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All aboard: Will molecular tumor boards help cancer patients?

Tuesday, July 7, 2015

If anyone understands the promise of precision medicine, oncologist Lukas Wartman does. In 2003, at the end of his final year of medical school at Washington University in St. Louis, Wartman was diagnosed with acute lymphoblastic leukemia. He remained at the university through his treatment, his relapse, and a stem cell transplant from his brother. In 2011, while Wartman was finishing up a fellowship in a leukemia research lab, the cancer returned. This time, his colleagues at Washington University's genome sequencing center directed their arsenal of weapons at Wartman's leukemia.

A look at the transcriptome of his tumor found a gene—FLT3--that was overexpressed, likely due to acquired mutations in regulatory elements of the gene. The discovery allowed his colleagues to match his leukemia's FLT3 mutation with a drug used in kidney cancer, putting Wartman into remission and allowing a second stem cell transplant, this time from an unrelated donor, which got him on the road back to health.

Treating late-stage cancer according to its genetic mutations rather than its site of origin is already changing medical practice, and it has helped keep Wartman and others in remission. Yet, not all cancer patients carry tumors that are candidates for such treatment. For instance, if a patient's cancer typically has a high survival rate, sequencing the tumor may not help that person, and not all tumors hold cancer-driving mutations that can be matched with drugs. Making matters worse, next-generation sequencing (NGS) technologies are so new that many oncologists are not trained in how to interpret the data they generate.

“Physicians don't have time to go back to school and get a degree in genetics,” says Roy Herbst, chief of medical oncology at the Yale School of Medicine in New Haven, Connecticut. “Still, they need to understand which patients might be good candidates for sequencing, and they need help reading the reports.”

When oncologists need guidance on treatment for a patient with difficult cancer, they can turn to traditional tumor 'boards'—jargon for group meetings of doctors—and seek the opinions of pathologists and radiologists. Each of these long-established gatherings focuses on specific cancer types, such as lung, colon or breast. Because NGS can sort cancer by mutation, patients who have failed on standard therapy, or who have a cancer so rare that treatment options are limited, might benefit from a new type of tumor board focused on cancer genomics.

These new gatherings that incorporate DNA sequencing results are described alternately as 'genomic', 'precision medicine' or 'molecular' tumor boards, and they are cropping up in academic medical centers.

Genomic tumor boards include a broad variety of professionals, such as bioinformatics experts, bioethicists and genetic counselors. During the molecular tumor board meetings, specialized pathologists or oncologists discuss sequencing results as a radiologist would clarify results from an MRI or a PET scan, detailing the significance of mutations listed in the sequencing report and the signaling pathways affected by the mutated genes. Attendees might debate the possible influence of particular mutations, and whether a particular drug might work. Oncologists who are experts in available clinical trials might weigh in on whether a particular drug is the right match for the patient. Because of the deep dive into genomic information, molecular boards discuss two, perhaps three patients per session. By comparison, traditional oncology boards sometimes discuss as many as 20 patients per meeting.

Mark Rubin, M.D. The team of experts at molecular tumor boards can provide a nuanced level of detail not found in sequencing reports from a commercial company or a hospital lab. “That's why I think molecular tumor boards are so important, because they are a way to synthesize data and make real-world decisions as to what should be done,” says Mark A. Rubin, a professor of oncology and pathology at Weill Cornell Medical College in New York City. The precision medicine tumor board at Weill Cornell has been in place for two years. Recently, the board members wanted to see whether whole-exome sequencing (WES) was realistic for a wide variety of late-stage cancer patients. In almost all of the 97 cases they reviewed, the molecular tumor board was able to make treatment recommendations, but only 5% of the patients could receive the recommended treatment, because of limited access either to a clinical trial or a drug. (JAMA Oncol. 10.1001/jamaoncol.2015.1313,2015)

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By the numbers

There are perhaps as many as 30 molecular tumor boards across the United States. Not all genomic tumor boards take the same approach, however. The molecular tumor board at the University of California San Diego (UCSD) Moores Cancer Center in California was initiated in late 2012. It is clinically focused, and all patients discussed have already had their tumors evaluated by either UCSD-based or commercially available gene assays. In a 2014 paper in The Oncologist that detailed what their molecular board saw, Razelle Kurzrock, Director of the Center for Personalized Cancer Therapy at the Moores Cancer Center, and her team published initial findings of 34 patients whose cases were presented. Of the 12 patients referred for additional treatment, three achieved a partial remission. Sequencing results could not help the remaining 22 patients with their treatment, most commonly because of a lack of access to medication, either because of insurance coverage issues or restricted eligibility for clinical trials, lack of a treatment match for their mutation, or death before treatment could begin (The Oncologist 19, 631–636, 2014). A follow-up paper has been submitted for publication.

“We embrace molecular diagnostic tests,” says Kurzrock. “For individuals with advanced diseased who are running out of options, or patients with rare tumors, the need for testing is becoming clear cut.” Kurzrock adds that addressing medication access and performing molecular diagnostics earlier in the course of the disease will increase the proportion of patients of late-stage cancer patients treated.

The genomic tumor board at Washington University School of Medicine launched in January 2014. The effort there is still a work in progress, says Wartman, who has remained with the university's medical school. Wartman organizes the genomic board and screens the cases. He's still encouraging more oncologists to participate. “To be fair, there is not a lot of evidence to support that genomic testing is going to be of any benefit,” says Wartman. “So while there are anecdotal cases like my own that are very powerful, I think overall the culture hasn't necessarily accepted that. What they have accepted more are the gene panel tests that are offered commercially.”

The genomic tumor board at Washington University meets monthly to decide whether tumors from particular patients should be sequenced, and, if so, by which platform. Sequencing here is paid for by research protocols, and any patient considered needs to have been consented to a protocol that allows both for genomic sequencing and also for return of results. Any actionable results would need to be verified in a lab specially certified under the government's Clinical Laboratory Improvement Amendments (CLIA) regulations.

The genomic tumor board there will continue to investigate cases even after patients have died. “Here, the genomic tumor board is something very different,” says John DiPersio, chief of oncology at the Washington University School of Medicine, and one of the genetic tumor board's founders. “There's nothing we can bill and collect for. This is really for research purposes to try and understand [the] biology of tumors and how they evolve, and what the underpinnings are for the disease.”

Rubin of Weill Cornell sees a time, perhaps by next year, that WES is used on all late-stage cancer patients, or perhaps on patients with early-stage cancer to provide a mutation baseline. In the meantime, molecular tumor boards are helping skeptical oncologists embrace genomic testing. “We are seeing oncologists participate a lot more in the molecular boards. I think it's quite exciting to see people getting engaged in this,” he says. “It's a whole new culture.”

This is an excerpt of a feature that appeared in Nature Medicine. Read the full article here.