ACMG Statement on Genetic Testing for All Breast Cancer Patients

CLINICAL ACTIONS:

With the move toward massively parallel sequencing (MPS), and away from the more expensive Sanger methodology, the cost of genetic testing for breast cancer has dropped significantly. This has raised the debate as to whether all patients with a diagnosis of breast cancer should be offered more expansive breast cancer genetic testing panels as part of their routine care. 

• Potential benefits of genetic testing for all breast cancer patients
  • Finding pathogenic variants can help guide management
    • Therapy: Option of mastectomy vs lumpectomy and radiation
    • Cascade testing: Benefit to family members who may not have known they were at risk but can now be offered prophylactic medications or surgeries
  • A recent study (see ‘Related ObG Topics’ below) found that offering genetic testing to all breast cancer patients would also be cost-effective
• Potential concerns for broad based testing
  • Penetrance and natural history of pathogenic and likely pathogenic variants are not yet well understood for some of the genes incorporated into expanded panels
  • Data is lacking regarding clinical utility for some gene variants regarding mortality and outcomes  
  • Best management approaches based on genetic testing results are still under investigation 
  • Costs, especially downstream (e.g., need for additional counseling, additional tests) are being evaluated

ACMG Points to Consider

• ACMG has released a ‘Points to Consider’ document on this subject to help provide guidance and direct the discussion on this important question. The ACMG document upon review of the current literature states

When discussing genetic testing for breast cancer patients, clinicians should be aware of the current insufficient evidence to support genetic testing for all patients with breast cancer, especially with multigene panels that include genes without evidence to support follow-up care

• Evaluate all patients with breast cancer to determine if germline genetic testing is appropriate | ACMG references guidance that considers age, family history, tumor characteristics and disease stage
• During counseling, patients should be made aware that some of the larger panels may include genes where evidence may be lacking with respect to follow up
• If a pathogenic or likely pathogenic variant in a moderately penetrant gene (e.g., ATM and CHEK2)  does appear on a patient report, clinicians should be aware that research is ongoing and that recommendations may be based upon consensus recommendations | Evidence for clinical utility (extended survival) for enhanced cancer panels is still lacking
• When genetic testing is performed, ACMG recommends that these tests be performed in a CLIA-certified and/or College of American Pathologists (CAP)–accredited genetic testing laboratory that has all the appropriate technologies available
• “…counseling should include the expertise of a trained genetics professional or health-care provider with special expertise in cancer genetics principles”
• If a significant variant is found, clinicians should work with patients and emphasize the importance of cascade testing for the patient’s family (see ‘Related ObG Topic’ below)

SYNOPSIS:  

Controversy remains whether all patients with breast cancer should be offered genetic testing. While there is no argument regarding those with significant family/personal history or clinical findings that may suggest a heritable cancer syndrome, questions remain regarding risks and benefits. ACMG points out that currently “only a small proportion of the at-risk population has been tested. It has been estimated that less than 10% of all adults with BRCA1/2 P/LP variants in the United States have been identified.” Furthermore, minorities seem to be  disproportionately affected when it comes to not being tested even when appropriate.

KEY POINTS:

BRCA1/2 and Other Breast Cancer Associated Genes

• Genes themselves are not ‘pathogenic’ or disease-causing | Rather, pathogenic or likely pathogenic variants in certain genes may alter the gene’s function and increase cancer risk  | Approximately 5 to 10% of breast cancers can be attributed to underlying genetic issues and are considered heritable such that a change in germline DNA can be passed down to offspring (usually autosomal dominant inheritance)  
• BRCA1/2 disease-associated variants
  • Occur in an estimated 1/300 to 1/500 women and account for the following percent of cancer cases
    • Breast cancer: 5% to 10%
    • Ovarian cancer: 15%
• Breast cancer risk
  • Significantly increase cancer risk breast cancer: 45% to 65% (cumulative age 70)
• Ovarian cancer risk
  • Significantly increase ovarian, fallopian tube, or peritoneal cancer risk (cumulative age 70)
    • BRCA1: 39% 
    • BRCA2: 10% to 17% 
• While most heritable breast cancers are a result of pathogenic or likely pathogenic variants primarily in BRCA1/2 genes, other gene targets include
  • PALB2 | TP53 | PTEN | CDH1 | CHEK2 | ATM
• Individuals of AJ heritage have an increased risk for carrying a pathogenic BRCA1/2 variant (1/40 risk)

Professional Guidelines 

• Professional recommendations are aligned that women should be evaluated to determine if they are at high or average risk for breast cancer
• There are multiple tools available to identify those at risk for hereditary breast cancer (see ‘Related ObG Topics’ below)
  • Note: Family history remains a key approach to identifying families at higher risk
• Currently, NCCN and most other organizations do not call for routine genetic evaluation for all breast cancer patients | Exception: Women of AJ background should be offered genetic testing due to high risk of carrying a BRCA1/2 mutation
• Societies that do call for broader testing
  • The American Society of Breast Surgeons does recommend broadly offering genetic testing for BRCA1/2 and PALB2 for all individuals with breast cancer and possibly other genes depending on family history and clinical scenario
  • ASCO recommends BRCA1/2 testing for all newly diagnosed breast cancer (stage I to III) and de novo stage IV/metastatic disease ≤65 years

Additional Considerations

• According to ACMG
  • The above ‘Points to Consider’ are not static and may change with additional research and data
  • Further research and a better understanding of natural history and penetrance of variants on a gene-by-gene basis is imperative to formulate professional guidance (for testing in patients with breast cancer as well as broad-based screening programs for those without cancer)

Learn More – Primary Sources:

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

ASCO: Germline Testing in Patients With Breast Cancer

Related ObG Topics:

NCCN: New Genetic Risk Assessment Recommendations for Breast, Ovarian and Pancreatic Cancers

USPSTF Guidelines for Primary Care Clinicians: BRCA-Related Cancer Risk Assessment

BRCA1 & BRCA2 Mutations: What Are the Risks for Developing Breast and Ovarian Cancer?

Cascade Testing: Notifying and Counseling Relatives of Individuals who are BRCA Mutation Carriers

Is Multigene Testing in All Women with Breast Cancer Cost-Effective? And is it a Good Idea?