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Promising Results in Cervical Cancer Subtype Study Fuel PI3K Inhibitor Trial at Dana Farber

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Researchers from the Dana Farber Cancer Institute have published results of a preliminary study tracking the patterns of mutations in the two histological subtypes of cervical cancer, which they are now planning to put to the test in a clinical trial of PI3 kinase inhibitors.

According to the authors, the study published last month in the journal Cancer is the first comprehensive screen of potentially targetable mutations in cervical cancer overall, as well as the first to look at whether the two main subtypes of cervical cancer — adenocarcinomas and squamous cell carcinomas — have different mutational profiles.

Alexi Wright, the study's first author, told PGx Reporter that while the results — based on a genotyping approach interrogating 1,250 mutations in 129 cancer genes — were preliminary, the findings were strong enough to inform an upcoming clinical trial testing targeted treatment with PI3 kinase inhibitors.

According to Wright, cervical cancer, like other gynecologic cancers, has lagged behind other diseases in the effort to define molecular subtypes and distinct, targetable populations.

Before the Dana Farber team's study, Wright said, most of the genomics research was focused on EGFR, with disappointing clinical results. The genotyping approach offered the researchers an opportunity to take a broader look.

In the study, launched in 2010, Wright and her colleagues genotyped 80 cervical tumors — 40 adenocarcinomas and 40 squamous cell carcinomas — and identified validated mutations in 60 percent of them. Among the main findings was that mutations did indeed seem to be differently distributed between the two cervical cancer subtypes— with KRAS mutations, for example, appearing only in adenocarcinomas. The study also found that a relatively high frequency — about 30 percent —of the alterations, regardless of subtype, were PIK3CA mutations.

"For a long time we have noticed that there are clinical differences between adenocarcinomas and squamous cell carcinomas," said Wright. Studies have shown, for example, that adenocarcinoma confers a worse prognosis, with higher rates of metastasis and decreased survival compared to squamous cell carcinoma.

"I think what is unique here is that the results — for example the fact that KRAS mutations are present only adenocarcinomas — suggest that there may be distinct mechanisms of how these cancers develop and also distinct ways of treating them," Wright said.

"And it was nice to see that PIK3CA mutations were present across the two types, and that we didn’t see dual mutations with KRAS," she explained. "Because that suggests that you could try PI3 kinase treatments in both subtypes."

According to Wright, the team is now planning to do just that in a multi-center trial led by Dana Farber investigating PI3 kinase inhibitors in cervical cancer patients with metastatic disease. Depending on results of this trial, Wright said that the group would also like to be able to move to testing PI3 kinase inhibitors in the adjuvant setting.

Another finding from the team's genotyping study was that PIK3CA mutations were associated with shorter survival: 67 months compared with 90 months in patients without such mutations. "Particularly for patients with adenocarcinomas, knowing that these mutations are associated with decreased survival now, if we can find a signal in the metastatic setting, we would next explore integrating PI3 kinase inhibitors in adjuvant treatment," she said.

According to Wright, the group has also since followed up its initial genotyping study with a more comprehensive genome-wide and RNA-sequencing approach in a different set of samples in collaboration with the lab of Dana Farber's Mathew Meyerson.

"At the time, the genotyping approach was the most cost-effective, broad testing that we could do in a way that could be clinically relevant," Wright said. "But obviously now we are looking [more deeply.]"

The team's follow up work is unpublished, so Wright could not share any updated results.

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