PIK3CA Mutation Does Not Predict Outcome in Patients With Luminal Breast Cancer Receiving Endocrine Therapy
In a study reported in the Journal of Clinical Oncology, Sabine et al found that PIK3CA mutation was not an independent predictor of distant relapse-free survival among postmenopausal women with estrogen receptor–positive breast cancer receiving endocrine therapy in the TEAM (Exemestane Versus Tamoxifen-Exemestane) trial. There is clinical evidence suggesting that PIK3CA-mutant breast cancers represent an endocrine-responsive phenotype. The investigators had hypothesized that survival would be increased in patients with PIK3CA mutation but not in those with coordinate PIK3CA/RAS mutations, which have been associated with relapse during endocrine therapy.
The TEAM trial is an open-label phase III trial in which 9,776 postmenopausal women with hormone receptor–positive luminal early breast cancer were randomly assigned to receive exemestane or tamoxifen once daily for the first 2.5 to 3 years followed by exemestane for a total of 5 years of treatment.
Mutation Status
In the TEAM pathology study, DNA was extracted from 4,540 formalin-fixed paraffin-embedded samples. The primary outcome measure was distant relapse-free survival. PIK3CA mutations were found in 39.8% of patients. RAS pathway mutations were extremely uncommon (RAS/RAF mutations in < 1% of patients), indicating that coordinate PIK3CA/RAS mutations were not drivers of de novo endocrine resistance in this setting.
No Significant Effect of PIK3CA Mutation
In univariate analysis, PIK3CA mutations were associated with significantly improved 5-year distant relapse-free survival (91% vs 88%, hazard ratio [HR] = 0.76, P = .003). However, in multivariate analysis adjusting for predictive clinical and biologic factors, there was no significant association between PIK3CA mutation status and distant relapse-free survival (HR = 0.92, P = .4012). Analysis of disease-free survival provided similar results. PIK3CA mutations were more common in low-risk cancers (eg, lower tumor grade, node-negative disease), potentially confounding the relationship between mutation and outcome.
There was no evidence of a tamoxifen then exemestane vs exemestane alone treatment effect in the association of mutation status with distant relapse-free survival (HR = 1.02, 95% confidence interval = 0.71–1.47 for interaction). No difference in predictive ability was observed for PIK3CA mutations located in helical vs kinase domains.
The investigators concluded: “PIK3CA mutations are present in approximately 40% of luminal [breast cancers] but are not an independent predictor of outcome in the context of endocrine therapy, whereas RAS/RAF mutations are rare in luminal [breast cancer]. A complex relationship between low-risk cancers and PIK3CA mutations was identified. Although the PI3K/AKT pathway remains a viable therapeutic target as the result of a high mutation frequency, PIK3CA mutations do not seem to affect residual risk following treatment with endocrine therapy.”
John M.S. Bartlett, PhD, of the Ontario Institute for Cancer Research, Toronto, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the Ontario Ministry of Research and Innovation. The TEAM trial is supported by Pfizer. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
