Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study

• Published in: Journal of clinical oncology Vol. 32; no. 27; pp. 2951 - 2958
• Main Authors: Sabine, Vicky S, Crozier, Cheryl, Brookes, Cassandra L, Drake, Camilla, Piper, Tammy, van de Velde, Cornelis J H, Hasenburg, Annette, Kieback, Dirk G, Markopoulos, Christos, Dirix, Luc, Seynaeve, Caroline, Rea, Daniel W, Bartlett, John M S
• Format: Journal Article
• Language: English
• Published: United States 20.09.2014
• Subjects: Adult; Aged; Androstadienes - administration & dosage; Antineoplastic Agents, Hormonal - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor - genetics; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Class I Phosphatidylinositol 3-Kinases; Disease-Free Survival; DNA Mutational Analysis; DNA, Neoplasm - analysis; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Mutation; Phosphatidylinositol 3-Kinases - genetics; Proto-Oncogene Proteins c-akt - genetics; Signal Transduction - genetics; Tamoxifen - administration & dosage
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2013.53.8272

Deregulation of key PI3K/AKT pathway genes may contribute to endocrine resistance in breast cancer (BC). PIK3CA is the most frequently mutated gene in luminal BC (35%); however, the effect of mutations in helical versus kinase domains remains controversial. We hypothesize that improved outcomes occur in patients with estrogen receptor–positive (ER positive) BC receiving endocrine therapy and possessing PIK3CA mutations. DNA was extracted from 4,540 formalin-fixed paraffin-embedded BC samples from the Exemestane Versus Tamoxifen-Exemestane pathology study. Mutational analyses were performed for 25 mutations (PIK3CAx10, AKT1x1, KRASx5, HRASx3, NRASx2 and BRAFx4). PIK3CA mutations were frequent (39.8%), whereas RAS/RAF mutations were rare (1%). In univariable analyses PIK3CA mutations were associated with significantly improved 5-year distant relapse-free survival (DRFS; HR, 0.76; 95% CI, 0.63 to 0.91; P = .003). However, a multivariable analysis correcting for known clinical and biologic prognostic factors failed to demonstrate that PIK3CA mutation status is an independent prognostic marker for DRFS (HR, 0.92; 95% CI, 0.75 to 1.12; P = .4012). PIK3CA mutations were more frequent in low-risk luminal BCs (e.g., grade 1 nodev 3, node-negative v -positive), confounding the relationship between mutations and outcome. PIK3CA mutations are present in approximately 40% of luminal BCs but are not an independent predictor of outcome in the context of endocrine therapy, whereas RAS/RAF mutations are rare inluminal BC. 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 ahigh mutation frequency, PIK3CA mutations do not seem to affect residual risk following treatment with endocrine therapy.