PIK3CA Mutations in Advanced Cancers: Characteristics and Outcomes
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Filip Janku1, Jennifer J. Wheler1, Aung Naing1, Vanda M. Stepanek1, Gerald S. Falchook1, Siqing Fu1, Ignacio Garrido-Laguna1, Apostolia M. Tsimberidou1, Sarina A. Piha-Paul1, Stacy L. Moulder1, J. Jack Lee2, Rajyalakshmi Luthra3, David S. Hong1, Razelle Kurzrock4
1 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3 Molecular Diagnostic Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4 Moores Cancer Center, The University of California San Diego, La Jolla, California, USA
Filip Janku, email:
Keywords: PIK3CA mutation, phenotypic taxonomy, clinical outcome
Received: October 19, 2012, Accepted: November 30, 2012, Published: November 30, 2012
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.
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