Ovarian cancer causes more deaths than any other reproductive cancer, largely because there is little doctors can do to prolong women’s lives after they are diagnosed. Surgery can remove the most obvious growths and chemotherapy is also recommended, but for some patients, researchers have found, the most commonly prescribed chemotherapy can worsen their disease.
Reporting in the journal Oncogene, scientists led by Dr. Joanne Weidhaas at Yale University School of Medicine say they have found a way to identify these women by gene testing. Those with a specific genetic mutation were three times more resistant to the standard chemo treatment using platinum-based drugs like carboplatin and paclitaxel than women without the gene mutation.
The DNA change involves the KRAS pathway, which regulates cell growth, division and survival. In the presence of platinum drugs, which are the first-line chemotherapy agents used to treat ovarian cancer, the mutated KRAS gene activates cells’ ability to bypass and shrug off the effects of chemotherapy, making the cancer drug-resistant.
About 12% to 15% of the Caucasian population harbors the KRAS change, and it appears in about a quarter of all patients who are newly diagnosed with ovarian cancer.
“Certain drugs work against these cancers, and certain drugs actually turn on processes that help the cells not to die,” says Weidhaas. “Platinum just turns out to be a bad choice for women with this mutation. In the presence of this mutation, it just turns on resistance even more.”
If standard chemotherapy isn’t a good idea, what other treatment options do women have? At the moment, unfortunately, none. Although a test to detect the KRAS mutation is commercially available, medical research on usable treatments hasn’t caught up yet. Rigorous studies of new agents that might suppress or shut down KRAS’s tumor-promoting effect are underway, but they haven’t been completed.
The good news is that these agents do exist, says Weidhaas. In her lab, she and her team have tested human ovarian cancer cells with the KRAS mutation against a number of already approved anticancer drugs, and found that some of them do inhibit tumor growth. “We see that certain drugs work super-well against cell lines with this mutation, so there’s definitely hope,” she says. “KRAS is the No. 1 targeted pathway in cancer, so our hope is that in the near future, we will know that current chemotherapy agents don’t work, but we will have something that works better.”
In the meantime, testing for the KRAS mutation can still be helpful. Some women, for example, may weigh whether they should get surgery first or start with platinum chemotherapy for a few months. For those with the mutation, starting with chemotherapy might worsen their prognosis, so opting for immediate surgery may give them a few more months of disease-free life and improve quality of life.
In addition, for the more than three-quarters of patients who see their cancers recur after their initial treatment, testing for the KRAS mutation can help direct them away from another round of platinum-based therapy. They might try combinations of different chemotherapy agents instead, either already on the market or being tested in clinical trials. “If you make the wrong decision in ovarian cancer, you can go down a very bad path,” says Weidhaas. “Putting off surgery could be a wrong decision, and going on platinum drugs when your cancer recurs could also be a wrong decision, if you have the KRAS mutation. No one wants to make that mistake if it’s avoidable. It’s like navigating a minefield. You could make it [safely] for miles if you make the right decisions, or you might only make it one or two steps.”
Testing for the KRAS mutation could help guide patients and doctors toward more right decisions, she says, and when new drugs that target the KRAS pathway are approved, those decisions may be made easier. But until then, it’s too early for women newly diagnosed with ovarian cancer to refuse platinum-based therapy, since there isn’t any other option available to them — and a small percentage of women with the mutation do respond to the drug. For women who have already tried platinum-based drugs and are facing a recurrence of their disease, however, it may make sense to talk to their oncologists about trying a new course of treatment.