Researchers Identify Genomic Alterations That Drive Disease Progression and Endocrine Resistance in Invasive Lobular Cancer

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Results from the largest metastatic ILC series in which matched primary tumor and metastases samples were interrogated.
Results from the largest metastatic ILC series in which matched primary tumor and metastases samples were interrogated.
The following article features coverage from the San Antonio Breast Cancer Symposium (SABCS) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.

Metastases developed from invasive lobular breast cancer (ILC) acquire copy number alterations (CNAs) and other mutations in multiple genes compared with the primary tumor, according to data presented at the 2018 San Antonio Breast Cancer Symposium in Texas.1

“To our knowledge, this is the largest metastatic ILC series in which matched primary tumor and metastases samples were interrogated,” the authors wrote.

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The second most common histology, ILC represents 10% to 15% of invasive breast cancer cases, but genomic changes associated with metastasis are not well understood. The aim of this study was to characterize these genomic changes between matched primary tumor and metastases.

This multicenter retrospective study included 80 patients with metastatic, estrogen receptor–positive ILC with DNA from both the primary tumor, metastatic sites, and normal tissue. CNAs and genomic mutations were detected using low pass whole genome and targeted sequencing, with droplet digital polymerase chain reaction used to evaluate ESR1 mutations. Publicly available datasets were used to validate the frequencies of genomic alterations in this population.

There was a significant association between the genomic distance of the number of CNAs between the primary tumor and metastatic sites (r2=0.52; P < .001), suggesting that as the disease progresses, metastatic sites increasingly differ from the primary tumor. There were CNA changes acquired by metastatic sites, including amplifications of MYC in 17% of patients, CCND1 in 9%, FGFR1/ZNF703 in 6%, and ZNF217 in 6%, as well as deletions of PTEN in 11%, TP53 in 11%, and RB1 in 9% of patients.

There were also acquired mutations by the metastatic sites, with the most common present in CDH1 in 11% of patients, followed by ESR1 in 10%, ADID1A in 8%, and ERBB2, GATA3, IGF1R, MAP3K1, and PIK3CA each in 5%.

The current population demonstrated a higher CNA frequency of metastatic sites compared with 2 of the 3 publicly available datasets for CCND1 and MYC amplifications, PTEN, RB1, and TP53 deletions, as well as mutations in ERBB2, IGF1R, ESR1, and AKT1.

The study also assessed immune infiltration and demonstrated that higher tumor-infiltrating lymphocyte levels in the primary tumor was associated with higher grade tumors, younger age at diagnosis, and mixed nonclassic and trabecular histology. However, there was no difference in tumor-infiltrating lymphocyte levels between the primary tumor and the metastatic sites.

The authors concluded that these data suggest there are several genomic alterations that are acquired by ILC metastases, which may be targetable.

Read more of Cancer Therapy Advisor's coverage of the SABCS 2018 meeting by visiting the conference page.

Reference

  1. Desmedt C, Richard F, Majjaj S, et al. Unraveling lobular breast cancer progression and endocrine resistance mechanisms through genomic and immune characterization of matched primary and metastatic samples. Presented at: 2018 San Antonio Breast Cancer Symposium; San Antonio, TX: December 4-8, 2018. Abstract GS1-06.

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