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Genomic differences observed in cervical cancer subtypes
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The two most common subtypes of cervical cancer harbor high rates of potentially targetable oncogenic mutations, study results suggest.
Because cervical adenocarcinomas and squamous cell carcinoma feature distinct molecular profiles, personalized treatment strategies could significantly improve outcomes, researchers wrote.
“We have historically treated cervical cancers as one disease,” Alexi Wright, MD, MPH, a medical oncologist at the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School, said in a press release. “However, our findings suggest that some patients may be at higher risk of dying from their disease and might benefit from a more tailored treatment approach.”
Wright and colleagues analyzed DNA from 80 cervical cancer tumors — 40 adenocarcinomas and 40 squamous cell carcinomas. They used the OncoMap system to search for 1,250 mutations in 139 cancer genes.
Overall, they found PIK3CA mutations in 31% of tumors, including 25% of adenocarcinomas and 37.5% of squamous cell carcinomas (P=.33). They identified KRAS mutations in 17.5% of adenocarcinomas but none of the squamous cell carcinomas (P=.01). They identified a rare EGFR mutation in 7.5% of squamous cell carcinomas but none of the adenocarcinomas (P=.24).
Results of an adjusted analyses showed PIK3CA mutations were associated with shorter survival (67.1 months vs. 90.3 months; HR= 9.1; 95% CI, 2.8-29.5).
“While current treatment strategies don’t take into account whether cervical tumors are adenocarcinomas or squamous cell carcinomas, our study suggests that identifying and targeting distinct subsets of patients may improve outcomes for women with early- or late-stage disease,” Wright said.
Disclosure: The study was funded by the American Cancer Society, ASCO’s Conquer Cancer Foundation, the Team Maureen Cervical Cancer Fund and the Friends of Dana-Farber Cancer Institute. The researchers report consultant roles with Eisai, Foundation Medicine, Novartis and Sanofi-Aventis; employment relationships with Janssen and Novartis; and stock ownership in Foundation Medicine.
Perspective
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Bradley Monk
Recurrent and metastatic cervical cancer carries a poor prognosis, with current treatment options generally focusing on systemic chemotherapy, which is not curative. Previous randomized trials have investigated the efficacy of various chemotherapeutic regimens in such patients. Gynecologic Oncologic Group protocol 204 studied four platinum-based doublets and established cisplatin and paclitaxel as the standard regimen (Monk BJ. J Clin Oncol. 2009;27:4649-4655).
Given the toxicity of cisplatin, including significant nausea and vomiting as well as neurotoxicity, further investigation suggested that the substitution of cisplatin with carboplatin was not inferior in efficacy and was much better tolerated (Saito I. J Clin Oncol. 2010;40:90-93), although the resulting tradeoff was an increase in hematologic toxicity, especially thrombocytopenia.
Cassandra Foss
A recent phase 3 randomized trial investigated the addition of an antiangiogenesis agent, bevacizumab (Avastin, Genentech), to doublet chemotherapy, which showed a significant improvement in response rate, PFS and OS (Tewari KS. Abstract #3. Presented at: ASCO Annual meeting; May 31-June 4, 2013; Chicago). This is the first study in a gynecologic cancer to show an improvement in survival with the addition of a targeted agent. Together, triplet therapy including paclitaxel, cisplatin or carboplatin, plus bevacizumab, is rapidly becoming the favored regimen in treating those with recurrent and metastatic cervical cancers.
Studies to date have enrolled unselected patients, including both squamous cancers and adenocarcinomas, without informative biomarkers. Individualized therapy might increase efficacy and reduce the use of ineffective therapy in this difficult-to-treat scenario. In the article by Wright and colleagues, actionable molecular targets were identified in 60% of cervical tumors studied. The genes with the highest mutation rates were PIK3CA (31.3% of tumors), KRAS (8.8% of tumors) and EGFR (3.8% of tumors). KRAS mutations were detected only in adenocarcinomas (17.5% vs. 0%; P=.01). These data suggest that investigating the use of agents to target these pathways would be a promising new direction in the treatment of cervical carcinoma. PI3K, EGFR and MEK inhibitors are already available in clinical practice and should, therefore, be investigated in this disease. Establishing oncogenic mutations as the basis of future clinical trials is a novel approach and establishes the groundwork for upcoming clinical investigations.
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