Scientists find great potential in using DNA, RNA sequencing to gain better understanding of metastatic cancer and help direct targeted therapy.

The idea of precision medicine has inspired cancer scientists and spurred a new type of cancer clinical trials – based on genes and biomarkers rather than tumor type. But the uncertain promise of precision medicine in cancer care can be seen in two examples.

Woods Brown came to the University of Michigan Comprehensive Cancer Center with prostate cancer that had spread to his bones, lung and liver. Genetic sequencing uncovered a mutation in the BRCA2 gene. He enrolled in a clinical trial in which he received abiraterone, a standard therapy for prostate cancer, plus a PARP inhibitor, a new type of targeted therapy that has shown success against BRCA2 mutations.

His liver metastases shrank and his PSA dropped to near 0. He’s been in remission with no sign of cancer for more than three years.

One floor above at the Cancer Center, a patient with metastatic triple-negative breast cancer was running out of standard treatment options. She underwent genetic sequencing that suggested a PARP inhibitor would be effective, but in her case the disease progressed within a few weeks of being on the treatment.

As precision medicine gains more traction, limitations clearly remain. For starters, why do some patients have long-lasting responses that look like a cure, while other patients have little success?

“Generally these responses are not long-lived. But when we find the right combination of agents matched to the right combination of mutations, it can lead to durable responses,” says Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology.

Unique program yields new understanding

Chinnaiyan started a program at Michigan Medicine in 2010 called Mi-ONCOSEQ, which involves sequencing the DNA and RNA of metastatic cancers and normal tissue to identify alterations that could help drive treatment. About 2,300 patients –adults and children, with a variety of cancer types – have had their tumors sequenced through the program.

Results from Mi-ONCOSEQ have demonstrated how precision medicine can potentially help direct cancer treatment. Researchers reported on the first 500 patients sequenced in one of the largest and most comprehensive efforts to examine the genetic and molecular landscape of advanced cancer. The paper was featured on the cover of Nature.

Three things make this analysis unique:

• Researchers obtained fresh biopsies for most patients, extracting samples from the metastatic tumors, rather than the primary tumor.
• They sequenced both DNA and RNA.
• They compared the cancerous tissue to the patient’s normal DNA.

“This is a more comprehensive approach than most commercially available clinical sequencing programs. Our results suggest value on several levels to this more detailed approach,” Chinnaiyan says.

Researchers found a significant increase in the number and type of mutations between patients’ metastatic cancer and primary cancer. This suggests tumors are evolving as part of metastasis and under therapy, which means a biopsy of the metastatic tumor will provide better information than archival tissue.

In addition, researchers found a number of clues by sequencing patients’ RNA. While DNA sequencing reveals genetic alterations involved in metastatic cancer, researchers found RNA sequencing shed light on the underlying mechanisms that either turn on cancer-causing genes or turn off the genes meant to stop cancer. Their findings could help identify potential targets for treatment.

Clinical trials increasing – more needed

Indeed, an increasing number of patients are enrolling in clinical trials based on genomic sequencing. Preliminary data presented earlier this year at the American Society of Clinical Oncology annual meeting suggested that three-quarters of patients whose tumors were sequenced had an “actionable mutation,” meaning treatments exist to target that specific aberration.

While only a portion of those patients were able to enroll in a trial based on other eligibility factors and trial location, the number who did enroll doubled from approximately 5 percent of patients in 2012 to 11 percent in 2016.

“Sequencing is beginning to have a real impact on treatment recommendations. It’s important to consider this testing early in the patient’s clinical course in order to improve our ability to act on the results and impact the patient’s course,” says Erin Cobain, M.D., clinical lecturer of hematology/oncology at the University of Michigan Medical School.

“Availability of biomarker trials is crucial for being able to act on these results. Over time, we became better at matching patients to clinical trials as more of these basket trials opened,” she says.

Increased trial enrollment occurred as several major national trials based on next generation sequencing opened. Researchers note that the possibility of receiving a targeted therapy based on gene sequencing is influenced by the number of available clinical trials. In the federally funded NCI-MATCH trial, the chance that a patient will match to a clinical trial is about 1 percent per trial arm open, says Anne Schott, M.D., associate director of clinical research at the U-M Comprehensive Cancer Center.

Practical limitations

But for Schott, a medical oncologist who sees patients with breast cancer, it’s not that simple.

“I practice in the brick and mortar of the Cancer Center. I have to deal with the reality of a patient with a lethal disease in front of me and translate this promise into something that might be meaningful to them,” Schott says.

One major issue is cost. Commercial sequencing tests are not always reimbursed by insurance, which could leave patients on the hook for a bill that’s typically $4,000-$6,000. (MiONCOSEQ is run as a research study at Michigan Medicine at no cost to patients.)

Then, if a patient matches to a commercially available drug, the drug may not be covered by insurance. Targeted therapies are in the range of $10,000 or more per month.

“This is one of the realities we face with enacting precision oncology – who pays?” Schott says.

In addition, the field is evolving so rapidly that even an active clinical researcher like Schott can’t keep up. Of the roughly 50 targeted cancer therapies that are FDA-approved, Schott says she has prescribed only nine.

Despite the promise of precision medicine, she says, treatments prescribed based on the specific tumor type, and not for a gene mutation,will likely remain the best option for many patients.

“I believe in pursuing this line of research, but we need to pursue carefully,” Schott says. “I hope these trials will tell us the subset of patients for which precision medicine will work.”