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. 2011 Mar;10(3):558-65.
doi: 10.1158/1535-7163.MCT-10-0994. Epub 2011 Jan 7.

PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors

Filip Janku  1 , Apostolia M Tsimberidou, Ignacio Garrido-Laguna, Xuemei Wang, Rajyalakshmi Luthra, David S Hong, Aung Naing, Gerald S Falchook, John W Moroney, Sarina A Piha-Paul, Jennifer J Wheler, Stacy L Moulder, Siqing Fu, Razelle Kurzrock
Affiliations

PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors

Filip Janku et al. Mol Cancer Ther. 2011 Mar.

Abstract

Preclinical data suggest that PIK3CA mutations predict response to PI3K/AKT/mTOR inhibitors. Concomitant KRAS or BRAF mutations may mediate resistance. Therefore, tumors from patients referred to the phase I program for targeted therapy starting in October 2008 were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exons 9 and 20. Consecutive patients with diverse tumor types and PIK3CA mutation were treated whenever possible with agents targeting the PI3K/AKT/mTOR pathway. Overall, PIK3CA mutations were detected in 25 of 217 patients (11.5%; exon 9, n = 11; exon 20, n = 14). In tumor types with more than 10 patients tested, PIK3CA mutations were most frequent in endometrial (3 of 14, 21%), ovarian (5 of 30, 17%), colorectal (9 of 54, 17%), breast (2 of 14, 14%), cervical (2 of 15, 13%), and squamous cell cancer of the head and neck (1 of 11, 9%). Of the 25 patients with PIK3CA mutations, 17 (68%) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor, and 6 (35%) achieved a partial response. In contrast, only 15 of 241 patients (6%) without documented PIK3CA mutations treated on the same protocols responded (P = 0.001). Of the 17 patients with PIK3CA mutations, 6 (35%) had simultaneous KRAS or BRAF mutations (colorectal, n = 4; ovarian, n = 2). Colorectal cancer patients with PIK3CA and KRAS mutations did not respond to therapy, whereas both ovarian cancer patients with PIK3CA and KRAS or BRAF mutations did. In conclusion, PIK3CA mutations were detected in 11.5% of patients with diverse solid tumors. The response rate was significantly higher for patients with PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors than for those without documented mutations.

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Conflict of interest statement

Conflict of Interest: None of the authors have any conflict of interest relevant to the subject of this manuscript.

Figures

Figure 1
Figure 1. Waterfall plot of patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors
Six PRs (5 confirmed) and 6 minor responses less than PR were observed. The overall response rate was 35%. The best response was complete resolution of all measurable disease with persistence of non-measurable disease in a patient with squamous cell cervical carcinoma treated with an mTOR-based regimen. Four patients with colorectal cancer and 1 patient with ovarian cancer had simultaneous KRAS mutations. One patient with ovarian cancer had a simultaneous BRAF mutation.
Figure 2
Figure 2. Computed tomography (CT) scans of responding patients. Red arrows or red circles indicate locations of metastases
A. Patient with endometrial cancer demonstrating partial response in pelvic mass. B. Patient with squamous cell cervical cancer demonstrating partial response in gastrohepatic metastasis. C. Patient with endometrial cancer demonstrating partial response in liver metastases. D. Patient with ovarian cancer demonstrating partial response in pelvic and subcutaneous metastases. E. Patient with ovarian cancer demonstrating partial response in liver and aortocaval metastases.
Figure 2
Figure 2. Computed tomography (CT) scans of responding patients. Red arrows or red circles indicate locations of metastases
A. Patient with endometrial cancer demonstrating partial response in pelvic mass. B. Patient with squamous cell cervical cancer demonstrating partial response in gastrohepatic metastasis. C. Patient with endometrial cancer demonstrating partial response in liver metastases. D. Patient with ovarian cancer demonstrating partial response in pelvic and subcutaneous metastases. E. Patient with ovarian cancer demonstrating partial response in liver and aortocaval metastases.
Figure 2
Figure 2. Computed tomography (CT) scans of responding patients. Red arrows or red circles indicate locations of metastases
A. Patient with endometrial cancer demonstrating partial response in pelvic mass. B. Patient with squamous cell cervical cancer demonstrating partial response in gastrohepatic metastasis. C. Patient with endometrial cancer demonstrating partial response in liver metastases. D. Patient with ovarian cancer demonstrating partial response in pelvic and subcutaneous metastases. E. Patient with ovarian cancer demonstrating partial response in liver and aortocaval metastases.
Figure 2
Figure 2. Computed tomography (CT) scans of responding patients. Red arrows or red circles indicate locations of metastases
A. Patient with endometrial cancer demonstrating partial response in pelvic mass. B. Patient with squamous cell cervical cancer demonstrating partial response in gastrohepatic metastasis. C. Patient with endometrial cancer demonstrating partial response in liver metastases. D. Patient with ovarian cancer demonstrating partial response in pelvic and subcutaneous metastases. E. Patient with ovarian cancer demonstrating partial response in liver and aortocaval metastases.
Figure 2
Figure 2. Computed tomography (CT) scans of responding patients. Red arrows or red circles indicate locations of metastases
A. Patient with endometrial cancer demonstrating partial response in pelvic mass. B. Patient with squamous cell cervical cancer demonstrating partial response in gastrohepatic metastasis. C. Patient with endometrial cancer demonstrating partial response in liver metastases. D. Patient with ovarian cancer demonstrating partial response in pelvic and subcutaneous metastases. E. Patient with ovarian cancer demonstrating partial response in liver and aortocaval metastases.
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