Characterization of Stromal Tumor-infiltrating Lymphocytes and Genomic Alterations in Metastatic Lobular Breast Cancer.

Invasive lobular carcinoma (ILC) represents the second most common histologic 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. We retrospectively assembled the multicentric EuroILC series of matched primary and metastatic samples from 94 patients with estrogen receptor (ER)-positive ILC. Stromal tumor-infiltrating lymphocytes (sTILs) 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. Low sTIL levels were observed in ILC metastases, with higher levels in the mixed nonclassic 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 with IDC metastases. ILC metastases harbor genomic alterations that may potentially explain endocrine resistance in a large proportion of patients, and present genomic differences as compared with IDC metastases.

Richard F ，Majjaj S ，Venet D ，Rothé F ，Pingitore J ，Boeckx B ，Marchio C ，Clatot F ，Bertucci F ，Mariani O ，Galant C ，Eynden GVD ，Salgado R ，Biganzoli E ，Lambrechts D ，Vincent-Salomon A ，Pruneri G ，Larsimont D ，Sotiriou C ，Desmedt C ... -  《-》

Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer.

Sokol ES ，Feng YX ，Jin DX ，Basudan A ，Lee AV ，Atkinson JM ，Chen J ，Stephens PJ ，Frampton GM ，Gupta PB ，Ross JS ，Chung JH ，Oesterreich S ，Ali SM ，Hartmaier RJ ... -  《-》

Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets.

Kurozumi S ，Alsaleem M ，Monteiro CJ ，Bhardwaj K ，Joosten SEP ，Fujii T ，Shirabe K ，Green AR ，Ellis IO ，Rakha EA ，Mongan NP ，Heery DM ，Zwart W ，Oesterreich S ，Johnston SJ ... -  《-》

Specific sites of metastases in invasive lobular carcinoma: a retrospective cohort study of metastatic breast cancer.

Inoue M ，Nakagomi H ，Nakada H ，Furuya K ，Ikegame K ，Watanabe H ，Omata M ，Oyama T ... -  《-》

Immune Infiltration in Invasive Lobular Breast Cancer.

Desmedt C ，Salgado R ，Fornili M ，Pruneri G ，Van den Eynden G ，Zoppoli G ，Rothé F ，Buisseret L ，Garaud S ，Willard-Gallo K ，Brown D ，Bareche Y ，Rouas G ，Galant C ，Bertucci F ，Loi S ，Viale G ，Di Leo A ，Green AR ，Ellis IO ，Rakha EA ，Larsimont D ，Biganzoli E ，Sotiriou C ... -  《-》