TY - JOUR
T1 - Characterization of stromal tumor-infiltrating lymphocytes and genomic alterations in metastatic lobular breast cancer
AU - Richard, François
AU - Majjaj, Samira
AU - Venet, David
AU - Rothe, Françoise
AU - Pingitore, Julien
AU - Boeckx, Bram
AU - Marchio, Caterina
AU - Clatot, Florian
AU - Bertucci, François
AU - Mariani, Odette
AU - Galant, Christine
AU - van den Eynden, Gert
AU - Salgado, Roberto
AU - Biganzoli, Elia
AU - Lambrechts, Diether
AU - Vincent-Salomon, Anne
AU - Pruneri, Giancarlo
AU - Larsimont, Denis
AU - Sotiriou, Christos
AU - Desmedt, Christine
N1 - Funding Information:
This work has been supported by “Les Amis de Bordet,” the “Fondation contre le cancer” (FAF-C/2016/762), “The Breast Cancer Research Foundation,” and the Belgian Fonds National de la Recherche Scientifique (F.R.S-FNRS). F. Richard is supported by a grant from the “Fondation Cancer Luxembourg” (FC/2018/07). C. Marchio was supported in part by a grant from the Mayent-Rothschild Foundation to Institut Curie.
Funding Information:
C. Marchio reports personal fees from Roche, Bayer, MSD, and Thesaro outside the submitted work. F. Clatot reports personal fees and nonfinancial support from BMS and Merck (outside this work), grants from Astra Zeneca (outside this work), personal fees from Lilly (outside this work), and grants, personal fees, and nonfinancial support from Roche (outside this work) outside the submitted work. A. Vincent-Salomon reports personal fees from Roche, AstraZeneca, and Daichi outside the submitted work. C. Sotiriou reports grants from Fondation Contre le Cancer, Breast Cancer Research Foundation, FNRS, and Les Amis de Bordet during the conduct of the study. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - Purpose: 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. Experimental Design: 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 ¼ 135) and IDC (n ¼ 563) from MSK-IMPACT. Results: 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. Conclusions: 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.
AB - Purpose: 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. Experimental Design: 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 ¼ 135) and IDC (n ¼ 563) from MSK-IMPACT. Results: 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. Conclusions: 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.
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U2 - 10.1158/1078-0432.CCR-20-2268
DO - 10.1158/1078-0432.CCR-20-2268
M3 - Article
AN - SCOPUS:85092463274
VL - 26
SP - 6254
EP - 6265
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 23
ER -