Updated: Jan 3
Genetic Testing for breast cancer in India was heretofore limited the high cost of patented tests, need to ship samples overseas and social stigma towards genetic disease. Recent emergence of new technology such as next generation sequencing and local presence of genetic labs has brought down costs considerably. Hollywood actress Angelina Jolie’s story in the media brought a lot of public interest and debate to the topic. Patient interest in the topic is higher than it has been. Meaningful dialogue about genetic testing is still hindered because of misconceptions amongst patients, unfamiliarity of general practitioners with these tests and commercial interests of companies offering testing. I am going to visit some common questions about genetic testing that arise in the breast clinic.
1) What do we need to know about genes and mutations?
Everyone is born with two copies of approximately 25000 genes that are present in all nucleated cells of the body. One copy is inherited from each parent. Every time a cell divides this large volume of genetic information is copied into the daughter cells. This process is prone to errors which lead to DNA damage or mutations. Cancerous cells are often cells that have accumulated several such mutations over a period of time and have acquired the ability to grow and spread uncontrollably. In this respect all cancers are “genetic” however not all cancers are “ hereditary”
Is breast cancer hereditary?
Only 5-10 percent of breast cancers can be attributed to known genetic mutations. Up to 20 percent cases may be familial even if no mutations are known or found. Most patients of breast cancer have no family history of the disease and children of most patients will not develop the disease i.e. these are sporadic cases.
What are the types of Genetic Testing in Breast Cancer?
There’s two broad categories of genetic tests we use in breast cancer.
Germline Testing : Germline DNA Analysis studies a person’s genetic make-up by testing DNA that is common to all cells in the body. Saliva swabs and blood are commonly used for this type of testing.
Somatic Testing or Tumor DNA testing: This is performed on the patient’s tumor sample for prognostic testing (eg Oncotype Dx) or pharmacogenetic testing for targeted therapies against the tumor.
The discussion below pertains mainly to germline testing for Hereditary Breast and Ovarian Cancer (HBOC) Syndromes
What is the process of Genetic testing like?
Genetic testing is a multi-step process that involves
1)Genetic Counseling: Genetic counseling is an imperative step prior to genetic testing. The session usually takes an hour or more and may need several sessions.
A genetic counselor obtains the relevant clinical history, plots a pedigree chart, obtains a detailed history of cancers, verifies pathology reports, physical measurements may be taken when needed. A computer model may be used to predict possibility of a hereditary breast ovarian cancer syndrome (BRCA 1/ BRCA 2) or other syndrome such as Cowden (PTEN) or Li Fraumini (p53).
Benefits and risks of testing are discussed. The possibility of a positive, negative or inconclusive result and their implications are discussed. The appropriate family member to be tested is identified and brought into the picture as needed.
After assessing the need for testing, the patient is given a choice to proceed with testing. Testing should be undertaken only after formal genetic counseling and informed consent.
2)Genetic Testing: The actual test involves collection of the patients blood/saliva sample. The genetics lab isolates the DNA and sequences part of the exome to look for a single or multiple mutations. Different techniques such as Sanger, NGS are used for this. The raw data needs extensive analysis with a reference database or repository to determine which of the mutations found are clinically relevant. A report is then generated which may describe absence or presence of certain mutations, that may be know pathogenic, known benign or have uncertain significance.
3)Post Test Counseling: This should be undertaken with an oncologist familiar with breast cancer genetics, who can guide the patient on interpretation of the test. If a known deleterious mutation in BRCA is found, options of prophylactic surgery versus heightened surveillance or pharmacological interventions should be discussed.
What is the cost of Genetic testing?
With use of Next Generation Sequencing, the cost of testing has lowered considerably. The additional cost of looking at multiple mutations is low, and once a familial mutation is known, other family members can be tested at much lower cost.
How long does genetic testing take?
The turnaround time from sample collection is usually 4-6 weeks. Depending on the data obtained, the time to analysis and interpretation may vary.
What are the limitations of Genetic testing in India?
*Most criteria used to predict risk of genetic mutations are written for western populations and the true prevalence for most Indian breast cancer patients is unknown.
*Social stigma in a world of arranged marriages, illiteracy; fear of social discrimination and misunderstanding of the disease or process may limit patients from using this information for making positive healthcare decisions.
* With high costs of oncological treatments, the additional expense of genetic testing, limits its availability to only a few of patients that may be eligible for it.
Who should be offered genetic testing?
Genetic “counseling” can be offered to any breast cancer patient or family member wanting to discuss this. Decision to perform “testing” should only be conducted after assessing need and implications of the test in a patient who is willing to use this information positively in their care.
What are the common criteria for BRCA testing ?
Young breast cancer < 45 yrs, < 50y with at least 1 close blood relative with breast/ovarian cancer
Multiple breast cancers or bilateral breast cancer, first diagnosed before the age of 50 years
Triple negative breast cancer (TNBC) < 60 years
Male breast cancer, relative with male breast Cancer
Ethnicities with high BRCA mutation frequency
Previously detected BRCA1/2 mutations in the family
2 relatives with breast /ovarian/ pancreatic cancer
What is a close blood relative?
First degree relatives: mother father sister, brother, son, daughter
Second degree relatives: aunt, uncle, grandparents, grandchildren, niece, nephew, half brother or half sister.
Risk of breast cancer can be inherited from the maternal and paternal side and a pedigree chart should collect information on all of these relatives.
What does a “ positive” test result imply?
A patient with a known deleterious mutation in BRCA may have a 60-80% lifetime risk of developing breast and 40-60 % risk of developing ovarian cancer. In a patient with known breast cancer, the risk of developing a contralateral breast cancer may be as high as 40%.
What are the options for a BRCA positive patient?
Risk reducing surgery : This includes bilateral salpingo-oopherectomy after completion of child bearing and bilateral prophylactic mastectomy are proven to decrease risk of ovarian and breast cancer in over 90% . Bilateral mastectomy when performed using nipple-skin sparing technique and immediate reconstruction may not be as mutilating a procedure as it once was thought.
Increased surveillance: This does not decrease risk, but allows early detection of potential cancer. Annual transvaginal /pelvic ultrasound with CA-125 levels and 6 monthly breast imaging (alternating Mammography and breast MRI) are typically used.
Pharmaco-prophylaxis: Use of medications such as Tamoxifen should be discussed. These can potentially lower risk (but not completely prevent cancers) in these patients.
What does a “positive” result mean to the patients children?
Every child has a 50% probability of inheriting an autosomal dominant mutation. They should be offered genetic testing once they are of age to given consent and understand implications of testing for themselves. If a child tests negative for the mutation known in the parent, their risk of breast cancer is the same as the average population. If the child has inherited the mutation, then similar counseling and decision-making should be offered as above.
What are genetic tests done on the tumor sample ?
Theres 2 broad categories of somatic gene testing done on breast tumors
1) Prognostic testing: One such assay Oncotype Dx gives a 21-gene recurrence score that predicts a patients risk of recurrence at 10 years. Small node negative breast tumors (T1-2, N0) that are ER+PR+ HER2 – can be stratified by their genetic makeup into low, intermediate and high risk. There is evidence that endocrine therapy alone may be sufficient for patients in the low risk category and adjuvant chemotherapy may be avoided.
2) Predictive Pharmaco-genetic testing: Tumor DNA is analysed to determine benefit from targeted therapies. ERBB2 (HER2/neu) gene amplification testing using FISH is widely used test for the decision to use anti-Her2 agents like trastuzumab. There is interest in developing “Personalized oncology’ treatments where genetic make up of the individual’s tumor would be used to select appropriate targeted therapies. This is an area of ongoing research. I discourage patients from using commercially available tests without guidance of an oncologist at this time.
What are circulating tumor cells and circulating tumor DNA?
CTCs are cells shed from the tumor that can be detected and measured in the patient’s blood. This is an area of intense research, which holds promise for early detection of recurrence, assessment of response to therapy, identification of targeted therapies etc. The optimal isolation techniques and definite guidelines for clinical use in breast oncology are still awaited.