Somatic ER+ Breast Cancer Mutations Predict Worse Patient Outcomes

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Gene mutation status is prognostic for postmenopausal women with early-stage estrogen receptor-positive (ER+) breast cancer.
Gene mutation status is prognostic for postmenopausal women with early-stage estrogen receptor-positive (ER+) breast cancer.

Gene mutation status is prognostic for postmenopausal women with early-stage estrogen receptor-positive (ER+), HER2-negative breast cancer, according to findings from the BIG 1-98 (ClinicalTrials.gov Identifier: NCT00004205) trial, presented at the 2016 San Antonio Breast Cancer Symposium.

“Genetic alterations often co-exist with each other,” reported lead study author Sherene Loi, MD, PhD, associate professor at Peter MacCallum Cancer Centre in Victoria, Australia. “Higher numbers of alterations were associated with significantly worse outcomes. The PIK3CA mutant group demonstrated molecular heterogeneity but in general had a better outcome.”

TP53 mutation, MYC amplifications, 8p11 (FGFR1) and 11q13 (CCND1) were associated with more proliferative, aggressive tumor phenotypes.

Next generation sequencing studies have uncovered diverse primary tumor mutation profiles in breast cancers but their clinical relevance is poorly understood, Dr Loi said.

There is an urgent need to identify ways to use this information to help patients, “particularly with ER+ disease,” she said.

Dr Loi's team evaluated the prognostic and predictive value of somatic gene mutations among post-menopausal women with early-stage ER+/HER2-negative breast cancer who were treated with adjuvant letrozole and/or tamoxifen. BIG 1-98 enrolled 8010 women and assigned them to receive tamoxifen, letrozole, tamoxifen-then-letrozole, or letrozole-then-tamoxifen, for 5 years.

At a median followup of 8.1 years, the study revealed an 18% reduction in the risk of tumor recurrence or death, and a 21% reduction in risk of death associated with letrozole, Dr Loi said.

Tumor DNA was extracted from archival samples and sequenced at the exons of 286 known cancer genes. More than 600 patients were excluded from the analysis because of poor quality or insufficient quantity of DNA. Evaluable data was assessed for 538 study participants.

“Only somatic variants that were predicted to be ‘known oncogenic' or ‘likely oncogenic' genes were used in the analyses,” she said.

PIK3CA mutations are often mutually exclusive from amplifications,” whereas gene amplifications commonly occurred together, noted Dr Loi. “TP53 mutations commonly occur along with amplifications.”

RELATED: Biomarkers and MammaPrint Status Predict Breast Cancer Response to Veliparib and Carboplatin

PIK3CA genotype was significantly associated with lower recurrence rates. Among patients with no prior chemotherapy, PIK3CA mutant genotype interacted with letrozole (5-year distant tumor recurrence-free with letrozole: 99% vs 94% for tamoxifen).

Reference

  1. Loi S, Asher R, Lee CK, et al. Clinical implications of somatic mutations in post-menopausal early-stage estrogen receptor (ER)-positive HER2-negative breast cancer (BC): Results from the BIG 1-98 study. Paper presented at: 39th San Antonio Breast Cancer Symposium; Dec 2016; San Antonio, TX.

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