Germline Genetic Testing Gap Persists in Ovarian Cancer, More Delimited Panel Composition Needed to Improve Utility

Only 34.3% of 14,689 patients with ovarian cancer received germline genetic testing between 2013 and 2019, revealing persistent underuse of testing among this population, according to data from a 7-year analysis of testing trends among patients diagnosed with either breast or ovarian cancer published in the Journal of Clinical Oncology. Moreover, testing more genes per patient was found to be associated with a growing racial or ethnic disparity in uncertain results.

Among the 187,535 patients with breast cancer included in the analysis, 25.2% received germline genetic testing. Differences in testing rates were observed between states. Testing rates in Georgia were 31.9% and 42.8%, respectively, for breast and ovarian cancers, while these rates were 23.4% and 32.1%, respectively in California (P <.001).

Rates of testing were found to have slightly increased by an average of 2% annually. However, a clear increase in the number of genes tested was noted. Moreover, an upward trend in gene number for patients with breast cancer and ovarian cancer was observed, going from about 10 genes to 35 genes. After adjusting for geographic site, race, and age, the annual increase in tested gene number for patients with breast cancer was 28.0% (95% CI, 27.5-28.8).

An increase in testers who received a pathogenic variant (PV)– or variants of uncertain significance (VUS)–only result was reported from early 2013 to late 2017, jumping from 30.8% to 43.0%, although this was mainly attributed to increases in VUS-only rates. Although the PV yield in BRCA1/2 decreased from 15.7% to 12.4% (P <.001), it increased in breast and ovarian genes (3.9% to 4.3%) and in other actionable genes (0.3% to 2.0%). VSU-only rates experienced a marked increased from 8.1% to 28.3% in patients diagnosed in early 2013 versus those diagnosed in late 2017, respectively.

Only small race and ethnicity differences in PV rates were observed among in patients with breast or ovarian cancer, with larger differences noted in VUS-only rates. Notably, VSU-only rates in breast cancer were markedly higher in Asian (42.4%), Black (36.6%) and Hispanic (27.7%) patients versus non-Hispanic White patients (24.5%; P <.001). In those with ovarian cancer, PV rates across racial and ethnic groups were found to diminish over time. However, large differences in VUS–only rates persisted. In 2017, VUS-only rates were markedly higher in Asian (47.8) Black (46.0%) and Hispanic (36.8%) patients compared with non-Hispanic white patients (24.6%; P <.001).

“We observed marked expansion in the number of genes sequenced; a modest trend in selection toward patients with lower pretest risk; no sociodemographic differences in testing trends; a small increase in PV rates; and a substantial increase in VUS-only rates,” the authors wrote. “Contrary to our hypotheses, we observed a major, sustained deficit in testing of patients with ovarian cancer (only 34.3% v nearly 100% recommended) and no evidence of reduction in the racial or ethnic disparity in VUS: these persistent gaps are key targets for intervention.”

In this analysis, investigators set out to understand how the use and results of germline testing were evolving over time among patients diagnosed with either breast or ovarian cancers.

Due to increasing interest in genetic risk evaluation, investigators theorized that MGP would entirely replace testing for BRCA1/2 only and there would be improvements in testing underutilization in patients with ovarian cancer. Additionally, they hypothesized that more patients would be tested for PVs at lower pretest risk levels and that there would be no observed differences in sociodemographic testing trends. Lastly, they expected to see increases in the detection of PVs and VUS, as well as decreased disparities in VUS for racial and ethnic subgroups.

The cohort for the study included women who were diagnosed with breast or ovarian cancer between January 1, 2013 and December 31, 2017. These diagnoses needed to have been reported to 1 of 4 SEER registries that provided statewide coverage to germline genetic testing results from 4 laboratories responsible for conducting the majority of clinical testing within the regions. The dataset comprised laboratory testing data, pertaining to genetic tests and laboratory results, combined with variables from SEER registries.

Patients under the age of 20 years who were missing race or ethnicity information, had more than 1 primary tumor, or were diagnosed from death certificate only were excluded from the analysis.

The majority of patients in the breast cancer cohort were non-Hispanic White (n = 113,906). Other races included Hispanic (n = 27,883), Asian (n = 23,180), Black (n = 22,040), and Native American (n = 526). The poverty level of patients was identified, with 84,630 patients determined to be low, defined as poverty less than 10%, 60,861 patients falling into the medium category, defined as poverty between 10% and 19%, and 41,737 patients determined to have a high poverty level of 20% or higher. In total, 37,583 patients had been diagnosed with grade 1 disease, 77,625 had grade 2 disease, and 40,956 had grade 3 disease.

The majority of patient with ovarian cancer included in the analysis were non-Hispanic white (n = 8,808), with other races including Hispanic (n = 2724), Asian (n = 1772), Black (n = 1347), and Native American (n = 38). In total, 6062 patients had a low poverty level, while 4811 were at the medium level and 3785 were at the high level. Additionally, 779 patients had grade 1 disease, 755 had grade 2 disease, 2061 had grade 3 disease, and 1617 had grade 4 disease.

Additional data indicated that 87.3% of patients received at least 1 test, 10.7% received 3, and 2.0% were given 3 or more. The majority of patients, or 71.8%, were tested within 6 months of being diagnosed, while the rest received testing more the 6 months after diagnosis (24.2%) or prior to diagnosis (4.0%). One-quarter of patients with breast cancer who received testing in 2013 were given MGP versus more than 80% of those diagnosed in 2017. The majority of patients who were diagnosed with breast cancer in 2017 received BRCA1/2 testing prior to being diagnosed. Similarly, 40% of patients with ovarian cancer who were diagnosed in 2013 received MGP compared with over 90% in late 2017. These findings appeared to be similar between states.

Additionally, older patients were more likely to be tested in later years, with patients over 60 years having increased testing rates in 2013 (from 11.1% to 14.9%) for breast cancer and ovarian cancer (25.3% to 31.4%). Conversely, patients who were under the age of 45 years were found to have lower rates of testing over time. Sociodemographic and clinical variables did not appear to notably impact testing rates over time.

In early 2013, 18.3% of testers had PV- or VUS-only result that increased to 37.2% in late 2017. A decrease in the proportion of patients with breast cancer who were tested and had pathogenic variants in BRCA1/2 was observed, going from 7.5% to 5.0% (P <.001). However, the pathogenic yield of patients with breast or ovarian cancer and other actionable genes increased from 1.3% to 4.6% and 0.3% to 4.6% in both groups, respectively.

Pathogenic variants were found in several breast and ovarian cancer genes including ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53. Additionally, pathogenic variants were identified in other actionable genes such as APC, MUTYH, RB1, RET, SDHB, SDHC, SDHD, SMAD4, and VHL.

“Our findings suggest that a more delimited panel composition could improve the clinical validity and utility of genetic testing for women with breast cancer or ovarian cancer,” the authors concluded. “Most PVs were found in 20 genes among patients with breast and ovarian cancer [ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53]; testing only these genes could maximize clinically relevant PV yield while minimizing VUS results, particularly for racial or ethnic minority patients.”

Reference

Kurian AW, Ward LC, 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. Published online 2021. doi:10.1200/JCO.20.02785