Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy

Samstein, Robert M.; Krishna, Chirag; Ma, Xiaoxiao; Pei, Xin; Lee, Ken Wing; Makarov, Vladimir; Kuo, Fengshen; Chung, Jonathan H.; Srivastava, Raghvendra M.; Purohit, Tanaya A.; Hoen, Douglas R.; Mandal, Rajarsi; Setton, J.; Wu, Wei; Shah, Rachna; Qeriqi, Besnik; Chang, Qing; Kendall, Sviatoslav M.; Braunstein, Lior Z.; Weigelt, Britta; Blecua, Pedro; Morris, Luc G.T.; Mandelker, Diana; Reis‐Filho, Jorge S.; Stanchina, Elisa de; Powell, Simon N.; Chan, Timothy A.; Riaz, Nadeem

doi:10.1038/s43018-020-00139-8

Cited by 126 publications

(102 citation statements)

References 83 publications

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“…The genomic instability and increased total mutational load of BRCA -mutated and other HRD tumors results in neoantigens which may increase efficacy of immunotherapy in these tumors[ 11 ]. Recent translational studies have showed that specifically BRCA2 -mutated tumors show increased sensitivity to immune checkpoint blockade as a result of their effect on the tumor immune microenvironment[ 76 ]. This is in line with previous findings of associations between BRCA mutations and PD-L1 expression in PDAC, a predictive marker for immunotherapy[ 77 , 78 ].…”

Section: Management Of Brca-mutated Pdac: Systemic Therapymentioning

confidence: 99%

BRCA mutated pancreatic cancer: A change is coming

Rosen

Goodwin

Vickers

2021

WJG

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Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease. Recently, patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors. Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8% of patients with sporadic pancreatic cancer. In patients with germline BRCA mutations, platinum-based chemotherapies and poly (ADP-ribose) polymerase inhibitors are effective treatment options which may offer survival benefits. This review will focus on the molecular biology, epidemiology, and management of BRCA -mutated pancreatic cancer. Furthermore, we will discuss future directions for this area of research and promising active areas of research.

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Section: Management Of Brca-mutated Pdac: Systemic Therapymentioning

confidence: 99%

BRCA mutated pancreatic cancer: A change is coming

Rosen

Goodwin

Vickers

2021

WJG

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“…and the likely response to immune checkpoint therapy as in this trial. 34 Furthermore, recent clinical trial data on homologous repair-deficient PCa responsiveness to immunotherapy is mixed overall. 30,35 Also, while patients with high CTC heterogeneity had favorable responses in Cohort 1, this trend was not statistically significant in Cohort 2.…”

Section: Statistical Analysesmentioning

confidence: 99%

Nivolumab plus ipilimumab, with or without enzalutamide, in AR‐V7‐expressing metastatic castration‐resistant prostate cancer: A phase‐2 nonrandomized clinical trial

Shenderov

Boudadi

et al. 2021

The Prostate

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Background: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival. Methods: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7-expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-toclinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS). Results: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%)

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“…The distinct tumor-immune microenvironments in BRCA1 and BRCA2 -deficient tumors are modulated by distinct mutational and copy-number profiles, which can predispose to distinct immune checkpoint blockade response. Whole genome sequencing of 4T1 Brca2 null cells revealed an accumulation of single-nucleotide variants (SNVs) and insertions or deletions (indels) compared to 4T1 BRCA1 null cells [ 127 ]. Additionally, others observed that distinct patterns of genomic alterations were associated with BRCA1- and BRCA2 -deficient breast tumors and revealed elevated levels of large rearrangements and tandem duplications in BRCA1 -deficient tumors, and increased SNVs and indels with microhomology in BRCA2 -deficient tumors ( Figure 2 ) [ 128 , 129 ].…”

Section: Future Prospects and Therapeutic Strategies For mentioning

confidence: 99%

“…They retrospectively analyzed a cohort of patients profiled with targeted next-generation sequencing (the MSK-IMPACT) and noted a 44.4% rate of clinical benefit among patients receiving immune checkpoint blockade (ICB) with truncating BRCA2 germline or somatic mutations relative to truncating mutations in BRCA1 (hazard ratio 0.48, 95% CI 0.29–0.80, p = 0.004 for BRCA2 vs. 0.76, 95% CI 0.48–1.54, p = 0.45 in BRCA1 ). [ 127 , 130 ]. These data suggest that the tumor cell-intrinsic differences between BRCA1 and BRCA2 deficiency result in differences in immune landscapes, immune cell infiltration of tumors and distinct resistance mechanisms, and require further investigation for the future clinical trials design.…”

Section: Future Prospects and Therapeutic Strategies For mentioning

confidence: 99%

The Role of BRCA1/2-Mutated Tumor Microenvironment in Breast Cancer

Miklikova

Trnkova

Plavá

et al. 2021

Cancers

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Taking into account the factors of high incidence rate, prevalence and mortality, breast cancer represents a crucial social and economic burden. Most cases of breast cancer develop as a consequence of somatic mutations accumulating in mammary epithelial cells throughout lifetime and approximately 5–10% can be ascribed to monogenic predispositions. Even though the role of genetic predispositions in breast cancer is well described in the context of genetics, very little is known about the role of the microenvironment carrying the same aberrant cells impaired by the germline mutation in the breast cancer development and progression. Based on the clinical observations, carcinomas carrying mutations in hereditary tumor-suppressor genes involved in maintaining genome integrity such as BRCA1/2 have worse prognosis and aggressive behavior. One of the mechanisms clarifying the aggressive nature of BRCA-associated tumors implies alterations within the surrounding adipose tissue itself. The objective of this review is to look at the role of BRCA1/2 mutations in the context of breast tumor microenvironment and plausible mechanisms by which it contributes to the aggressive behavior of the tumor cells.

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Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy

Cited by 126 publications

References 83 publications

BRCA mutated pancreatic cancer: A change is coming

BRCA mutated pancreatic cancer: A change is coming

Nivolumab plus ipilimumab, with or without enzalutamide, in AR‐V7‐expressing metastatic castration‐resistant prostate cancer: A phase‐2 nonrandomized clinical trial

The Role of BRCA1/2-Mutated Tumor Microenvironment in Breast Cancer

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