Clinical-Pathological Characteristics of HER2+ Breast Cancers patients among BRCA1/2+ carriers tested in Modena Cancer Center.

Background and Objectives Prevalence of HER2 positive breast cancer (BC) in BRCA1/2 carriers is still underestimated. Clinical behaviour of HER2+/BRCA+ BC could be in some ways different from sporadic HER2+ disease. The aim of this research is to describe clinical-pathological characteristics of this rare entity in patients treated at Modena Cancer Center. Methods Between January 2005 and July 2019, 2911 BC patients have been tested for BRCA1/2. 231 (7.9%) and 173 (5.9%) were found positive for BRCA1 and BRCA2 pathogenetic mutations respectively. We considered the HER2+ subgroup (14 patients), focusing on hormone receptor status, IGF-1R expression (semi-quantitative expression by immunohistochemistry with Anti-IGF-1R rabbit monoclonal), PI3K mutation (NGS Sequenom analysis) and clinical characteristics. Results All but one patients received trastuzumab as part of their treatment. Six patients were treated with neoadjuvant chemotherapy (NACT), comprehensive of trastuzumab +/- pertuzumab, achieving a pathological complete response in 33% of cases. Two patients experienced disease recurrence after NACT (median EFS = 5.7 years). From a pathological point of view, the majority of cancers were ductal infiltrating, grading 3 and hormone receptor positive. 3 cases a PI3K mutation was found: in one of them a double mutation (p.R38H + p.E545K) was detected. IGF-1R showed high expression in 2 cases (IHC score 3+), intermediate expression in 2 cases (score 2+), low or absent expression in 3 cases. Interestingly one HER2+/BRCA1 mutated patient shows both PI3K mutation and IGF-1R overexpression, achieving a partial response after NACT and still NED.  Conclusions Here we report a low frequency of HER2+ BC in BRCA1/2 germline carriers. This rate is higher in patients with BRCA2 mutation, accordingly with previous literature. It is not clear, in this peculiar population that displays different possible pathogenetic drivers, which could be the main druggable