Mutational Analysis of PI3K/AKT Signaling Pathway in Tamoxifen Exemestane Adjuvant Multinational Pathology Study

Authors:
  • VSVicky S. Sabine
    Vicky S. Sabine
  • CCCheryl Crozier
    Cheryl Crozier
  • CBCassandra L. Brookes
    Cassandra L. Brookes
  • CDCamilla Drake
    Camilla Drake
  • TPTammy Piper
    Tammy Piper
  • CVCornelis J.H. van de Velde
    Cornelis J.H. van de Velde
  • AHAnnette Hasenburg
    Annette Hasenburg
  • DKDirk G. Kieback
    Dirk G. Kieback
  • LDLuc Dirix
    Luc Dirix
  • CSCaroline Seynaeve
    Caroline Seynaeve
  • DRDaniel W. Rea
    Daniel W. Rea
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Abstract
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 improved 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 Exemestane 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 v 3, 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 luminal 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.

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