Postmenopausal women with early-stage estrogen receptor (ER)-positive, HER2-negative breast cancer whose tumors harbor PIK3CA mutations may derive greater benefit from letrozole than tamoxifen monotherapy, especially if a patient has wild-type CCND1 and TP53, according to findings that will be presented at the 2016 San Antonio Breast Cancer Symposium (SABCS).1
Although next generation sequencing has revealed the diverse mutation profiles of ER-positive, HER2-negative breast cancers, the clinical relevance of these findings remains unclear.
Researchers evaluated for molecular alterations in postmenopausal patients with primary breast cancer who received adjuvant letrozole or tamoxifen as part of the phase 3 BIG 1-98 trial (ClinicalTrials.gov Identifier: NCT00004205) and evaluate associations between these alterations and prognosis.
Using next generation sequencing, researchers found that among 538 samples, there were an average of 11 mutations per sample. A quarter of samples had 13 or more mutations; no tumors were without a mutation.
The most commonly mutated genes were PIK3CA (49.3%), NCOR1 (27.2%), MAP3K1 (23.8%), TP53 (16.6%), CCND1 (17.8%), and GATA3 (17.1%).
TP53 (hazard ratio [HR], 2.16), ARID1A (HR, 2.43), CHEK2 (HR, 2.54), BRCA2 (HR, 1.93), PTEN (HR, 2.03), CCND1 (HR, 1.82), and FGFR1 (HR, 1.78) were significantly associated with shorter distant recurrence-free survival.
PIK3CA was significantly associated with lower risk of distant relapse (HR, 0.64; 95% CI, 0.43-0.97), and increasing number of total mutations was significantly associated with shorter distant recurrence-free survival (HR, 1.04; 95% CI, 1.01-1.07; P = .006).
Patients harboring a PIK3CA mutation derived greater benefit with letrozole vs tamoxifen monotherapy (HR, 0.32; 95% CI, 0.13-0.8) than those without a PIK3CA mutation (HR, 0.70; 95% CI, 0.33-1.48; P = .06). Investigators observed the strongest effect in the subgroup of PIK3CA-mutated patients who were CCND1 and TP53 wild-type (HR, 0.24; 95% CI, 0.12-0.48; P = .02), which had a 5-year relapse rate of 1%.
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These findings could be used to improve prognostic risk classification and to guide future clinical trials of targeted treatments for patients with ER-positive, HER2-negative breast carcinomas.
- 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 to be presented at: 2016 San Antonio Breast Cancer Symposium (SABCS); December 6-10, 2016; San Antonio, TX.