43P High intratumoral density of double-positive CD8/GRMZ lymphocytes, BRCAness and elevated TAP2 expression are predictive for improved breast cancer (BC) response to neoadjuvant chemotherapy (NACT)

This study aimed to evaluate the predictive role of immune-related markers, BRCA1 germ-line status and BRCAness phenotype in BC patients undergoing NACT. The study involved 70 BC patients with germline BRCA1 pathogenic alleles [49 triple-negative (TNBC) and 21 hormone receptor-positive (HR+)], 73 BRCA1 wild-type TNBCs and 130 BRCA1 wild-type/HR+ patients. The “inflamed” phenotype was identified by IHC on hematoxylin-eosin stained slides as an abundance of double-positive CD8/GZMB infiltrating lymphocytes (TILs) across the tumor. BRCAness was detected by multiplex PCR and fragment analysis. The expression of critical immune genes (PD1, PD-L1, LAG3, TAP2, IL10B, TGFB, HLA-E, HLA-G) was quantified using RT-PCR. The incidence of “inflamed” immune phenotype was significantly higher in BRCA1 mutation-driven vs. BRCA1 wild-type BCs regardless of tumor hormone receptor status [32% vs. 7%, p = 0.000]. Logistic regression showed that the abundance of CD8/GRMZ TILs was associated with up-regulation of immune checkpoint molecules PD1, PD-L1 and HLA-G [p = 0.07, 0.002 and 0.000, respectively]. Independent predictive markers of tumor response to NACT were “immune-inflamed” vs. “immune dessert” histological appearance [p = 0.014], BRCAness phenotype irrespective of BRCA1 germ-line status [p = 0.026], high expression of antigen presenting-related gene TAP2 [p = 0.08] and age at onset <39 years [p = 0.043]. Tumor immune phenotype is predictive for BC response to NACT in addition to BRCA-related markers.