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. 2013 Dec;12(12):2857-63.
doi: 10.1158/1535-7163.MCT-13-0319-T. Epub 2013 Oct 3.

Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations

Prasanth Ganesan  1 , Filip Janku, Aung Naing, David S Hong, Apostolia M Tsimberidou, Gerald S Falchook, Jennifer J Wheler, Sarina A Piha-Paul, Siqing Fu, Vanda M Stepanek, J Jack Lee, Rajyalakshmi Luthra, Michael J Overman, E Scott Kopetz, Robert A Wolff, Razelle Kurzrock
Affiliations

Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations

Prasanth Ganesan et al. Mol Cancer Ther. 2013 Dec.

Abstract

Target-matched treatment with PI3K/AKT/mTOR pathway inhibitors in patients with diverse advanced cancers with PIK3CA mutations have shown promise. Tumors from patients with colorectal cancer were analyzed for PIK3CA, KRAS, and BRAF mutations. PIK3CA-mutated tumors were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Of 194 patients analyzed, 31 (16%) had PIK3CA mutations and 189 (97%) were assessed for KRAS mutations. Patients with PIK3CA mutations had a higher prevalence of simultaneous KRAS mutations than patients with wild-type PIK3CA (71%, 22/31 vs. 43%, 68/158; P = 0.006). Of 31 patients with PIK3CA mutations, 17 (55%) were treated with protocols containing PI3K/AKT/mTOR pathway inhibitors [median age, 57 years; median number of prior therapies, 4; mTORC1 inhibitors (11), phosphoinositide 3-kinase (PI3K) inhibitors (5), or an AKT inhibitor (1)]. None (0/17) had a partial or complete response (PR/CR) and only 1 [6%, 95% confidence interval (CI), 0.01-0.27] had stable disease 6 months or more, which was not significantly different from a stable disease ≥6 month/PR/CR rate of 16% (11/67; 95% CI, 0.09-0.27) in patients with colorectal cancer without PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors (P = 0.44). Median progression-free survival was 1.9 months (95% CI, 1.5-2.3). In conclusion, our data provide preliminary evidence that in heavily pretreated patients with PIK3CA-mutant advanced colorectal cancer, protocols incorporating PI3K/AKT/mTOR inhibitors have minimal activity. PIK3CA mutations are associated with simultaneous KRAS mutations, possibly accounting for therapeutic resistance.

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Conflict of interest statement

Conflicts of interest/ Disclosure: Filip Janku has research support from Novartis, Roche, Biocartis, Transgenomic, Trovagene. Razelle Kurzrock has research support from GlaxoSmithKline, Novartis, Merck, and Bayer. Scott Kopetz is a consultant for Roche, Sanofi, Amgen, Bristol-Meyers Squibb, Bayer.

Figures

Figure 1
Figure 1
Waterfall plot describing responses per RECIST in 17 patients with metastatic colorectal cancer and PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors
Figure 2
Figure 2
A. Progression-free survival (PFS) in 17 patients with metastatic colorectal cancer and PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors compared to median PFS in the same patients treated with the last FDA-approved therapy for metastatic disease (median PFS of 1.9 months vs. 3.1 months; p=0.1). B. PFS in patients with PIK3CA mutations who received PI3K/AKT/mTOR-directed therapy (n=17) compared to patients without PIK3CA mutations (n=67) treated with same therapies (median PFS of 1.9 months vs. 2.3 months, p=0.44) C. PFS in patients with PIK3CA mutations who received PI3K/AKT/mTOR directed therapy (n=17) compared to patients (n=9) treated with other phase 1 therapies (median PFS of 1.9 months vs. 1.9 months; p=0.77).
See this image and copyright information in PMC

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