James L. Mohler, MD
Amid continuing concerns about overtreatment of patients with prostate cancer, the National Comprehensive Cancer Network (NCCN) has overhauled its guidelines for managing the malignancy with a greater emphasis on risk stratification for molecular testing and therapy choices. The new version of the guidelines features recommendations on germline testing, molecular testing, and initial therapy for each risk category, each of which has its own management page (Table
“What we’re trying to do is develop a more personalized medicine” for men with prostate cancer, said James L. Mohler, MD, associate director and senior vice president for translational research, Roswell Park Comprehensive Cancer Center, during a presentation at the 2017 NCCN Annual Conference.
Risk stratification by family history is also emphasized, “and for the first time we finally know what a strong family history is,” Mohler said. A brother or father or multiple family members diagnosed with prostate cancer before age 60 constitutes a strong family history. “Now we’re learning more about the need to identify DNA repair gene abnormalities and also to search for Lynch syndrome, which is something that most urologists probably weren’t familiar with until recently,” he said.
Table. Risk Stratification and Staging Workup of Prostate Cancer1
Avoid Overdetection, Overtreatment
Prostate cancer guidelines are needed because overdetection leads to overtreatment. Additionally, financial incentives are such that providers are rewarded for imaging studies and treatment, and new agents treating castrationresistant prostate cancer are expensive and their optimal sequence of use is uncertain.
The cost of treatment for castration-resistant disease to add 2 years of survival is about $1.3 million, so the financial burden is substantial, said Mohler.
Estimating life expectancy is important for molecular testing and treatment decisions, especially in low-risk groups. The estimation is possible by using life insurance or Social Security Administration life expectancy tables, and adjusting the finding for individual patients by adding or subtracting 50% based upon whether one believes that the patient is in the healthiest or unhealthiest quartile, respectively.
In low-risk or very low-risk prostate cancer, immediate treatment is rarely needed, said Mohler. Prostate cancer is a slow-growing tumor, “and if we continue to treat men who have slowgrowing prostate cancer, you’re not going to help, but we cannot ignore the rapidly growing highrisk potentially fatal cancers,” he said.
Several studies have shown that there’s no harm in treatment delays of up to 2 years. “We have this window of opportunity to follow patients carefully and select those who actually need to be treated from among the majority who do not,” Mohler said.
Retrospective studies have shown that molecular assays of tissue from prostate biopsy or radical prostatectomy provide prognostic information independent of NCCN risk groups. These assays are fairly good at predicting the likelihood of death with conservative management, the likelihood of biochemical progression after radical prostatectomy or external beam therapy, and the likelihood of developing metastasis after radical prostatectomy or salvage radiotherapy.
Molecular and germline testing should also be considered in more advanced disease, “but it’s a little more complicated here,” Mohler said. “We should test for germline or somatic mutations in the DNA homologous recombination genes in all men with high-risk cancer, very high risk, regional, and especially metastatic disease.”
Mohler noted that mutations in homologous recombination genes—particularly BRCA1/2, ATM, PALB2,
—can be found in 6% of men with high-risk prostate cancer, and in 11.8% of men with metastatic prostate cancer.
Men with a positive test should be referred for genetic counseling, he advised. The results have treatment implications in that men with a positive genomic test may be considered for earlier use of platinum chemotherapy or referral for clinical trials in which PARP inhibitors are being tested.
DNA analysis for microsatellite instability (MSI) and immunohistochemistry for mismatch repair deficiency (dMMR) should also be considered. If either is found, the patient should be referred to a genetic counselor to assess for the possibility of Lynch syndrome and potential use of treatment with pembrolizumab (Keytruda) once androgen deprivation therapy (ADT) fails.