When standard cancer treatments don't work, or if doctors can't determine where a patient's cancer originated, genomic sequencing can help pinpoint mutations in a tumor that might be matched with medicines targeting those specific alterations.

But how much does this "next-generation" sequencing actually influence clinical care and improve outcomes?

A study of more than 1,000 patients seen at the University of Michigan Rogel Cancer Center suggests the answer is quite a bit — especially for certain subsets of patients.

The findings, which recently appeared in JAMA Oncology, showed that potentially actionable genomic alterations were found in nearly 80% of patients. And of the 130 patients who received sequencing-directed therapy, nearly 40% experienced some clinical benefit, with 20% experiencing exceptionally good responses — defined as keeping their disease under control for at least one year.

Moreover, for patients with cancers of unknown origin, sequencing was able to decode the tissue of origin for the cancer in half of cases — giving doctors much better clues about what standard therapies, as well as targeted therapies, might help. 

One of the most telling results of the study was that potentially inheritable cancer risk was identified in 16% of patients, says study first author Erin Cobain, M.D., an oncologist at Michigan Medicine.

"Any family members who have also inherited those same mutations may be at increased risk for cancer," she says. "So, a lot of this testing prompted downstream genetic testing and counseling across families. That's how sequencing can have even more far-reaching impact than just looking for therapies to directly help a current patient."

The study examined nearly seven years' worth of data from 1,015 patients who participated in the Michigan Oncology Sequencing Program (Mi-ONCOSEQ) between 2011 and 2018. Today, more than 3,500 patients have had their tumors sequenced.

"The way that I describe next-generation sequencing to patients is that the test is looking for changes in the DNA and RNA of the tumor," Cobain says. "The tumor develops these changes that don't happen in the rest of the cells in our body and sometimes we can find medications that target those changes — and that won't have as great of an impact on the normal cells in the body because they're specifically targeted against something that is different or abnormal in the cancer cells."

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The testing through Mi-ONCOSEQ is more comprehensive than most commercial genomic testing, she notes. And, at U-M, a precision medicine tumor board regularly brings together doctors and the scientists who conduct the screening analysis to discuss the intricacies of findings, which can be quite complex.

"One goal for Mi-ONCOSEQ is to inform standards of practice as clinical sequencing increasingly becomes adopted as a routine standard of care," says Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and senior author of the study. "This study helps demonstrate that the promise of individualized, precision medicine and precision oncology is becoming a reality for patients."

Over time, too, as next-generation sequencing has become more widespread and cheaper to do, more clinical trials are available to patients based on their results, Cobain adds.

Still, not all patients with potentially actionable mutations end up receiving therapy based on the sequencing. There are a number of reasons why that's the case, she says. For example, clinical trials may be offered too far away for patients to participate, or their overall health may not be good enough for them to enroll.

An editorial that accompanied the study stressed the importance of the findings for patients with cancers of unknown origins.

"Based on the data presented by Cobain et al. and others, it is evident that such precision medicine strategies are especially fruitful in cancer types without clear standard-of-care options, such as carcinoma of unknown primary and other rare tumors," the authors wrote. "Such efforts will allow us to deliver personalized therapies with potential therapeutic benefit to patients and to further refine the development of precision medicine efforts in oncology."

Cobain notes that some people might question whether the expense of sequencing, which runs several thousand dollars per test, is worth it to identify the small number of individuals — about 3% of the total analyzed in the study — who saw exceptional clinical results.

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She notes that compared to the relatively high costs of ongoing cancer care, including imaging scans and medications, the cost of testing is a relatively small, one-time expense.

"We identified a group of patients with advanced cancer and no therapeutic options, and we were able to keep their disease under control for a year or more," Cobain says. "Additionally, we were able to provide some answers and therapeutic directions for a significant number of people with cancer of unknown origins. And we identified mutations in 16% of patients where we might be able to provide genetic testing and counseling to help other family members lower their cancer risk."

Additional authors include Yi-Mi Wu, Pankaj Vats, Rashmi Chugh, Francis Worden, David C. Smith, Scott M. Schuetze, Mark M. Zalupski, Vaibhav Sahai, Ajjai Alva, Anne F. Schott, Megan E. V. Caram, Daniel F. Hayes, Elena M. Stoffel, Michelle F. Jacobs, Chandan Kumar-Sinha, Xuhong Cao, Rui Wang, David Lucas, Yu Ning, Erica Rabban, Janice Bell, Sandra Camelo-Piragua, Aaron M. Udager, Marcin Cieslik, Robert J. Lonigro, Lakshmi P. Kunju, Dan R. Robinson and Moshe Talpaz, all of U-M.

This study was supported by grants from the Prostate Cancer Foundation, National Institutes of Health (1UM1HG006508) and National Cancer Institute (CA214170, CA186786, CA231996, CA046592).

Paper cited: "Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors," JAMA Oncology. DOI: 10.1001/jamaoncol.2020.7987