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Purpose: Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC)., Patients and Methods: From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes., Results: One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy., Conclusion: Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting., Competing Interests: Bryan P. SchneiderHonoraria: Lilly, Research to PracticeResearch Funding: Genentech/Roche, Pfizer, Foundation Medicine, Epic Sciences Tarah J. BallingerConsulting or Advisory Role: Medscape, Novartis Rita NandaConsulting or Advisory Role: Merck, Genentech/Roche, Pfizer, Macrogenics, Aduro Biotech, Ionis Pharmaceuticals, Immunomedics, OncoSec, Cardinal Health, Seattle Genetics, Fujifilm, Clovis Oncology, G1 Therapeutics, Cardinal Health, ITeos TherapeuticsResearch Funding: Corcept Therapeutics (Inst), Celgene (Inst), Merck (Inst), Seattle Genetics (Inst), Genentech/Roche (Inst), Odonate Therapeutics (Inst), Pfizer (Inst), AstraZeneca (Inst), Immunomedics (Inst), OncoSec (Inst), Arvinas (Inst), Taiho Oncology (Inst), OBI Pharma (Inst)Other Relationship: G1 Therapeutics Carla FalksonHonoraria: Exact Sciences, Curio ScienceResearch Funding: Oncolytics Biotech, QuantumLeap Health (Inst), Lilly (Inst), Seattle Genetics (Inst), Pfizer/EMD Serono (Inst), Novartis (Inst), Genentech/Roche (Inst) Filipa C. LynceConsulting or Advisory Role: Bristol Myers Squibb, Pfizer/EMD Serono, ASCO, AstraZenecaResearch Funding: Pfizer (Inst), Bristol Myers Squibb (Inst), Immunomedics (Inst), Inivata (Inst) Christopher GallagherConsulting or Advisory Role: Daiichi Sankyo, Seattle Genetics, LillySpeakers' Bureau: Daiichi Sankyo/UCB Japan Claudine IsaacsHonoraria: Genentech/RocheConsulting or Advisory Role: Pfizer, Genentech/Roche, Novartis, AstraZeneca, Puma Biotechnology, Seattle Genetics, Sanofi/Aventis, Eisai, Ion Solutions,Speakers' Bureau: GenentechResearch Funding: Tesaro, Merck, Seattle Genetics, McGraw Hill PublishingPatents, Royalties, Other Intellectual Property: UpToDate—Wolters Kluwer—Author of chapters, Elsevier—Editor of Book,Other Relationship: Side-Out Foundation Elisavet PaplomataHonoraria: Novartis, R-Pharm, Pfizer, Mylan, Puma BiotechnologyConsulting or Advisory Role: Novartis, R-Pharm, Pfizer, Mylan, Puma Biotechnology, bioTheranostics, OncLive Clinical Congress ConsultantsResearch Funding: Novartis (Inst), Genentech (Inst), Corcept Therapeutics (Inst), Hoosier Cancer Research Network (Inst), Cascadian Therapeutics (Inst), AbbVie (Inst), Merck (Inst), Seattle Genetics (Inst), Immunogen (Inst)Travel, Accommodations, Expenses: Novartis, Genentech, Tesaro, Merck, AmgenOpen Payments Link: https://openpaymentsdata.cms.gov/physician/176406 Radhika WallingHonoraria: DAVA Pharmaceuticals, Cureus, Biotheranostics Karen DailyConsulting or Advisory Role: Pfizer Reshma MahtaniConsulting or Advisory Role: Genentech, Amgen, Pfizer, bioTheranostics, Agendia, Eisai, Novartis, Lilly, AstraZeneca, Puma Biotechnology, Seattle Genetics, Daaichi, Immunomedics/Gilead, Merck, SanofiResearch Funding: GenentechTravel, Accommodations, Expenses: Pfizer, Genentech/Roche, Amgen, bioTheranostics, AstraZeneca, Lilly, Novartis, Agendia, Puma Biotechnology, Seattle Genetics, Daiichi Sankyo/Lilly, Eisai, Sanofi, Merck Michael A. ThompsonStock and Other Ownership Interests: DoximityConsulting or Advisory Role: Celgene, VIA Oncology, Takeda, GlaxoSmithKline, Syapse, Adaptive Biotechnologies, AbbVie, GRAIL, Epizyme, Janssen Oncology, SanofiResearch Funding: Takeda (Inst), Bristol Myers Squibb (Inst), TG Therapeutics (Inst), Cancer Research and Biostatistics (Inst), AbbVie (Inst), PrECOG (Inst), Strata Oncology (Inst), Lynx Biosciences (Inst), Denovo Biopharma (Inst), ARMO BioSciences (Inst), GlaxoSmithKline (Inst), Amgen (Inst)Patents, Royalties, Other Intellectual Property: UpToDate, Peer Review for Plasma Cell Dyscrasias (Editor: Robert Kyle)Travel, Accommodations, Expenses: Takeda, GlaxoSmithKline, SyapseOther Relationship: DoximityUncompensated Relationships: Strata OnoclogyOpen Payments Link: https://openpaymentsdata.cms.gov/physician/192826/summary Maureen E. CooperEmployment: Foundation MedicineStock and Other Ownership Interests: Foundation Medicine, Roche Dean C. PavlickEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Lee A. AlbackerEmployment: Foundation MedicineStock and Other Ownership Interests: Roche Jeffrey GreggStock and Other Ownership Interests: Harbinger OncologyConsulting or Advisory Role: LuninexSpeakers' Bureau: AstraZeneca, Blueprint Medicines Yu-Hsiang ChenEmployment: Foundation Medicine, FreenomeStock and Other Ownership Interests: Roche/Foundation Medicine Bradley A. HancockEmployment: Lifeomic LLCStock and Other Ownership Interests: Lifeomic LLC Bert O'NeilEmployment: LillyHonoraria: AstraZeneca Anna Maria V. StornioloEmployment: Sophren Therapeutics (I), Q32Bio, Inc (I)Leadership: Sophren Therapeutics (I), Q32Bio, Inc (I)Stock and Other Ownership Interests: Gilead Sciences (I), Moderna Therapeutics (I), Merck (I), Lilly (I), Giead (I)¸ Moderna Therapeutics, Merck, Pfizer (I), Meridian Bioscience Inc (I)Consulting or Advisory Role: Q32bio (I), Tri-I TDI (I), Deerfield Management (I), Atlas Venture (I), Boston Pharmaceuticals (I)Research Funding: QUE Oncology, Pfizer Sunil BadveHonoraria: Athenex, Personalis, Paige AI, Ventana Medical Systems, Agilent, BMSSpeakers' Bureau: Genomic Health, Targos Molecular Pathology, AgilentResearch Funding: Dako/Agilent Technologies, LillyPatents, Royalties, Other Intellectual Property: EarlyR - signature for ER+ breast cancer, E-Score for predicting recurrence of DCIS Kathy D. MillerConsulting or Advisory Role: Merck, Genentech/Roche, Athenex, AstraZeneca, Bristol Myers Squibb/CelgeneResearch Funding: Taiho Pharmaceutical (Inst), Novartis (Inst), Seattle Genetics (Inst), Pfizer (Inst), Astex Pharmaceuticals (Inst), British Biotech (Inst), CytomX Therapeutics (Inst), alphamab (Inst) Milan RadovichStock and Other Ownership Interests: LifeOmic, Macrogenics, Immunomedics, Tyme TechnologiesHonoraria: LillyResearch Funding: Lilly (Inst), Boston Biomedical (Inst), Foundation Medicine (Inst), Epic Sciences (Inst), Pfizer (Inst), Genentech (Inst)Patents, Royalties, Other Intellectual Property: Combination therapy for the treatment of TNBC with a PI3K pathway inhibitor that targets PI3KDelta and PI3KGammaNo other potential conflicts of interest were reported.

Introduction: Several studies have shown clinical outcomes data that support the use of CD274 (PD-L1 ) copy-number (CN) gains and/or losses as a biomarker for immune checkpoint inhibitor (ICPI). Here, we present the landscape of CD274 CN changes across a large cohort of solid tumor cases and correlate these with PD-L1 protein expression by immunohistochemistry., Methods: We analyzed all cases that underwent comprehensive genomic profiling (CGP) testing at Foundation Medicine between August 2014 and June 2020. CD274 CN changes were correlated with PD-L1 expression in tumor types where there were Food and Drug Administration approved companion diagnostic (CDx) claims and the CDx assay was used to assess PD-L1 expression., Results: In all, 244 584 samples representing 290 solid tumor types were included in the study. Overall, 17.6% (42 983/244 584) had CD274 CN gains (>specimen ploidy), 44.6% (108 970/244 584) were CD274 CN neutral, and 37.9% (92 631/244 584) had CD274 CN loss. Using different CN cut offs to define CD274 positivity resulted in different prevalence estimates: ploidy +1, 17.4% (42 636/244 584); ploidy +2, 6.2% (15 183/244 584); ploidy +3, 2.2% (5375/244 584); ploidy +4, 1.1% (2712/244 584); and ploidy +8, 0.2% (434/244 584). The prevalence of CN changes and CN positivity varied based on tumor type. CD274 CN gains were significantly associated with PD-L1 positivity in NSCLC, urothelial carcinoma, breast carcinoma, cervical carcinoma, esophagus squamous cell carcinoma (SCC) and head and neck SCC (ORs 3.3, 3.0, 2.0, 4.5. 3.8, 8.4, 1.4, respectively; p<0.05) and with microsatellite instability status in only clinically relevant tumor types (gastric adenocarcinoma, colorectal adenocarcinoma, uterine endometrial adenocarcinoma, esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma (OR: 5.2, 1.9, 3.2, 3.7 and 6.5, respectively; p<0.05)). Conversely, CD274 CN changes were not significantly correlated with tumor mutational burden in almost all the tumor types., Conclusion: CD274 CN changes and PD-L1 expression were highly correlated in multiple tumor types. These prevalence data on CD274 CN changes across a large cohort of different solid tumors can be used to design future clinical studies to assess whether CD274 CN changes could be a potential biomarker for ICPI., Competing Interests: Competing interests: All authors of the manuscript are employees of Foundation Medicine, which is a wholly owned subsidiary of Roche and receives stock from Roche., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We examined a large dataset of female metastatic breast cancers (MBCs) profiled with comprehensive genomic profiling (CGP) to identify the prevalence and distribution of immunotherapy responsiveness-associated biomarkers. DNA was extracted from 3831 consecutive MBCs: 1237 (ER pos /HER2 neg ), 1953 ER neg /HER2 amp , and 641 triple-negative breast cancer (TNBC). CGP was performed using the FoundationOne ® or FoundationOne ® CDx NGS assay. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined in a subset of cases. PD-L1 expression in immunocytes in a subset of cases was determined by immunohistochemistry using the companion diagnostic VENTANA PD-L1 SP142 Assay. The median age of the cohort was 54 years (range 20-89). Genomic alterations (GAs)/tumor were similar (range: 5.9-7.3). Markers of potential immune checkpoint inhibitor (ICPI) benefit included: CD274 (PD-L1) amplification (1%-3%), BRAF GA (1%-4%), TMB of ≥10 mutations/Mb (8%-12%), MSI-high (0.1%-0.4%), PBRM1 GA (1%), and positive PD-L1 staining of immunocytes ranging from 13% in ER pos /HER2 neg and 33% in ER neg /HER2 amp to 47% in the TNBC group. Potential markers of ICPI resistance included inactivating STK11 GA (1%-2%) and MDM2 amplification (3%-6%). MTOR pathway targets were common with lowest frequency in TNBC. ERBB2 short variant mutations were most frequent ER pos /HER2 neg and absent in TNBC. BRCA1/2 GA were least frequent in ER neg /HER2 amp . The demonstrations of clinical benefit of immunotherapy in MBC support the need for development and utilization of biomarkers to guide the use of ICPIs for these patients. In addition to guiding therapy selection, CGP shows potential to identify GA linked to response and resistance to ICPI in MBC., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Metastatic breast cancer is the leading cause of cancer death in women, but the genomics of metastasis in breast cancer are poorly studied., Methods: We explored a set of 11,616 breast tumors, including 5,034 metastases, which had undergone targeted sequencing during standard clinical care., Results: Besides the known hotspot mutations in ESR1, we observed a metastatic enrichment of previously unreported, lower-prevalence mutations in the ligand-binding domain, implying that these mutations may also be functional. Furthermore, individual ESR1 hotspots are significantly enriched in specific metastatic tissues and histologies, suggesting functional differences between these mutations. Other alterations enriched across all metastases include loss of function of the CDK4 regulator CDKN1B, and mutations in the transcription factor CTCF. Mutations enriched at specific metastatic sites generally reflect biology of the target tissue and may be adaptations to growth in the local environment. These include PTEN and ASXL1 alterations in brain metastases and NOTCH1 alterations in skin. We observed an enrichment of KRAS, KEAP1, STK11 and EGFR mutations in lung metastases. However, the patterns of other mutations in these tumors indicate that these are misdiagnosed lung primaries rather than breast metastases., Conclusions: An order-of-magnitude increase in samples relative to previous studies allowed us to detect novel genomic characteristics of metastatic cancer and to expand and clarify previous findings., Competing Interests: All authors were employees and may have held shares of Genentech/Roche or Foundation Medicine at the time this work was completed. Both companies are involved in the development of cancer drugs and clinical assays for metastatic breast cancer, and have multiple patents in related areas. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy, which has demonstrated sensitivity to immune checkpoint inhibitor therapy. Here, we perform the largest genomics study in MCC to date to characterize the molecular landscape and evaluate for clinical and molecular correlates to immune checkpoint inhibitor response., Experimental Design: Comprehensive molecular profiling was performed on 317 tumors from patients with MCC, including the evaluation of oncogenic mutations, tumor mutational burden (TMB), mutational signatures, and the Merkel cell polyomavirus (MCPyV). For a subset of 57 patients, a retrospective analysis was conducted to evaluate for clinical and molecular correlates to immune checkpoint inhibitor response and disease survival., Results: Genomic analyses revealed a bimodal distribution in TMB, with 2 molecularly distinct subgroups. Ninety-four percent ( n = 110) of TMB-high specimens exhibited an ultraviolet light (UV) mutational signature. MCPyV genomic DNA sequences were not identified in any TMB-high cases (0/117), but were in 63% (110/175) of TMB-low cases. For 36 evaluable patients treated with checkpoint inhibitors, the overall response rate was 44% and response correlated with survival at time of review (100% vs. 20%, P < 0.001). Response rate was 50% in TMB-high/UV-driven and 41% in TMB-low/MCPyV-positive tumors ( P = 0.63). Response rate was significantly correlated with line of therapy: 75% in first-line, 39% in second-line, and 18% in third-line or beyond ( P = 0.0066). PD-1, but not PD-L1, expression was associated with immunotherapy response (77% vs. 21%, P = 0.00598, for PD-1 positive and negative, respectively)., Conclusions: We provide a comprehensive genomic landscape of MCC and demonstrate clinicogenomic associates of immunotherapy response., (©2019 American Association for Cancer Research.)

Background: PD-L1 expression and tumor mutational burden (TMB) have emerged as important biomarkers of response to immune checkpoint inhibitor (ICI) therapy. These biomarkers have each succeeded and failed in predicting responders for different cancer types. We sought to describe the PD-L1 expression landscape across the spectrum of ICI-responsive human cancers, and to determine the relationship between PD-L1 expression, TMB, and response rates to ICIs., Methods: We assessed 9887 clinical samples for PD-L1 expression and TMB., Results: PD-L1 expression and TMB are not significantly correlated within most cancer subtypes, and they show only a marginal association at the tumor sample level (Pearson's correlation 0.084). Across distinct tumor types, PD-L1 expression and TMB have nonoverlapping effects on the response rate to PD-1/PD-L1 inhibitors and can broadly be used to categorize the immunologic subtypes of cancer., Conclusion: Our results indicate that PD-L1 expression and TMB may each inform the use of ICIs, point to different mechanisms by which PD-L1 expression regulates ICI responsiveness, and identify new opportunities for therapeutic development., Funding: Funding was provided by Foundation Medicine Inc., the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, the Viragh Foundation, the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924), the NIH Center Core Grant (P30 CA006973), the Norman & Ruth Rales Foundation, and the Conquer Cancer Foundation.