Cancer Genetics Highlight Mutations Linked to Drug Response

A range of somatic driver alterations has been described in estrogen receptor–positive, HER2-negative (ER+/HER2−) early breast cancer (BC); however, the clinical relevance is unknown.

The associations of driver alterations with prognosis and the role of Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha, (PIK3CA) mutations in prediction of benefit associated with endocrine therapy in postmenopausal patients with ER+/HER2− early BC treated with tamoxifen or letrozole has been investigated.

A team of scientists collaborating with the University of Melbourne (Melbourne, Australia) randomized 8,010 postmenopausal patients with hormone receptor–positive, operable, invasive BC to monotherapy with letrozole, tamoxifen, or a sequential strategy for five years. Driver alterations were characterized using next-generation sequencing in primary tumors from a subset of 764 patients from 7,329 eligible patients with ER+/HER2− BC, with 841 distant recurrences after a median of 8.1 years of follow-up. To correct for the oversampling of distant recurrences, weighted analysis methods were used. This analysis was conducted from April 4, 2016, to November 30, 2016.

The team found that of 764 samples, 538 (70.4%), including 140 distant recurrence events, were successfully sequenced. Nineteen driver alterations were observed with 5% or greater frequency, with a mean of four alterations (range, 0-15) per tumor. PIK3CA mutations were the most common (49%) and were significantly associated with reduction in the risk for distant recurrence. Tumor protein p53 (TP53) mutations, amplifications on 11q13 and 8p11, and increasing number of driver alterations were associated with significantly greater risk. Amplifications on 11q13 and 8p11 remained significant predictors in multivariable analysis, but not PIK3CA and TP53 mutations. Patients with tumors harboring kinase or helical domain PIK3CA mutations derived significantly greater benefit from letrozole over tamoxifen than patients whose tumors did not.

The authors concluded that DNA-based classifications have promise to add to current prognostic markers and aid adjuvant treatment decisions in ER+/HER2- disease. In ER+/HER2− postmenopausal, early-stage BC, amplifications on 11q13 and 8p11 were significantly associated with increased risk for distant recurrence and PIK3CA mutations were predictive of greater magnitude of benefit from letrozole. The study was published originally published online on June 14, 2018, in the journal JAMA Oncology.

Related Links:
University of Melbourne