PD-1 and PD-L1 Expression in HER2-Positive Breast Carcinomas

Background: HER2 amplification is found in 20-30% of breast carcinomas and is associated with a poor prognosis. While treatment with anti-HER2 therapies has improved outcomes within this group, a subset of these tumors develop resistance urgently requiring novel therapeutic options. In addition to the classic HER2+ subtype, Luminal B tumors are another subtype of HER2-positive breast carcinomas which could benefit from new therapies. Targeting the PD-1 and PD-L1 axis may represent a potential new therapeutic strategy in breast carcinoma, especially in aggressive tumor subtypes. In this study, we evaluated expression of PD-1 and PD-L1 in both the tumor cells and tumor-infiltrating lymphocytes (TILs) in the classic HER2+ and the Luminal B subsets of HER2-positive breast carcinomas. Design: The study population consisted of 114 patients with HER2-positive invasive breast carcinoma diagnosed from 2009-2014 (mean age: 53, range 18-80). Slides with tumor from each case were stained with PD-1 and PD-L1. The extent of staining (0%=0, 1-10%=1, 11-50%=2, and 51-100%=3) and staining intensity (0, 1+, 2+, 3+) were assessed in both the tumor cells and TILs. Then a composite score (CS) was calculated multiplying the extent and intensity results (range 0-9; 0-3=negative, 4-9=positive). Results: Overall, PD-1 was positive in TILs in 57/114 cases (50%). 28/54 (52%) of TILs in HER2+ tumors and 29/60 (48%) in Luminal B tumors expressed PD-1. None of the cases examined expressed PD-1 in the tumor cells. As a group, PD-L1 was positive in the tumor cells in 10/114 (8.8%); of those, 6 were HER2+ cases (6/54, 11%) and 4 were Luminal B cases (4/60, 6.7%). Of interest, PD-L1 was expressed in 37/114 (32.4%) of the TILs. Notably, TILs expressed PD-L1 in 23/54 cases (43%) in the HER2+ subgroup while only 14/60 (23%) expressed PD-L1 in the Luminal B subgroup (p= 0.04). Finally, PD-L1 expression in TILs was more common in grade 3 tumors (30/83, 36%) than in grade 2 tumors (7/31, 23%). Conclusions: 1. PD-L1 is expressed in TILs in almost half of HER2+ tumors and a quarter of Luminal B tumors. 2. PD-L1 is only rarely seen in the tumor cells in these two HER2-positive subtypes. 3. PD-1 is expressed in 50% of the TILs but is not present in the tumor cells of any of our cases. 4. PD-L1 in TILs is more common in grade 3 carcinomas. Our findings add to the understanding of the role of host/tumor microenvironment in the classic HER2+ and Luminal B subtypes of breast tumors and raise the possibility that targeted immune-based therapeutic strategies may show a benefit against these aggressive breast carcinomas.