Andrew Siegel MD 12/28/2019
As the year draws to a close, it is time to think about what 2020 and the future have in store for prostate cancer, the #1 cancer in men. Major research efforts and advances are being made in prostate cancer screening, detection, risk assessment, treatment and follow-up. Numerous ongoing clinical trials are exploring novel therapeutic strategies and investigational agents.
Image by Rilsonav from Pixabay
Screening
Prostate cancer screening has evolved beyond the digital rectal exam and PSA (prostate specific antigen) blood testing. The concept of “targeted” screening is being employed more often and that trend will accelerate, using tests that can potentially reduce the number of biopsies performed in men with a suspicion of prostate cancer based upon a PSA elevation. A sophisticated blood test, 4K score, has become widely available and is frequently used to help to make the decision whether to biopsy the prostate or not. Furthermore, a urine test, exosomal RNA, is now available to test for the expression of 3 genes (TMPRSS2:ERG; PCA3; SPDEF) that play a role in prostate cancer initiation and progression. This urine test can help discriminate high grade prostate cancer from low grade cancer/benign disease.
Imaging
The recent incorporation of powerful magnets has resulted in more sophisticated multi-parametric prostate MRI capabilities, improving both prostate cancer screening and staging. PET/CT and PET/MRI imaging are in their infancy and their evolution are rapidly improving the precision of prostate cancer staging.
Risk Assessment
Advances in prostate cancer risk assessment continue to evolve, of fundamental importance as prostate cancer behavior can be so variable, ranging from indolent and innocuous to aggressive and lethal. Genetics-based biomarkers show great promise in improving the accuracy of assessing the potential of any given prostate cancer, helping stratify the cancer into risk categories ranging from very low risk to very high risk and informing appropriate treatment choices.
Focal Therapy
Focal therapies (HIFU, cryoablation, and focal laser ablation)—treatments directed at only the cancerous parts of the prostate gland—show potential yet remain controversial because of the multifocal nature of prostate cancer and the lack of long-term outcome data. In select patients, focal therapy can offer an intermediate option between active surveillance at one extreme and active treatment (surgery or radiation) on the other.
Surgery: Minimally-invasive surgery becomes more minimal
Robotic assisted laparoscopic prostatectomy (RALP) is the surgical standard of care for the surgical management of prostate cancer. The newest robotic innovation is single port robotic surgery. Used in select cases, instead of multiple keyhole incisions in the abdomen that are used in traditional RALP, this breakthrough technology uses a single incision near the belly button. Within this single port of entry into the body are introduced the endoscopic instruments and camera. This new method of reducing surgical access points and the capability of performing complex maneuvers in smaller spaces compared with multiport procedures has the potential to result in less pain, less scarring, and shorter hospital stays.
Our urology practice—New Jersey Urology (Maywood and Teaneck)—pioneered robotic urology in the early 2000s and because of our high volume of cases and superior outcomes in multiport robotic surgery has been chosen to be one of the first group of surgeons in the United States to trial this new technology. Our practice has successfully performed almost 100 cases to date.
Maywood/Teaneck NJU; standing: A. Siegel, V. Lanteri, M. Goldstein, C. Wright, M. Ahmed; sitting: M. Esposito, G. Lovallo, T. Christiano
Advanced Therapies
The FDA has recently approved a host of new agents for advanced prostate cancer that potentially can increase life expectancy and prolong survival. The availability of so many options has made clinical decision-making more challenging, raising questions as to the most advantageous timing and sequencing of the different agents and the best combinations of agents to optimize treatment. These questions will be answered over the course of the next few years.
Targeted Therapies
As opposed to chemotherapy that is cytotoxic and does not distinguish between normal and malignant cells, targeted medical therapies designed to treat only the prostate cancer cells are being explored. Ongoing trials include medications that inhibit the activity of growth factor receptors, those that interfere with the blood supply to prostate cancer cells, and those that stimulate the immune system to fight cancer cells. The emerging field of immunotherapy is an exciting new direction for prostate cancer, with great potential for checkpoint inhibitors/immune modulators (all have in common names that end in “-umab”), adoptive cell therapy and prostate cancer vaccines such as PROSTVAC that activate the immune system to target PSA.
Genetics, Genomics and Precision Medicine
Certain inherited mutations (germline mutations) increase cancer risk because the mutation interferes with the cell’s ability to repair damaged DNA. The BRCA1 and BRCA2 genes (better known for their role in increasing risk for breast and ovarian cancer) are important DNA repair genes that when mutated can substantially increase the risk of prostate cancer. Mutations in the BRCA1 and BRCA2 genes account for about 10% of metastatic prostate cancers. DNA sequencing in patients with metastatic prostate cancer has come into vogue and in the future will likely be routine since about 20% of men with metastatic prostate cancer are found to have inherited mutations.
A specific class of drugs is now being used for men with advanced prostate cancer who have inherited genetic mutations that interfere with the ability to repair damaged DNA. PARP-inhibitors {poly (ADP-ribose) polymerase inhibitors)} are the first class of drugs for the treatment of advanced prostate cancer that are specifically targeted to inherited genetic mutations. PARP-inhibitors are FDA approved and have found utility for breast and ovarian cancer. The BRCA genes are DNA repair genes, meaning that when an error is made in cellular replication, they are responsible for coding for proteins that repair double-strand DNA breaks. Single-strand DNA breaks are repaired by PARP enzymes. Cancer cells that have mutations in the BRCA1 and BRCA2 genes are unable to fix double-strand DNA breaks as they accumulate DNA damage so have to rely on single-strand mechanisms for the repair using the PARP enzyme. PARP-inhibitors cripple the cell’s ability to fix the DNA damage resulting in death of the cancer cell.
The PROfound trial compared olaparib (Lynparza), a PARP-inhibitor, to abiraterone (Zytiga) and enzalutamide (Xtandi) in men with prostate cancer progression despite the use of advanced hormonal therapy. This study showed a significant improvement in progression-free survival in the PARP-inhibitor arm. This drug was granted FDA “breakthrough designation” for men with metastatic castrate resistant prostate cancer due to BRCA1 or BRCA2 mutations. Two other PARP-inhibitors have been granted the same fast-tracking, niraparib and rucaparib. Others in the pipeline are veliparib and talazoparib. Olaparib will likely be the first in class to be approved by the FDA.
Arguably, the development of precision-medicine targeted treatments based upon genetics– such as PARP-inhibitors– was the most noteworthy prostate cancer advance of 2019.
Of recent, 63 new inherited DNA variants associated with increased prostate cancer risk have been identified, increasing the number of genetic risk regions to more than 170. Many of these newly discovered genetic variants are located in the sector of genes involved with communication among cells of the immune system, confirming the vital role of properly functioning immune pathways in decreasing prostate cancer risk.
Advances in the branch of genomics concerned with the structure and activity of genetic material at the molecular level will play a pivotal role in the future. Genomic science has enabled the ability to determine the molecular “blueprint” of any given prostate cancer, the key to assessing its biological potential. Determining a cancer’s unique genetic profile offers the potential for “precision medicine,” individualized and customized treatment strategies with agents targeted against the specific mutations, a treatment based upon cancer biology and no longer only on cancer histology.
The signature of the tumor will allow us to fully assess the genetic nature of the enemy, how aggressive it is, what its metastatic intentions are, what it is sensitive to, and how best to attack it. At the same time, we will be armed with a whole battery of potent oral agents capable of targeting specific signaling pathways in the tumor.
Dr. Arie Belldegrun, Surgical Director of GU Oncology, UCLA School of Medicine
Bottom Line: The future appears bright for the ongoing war with the most common cancer in men, affecting one in nine American males. Transcending the “slash, burn and poison” (surgery, radiation and chemotherapy) traditional approaches to prostate cancers, the fields of immunology, molecular biology and genetics are coalescing to provide a better understanding of prostate cancer at the cellular level and to guide customized targeted strategies based upon inherited genetics, acquired tumor genomics, and harnessing the powers of the immune system.
Wishing you the best of health in 2020 and beyond,
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Dr. Andrew Siegel is a physician and urological surgeon who is board-certified in urology as well as in female pelvic medicine and reconstructive surgery. He is an Assistant Clinical Professor of Surgery at the Rutgers-New Jersey Medical School and is a Castle Connolly Top Doctor New York Metro Area, Inside Jersey Top Doctor and Inside Jersey Top Doctor for Women’s Health. His mission is to “bridge the gap” between the public and the medical community. He is a urologist at New Jersey Urology, the largest urology practice in the United States.
The content of this entry is excerpted from his new book, PROSTATE CANCER 20/20: A Practical Guide to Understanding Management Options for Patients and Their Families
Video trailer for Prostate Cancer 20/20
Preview of Prostate Cancer 20/20
Andrew Siegel MD Amazon author page
Prostate Cancer 20/20 on Apple iBooks
PROSTATE CANCER 20/20: A Practical Guide to Understanding Management Options for Patients and Their Families is now on sale at Audible, iTunes and Amazon as an audiobook read by the author (just over 6 hours).
Dr. Siegel’s other books:
PROMISCUOUS EATING— Understanding and Ending Our Self-Destructive Relationship with Food
MALE PELVIC FITNESS: Optimizing Sexual and Urinary Health
THE KEGEL FIX: Recharging Female Pelvic, Sexual, and Urinary Health
Tags: Andrew Siegel MD, future, genetics, genomics, immunology, molecular biology, precision medicine, prostate cancer, Prostate Cancer 20/20, targeted therapies
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