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Figure 1.  Frequency of BRCA1/2 Alteration Across Multiple Tumors and Correlation With Tumor Mutation Burden (TMB)
Frequency of BRCA1/2 Alteration Across Multiple Tumors and Correlation With Tumor Mutation Burden (TMB)

MSKCC indicates Memorial Sloan Kettering Cancer Center; WT, wild type. B, unpaired t test was applied with 2-tailed P value. C, Cochran-Mantel-Haenszel test was applied.

Figure 2.  Prognostic Association of Tumor Mutation Burden (TMB) and BRCA1/2 Alteration in Patients Receiving Immune Checkpoint Inhibitors
Prognostic Association of Tumor Mutation Burden (TMB) and BRCA1/2 Alteration in Patients Receiving Immune Checkpoint Inhibitors

MSKCC indicates Memorial Sloan Kettering Cancer Center; WT, wild type.

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    2 Comments for this article
    BRCA1/2 alteration in TMB-H as a New Cancer Treatment Option
    Takuma Hayashi, MBBS, DMSci, MGRC, PhD | National Hospital Organization Kyoto Medical Center
    The authors hypothesized that BRCA1/2 alteration is associated with TMB and may serve as a novel indicator associated with better treatment outcomes with ICIs.

    In Japan, the immune checkpoint inhibitors pembrolizumab and nivolumab are prescribed for high TMB (TMB-H) (10 and above) cancers. On the other hand, the PARP inhibitor olaparib is prescribed for patients with BRCA1/2 pathogenic variant positive HER2-negative inoperable or recurrent breast cancer; castration-resistant prostate cancer with BRCA1/2 pathogenic variant-positive distant metastases; or as maintenance therapy after chemotherapy containing platinum-based antineoplastic agents in unresectable pancreatic cancer positive for the BRCA1/2 pathogenic variant. In addition, the PARP
    inhibitors olaparib or niraparib are prescribed as maintenance therapy after initial chemotherapy in homologous recombination deficiency (HRD) tumors including BRCA1/2 pathogenic variants-positive ovarian cancer.

    From January 2020 to April 2021, cancer genomic analysis was performed for 766 cases at a national university hospital in Japan. The number of cases with TMB-H (10 or more) was 29 (3.7% 29/776). The number of BRCA1/2 pathogenic variant-positive cases was 37 (4.8% 37/776). In the course of cancer therapy the companion test BRACAnalisis for platinum-sensitive ovarian cancer observed the BRCA1/2 pathogenic variant, therefore olaparib was prescribed for patients with ovarian cancer, resulting in progressive disease (PD). After that, a cancer genome panel test (Foundation 1CDx) has determined that MSI-H is positive, so pembrolizumab has been administered to patients with ovarian cancer.

    In our National Cancer Genome database of medical care that has been carried out at the University Hospital, cases of MSI-H or TMB-H positive in such a BRCA1/2 pathogenic variant positive, is rare. However, in future treatment reviews of cancer genomic medicine, we oncologists must consider the results of this study.

    Disclosure of potential conflicts of interest
    The authors declare no potential conflicts of interest.

    We thank all the medical staffs and co-medical staffs for providing and helping medical research at National Hospital Organization Kyoto Medical Center.

    Dr. Hayashi T. and Dr. Konishi I.
    National Hospital Organization Kyoto Medical Center
    Biomarkers of Immunotherapy Response and Toxicity
    Eleftherios Diamandis, MD, PhD | Mount Sinai Hospital
    Zhou and Li evaluated BRCA1 and BRCA2 as biomarkers of response to immune checkpoint inhibitors (1). They concluded that BRCA2 alterations, in combination with tumor mutational burden, has some potential in this regard.

    Immunotherapy is a revolutionary new treatment for various cancer types. Despite its effectiveness, this therapy suffers from 3 major limitations: 1) high cost; 2) low response rates; and 3) serious and potentially life-threatening side effects. It is thus highly desirable to be able to predict which patients are likely to respond or not respond to these therapies, to optimize and personalize their clinical use. There is
    a great need to identify and validate non-invasive biomarkers in serum that are strong predictors of immunotherapy response or toxicity. This way biomarkers can be measured shortly after treatment initiation with a simple blood test (liquid biopsy) to identify patients who are likely to respond or not respond. With this modality, therapeutic outcomes will be optimized and side effects will be minimized. Recently, we published a comprehensive review of the most promising biomarkers of immunotherapy response and toxicity (2). One class of compounds that seems particularly promising are serum circulating autoantibodies. Presumably, due to intensified immunogenic responses triggered by checkpoint inhibitor therapy, the host produces autoantibodies against tumor-associated antigens (indicative of response) or against non-malignant tissues (indicative of toxicity). Recently, we have shown in a proof-of-principle study that autoantibodies against thyroid peroxidase and thyroglobulin are biomarkers of both response and toxicity in patients treated with pembrolizumab. We also identified a plethora of autoantibodies in a patient treated with durvalumab who developed life-threatening myocarditis (4).

    We expect that many more serum autoantibodies are yet to be discovered, as biomarkers of response and toxicity in patients receiving immune checkpoint inhibitors.


    1. Zhou Z, Li M. Evaluation of BRCA1 and BRCA2 as Indicators of Response to Immune Checkpoint Inhibitors. JAMA Netw Open. 2021;4(5):e217728. doi:10.1001/jamanetworkopen.2021.7728

    2. Music M, Prassas I, Diamandis EP. Optimizing cancer immunotherapy: Is it time for personalized predictive biomarkers? Crit Rev Clin Lab Sci. 2018 Nov;55(7):466-479. doi: 10.1080/10408363.2018.1499706. Epub 2018 Oct 2. PMID: 30277835.

    3. Music M, Iafolla M, Soosaipillai A, Batruch I, Prassas I, Pintilie M, Hansen AR, Bedard PL, Lheureux S, Spreafico A, Razak AA, Siu LL, Diamandis EP. Predicting response and toxicity to PD-1 inhibition using serum autoantibodies identified from immuno-mass spectrometry. F1000Res. 2020 May 7;9:337. doi: 10.12688/f1000research.22715.1. PMID: 33299547; PMCID: PMC7707117.

    4. Aghel N, Gustafson D, Di Meo A et al., Recurrent myocarditis induced by immune-checkpoint inhibitor treatment is accompanied by persistent inflammatory markers despite immunosuppressive treatment. JCO Precision Oncology 2021 :5, 485-491
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    Research Letter
    May 7, 2021

    Evaluation of BRCA1 and BRCA2 as Indicators of Response to Immune Checkpoint Inhibitors

    Author Affiliations
    • 1Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City
    JAMA Netw Open. 2021;4(5):e217728. doi:10.1001/jamanetworkopen.2021.7728

    Immune checkpoint inhibitors (ICIs) have achieved impressive success in a subset of malignant tumors. Tumor mutation burden (TMB), programmed cell death ligand 1 expression, and deficient DNA mismatch repair are the few biomarkers known to be associated with response to ICIs. Breast cancer type 1 or 2 susceptibility gene (BRCA1 [OMIM 113705] and BRCA2 [OMIM 600185]) play critical roles in DNA repair. However, the roles of BRCA1/2 alteration in tumor immunotherapy remains uncharacterized, to our knowledge. Several early phase clinical trials are examining the combination of ICIs and poly(ADP-ribose) polymerase inhibitor in BRCA1/2 altered tumors. The role of BRCA1/2 alteration in immunotherapy remains controversial across different tumor types. We hypothesized that BRCA1/2 alteration is associated with TMB and may serve as a novel indicator associated with better treatment outcomes of ICIs.


    This cohort study was deemed exempt from institutional review board approval and informed consent by the University of Oklahoma Health Sciences Center ethics committee, as only deidentified human samples were used. This study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    BRCA alteration status data were obtained from the cBioPortal platform.1 The included alteration types are missense, nonsense, nonstart, fusion, frame-shift deletion or insertion, in-frame deletion, and splice. Patients in the Memorial Sloan Kettering Cancer Center (MSKCC) cohort who received ICIs and genome sequencing were enrolled in the survival analysis.2 TMB was determined by normalizing the number of nonsynonymous alterations based on the sequenced genome.2 High TMB was defined as the top 10% of TMB in each tumor type, while the bottom 90% was regarded as low TMB.2

    The primary outcome was overall survival (OS), started from the first day receiving ICIs. Kaplan-Meier analysis was performed to compare OS in patients with or without BRCA1/2 alteration, and log-rank test was applied. The significance level was α = .05 for a 2-sided test. Statistical analysis was performed in SPSS version 20.0 (IBM), Prism version 5.0 (GraphPad) and R version 3.6.3 (R Project for Statistical Computing). Data were analyzed from July to November 2020.


    A total of 39 307 tumor samples from 37 259 patients were included in the study, including 1977 patients (5.3%) with a BRCA1/2 alteration. Among them, 164 patients (0.4%) had double alteration, 662 patients (1.8%) had BRCA1 single alteration, and 1151 patients (3.1%) had BRCA2 single alteration. The prevalence of BRCA1/2 alteration across multiple tumor types is presented in Figure 1A. BRCA1/2 altered tumors had higher median (interquartile range [IQR]) TMB (24.59 [9.84-52.14]) than that in wild-type (WT) tumors (5.90 [2.95-10.00]; P < .001) (Figure 1B). A total of 49 patients (34.8%) with BRCA1/2 alteration also had high TMB, while 1399 patients (92.0%) with WT BRCA1/2 had low TMB (P < .001) (Figure 1C).

    A total of 1661 patients in the Memorial Sloan Kettering Cancer Center (MSKCC) cohort who received ICIs and genome sequencing were enrolled in the survival analysis.2 There were 141 patients (8.5%) with BRCA1/2 alteration in the MSKCC immunotherapy cohort. BRCA1 alteration was not associated with OS in the MSKCC cohort (Figure 2A). Patients with BRCA2 altered tumors had better OS than those without (median [IQR] OS, 31.0 [10.0-80.0] months vs 18.0 [6.0-58.0] months; P = .02) (Figure 2B). Patients with low TMB BRCA2 altered tumors had comparable OS with patients with high TMB tumors (median [IQR] OS, 44.0 [10.0-67.0] months vs 41.0 [13.0-80.0] months), and both groups had better OS than patients with low TMB WT BRCA2 tumors (median [IQR] OS, 16.0 [6.0-57.0] months; P < .001) (Figure 2C).


    The findings of this cohort study suggest that BRCA2 alteration in combination with TMB was a potential biomarker associated with response to ICIs. BRCA1/2 altered tumors have shown enhanced immunosurveillance in several preclinical studies, but their correlation with ICI treatment outcomes remains uncharacterized. Early phases of randomized clinical trials have shown promising results of combining poly(ADP-ribose) polymerase inhibitor with ICIs in BRCA1/2 altered tumors.3,4

    This study has some limitations, such as that the role of BRCA2 alteration in immunotherapy in specific tumor type warrants further study. This study includes both pathogenic and undefined variants, which may result in higher alteration rates. Previous studies from our group and others have reported that CXC chemokine receptor 2 (CXCR2) plays critical roles in tumor immune evasion and progression.5,6 Further studies are warranted to pinpoint the specific tumor types that are responsive to ICIs when BRCA2 is altered, and to verify whether the addition of CXCR2 inhibition can further improve survival in these patients.

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    Article Information

    Accepted for Publication: March 8, 2021.

    Published: May 7, 2021. doi:10.1001/jamanetworkopen.2021.7728

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Zhou Z et al. JAMA Network Open.

    Corresponding Author: Min Li, PhD, Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, 975 NE 10th St, BRC 1262A, Oklahoma City, OK 73104 (Min-Li@ouhsc.edu).

    Author Contributions: Drs Zhou and Li had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Both authors.

    Acquisition, analysis, or interpretation of data: Both authors.

    Drafting of the manuscript: Both authors.

    Critical revision of the manuscript for important intellectual content: Both authors.

    Statistical analysis: Zhou.

    Obtained funding: Li.

    Administrative, technical, or material support: Li.

    Supervision: Li.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This work was supported in part by the William and Ella Owens Medical Research Foundation and the Department of Medicine at University of Oklahoma Health Sciences Center.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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