Characterization of stromal tumor-infiltrating lymphocytes and genomic alterations in metastatic lobular breast cancer

ABSTRACT: Purpose Invasive lobular carcinoma (ILC) represents the second most common histological breast cancer subtype after invasive ductal carcinoma (IDC). While primary ILC has been extensively studied, metastatic ILC has been poorly characterized at the genomic and immune level. Experimental design We retrospectively assembled the multi-centric EuroILC series of matched primary and metastatic samples from 94 patients with estrogen receptor (ER)-positive ILC. Stromal tumor infiltrating lymphocytes (sTIL) were assessed by experienced pathologists. Targeted sequencing and low pass whole genome sequencing were conducted to detect mutations and copy number aberrations (CNAs). We compared the frequencies of the alterations in EuroILC with those from patients with ER-positive metastatic ILC (n=135) and IDC (n=563) from MSK-IMPACT. Results Low sTIL levels were observed in ILC metastases, with higher levels in the mixed non-classic histology. Considering ILC metastases from EuroILC and MSK-IMPACT, we observed that >50% of tumors harbor genomic alterations that have previously been associated with endocrine resistance. A matched primary/metastasis comparison in EuroILC revealed mutations (AKT1, ARID1A, ESR1, ERBB2 or NF1) and CNAs (PTEN or NF1 deletion, CYP19A1 amplification) associated with endocrine resistance that were private to the metastasis in 22% (7/32) and 19% (4/21) of patients, respectively. An increase in CDH1, ERBB2, FOXA1 and TBX3 mutations, in CDH1 deletions and a decrease in TP53 mutations was observed in ILC as compared to IDC metastases. Conclusions ILC metastases harbor genomic alterations that may potentially explain endocrine resistance in a large proportion of patients, and present genomic differences as compared to IDC metastases.

PROVIDER: EGAS00001004641 | EGA |

REPOSITORIES: EGA