NEW YORK – Recognizing the need to improve access to genetic testing for cancer risk, several groups set out to explore the use of technology-enabled pre-test education and showed that these strategies are effective at diminishing certain logistical barriers.
However, the studies also revealed that more work is needed to cross socioeconomic and racial divides hindering access.
Although practice guidelines still largely recommend using people's personal and family history of cancer as key factors in determining who should receive genetic testing, there is greater recognition among genetics experts and oncologists that this strategy misses a substantial number of at-risk individuals. Guideline bodies, such as the National Comprehensive Cancer Network or the American College of Medical Genetics and Genomics, don't support population screening approaches, but in recent years have expanded testing recommendations for all patients with certain high-risk cancers, such as ovarian cancer patients and prostate cancer patients with high-risk, extremely high-risk, regional, or metastatic disease.
Even so, only an estimated 20 percent of patients who should be tested according to guidelines end up receiving it. For example, although guidelines have recommended testing all women with ovarian cancer for their genetic risk, only a third of patients are being tested. Meanwhile, the genetic risk assessment rates among men with prostate cancer are not well studied, but are probably low, experts suspect, since most men get treated in community settings with reduced access to genetics medical specialists or counselors.
A big part of the problem is the manner in which genetic testing has been historically deployed. Traditionally, in order to receive genetic testing a patient would have to come into a doctor's office. If after a pre-test evaluation of the patient's health and family history the doctor or a genetic counselor determined testing was needed, the patient would provide a sample for analysis. Upon return of results, the patient would have to come to a healthcare facility again to speak with a genetic counselor and discuss the findings and the healthcare implications.
"Costs due to multiple clinic visits and high drop rates for referred patients to in-person genetic counseling remains a significant barrier," Jennifer Klemp from the University of Kansas Cancer Center said at the American Society of Clinical Oncology's virtual annual meeting this week, reviewing the data from two studies that demonstrated that video-based online and in-clinic education in the pretest setting can increase access to genetic testing.
Most patients assessed for inherited cancer risk mutations will receive negative results. However, as demand for such testing grows, putting pressure on health systems and the genetic counseling community, there has been a need to rigorously study the risks and benefits of technology-enabled approaches, and the level of pre- and post-test education that patients need to understand how the results impact them and their families.
In one study, called Make Genetic Testing Accessible (MAGENTA), researchers led by University of Washington's Elizabeth Swisher explored how online pre- and post-test counseling impacted the distress levels of patients whose test results were negative for breast and ovarian cancer risk mutations, compared to those who received telephone counseling. In another study, called ProGen, researchers led by Dana-Farber Cancer Institute's Huma Rana focused on men with potentially lethal prostate cancer and assessed whether video pretest education provided at a cancer center, instead of in-person genetic counseling, impacted their willingness to be tested.
The results of these studies "have suggested tools for breaking down established barriers by incorporating technology into clinical pathways," Klemp said, noting that in both studies technology-enabled interventions resulted in more or equal numbers of patients getting genetic testing compared to the traditional intervention arms.
However, the studies also showed there were other more entrenched barriers that needed more work to topple. Race, insurance coverage, and rural zipcodes are also important factors limiting testing uptake, Klemp observed, and noted that these studies still did not enroll patients from different socio-economic and racial groups in equal numbers.
MAGENTA: A randomized investigation
Some years ago, consumer genetics companies such as 23andMe recognized the challenges with the traditional testing paradigm and attempted to use technology to upend this model by allowing patients to order testing for themselves online, receive spit kits in the mail so they could submit a sample for testing form their homes, and receive genetic education and test results also online, without needing to see a physician. But this model has been criticized for not offering genetic counseling support, especially for those with a personal or family history of certain diseases and for those with clinically significant test results.
Subsequently, newer companies, like Color, came on the scene, that used at-home sample collection and online education modules, but also offered telephone counseling for those with positive results and for anyone who wanted to speak to a counselor. The participants in the MAGENTA trial, most of whom didn't have a personal history of cancer, received genetic testing from Color, and as such, the study may be viewed as a validation of the education and counseling approach the company has been using in its commercial testing service.
"We knew going into MAGENTA that we were going to learn about how effective our model was … [and that it] may have consequences for how we were doing things," said Color's Chief Science Officer Alicia Zhou in an interview.
The trial, launched in 2018, recruited 3,000 patients into two cohorts — 2,250 patients who were getting testing because they had a family history of breast or ovarian cancer or personal history of breast cancer; and 750 patients who were receiving cascade testing because they had a relative with a breast or ovarian cancer risk mutation. The patients were randomized into four arms: arm A included pre-test online video education and released results online; arm B included online pre-test education but a counselor communicated the results over the phone; arm C included pre-test online education and telephone counseling and a counselor also called the patient to discuss the results; and arm D included pre-test online and telephone counseling and online receipt of results.
Arm C, where genetic counselors were involved in both the pre- and post-test setting, was the control arm. Arm A, which didn't involve pre- or post-test telephone counseling, is the model used by Color for those with negative results. Within MAGENTA, all patients who had pathogenic mutations received post-test telephone counseling, which is also Color's policy. The company attempts to contact individuals multiple times using different methods to ensure that nearly 100 percent of those with positive results receive post-test telephone counseling.
"This has always been our model," Zhou said. "At the end of the day, there are very important and nuanced conversations that must be had for individuals who carry a mutation … The result is just the beginning of the journey and we have to make sure we're helping these individuals achieve a better health outcome."
As such, the goal within MAGENTA was to assess whether there was any harm in not providing this same level of tele-counseling support to the majority of patients with negative results. Out of 14,467 individuals who completed the eligibility questionnaire for the study, ultimately, 3,833 completed the baseline questionnaire and were randomized. Of those individuals, 88 percent completed pre-test counseling or video education, 84 percent returned the test kit, and 73 percent completed post-test counseling or viewed results online.
Among the around 2,000 individuals who completed the post-test survey after three months, the researchers found that the level of distress was statistically no different upon learning their test results across the four arms in both the cascade testing and family history testing cohorts. There were 360 participants whose surveys indicated high distress at three-month follow up, but a statistically similar proportion of patients experienced distress across the intervention arms. Levels of anxiety, depression, and decisional regret were also not different across the arms.
In the future, investigators will analyze whether the level of distress among individuals with pathogenic results was different based on the type of pretest intervention they received. But based on the analysis so far, the data "support the use of a genetic testing paradigm providing individualized post-test genetic counseling only for patients with positive results and for those patients who request additional information," Swisher said.
Notably, individuals in arms A and B, which involved online education but no pre-test counseling, had the highest test completion rate, around 88 percent in each arm. In comparison, only 80 percent completed testing in the control arm C, which required pre- and post-test counseling, and 75 percent in arm D, which involved only post-test counseling.
Although the randomized design gives strength to the study findings, Swisher noted that the findings may not be broadly generalizable. MAGENTA showed that the strategies used in the study can make it easier for people to access genetic testing, but the study still enrolled mostly Caucasian, highly educated women, Swisher noted, despite efforts through media stories and targeted social-media advertising to recruit under-represented groups.
"When we embarked on MAGENTA it was uncharted territory to do purely digital recruitment," said Zhou. "Internet ads and social media ads probably lend themselves to a specific social demographic."
Sung Poblete, CEO of Stand Up To Cancer, which designed MAGENTA in collaboration with the Ovarian Cancer Research Fund Alliance and the National Ovarian Cancer Coalition, noted in an email that the organization has learned that community-based approaches can help increase cancer clinical trial participation among people of color. For example, collaborations with church leaders and local business owners, providing information in culturally sensitive language, and education materials that address beliefs and knowledge gaps specific to communities can all help build trust.
As of earlier this year, Poblete said that future grantees of SU2C-supported trials will be required to detail how they will recruit diverse populations. "These plans must target underserved communities surrounding participating institutions," she said.
The results of MAGENTA come as Color has been building a genetic counseling resource for the National Institutes of Health's All of Us Research Program, a research project that aims to genetically test 1 million individuals and return results on disease risk and drug response. Though only a subset of study participants will need genetic counseling, Color must make the counseling service work on a national scale, and meet the needs of people who speak different languages and span the socio-economic spectrum.
In contrast to MAGENTA where recruitment relied heavily on digital advertising, she noted that All of Us is approaching enrollment not only digitally, but also using billboards, community engagement strategies, and local clinics and regional healthcare systems around the country. As for Color's telegenetics services, the company has conducted telephone counseling to more than a thousand patients in 53 countries, including in the United Arab Emirates and Trinidad and Tobago, and the interactions have been positive, Zhou said.
"The counseling, we've found, works well in many different environments," she said, highlighting that Color last year worked with the Teamsters Union in Philadelphia, which represents truck drivers. In working with this group of largely men, who are often on the road, as well as their families, Color learned that many didn't have a primary care doctor. By having them fill out a health questionnaire, Color was able to identify not only those at risk for cancer but also individuals at risk for common health conditions, such as diabetes, and nudge them to see a primary care doctor. "We've been trying to adapt our service to make sure we can serve everyone, and these learnings will help us adapt our service for the All of Us population," Zhou said.
Timely prostate cancer testing
Men, in particular, are an underserved group when it comes to genetic risk assessment and genetic counseling. A survey published in JAMA Oncology of 378 adults in the US showed that men got tested for breast and ovarian cancer-linked gene mutations at one-tenth the rate that women did. This is the case, even though men's cancer risk can also be impacted if they have mutations in genes such as BRCA1/2, and even though they can pass these mutations on to their children at the same rate as women.
"That was one of the reasons to do the [ProGen] study," Dana-Farber Cancer Institute's Rana said in an interview. "Here was a population where the importance of these inherited mutations in these genes had not been previously highlighted. Even if men knew that there was a BRCA1/2 mutation in their family, they thought that it had very little implication for them."
ProGen, Rana's group decided to study the efficacy of video-based education compared to traditional genetic counseling to try to improve the likelihood that more men will get genetic testing. They focused on a group, men with potentially lethal prostate cancer, where there was a reasonable likelihood that test results will have clinical utility.
There are guidelines recommending genetic testing for men with high-risk prostate cancers, and an estimated 10 percent of men with advanced prostate cancer have pathogenic or likely pathogenic variants in cancer risk genes. However, it has become even more important to increase testing rates among men because the results can increasingly inform their cancer treatment.
The US Food and Drug Administration this month approved two PARP inhibitors, rucaparib (Clovis Oncology's Rubraca) and olaparib (AstraZeneca/Merck's Lynparza) for men with castration-resistant prostate cancer, which has a very poor prognosis. In order to receive rucaparib, men must have BRCA1/2 mutations, and to receive olaparib men must have homologous recombination deficiency based on mutations in BRCA1/2, ATM, and a dozen other genes involved in DNA repair.
"Genetic information has always been important because it can explain why people develop cancer and can inform risk for their relatives, but this idea that having this information could change their treatment puts a time pressure on receipt of this information that didn't exist otherwise," said Rana. "In people with prostate cancer, actually knowing whether or not you have a pathogenic variant in one of these homologous recombination repair genes is quite impactful from a treatment perspective."
In ProGen, researchers recruited 662 men between 2017 and 2019 at Dana-Farber in Boston, Barbara Karmanos Cancer Institute in Detroit, and at the University of Texas Southwestern Medical Center, and randomized them three-to-one to the video education arm in the hospital setting or the in-person genetic counseling arm.
In the video education arm, a research coordinator at the cancer center played a seven- to eight-minute video for patients, which reviewed the same pre-test education topics a genetic counselor would, such as what having a mutation means, how mutations are passed on in families, and what legal protections there are for people's genetic information. After the pre-test session, patients were asked whether they wanted to get tested for a panel of 67 cancer-associated genes performed by Ambry Genetics.
"People say they'll do genetic testing, but then they never show up for their visit," Rana said. "We see that a fair amount."
To date, 93 percent of men randomized to the video education arm saw the video and 88 percent in the genetic counseling arm spoke to a counselor; the difference wasn't statistically significant. Overall, 597 patients consented to genetic testing and 593 patients got tested — 99 percent in the video education arm and 98 percent in the genetic counseling arm, which again, was not a statistically significant difference.
"There was drop-off along the way" in terms of who ended up getting genetic testing, Rana said, "but that’s still very high." The higher-than-usual rate of participation in the genetic counseling arm she attributed to the availability of PARP inhibitors as potential treatment options and the endorsement of the ProGen study by patients' doctors.
Of those tested, 78 men, or 13 percent, learned they had a pathogenic cancer-risk mutation, one third of whom harbored pathogenic mutations in BRCA1/2. Additionally, 87 percent had a non-actionable report, either a negative result or a variant of unknown significance.
Regardless of whether patients had positive, negative, or VUS results, they were communicated to them by a genetic counselor. While researchers are still collecting data on the impact of these interventions through post-test surveys, the first set of surveys found no difference between patients who got pre-test video education or genetic counseling in their satisfaction or willingness to disclose results to family members. Rana recounted how one of the men in the video education arm told her that after learning about his BRCA2 mutation through the study, he told his sister to get tested. His family didn't previously know about this mutation.
Based on the results of this program, Dana-Farber has implemented pre-test video education within the Rapid Access to Cancer Genetic Testing program. Although the program was launched in February for prostate cancer patients, and a handful of patients got the video education ahead of testing, it has been put on hold due to COVID-19-related restrictions on patients coming into the cancer center.
In the meantime, patients can partake in the OptIn study remotely, Rana said. That trial is randomizing advanced cancer patients to either pre-test video education or a chatbot (provided by Invitae subsidiary Clear Genetics) and is gauging participants' genetics knowledge and satisfaction.
During her presentation at ASCO, Klemp noted that while both ProGen and MAGENTA demonstrated the potential of alternative genetic education models in expanding testing access, the studies also have their limitations in terms of lack of diversity. Similar to MAGENTA, the majority of participants (88 percent) in ProGen were Caucasian. "But their strengths outweigh their limitations, and open up opportunities," she said, suggesting that researchers form multi-center collaborations to explore alternative testing paradigms for high- and low-resource environments.