Examining the NCCN Recommendations for Genetic Testing in Prostate Cancer

James L. Mohler, MD

James L. Mohler, MD

A key recommendation from the 2019 National Comprehensive Cancer Network (NCCN) guidelines on genetic testing and counseling in prostate cancer is that men with high-risk, extreme high-risk, regional, or metastatic disease should receive genetic testing and counseling.¹The guidelines also provide more in-depth information regarding family history, making it more clear what history to collect and how to use the information.

James L. Mohler, MD, stated, “we prescribed what a family history should be, as well as other things that should be captured in addition to diagnoses of prostate cancer. [This may include] other hereditary syndromes, whether they're Ashkenazi Jewish or not, whether they have known mutations in their families, and of course, whether they're African American or not. Also, if they have family members with prostate cancer, where are they in the family tree?”

By understanding this additional background information, oncologists may be able to determine the number of genes that should be assayed for mutations, which may ultimately improve treatment outcomes.

Earlier this year, the NCCN Prostate Cancer Panel reported updated guidelines for genetic testing in prostate cancer during the NCCN Annual Meeting, held March 21 through March 23 in Orlando, Florida. The guidelines highlight a 2016 study evaluating inherited DNA-repair gene mutations in men with metastatic prostate cancer.²

The results showed no difference in mutation frequency among patients with a family history of prostate cancer and those without. Additionally, men with metastatic disease had a significantly higher frequency of germline mutations in DNA-repair genes than men with localized disease (P<.001). Among the mutations found in all patients, the most common were&nbsp;BRCA2(44%),ATM(13%),&nbsp;CHEK2(12%), andBRCA1(7%), which make patients resistant to certain therapies.²

In an interview withTargeted Oncologyduring the 2019 Prostate Cancer Consensus Conference, Mohler, associate director and senior vice president for translational research, and professor of oncology, Roswell Park Comprehensive Cancer Center, explained the reasons for changes to the NCCN guidelines on genetic testing and counseling in prostate cancer. He also discussed what needs to be addressed in the future to further increase knowledge of genetic testing and improve its use.

TARGETED ONCOLOGY: Can you give an overview of your presentation at the 2019 Prostate Cancer Consensus Conference?

Mohler: The NCCN guidelines were delayed last year from their normal release in November until March. The delay was largely due to the fact that we improved the indications for genetic testing, [including] how to perform those tests and how to utilize the information. We did that both in the localized prostate cancer [setting], as well as for advanced disease, where the situation is quite different. With one, we're talking about genomic testing and with the other, we're talking about somatic testing.

We made so many changes that we also thought that we should explain it. We published an article in the Journal of the National Comprehensive Cancer Network (JNCCN). We also participated in the Prostate Cancer Consensus Conference to present the reasons for our changes and to gain insight from the experts at the meeting as to how we can improve further. My presentation focused on the changes that we made, but I mostly talked about what we can do better because of the rapidly emerging data on genetic testing abnormalities as they pertain to prostate cancer early detection, risk assessment, cascade testing, and finally to the treatment of prostate cancer.

TARGETED ONCOLOGY: What changes were made to these guidelines?

Mohler: The most important thing is that it's never been clear what a family history should consist of when you're addressing a man with prostate cancer. Too often our family history is recorded in an electronic health record as positive or negative, or it may even say which relative had cancer. However, it doesn't often capture the age of diagnoses, treatment received, whether they developed or presented with metastatic disease, and most importantly, did they die of it.

We prescribed what a family history should be, as well as other things that should be captured in addition to diagnoses of prostate cancer. [This may include] other hereditary syndromes, whether they're Ashkenazi Jewish or not, whether they have known mutations in their families, and of course, whether they're African American or not. Also, if they have family members with prostate cancer, where are they in the family tree? All of this was made so it could be routinized in clinical practice and we can do a better job of capturing family history.

The next thing we did was try and specify the minimum number of genes that should be assayed for mutations. In the situation of a positive family history or whether the man's tumor was sequenced or whether one had failed androgen deprivation therapy and was having a metastatic site biopsied and sequenced. Finally, as always, we called for more clinical trials to determine whether taking action based upon our new genetic testing information impacts outcome, which is the important question that remains unknown.

TARGETED ONCOLOGY: What clinical trials are coming down the pipeline that you want to highlight?

Mohler: There are many [clinical trials]. There's one study going on at the National Cancer Institute in the early detection space for people with knownBRCA1/2mutations. There are many clinical trials now that are collecting germline and somatic data as a qualification for entry into the trial and either as a stratification or randomization. Then there is an addition of sequencing in many clinical trials as correlative science, which will inform the development of future clinical trials.

TARGETED ONCOLOGY:In terms of the guidelines, have there been any clinical trials that have taken the updates into account?

Mohler: That's part of the problem. There are so few clinical trials that are acting upon either germline or somatic sequencing results. The ones that are coming along, for the most part, are not yet replicated. It's difficult to make any kind of definitive statement about how one acts on any of these data at the present time.

TARGETED ONCOLOGY: What are the main factors that oncologists should look for to determine whether or not an individual should undergo genetic testing?

Mohler: If you have a strong family history of prostate cancer, especially when diagnosed at an early age, which I would consider under the age of 55, and metastatic or that became fatal. That raises the question of whether you have a DNA repair gene abnormality in your family. If you have a regional or metastatic prostate cancer, especially at a young age, that raises the question of whether you have a mutation in that tumor that is affecting the aggressiveness that it presents as and could be a potential target for new therapies.

Once you failed conventional therapy for advanced disease, I think everybody who has an accessible legion [should have] a biopsy to see if you can do a better job of selecting what their tertiary or quaternary treatment might be.

TARGETED ONCOLOGY:Moving forward, how do you see prostate cancer and genetic testing changing over the next few years? How will these guidelines be used?

Mohler: Everyone at this meeting has recognized the importance of genetic counselors, and we're functioning when we have a deficit in the number of highly trained and highly qualified genetic counselors. There are all kinds of certificate programs now, they are people who can take short courses to try and improve their knowledge so that physicians can do a better job of the pre-genetic testing counseling. As a urologist, I can tell you that I'm woefully inadequate to do this. We need to train more genetic counselors. As urologists, radiation oncologists, and medical oncologists, we also need to become much more knowledgeable in dealing with this rapidly expanding database.

TARGETED ONCOLOGY: What are some ongoing challenges that should be addressed in relation to genetic testing for prostate cancer and for prostate cancer in general?

Mohler: This conference causes me to go back to NCCN and make sure that we do a better job of integrating our recommendations among the various guidelines so that we are consistent. We also have to be very aware of the fact that we do not fully understand just how much clinical utility any of these findings have. We're also a little bit deficient in our understanding of what the medical and legal repercussions may be for patients because the GINA (Genetic Information Nondiscrimination Act) does not cover well on a federal level beyond workplace discrimination and insurability. It has nothing to do with life insurance or disability insurance. Because of this, many of the states are making stronger GINAs but that is in a minority of the states and is another area that needs further attention.

The last thing that needs some attention is that there is a perception among patients and providers that genetic testing is quite expensive. Some people have told me that it has become less expensive, but I am skeptical about that. It appears that patient out-of-pocket costs are very for what most patients would consider affordable. But, we have to remember that out-of-pocket cost is not the same as the cost to our healthcare system. Before we commit every man diagnosed with prostate cancer to genetic testing, we need to think more about it because of the expense involved and also the repercussions for family members with cascade testing. We don't want to get into a situation where we ask for these tests reflexively from everyone when we don't yet know how the test be done and what gene should be assayed so we can make well-informed decisions. We need more data.

References

1. NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines), Prostate Cancer. August 19, 2019. https://bit.ly/34FrbWu. Accessed November 7, 2019.
2. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.N Engl J Med. 2016;375:443-453. doi: 10.1056/NEJMoa1603144.