Basket Cases: Changing the Way Cancer Is Treated

When determining treatment plans, some doctors are turning to genetic mutations that caused the cancer instead of the cancer type. 
BY BARBARA SADICK
PUBLISHED: APRIL 15, 2016
The gene mutations that occur in cancer are numerous. Primo Lara, a clinician-scientist at UC Davis Comprehensive Cancer Center, uses the commonly mutated gene KRAS as an example. It appears in 25 percent of lung cancers, 90 percent of pancreatic cancers and about half of all colon cancers. Further, approximately one-half of all cancers have a mutation in the tumor suppressor gene p53; this mutation releases the brakes on tumor growth, allowing unfettered cancer cell proliferation. Efforts are underway to identify and develop drugs that specifically target KRAS and p53, and to identify and clinically validate many more cancer-related mutations that could be clinically actionable.

Among approved drugs are those that target EGFR, the epidermal growth factor receptor. Mutations to EGFR are found in 10 to 15 percent of lung cancers in the U.S. and in more than 50 percent of lung cancers in Asian populations, more prevalently in females than in males, according to Shakun Malik, head of thoracic and head and neck cancer therapeutics at NCI’s Cancer Therapy Evaluation Program.

Mutations to a different gene, BRAF, were at the heart of the first published results of a basket study — the Zelboraf (vemurafenib) trial — reported just last year by researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York. BRAF inhibitor Zelboraf was approved by the U.S. Food and Drug Administration (FDA) in August 2011 for the treatment of metastatic melanoma, but since BRAF mutations occur across a variety of cancers, investigators wanted to test the drug's effect on other cancer types, including lung, colorectal and ovarian. They enrolled 122 patients from centers around the world, all of whose cancers carried the BRAF mutation.

In general, results showed that Zelboraf was able to target this mutation across a wide variety of cancers, proving that cancer type does not always matter.

Medical oncologist David Hyman, acting director of developmental therapeutics at MSKCC and the study’s first author, says an advantage of basket studies is that they can democratize access to targeted therapy for those who have rare cancers, who are often underrepresented in clinical trials. "The discovery has been that some patients with very rare cancers have similar mutations (as more common cancers) at even higher rates, and some have no ongoing trials or therapies available (specifically for their disease types)," he says.

A number of large precision medicine trials are underway now, with the eyes of the scientific and patient communities watching closely to see where this kind of study will take us.

LUNG-MAP

Throughout the country, lung cancer is the No. 1 cancer killer, causing over 27 percent of cancer deaths, or 150,000, each year. But because squamous cell lung cancers that are often caused by smoking include a wide variety of cell types and can be deadly, progress in finding treatments has been slow.

Mary Redman, the architect of the statistical design of the Lung-MAP trial and a biostatistician at Fred Hutchinson Cancer Center in Seattle, says the hope is that by using targeted therapy — both single-agent and combination regimens — treatments will be found that are effective and can prolong lives. Lung-MAP is a public-private collaboration composed of the NCI, SWOG Cancer Research (a worldwide network of researchers that designs and conducts clinical trials), Friends of Cancer Research, the Foundation for the National Institutes of Health, five pharmaceutical companies, Foundation Medicine and several lung cancer advocacy organizations. It's a large trial for individuals with advanced squamous NSCLCs who have undergone no more than one round of chemotherapy treatment and are not responding to that treatment.

Lung-MAP's co-principal investigator and co-chair of its trial oversight and drug selection committees, Roy S. Herbst, says patients can join the trial at any of more than 700 medical centers, where their cancer cells will be tested for over 200 possible gene alterations. Based on the results of this screening, eligible patients are assigned to one of four sub-studies testing investigational or FDA-approved treatments, based on which best suits their cancer's genomic profile. Three arms are testing targeted drugs, and the fourth is testing immunotherapeutic treatments that do not target a specific mutation, possibly benefiting patients whose cancers lack genetic alterations that match any of the targeted investigational therapies. Specifically, the immunotherapy arm is testing the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) compared with Opdivo alone.



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