TY - JOUR
T1 - BRCA mutations, homologous DNA repair deficiency, tumor mutational burden, and response to immune checkpoint inhibition in recurrent ovarian cancer
AU - Liu, Ying L.
AU - Selenica, Pier
AU - Zhou, Qin
AU - Iasonos, Alexia
AU - Callahan, Margaret
AU - Feit, Noah Z.
AU - Boland, Julia
AU - Vazquez-Garcia, Ignacio
AU - Mandelker, Diana
AU - Zehir, Ahmet
AU - Burger, Robert A.
AU - Powell, Daniel J.
AU - Friedman, Claire
AU - Cadoo, Karen
AU - Grisham, Rachel
AU - Konner, Jason A.
AU - O'Cearbhaill, Roisin E.
AU - Aghajanian, Carol
AU - Reis-Filho, Jorge S.
AU - Weigelt, Britta
AU - Zamarin, Dmitriy
N1 - Publisher Copyright:
© 2020 by American Society of Clinical Oncology
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85091502895&partnerID=8YFLogxK
U2 - 10.1200/PO.20.00069
DO - 10.1200/PO.20.00069
M3 - Article
AN - SCOPUS:85091502895
SN - 2473-4284
VL - 4
SP - 665
EP - 679
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -