Genetic Variant of p53 Associated With Poor Breast Cancer Survival

MedicalResearch.com Interview with:
Maureen E. Murphy, Ph.D.
Program Leader and Professor
Molecular and Cellular Oncogenesis and
Subhasree Basu PhD
Postdoctoral researcher
The Wistar Institute
Philadelphia, PA 19104

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Unlike most other genes that are intimately involved in the cause of cancer, the p53 gene displays considerable genetic variation; in other words, p53 is unusual among cancer genes in that the amino acids in p53 protein can frequently differ amongst different populations and ethnic groups. Additionally, unlike most other tumor suppressor genes, when p53 is mutated in a tumor, as it is in 50% of human cancers, that mutant protein now has a positive function in cancer progression, changing tumor metabolism and promoting tumor metastasis.

In this study, the authors analyze for the first time the impact of a common genetic variant in p53 (single nucleotide polymorphism, or SNP) in the ability of mutant p53 to promote tumor metabolism and metastasis, and they find significant differences.  Continue reading

Genetic Cell Cycle Proliferation Score Stratifies Risk For Prostate Cancer

Michael Brawer, M.D. Vice president of Medical Affairs Myriad Genetic LaboratoriesMedicalResearch.com Interview with:
Michael Brawer, M.D
.
Vice president of Medical Affairs
Myriad Genetic Laboratories

Editor’s Note: Dr. Brawer spoke with MedicalResearch.com regarding two studies presented by Myriad Genetic Laboratories at the American Urological Association’s 2015 Annual Meeting, May 15 2015 on the use of the Clinical Cell Cycle Risk (CCR) Score or Prolaris Test made by Myriad Genetic Laboratories.

The Prolaris Test provides a quantitative measure of the RNA expression levels of multiple genes related to the progression of tumor cell division.

MedicalResearch: Would you tell us a little about yourself and your work at Myriad?

Dr. Brawer: I am a Urologist, and did my urology training at Stanford. I practiced urology, first at the University of Arizona and then at the University of Washington. My entire career has been focused on prostate cancer. Early on I was interested in serum and tissue markers for prostate cancer and helped develop PSA testing as a diagnostic tool. In 2012, shortly after joining Myriad, my colleagues and I reported findings from the PIVOT trial in the NEJM1. This study found ‘Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points.’

The PIVOT study of 731 men compared ‘watchful waiting’ or observation versus medical prostatectomy. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer specific mortality. The surprising finding was that for both endpoints, men did no better with radical prostatectomy.

Our most important concern has been to develop more precise risk assessment to determine which prostate cancer patients to treat and which will do well with conservative management.

Myriad has developed testing for hereditary breast and ovarian cancer (the 25-gene Myriad myRisk™ Hereditary Cancer test) as well as other hereditary malignancies. As in breast cancer, cell cycle progression genes are important in allowing unregulated cell proliferation in prostate cancer. The Prolaris test is an assay performed on a diagnostic prostate biopsy. The test compares the genetic signature of low and high-risk Cell Cycle Progression (CCP) genes and determines a score correlated with risk of cancer progression.

We tested nine separate cohorts of men with prostate cancer who had known outcomes. These patients ranged from conservatively managed men, to those managed with radical prostatectomy or treated with radiation therapy. In each group, Prolaris provided unique and useful information over what is typical current risk assessment, (Gleason score, PSA); the test enhanced the ability to individualize prognostic risk. We looked at real outcomes, including death from prostate cancer, metastases or biochemical failure after treatment.

MedicalResearch: What is active surveillance? How does active surveillance benefit the patient?

Dr. Brawer: Prostate cancer is a variable disease and for each patient, the clinician is trying to determine the most appropriate treatment. In many cases, prostate cancer is over detected and over treated. Treatment of prostate cancer can have significant side effects that may be unnecessary in low-risk patients. On the other hand, some prostate cancer is aggressive and results in thousands of deaths each year. Because current testing is useful but not precise enough to adequately assess risk, some patients are over treated and some are undertreated. We need a more accurate prediction to determine who is a candidate for conservative management and who should have aggressive intervention.

Active surveillance (AS) means withholding treatment after diagnosis and following the patient for evidence of recurrence. Active surveillance avoids the consequences of interventional therapy without putting the patient at risk. But just as important is the ability to determine who is not a candidate for active surveillance. In our study, 60% of patients’ risk assessment was deemed lower or higher after Prolaris testing.

Dr. Cuzick is presenting two papers discussing an active surveillance threshold, which can provide a meaningful cutoff for who is or is not candidate for further treatment. In these studies of over 500 men, who were currently being considered for AS, a threshold CCP score of 0.80 was selected, such that 90% of the men in the training cohort had scores below the threshold. At this threshold value, 21 had died of prostate cancer if their value was greater than 0.80 and there were no deaths in patients below the threshold.

Just as important as allowing low risk men to avoid aggressive treatment is the ability of the test to help predict which cancers should be treated more aggressively. After calculating patient risk with CCP in these studies, 17% of the AUA classified low risk men were reclassified to intermediate risk, 31% of the AUA intermediate risk men were reclassified (16% low and 15% high risk), and 14% of the AUA high risk was reclassified to intermediate risk.

Thus CCP testing allows more appropriate treatment or observation for both low and high-risk prostate cancers.

MedicalResearch: Can you give us more specifics of how the test is done? How widespread is the testing in current practice?

Dr. Brawer: The CCR testing is performed on about a 0.5mm core tumor tissue sample. The specimen is sent to the Myriad lab and the results typically take 7-10 days. About 20% of US urologists are currently employing the testing in their practices and this number has increased markedly over the past two quarters.

MedicalResearch: Is the CCR testing covered by insurance?

Dr. Brawer: Myriad has submitted an application for insurance coverage to Medicare with a reimbursement decision expected shortly.

MedicalResearch: What further research are you planning?

Dr. Brawer: Multiple further utility studies are planned for CCR testing in prostate cancer, including a large study at the VA hospitals.

In addition, a similar set of gene signature testing of small renal masses is planned.

Reference:

Radical Prostatectomy versus Observation for Localized Prostate Cancer

Timothy J. Wilt, M.D., M.P.H., Michael K. Brawer, M.D., Karen M. Jones, M.S., Michael J. Barry, M.D., William J. Aronson, M.D., Steven Fox, M.D., M.P.H., Jeffrey R. Gingrich, M.D., John T. Wei, M.D., Patricia Gilhooly, M.D., B. Mayer Grob, M.D., Imad Nsouli, M.D., Padmini Iyer, M.D., Ruben Cartagena, M.D., Glenn Snider, M.D., Claus Roehrborn, M.D., Ph.D., Roohollah Sharifi, M.D., William Blank, M.D., Parikshit Pandya, M.D., Gerald L. Andriole, M.D., Daniel Culkin, M.D., and Thomas Wheeler, M.D. for the Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group

N Engl J Med 2012; 367:203-213
July 19, 2012 DOI: 10.1056/NEJMoa1113162

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Citations: Abstracts presented at the American Urological Association May 2015

Friday, May 15, 2015 10:30 AM-12:30 PM
NOMCC: 220-221
Prostate Cancer: Markers I
Funding: Myriad Genetics, Inc.
MP1-08: Patient AUA Risk Classification Based on Combined Clinical Cell Cycle Risk (CCR) Score
Jack Cuzick*, London, United Kingdom, Steven Stone, Julia Reid, Salt Lake City, UT, Gabrielle Fisher, Henrik Møller, London, United Kingdom, Michael Brawer, Salt Lake City, UT, Peter Scardino, New York, NY, Neal Shore, Myrtle Beach, SC

Friday, May 15, 2015 10:30 AM-12:30 PM
NOMCC: 220-221
Prostate Cancer: Markers I
Funding: Myriad Genetics, Inc.
MP1-10: Validation of an Active Surveillance Threshold for the CCP Score in Conservatively Managed Men with Localized Prostate Cancer
Jack Cuzick*, London, United Kingdom, Steven Stone, Salt Lake City, UT, Gabrielle Fisher, Zi Hua Yang, Bernard North, Daniel Berney, Luis Beltran, London, United Kingdom, David Greenberg, Cambridge, United Kingdom, Henrik Møller, London, United Kingdom, Julia Reid, Alexander Gutin, Jerry Lanchbury, Michael Brawer, Salt Lake City, UT, Peter Scardino, New York, NY

MedicalResearch.com Interview with: Michael Brawer, M.D. (2015). Genetic Cell Cycle Risk Score Stratifies Risk For Prostate Cancer 

Cancer Risk: Multiple Gene Testing Can Benefit Selected Patients

MedicalResearch.com Interview with:
Allison W. Kurian, M.D., M.Sc. Assistant Professor of Medicine and of Health Research and Policy Divisions of Oncology and Epidemiology Allison W. Kurian, M.D., M.Sc.
Assistant Professor of Medicine and of Health Research and Policy
Divisions of Oncology and Epidemiology

and

James M. Ford, MD Associate Professor of Medicine Pediatrics and Genetics, Division of Oncology, Stanford University School of MedicineJames M. Ford, MD
Associate Professor of Medicine
Pediatrics and Genetics, Division of Oncology,
Stanford University School of Medicine


MedicalResearch.com: What are the main findings of the study?

Answer: We found that 11% of women who met standard clinical criteria for BRCA1 and BRCA2 (BRCA1/2) mutation testing, yet had tested negative, actually carried an actionable mutation in another cancer-related gene.  We found that patients were highly motivated to learn about their genetic test results and new recommendations for cancer risk reduction.  Over a short follow-up period, colonoscopy screening resulted in early detection of a tubular adenoma in a patient found to have a high-risk MLH1 mutation, and thus the multiple-gene testing in our study has likely prevented at least one cancer to date.  We conclude that multiple-gene sequencing can benefit appropriately selected patients.

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