Abstract B191: Target-matched therapies in patients with advanced cervical cancers harboring PIK3CA mutations and/or PTEN loss.

Purpose: To evaluate whether PIK3CA mutations and/or PTEN loss predict better clinical outcomes to phase I trials of PI3K/AKT/mTOR inhibition-based therapies in patients with metastatic, recurrent or refractory cervical cancers. Methods: Outcome analyses were conducted on 36 consecutive patients with advanced cervical cancers who were initially seen in a designated Phase I clinic at MD Anderson Cancer Center from 1/1/2006 to 6/30/2012, and tested for PIK3CA mutations and/or PTEN loss in a CLIA-certified molecular diagnostic laboratory, in accordance with the IRB guidelines. All data were obtained from patients’ electronic medical records. Results: All patients (n=36) had received at least one systemic therapy before the referral. Approximately 50% of tested patients (n=18/36) harbored PIK3CA mutations (n=9/34, 26% including seven E545K, one E542K, and one E545K/D549H in squamous cell carcinoma [7/19, 37%], adenocarcinoma [1/12, 8%] and small cell carcinoma [1/1, 100%]) and/or PTEN loss (n=12, 63%). Six patients were removed from further analyses because they did not enroll to a phase I study (n=2) or had only one negative result while the other test was not done (n=4). At their initial phase I therapy, the patients with PIK3CA mutations and/or PTEN loss (n=18) achieved four PR and seven SD ≥ 6 months (61% CR/PR/SD≥6months) with a median progression-free survival (PFS) of 6.7 months, compared to one CR and one SD ≥ 6 months (17% CR/PR/SD≥6months, p=0.026) with a median PFS of 2.5 months (p=0.001) in patients without PIK3CA mutations and/or PTEN loss (n=12). Analyses in patients receiving mTOR inhibitor-based phase I regimens showed that patients with PIK3CA mutations and/or PTEN loss (n=10) achieved three PR and four SD ≥ 6 months (70% CR/PR/SD≥6months) with a median PFS of 6.6 months, compared to one SD ≥ 6 months (17% CR/PR/SD≥6months, p=0.119) with a median PFS of 3.2 months (p=0.014) in patients without PIK3CA mutations and/or PTEN loss who received mTOR inhibitor-based phase I regimens (n=6); or one PR and three SD ≥ 6 months (50% CR/PR/SD≥6months, p=0.63) with a median PFS of 5.3 months (p=0.86) in patients with PIK3CA mutations and/or PTEN loss who did not receive mTOR inhibitor-based phase I regimens (n=8). Conclusions: The most frequent PIK3CA mutation in patients with advanced cervical cancers was E545K. Matched therapy using mTOR inhibitor-based regimens led to dramatic clinical responses, and a significantly longer PFS in patients with PIK3CA mutations and/or PTEN loss. Thus, targeting aberrant PI3K pathway is warranted for further evaluation in patients with advanced cervical cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B191. Citation Format: Ming-Mo Hou, Xiaochun Liu, Sarina A. Piha-Paul, Filip Janku, Jennifer Wheler, Aung Naing, Diane Bodurka, Kathleen Schmeler, Karen Lu, Ralph Zinner, David Hong, Funda Meric-Bernstam, Razelle Kurzrock, Siqing Fu. Target-matched therapies in patients with advanced cervical cancers harboring PIK3CA mutations and/or PTEN loss. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B191.