Scientists are studying cancer genomes to more precisely diagnose their patients' diseases - offering hope for targeted drug treatments.
Next, he recalls, he felt ushered into “the jaws of the medical system very quickly.” He spent a couple of days meeting with a team of doctors at Beth Israel Deaconess Medical Center in nearby Boston. One of them was from a medical field he hadn’t even known existed, a pulmonary interventionist, who would perform a biopsy on the mass in his lung.
“Knowing there was a medicine for my particular type of cancer was like a weight lifted off my shoulders."
A week later he and his wife Allison returned to meet with the oncologist, radiologist, pulmonary interventionist – his medical team. They confirmed his initial diagnosis: Stage 4 metastatic lung cancer that had spread to several parts of his body. “We just sat there, stunned,” he says. “I felt like I was getting hit by a wrecking ball over and over.”
An onslaught of medical terminology about what they had identified flowed over the shocked couple, but then the medical team switched gears, he recalls. They offered hope. “They told me, ‘Hey, you’re not a smoker, so that’s good,’” Reiner says. “‘There’s a good chance that what’s driving this disease for you is actually a genetic mutation, and we have ways to understand more about what that could be through some simple testing.’”
They told him about Foundation Medicine, a company launched in neighboring Cambridge, MA, in 2009 that develops, manufactures, and sells genomic profiling assays. These are tests that, according to the company’s website, “can analyze a broad panel of genes to detect the four main classes of genomic alterations known to drive cancer growth.” With these insights, certain patients can be matched with therapies targeted specifically for the genetic driver(s) of their cancer. The company maintains one of the largest cancer genomic databases in the world, with more than 500,000 patient samples profiled, and they have more than 65 biopharma partners.
According to Foundation Medicine, they are the only company that has FDA-approved tests for both tissue- and blood-based comprehensive genomic profiling tests. One other company has an FDA-approved biopsy test, and several other companies offer tissue-based genomic profiling. Additionally, several major cancer centers like Memorial Sloan Kettering in New York and Anderson Cancer Center in Texas have their own such testing platforms.
Currently, genomic profiling is more accessible for patients with advanced cancer, due to broader insurance coverage in later stages of disease.
“Right now, the vast majority of patients either have cancers for which we don’t have treatments or they have genetic alterations that are not known,” says Jorge Garcia, MD, Division Chief, Solid Tumor Oncology, UH Cleveland Medical Center, which has its own CGP testing platform. “However, a significant proportion of patients with advanced cancer have alterations that we can tap for therapeutic purposes.”
Foundation Medicine estimates that in 2017, just over 5 percent of advanced solid cancer patients in the U.S. received CGP testing. In 2021, they estimate that number is between 25 to 30 percent of advanced solid cancer patients in the U.S., which doesn’t include patients who are tested with small (less than 50 genes) panels. Their panel tests for more than 300 cancer-related genes.
“The good news is the platforms we are developing are better and more comprehensive, and they’re going to continue to be larger data sets,” Dr. Garcia adds.
In Reiner’s case, his team ordered comprehensive genetic profiling on both his tissue and blood, from Foundation Medicine.
At this point, Reiner still wasn’t sure what genetic mutations were or how they factored into cancer or what comprehensive genomic profiling entailed. That day, though, his team ushered the Reiners into the world of precision oncology that placed him on much more sure footing to learn about and fight the specific lung cancer that had been troubling him for more than a year.
What genetic alterations were driving his cancer? Foundation Medicine’s tests were about to find out.
At the core of these tests is next generation sequencing, a DNA sequencing technology. Since 2009, this has revolutionized genomic research, according to the National Center for Biotechnology Information, because it allows an entire human genome to be sequenced within one day. Cancer genomics posits that cancer is caused by mutations and is a disease of the genome. Now, cancer genomes can be systemically studied in their entirety. For cancer patients such as Reiner, NGS can provide a more precise diagnosis and classification of the disease, more accurate prognosis, and potentially the identification of targeted drug treatments. Ultimately, the technology can provide the basis of personalized cancer management.
The detailed reports supply patients and their oncologists with extensive information about the patient’s genomic profile and potential treatment options that they can discuss together. Reiner trusted his doctors that this approach was worth the two- or three-week wait to receive the Foundation Medicine report and the specifically targeted treatment, rather than immediately jump into a round of chemotherapy. He is especially grateful now, he says, because the report delivered a great deal of relief from his previously exhausting and growing anxiety about having cancer.
Reiner and his team learned his lung cancer contained the epidermal growth factor receptor (EGFR) mutation. That biomarker enabled his oncologist to prescribe Tagrisso (osimertinib), a medication developed to directly target that genetic mutation.
“Knowing there was a medicine for my particular type of cancer was like a weight lifted off my shoulders,” he says. “It only took a week or two before my cough finally started subsiding. This pill goes right after the particular piece of genetic material in the tumor that’s causing its growth.”
Dr. Jerry Mitchell, director field medical oncology, Foundation Medicine, in Columbus, Ohio, explains that genomic profiling is generating substantial impacts today. “This is a technology that is the standard of care across many advanced malignancies that takes patients from chemotherapy-only options to very targeted options or immunotherapy options,” he says. “You can also look at complex biomarkers, and these are not specific genetic changes but different genes across the tumor to get a biomarker.”
According to Dr. Mitchell, Foundation Medicine’s technology can test more than 324 different cancer-related genes in a single test. Thus, a growing number of patients are benefitting from comprehensive genetic profiling, due to the rapidly growing number of targeted therapies. While not all of the cancers are treatable yet, the company uses that information to partner with researchers to find new potential therapies for patient groups that may have rare mutations.
Since his tumor’s diagnosis, Reiner has undergone chemotherapy and a couple surgeries to treat the metastatic cancer in other parts of his body, but the drug Tagrisso has significantly reduced his lung tumor. Now, having learned so much during the past couple of years, he is grateful for precision oncology. He still reflects on the probability that, had the Tagrisso pill not been available in May 2019, he might have only survived for another six months or a year.
“Comprehensive Genomic Profiling is not some future state, but in both the U.S. and Europe, it is a very standard, accepted, and recommended first step to knowing how to treat your cancer,” says Dr. Mitchell, adding that he feels fortunate to be an oncologist in this era. “However, we know there are still people not getting this recommended testing, so we still have opportunities to find many more patients and impact them by knowing the molecular profile of their cancer.”
The U.S. population is becoming more diverse, but clinical trials don't reflect that, experts say. Some are focusing on recruiting minorities to participate in research.
While racial and ethnic minority groups represent almost half of the U.S. population, the lack of diversity in clinical trials poses serious challenges. Limited awareness and access impede equitable representation, which is necessary to prove the safety and effectiveness of medical interventions across different groups.
A Yale University study on clinical trial diversity published last year in BMJ Medicine found that while 81 percent of trials testing the new cancer drugs approved by the U.S. Food and Drug Administration between 2012 and 2017 included women, only 23 percent included older adults and 5 percent fairly included racial and ethnic minorities. “It’s both a public health and social justice issue,” said Jennifer E. Miller, an associate professor of medicine at Yale School of Medicine. “We need to know how medicines and vaccines work for all clinically distinct groups, not just healthy young White males.” A recent JAMA Oncology editorial stresses out the need for legislation that would require diversity action plans for certain types of trials.
Ensuring meaningful representation of racial and ethnic minorities in clinical trials for regulated medical products is fundamental to public health.--FDA Commissioner Robert M. Califf.
But change is on the horizon. Last April, the FDA issued a new draft guidance encouraging industry to find ways to revamp recruitment into clinical trials. The announcement, which expanded on previous efforts, called for including more participants from underrepresented racial and ethnic segments of the population.
“The U.S. population has become increasingly diverse, and ensuring meaningful representation of racial and ethnic minorities in clinical trials for regulated medical products is fundamental to public health,” FDA commissioner Robert M. Califf, a physician, said in a statement. “Going forward, achieving greater diversity will be a key focus throughout the FDA to facilitate the development of better treatments and better ways to fight diseases that often disproportionately impact diverse communities. This guidance also further demonstrates how we support the Administration’s Cancer Moonshot goal of addressing inequities in cancer care, helping to ensure that every community in America has access to cutting-edge cancer diagnostics, therapeutics and clinical trials.”
Lola Fashoyin-Aje, associate director for Science and Policy to Address Disparities in the Oncology Center of Excellence at the FDA, said that the agency “has long held the view that clinical trial participants should reflect the clinical and demographic characteristics of the patients who will ultimately receive the drug once approved.” However, “numerous studies over many decades” have measured the extent of underrepresentation. One FDA analysis found that the proportion of White patients enrolled in U.S. clinical trials (88 percent) is much higher than their numbers in country's population. Meanwhile, the enrollment of African American and Native Hawaiian/American Indian and Alaskan Native patients is below their national numbers.
The FDA’s guidance is accelerating researchers’ efforts to be more inclusive of diverse groups in clinical trials, said Joyce Sackey, a clinical professor of medicine and associate dean at Stanford School of Medicine. Underrepresentation is “a huge issue,” she noted. Sackey is focusing on this in her role as the inaugural chief equity, diversity and inclusion officer at Stanford Medicine, which encompasses the medical school and two hospitals.
Until the early 1990s, Sackey pointed out, clinical trials were based on research that mainly included men, as investigators were concerned that women could become pregnant, which would affect the results. This has led to some unfortunate consequences, such as indications and dosages for drugs that cause more side effects in women due to biological differences. “We’ve made some progress in including women, but we have a long way to go in including people of different ethnic and racial groups,” she said.
A new mural outside Guadalupe Centers Middle School in Kansas City, Missouri, advocates for increasing diversity in clinical trials. Kim Jones, 51-year-old African American breast cancer survivor, is second on the left.
Artwork by Vania Soto. Photo by Megan Peters.
Among racial and ethnic minorities, distrust of clinical trials is deeply rooted in a history of medical racism. A prime example is the Tuskegee Study, a syphilis research experiment that started in 1932 and spanned 40 years, involving hundreds of Black men with low incomes without their informed consent. They were lured with inducements of free meals, health care and burial stipends to participate in the study undertaken by the U.S. Public Health Service and the Tuskegee Institute in Alabama.
By 1947, scientists had figured out that they could provide penicillin to help patients with syphilis, but leaders of the Tuskegee research failed to offer penicillin to their participants throughout the rest of the study, which lasted until 1972.
Opeyemi Olabisi, an assistant professor of medicine at Duke University Medical Center, aims to increase the participation of African Americans in clinical research. As a nephrologist and researcher, he is the principal investigator of a clinical trial focusing on the high rate of kidney disease fueled by two genetic variants of the apolipoprotein L1 (APOL1) gene in people of recent African ancestry. Individuals of this background are four times more likely to develop kidney failure than European Americans, with these two variants accounting for much of the excess risk, Olabisi noted.
The trial is part of an initiative, CARE and JUSTICE for APOL1-Mediated Kidney Disease, through which Olabisi hopes to diversify study participants. “We seek ways to engage African Americans by meeting folks in the community, providing accessible information and addressing structural hindrances that prevent them from participating in clinical trials,” Olabisi said. The researchers go to churches and community organizations to enroll people who do not visit academic medical centers, which typically lead clinical trials. Since last fall, the initiative has screened more than 250 African Americans in North Carolina for the genetic variants, he said.
Other key efforts are underway. “Breaking down barriers, including addressing access, awareness, discrimination and racism, and workforce diversity, are pivotal to increasing clinical trial participation in racial and ethnic minority groups,” said Joshua J. Joseph, assistant professor of medicine at the Ohio State University Wexner Medical Center. Along with the university’s colleges of medicine and nursing, researchers at the medical center partnered with the African American Male Wellness Agency, Genentech and Pfizer to host webinars soliciting solutions from almost 450 community members, civic representatives, health care providers, government organizations and biotechnology professionals in 25 states and five countries.
Their findings, published in February in the journal PLOS One, suggested that including incentives or compensation as part of the research budget at the institutional level may help resolve some issues that hinder racial and ethnic minorities from participating in clinical trials. Compared to other groups, more Blacks and Hispanics have jobs in service, production and transportation, the authors note. It can be difficult to get paid leave in these sectors, so employees often can’t join clinical trials during regular business hours. If more leaders of trials offer money for participating, that could make a difference.
Obstacles include geographic access, language and other communications issues, limited awareness of research options, cost and lack of trust.
Christopher Corsico, senior vice president of development at GSK, formerly GlaxoSmithKline, said the pharmaceutical company conducted a 17-year retrospective study on U.S. clinical trial diversity. “We are using epidemiology and patients most impacted by a particular disease as the foundation for all our enrollment guidance, including study diversity plans,” Corsico said. “We are also sharing our results and ideas across the pharmaceutical industry.”
Judy Sewards, vice president and head of clinical trial experience at Pfizer’s headquarters in New York, said the company has committed to achieving racially and ethnically diverse participation at or above U.S. census or disease prevalence levels (as appropriate) in all trials. “Today, barriers to clinical trial participation persist,” Sewards said. She noted that these obstacles include geographic access, language and other communications issues, limited awareness of research options, cost and lack of trust. “Addressing these challenges takes a village. All stakeholders must come together and work collaboratively to increase diversity in clinical trials.”
It takes a village indeed. Hope Krebill, executive director of the Masonic Cancer Alliance, the outreach network of the University of Kansas Cancer Center in Kansas City, which commissioned the mural, understood that well. So her team actively worked with their metaphorical “village.” “We partnered with the community to understand their concerns, knowledge and attitudes toward clinical trials and research,” said Krebill. “With that information, we created a clinical trials video and a social media campaign, and finally, the mural to encourage people to consider clinical trials as an option for care.”
Besides its encouraging imagery, the mural will also be informational. It will include a QR code that viewers can scan to find relevant clinical trials in their location, said Vania Soto, a Mexican artist who completed the rendition in late February. “I’m so honored to paint people that are survivors and are living proof that clinical trials worked for them,” she said.
Jones, the cancer survivor depicted in the mural, hopes the image will prompt people to feel more open to partaking in clinical trials. “Hopefully, it will encourage people to inquire about what they can do — how they can participate,” she said.