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Genomic and Clinical Landscape of Metastatic HR+ Breast Cancers With ESR1 Alterations
TAKE-HOME MESSAGE
- This analysis evaluated the clinical and genomic landscape of endocrine therapy–resistant metastatic ER+/HER2− breast cancer. ESR1 mutations represented approximately 20% of tumors and were enriched in liver metastasis. Patients with invasive lobular cancer carried a lower frequency of ESR1 mutations than those with invasive ductal cancer. The mutual exclusivity between ESR1 mutations and genetic alterations occurring in CDH1 suggested that invasive lobular cancer may leverage non–estrogen-related genomic pathways to acquire endocrine therapy resistance.
- ESR1-mutant ER+/HER2− breast cancer displays a peculiar genetic landscape and distinct genomic signatures. Potentially actionable genetic alterations are differently distributed according to the presence of ESR1 alterations. ER+/HER2− breast cancer carrying the ESR1 p.E380Q mutation might be particularly susceptible to the use of immunotherapy.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Somatic genetic alterations of the estrogen receptor 1 gene (ESR1) are enriched in endocrine therapy-resistant, estrogen receptor-positive (ER+) metastatic breast cancer (mBC). Herein, we investigated and compared the clinical and genomic landscape of ESR1-mutant (ESR1MUT) and ESR1 wild type (ESR1WT) ER+/ human epidermal growth factor receptor 2 (HER2)- mBCs.
METHODS
Clinical and genomic data were retrieved from cBioPortal using the publicly-available MSK MetTropism dataset. Metastatic, ER+/HER2- mBC samples were included in the analysis. Only oncogenic and likely oncogenic alterations according to OncoKB were included. Statistical analyses were carried out using alpha level of 0.05, with a false discovery rate threshold of 10% for multiple comparisons using the Benjamini-Hochberg method.
RESULTS
Among 679 samples, 136 ESR1MUT among 131 tumors were found (19.2%). The frequency of ESR1MUT was higher in ductal versus lobular mBC (21.2% versus 13.8%, P = 0.052) and enriched in liver metastasis compared with other sites (22.5% versus 12.7%; q = 0.02). Compared with ESR1WT mBC, ESR1MUT tumors showed higher fraction of genome altered (FGA) {[0.28 interquartile range (IQR), 0.15-0.43] versus 0.22 (0.11-0.38); P = 0.04} and tumor mutational burden (TMB) [4.89 (IQR 3.46-6.85) versus 3.92 (2.59-6.05) mut/Mb; P = 0.001]. Tumors harboring p.E380X alterations showed higher TMB compared with those with H11-12 alterations [8.24 (IQR 5.06-15.3) versus 4.89 (IQR 3.46-6.75) mut/Mb; P = 0.01]. Genetic alterations of TP53 were enriched in ESR1WT tumors (36% versus 14%) [odds ratio (OR) 3.17, 95% confidence interval (CI) 1.88-5.64, q = 0.001]. Considering signaling pathways, ESR1MUT tumors showed a lower occurrence of TP53 (OR 0.48, 95% CI 0.30-0.74; q = 0.003) and MAPK (OR 0.29, 95% CI 0.11-0.65; q = 0.009) alterations. TP53 (q < 0.001), CDH1 (q < 0.001), and ERBB2 (q < 0.001) demonstrated mutual exclusivity with ESR1MUT.
CONCLUSIONS
ER+/HER2- mBCs carrying ESR1MUT exhibit a divergent genomic background, characterized by a lower prevalence of TP53 and MAPK pathway alterations. Less common ESR1 alterations falling outside the H11-H12 region seem to occur in tumors with higher TMB, deserving further investigation to understand their potential actionability.
Additional Info
Genomic and clinical landscape of metastatic hormone receptors-positive breast cancers carrying ESR1 alterations
ESMO Open 2024 Oct 01;9(10)103731, L Boscolo Bielo, E Guerini Rocco, D Trapani, P Zagami, B Taurelli Salimbeni, A Esposito, C Belli, E Crimini, K Venetis, E Munzone, N Fusco, C Criscitiello, A Marra, G CuriglianoFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.