Enhanced Clinical Education and Simplified Guidelines Needed to Address Germline Testing Gaps in Breast Cancer

Sonya Reid, MD, MPH

Although the use of precision oncology has transformed breast cancer management, there is a notable under-utilization of germline testing in clinical practice, particularly among racial and ethnic minorities, as well as rural populations, according to Sonya Reid, MD, MPH. Broader testing implementation could increase access to targeted interventions and cost-effective, personalized preventive care for patients and their families if accompanied by enhanced clinical education and infrastructure, Reid said.

“We have to make sure that we’re identifying all our patients with breast cancer who benefit from germline testing, not only for risk reduction, but also for therapy recommendations,” Reid said in a presentation delivered during the 23rd Annual International Congress on the Future of Breast Cancer® East.¹ “Simplifying our germline testing guidelines may be a potential solution to increasing access as well as uptake of germline testing. However, implementing this in practice is not going to be without challenges and perhaps cost. Therefore, there will need to be modifications of course depending on the health care system.”

In her presentation, Reid discussed the current role and indications for genetic testing in breast cancer; outlined significant barriers to testing utilization among racial or ethnic minorities and underserved populations; and proposed strategies to ensure equitable access to testing.

Reid is an assistant professor in the Division of Hematology/Oncology at Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, in Nashville, Tennessee.

Current Guidelines for Germline Testing in Clinical Practice

Hereditary breast cancer (HBC) accounts for approximately 5% to 10% of all breast cancer cases, with BRCA1/2 mutations present in approximately 80% of HBC tumors. Accordingly, female patients harboring BRCA mutations have a 60% to 70% lifetime risk of developing breast cancer compared with a 12% risk in the general population. These patients also have a 50% or greater risk of developing a second primary breast cancer tumor.²

“Historically, germline testing for hereditary breast cancer was used to guide screening recommendations, recommendations regarding risk-reducing surgery, and family planning,” Reid stated in her presentation. “Today, it is increasingly clear that this information is useful to guide treatment recommendations.”

Germline testing can aid systemic treatment decisions using PARP inhibitors in the metastatic setting or adjuvant treatment decisions with olaparib (Lynparza) for high-risk, HER2-negative breast cancer. Guidelines for germline testing in breast cancer, including those from the National Comprehensive Cancer Network (NCCN) and the ASCO-Society of Surgical Oncology, advocate for testing based on age, cancer type, and family history to guide treatment decisions.^3,4

Appropriate patients should receive testing for high-penetrance cancer susceptibility genes other than BRCA1/2, including those with supportive family histories. Testing for moderate-penetrance genes may be offered to inform personal and family cancer risk. All patients should receive sufficient pre-test information for informed consent, and those with pathogenic variants should receive individualized post-test counseling.

Under-Utilization of Germline Testing Persists Despite Increasing Indications

According to data from a SEER analysis, 25.2% of patients with newly diagnosed breast cancer who were at least 20 years of age (n = 187,535) underwent BRCA1/2 or multi-gene panel testing between 2013 and 2017 in California or Georgia. Annual rates of germline testing increased by 2%, and the number of genes tested rose by 28%, Reid reported. Moreover, the incidence of variants of uncertain significance (VUS) doubled during this period, particularly among racial and ethnic minorities. The study recommended prioritizing testing for indicated patients rather than expanding the number of genes tested to avoid exacerbating the racial or ethnic disparities in VUS results.⁵

To further understand testing barriers, Deborah Cragun, PhD, of Moffitt Cancer Center, and colleagues performed an additional study of 1,182 non-Hispanic White and Hispanic patients with breast cancer who were 50 years of age or younger. Untested patients (109 Hispanic, 317 non-Hispanic White) completed questionnaires to understand barriers to not receiving testing, and tested participants (176 Hispanic, 580 non-Hispanic White) were asked about testing facilitators. Overall, the most common barriers to testing were cost and lack of testing recommendation.⁶

Provider recommendation, low cost, and implications for family sharing and testing were the main facilitators. Of note, Hispanic women were twice as likely as non-Hispanic White women to be unaware of genetic testing (P = .04), and Black women were 5.6 times less likely to undergo genetic testing (P < .001). Non-English–speaking Hispanic patients were also less likely to receive testing. However, differences in genetic testing rates were not found to be significant after controlling for clinical and socioeconomic factors.

This and other research has shown that disparities in utilization of germline testing services exist among racial/ethnic minority groups, those in rural areas, and those with a lower socioeconomic status, Reid emphasized.

These gaps in germline testing implementation could also be attributed to challenges with testing delivery. A national shortage of genetics health professionals (GHPs) has resulted in most testing being conducted without their involvement. Consequently, many patients treated by medical oncologists or surgeons do not consistently receive pretest counseling, Reid detailed.⁶

“We have seen prior studies [showing that] patients definitely have a high interest in receiving germline testing once they know the treatment implications, not only for themselves, but also for their family members,” Reid added. “The delivery of germline testing services can be complicated today, because not only are you doing point-of-care testing, but [you also must] ensure that patients have counseling to understand what germline testing is and the possible implications.”

Among BRCA carriers, disparities also persist in screening and risk-reduction strategies. Analysis of a population-based sample showed that Black women have lower rates of risk-reducing mastectomy and bilateral salpingo-oophorectomy compared with Hispanic and non-Hispanic White women, after adjusting for clinical and demographic variables (P = .025 and P = .008, respectively).⁷ Additionally, 76%, 28%, and 90% of Black (n = 440), Hispanic (n = 284), and non-Hispanic White (n = 897) women, respectively, underwent risk-reducing mastectomy.

“The crux of it is the delivery of follow-up care,” Reid emphasized. “Are [patients] getting the guideline-recommended [treatment] now that you have wrap-up or germline test results? …Because of where we are in this landscape, we need to make sure that we have increased education [of medical and surgical oncologists] but also [better] access to these services.”

Germline Testing Guidelines: A Valuable Tool or an Obstacle to Implementation?

Simplifying genetic testing guidelines may significantly increase the uptake of germline testing for Medicare recipients, low-income patients, and other underserved populations, particularly as more insurance companies cover testing delivery and commercial laboratories offer testing programs to facilitate access.

An institutional review board–approved multicenter prospective registry was initiated across 20 community and academic sites proficient in cancer genetic testing and counseling. The study enrolled over 1,000 patients, and data records were analyzed for 959 of the 1,000 patients originally enrolled. Results showed that 49.95% of these patients met NCCN criteria for germline testing, and 8.65% had a pathogenic or likely pathogenic variant. Among patients who met NCCN guidelines and had test results, 9.39% had a pathogenic or likely pathogenic variant. For patients who did not meet the guidelines, 7.9% had a pathogenic or likely pathogenic variant. The difference in positive results between these two groups was not statistically significant (Fisher’s exact test P = .4241).⁸

The study concluded that approximately half of patients with breast cancer and a clinically actionable pathogenic or likely pathogenic variant are missed by testing guidelines, and all patients diagnosed with breast cancer should accordingly undergo expanded panel testing.

“Guideline-based testing is what we have been using for quite some time now. But we continue to see low uptake in the real-world setting. We know it gets complicated and [the guidelines] get updated… frequently, and there’s variability depending on [which version] you’re using…” Reid said, adding that, “Some folks are now thinking, ‘Is universal germline testing [UGT] a simple test for everybody? Is it going to [result in] increased uptake?’ They feel perhaps that is going to make the process more streamlined. I think it’s a bit more complicated than that.”

Mainstreaming Universal Germline Testing Through Multi-Level Strategies

Universal genetic testing (UGT) of patients with breast cancer, including those from currently underserved populations, could fully elucidate the genetic factors involved in breast cancer development irrespective of the patient’s age or family history. However, the broad implementation of UGT in clinical practice presents several key challenges.

Many arguments against broad testing center around the cost. Although this has markedly decreased over the past decade, patients often undergo repeat routine preventive testing—such as mammograms, CT scans for lung cancer, colonoscopies, or lab tests—which may be expensive compared with the one-time cost of hereditary testing, Reid explained. The cost of testing must also be weighed against the expense of non-optimal therapies that a patient may receive if this genetic information is not made available in a timely manner.

In addition to financial barriers, there are also concerns about the impact of provider education, as oncology providers are not routinely trained in genetics. An observational study explored breast surgeons’ attitudes toward UGT and found that 90.3% expressed concerns about using this testing modality. Common reasons for concern included inadequate training, lack of access to genetic services in clinics, and the potential psychosocial impact on patients.

Incorporating UGT in clinical practice is also hindered by management challenges, such as the risk of over-treatment of patients with moderate-penetrance genes and the likelihood of patients with germline BRCA1/2 mutations receiving more aggressive treatments. Additionally, there is limited access to genetic counselors and follow-up care for many patients. The increased use of multi-gene panels has also led to a rise in VUS, which can widen racial and ethnic gaps in VUS rates, further complicating the clinical utility of genetic testing.

To address barriers to germline testing, several strategies should be considered. Integrating telemedicine into testing practices can make genetic testing more accessible for patients. Increasing collaboration between GHP and non-GHP practitioners, as well as utilizing genetic counselor extenders, could also enhance the reach and effectiveness of genetic counseling and testing services.

System adjustments include the use of automated real-time prompts in electronic health records, utilizing a navigation system to assist with resources for underinsured patients, and insurance regulations to increase access to germline testing, and providing webinars and other educational tools to inform providers about genetic testing indications and available resources.

Potential strategies to alleviate provider concerns include establishing partnerships between GHPs and non-GHPs to provide specialized training, implementing point of care testing to streamline the process and make it more accessible, developing academic-community partnerships to assist with interpreting genetic testing results through molecular tumor boards, and engaging in culturally targeted discussions. On a patient level, increased awareness and education on the germline testing process, as well as the benefits and implementations of testing, are crucial.

Addressing these issues will help optimize the benefits of germline testing and ensure equitable access and effective implementation across diverse patient populations, Reid concluded.

References

1. Reid S. Implications of mainstream germline testing in oncology practice. Presented at: 23rd Annual International Congress on the Future of Breast Cancer East; July 19-20, 2024; New York, NY.
2. Reid S, Cadiz S, Pal T. Disparities in genetic testing and care among Black women with hereditary breast cancer. Curr Breast Cancer Rep. 2020;12(3):125-131. doi:10.1007/s12609-020-00364-1
3. NCCN. Clinical Practice Guidelines in Oncology. Breast Cancer, version 4.2024. Accessed July 22, 2024. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
4. Bedrosian I, Somerfield MR, Achatz MI, et al. Germline testing in patients with breast cancer: ASCO-Society of Surgical Oncology guideline. J Clin Oncol. 2024;42(5):584-604. doi:10.1200/JCO.23.02225
5. Kurian AW, Ward KC, Abrahamse P, et al. Time trends in receipt of germline genetic testing and results for women diagnosed with breast cancer or ovarian cancer, 2012-2019. J Clin Oncol. 2021;39(15):1631-1640. doi:10.1200/JCO.20.02785
6. Reid-Lawrence S, Pal T, Mayer IA, et al. Disparities in pretest genetic counseling among a population-based sample of young breast cancer patients. J Clin Oncol. 2019;37(suppl 15):1579. doi:10.1200/JCO.2019.37.15_suppl.1579
7. Cragun D, Weidner A, Lewis C, et al. Racial disparities in BRCA testing and cancer risk management across a population-based sample of young breast cancer survivors. Cancer. 2017;123(13):2497-2505. doi:10.1002/cncr.30621
8. Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2019;37(6):453-460. doi:10.1200/JCO.18.01631