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. 2020 Jun 16:4:PO.20.00069.
doi: 10.1200/PO.20.00069. eCollection 2020.

BRCA Mutations, Homologous DNA Repair Deficiency, Tumor Mutational Burden, and Response to Immune Checkpoint Inhibition in Recurrent Ovarian Cancer

Ying L Liu  1   2 , Pier Selenica  3 , Qin Zhou  4 , Alexia Iasonos  4 , Margaret Callahan  1   2   5 , Noah Z Feit  1 , Julia Boland  1 , Ignacio Vazquez-Garcia  4 , Diana Mandelker  6 , Ahmet Zehir  6 , Robert A Burger  7 , Daniel J Powell Jr  8 , Claire Friedman  1   2 , Karen Cadoo  1   2 , Rachel Grisham  1   2 , Jason A Konner  1   2 , Roisin E O'Cearbhaill  1   2 , Carol Aghajanian  1   2 , Jorge S Reis-Filho  3 , Britta Weigelt  3 , Dmitriy Zamarin  1   2   5
Affiliations

BRCA Mutations, Homologous DNA Repair Deficiency, Tumor Mutational Burden, and Response to Immune Checkpoint Inhibition in Recurrent Ovarian Cancer

Ying L Liu et al. JCO Precis Oncol. .

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.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Alexia IasonosConsulting or Advisory Role: Mylan, Brightpath, IntelligenciaMargaret CallahanEmployment: Bristol Myers Squibb (I), Celgene (I), Kleo Pharmaceuticals (I) Consulting or Advisory Role: AstraZeneca, Moderna Therapeutics, Merck, Immunocore Research Funding: Bristol Myers Squibb (Inst) Other Relationship: Clinical Care Options, Potomac Center for Medical EducationIgnacio Vazquez-GarciaStock and Other Ownership Interests: CRISPR Therapeutics, Editas MedicineAhmet ZehirHonoraria: IlluminaRobert A. BurgerEmployment: Genentech Stock and Other Ownership Interests: Genentech Consulting or Advisory Role: AstraZeneca, Tesaro, Merck, Genentech, Morphotek, Myriad Genetics Research Funding: Incyte (Inst), Astra Zeneca (Inst), and Genzyme (Inst) Travel, Accommodations, Expenses: Tesaro, GenentechDaniel J. Powell JrStock and Other Ownership Interests: Atara Biotherapeutics, InsTIL Bio Consulting or Advisory Role: Neon Therapeutics, Iovance Biotherapeutics, Tmunity Therapeutics, InsTIL Bio, Bellicum Pharmaceuticals Research Funding: Eli Lilly, Tmunity Therapeutics, Incyte, Monojul, AstraZeneca/MedImmune Patents, Royalties, Other Intellectual Property: I hold patents in the field of chimeric antigen receptor (CAR) T-cell therapy in oncology and have received royalties related to their licensing to Novartis; I hold patents in the field of CAR T cell therapy in Oncology and have received royalties related to their licensing to Tmunity Travel, Accommodations, Expenses: Iovance BiotherapeuticsClaire FriedmanConsulting or Advisory Role: AstraZeneca/MedImmune Research Funding: Bristol Myers Squibb (Inst), Arcus Biosciences (Inst), Genentech (Inst), Merck (Inst) Other Relationship: Guidepoint Global Uncompensated Relationships: Genentech, Merck Open Payments Link: https://openpaymentsdata.cms.gov/physician/477023/summaryKaren CadooHonoraria: OncLive Consulting or Advisory Role: GSK Tesaro Research Funding: AstraZeneca (Inst), Syndax (Inst) Travel, Accommodations, Expenses: AstraZenecaRachel GrishamConsulting or Advisory Role: Mateon Therapeutics, Clovis Oncology, Regeneron Research Funding: Context Therapeutics (Inst) Travel, Accommodations, Expenses: EMD Serono Other Relationship: Prime Oncology, MCM Education, OncLiveJason A. KonnerConsulting or Advisory Role: Immunogen, AstraZeneca, Tesaro, AbbVie Research Funding: Genentech Travel, Accommodations, Expenses: AstraZenecaRoisin E. O'CearbhaillConsulting or Advisory Role: Tesaro, GlaxoSmithKline Research Funding: Juno Therapeutics (Inst), Sellas Life Sciences (Inst), Ludwig Institute for Cancer Research (Inst), Stem CentRx (Inst), TapImmune (Inst), TCR2 Therapeutics (Inst), Regeneron (Inst), Genmab (Inst)Carol AghajanianConsulting or Advisory Role: Tesaro, Mersana, Eisai, Roche Research Funding: Genentech (Inst), AbbVie (Inst), Clovis Oncology (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), AstraZeneca (Inst)Jorge S. Reis-FilhoConsulting or Advisory Role: Genentech, Invicro, Ventana Medical Systems, Volition RX, Paige AI, Goldman Sachs, Novartis, Repare TherapeuticsBritta WeigeltConsulting or Advisory Role: Genentech (I), Invicro (I), Ventana Medical Systems (I), Volition RX (I), Page AI (I), Goldman Sachs (I), Repare Therapeutics (I)Dmitriy ZamarinConsulting or Advisory Role: Merck, Synlogic, Western Oncolytics, Tesaro, Agenus, Trieza Therapeutics, ACM Biolabs Research Funding: Genentech (Inst) Patents, Royalties, Other Intellectual Property: I hold a patent regarding the use of recombinant Newcastle disease virus (NDV) for cancer therapy (Inst) No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Patient selection, BRCA mutations, and genomic analysis. FGA, fraction of genome altered; g, germline; ICI, immune checkpoint inhibition; IMPACT, Integrated Mutation Profiling of Actionable Cancer Targets targeted sequencing; LST, large-scale transition; s, somatic; TMB, tumor mutation burden; WES, whole-exome sequencing.
FIG 2.
FIG 2.
Association of immune checkpoint inhibitor (ICI) response with molecular alterations in ovarian cancer. (A) Somatic mutations in high-grade serous ovarian cancer (HGSOC; left) and non-HGSOC (right). Mutation types, mutational signatures, response to ICI, and BRCA1/2 status are indicated by the labels. (B) Relative percentages of patients with deleterious germline and somatic BRCA1 or BRCA2 mutations in each response group. (C) Differences in progression-free survival (PFS; left) and overall survival (OS; right) from the start of ICI as a function of presence of deleterious germline or somatic BRCA1/2 mutations. (D) Association of homologous DNA repair deficiency (HRD) status (defined by large-scale transition [LST] scores) with response in all patients (left) and the HGSOC-only cohort (right). (E) Association of tumor mutational burden (TMB) with response in all patients (left) and the HGSOC-only cohort (right). (F) Differences in PFS (left) and OS (right) from the start of ICI as a function of HRD status. (G) Differences in PFS (left) and OS (right) from the start of ICI as a function of TMB at a median cutoff. (C, F, and G) Log-rank P value is displayed. NA, not applicable; SNV, single nucleotide variant; WT, wild-type.
FIG 3.
FIG 3.
Association of fraction of genome altered (FGA) with response to immune checkpoint inhibitor (ICI) and survival. (A) FGA by response to ICI (left: overall cohort, right: high-grade serous ovarian cancer [HGSOC] only). (B) Association of FGA with progression-free survival (PFS; left) and overall survival (OS; right) in all overall cancer. Log-rank P values are shown. (C) Association of FGA with PFS (left) and OS (right) in the HGSOC subset only. Log-rank P values are shown. Cutoff of 34%, derived using maximally selected standardized log-rank statistic, was used for survival analysis.
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