Stacy Gray, medical oncologist at City of Hope in Los Angeles, can vouch for the value of molecular testing. In 2016, clinicians at the cancer research and treatment organization successfully treated a middle-aged woman with breast cancer, but she did not qualify for genetic testing. She remains cancer-free today. However, during a follow-up visit in March 2021, she was offered genetic testing through an innovative precision medicine programme, where she tested positive for a BRCA2 mutation that puts her at risk of developing a new primary cancer.
When City of Hope staff tested her close relatives, three also had BRCA2 mutations. Her husband and son, who also underwent testing through the programme, had risk genes for different cancers. Molecular testing in this case “was transformative for the entire family”, says Gray. “We identified six individuals who now have access to lifesaving cancer prevention measures.”
Gray is deputy director of City of Hope’s Center for Precision Medicine, which is undertaking a major effort to broaden cancer patients’ access to molecular testing. Precision medicine uses knowledge of molecular risk factors to identify targeted therapies that destroy cancer while sparing healthy tissues. More effective and less toxic than chemotherapy, it has tended to be restricted to late-stage cancer patients.
By contrast, City of Hope now extends precision medicine to patients seen at the organization’s comprehensive cancer centre. It will eventually be offered throughout its network of more than 30 clinical locations in Southern California, and at the newly acquired Cancer Treatment Centers of America, which has centres in Arizona, Illinois and Georgia. “We believe comprehensive molecular profiling is the future standard of care in oncology,” Gray says. “We want to bring it as quickly as we can to as many patients as possible.”
A comprehensive testing programme
The programme starts when patients are offered a comprehensive genomic analysis. Roughly 90% of patients given that opportunity agree to it, and the number of participants so far exceeds 12,000. Participants donate blood and tissue samples to a City of Hope-based biorepository for future research, then undergo a battery of tests to expose the molecular landscapes of their disease.
The first test screens samples across 155 genes associated with inherited risks for cancer, results from which may pinpoint the genetic cause of a patient's malignancy, or yield “incidental findings that could be significant for family members”, says Heather Hampel, a genetic counselor and associate director of City of Hope’s Division of Clinical Cancer Genomics. “For instance, you might detect a gene change in a female patient that increases the risk of prostate cancer in her male relatives.”
The second test screens for 59 medically actionable genes recommended by the American College of Medical Genetics and Genomics. Awareness of these genes can lead doctors to recommend proactive steps, ranging from lifestyle choices to certain medications, or more drastic measures such as prophylactic mastectomy to ward off breast cancer. Roughly half the genes in this panel are associated with cancer, while the other half are associated with risks for other conditions, such as familial hypercholesterolaemia, various cardiomyopathies, or anaesthesia complications. Evidence gathered so far at City of Hope shows that nearly 20% of patients tested have actionable findings that may impact them or their family members.
The final test entails an ultra-comprehensive whole-exome and whole-transcriptome profile of the patient's tumour. Instead of just analysing germline DNA – which can be inherited – this widely available test, which medical oncologist and Center for Precision Medicine director Stephen Gruber describes as “best in class”, also looks for non-heritable somatic mutations that emerge in cells over a lifetime. The test, called Oncomap™ ExTra, was developed at City of Hope’s Translational Genomics Research Institute (TGen), and because it includes RNA analysis, it can detect gene fusions that arise from faulty breakpoints in the DNA sequence that can be missed with DNA sequencing alone. Fusions occur when unrelated pieces of genes stick together, generating abnormal proteins that cause cancer.
Gruber says results from the test can point doctors to therapies they may not have otherwise considered. In one instance, City of Hope analysed the tumour of a patient with metastatic ovarian cancer who was refractive to standard-of-care treatments. “Her results showed a specific mutational signature of DNA repair defects that made it overwhelmingly likely that she would respond to poly (ADP-ribose) polymerase inhibitors,” Gruber says. That treatment worked, and the patient remains in remission today.
Making the most of genetic data
To ensure quality control of all incoming information, City of Hope and its collaborators are developing big data systems powered by artificial intelligence and machine learning. Importantly, all the molecular information generated by a given patient is securely combined for a systematic review by City of Hope's precision oncology tumour board, which is staffed by experts in oncology, pathology, genetic counselling, bioinformatics and other fields. The board submits its conclusions into the patient's electronic medical record “along with the curation and annotation that doctors need to optimize treatment”, Gruber says.
Patients who test positive for a heritable mutation, Gruber adds, are referred for genetic counselling. The City of Hope approach flips a standard paradigm in the field that has been problematic. Rather than spending too much time with anticipatory guidance about hypothetical results for each patient, City of Hope concentrates on providing meaningful information after test results are available.
“The people who test positive come to me and my team,” says Hampel. “That way we streamline the process and ensure the individuals who need it most receive genetic counselling. City of Hope has one of the largest cancer genetic counselling teams in the United States, and they’re focused on treating the whole family if the mutations are heritable.”
While the organization’s approach to genetic counselling is to deploy it smartly and selectively, the wider mission is to extend access to precision oncology to the broadest possible population. Hampel says City of Hope's efforts are helping to correct longstanding disparities in access to cancer genetic information.
Gruber agrees. The aim, he says, should be to move away from waiting to find out if a patient qualifies for molecular testing. “Those criteria are established in part by insurers to determine whether testing should be reimbursed,” he says. “Those guidelines are complex, arbitrary and evolving. In our view, if you are a cancer patient, molecular testing is indicated.” After all, the wider the net is cast on testing, the greater the chances of success stories like the one Gray’s team achieved last year, where potentially life-saving preventive measures and precision treatments can be extended not only to cancer patients and survivors, but their families too.