With increasing awareness of genetic testing and advancements in precision medicine, more patients are seeking counsel from clinicians about what steps they should take if mutations are found. This requires physicians to become more informed, and a recent article discusses the hypothetical case of an Ashkenazi Jewish woman with breast cancer.
With increasing awareness of genetic testing and advancements in precision medicine, more patients are seeking counsel from clinicians about what steps they should take if mutations are found. This requires physicians to become more informed, and a recent article in Annals of Internal Medicine discusses the hypothetical case of an Ashkenazi Jewish woman with breast cancer.
In this scenario, the patient, aged 47, was recently diagnosed with a 0.9-cm unilateral breast tumor that was estrogen receptor (ER)— and progesterone receptor (PR)–positive, and human epidermal growth factor receptor 2 (HER2)—negative.
Lymph nodes are not involved, and she is trying to make treatment decisions about surgery, radiation, and chemotherapy, and visits her internist with questions. She is worried about her 2 daughters' cancer risks; 2 of her paternal aunts had breast cancer.
Visits like these are likely to increase as the decreasing cost of testing, combined with the availability of next-generation sequencing and the elimination of gene patents, have increased the options for cancer genetic testing of both the tumor for somatic mutations and the blood for heritable germline mutations.
The authors note that use term "genetic testing" can be understood in a more specific way:
There are several reasons why a patient described here might be guided to germline genetic testing for cancer. Besides informing care, the results can assess future cancer risk for second primaries. Results can give data about cancer drivers and tumor characteristics that can not only inform therapy selection but also clinical trial opportunities. Molecular analysis of the tumor can inform which patients are more likely to benefit from systemic chemotherapy as well as targeted therapies.
For patients with a family history of cancer, testing can stratify the level of future risk and guide surveillance and risk-reducing strategies if necessary.
This patient is told that decisions about adjuvant chemotherapy should consider tumor size, grade, characteristics, and lymph node involvement. She has germline testing, and a BRCA2 6174delT mutation is identified. This mutation is 1 of the 3 common BRCA1/2 founder mutations found in the Ashkenazi Jewish population, and in this population, there is a 1 in 40 prevalence of carrying 1 of 3 BRCA1/2 mutations.
The patient's tumor is evaluated and is found to have a low recurrence score; on the basis of that knowledge, she decides against adjuvant chemotherapy.
On the basis of the 10.8% risk for future independent primary breast cancer in the next 10 years and the 62% risk by the age of 70 for patients with BRCA2 mutations, the patient decides to have a bilateral mastectomy, which does not completely eliminate the risk of another breast cancer, though it does reduce it.
In addition, she decides to have a prophylactic bilateral salpingo-oophorectomy because of the 16.5% to 27% risk for ovarian cancer in patients with her BRCA2 mutations and her postmenopausal status.
Since BRCA2 mutations are inherited in an autosomal dominant manner, each of her children has a 50% chance of having inherited the BRCA2 mutation. Her daughters are 19 and 25 years old. The younger child decides not to get tested and to wait, but the older one does and is found to carry the mutation.
The older daughter is advised to start annual magnetic resonance imaging screening with contrast until the age of 30, when yearly mammograms will be recommended. She is also advised to receive a clinical breast examination every 6 to 12 months and is taught breast self-examination. She decides to start oral contraceptives, which can reduce her risk for ovarian cancer by up to 40%.
Some of the other genes for breast cancer that are now considered to be actionable are TP53 and PTEN. Other genes carry more modest risk, such as ATM, CDH1, CHEK2, NF1, and PALB2.
The authors note that, prior to 2011, only the BRCA1/2 test was available; now, hereditary genetic testing panels for 5 to 50 genes are available. Women screened previously, such as long-term survivors who only had BRCA1/2 testing done, may want to update their profile, given the expansion of germline testing and the efficacy of risk-reducing measures.
Tischler J, Crew KD, Chung WK. Cases in precision medicine: The role of tumor and germline genetic testing in breast cancer management [published online October 22, 2019]. Ann Intern Med. doi:10.7326/M18-2417.