Genetic testing can have implications for management of the cancer patients, including: surgical treatment, chemotherapy choices, prognosis and risk for additional cancers. It is therefore important to assess the risk of a hereditary syndrome at diagnosis, at decision points along the cancer treatment trajectory and again when entering survivorship or surveillance. An exhaustive list of implications of all cancer predisposition syndromes or germline alterations is beyond the scope of this toolkit; however we will provide some of the more common implications of identification of germline mutations in patients with cancer.
Germline vs. Tumor Somatic Genetic Testing
Genetic testing of a cancer assesses somatic genetic changes that may guide therapeutic choices (e.g., EGFR mutations for treatment of lung cancer). Some tumor (somatic) genetic testting will include mutations potentially inherited (germline) as well as those acquired in the tumor (somatic). Other genetic tests of the tumor will "subtract out" germline mutations by comparing mutations in the tumor to those found in sample of normal tissue or blood. It is important to understand which approach the genetic test you are reviewing has used. This toolkit does not address tumor somatic mutations. Germline genetic testing, usually performed on a blood sample, evaluates inherited genetic changes that increase the risk of certain cancers in an individual.
Benefits of Germline Genetic Testing
Genetic testing can help identify cancers for which an individual is at increased risk. This increased risk can often be managed by increased surveillance, consideration of preventive medication or prophylactic surgery. In addition, identification of a familial germline mutation in a cancer susceptibility gene can alert family members who would also undergo genetic testing to clarify their own risk of cancer. Finally, identifying certain germline mutations may guide local and systemic treatment of a cancer (e.g., colectomy for a patient with colorectal cancer and Lynch syndrome; PARP inhibitor for a patient with ovarian cancer with a BRCA1/2 mutation; avoidance of therapeutic radiation in a patient with breast cancer with inherited TP53 mutation).
Implications of Testing for Initial Management
- Lynch syndrome testing for colon cancer: Patients with newly diagnosed colon cancer and pathogenic mutations in one of the mismatch repair genes (MLH1, MSH2 (EPCAM), MLH6, PMS2) should be considered for near-total colectomy. Women would be additionally considered for hysterectomy and bilateral salpingo-oophorectomy (BSO).
- BRCA testing for breast cancer: Patients with newly diagnosed breast cancer and BRCA1 or BRCA2 pathogenic mutations would have the option of considering bilateral mastectomy for their initial surgery, given the high risk of a second primary (ipsilateral or contralateral) breast cancer. These women may also consider BSO if they have completed childbearing.
- TP53 testing for any cancer: Patients with newly diagnosed cancer and found to have pathogenic TP53 germline mutations should, whenever possible, avoid radiation therapy.
- VHL testing for kidney cancer: Patients with newly identified kidney cancer and pathogenic mutations in the VHL gene should be considered for nephron-sparing procedures such a partial nephrectomy or radiofrequency ablation. Evaluation for pheochromocytoma should be considered before surgery.
- CDH1 testing for gastric cancer: Individuals with newly diagnosed gastric cancer and pathogenic mutations in CDH1 should have total gastrectomies instead of partial gastrectomies.
Testing at Decision Points in Treatment
- BRCA testing in breast cancer: Patients with breast cancer and BRCA1 or BRCA2 mutations may respond better to platinum treatment and may also be candidates for clinical trials using PARP inhibitors.
- BRCA testing in ovarian cancer: Patients with ovarian cancer and either BRCA1 or BRCA2 mutations have a better prognosis than sporadic patients with the same stage, grade or histology. BRCA1 and BRCA2 carriers may have greater chemotherapy sensitivity but may be at risk for earlier platinum hypersensitivity. Women with ovarian cancer and BRCA1 or BRCA2 mutations are also candidates for treatment using PARP inhibitors.
- Testing for DNA repair gene mutations in Prostate cancer: Patients with metastatic prostate cancer and a germline (or somatic) mutation in DNA repair genes (e.g. BRCA1/2 or ATM) may have an increased response to PARP inhibitors. Consideration of a next-generation sequencing panel that includes analysis of these genes should be considered in this population.
- Testing for mismatch repair gene mutations in advanced cancer: Patients with metastatic colorectal and other cancers who have a germline or somatic mutation in a mismatch repair gene (MLH1, MSH2, MSH6, PMS2) have been found to have a higher response to immune checkpoint inhibitors such as pembrolizumab than patients without these mutations.
Testing when Entering Survivorship/Surveillance
Germline mutations and second cancer risk: Second primary cancers occur in approximately 16% of all patients with cancer. Those individuals with strong family histories and/or pathogenic germline mutations in cancer-causing genes are at highest risk of second primary cancers. Genetic testing during survivorship or surveillance can identify those at greatest risk and action (more intense screening or preventive surgery) can be taken.
Guidelines on Genetic Testing
The guidelines below represent a selection of publicly available resources on genetic testing for specified cancer syndromes; this list is not exhaustive due to restrictions of member-only content. **Inclusion of third-party guidelines and recommendations should not be interpreted as formal endorsement by ASCO.**
Breast and Ovarian Cancer
- American Congress of Obstetrics and Gynecology Guidelines for Managing Hereditary Breast and Ovarian Cancer Syndrome
- NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High Risk Assessment, Breast and Ovarian Cancer
- Risk Assessment and Genetic Counseling for Hereditary Breast and Ovarian Cancer: Recommendations of the National Society of Genetic Counselors
- Society of Gynecologic Oncology Statement on Risk Assessment for Inherited Gynecologic Cancer Predispositions
- Society of Gynecologic Oncology Clinical Practice Statement: Genetic Testing for Ovarian Cancer
- Society of Gynecologic Oncology White Paper on Ovarian Cancer: Etiology, Screening and Surveillance
- US Preventive Services Task Force: Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Recommendation Statement
- American Gastroenterological Association Medical Position Statement: Hereditary Colorectal Cancer and Genetic Testing
- Hereditary Colorectal Cancer Syndromes: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the Familial Risk–Colorectal Cancer: European Society for Medical Oncology Clinical Practice Guideline
- Identification of Individuals at Risk for Lynch Syndrome Using Targeted Evaluations and Genetic Testing: Recommendations of the National Society of Genetic Counselors and Collaborative Group of the Americas on Inherited Colorectal Cancer Joint Practice Guideline
- National Cancer Institute, Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability
- NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal
- Society for Gynecologic Oncology Practice Bulletin: Lynch Syndrome
- Society of Gynecologic Oncology Clinical Practice Statement: Screening for Lynch Syndrome in Endometrial Cancer
- Cancer Genetics Studies Consortium (CGSC) Task Force on Informed Consent: Genetic Testing for Susceptibility to Adult-Onset Cancer: The Process and Content of Informed Consent
- Essential Elements of Genetic Cancer Risk Assessment, Counseling, and Testing: Updated Recommendations of the National Society of Genetic Counselors
- Referral Indications for Cancer Predisposition Assessment: Joint Practice Guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors
- American Society of Clinical Oncology Policy Statement Update: Genetic and Genomie Testing for Cancer Susceptibility (See Table 1: Components of Informed Consent)
Heredity Diffuse Gastric Cancer
- Hereditary Diffuse Gastric cancer: Updated Consensus Guidelines for Clinical Management and Directions for Future Research: International Gastric Cancer Linkage Consortium (IGCLC) Consensus Guidelines 201C
Medullary Thyroid Cancer
- Medullary Thyroid Cancer: Management Guidelines of the American Thyroid Association
- 2012 European Thyroid Association Guidelines for Genetic Testing and Its Clinical Consequences in Medullary Thyroid Cancer
von Hippel-Lindau Syndrome
- VHL Alliance: von Hippel-Lindau Syndrome Screening Guidelines
- VHL National Clinical Guideline for Screening and Surveillance in Denmark
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