Take Home Message

  • Germline testing is inexpensive and drastically changes screening and reproductive approaches yet is currently underutilized.

  • Caution is warranted when interpreting Variant of Uncertain Significance (VUS) results and they should not be used to guide clinical care as this could lead to inappropriate interventions and false reassurances.

  • Germline Pathogenic Variants (PVs) can affect tumor biology in variable ways, and implications on outcomes are not always known.

Challenges and Opportunities in Germline Testing

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.

i. Breast Cancer

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

ii. Pancreatic Cancer

Pancreatic cancer is the 3rd 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

iii. Prostate Cancer

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.

Diagnostic and Therapeutic Opportunities from Germline DNA Sequence Analysis

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.

Conflict of Interest

Siddhartha Yadav 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.

Funding Information

N/A

Ethical Statements

N/A

Acknowledgement

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

Author Contributions

  • All authors: conception and design

  • All authors: data collection and assembly

  • IA: data analysis, manuscript writing

  • All authors have approved this manuscript.