Elsevier

Gynecologic Oncology

Volume 128, Issue 3, March 2013, Pages 409-414
Gynecologic Oncology

PIK3CA mutational status and overall survival in patients with cervical cancer treated with radical chemoradiotherapy

https://doi.org/10.1016/j.ygyno.2012.12.019Get rights and content

Abstract

Objective

Mutational activation of PIK3CA is associated with poor prognosis in patients with solid tumors, and may predict favorable response to PI3K/AKT/mTOR pathway inhibitors. However, PIK3CA mutational status has not previously been evaluated in patients with cervical carcinoma treated with radical chemoradiotherapy (CRT). The aims of this study were (1) to evaluate the frequency of PIK3CA mutations in patients with cervical cancer treated with radical CRT and (2) to examine the effect of tumor PIK3CA mutational status in pre-treatment biopsies on overall survival (OS) and progression-free survival (PFS).

Methods

Patients with cervical cancer, treated at a single institution with radical CRT, from 1999 to 2008, were eligible for this retrospective study. Pre-treatment tumor biopsies (n = 157) were retrieved. Genomic DNA was extracted from tumor blocks, and exons 9 and 20 of the PIK3CA gene were sequenced for mutations.

Results

Eighty-two tumors were sequenced for both exon 9 and exon 20. 19/82 (23%) tumors were PIK3CA mutation positive; of these 84% were squamous cell carcinomas. 79% of mutations were in exon 9. PIK3CA mutation status was strongly associated with overall survival (OS) in FIGO stage IB/II patients, unadjusted HR 6.0 (95% CI 2.1–17.5), p = 0.0002, but not stage III/IVA patients, unadjusted HR 1.0 (95% CI 0.32–3.1), p = 0.98.

Conclusions

In cervical cancer patients treated with CRT, tumor PIK3CA mutation status was associated with overall survival in FIGO stage IB/II cervix cancers. Further evaluation with a larger dataset will be required to validate these findings to inform potential clinical trials designs involving PI3K/AKT/mTOR pathway inhibitors.

Highlights

PIK3CA mutation status was evaluated in locally advanced cervical cancer patients treated with radical chemoradiotherapy ► PIK3CA mutations were found in 23% of evaluable patient tumors ► Overall survival effect in FIGO stage I/II patients with PIK3CA mutant tumors is worse, compared to stage III/IV patients

Introduction

Cervical cancer is the third most common cancer affecting women worldwide, with an estimated 500,000 new cases diagnosed annually, of whom 270,000 will die of their disease [1]. The standard of care for patients with locally advanced cervical cancer is cisplatin-based chemoradiotherapy (CRT), which has essentially remained unchanged over the last decade. When compared to radiotherapy alone, CRT improves local control as well as overall survival; however there still remains a significant subset of patients who either suffer incomplete CRT response or experience relapse of disease and cancer-related death [2], [3].

In an effort to improve outcomes for cancer patients, there is increasing interest in the study of specific molecular characteristics of tumors and the application of relevant targeted therapeutics [4]. Although these areas of scientific and clinical research are advancing in other tumor sites such as lung, colon and breast, there are limited data investigating predictive molecular factors of response to CRT in cervical cancer patients [5]. Targeted molecular screening represents a promising area for the development of novel chemotherapeutic agents or for the more effective use of existing therapeutics in the treatment of cervical cancer.

In recent years there has been a focused effort to identify patients whose tumors have specific genetic alterations that affect signaling pathways such as cellular proliferation, survival and apoptosis, particularly in the context of identifying relevant therapeutic pathway inhibitors. There has been much focus on the PI3K/AKT/mTOR pathway as a potential therapeutic target for many different types of cancers [6]. Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases comprised of three classes that regulate signaling pathways involved in cell proliferation, transformation, cell survival, apoptosis and metastasis [7]. Class IA PI3Ks are heterodimeric proteins composed of an 85-kDa regulatory subunit and a 110-kDa catalytic subunit encoded for by the PIK3CA gene. To date, somatic mutations in PIK3CA have been documented in a wide variety of human cancers [7], [8]. Samuels et al. in 2004 reported a high frequency of mutations within coding regions of the PIK3CA gene in tissues from primary tumors of the colon, brain, stomach, breast and lung [9]. The majority of these mutations were clustered within exons 9 and 20, encoding the helical and kinase domains respectively. Subsequently, three specific “hot spot” mutations within the helical and kinase domains (E542K, E545K and H1047R) have been shown to increase PIK3CA kinase activity resulting in the over-activation of the PI3K/AKT/mTOR signaling pathway, a pathway often perturbed in endometrial [10], [11] and breast cancers [8], [12], [13], [14], [15]. PIK3CA mutations have also been identified in cervical cancers with the prevalence varying from 13% to 36% [16], [17], [18]. Although these studies were conducted in very small patient cohorts, the results suggest PIK3CA mutation might play an important role in cervical cancer development and progression. Furthermore, a number of preclinical studies indicate that PIK3CA mutation may be a positive predictor of response to PI3K/AKT/mTOR inhibitors [17], [19], [20]. Taken together, these observations suggest that PIK3CA could represent a potential drug targetable molecule for the treatment of cervical cancer.

With this in mind, we conducted a retrospective study investigating the frequency of PIK3CA mutations in pre-treatment biopsies from a cohort of patients with cervical cancer treated with radical CRT, and correlated PIK3CA mutational status with overall survival (OS) and progression-free survival (PFS).

Section snippets

Patient selection and chart review

Patients with cervical cancer, FIGO stages IB-IVA, treated with radical CRT with curative intent at a single institution (Tom Baker Cancer Centre, Calgary, Alberta), from 1999 to 2008, were reviewed for this retrospective study. Cases were identified from the Alberta Cancer Registry. Only patients who completed the planned CRT within 180 days from diagnosis were included. Clinical and treatment details were extracted from the patient charts. Standard pre-treatment staging procedures were

Results

One hundred and fifty-seven patients with cervical cancer (FIGO stages IB-IVA) treated with radical CRT were identified. Eighty-two specimens were successfully sequenced for both exon 9 and exon 20. Another 8/157 specimens did not yield conclusive PIK3CA status. In 67/157 (43%) cases, specimens were insufficient for DNA extraction, therefore categorized as “DNA not tested.” Age at diagnosis, tumor size, FIGO stage, histological subtype, CT nodal status, and pre-treatment hemoglobin status were

Discussion

In study patients with cervical cancer treated with radical CRT, we detected PIK3CA mutations in 19 of 82 (23%) pre-treatment tumor specimens, with exon 9 mutations being the most common type found (15 of 19 cases). PIK3CA status is associated with OS, irrespective of age (a modest confounder in this study sample), but its effect is striking only among FIGO stage IB/II patients, and not among FIGO stage III/IVA patients. We postulate that this observation is related to the relatively poorer

Conflict of interest statement

The authors have no conflict of interest to declare.

Acknowledgements

This work was supported by a grant from the Gynecologic Oncology Society of Canada and GlaxoSmithKline, and the Alberta Cancer Foundation. We would like to acknowledge Mie Konno for her assistance with data entry, specimen collection and coordination.

References (27)

  • G. Ligresti et al.

    PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches

    Cell Cycle

    (2009)
  • Y. Samuels et al.

    High frequency of mutations of the PIK3CA gene in human cancers

    Science

    (2004)
  • K. Oda et al.

    High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma

    Cancer Res

    (2005)
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