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The Importance and Underuse of Germline Testing

Summary in Thirty Seconds

  • Germline genetic testing identifies inherited pathological variants that drive cancers. Having such a variant can increase the risk of developing a cancer by as much as 20 times.

  • Germline testing is recommended at varying rates depending on the cancer type, yet recent research of over a million people with cancer found that less than 7% underwent germline testing within 2 years of their cancer diagnosis.

  • Germline testing may not be done because people with cancer are not made aware of the need for it by their healthcare provider, and/or patients do not know of its utility and benefits.

  • Germline testing can help in selecting a precision medicine and/or a surgical approach to a person’s cancer. Identification of a germline pathological variant can also spur testing in at-risk family members. In pan-cancer and specific cancer germline testing, pathological variants are found in at least and often more than 10% of cases.

  • Experts recommend germline testing for all people with cancer who meet currently established testing guidelines. In some specific cancers (e.g., male breast cancer and ovarian cancer), this recommendation includes essentially all patients.

Recommended Germine Testing Versus Real-World Practice

Genetic mutations drive cancer, and such mutations or variants can be identified through NGS, although this testing is not performed as consistently or often as recommended.[1] Cancer-driving mutations can be germline (inherited), somatic (developed during a lifetime), or both. Having an inherited (germline) genetic variant increases the risk of developing cancer, sometimes by as much as 20-fold. The earlier a germline variant is detected, the earlier the disease is diagnosed, and the better, most effective treatments can be chosen (including, in some cases, prophylactic surgery). However, despite guidelines recommending germline genetic testing for many cancer patients and the increasingly low cost of NGS, a very small percentage of people with cancer undergo such testing, according to recent research.[2]


In this 2023 research, Kurian et al. used data from California and Georgia cancer registries on 1,369,602 adult patients diagnosed with cancer between 2013 and 2019 and found only 6.8% underwent germline genetic testing within two years of diagnosis.[3] The researchers focused on breast, colorectal, endometrial, ovarian, pancreatic, prostate, and lung cancers. Patients who had specific cancer types associated with greater oncogenic germline mutations had the highest testing rates: male breast (50%), ovarian (39%), and female breast (26%); nevertheless, even these patients were not tested as often as guidelines recommend. For male breast cancer—which strongly suggests an inherited gene variant—and ovarian cancer, testing is recommended in all cases.


Testing rates were lower for ethnic minority patients versus white patients. For example, while 25% of Asian, Black, and Hispanic patients with breast or ovarian cancer received testing, the rate was 31% for white patients. Ethnic minority patients also were more likely to receive inconclusive results (variants of uncertain significance). Inconclusive results in these populations are likely due to less genetic research to establish normal versus pathogenic variations.


Why Germline Testing Isn’t Done

One reason people with cancer may not undergo testing is that they are not made aware of the possibility, need for, or value of it by their healthcare provider. A survey of over 5,000 women with breast cancer found 1,511 had indications for formal genetic evaluations. However, 29.7% received a focused BRCA1/2 test, and 22.9% received a multi-gene test. Thus, 52.6% of the patients in this study underwent actual genetic testing. The authors concluded that “…there is a large gap between mandates for timely pretest formal genetic counseling in higher-risk patients and the reality of practice today.”[4]


Increasing Rates of Germline Testing and Genes Tested

More results from the study of California and Georgia patients with cancer found that the rate of germline testing for women with breast or ovarian increased annually by 2% over the 7 years studied, while the number of genes tested increased by 28% annually (from a median of 2 to 34). The authors concluded that for breast and ovarian cancer, increasing the number of genes widened the racial gap and increased the number of variants of uncertain significance, while the rate of patients being tested fell far below recommendations. The authors, therefore, concluded, “Quality improvement should focus on testing indicated patients rather than adding more genes.”[5]


Why Does Germline Testing Matter?

Risk Assessment: Germline testing is important because specific variants dramatically increase the risk of developing cancer. As examples, the risk of breast cancer in women by age 80 is 72% for BRCA1 carriers and 69% for BRCA2 carriers,[6] compared with 13% for the general population.[7] Similarly, the risk of ovarian cancer for BRCA1 carriers is 44%[8] compared to a lifetime risk of 1.3% in the general population.[9] For people with mismatch repair genes found in Lynch syndrome, the lifetime risk of colorectal cancer is up to 68%[10] versus 4.2% in the general population.[11] Looked at another way, germline variants influence between 3% and 10% of the total cancers diagnosed annually.[12]


Treatment Choices: Germline testing can also inform the selection of a medication or surgical treatment best matched for a patient. Some cancer drugs, such as those that target DNA repair in cancer cells, are more effective in people with certain gene variants. Additionally, germline testing can guide surgical choices, with recommendations that women with certain germline variants driving their breast cancer undergo a bilateral mastectomy.[13] Germline testing can also identify potential participants for clinical trials focused on treatments tailored to pathological germline variants.


Cascade Genetic Testing: Furthermore, patients with high-risk genes—as well as their relatives—can benefit from more preventive screening. Recognition of these germline variants is essential not only for optimal care of the patient with cancer but also to initiate cascade genetic testing (the testing of the biological relatives of an individual who has tested positive for a hereditary cancer) in at-risk family members who also may carry the familial mutation.


How Frequently Are Pathogenic Germline Variants Found?

Studies have identified a range of findings regarding the frequency with which oncogenic germline variants are found, although rates tend to hover at or above 10%.

Pan-Cancer: A 2019 study found up to 12% of tumor genomic profiling reports reveal a germline pathogenic variant across cancer types.[14] A 2020 study examined germline testing following tumor DNA sequencing in a diverse population of over 2,000 people with cancer. Pathogenic germline variants were detected in 617 patients (30.5%) and cancer types, including breast, colorectal, renal, lung, and bladder. Specific variants included 39% with BRCA1 and BRCA2 and 28% with MLH1, MSH2, MSH6, and PMS2 (the Lynch syndrome mismatch repair genes). The authors of this study suggested that germline analysis following tumor sequencing “…often produces findings that may impact patient care by influencing systemic therapy choices, surgical decisions, additional cancer screening, and genetic counseling in families.” They concluded by stating, “Current guidelines and tumor testing approaches…[reinforce] the utility of both expanded germline follow-up testing as well as germline analysis independent of tumor sequencing in appropriate patients.”[15]

A 2021 study of almost 12,000 patients across over 50 malignancies found that 17% (2,037) had a germline likely pathogenic or pathogenic variant. BRCA1/2 variants accounted for 42% of therapeutically actionable findings, followed by CHEK2 (13%), ATM (12%), mismatch repair genes (11%), and PALB2 (5%).[16] A 2022 JAMA study of almost 35,000 people with cancer types not having hereditary testing guidelines found pathogenic or likely pathogenic germline mutations in 7% of patients.[17] A study of 751 children with a range of pediatric cancers found pathogenic or likely pathogenic variants in 18% of individuals.[18]


In a 2021 analysis of almost 12,000 people with a range of advanced cancers, 8% of patients harbored a germline variant, and 40% of these patients received germline genotype-directed treatment. The authors conclude, “Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer.”[19]


Colorectal Cancer: In a 2023 study of people 50 and younger with CRC, pathogenic germline mutations were identified in 25 of 130 (19%, or almost 1 in 5) patients. Additionally, a variant of uncertain significance was found in 23 (18%) patients. The authors conclude, “This detection rate, coupled with a high level of interest and acceptance from patients and feasibility of implementation, supports universal germline cancer risk assessment in this patient population.”[20] Another study of adults under 50 with CRC found that 27% had a pathogenic or likely pathogenic variant in a cancer susceptibility gene, emphasizing the importance of universal genetic testing in young-onset CRC.[21] A 2022 study of people across all ages with colorectal cancer found that 1 in 6 patients who underwent germline testing had pathogenic or likely pathogenic germline variants, and most of these variants were clinically actionable.[22]


Prostate Cancer: In a study of almost 600 men with prostate cancer, testing revealed actionable germline variants in 13% of the patients; furthermore, as seen in other studies, ethnic minority patients were less likely to receive such testing.[23] Carriers of germline BRCA2 mutations have a twofold to fourfold higher risk of prostate cancer than the general population.[24] A review of prostate cancer and germline testing concludes that “Germline evaluation is increasingly important in the management of men with metastatic prostate cancer and may also affect the prognosis for men with localized disease. The presence of germline mutations has important hereditary cancer implications for men and their families. Uptake of germline evaluation may be underutilized in some practice settings, so strategies for optimization are required.”[25]


Breast Cancer: According to an ASCO review, approximately 10% of high-risk patients with breast cancer,[26] are found to carry a pathogenic variant in one of the breast cancer predisposition genes.[27] Approximately 20% of hereditary breast cancers are attributable to pathogenic variants in BRCA1 and BRCA2 genes. Additional pathogenic variants in other breast cancer susceptibility genes include ATM, CHEK2, PALB2, RAD51C, RAD51D, and BARD1.[28]


In a study of over 5,000 African American women with breast cancer, pathogenic germline variants were identified in 10.3% of women with estrogen receptor-negative breast cancer, and 5.2% of women with estrogen receptor-positive breast cancer. Mutations in BRCA1, BRCA2, and PALB2 were associated with the highest risks of breast cancer.[29] In a 2020 study out of Korea, 496 patients were tested for pathological germline variants (PGVs), and 95 (19%) were found to have PGVs in 16 cancer susceptibility genes. The variants were most frequently found in patients (34.5%) who were diagnosed with breast cancer younger than 40 years of age. Of the 95 patients with PGVs, 60 patients (63.2%) had BRCA1/2 mutations.[30]


Ovarian Cancer: A 2023 ASCO Educational Book estimates that 10-15% of ovarian cancer cases have germline mutations.[31] A study out of Greece found similar results with germline BRCA1/2 mutations identified in 13-15% of ovarian cancers.[32] Additionally, a 2022 summary of 28 studies of ovarian carcinoma found the overall estimated proportion of germline BRCA1/2 germline pathological variants was 16.8%, with the proportions being highest in high-grade serous (22.2%) and lowest in clear cell (3.0%) and mucinous (2.5%) carcinomas.[33] An additional 5-6% of ovarian cancers were due to other germline mutations.[34]



The Bottom Line

Numerous cancers are driven by pathological germline variants. Identifying such variants can not only help guide treatment decisions but doing so can also inform the family members of that patient about their risk for developing certain cancers and proactive steps to take in response to this knowledge. The continued development of high-throughput NGS has notably lowered the cost of conducting somatic and germline testing.


Yap et al. recommend an integrated approach for the optimal management of patients with different cancers. The authors state, “NGS tests built to more uniformly and comprehensively evaluate both the germline and tumor simultaneously are urgently required and are in development. We also recommend offering germline testing to all patients who meet current established guidelines for testing even in the absence of a mutation in a risk-conferring gene on a tumor NGS test.”[35]


[1] J Clin Oncol. 2021; 39(suppl 15):abstr 9004 [2] J Clin. Oncol. 2023; 41(16_suppl):10500 [3] JAMA. 2023;330(1):43-51 [4] J Clin Oncol. 2018 Apr 20; 36(12): 1218–1224 [5] J Clin Oncol. 2021 May 20; 39(15):1631–1640 [6] JAMA 2017; 317(23):2402-2416 [7] seer.cancer.gov/csr/1975_2016 [8] JAMA 2017; 317(23):2402-2416 [9] seer.cancer.gov/csr/1975_2016 [10] Fam Cancer 2016;15(3):385-393 [11] seer.cancer.gov/csr/1975_2016 [12] Exp. Review on Anticancer Ther. 2009; 9(4):389-392 [13] JAMA Netw Open. 2021; 4(4):3216391 [14] J of Oncol. Pract. 2019; 15(9):465-473 [15] JAMA Netw. Open. 2020; 3(1):e2019452 [16] J Clin. Oncol. 2021; 39(4):2698-2709 [17] JAMA Netw Open. 2022 May; 5(5):e2213070 [18] Nat. Cancer. 2021; 2:357-365 [19] J Clin. Oncol. 2021; 39(24):2698-2709 [20] Diseases of the Colon & Rectum. 2023; 66(4):531-542 [21] Clin. Gastroent. & Hepatol. 2022; 20(2): 353-361 [22] JAMA Netw Open. 2022;5(10):e2238167 [23] JCO Oncology Practice. 2023; 19(5):e773-e783 [24] Nature Rev. Urol. 2023; 20:205-216 [25] Euro. Urol. Oncol. 2019; 4(1):10-11 [26] J Clin Oncol. 2016; 34(13):1460–1468 [27] ASCO Educational Book. 2019; 39:61-74 [28] Histopath. 2023; 82(1):70-82 [29] J of National Canc. Inst. 2020; 112(12):1213-1221 [30] Cancer Res Treat 2020;52(3):697-713 [31] ASCO Educational Book. 2023; 43:e390738 [32] Front Oncol. 2022; 12:1030786 [33] Gyn Oncol. 2022; 164(1):221-230 [34] Am J of Managed Care. 2019; 25(9) [35] ASCO Educational Book. 2023; 43:e390738

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