Abstract GS1-06: Unraveling lobular breast cancer progression and endocrine resistance mechanisms through genomic and immune characterization of matched primary and metastatic samples
Authors: Desmedt C , Richard F , Majjaj S , Pingitore J , Brown D , Rothé F , Marchio C , Clatot F , Mariani O , Boeckx B , Rouas G , Bertucci F , Galant C , Van den Eynden G , Salgado R , Lambrechts D , Vincent-Salomon A , Piccart M , Pruneri G , Larsimont D , Sotiriou C 
Published: May 2019

Abstract
Background:
Invasive lobular breast cancer (ILC) represents the second most common histology of breast cancer, accounts for 10-15% of all invasive cases and generally expresses the estrogen receptor (ER, coded by the ESR1 gene). Little is known about the genomic alterations associated with tumor progression and endocrine resistance in ILC. Here, we therefore molecularly characterized a unique series of matched primary and metastatic ILC.
Patients and methods:
We retrospectively identified 129 metastatic ER-positive ILC patients from 6 institutions. Following central pathology review and available DNA from the primary tumor (P), the metastasi(e)s (M), as well as from normal tissue, 80 patients (279 samples) were eligible for this study. All but 6 patients (7.5%) received endocrine treatment before metastatic sampling. Low pass whole genome and targeted gene screen (N=20 genes) sequencing was conducted to detect copy number aberrations (CNAs) and mutations associated with ILC metastatic progression respectively. ESR1 mutations were further assessed using droplet digital PCR (ddPCR). Publicly available data from IJB (n=413 ILC Ps), TCGA (n=172 ILC Ps), and MSKCC-IMPACT (n=116 ILC Ms) were used to compare and validate the frequencies of the detected alterations in ILC. Stromal tumor infiltrating lymphocytes (TILs) were assessed by two experienced pathologists.
Results:
The overall matched CNA comparison revealed a significant positive association between relapse-free survival and the P/M genomic distance defined by the number of CNAs private to P or M (r2= 0.52, p&lt;.001), suggesting that the longer the disease evolution, the more M differs from P. Regarding CNA changes in cancer genes, we observed the acquisition in M of MYC, CCND1, FGFR1/ZNF703, and ZNF217 amplifications in 17, 9, 6 and 6% of the patients, as well as RB1, PTEN, and TP53 deletions in 9, 11, and 6% of the patients, respectively. The matched P/M comparison of the mutations highlighted the acquisition in M of mutations in 11% of the patients for CDH1, in 10% for ESR1, in 8% for ARID1A, in 5% for ERBB2, GATA3, IGF1R, MAP3K1, and PIK3CA, and in 3% for AKT1 and TBX3. Of interest, when comparing the overall CNA frequencies of our Ms to publicly available data from ILC Ps, we observed a higher frequency of CCND1 and MYC amplification, of PTEN, RB1 and TP53 deletions, as well of AKT1, ERBB2, ESR1 and IGF1R mutations in our ILC Ms. Of note, we did not detect any significant difference in CNA or mutational frequency when comparing our ILC Ms to those from MSKCC-IMPAKT.
Regarding the immune infiltration, higher TILs in Ps were significantly associated with younger age at diagnosis, high grade tumors, and with mixed non-classic and trabecular histology. A paired analysis revealed no significant difference in TIL levels between P and M. TIL levels in the P or M were not associated with survival.
Conclusion:
This is to our knowledge the largest metastatic ILC series in which matched P and M samples were interrogated, revealing several genomic alterations, some of which potentially targetable, driving disease progression and endocrine resistance.
Citation Format: Desmedt C, Richard F, Majjaj S, Pingitore J, Brown D, Rothé F, Marchio C, Clatot F, Mariani O, Boeckx B, Rouas G, Bertucci F, Galant C, Van den Eynden G, Salgado R, Lambrechts D, Vincent-Salomon A, Piccart M, Pruneri G, Larsimont D, Sotiriou C. Unraveling lobular breast cancer progression and endocrine resistance mechanisms through genomic and immune characterization of matched primary and metastatic samples [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS1-06.