Volume 6, Issue 2, Pages (January 2014)

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Volume 6, Issue 2, Pages 377-387 (January 2014) Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors Filip Janku, David S. Hong, Siqing Fu, Sarina A. Piha-Paul, Aung Naing, Gerald S. Falchook, Apostolia M. Tsimberidou, Vanda M. Stepanek, Stacy L. Moulder, J. Jack Lee, Rajyalakshmi Luthra, Ralph G. Zinner, Russell R. Broaddus, Jennifer J. Wheler, Razelle Kurzrock Cell Reports Volume 6, Issue 2, Pages 377-387 (January 2014) DOI: 10.1016/j.celrep.2013.12.035 Copyright © 2014 The Authors Terms and Conditions

Cell Reports 2014 6, 377-387DOI: (10.1016/j.celrep.2013.12.035) Copyright © 2014 The Authors Terms and Conditions

Figure 1 PIK3CA Mutations and PTEN Aberrations Proportion of PIK3CA mutations and PTEN aberrations in 1,090 patients who had both PIK3CA and PTEN testing. Cell Reports 2014 6, 377-387DOI: (10.1016/j.celrep.2013.12.035) Copyright © 2014 The Authors Terms and Conditions

Figure 2 PIK3CA and KRAS Mutations PIK3CA mutations are more frequent in tumors with simultaneous KRAS mutations (42/225, 19% versus 89/975, 9%; p < 0.001). Cell Reports 2014 6, 377-387DOI: (10.1016/j.celrep.2013.12.035) Copyright © 2014 The Authors Terms and Conditions

Figure 3 Therapies Targeting the PI3K/AKT/mTOR Pathway Most patients (104, 76%) received mTORC1 inhibitor (rapalog)-based therapy, 20 (15%) received PI3K inhibitor-based therapy, 6 (4.5%) received dual PI3K and mTOR kinase inhibitor-based therapy, and 6 (4.5%) received AKT inhibitor-based therapy. Cell Reports 2014 6, 377-387DOI: (10.1016/j.celrep.2013.12.035) Copyright © 2014 The Authors Terms and Conditions

Figure 4 Waterfall Plot Shows Best Response for Patients with PIK3CA Mutations or PTEN Aberrations Treated with PI3K/AKT/mTOR Inhibitors Of the 136 treated patients, 135 are depicted in the waterfall plot (one patient died of unrelated causes prior to her first restaging). A total of 25 PRs and 33 minor regressions less than PR were observed. The overall PR rate was 18%. Cell Reports 2014 6, 377-387DOI: (10.1016/j.celrep.2013.12.035) Copyright © 2014 The Authors Terms and Conditions

Figure 5 Kaplan-Meier Plot for PFS (A–C) Tick marks represent patients who were progression free at last follow up and are censored at that point. (A) Patients with PIK3CA mutations and/or PTEN aberrations treated with combination therapies (yellow, n = 95) compared to patients treated with single-agent therapies (blue, n = 41) had a longer median PFS (3.0 months, 95% CI 2.0–4.0 versus 1.8 months, 95% CI 1.6–2.0; p < 0.001). (B) Patients with PIK3CA mutations and/or PTEN aberrations and simultaneous KRAS mutations in codon 12 or 13 (yellow) compared to patients without KRAS mutations in codon 12 or 13 (blue) had a shorter median PFS (1.8 months, 95% CI 1.6–2.0 versus 2.9 months, 95% CI 1.9–3.9; p = 0.004). (C) Patients with an H1047R mutation (yellow) compared to patients with other PIK3CA mutations (blue) had a longer median PFS (4.6 months, 95% CI 0.6–8.6 versus 2 months, 95% CI 1.6–2.4; p = 0.03). Cell Reports 2014 6, 377-387DOI: (10.1016/j.celrep.2013.12.035) Copyright © 2014 The Authors Terms and Conditions