5 Big Questions (and Answers) on Inherited Prostate Cancer Testing

Nick Mulcahy

May 18, 2017

BOSTON — Prostate cancer not only runs in families but sometimes is associated with heritable genetic mutations, said various presenters here at the American Urological Association (AUA) 2017 Annual Meeting.

The mutations are important because they are tied to the development of prostate cancer and, in some cases, more aggressive disease. Their presence may also help indicate the usefulness of specific treatment in advanced disease.

In short, a man's mutation status can affect screening and treatment decisions.

The technology for detecting these germline, inherited mutations related to prostate cancer "is already there," said Marc Dall'Era, MD, from the University of California, Davis, during a meeting press conference on the subject. He continued: "The question is, how do we apply it?"

He got an answer the same day, about 4 hours later, when the conclusions of a March 2017 consensus conference on the subject were presented.

To date, there have been only "very limited guidelines" about who should undergo genetic evaluations for prostate cancer risk, said Veda Giri, MD, from Thomas Jefferson University in Philadelphia, Pennsylvania, and co-chair of the consensus effort.

She spoke at a standing-room-only session of the meeting of the Society of Urologic Oncology, which took place in conjunction with the AUA meeting.

The need for comprehensive guidance on genetic testing for prostate cancer has been steadily accumulating since the late 1990s as scientific discoveries started having clinical implications, said Dr Giri. And all of this was aided by a monumental US Supreme Court decision that has led to a proliferation of more affordable testing.

Dr Giri explained that the ball got rolling with the discovery that families that were BRCA positive (they were mostly breast cancer families) had a higher risk for prostate cancer. Then BRCA2 was, in multiple studies, associated with both breast and prostate cancer.

Next, tumor sequencing studies in metastatic prostate cancer identified substantial rates of BRCA mutations, many of which are germline mutations, which means that they are inherited and not related to changes in the tumor.

In addition, "much higher" rates of prostate cancer were seen in other inherited cancer syndromes, including Lynch syndrome, Dr Giri said.

In 2012, a landmark report identified HOXB13 as the first hereditary prostate cancer gene, as reported by Medscape Medical News.  Also, tumor sequencing studies have been identifying DNA repair mutations in metastatic prostate cancer.

Furthermore, in 2015, researchers found that men with metastatic castration-resistant prostate cancer (mCRPC) whose tumors harbored certain DNA-repair defects were much more likely to respond to the oral poly (adenosine diphosphate-ribose) polymerase inhibitor olaparib (Lynparza, AstraZeneca) than their peers whose tumors did not have these mutations.

But another key event was in 2013, when the US Supreme Court ruled that naturally isolated DNA could not be patented. "This really opened the door, along with the advent of next-generation sequencing, to have multiple commercial genetic testing laboratories be able to offer prostate cancer multigene panels for commercial availability for genetic testing," said Dr Giri.

Many panels are now available and include BRCA1 and BRCA2, as well as several other genes, she said.

However, the current guidance on using such tests is centered on BRCA1 and BRCA2 testing, such as the National Comprehensive Cancer Network guidelines on hereditary breast and ovarian cancer, which call for men in such families to also have BRCA testing (for prostate cancer).

"The scope has been very limited about how to apply these multigene panels," said Dr Giri.

Big Questions and Answers

This all led to the Prostate Cancer International Consensus Conference, held 2 months ago in Philadelphia, which featured 70-plus experts.

"This is the first centralized, comprehensive, multidisciplinary consensus effort to create a framework for gene testing for inherited prostate cancer in the era of multigene panel testing," summarized Dr Giri.

She reviewed five "big" questions addressed at the conference. Each one describes an issue that "garnered the highest level of consensus" among the gathered experts or had moderate consensus but was "very timely right now in the clinical setting."

She also explained that there were three grades for assessing the level of consensus among the experts for the recommendations: High (75% or above), Moderate (50% to 74%), and None (less than 50%).

Question 1: Who should be referred for genetic counseling and for consideration of genetic testing to assess for inherited prostate cancer?

Answer:

  • Men with a first-degree relative (FDR; a father or brother) diagnosed with prostate cancer at age 55 years or younger, men with a personal diagnosis at that age with an FDR diagnosed with prostate cancer at any age, or men with an FDR who died of prostate cancer at age younger than 60 years (High);

  • Men with two close blood relatives (not just an FDR) with prostate cancer on the same side of a family, with at least one diagnosed with prostate cancer at age 55 years or younger (High);

  • Men with any FDR with cancer in the spectrum of hereditary breast and ovarian cancer or Lynch syndrome who were diagnosed at age younger than 50 years (High); and

  • Men whose tumor sequencing has shown mutations in hereditary cancer genes (High).

The impact of these statements is that it "expands on existing referral criteria" to include age of diagnosis, Lynch syndrome, and tumor sequencing results, said Dr Giri.

Question 2: What criteria should be considered to recommend genetic testing for inherited prostate cancer?

Answer:

  • Patients should be part of shared decision-making for this testing (High).

  • In terms of the criteria for recommending testing, all men with prostate cancer in FDR families that meet established criteria for hereditary breast and ovarian cancer, hereditary prostate cancer, or Lynch syndrome should be considered for testing (High).

  • Men with prostate cancer who have two or more close blood relatives on the same side of the family with those same three syndromes should be considered for testing (High).

  • All men with mCRPC should undergo genetic testing (Moderate).

Most notably, this question "really tried to get at the question of genetic testing for metastatic prostate cancer," said Dr Giri.

Question 3: What genes should be tested for inherited PCA?

Answer:

This question focuses on the multigene panels that are available at this time. Strong and consistent data show that BRCA2 and HOXB13 raise the risk for prostate cancer; to a lesser extent, so do BRCA1 and the DNA mismatch repair genes. Also, in terms of aggressive prostate cancer, consistent data implicate BRCA2 and emerging data implicate ATM. The rest of the genes on the various commercial panels have limited or unknown data.

  • HOXB13 should be tested in males suspected of having hereditary prostate cancer (High), BRCA1 and BRCA2 should be tested in men suspected of having hereditary breast and ovarian cancer (High), and DNA mismatch repair genes should be tested in those with Lynch syndrome (Moderate).

  • The following genes should be tested in men with two or more close blood relatives on the same side of the family with the cancer syndromes: BRCA1 and BRCA2 in hereditary breast and ovarian cancer and DNA mismatch repair genes in Lynch syndrome (High).

  • To help determine their treatment, men with mCRPC should undergo testing for BRCA1 and BRCA2 (Moderate).

These recommendations expand testing to include hereditary cancer syndromes and broader family cancer histories, said Dr Giri.

Question 4: How should genetic test results inform prostate-specific antigen (PSA) screening?

Answer:

  • BRCA2 mutation status should influence prostate cancer screening discussions. The strategy is to perform baseline PSA testing at age 40 years or 10 years before the youngest age at which prostate cancer was diagnosed in a family (Moderate). The screening interval is 1 year or as determined by baseline PSA (High).

  • HOXB13 status should also influence discussions. If positive, then the same screening strategy as for BRCA2 applies, as do the same consensus scores.

Dr Giri commented that this guidance is the first to address HOXB13 and its role in prostate cancer screening.

Also, at the AUA press conference on the subject of genetic mutations, Scott Eggnerr, MD, from the University of Chicago, Illinois, said that the "take-home message" for clinicians is that careful family history, including the history of women in the family, is important in helping establish the need for prostate cancer screening

Question 5: Should genetic test results inform management of actual prostate cancer?

Answer:

  • Of the genes on multigene panels, only BRCA2 results should be factored into management of early-stage/localized and high-risk/advanced prostate cancers (Moderate).

  • In the treatment of mCRPC, BRCA1 and BRCA2 (High) and ATM (Moderate) should help inform decisions.

Dr Dall'Era has financial ties to Genomic Health, Bayer, Janssen, and MDxHealth. Dr Giri has disclosed no relevant financial relationships.

American Urological Association (AUA) 2017 Annual Meeting. Presented Monday, May 15.

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc

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