For patients with ovarian cancer, approximately 28% were uninsured, 27% had Medicaid, and 39% had private insurance, Medicare, or other insurance.
The authors had previously found that less testing was associated with Black race, greater poverty, and less insurance coverage (J Clin Oncol. 2019 May 20;37[15]:1305-15). However, they noted no changes in testing rates by sociodemographic variables over time.
Hypothesis #5: Detection of both PVs and VUS will increase.
The proportion of tested breast cancer patients with PVs in BRCA1/2 decreased from 7.5% to 5.0% (P < .001), whereas PV yield for the two other clinically salient categories (breast or ovarian and other actionable genes) increased.
The proportion of PVs in any breast or ovarian gene increased from 1.3% to 4.6%, and the proportion in any other actionable gene increased from 0.3% to 1.3%.
For breast cancer patients, VUS-only rates increased from 8.5% in early 2013 to 22.4% in late 2017.
For ovarian cancer patients, the yield of PVs in BRCA1/2 decreased from 15.7% to 12.4% (P < .001), whereas the PV yield for breast or ovarian genes increased from 3.9% to 4.3%, and the yield for other actionable genes increased from 0.3% to 2.0%.
In ovarian cancer patients, the PV or VUS-only result rate increased from 30.8% in early 2013 to 43.0% in late 2017, entirely due to the increase in VUS-only rates. VUS were identified in 8.1% of patients diagnosed in early 2013 and increased to 28.3% in patients diagnosed in late 2017.
Hypothesis #6: Racial or ethnic disparities in rates of VUS will diminish.
Among patients with breast cancer, racial or ethnic differences in PV rates were small and did not change over time. For patients with ovarian cancer, PV rates across racial or ethnic groups diminished over time.
However, for both breast and ovarian cancer patients, there were large differences in VUS-only rates by race and ethnicity that persisted during the interval studied.
In 2017, for patients with breast cancer, VUS-only rates were substantially higher in Asian (42.4%), Black (36.6%), and Hispanic (27.7%) patients than in non-Hispanic White patients (24.5%, P < .001).
Similar trends were noted for patients with ovarian cancer. VUS-only rates were substantially higher in Asian (47.8%), Black (46.0%), and Hispanic (36.8%) patients than in non-Hispanic White patients (24.6%, P < .001).
Multivariable logistic regressions were performed separately for tested patients with breast cancer and ovarian cancer, and the results showed no significant interaction between race or ethnicity and date. Therefore, there was no significant change in racial or ethnic differences in VUS-only results across the study period.
Where these findings leave clinicians in 2021
Among the patients studied, there was:
- Marked expansion in the number of genes sequenced.
- A likely modest trend toward testing patients with lower pretest risk of a PV.
- No sociodemographic differences in testing trends.
- A small increase in PV rates and a substantial increase in VUS-only rates.
- Near-complete replacement of selective testing by MGP.
For patients with breast cancer, the proportion of all PVs that were in BRCA1/2 fell substantially. Adoption of MGP testing doubled the probability of detecting a PV in other tested genes. Most of the increase was in genes with an established breast or ovarian cancer association, with fewer PVs found in other actionable genes and very few PVs in other tested genes.
Contrary to their hypothesis, the authors observed a sustained undertesting of patients with ovarian cancer. Only 34.3% performed versus nearly 100% recommended, with little change since 2014.
This finding is surprising – and tremendously disappointing – since the prevalence of BRCA1/2 PVs is higher in ovarian cancer than in other cancers (Gynecol Oncol. 2017 Nov;147[2]:375-380), and germline-targeted therapy with PARP inhibitors has been approved for use since 2014.
Furthermore, insurance carriers provide coverage for genetic testing in most patients with carcinoma of the ovary, fallopian tube, and/or peritoneum.
Action plans: Less could be more
During the period analyzed, the increase in VUS-only results dramatically outpaced the increase in PVs.
Since there is a substantially larger volume of clinical genetic testing in non-Hispanic White patients with breast or ovarian cancer, the spectrum of normal variation is less well-defined in other racial or ethnic groups.
The study showed a widening of the “racial-ethnic VUS gap,” with Black and Asian patients having nearly twofold more VUS, although they were not tested for more genes than non-Hispanic White patients.
This is problematic on several levels. Identification of a VUS is challenging for communicating results to and recommending cascade testing for family members.
There is worrisome information regarding overtreatment or counseling of VUS patients about their results. For example, the PROMPT registry showed that 10%-15% of women with PV/VUS in genes not associated with a high risk of ovarian cancer underwent oophorectomy without a clear indication for the procedure.
Although population-based testing might augment the available data on the spectrum of normal variation in racial and ethnic minorities, it would likely exacerbate the proliferation of VUS over PVs.
It is essential to accelerate ongoing approaches to VUS reclassification.
In addition, the authors suggest that it may be time to reverse the trend in increasing the number of genes tested in MGPs. Their rationale is that, in Georgia and California, most PVs among patients with breast and ovarian cancer were identified in 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53).
If the Georgia and California data are representative of a more generalized pattern, a panel of 20 breast cancer– and/or ovarian cancer–associated genes may be ideal for maximizing the yield of clinically relevant PVs and minimizing VUS results for all patients.
Finally, defining the patient, clinician, and health care system factors that impede widespread genetic testing for ovarian cancer patients must be prioritized. As the authors suggest, quality improvement efforts should focus on getting a lot closer to testing rates of 100% for patients with ovarian cancer and building the database that will help sort VUS in minority patients into their proper context of pathogenicity, rather than adding more genes per test.
This research was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. The authors disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Genomic Health, Roche/Genentech, Oncoquest, Tesaro, and Karyopharm Therapeutics.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.