Somatic Driver Alterations and Distant Recurrence in Postmenopausal Early Breast Cancer Patients Receiving Endocrine Therapy


Key Points

  • Amplifications on 11q13 and 8p11 were significantly associated with increased risk for distant recurrence.
  • Letrozole was associated with benefit vs tamoxifen in patients PIK3CA mutation.

In an analysis from the BIG 1-98 trial reported in JAMA Oncology, Luen et al found that 11q13and 8p11 amplifications were associated with an increased risk of distant recurrence among patients with postmenopausal hormone receptor–positive, HER2-negative breast cancer receiving adjuvant endocrine therapy.  PIK3CA mutation was associated with relative benefit of letrozole vs tamoxifen.

In the trial, 8,010 postmenopausal patients with hormone receptor–positive operable invasive disease were randomized to letrozole, tamoxifen, or a sequential treatment strategy for 5 years. Driver alterations were identified with next-generation sequencing in primary tumors from a subgroup of 764 patients from 7,329 eligible patients with estrogen receptor (ER)-positive, HER2-negative disease who had 841 distant recurrences after a median follow-up of 8.1 years.

Weighted analysis methods were used to correct for oversampling of distant recurrences. Multivariate analyses were performed to adjust for clinicopathologic factors. 

Associations With Distant Recurrence

Among the 764 samples, 538 (70.4%), including 140 distant recurrences, were successfully sequenced. A total of 19 somatic driver alterations were observed with ≥ 5% frequency, with a mean of 4 alterations per tumor (range = 0–15). The most common alteration was PIK3CA mutation, with presence of these mutations being associated with a reduced risk of distant recurrence (hazard ratio [HR] = 0.57, P = .006).

An increased risk of distant recurrence was associated with TP53 mutations (HR = 1.92, P = .006), amplifications on 11q13 (HR = 2.14, P = .001), amplifications on 8p11 (HR = 3.02, P < .001), and an increasing number of driver alterations (HR per additional alteration = 1.18, P < .001). In multivariate analysis, amplifications on 11q13 (HR = 1.72, P = .01) and 8p11 (HR = 2.0, P = .004) and number of alterations (HR = 1.11, P = .002), but not PIK3CA or TP53 mutations, remained significant predictors of distant recurrence.

Among 114 patients with kinase or helical domain PIK3CA mutation, those who received letrozole exhibited benefit vs tamoxifen (HR = 0.18, 95% confidence interval [CI] =0.06–0.50) compared with outcome among 184 patients without such mutations (HR = 1.26, 95% CI = 0.65–2.45; P for interaction = .002).

The investigators concluded, “In ER-positive/HER2-negative postmenopausal, early-stage [breast cancer], 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. With these findings, DNA-based classification may aid adjuvant treatment decision making in this setting.”

The study was funded by Novartis and by Susan G. Komen for the Cure.

Sherene Loi, MD, PhD, of Peter MacCallum Cancer Centre, University of Melbourne, is the corresponding author for the JAMA Oncology article.

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