Quest Quest Summer/Fall 2017 : Page 2

Genetic Tests for Germline Mutations U nlike “genomic” tests, which look at gene expression in men with newly diagnosed prostate cancer, “genetic” tests look for germline mutations known to be associated with hereditary prostate cancer. Genetic tests may be useful in identifying patients and their relatives who may have more aggressive disease and/or be susceptible to other life-threatening cancers. Commercial "genetic" tests vary in cost from a few hundred to several thousand dollars and are available to any man with prostate cancer. Some of the mutations the tests look for are DNA repair gene mutations, BRCA1 and BRCA2 , Lynch syndrome mutations, HOXB13 , and ATM mutations, among others. less effective than normal. BRCA1 and BRCA2 BRCA1 and BRCA2 are tumor suppressor genes involved in the repair of DNA damage. They occur very infrequently in the general population, but men who carry mutations in the gene have an Gemline genetic mutations are mutations that are inherited and therefore tend to be common increased risk of developing among families. prostate cancer. Men who mismatch repair (MMR) genes. This carry BRCA1 mutations have an leads to accumulation of mutations that approximately 3.8-fold increased risk of can lead to cells becoming malignant. developing prostate cancer before age Mutation carriers have a 3.2-fold 65, and men younger than 65 who increased risk of developing prostate carry a BRCA2 pathogenic mutation cancer. For the MMR gene MSH2 , the have an up to 7.3-fold increased risk in risk is 5.8-fold higher. Lynch syndrome developing prostate cancer. In addition, germline mutations predispose to a prostate cancers with BRCA2 mutations high lifetime risk of colorectal, upper are more aggressive. GI, ovarian and upper urinary tract Lynch syndrome cancers. Germline gene sequencing can Lynch syndrome mutations are provide a definitive diagnosis. germline mutations in one of the DNA repair gene mutations At least 34 are associated with prostate cancer. Many of these DNA repair mutations cause DNA repair to be Advances in Precision Medicine: New “Liquid Biopsy” Blood Test Targets Advanced Prostate Cancer Treatment An ongoing early clinical trial in the UK is using a “liquid biopsy” to individualize treatment for advanced prostate cancer in patients who have BRCA genetic mutations. olaparib. PARP inhibitors prevent cancer cells from repairing their damaged DNA, and thus the cells die. While PARP inhibitors can be effective, not all men respond to PARP inhibitors, or their cancers mutate and develop resistance to the treatment. This study aims to address the issue of more precisely selecting—and monitoring—patients who will respond best to olaparib. A major advantage of T he researchers are studying a new 3-in-1 blood test as a way to identify patients who are good candidates for PARP inhibitors, such as using a blood test for this task is that it is noninvasive. The blood test has three functions. First, it checks a man’s DNA to see if he would benefit from treatment with PARP inhibitors. Olaparib is especially successful in killing cancer cells that have damaged DNA repair genes such as BRCA1 or BRCA2 . Second, the test analyzes the patient’s blood after he starts treatment to determine if the treatment is working. If it is not working, the patient can switch to a different (continued on page 3.) Q uest The mission of the Urological Research Foundation is to support research and patient education in prostate cancer. Q UEST is a free newsletter, but we need and appreciate your voluntary contributions. Q UEST is published three times a year by the Urological Research Foundation. ©2017 Urological Research Foundation No material reproduced without permission. Circulation: 42,000 Medical Editor: William J. Catalona, M.D. Editor: Betsy Haberl Graphics: Amy L. Davis 2 To subscribe to Q UEST , send your name and address to: Q UEST , PO Box 855, Manchester, MO 63011 . To receive Q UEST by email, send your request to URF@drcatalona.com. To unsubscribe, email your name and address to URF@drcatalona.com. Find Q UEST online at: www.drcatalona.com Q UEST Summer/Fall 2017

Genetic Tests For Germline Mutations

Unlike “genomic” tests, which look at gene expression in men with newly diagnosed prostate cancer, “genetic” tests look for germline mutations known to be associated with hereditary prostate cancer. Genetic tests may be useful in identifying patients and their relatives who may have more aggressive disease and/or be susceptible to other life-threatening cancers. Commercial "genetic" tests vary in cost from a few hundred to several thousand dollars and are available to any man with prostate cancer.

Some of the mutations the tests look for are DNA repair gene mutations, BRCA1 and BRCA2, Lynch syndrome mutations, HOXB13, and ATM mutations, among others.

DNA repair gene mutations

At least 34 are associated with prostate cancer. Many of these DNA repair mutations cause DNA repair to be less effective than normal.

BRCA1 and BRCA2

BRCA1 and BRCA2 are tumor suppressor genes involved in the repair of DNA damage. They occur very infrequently in the general population, but men who carry mutations in the gene have an increased risk of developing prostate cancer. Men who carry BRCA1 mutations have an approximately 3.8-fold increased risk of developing prostate cancer before age 65, and men younger than 65 who carry a BRCA2 pathogenic mutation have an up to 7.3-fold increased risk in developing prostate cancer. In addition, prostate cancers with BRCA2 mutations are more aggressive.

Lynch syndrome

Lynch syndrome mutations are germline mutations in one of the mismatch repair (MMR) genes. This leads to accumulation of mutations that can lead to cells becoming malignant. Mutation carriers have a 3.2-fold increased risk of developing prostate cancer. For the MMR gene MSH2, the risk is 5.8-fold higher. Lynch syndrome germline mutations predispose to a high lifetime risk of colorectal, upper GI, ovarian and upper urinary tract cancers. Germline gene sequencing can provide a definitive diagnosis.

Read the full article at http://epubs.democratprinting.com/article/Genetic+Tests+For+Germline+Mutations/2867454/434322/article.html.

Advances In Precision Medicine: New “Liquid Biopsy” Blood Test Targets Advanced Prostate Cancer Treatment

An ongoing early clinical trial in the UK is using a “liquid biopsy” to individualize treatment for advanced prostate cancer in patients who have BRCA genetic mutations.

The researchers are studying a new 3-in-1 blood test as a way to identify patients who are good candidates for PARP inhibitors, such as olaparib. PARP inhibitors prevent cancer cells from repairing their damaged DNA, and thus the cells die.

While PARP inhibitors can be effective, not all men respond to PARP inhibitors, or their cancers mutate and develop resistance to the treatment. This study aims to address the issue of more precisely selecting—and monitoring—patients who will respond best to olaparib. A major advantage of using a blood test for this task is that it is noninvasive.

The blood test has three functions. First, it checks a man’s DNA to see if he would benefit from treatment with PARP inhibitors. Olaparib is especially successful in killing cancer cells that have damaged DNA repair genes such as BRCA1 or BRCA2.

Second, the test analyzes the patient’s blood after he starts treatment to determine if the treatment is working. If it is not working, the patient can switch to a different treatment. For patients who responded well to olaparib, the test showed a nearly 50% reduction in the levels of cancer DNA in the blood after only 8 weeks of treatment. These men lived an average of 17 months after starting the treatment. Comparatively, men who did not respond well to the treatment had an average 2% rise of cancer DNA in their blood, and they lived an average of only 10 months after starting treatment.

Third, the test allows physicians to monitor the cancer’s DNA to see if the cancer cells are developing resistance to the drug treatment. In patients who stopped responding to olaparib, the blood test showed that the cancer cells had acquired new genetic changes that cancelled out the original errors in the DNA genes, thus signaling that the treatment would stop working.

At this time, the liquid biopsy is being tested in only 49 patients. But, the researchers hope their work could lead to olaparib becoming a new standard of care for patients with advanced prostate cancer who meet the genetic criteria.

Read the full article at http://epubs.democratprinting.com/article/Advances+In+Precision+Medicine%3A+New+%E2%80%9CLiquid+Biopsy%E2%80%9D+Blood+Test+Targets+Advanced+Prostate+Cancer+Treatment/2867455/434322/article.html.

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