PIK3CA Mutations in Advanced Cancers: Characteristics and Outcomes

Rajyalakshmi Luthra,Sarina A. Piha-Paul,Filip Janku,Siqing Fu,Gerald S. Falchook,Stacy L. Moulder,Aung Naing,Ignacio Garrido-Laguna,Apostolia M. Tsimberidou,David S. Hong,Jennifer J. Wheler,Vanda M. Stepanek,Razelle Kurzrock,J. Jack Lee

doi:10.18632/oncotarget.716

Rajyalakshmi Luthra, Sarina A. Piha-Paul

Open Access

https://doi.org/10.18632/oncotarget.716

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Abstract

PIK3CA mutations are frequently diagnosed in diverse cancers and may predict response to PI3K/AKT/mTOR inhibitors. It remains unclear whether they are associated with other characteristics. We analyzed characteristics and outcome of 90 consecutive patients with diverse advanced tumors and PIK3CA mutations and 180 wild-type PIK3CA controls matched by tumor type, gender, and age referred to the Clinical Center for Targeted Therapy. PIK3CA and MAPK mutations (KRAS, NRAS, and BRAF) were analyzed using polymerase chain reaction-based DNA sequencing. The most frequent PIK3CA mutations were E545K (31/90, 34%), E542K (16/90, 18%) in exon 9, and H1047R (20/90, 22%) in exon 20. PIK3CA mutations compared to wild-type PIK3CA were associated with simultaneous KRAS (p=0.047) and MAPK mutations (p=0.03), but only MAPK mutations were confirmed as having an independent association in multivariate analysis. Rates of lung, bone, liver and brain metastases were similar in PIK3CA-mutant and wild-type patients. Patients with PIK3CA mutations treated on trials with PI3K/AKT/mTOR inhibitors had a higher partial/complete response (PR/CR) rate than wild-type PIK3CA patients treated with their best phase I therapy (10/56, 18% vs. 12/152, 8%; p=0.045), but not a prolonged progression-free survival. Patients with H1047R PIK3CA mutations had higher PR/CR rate with PI3K/AKT/mTOR inhibitors compared to wild-type PIK3CA patients treated with their best phase I therapy (6/16, 38% vs. 12/152, 8%; p=0.003). In conclusion, PIK3CA mutations in diverse cancers were not associated with clinical characteristics, but were correlated with MAPK mutations. PIK3CA mutations, especially, H1047R, were associated with attaining a PR/CR to PI3K/AKT/mTOR pathway inhibitors.

Highlights

When analyzing tested mitogenactivated protein kinase (MAPK) mutations, of the 132 patients tested for KRAS, NRAS, and BRAF mutation status, 71 (54%) had KRAS, NRAS or BRAF mutations
In this study of 90 patients with PIK3CA mutations and 180 wt PIK3CA controls we identified having a history of DVT as the only clinical characteristic potentially associated with PIK3CA mutations
In disease-specific subanalyses, in agreement with previous reports, there was a trend toward an association between PIK3CA and KRAS mutations in colorectal cancer (71% vs. 48%, p=0.08); associations between PIK3CA and KRAS (35% vs. 7%, p=0.04), and PIK3CA and MAPK mutations (62% vs. 13%, p=0.02) in ovarian and endometrial cancers.[13, 14]

Summary

Introduction

PIK3CA mutations frequently occur in diverse cancers and are associated with constitutive activation of the PI3K/AKT/mTOR pathway.[1,2,3,4,5] In addition, PIK3CA mutations predicted sensitivity to PI3K/AKT/mTOR inhibitors in multiple tumor types in preclinical and early clinical experiments.[1, 2, 5,6,7,8,9,10,11,12] A seminal question is whether PIK3CA mutations are associated with a distinct phenotypic taxonomy. [13] In addition, our group reported that, regardless of histology, PIK3CA mutations often coexist with mitogenactivated protein kinase (MAPK) mutations, such as mutated KRAS, NRAS, and BRAF.[14] A partial answer to the question posed about the relationship between PIK3CA mutations and specific subtypes of cancer is generally that different cancers seem to have different types of PIK3CA mutations and associations with still other mutations.[15] For example, in colorectal cancer PIK3CA mutations in exon 9, but not exon 20, trended toward an association with KRAS mutations, whereas only PIK3CA exon 20 mutations were associated with KRAS mutations in ovarian cancer.[13, 16] Other oncogenic mutations have been correlated with clinical characteristics and outcome. BRAF mutations predicted poor outcome and KRAS mutations were associated with lung metastases. [13, 18] We investigated characteristics and outcomes of patients with advanced cancers with and without PIK3CA mutations

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