Ask the Experts – Manish Kohli

Question 1. Where are we in the science of genetic testing for hereditary prostate cancer?

Answer
Hereditary prostate cancer is a small subset of all prostate cancers. There are specific gene mutations we know indicate an increased risk. The number of genes that we are most sure about, such as BRCA1 and BRCA2, are those in which we have a high degree of confidence in terms of hereditary prostate cancer. But there are many unknowns.

There are many commercially available tests as well as in-house tests developed at institutions that look at a bunch of culprit DNA repair genes and homologous repair deficiency genes, such as BRCA1 and BRAC2. Less frequent genes such as TP53, PTEN, CDH1, ATM, CHEK2 or PALB2 can be implicated. Identification of one of these mutated genes can be done using age-old sequencing techniques that are very reliable. Testing for multiple mutations can also be done with multi-gene panels which simultaneously test for suspected genes beyond these known genes. The sensitivity and specificity of these tests are very high, but in a very small fraction, despite the central mutations in these genes, if there is an unknown mutation in the same genes that are not tested for in the panel, we can sometimes miss them. That is why multi-gene panel testing can sometimes be negative even though a patient’s clinical profile is highly suggestive of hereditary prostate cancer. In these cases, we will go with single-gene Sanger sequencing, which is more specific for mutations than a multi-gene panel. Together, between gene panel testing and Sanger sequencing, we can nail down vast numbers of these hereditary mutations, in the context of the patient’s clinical presentation.

Question 2.  What are the key questions that clinicians need to ask men when selecting them for testing?

Answer
Questions should focus on family history of cancer. In particular, for men diagnosed with prostate cancer younger than 60 years of age, clinicians should ask about a family history of prostate cancer, breast cancer, ovarian cancer, and pancreatic cancer, especially in first-degree relatives who might have been younger than 50 years of age. These raise red flags for us. At the very least, ask if the patient’s father, male siblings, or paternal grandfather had a history of prostate cancer or if the patient’s female siblings or mother or maternal grandmother had a history of breast, ovarian, or pancreatic cancers at an early age.

Question 3. Should genetic testing be offered to all men who have a family history of prostate cancer or any cancer?

Answer
Patients should be offered genetic testing if they present with metastatic prostate cancer before the age of 60 years; patients presenting with localized stage disease if there is a strong family history suggestive of the hereditary breast and ovarian cancer syndrome (HBOC), such as a history of cancer in first-degree relatives with prostate, breast, ovarian, and pancreatic cancers; and patients who have no history of prostate cancer but are concerned about developing cancer because of a strong family history (brother, father).

Question 4. During patient counseling, what aspects of testing must patients understand clearly?

Answer
If a relatively young patient newly diagnosed with prostate cancer says he has a brother with a history of prostate cancer, we should ask whether the brother had undergone gene panel testing for hereditary prostate cancer perhaps as a result of a history of multiple cancers in the family. If not, the patient becomes the proband: the first patient in the family being referred for genetic testing. If the answer is yes, and testing had been done in the family previously, we ask whether the results were positive or negative. If positive, then we know the patient has been sensitized to understand what genetic testing and counseling will entail. If negative, or if the patient does not know, we have to start from scratch with counseling the patient about how genetic testing is performed, what these tests look for, and the ramifications of genetic testing. If the patient tests positive for mutations that increase the risk of prostate cancer, we explain to the patient that the test results may have implications for siblings and children, including adverse psychological and occupational effects.

Psychologically, this could entail loss of a “sense of good health and a feeling of helplessness,” as the patient realizes that despite enjoying good health and maintaining healthy habits, he could still be destined to be at high-risk for developing cancers.

Counseling can help relay context in the interpretation of test results so as to ease anxiety about the implications of a positive test result. Even though there is a federal law (the Genetic Information Nondiscrimination Act) that protects individuals from employment discrimination on the basis of genetic information, electronic medical records of the patient could be used illegally to deny employment perks. Counseling provides education to the patient on his or her rights in this regard.

Question 5. Could genetic test results be helpful in therapeutic decision making?

Answer
Yes. Prostate cancer, as it evolves goes through successive stages of progression to advanced metastatic castration resistant states. There are drugs approved by the FDA for advanced prostate cancer that target deleterious mutations in genes such as BRCA1 and BRCA2. Patients with these mutations may respond to PARP inhibitors, such as olaparib, as well as platinum compounds.

Question 6. What are the drawbacks of genetic testing?

Answer
Most prostate cancers are sporadic. Genetic testing for hereditary prostate cancer is not appropriate as a population-based strategy because it would greatly increase the amount testing to identify a very small percentage of men with prostate cancer-causing mutations. In addition, if genetic testing is done without consultation with a genetic counselor, but performed using commercially available testing kits available online, patients would not understand how to interpret test results and their implications for the patients and perhaps their families.