The Revolution in Germline DNA Testing: Actionable Takeaways from the 2023 Precision Oncology Summit

Breast, prostate, and pancreatic cancers are among the top ten leading causes of cancer-related deaths and are frequently associated with known pathogenic variants in genes such as BRCA1 and BRCA2 which serve as malignancy drivers, with significant implications on management including the use of targeted therapies. However, despite clinical implications, the prevalence of germline testing is very low. In a study by Kurian et al, the rates of germline genetic testing were 38.6% among women with ovarian cancer, 26% for female breast cancer, 50% for male breast cancer, 5.6% for pancreatic cancer, and 1.1% for prostate cancer. Additionally, there is a disparity in germline testing with lower rates of testing among Asian, Black, and Hispanic patients as compared with non-Hispanic White patients.¹

Below are key highlights pertaining to germline testing in breast, pancreatic and prostate malignancies.

There is an increased lifetime risk of breast cancer associated with various pathogenic variants in several genes including BRCA1, BRCA2, PALB2, CHEK2 and ATM, with BRCA1 and BRCA2 specifically representing a missed opportunity for screening.² Population-based studies such as the CARRIERS study and the Breast Cancer Association Consortium (BCAC) provide estimates of the prevalence and risk of breast cancer associated with pathogenic variants, which can inform screening and clinical management strategies.^3,4

Pancreatic cancer is the most common malignancy linked to pathogenic variants in BRCA with a 4.6% incidence noted in one study (3.6% BRCA2 and 1.0% BRCA1).⁵ Up to 20% of patients with pancreatic cancer are noted to have familial clustering (31% with a first-degree relative and 53% with a second-degree relative).⁶ Large prospective studies for pancreatic cancer screening in high-risk individuals are not available, but some centers have adopted screening with MRI and endoscopy ultrasound starting at age 50 in patients who are BRCA2 pathogenic variant carriers with a significant family history. Pathogenic variants in BRCA1 and BRCA2 may also affect therapeutic strategies as these patients are found to have improved overall survival with platinum-based chemotherapy.⁷ In addition, there is a role for maintenance Olaparib in increasing time off chemotherapy and long-term survival in a subset of patients.⁸

In the study by Pritchard et al., germline DNA of men with documented metastatic prostate cancer were isolated to assess mutations in 20 DNA-repair genes. 84 out of 692 patients (11.8%) were found to have pathogenic variants including BRCA2 (5.3%), CHEK2 (1.9%), BRCA1 (0.9%), and PALB2 (0.4%). Overall, the frequency of germline pathogenic variants in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among men with localized prostate cancer.⁹ Furthermore, studies also highlight high progression rates for BRCA2 carriers in prostate cancer,¹⁰ and overall worse outcomes.¹¹

It is important for clinicians to review the updated NCCN screening recommendations for select hereditary cancer genes, and the indications of genetic testing evaluation based on personal and family history. Ultimately, germline assessment has therapeutic implications, reproductive considerations, and cost-risk benefits.

In clinical practice, Variants of Undetermined Significance (VUS) and germline Pathogenic Variants (PVs) carry many nuanced implications. It is important to note that VUS are indeterminate results without a definitive clinical correlation to a benign or malignant process. Consequently, it is imperative that VUS results should not directly inform clinical decision-making. Furthermore, there is variability in how VUS is interpreted, and reclassification is a dynamic process.¹² The National Institute of Health's database called ClinVaris is a useful updated tool for clinicians reviewing these results as it aggregates information about genomic variation and its relationship to human health.

There is significant variability in the risk of breast cancer based on the genes involved by pathogenic variants: BRCA1, BRCA2, PALB2, CHEK2 and ATM. Furthermore, there appears to be variability based on race/ethnicity of PV carriers, with population-based studies raising the question of whether the penetrance of BRCA1 PV for breast cancer is higher in Black women as compared to Non-Hispanic White women.¹³ Recent attention has also focused on the influence of Polygenic Risk Scores (PRS) on cancer risk in PV carriers.¹⁴ Ultimately, it is important to note that multiple factors play a role in increasing the risk of breast cancer, such as family history, age of assessment, hormonal factors, environmental exposures, PRS and germline PVs. Personalized cancer prevention strategies based on genetic, personal history, and environmental exposures are essential and must be tailored to each individually unique patient.

Clinicians need to be aware of therapeutic and risk management implications of germline PVs in patients with cancer. For example, the risk of contralateral breast cancer is significantly elevated among BRCA1, BRCA2, CHEK2and ER-negative PALB2 PV carriers, but not in ATM PV carriers. In addition, the contralateral breast cancer risk is also influenced by age at diagnosis and menopausal status in germline PV carriers, and these factors need to be considered when reviewing the role of contralateral prophylactic mastectomy.¹⁵ In the OlympiA study, PARP inhibitors in adjuvant treatment of HER2 negative breast cancer with germline BRCA1 and BRCA2 PV were explored.¹⁶ Results demonstrated a 3-year distant disease-free survival (DDFS) of 87.5% vs. 80.4% (p-value <0.001) and a 3-year overall survival (OS) of 92.0% vs. 89.1% (p-value 0.009) for Olaparib vs placebo.

Some unanswered questions that future studies will help answer include the benefit of Olaparib vs. other adjuvant therapy choices in HER2 negative locoregional breast cancer, and the sequence of PARP inhibitors in relation to other treatments in metastatic breast cancer. However, it is important to note that not all germline predisposition pathogenic variants lead to similar tumor biology, so while it is reasonable to use PARP inhibitors in germline BRCA1, BRCA2 and PALB2 PV carriers with metastatic breast cancer, they were not found to be effective in germline CHEK2 or ATM PV carriers with metastatic breast cancer.

Finally, future directions for upcoming systemic therapies in germline PV carriers, include PARP1-selective inhibitors, POLθ Inhibitors, combination strategies, and identification of new biomarkers, all which will help shape this field moving forward.

SY has received research grants from AstraZeneca and Repare Therapeutics, and has served on an advisory board for Astrazeneca.

The rest of the authors report no conflicts.

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The authors thank the Binaytara Foundation for the opportunity to highlight this important topic.

Concept and design: IA, HA, AMK, IR, PM, SY, MDG

Data acquisition: IA, HA, AMK, IR, PM, SY, MDG

Data analysis and interpretation: IA

Drafting of the manuscript: IA

Critical revision of the manuscript: IA, HA, AMK, IR, PM, SY, MDG

All authors (IA, HA, AMK, IR, PM, SY, MDG) approved the final version of the manuscript and agree to be accountable for all aspects of the work, in accordance with the International Committee of Medical Journal Editors criteria.

1. Kurian AW, Abrahamse P, Furgal A, et al. Germline genetic testing after cancer diagnosis. JAMA. 2023;330(1):43-51. doi:10.1001/jama.2023.9526

2. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-2416. doi:10.1001/jama.2017.7112

3. Hu C, Hart SN, Gnanaolivu R, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384(5):440-451. doi:10.1056/NEJMoa2005936

4. Breast Cancer Association Consortium, Dorling L, Carvalho S, et al. Breast cancer risk genes—association analysis in more than 113,000 women. N Engl J Med. 2021;384(5):428-439. doi:10.1056/NEJMoa1913948

5. Holter S, Borgida A, Dodd A, et al. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J Clin Oncol. 2015;33(28):3124-3129. doi:10.1200/JCO.2014.59.7401

6. Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA Oncol. 2021;7(2):230-237. doi:10.1001/jamaoncol.2020.6252

7. Emelyanova M, Pudova E, Khomich D, et al. Platinum-based chemotherapy for pancreatic cancer: impact of mutations in the homologous recombination repair and Fanconi anemia genes. Ther Adv Med Oncol. 2022;14:17588359221083050. doi:10.1177/17588359221083050

8. Kindler HL, Hammel P, Reni M, et al. Overall survival results from the POLO trial: a phase III study of active maintenance olaparib versus placebo for germline BRCA-mutated metastatic pancreatic cancer. J Clin Oncol. 2022;40(34):3929-3939. doi:10.1200/JCO.21.01604

9. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144

10. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708. doi:10.1056/NEJMoa1506859

11. Cui M, Gao XS, Gu X, et al. BRCA2 mutations should be screened early and routinely as markers of poor prognosis: evidence from 8,988 patients with prostate cancer. Oncotarget. 2017;8(25):40222-40232. doi:10.18632/oncotarget.16712

12. Hu C, Susswein LR, Roberts ME, et al. Classification of BRCA2 variants of uncertain significance (VUS) using an ACMG/AMP model incorporating a homology-directed repair (HDR) functional assay. Clin Cancer Res. 2022;28(17):3742-3751. doi:10.1158/1078-0432.CCR-22-0203

13. Palmer JR, Polley EC, Hu C, et al. Contribution of germline predisposition gene mutations to breast cancer risk in African American women. J Natl Cancer Inst. 2020;112(12):1213-1221. doi:10.1093/jnci/djaa040

14. Barnes DR, Rookus MA, McGuffog L, et al. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genet Med. 2020;22(10):1653-1666. doi:10.1038/s41436-020-0862-x

15. Yadav S, Boddicker NJ, Na J, et al. Contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. J Clin Oncol. 2023;41(9):1703-1713. doi:10.1200/JCO.22.01239

16. Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215