Abstract P4-04-01: PDL-1 expression in primary breast cancers with germline mutations in BRCA 1 and 2
Authors: Audeh MW , Dadmanesh F , Yearley J 
Published: May 2016

Background: The PD-1/PDL-1 pathway is a major inhibitory regulator of the immune response to tumors. Tumors responding to anti-PD-1 therapy appear to be characterized by a high "load" of somatic mutations, e.g.carcinogen-induced cancers (melanoma, lung) and tumors with a high intrinsic mutation rate (colorectal cancers with defects in DNA mismatch repair).High mutational load in these tumors may cause the expression of neoantigens which may induce an immune response unless the inhibitory PD-1/PDL-1 pathway is upregulated.Tumors in carriers of germline mutations in BRCA1/2 lack effective DNA repair and are genomically unstable, with a high mutational load and the possible expression of neoantigens. Breast cancers arising in carriers of germline mutations in BRCA1 and BRCA2 may rely on the PD-1/PDL-1 pathway to avoid immune destruction. Methods: Samples from thirty (30) treatment-naïve, primary breast cancers from 30 women with known germline mutations in BRCA 1 or BRCA2 were identified by records review in the Cedars-Sinai Department of Pathology, and selected for analysis of PD-1 and PDL-1 expression. Samples were analyzed for PD1 and PDL-1 expression utilizing immunohistochemical staining. Sections from FFPE tissue blocks were analysed with anti-PD-L1 clone 22C3(Merck); anti-PD-L1 clone SP142; or anti-PD-1 clone NAT105. IHC Scoring analyzed both tumor cell and non-tumor cell (inflammatory) infiltrate. A 0-5 scoring system (0= neg, 1 = rare, 2 = low, 3 = mod, 4 = high, 5 = very high) was applied. Tumors with IHC scores of 2 or greater were considered "positive" for expression of PD1 or PDL-1. Clinical Data: Age range 39-90 years, median age 61. Twenty(20) tumors were from BRCA 1 mutations carriers, and 10 were BRCA2. Sixteen (16) were basal type breast cancer (13 BRCA1, 3 BRCA2), 14 were estrogen receptor positive(ER+)(7 BRCA1, 7BRCA2), with 7 Luminal A and 7 Luminal B. There were no HER2 -amplified tumors in the cohort.Results: PD1 expression was observed in 11/30 (37%) of the cohort, and PDL-1 expression was detected in 21/30 (70%) of the cohort. PDL-1 expression was primarily seen in non-tumor, infiltrating immune cells. PDL-1 expression was seen in 15/20 (75%) of tumors from BRCA1 mutation carriers, and 6/10 (60%) of tumors from BRCA2 carriers. PDL-1 expression was present in 13/16 (81%) basal tumors and 8/14 (57%) ER+ tumors. Within the cohort of PDL-1 expressing cancers, 7/21 (33%) were scored as "high" or "very high", 5 basal breast cancers and 2 ER+ cancers. Conclusion: The current study has identified a high rate of PDL-1 expression in untreated primary breast cancers with germline BRCA1 and BRCA2 mutations, regardless of intrinsic subtype. Although the highest rate of expression was seen in basal breast cancers (81%), the majority of ER+ breast cancers, both Luminal A and Luminal B, also expressed PDL-1. Anti-PD-1 therapy has yielded a response rate of 19% in metastatic triple negative breast cancer, unselected for BRCA mutation.The current study suggests that tumors in carriers of germline mutations in BRCA1 or BRCA2 , regardless of intrinsic subtype, may rely on immune checkpoint inhibition for their growth and survival, and that therapy directed against the PD-1/PDL-1 pathway may be of benefit in this cohort of patients.

Citation Format: Audeh MW, Dadmanesh F, Yearley J. PDL-1 expression in primary breast cancers with germline mutations in BRCA 1 and 2. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-01.