30% of cases, with one-third of cases demonstrating HER2-positivity. There has been limited investigation into locoregional therapy utilization following HER2-directed systemic therapy for these patients, and their locoregional progression or recurrence (LRPR) and survival outcomes. Patients with de novo HER2-positive metastatic IBC (mIBC) were identified from an IRB-approved IBC registry at Dana-Farber Cancer Institute. Clinical, pathology, and treatment data were abstracted. Rates of LRPR, progression-free survival (PFS), overall survival (OS), and pathologic complete response (pCR) were determined. Seventy-eight patients diagnosed between 1998 and 2019 were identified. First-line systemic therapy comprised chemotherapy for most patients (97.4%) and HER2-directed therapy for all patients (trastuzumab [47.4%]; trastuzumab+pertuzumab [51.3%]; or trastuzumab emtansine [1.3%]). At a median follow-up of 2.7 years, the median PFS was 1.0 year, and the median OS was 4.6 years. The 1- and 2-year cumulative incidence of LRPR was 20.7% and 29.0%, respectively. Mastectomy was performed after systemic therapy in 41/78 patients (52.6%); 10 had a pCR (24.4%) and all were alive at last follow-up (1.3-8.9 years after surgery). Among 56 patients who were alive and LRPR-free at one year, 10 developed LRPR (surgery group = 1; no-surgery group = 9). In conclusion, patients with de novo HER2-positive mIBC who undergo surgery have favorable outcomes. More than half of patients received systemic and local therapy with good locoregional control and prolonged survival, suggesting a potential role for local therapy., (© 2023. The Author(s).)

We performed single-cell RNA-sequencing and T cell receptor clonotype tracking of breast and ovarian cancer patients treated with the CDK4/6 inhibitor ribociclib and PD-1 blockade. We highlight evidence of two orthogonal treatment-associated phenomena: expansion of T cell effector populations and promotion of T cell memory formation. Augmentation of the antitumor memory pool by ribociclib boosts the efficacy of subsequent PD-1 blockade in mouse models of melanoma and breast cancer, pointing toward sequential therapy as a potentially safe and synergistic strategy in patients., (© 2023 Ali et al.)

The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2. Downregulation of estrogen receptor (ER)-mediated cell-cell adhesion genes through DNA methylation mechanisms was observed in metastases. Microenvironment differences varied according to tumor subtype; the ER + /luminal subtype had lower fibroblast and endothelial content, while triple-negative breast cancer/basal metastases showed a decrease in B and T cells. In 17% of metastases, DNA hypermethylation and/or focal deletions were identified near HLA-A and were associated with reduced expression and lower immune cell infiltrates, especially in brain and liver metastases. These findings could have implications for treating individuals with metastatic breast cancer with immune- and HER2-targeting therapies., (© 2022. The Author(s).)

Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in the United States (US). Most patients are diagnosed with early-stage disease; however, there is still a need to prevent recurrences that often present as incurable metastatic disease. The treatment landscape of early-stage breast cancer is evolving rapidly. The immune checkpoint inhibitor pembrolizumab is approved in combination with neoadjuvant chemotherapy for the treatment of high-risk triple-negative breast cancer (TNBC). The cyclin-dependent kinase (CDK) 4 and 6 inhibitor abemaciclib is approved for adjuvant treatment of patients with high-risk hormone receptor (HR)-positive disease. While adjuvant olaparib has shown significant improvement in outcomes for patients with pathogenic/likely pathogenic BRCA1/2 mutations and high-risk human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and is approved in this setting. For the HER2-positive subtype, the post-neoadjuvant therapy can be tailored based on the response to neoadjuvant chemotherapy and HER2-targeted agents. In this narrative review, we summarize the most recent approvals for early-stage breast cancer as well as frequently encountered clinical challenges utilizing these medications., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: The addition of immune checkpoint inhibitors (ICIs) to frontline chemotherapy has improved survival for patients with advanced triple-negative breast cancer (TNBC) expressing programmed death-ligand 1 (PD-L1). Nonetheless, most patients develop resistance, with outcomes remaining poor for this population. Moreover, unsatisfactory activity has been observed with ICIs in PD-L1-negative TNBC and in other breast cancer (BC) subtypes, warranting a deeper understanding of resistance to ICIs in BC., Areas Covered: We discuss the immune landscape of distinct BC subtypes, review the clinical activity of immunotherapy in BC, and highlight strategies under development to overcome resistance to ICIs., Expert Opinion: Activity and resistance to ICIs in BC are strongly related to the intrinsic immunophenotype of the tumor tissue. Several promising biomarkers reflecting the immunological state of BC are emerging, with only PD-L1 expression currently adopted into clinical practice. However, limitations make of PD-L1 a sub-optimal biomarker for patient selection, which require efforts to integrate this marker with other immunological features. Concomitantly, a wide variety of drug combinations designed to overcome immune-resistance are being evaluated, with some encouraging signals observed in early-phase trials. Combination strategies tailored to patient and tumor immunophenotype may allow to overcome resistance and fully exploit the potential of ICIs.

Objectives: Dermal lymphatic invasion (DLI) with tumor emboli is a common pathologic characteristic of inflammatory breast cancer (IBC), although its presence is not required for diagnosis. We examined whether documented DLI on skin biopsy was associated with survival and time to recurrence or progression in IBC., Materials and Methods: A total of 340 women enrolled in the IBC Registry at Dana-Farber Cancer Institute between 1997 and 2019 were included in this study. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for associations of DLI and overall survival, time to locoregional recurrence/progression, and distant metastasis by stage at presentation., Results: DLI was detected in 215 (63.2%) of IBC cases overall. At disease presentation, IBC with DLI had a higher prevalence of de novo metastases (37.7% vs. 26.4%), breast skin ulceration (6.1% vs. 2.4%), and lymphovascular invasion within the breast parenchyma (52.9% vs. 25.5%) and a lower prevalence of palpable breast mass (48.2% vs. 70.6%) than IBC without DLI. Over a median follow-up of 2.0 years, 147 deaths occurred. DLI was not associated with survival or recurrence in multivariable models (all P ≥0.10). For example, among women with stage III disease, hazard ratios (95% confidence intervals) for DLI presence was 1.29 (0.77-2.15) for overall survival, 1.29 (0.56-3.00) for locoregional recurrence, and 1.71 (0.97-3.02) for distant metastasis., Conclusion: Although the extent of tumor emboli in dermal lymphatics may be associated with biological features of IBC, DLI was not an independent prognostic marker of clinical outcomes in this study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: In contrast to recurrence after initial diagnosis of stage I-III breast cancer [recurrent metastatic breast cancer (rMBC)], de novo metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS)., Experimental Design: Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC., Results: When comparing primary tumors by subtype, MYB amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, P = 0.0005, q = 0.111). Mutations in KMTD2, SETD2 , and PIK3CA were more prevalent, and TP53 and BRCA1 less prevalent, in primary HR + /HER2 - tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; P = 0.008, q = 0.107), MYC (79.7 vs. 23.3 months; P = 0.0003, q = 0.011), and cell-cycle (122.7 vs. 54.9 months; P = 0.034, q = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC ( P = 0.041)., Conclusions: Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments., (©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.

Purpose: The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME)., Experimental Design: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1-high (PD-1 HI ) CD8 + peripheral T cells and examination of a cytolytic gene signature in whole blood., Results: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden., Conclusions: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence., (©2020 American Association for Cancer Research.)

Purpose: Given regulatory approval of immune checkpoint inhibitors in patients with mismatch repair-deficient (MMR-D) cancers agnostic to tumor type, it has become important to characterize occurrence of MMR-D and develop cost-effective screening approaches. Using a next-generation sequencing (NGS) panel (OncoPanel), we developed an algorithm to identify MMR-D frequency in tumor samples and applied it in a clinical setting with pathologist review., Methods: To predict MMR-D, we adapted methods described previously for use in NGS panels, which assess patterns of single base-pair insertion or deletion events occurring in homopolymer regions. Tumors assayed with OncoPanel between July 2013 and July 2018 were included. For tumors tested after June 2017, sequencing results were presented to pathologists in real time for clinical MMR determination, in the context of tumor mutation burden, other mutational signatures, and clinical data., Results: Of 20,301 tumors sequenced, 2.7% (553) were retrospectively classified as MMR-D by the algorithm. Of 4,404 samples with pathologist sign-out of MMR status, the algorithm classified 147 (3.3%) as MMR-D: in 116 cases, MMR-D was confirmed by a pathologist, five cases were overruled by the pathologist, and 26 were assessed as indeterminate. Overall, the highest frequencies of OncoPanel-inferred MMR-D were in endometrial (21%; 152/723), colorectal (9.7%; 169/1,744), and small bowel (9.3%; 9/97) cancers. When algorithm predictions were compared with historical MMR immunohistochemistry or polymerase chain reaction results in a set of 325 tumors sequenced before initiation of pathologist assessment, the overall sensitivity and specificity of the algorithm were 91.1% and 98.2%, respectively., Conclusion: We show that targeted, tumor-only NGS can be leveraged to determine MMR signatures across tumor types, suggesting that broader biomarker screening approaches may have clinical value.

Purpose: Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and PTEN alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC., Experimental Design: We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features., Results: Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; P = 0.04), while PTEN alterations (29%) were associated with significantly lower ORR (6% vs. 48%; P = 0.01), shorter PFS (2.3 vs. 6.1 months; P = 0.01), and shorter OS (9.7 vs. 20.5 months; P = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy ( n = 90) and non-ICI regimens ( n = 169)., Conclusions: Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and PTEN alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets., (©2020 American Association for Cancer Research.)

Purpose: The yield of comprehensive genomic profiling in recruiting patients to molecular-based trials designed for small subgroups has not been fully evaluated. We evaluated the likelihood of enrollment in a clinical trial that required the identification of a specific genomic change based on our institute-wide genomic tumor profiling., Patients and Methods: Using genomic profiling from archived tissue samples derived from patients with metastatic breast cancer treated between 2011 and 2017, we assessed the impact of systematic genomic characterization on enrollment in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT01670877). Our primary aim was to describe the proportion of patients with a qualifying ERBB2 mutation identified by our institutional genomic panel (OncoMap or OncoPanel) who enrolled in the trial. Secondary objectives included median time from testing result to trial registration, description of the spectrum of ERBB2 mutations, and survival. Associations were calculated using Fisher's exact test., Results: We identified a total of 1,045 patients with metastatic breast cancer without ERBB2 amplification who had available genomic testing results. Of these, 42 patients were found to have ERBB2 mutation and 19 patients (1.8%) were eligible for the trial on the basis of the presence of an activating mutation, 18 of which were identified by OncoPanel testing. Fifty-eight percent of potentially eligible patients were approached, and 33.3% of eligible patients enrolled in the trial guided exclusively by OncoPanel testing., Conclusion: More than one half of eligible patients were approached for trial participation and, significantly, one third of those were enrolled in NCT01670877. Our data illustrate the ability to enroll patients in trials of rare subsets in routine clinical practice and highlight the need for these broadly based approaches to effectively support the success of these studies., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Rachel A. FreedmanResearch Funding: Puma Biotechnology (Inst), Eisai (Inst)Lorenzo TrippaConsulting or Advisory Role: Galera TherapeuticsRomualdo Barroso-SousaConsulting or Advisory Role: Lilly Speakers' Bureau: Roche, Bristol-Myers Squibb Travel, Accommodations, Expenses: RocheSimona Di LascioHonoraria: Roche/GenentechEthan CeramiStock and Other Ownership Interests: Blueprint Medicines Honoraria: Merck Travel, Accommodations, Expenses: MerckMargaret S. MerrillStock and Other Ownership Interests: Abbott Laboratories, AbbVie, Alcon, NovartisSara M. TolaneyConsulting or Advisory Role: Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech, Eisai, Immunomedics, Sanofi, Celldex, Bristol-Myers Squibb, Paxman, Seattle Genetics Research 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) Travel, Accommodations, Expenses: AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Eisai, NanoString Technologies, Puma Biotechnology, CelldexIan E. KropEmployment: AMAG Pharmaceuticals (I) Leadership: AMAG Pharmaceuticals (I) Stock and Other Ownership Interests: AMAG Pharmaceuticals (I) Honoraria: Genentech/Roche Consulting or Advisory Role: Genentech/Roche, Daiichi Sankyo, Context Therapeutics, Macrogenics, Taiho Pharmaceutical Research Funding: Genentech/Roche (Inst), Seattle Genetics (Inst), Pfizer (Inst), Daiichi Sankyo (Inst)Ron BoseHonoraria: Genentech, Foundation Medicine Consulting or Advisory Role: Genentech Research Funding: Puma Biotechnology (Inst)Bruce E. JohnsonResearch Funding: Novartis (Inst), Toshiba (Inst), Novartis (Inst), Novartis (Inst) Patents, Royalties, Other Intellectual Property: Dana-Farber Cancer InstituteCynthia X. MaConsulting or Advisory Role: Pfizer, Novartis, Syndax, Lilly, Biovica, Tempus, Seattle Genetics, Agendia, Myriad Genetics, Lilly Research Funding: Pfizer (Inst), Eisai (Inst), Puma (Inst) Travel, Accommodations, Expenses: Syndax, Lilly, Agendia, PfizerDeborah A. DillonConsulting or Advisory Role: Oncology Analytics, Novartis Travel, Accommodations, Expenses: NovartisEric P. WinerStock and Other Ownership Interests: Verastem Honoraria: Genentech/Roche, Tesaro, Genomic Health Consulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly Research Funding: Genentech (Inst), Novartis (Inst), Merck (Inst)Nikhil WagleStock and Other Ownership Interests: Foundation Medicine Honoraria: Lilly Consulting or Advisory Role: Novartis, Lilly Research Funding: Novartis, Puma BiotechnologyNancy U. LinConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Puma Biotechnology, Novartis, Daiichi Sankyo Research Funding: Genentech, Pfizer, Novartis, Seattle Genetics Patents, Royalties, Other Intellectual Property: Royalties for chapter in Up-to-Date regarding management of breast cancer brain metastases No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

Objectives: Aberrant PI3K/AKT/mTOR activation is common in gynaecological malignancies. However, predictive biomarkers of response to PI3K pathway inhibitors (PAMi) have yet to be identified., Methods: We analysed the outcomes of patients with advanced gynaecological cancer with available genomic data, treated with PAMi as single agents or in combination in phase I clinical trials. Clinical relevance of the PIK3CA mutant allele fraction (MAF) was investigated. MAF of each variant was normalised for tumour purity in the sample (adjMAFs) to infer clonality of PIK3CA mutations, defined as clonal (≥0.4) or subclonal (<0.4)., Results: A total of 50 patients with gynaecological cancer (24 ovarian; 15 endometrial; 11 cervical) with available targeted mutation profiling were selected. PAMi therapy was matched to PIK3CA/PTEN mutation in 30 patients (60%). The overall response rate, median time to progression (mTTP) and clinical benefit rate (CBR) of the entire population were 10% (N=5), 3.57 months (2.57-4.4) and 40% (N=18), respectively. Genotype-matched therapy did not lead to a favourable CBR (OR 0.91, p=1 (0.2-3.7)) or mTTP (3.57 months (2.6-4.4) vs 3.73 months (1.9-13.2); HR 1.41; p=0.29). We did not detect differences in mTTP according to therapy or PIK3CA codon mutation (HR 1.71, p=0.24). Overall, 41% of patients had a TTP ratio (TTP PAMi/TTP on immediately prior or subsequent palliative chemotherapy) ≥1.3, without statistically significant differences according to tumour type (p=0.39), molecular alteration status (p=0.13) or therapy (p=0.54). In univariate analysis, genotype-matched therapy in patients with PIK3CA clonal events was associated with improved mTTP (HR 3.6; p=0.03)., Conclusions: Our study demonstrates that patients with advanced gynaecological cancer, refractory to standard therapies, achieved meaningful clinical benefit from PAMi. The impact of PI3KCA clonality on response to selected PAMi in patients with gynaecological cancer deserves further investigation., Competing Interests: Competing interests: AO is a consultant/advisory board member of AstraZeneca, Clovis, Tesaro, Roche and PharmaMar. RD reports personal fees from Roche, outside the submitted work.

Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat. To date, therapies directed to specific molecular targets have rarely achieved clinically meaningful improvements in outcomes of patients with TNBC, and chemotherapy remains the standard of care. Here, we seek to review the most recent efforts to classify TNBC based on the comprehensive profiling of tumors for cellular composition and molecular features. Technologic advances allow for tumor characterization at ever-increasing depth, generating data that, if integrated with clinical-pathologic features, may help improve risk stratification of patients, guide treatment decisions and surveillance, and help identify new targets for drug development. SIGNIFICANCE: TNBC is characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival compared with other major breast cancer subtypes. The identification of biomarkers that can help guide treatment decisions in TNBC remains a clinically unmet need. Understanding the mechanisms that drive resistance is key to the design of novel therapeutic strategies to help prevent the development of metastatic disease and, ultimately, to improve survival in this patient population., (©2019 American Association for Cancer Research.)

The presence of disseminated tumor cells in breast cancer patient bone marrow aspirates predicts decreased recurrence-free survival. Although it is appreciated that physiologic, pathologic, and therapeutic conditions impact hematopoiesis, it remains unclear whether targeting hematopoiesis presents opportunities for limiting bone metastasis. Using preclinical breast cancer models, we discovered that marrow from mice treated with the bisphosphonate zoledronic acid (ZA) are metastasis-suppressive. Specifically, ZA modulated hematopoietic myeloid/osteoclast progenitor cell (M/OCP) lineage potential to activate metastasis-suppressive activity. Granulocyte-colony stimulating factor (G-CSF) promoted ZA resistance by redirecting M/OCP differentiation. We identified M/OCP and bone marrow transcriptional programs associated with metastasis suppression and ZA resistance. Analysis of patient blood samples taken at randomization revealed that women with high-plasma G-CSF experienced significantly worse outcome with adjuvant ZA than those with lower G-CSF levels. Our findings support discovery of therapeutic strategies to direct M/OCP lineage potential and biomarkers that stratify responses in patients at risk of recurrence. Significance: Bone marrow myeloid/osteoclast progenitor cell lineage potential has a profound impact on breast cancer bone metastasis and can be modulated by G-CSF and bone-targeting agents. Cancer Res; 78(18); 5300-14. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biologic therapies., Aims: To review, from an infectious diseases perspective, the safety profile of therapies targeting cell surface receptors and associated signaling pathways among cancer patients and to suggest preventive recommendations., Sources: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family., Content: Vascular endothelial growth factor (VEGF)-targeted agents (bevacizumab and aflibercept) are associated with a meaningful increase in the risk of infection, likely due to drug-induced neutropaenia, although no clear benefit is expected from the universal use of anti-infective prophylaxis. VEGF tyrosine kinase inhibitors (i.e. sorafenib or sunitinib) do not seem to significantly affect host's susceptibility to infection, and universal anti-infective prophylaxis is not recommended either. Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) induce neutropaenia and secondary skin and soft tissue infection in cases of severe papulopustular rash. Systemic antibiotics (doxycycline or minocycline) should be administered to prevent the latter complication, whereas no recommendation can be established on the benefit from antiviral, antifungal or anti-Pneumocystis prophylaxis. A lower risk of infection is reported for anti-ErbB2/HER2 monoclonal antibodies (trastuzumab and pertuzumab) and ErbB receptor tyrosine kinase inhibitors (including dual-EGFR/ErbB2 inhibitors such as lapatinib or neratinib) compared to conventional chemotherapy, presumably as a result of the decreased occurrence of drug-induced neutropaenia., Implications: With the exception of VEGF-targeted agents, the overall risk of infection associated with the reviewed therapies seems to be low., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Importance: If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune checkpoint inhibitor (ICI) regimens are unknown., Objective: To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration-approved ICI regimens., Data Sources: A PubMed search through July 18, 2016, using the following keywords was performed: "ipilimumab," "MDX-010," "nivolumab," "BMS-963558," "pembrolizumab," "MK-3475," "atezolizumab," "MPDL3280A," and "phase.", Study Selection: Thirty-eight randomized clinical trials evaluating the usage of these ICIs for treatment of advanced solid tumors were identified, resulting in a total of 7551 patients who were eligible for a meta-analysis. Regimens were categorized by class into monotherapy with a PD-1 (programmed cell death protein 1) inhibitor, a CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) inhibitor, or a PD-L1 (programmed cell death 1 ligand 1) inhibitor, and combination therapy with PD-1 plus CTLA-4 inhibitors., Data Extraction and Synthesis: The data were extracted by 1 primary reviewer (R.B.-S.) and then independently reviewed by 2 secondary reviewers (W.T.B. and A.C.G.-C.) following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inferences on the incidence of AEs were made using log-odds random effects models., Main Outcomes and Measures: Incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes., Results: Overall, 38 randomized clinical trials comprising 7551 patients were included in this systematic review and meta-analysis. The incidence of both hypothyroidism and hyperthyroidism was highest in patients receiving combination therapy. Patients on the combination regimen were significantly more likely to experience hypothyroidism (odds ratio [OR], 3.81; 95% CI, 2.10-6.91, P < .001) and hyperthyroidism (OR, 4.27; 95% CI, 2.05-8.90; P = .001) than patients on ipilimumab. Compared with patients on ipilimumab, those on PD-1 inhibitors had a higher risk of developing hypothyroidism (OR, 1.89; 95% CI, 1.17-3.05; P = .03). The risk of hyperthyroidism, but not hypothyroidism, was significantly greater with PD-1 than with PD-L1 inhibitors (OR, 5.36; 95% CI, 2.04-14.08; P = .002). While patients who received PD-1 inhibitors were significantly less likely to experience hypophysitis than those receiving ipilimumab (OR, 0.29; 95% CI, 0.18-0.49; P < .001), those who received combination therapy were significantly more likely to develop it (OR, 2.2; 95% CI, 1.39-3.60; P = .001). For primary adrenal insufficiency and insulin-deficient diabetes no statistical inferences were made due to the smaller number of events., Conclusions and Relevance: Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving ICI regimens. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis.

Purpose of Review: To describe the role of D-type cyclins and CDKs 4 and 6 in breast cancer, and to discuss potential biomarkers for sensitivity or resistance to CDK4/6 inhibitors., Recent Findings: A small number of preclinical and clinical studies have explored potential mechanisms of CDK4/6 inhibitor response and resistance in breast cancer. Putative markers of response include ER-positivity, luminal patterns of gene expression, high cyclin D1 levels, and low p16 levels. Possible resistance mechanisms include loss of Rb function, overexpression/amplification of cyclin E, and CDK6 amplification. Most these remain speculative and have not been validated in clinical specimens., Summary: If early successes with CDK4/6 inhibitors are to be capitalized upon, it is critical that our understanding of CDK4/6 biology in breast cancer extends beyond its current rudimentary state. Only then we will be able to develop rational therapeutic combinations that further enhance the efficacy of these agents., Competing Interests: Conflict of Interest Ana C. Garrido-Castro declares no conflict of interest.

Oncogenic driver mutations identified in non-small cell lung cancer (NSCLC) have triggered the development of drugs capable of interfering in intracellular signaling pathways involved in tumorigenesis. Tyrosine kinase inhibitors, such as erlotinib or gefitinib, have demonstrated promising results in patients with advanced NSCLC that harbor EGFR mutations. Human epidermal growth factor 2 (HER2/ERBB2/neu) is a member of the ERBB family of tyrosine kinase receptors, and is activated by homodimerization or heterodimerization with other ERBB receptors. Deregulation of HER2 gene, by overexpression and/or gene amplification has been proved important in breast and gastric cancer, in which overexpression of HER2 confers greater response to specific anti-HER2 treatment, including trastuzumab. In lung carcinogenesis, HER2 mutations are thought to be more clinically relevant than overexpression or gene amplification. HER2 mutations in NSCLC, described exclusively in adenocarcinoma histology, are present in approximately 4% of this subset of lung cancer patients, suggesting that thousands of patients per year may possibly benefit from targeted therapy. Therefore, we conclude that systematic genotypic testing in this subgroup of NSCLC patients should include detection of HER2 mutations. In addition, clinical trials with standard antiHER2 agents and new investigational therapies are ongoing, with promising preliminary results, as illustrated in this review, although further research is warranted in this field.