BRCA mutations, homologous DNA repair deficiency, tumor mutational burden, and response to immune checkpoint inhibition in recurrent ovarian cancer Journal Article
| Authors: | Liu, Y. L.; Selenica, P.; Zhou, Q.; Iasonos, A.; Callahan, M.; Feit, N. Z.; Boland, J.; Vazquez-Garcia, I.; Mandelker, D.; Zehir, A.; Burger, R. A.; Powell, D. J. Jr; Friedman, C.; Cadoo, K.; Grisham, R.; Konner, J. A.; O'Cearbhaill, R. E.; Aghajanian, C.; Reis-Filho, J. S.; Weigelt, B.; Zamarin, D. |
| Article Title: | BRCA mutations, homologous DNA repair deficiency, tumor mutational burden, and response to immune checkpoint inhibition in recurrent ovarian cancer |
| Abstract: | PURPOSE Homologous DNA repair-deficient (HRD) ovarian cancers (OCs), including those with BRCA1/2 mutations, have higher levels of genetic instability, potentially resulting in higher immunogenicity, and have been suggested to respond better to immune checkpoint inhibitors (ICIs) than homologous DNA repair-proficient OCs. However, clinical evidence is lacking. The study aimed to evaluate the associations between BRCA1/2 mutations, HRD, and other genomic parameters and response to ICIs and survival in OC. METHODS This is a single-institution retrospective analysis of women with recurrent OC treated with ICIs. BRCA1/2 mutation status and clinicopathologic variables were abstracted from the medical records. Targeted and whole-exome sequencing data available for a subset of patients were used to assess tumor mutational burden (TMB), HRD, and fraction of genome altered (FGA). ICI response was defined as lack of disease progression for ≥ 24 weeks. Associations of BRCA1/2 status and genomic alterations with progression-free survival (PFS) and overall survival (OS) were determined using Cox proportional hazards models. RESULTS Of the 143 women treated with ICIs, 134 had known BRCA1/2 mutation status. Deleterious germline or somatic BRCA1/2 mutations were present in 31 women (24%). There was no association between presence of BRCA1/2 mutations and response (P =.796) or survival. Genomic analysis in 73 women found no association between TMB (P =.344) or HRD (P =.222) and response, PFS, or OS. There were also no significant differences in somatic genetic alterations between responders and nonresponders. High FGA was associated with an improvement in PFS (P =.014) and OS (P =.01). CONCLUSION TMB, BRCA1/2 mutations, and HRD are not associated with response or survival, cautioning against their use as selection criteria for ICI in recurrent OC. FGA should be investigated further as a biomarker of response to immunotherapy in OC. © 2020 by American Society of Clinical Oncology |
| Journal Title: | JCO Precision Oncology |
| Volume: | 4 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2020-06-16 |
| Start Page: | 665 |
| End Page: | 679 |
| Language: | English |
| DOI: | 10.1200/po.20.00069 |
| PROVIDER: | scopus |
| PMCID: | PMC7446408 |
| PUBMED: | 32923884 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2020 -- Source: Scopus |
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