Abstract P3-09-05: Clinical outcome of patients with advanced triple negative breast cancer with germline and somatic variants in homologous recombination gene
Authors: N Stjepanovic, RH Kim, M Wilson, V Mandilaras, H Berman, E Amir, D Cescon, C Elser, S Randall Armel, J McCuaig, A Volenik, R Demsky, H Chow, M Misyura, L Wang, AM Oza, S Kamel-Reid, T Stockley, PL Bedard
Journal: Cancer Research (2017)

Abstract Background: Variants in homologous recombination (HR) genes other than BRCA1/2 may cause a BRCA-like phenotype triple negative breast cancer (TNBC), which includes the sensitivity to platinums and DNA repair inhibitors. Evaluation of HR proficiency may influence the clinical management of TNBC. Our aim was to evaluate germline and somatic HR gene variants in advanced TNBC patients (pts) and clinical outcome. Methods: Our cohort included advanced TNBC pts unselected for family history or age at diagnosis, enrolled in an institutional molecular screening program (NCT01505400). DNA from matched blood and FFPE tumor samples was assessed using a lab developed next generation sequencing Hereditary Cancer Panel (NGS-HCP) that includes all exons of 52 cancer predisposition genes, with 20 HR genes (Illumina MiSeq/NextSeq, germline coverage 100x, somatic coverage 500x). Medical records were reviewed for clinical outcome, pathology and prior germline BRCA1/2 testing results. All pts consented for research on banked samples and return of pathogenic germline variants was optional. Log rank test was used to determine time from surgery with curative intent to relapse (TTR) and overall survival from diagnosis to death (OS) differences based on presence of HR variants. Results: We included 32 pts who consented for return of pathogenic germline variants and had sufficient DNA for NGS-HCP analysis. Median age at diagnosis was 45 years (range 21-80). Initial stages at diagnosis were: I (12.5%), II (62.5%), III (19%) and IV (6%). Germline HR variants were detected in 17 pts (53%) with a median number of variants per patient of 1 (range 0-6). Five pts had likely pathogenic or pathogenic variants in HR genes: BRCA1 (2), BRCA2 (1) FANCC (1) and FANCC + BML (1). Another patient had a BRCA1 pathogenic variant previously detected by Multiplex Ligation-dependent Probe Amplification but was not detected by NGS-HCP. 26 variants of unknown significance (VUS) were identified in 13 HR genes, including FANCA (6), FANCF (3) and BRCA1 (3). Only one patient had a somatic HR variant in FANCA not found in the germline. 30 pts (94%) had somatic TP53 variants. Sporadic somatic BRCA1/2 variants were not seen. BRCA1/2 variants present in the tumor were equivalent to those detected in blood of BRCA1/2 carriers. Median (m) TTR was 17 months (range 1-119) and mOS was 49 months (range 8-123). Presence of likely pathogenic or pathogenic germline variants was not associated with TTR (p=0.78) and OS (p=0.23). Presence of germline VUS, likely pathogenic or pathogenic variants also did not correlate with TTR (p=0.72) and OS (p=0.47) Conclusions: In our cohort of pts with advanced TNBC, 12% had germline pathogenic variants in BRCA1/2, similar to the previously reported rate in early stage TNBC pts. Prevalence of likely pathogenic or pathogenic variants in non-BRCA HR genes was 6%. The presence of germline variants in HR genes was not associated with clinical outcome, however, the number of patients included was small and we had limited power to detect survival differences.Background: Variants in homologous recombination (HR) genes other than BRCA1/2 may cause a BRCA-like phenotype triple negative breast cancer (TNBC), which includes the sensitivity to platinums and DNA repair inhibitors. Evaluation of HR proficiency may influence the clinical management of TNBC. Our aim was to evaluate germline and somatic HR gene variants in advanced TNBC patients (pts) and clinical outcome. Methods: Our cohort included advanced TNBC pts unselected for family history or age at diagnosis, enrolled in an institutional molecular screening program (NCT01505400). DNA from matched blood and FFPE tumor samples was assessed using a lab developed next generation sequencing Hereditary Cancer Panel (NGS-HCP) that includes all exons of 52 cancer predisposition genes, with 20 HR genes (Illumina MiSeq/NextSeq, germline coverage 100x, somatic coverage 500x). Medical records were reviewed for clinical outcome, pathology and prior germline BRCA1/2 testing results. All pts consented for research on banked samples and return of pathogenic germline variants was optional. Log rank test was used to determine time from surgery with curative intent to relapse (TTR) and overall survival from diagnosis to death (OS) differences based on presence of HR variants. Results: We included 32 pts who consented for return of pathogenic germline variants and had sufficient DNA for NGS-HCP analysis. Median age at diagnosis was 45 years (range 21-80). Initial stages at diagnosis were: I (12.5%), II (62.5%), III (19%) and IV (6%). Germline HR variants were detected in 17 pts (53%) with a median number of variants per patient of 1 (range 0-6). Five pts had likely pathogenic or pathogenic variants in HR genes: BRCA1 (2), BRCA2 (1) FANCC (1) and FANCC + BML (1). Another patient had a BRCA1 pathogenic variant previously detected by Multiplex Ligation-dependent Probe Amplification but was not detected by NGS-HCP. 26 variants of unknown significance (VUS) were identified in 13 HR genes, including FANCA (6), FANCF (3) and BRCA1 (3). Only one patient had a somatic HR variant in FANCA not found in the germline. 30 pts (94%) had somatic TP53 variants. Sporadic somatic BRCA1/2 variants were not seen. BRCA1/2 variants present in the tumor were equivalent to those detected in blood of BRCA1/2 carriers. Median (m) TTR was 17 months (range 1-119) and mOS was 49 months (range 8-123). Presence of likely pathogenic or pathogenic germline variants was not associated with TTR (p=0.78) and OS (p=0.23). Presence of germline VUS, likely pathogenic or pathogenic variants also did not correlate with TTR (p=0.72) and OS (p=0.47) Conclusions: In our cohort of pts with advanced TNBC, 12% had germline pathogenic variants in BRCA1/2, similar to the previously reported rate in early stage TNBC pts. Prevalence of likely pathogenic or pathogenic variants in non-BRCA HR genes was 6%. The presence of germline variants in HR genes was not associated with clinical outcome, however, the number of patients included was small and we had limited power to detect survival differences. Citation Format: Stjepanovic N, Kim RH, Wilson M, Mandilaras V, Berman H, Amir E, Cescon D, Elser C, Randall Armel S, McCuaig J, Volenik A, Demsky R, Chow H, Misyura M, Wang L, Oza AM, Kamel-Reid S, Stockley T, Bedard PL. Clinical outcome of patients with advanced triple negative breast cancer with germline and somatic variants in homologous recombination gene [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-09-05.