Emmanuel S. Antonarakis, MD
Pivotal updates surrounding genetic testing have been incorporated into the National Comprehensive Cancer Network (NCCN) guidelines in prostate cancer, with a focus on germline testing in patients with metastatic or high-risk localized nonmetastatic disease and somatic testing in those with lymph node or distant metastases, explained Emmanuel S. Antonarakis, MD.
In a presentation during the 2019 NCCN Annual Conference, Antonarakis introduced the latest additions to the NCCN guidelines in terms of managing patients with prostate cancer, speaking to the role of genetic testing and how this can help determine treatment decisions.
The genes detected in patients with prostate cancer fall into 2 classes: mismatch repair (MMR) and homologous recombination deficiency (HRD). In some cases, the understanding of these mutations can help in determining the treatment course for a patient, he said, adding that the results can help define whether or not a patient’s family may also be at risk for developing cancer.
“These tests can help to form subsequent therapy if patients develop advanced or metastatic prostate cancer,” said Antonarakis. “They will not necessarily inform the first-line treatment for these patients, but they may inform the second- or third-line treatment.”
In an interview with OncLive
, Antonarakis, associate professor of oncology, John Hopkins University, discussed the prevalence of these different genes and how they may play a role in determining a patient’s treatment plan. He also highlights promising agents that have been introduced to the field in clinical trials, including PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca).
OncLive: What are the main points you covered in your presentation?
: The purpose of my talk this year was to update the audience with the new information about genetics in prostate cancer and how this information helps us to make treatment decisions. There are 2 main types of genetic testing that need to be considered. The first is called germline testing—looking for inherited gene mutations that can predispose patients to getting cancer in the first place, some of which can be used to make therapeutic decisions. The second type of testing is somatic testing, where we are looking for mutations in the tumor specimen itself.
Again, some of those can also be used to make decisions about treatments. The 2 newest things on the guidelines related to that are that germline inherited testing is being recommended for every patient with metastatic prostate cancer, so that’s a broad spectrum, and for every patient with high-risk, localized nonmetastatic prostate cancer. The only people right now that the guidelines are not recommending for germline inherited testing is men who have very low-risk prostate cancer. Secondly, who should we do the somatic testing in? The guidelines say that anyone who has lymph node metastases should also undergo tumor somatic testing.
This leads to the next question of, “How prevalent these genes are in prostate cancer, and secondly, what can you do with this information?” The first thing to address is the prevalence; the most informative type of gene mutations involves 2 classes of genes. The first class is MMR genes and the second class is HRD genes.
MMR genes are the ones that are responsible for Lynch syndrome if inherited, but they can also be acquired. These genes are MSH2, MSH6, MLH1
, and PMS2
. These are the genes that cause these hypermutated tumors; tumors have hundreds, if not thousands, of mutations. The therapeutic reason that this is important is that in prostate cancer and in other cancer types, if you have an MMR deficiency or mutation, you can receive pembrolizumab (Keytruda), a PD-1 inhibitor, which is now FDA approved for all cancer types that have the MMR
Unfortunately, in prostate cancer, this only represents about 3% to 5% of all advanced prostate cancers. Pembrolizumab can be used and is on the guidelines for prostate cancer; however, it only applies to the 3% to 5% of patients with this MMR
The second class of mutations, the HRD genes, are the ones that include BRCA2, BRCA1, ATM
, and a number of other genes. Collectively, these gene mutations make up between 20% to 25% of all advanced prostate cancers, so these are far more common than the MMR mutations. Even though testing for these HRD genes is recommended on the NCCN prostate guidelines, we do not currently have any FDA-approved therapies specifically targeting those patients. There is a lot of interest in using PARP inhibitors like olaparib or rucaparib, and others for those patients.