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


ABSTRACT:

Background

Invasive lobular carcinoma (ILC) as a disease entity distinct from invasive ductal carcinoma (IDC) has merited focused studies of the genomic landscape, but those to date are largely limited to the assessment of early-stage cancers. Given that genomic alterations develop as acquired resistance to endocrine therapy, studies on refractory ILC are needed.

Patients and methods

Tissue from 336 primary-enriched, breast-biopsied ILC and 485 estrogen receptor (ER)-positive IDC and metastatic biopsy specimens from 180 ILC and 191 ER-positive IDC patients was assayed with hybrid-capture-based comprehensive genomic profiling for short variant, indel, copy number variants, and rearrangements in up to 395 cancer-related genes.

Results

Whereas ESR1 alterations are enriched in the metastases of both ILC and IDC compared with breast specimens, NF1 alterations are enriched only in ILC metastases (mILC). NF1 alterations are predominantly under loss of heterozygosity (11/14, 79%), are mutually exclusive with ESR1 mutations [odds ratio = 0.24, P?20 mutations/mb; P?ConclusionsThis study identifies alteration of NF1 as enriched specifically in mILC. Mutual exclusivity with ESR1 alterations, polyclonality in relapsed ctDNA, and de novo acquisition suggest a role for NF1 loss in endocrine therapy resistance. Since NF1 loss leads to RAS/RAF kinase activation, patients may benefit from a matched inhibitor. Moreover, for an independent subset of mILC, TMB was elevated relative to breast ILC, suggesting possible benefit from immune checkpoint inhibitors.

SUBMITTER: Sokol ES 

PROVIDER: S-EPMC6336006 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Sokol E S ES   Feng Y X YX   Jin D X DX   Basudan A A   Lee A V AV   Atkinson J M JM   Chen J J   Stephens P J PJ   Frampton G M GM   Gupta P B PB   Ross J S JS   Chung J H JH   Oesterreich S S   Ali S M SM   Hartmaier R J RJ  

Annals of oncology : official journal of the European Society for Medical Oncology 20190101 1


<h4>Background</h4>Invasive lobular carcinoma (ILC) as a disease entity distinct from invasive ductal carcinoma (IDC) has merited focused studies of the genomic landscape, but those to date are largely limited to the assessment of early-stage cancers. Given that genomic alterations develop as acquired resistance to endocrine therapy, studies on refractory ILC are needed.<h4>Patients and methods</h4>Tissue from 336 primary-enriched, breast-biopsied ILC and 485 estrogen receptor (ER)-positive IDC  ...[more]

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