In May 2024, the American Society of Clinical Oncology (ASCO) published new guidelines for germline genetic testing in patients with cancer (1).
Contents
Introduction to hereditary cancer and germline genetic testing
Hereditary cancer refers to cancers that run in families due to inherited genetic changes, known as germline mutations. These mutations can be passed down from parents to children, increasing the risk of developing hereditary cancer in the future. It’s estimated that around 10% of all cancers are caused by inherited genetic factors (2). Common hereditary cancers include breast, colon, ovarian, melanoma, and gastric cancers and have been linked to various inherited gene mutations such as BRCA1/2, PTEN, CDH1, APC, and TP53. These genetic mutations may also lead to the development of different types of tumors. For example, BRCA1/2 is associated not only with breast cancer but also with ovarian, prostate, and pancreatic cancers.
Germline genetic testing is a valuable tool for identifying individuals with germline mutations. This can be useful for people who might be at high risk of developing cancer in the future but also for patients with an existing type of cancer who might want to test the hereditary nature of the tumor. Determining whether a cancer is due to a germline mutation can help in guiding therapeutic decisions, as well as in early detection of family members who may also carry the same mutations leading to early intervention and preventive measures for at-risk relatives (4).
Advances in medical genetics have expanded the availability and scope of germline genetic testing. Healthcare providers can now utilize multigene panels to identify inherited mutations associated with increased cancer risk. This information is crucial for determining appropriate patient testing and treatment plans. However, family history remains a vital factor in assessing the need for germline genetic testing. Understanding a patient’s family history is essential for providing personalized screening and prevention recommendations.
Purpose
These guidelines aim to help healthcare providers select the most appropriate multigene panel for germline genetic testing for patients with cancer, based on their personal and family history. The recommendations also guide the oncologists to identify when germline testing is indicated for cancer patients who already have had genetic tumor profiling.
Target population
The target population of these guidelines is adult patients with cancer, excluding hematologic types of cancer.
Methodology used to develop the recommendations
A multidisciplinary ASCO expert panel was convened and comprised 20 people from different areas of expertise including medical oncology, genetic counselling, patient advocacy, clinical genetics, and others. The team conducted a systematic review of guideline articles published since 2014 by other professional bodies and societies, such as the National Institute for Health and Care Excellence, the National Comprehensive Cancer Network (NCCN), the Scottish Intercollegiate Guidelines Network (SIGN), the European Society for Medical Oncology (ESMO), the College of American Pathologists (CAP), and the Association for Molecular Pathology (AMP). The articles were critically assessed and documents that did not meet certain criteria were excluded from the review. In total, 52 articles met eligibility criteria, and 14 studies were identified for Clinical Question 4 (see below). Draft recommendations and guidelines were developed and evaluated using the GRADE rating system. This method assessed the quality of the evidence by categorizing them as high, moderate, low, or very low. In addition, the developed recommendations were also assessed based on the strength of the recommendation and categorized as strong or weak. Before publishing the results, the recommendations were also released to the public for open comment.
The recommendations were developed based on 4 major Clinical Questions:
- What is the importance of family history collection in the setting of germline multigene panel testing and what elements of family history are most important?
- When and how should germline multigene panel testing be used?
- Which genes are generally recommended for germline genetic testing and for which patients?
- Which patients should be offered germline genetic testing who will have or have had somatic genetic tumor testing?
Recommendations developed
Recommendations for Question 1:
It is strongly suggested that:
- all patients should have a family history recorded.
- patients should provide information, if available, on whether they have first- or second-degree relatives with cancer, the type of cancer, if a relative already had germline genetic testing for hereditary cancer, the patient’s ethnicity as well as, the gender of the patient assigned at birth.
Recommendations for Question 2:
It is strongly suggested that:
- if germline genetic testing is indicated, a multigene panel should be offered if more than one gene is relevant.
For example, hereditary breast cancer can be caused by mutations in several genes such as BRCA1, BRCA2, CDH1, PTEN, and PALB2. To identify all possible genetic causes, a multigene germline genetic test that covers associated breast cancer genes, should be recommended for individuals with breast cancer.
It is also suggested that when healthcare providers consider a multigene germline genetic test, the panel should include at least the strongly recommended gene based on the patient’s family and personal history and may include the less strongly recommended genes. See Table 1 for the full list of recommended genes. In addition, it is recommended that a broader gene panel be considered if there are clear benefits such as screening for multiple genes that might increase the risk of developing cancer and can be inherited through families.
Recommendations for Question 3:
It is strongly suggested that:
- patients with specific types of cancer should be tested for a certain set of genes as summarized in Table 1. These genes can be strongly or less recommended for genetic testing, depending on their level of importance. However, testing all relevant genes based on a patient’s family and personal cancer history is generally advisable.
Recommendations for Question 4:
It is strongly suggested that:
- germline genetic testing should be offered to any patient who meets the criteria irrespective of tumor testing results, whether obtained by tissue or liquid biopsy.
- even if a patient doesn’t meet the standard criteria for germline testing, they should still be offered genetic testing if a pathogenic or likely pathogenic genetic mutation linked to cancer is discovered in their tumor and listed in Table 2.
Conclusion
Germline genetic testing is crucial for managing hereditary cancer. These new guidelines assist healthcare providers in understanding the benefits of germline genetic testing in patients with cancer and guide them toward selecting the most appropriate panel depending on each clinical case. Incorporating these guidelines into clinical practice, healthcare providers can offer more personalized and effective care to cancer patients.
References
[1] Tung N, Ricker C, Messersmith H, Balmaña J, Domchek S, Stoffel EM, et al. Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline. J Clin Oncol. 2024 Jul 20;42(21):2599–615. https://ascopubs.org/doi/10.1200/JCO.24.00662
[2] The Genetics of Cancer – NCI. 2015. https://www.cancer.gov/about-cancer/causes-prevention/genetics Accessed 23 Aug 2024
[3] Cancer Research UK 2015. Inherited genes and cancer types. Available from: https://www.cancerresearchuk.org/about-cancer/causes-of-cancer/inherited-cancer-genes-and-increased-cancer-risk/inherited-genes-and-cancer-types Accessed 23 Aug 2024
[4] OCRA. 2022. Germline vs Somatic, Genomic vs Genetic Testing. https://ocrahope.org/news/germline-vs-somatic-testing-genomic-vs-genetic-testing/ Accessed 23 Aug 2024
