CASE STUDY
A 48 year-old woman with a 2 cm breast mass underwent a biopsy that revealed a HER2-negative invasive ductal carcinoma. Her mother recently died of pancreas cancer without genetic testing and a maternal-side aunt was being treated for ovarian cancer and reportedly had a positive genetic test. The patient has two healthy daughters and a son ages 17 to 23. The post-biopsy clinic visit focused on treatment and risk management decisions.
What is the best step in genetic analysis for this patient?
A. A clinical basis for diagnosing Hereditary Breast and Ovarian Cancer Syndrome (HBOC) exists, and therefore, genetic testing is not required.
B. Obtain the aunt’s genetic test results because the patient will share the same mutation.
C. Send the core biopsy block for NGS because any tumor (i.e., ‘somatic’) variant in an HBOC gene (e.g., BRCA1/2, PALB2) will be germline and thus hereditary.
D. Advise germline testing at the time of the current clinic visit using a STAT breast cancer panel followed by a full hereditary cancer panel.
E. Refer to genetic counseling (six weeks to visit) for detailed risk analysis of the patient and her family, followed by testing.
F. Because the patient already has cancer, test only her children for monogenic genetic cancer risk using a broad hereditary cancer panel.
Learning Points
THE CORRECT ANSWER IS D.
This patient has four separate ‘Always Test’ indications: triple negative breast cancer, age 50 years or less, first degree relative with pancreas cancer, and second degree relative on her mother’s side with a positive genetic test. The results of her germline genetic testing can have a major impact on a number of cancer management and risk-reducing strategies for her and for her family. Surgical decisions may be time-sensitive. The oncologist should send germline genetic testing at the initial visit and simultaneously refer the patient for genetic counseling.
Considerations Regarding the Other Answers
This scenario raises numerous hereditary cancer genetics issues regarding testing management and results interpretation, cancer treatment decisions, interpretation of paired tumor testing results if available, risk management regarding risk of HBOC syndromic cancers in the patient and her family, among many others.
A. HBOC is a clinical syndrome that includes risk of breast, ovarian, prostate, and pancreas cancers, among others. The syndrome is produced by heterozygous germline mutations in a small number of genes involved in homologous recombination DNA damage repair (HRD). Inactivation of the second allele in a breast cell would lead to oncogenic transformation. Panel testing is needed to identify the gene underlying this family’s syndrome.
B. The aunt’s genetic test result is very important in the analysis of the family’s syndrome, however, it is not certain that the two individuals will have the same variant.
C. NGS on the tumor tissue can give additional important information about the molecular mechanisms of formation of the cancer. For instance, a positive germline test for BRCA1 would implicate a defect in HRD as the cause of the cancer, and the presence of a HRD mutation signature (e.g., gLOH) in the tumor and loss of heterozygosity (LOH) of the second BRCA1 allele would provide strong confirmatory evidence of HRD. Platinums and PARP inhibitors become important considerations. Notably, not all breast cancers in individuals with a germline BRCA1 pathogenic variant are caused by this molecular change.
E. Testing the patient’s children will become important only if her test is positive for a Pathogenic or Likely Pathogenic variant in a hereditary cancer gene. There is controversy about the timing/age of testing. Some genetic syndromes have implications for children at the time of birth (e.g., MEN2B) or even earlier (TSC), and all syndromes have relevance by the time reproductive age is reached. Carriers will need risk analysis. It is common for adult children to present for genetic testing with a family history like the one above, and it is always best to test the affected family first, when possible. If the affected individual is not available for any reason, the children should be tested.
RESULT: Germline NGS using a multi-gene panel showed a heterozygous Likely Pathogenic variant in BRCA2.
Approaches to be considerd in this situation include:
A. Casade (family testing). Note: Approximately 1/3 family members complete recommended testing in typical hereditary cancer practice. This suboptimal rate improves when practitions lower logistal barriers for the family.
B. Women. Discussions regarding risk reducting surgeries versus high-risk screening. There are many aspects the these discussions including age, other medical conditions, reproductive considerations, use of tamoxifen, onset of menopause with salpingo-oopherectomy, etc. Referrals to breast and gynecologic-oncology surgeons can help patients immensely with these decisions. Contralateral breast cancer risk in this patient is about 40%.
C. Men. BRCA2 positive men in the family will have a markedly elevated risk of breast cancer, although still of low in comparison to women’s risk. Prostate cancer risk is elevated. Appropriate measures can result in risk reduction and early detection.
D. Men and women. Because there is a relative with pancreas cancer (who likely was BRCA2+), pancreas cancer screening will be important for those family members who test positive. Melanoma screening is also important.
With multiple organs at risk of cancer in the individual and carrier relatives, and cascade testing to be pursued, it is usually difficult for one oncology or primary care specialist to manage these issues. Hereditary cancer clinics can provide a highly valuable service to patients by orchestrating these issues and referrals in serial clinic visits occuring over many years. Such clinics become very busy, very quickly, and provide excellent resources for patients and a service that identifies oncology groups with best practices.
