Purpose: 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 mproved outcomes occur in patients with estrogen receptor-positive (ER positive) BC receiving endocrine therapy and possessing PIK3CA mutations.Materials and Methods: DNA was extracted from 4,540 formalin-fixed paraffin-embedded BC samples from the Exemes-tane Versus Tamoxifen-Exemestane pathology study. Mutational analyses were performed for 25 mutations (PIK3CAx10, AKT1x1, KRASx5, HRASx3, NRASx2 and BRAFx4).Results: 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 (eg, grade 1 node v3, node-negative v-positive), confounding the relationship between mutations and outcome.Conclusion: 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 in uminal 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 a high mutation frequency, PIK3CA mutations do not seem to affect residual risk following treatment with endocrine therapy.

doi.org/10.1200/JCO.2013.53.8272, hdl.handle.net/1765/88637
Journal of Clinical Oncology
Erasmus MC: University Medical Center Rotterdam

Sabine, V. S., Crozier, C., Brookes, C., Drake, C., Piper, T., van de Velde, C., … Bartlett, J. (2014). Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. Journal of Clinical Oncology, 32(27), 2951–2958. doi:10.1200/JCO.2013.53.8272