Abstract P3-08-07: Distinct biological signatures describe differences in BRCA mutated subgroups
Authors: Force J , Plichta J , Stashko I , Kimmick G , Westbrook K , Sammons S , Hwang S , Hyslop T , Kauff N , Castellar E , Nair S , Weinhold K , Davis S , Mashadi-Hossein A , Brauer HA , Marcom PK 
Published: May 2019

Background: BRCA mutated (BRCA+) breast cancers are expected to have increased activation of Homologous Recombination Deficiency (HRD) and altered DNA damage repair pathways when compared to BRCA wildtype (BRCA-). To better understand differences in these populations, biological patterns and immune responses to BRCA+ breast cancers were evaluated. The primary aim of our study was to use novel gene expression tools to assess early stage breast cancers with and without germline BRCA mutations, and within distinct BRCA+ subgroups.

Methods: We identified 124 early stage untreated breast cancers with and without BRCA mutations (n = 62 and 62, respectively). Our BRCA- group was matched by hormone receptor (HR) status, age, and stage to the BRCA+ group. The NanoString Breast Cancer 360 panel was applied to RNA isolated from 80 breast tumors (BRCA+ = 39; BRCA- = 41). The BRCA+ group had a BRCA1+ subgroup (n=17) and a BRCA2+ subgroup (n=22).

Results: There was a significant increase in two BC360 signatures in both the BRCA1+ and BRCA2+ tumors compared with the BRCA- population: Prosigna™Risk of Recurrence (ROR) score [BRCA1+: HR: 1.142 (95% CI 1.019, 1.279), p=0.02; BRCA2+: HR: 1.321 (95% CI 1.190, 1.466), p&lt;0.001] and HRD [BRCA1+: HR: 3.576 (95% CI 2.174, 5.880), p=0.02; BRCA2+: HR: 1.801 (95% CI 1.142, 2.840), p&lt;0.001]. BRCA1+ tumors had lower expression of ESR1 [p=0.03], PGR [p=0.02], ER signaling [p&lt;0.001], and differentiation [p=0.005]; while BRCA2+ tumors had lower expression of stroma markers [p=0.02] and inflammatory chemokines [p=0.001]. The two BRCA+ subgroups had distinct molecular subtype correlation trends that were highly significant. BRCA1+ tumors were positively associated with a basal subtype [p&lt;0.001], whereas this association was not significant for BRCA2+ tumors. BRCA2+ tumors were associated with an increase in luminal B subtype [p=0.05]. All BRCA+ tumors had a decrease in luminal A subtype correlation [BRCA1+: p&lt;0.001; BRCA2+: p=0.002]. In addition to the BC360 signatures, a differential analysis of all genes in the BC360 panel revealed more single gene differences in BRCA2+ than BRCA1+ tumors when compared to BRCA- tumors.

Conclusions: In early stage BRCA+ breast cancer, tumors have higher ROR and increased HRD signature scores compared to BRCA- tumors. Furthermore, BRCA1+ and BRCA2+ tumors have both signature and single gene expression differences when compared to BRCA- tumors, indicating distinct subgroup-related biology. The greater correlation of BRCA1+ tumors with basal-like biology and BRCA2+ tumors with aggressive hormonal biology confirms these trends. Distinctions in hormone receptor signaling, DNA-damage pathways, and microenvironment/inflammatory features between BRCA1 and BRCA2 associated cancers suggest a need for different prevention and therapeutic strategies for each of these breast cancer subtypes. The unique biological patterns identified here should be further evaluated as predictive or prognostic tools that could be translated into clinical care for early stage BRCA+ patients.

Citation Format: Force J, Plichta J, Stashko I, Kimmick G, Westbrook K, Sammons S, Hwang S, Hyslop T, Kauff N, Castellar E, Nair S, Weinhold K, Davis S, Mashadi-Hossein A, Brauer HA, Marcom PK. Distinct biological signatures describe differences in BRCA mutated subgroups [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-07.