FAMILIAL CANCER CLINIC

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Medical information

WHAT IS HBOC?

Hereditary breast and ovarian cancer syndrome (HBOC) are an adult-onset, cancer predisposition syndrome. HBOC is characterized by a high risk of breast and ovarian cancers, and an increased risk of other cancers such as prostate, pancreatic, and melanoma. Individuals with HBOC tend to have cancer at an earlier age than the general population and have a higher risk for bilateral breast cancer, a second primary tumor in the ovaries, and pancreas.

WHAT ARE THE GENES INVOLVED?

The breast cancer-associated genes BRCA1 on chromosome 17q and BRCA2 on chromosome 13q are the most well-known breast cancer susceptibility genes. Not all families with multiple cases of breast and ovarian cancers have mutations in BRCA1 and BRCA 2. There are also other genes that have been linked with an increased risk of developing breast and other cancers. These genes are classified into high, moderate, and low penetrance genes. e.g. High Penetrance gene: BRCA1, BRCA2, PTEN, P53, STK11, CDH1,PALB2; Moderate Penetrance gene: ATM, CHEK2,, RAD50, RAD51C, RAD51D etc. Blood tests now include many of these genes including BRCA 1/2 in a single multiple-gene panel test

HOW MUCH IS THE RISK OF CANCER WITH BRCA1 AND BRCA2 MUTATIONS?

BRCA1 and BRCA2 mutations are inherited in an autosomal dominant fashion but act recessively on the cellular level as tumor suppressor genes involved in double-stranded DNA (dsDNA) break repair. Mutations in the BRCA1 and BRCA2 genes are responsible for ~60% (up to 85%) of HBOC. The lifetime risk of breast cancer and lifetime risk of ovarian cancer in women are as follows:
  • BRCA1 mutation 55 to 85 % for Breast cancer and 25 to 45 % for Ovarian cancer
  • BRCA2 mutation is 50 to 85% for Breast cancer and 13 to 23 % for Ovarian cancer
  • Cancers diagnosed in people with BRCA mutations often have specific characteristics.
  • 60% to 80% of the breast cancers in women with a BRCA1 mutation are triple negative.
  • 70% to 80% of breast cancers in women with a BRCA2 mutation are estrogen receptor-positive, progesterone receptor-positive, and HER2-negative.

WHAT IS THE BURDEN?

About 5-10% of breast cancers and 15-20% of ovarian cancers can be attributed to HBOC. An estimated 1 in 500-1000 individuals in the general population have a disease-causing BRCA1/2 variant. However, the likelihood of HBOC is influenced by an individual’s race or ethnicity. About 1 in 40 individuals of Ashkenazi Jewish ancestry carry a BRCA1 or BRCA2 mutation.

WHAT IS THE BURDEN IN INDIA?

The burden attributable to inherited mutations in Indian patients is not well characterized. In a study with 1010 unrelated patients and families from across India, mutations were detected in 30.1% of cases. A majority (84.9%) of the mutations were detected in the BRCA1/2 genes as compared to non-BRCA genes (15.1%). 75% of detection of hereditary variants was observed in patients whose age at diagnosis was below 40 years and who had a first-degree family member(s) affected by breast and/or ovarian cancers. Another study from India used a multi-gene panel test on 236 consecutive patients with breast cancer. P/LP mutations were found in 44/236 (18.64%) women; the most common mutations were in BRCA1 (46.8%) and BRCA2 (19.1%), with 34% of mutations present in non-BRCA genes. Thus, in the Indian population, there is a high prevalence of mutations in high-risk breast cancer genes.

WHAT IS PRACTICALLY DONE AT A CANCER GENETIC CLINIC?

The Cancer Genetic clinic is an important component of any comprehensive cancer center. It is a multidisciplinary team working just like any Multidisciplinary tumor board or Disease management group (DMG). The core anchor is the genetic counsellor and the other members working together. A trained physician or nurse may also perform the role of a genetic counsellor. Essential members include Genetic counsellors, Medical oncologists, Surgical oncologists, Radiation oncologists, Scientists or molecular geneticists, Psychiatrists, Social workers, Radiologists, and Pathologists. Patients attending the cancer clinics are referred on the suspicion of a hereditary condition from the clinics by any of the above clinicians. Patients or relatives may also walk in directly to the counsellor. After pre-test Counselling, a report is generated by the GC (genetic counsellor) about the necessity of the test and the recommended test. The pre-test Counselling step can also be performed by the clinician if he has adequate time and expertise. This is called MAINSTREAMING. The patient undergoes the testing after proper consent and the report comes to the counsellor and treating clinician after a turnaround time (TAT) of about 4 weeks. The report is discussed in a tumor board and the appropriate advice is given for personalized risk management and treatment of the patient. At the same time, at-risk relatives are identified and their risk management plan is developed. The final plan is communicated to the patient by the genetic counsellor about the necessity of the test and the recommended test.

WHAT ARE THE BENEFIT OF GENETIC TESTS?

The genetic tests identify germline mutations in the patient’s genetic material. The identification of mutations influences the patient’s treatment plan as well as the lives of their family members, particularly first-degree relatives. Patients with operable breast cancer and a germline BRCA (gBRCA) mutation, would be counselled and discussed thoroughly about the type of surgery (eg breast conservation versus bilateral mastectomy). A positive germline test will thus influence a number of therapeutic decisions that are immediately relevant to the patient’s management plan. Cascade testing will reveal unaffected carriers who have not yet manifested a tumour. The identified mutation will provide reliable estimates of her future cancer risk. Radiological surveillance and risk reduction surgeries performed at the appropriate time (e.g., risk reduction salpingo-oophorectomy, RRSO) are highly effective strategies for mitigating this risk. As a result, an almost unavoidable cancer can be completely avoided. This is known as the “Precision Prevention” potential.

WHO SHOULD OPT FOR GENETIC TESTS?

When choosing patients for germline testing, most clinicians follow the NCCN guidelines. These guidelines are updated regularly to reflect the most recent research. The criteria have been significantly relaxed in the 2023 version, which now recommends germline testing for all patients with a personal history of breast cancer and any of the following: Triple negative breast cancer (TNBC) at any age, 1 or more close relatives with breast cancer/ovarian cancer/prostate cancer/pancreatic cancer.

WHAT IS THE APPROPRIATE TIME FOR GENETIC TESTING?

It is essential to order germline testing as early in the treatment journey as possible, close to the diagnosis. All patients who were previously diagnosed with cancer, survived cancer, and are eligible for germline testing but have not yet been tested; should also be recommended for screening.

HOW IS A GENETIC TEST PERFORMED?

A multigene panel test using Next Generation Sequencing is the standard method for germline testing (NGS). Blood and saliva can both be used and the TAT (turnaround time is usually 4 weeks). There is no ideal panel, but the testing panel should include at least all of the high penetrance and moderate penetrance genes. The cascade testing for relatives is performed as a single-site mutation test.

WHAT ARE THE RISK MANAGEMENT STRATEGIES FOR PATIENTS?

Patients with breast cancer and BRCA mutations should be informed about their increased risk of a second primary cancer of as high as 2 to 5 percent per year, and for younger patients, bilateral mastectomy may reduce the risk of a second primary. Women with LFS (Li-Fraumeni syndrome) (p53 mutation) who develop breast cancer are generally recommended to undergo mastectomy (removal of the whole breast tissues), rather than lumpectomy (removal of the abnormal tissue from the breast). Risk reduction contralateral prophylactic mastectomy (removal of one or both the breasts) is often offered to patients with or without a previous history of breast cancer who carry a germline genetic mutation of BRCA1/2, TP53, PTEN, CDH1, or STK11 conferring a high risk for breast cancer mutation. Women with breast cancer and a family history of breast or ovarian cancer and who undergo a CPM have a 96 percent reduction in risk of developing contralateral cancer. A survival benefit with CPM exists for patients with a deleterious BRCA1 or BRCA2 mutation, and possibly for those diagnosed at a young age (<50 years). Risk-reducing bilateral salpingo-oophorectomy (rrBSO) is also recommended for women who carry a germline genetic mutation of BRCA1/2, and have completed childbearing. This should be performed by age 35 (BRCA1) or 45 (BRCA2).

WHAT ARE THE RISK MANAGEMENT STRATEGIES FOR THE PREVIVOR (UNAFFECTED CARRIER OF MUTATION)?

For BRCA carriers, (Risk-reducing bilateral salpingo-oophorectomy) rrBSO is recommended for women who have completed childbearing and should be performed by age 35 to 40 or individualized based on the age of onset of ovarian cancer in the family. In BRCA2 carriers, one can consider delaying this procedure until age 40 to 45. rrBSO not only decreases the risk of ovarian cancer in BRCA mutation carriers but also decreases mortality.
For female BRCA carriers who do not wish to pursue (or would rather delay) surgical risk reduction, breast cancer surveillance should be offered, and ovarian cancer screening may be performed.
  • Breast awareness from 18 years of age.
  • A self-breast examination from the age of 18 years.
  • Clinical breast Examination (CBE) 6–12 months is recommended from the age of 25.
  • Annual screening MRI (days 7-15 of the menstrual cycle) should be commenced from the age of 25 with the addition of annual mammography from the age of 30.

WHAT ARE THE MEDICAL IMPLICATIONS OF BRCA?

New targeted medicine called PARP inhibitor (Tab Olaparib) is indicated for adults with deleterious or suspected deleterious germline BRCA (gBRCAm) HER2 negative locally advanced or metastatic breast cancer. PARP inhibitors (Olaparib, Rucaparib, Niraparib) are approved for ovarian cancer for the maintenance treatment of adults with recurrent epithelial ovarian cancer who have responded to platinum-based chemotherapy (irrespective of BRCA status). In the frontline treatment of ovarian cancer also, the current recommendation is to give maintenance Olaparib after successful surgery and adjuvant chemotherapy.
Thus, the germline mutation status of a patient has a tremendous impact on the current state-of-the-art management of patients with breast and ovarian cancers. It also had significant implications for their relatives and would guide a robust personalized cancer prevention plan.