What this means for patients: The Prostate Cancer Foundation (PCF)-sponsored International Prostate Cancer Dream Team has released results from a landmark study that uses gene sequencing technologies to identify the mutations present in tumors from individual prostate cancer patients. These results can be used to match each patient with medicines that target his tumor’s mutations and are most likely to be beneficial. This study will likely change the practice of oncology from same-treatment-for-all strategies to precision medicine – where each patient receives therapies tailored to his unique tumor biology.
May 21, 2015 — At the 2015 American Association for Cancer Research (AACR) Annual Meeting, held from April 18-22, in Philadelphia, PA, Dr. Arul Chinnaiyan of the University of Michigan presented results from the largest cancer precision medicine study to date, which found that by using comprehensive genome sequencing technologies, “actionable” tumor mutations — those in molecular pathways that can be targeted by currently existing standard or experimental therapies — could be identified in ~90% of metastatic castrate-resistant prostate cancer (mCRPC) patients. These results greatly excited the researchers attending the AACR Meeting and were published online ahead of print today in the highly prestigious journal, Cell.
Currently, all prostate cancer patients are treated with the same repertoire of drugs without regard to their unique tumor characteristics. However, cancer is a heterogeneous disease because the mutations that initiate and drive each tumor can vary widely, even if they appear to have the same characteristics such as prostate adenocarcinoma bone metastases. For this reason, only a portion of patients derive benefit from many treatments. The remainder of patients suffer unnecessary side effects without receiving any clinical benefit. Furthermore, despite many recent additions to the prostate cancer treatment armamentarium, there is still no curative therapy for mCRPC, the lethal state of prostate cancer that arises after tumors develop resistance to androgen deprivation therapy (ADT).
In 2012, a massive collaborative effort began when the Prostate Cancer Foundation (PCF), Stand-Up 2 Cancer, and the AACR funded a $10M “International Prostate Cancer Dream Team” led by Chinnaiyan and Dr. Charles Sawyers of the Memorial Sloan Kettering Cancer Center, and composed of dozens of prostate cancer researchers from seven institutions throughout the U.S. and in the UK. The goal of this project is to identify genomic mutations in metastatic tumors from 500 mCRPC patients being enrolled in various clinical trials, and to associate tumor mutations with therapeutic responses and clinical outcome. This is a critical step in developing and proving the value of precision medicine treatment schemes, in which a patient’s specific actionable tumor mutations are identified and used to select medicines which target the affected pathway and are therefore most likely to be beneficial. For instance, patients with genetic mutations that cause hyper-activation of the androgen receptor (AR) pathway, the major pathway driving prostate cancer growth and survival, could be prescribed medicines that block AR activity or androgen production, while patients with mutations in RAS kinases may be enrolled in clinical trials for experimental treatment with RAS-inhibitors. This approach could also lead to identification of the best therapeutic combinations for a patient if multiple actionable tumor mutations are identified.
To comprehensively identify tumor mutations, the genomic studies being performed for each tumor include whole exome sequencing to examine the sequences of all protein-coding genes, as well as transcriptome RNA sequencing to examine the sequences and expression levels of all transcribed genes. Using these technologies, combined with high-level computational analyses of the results, a variety of genomic alterations can be identified including structural rearrangements, amplifications or deletions of genes, point mutations, and alterations in gene expression levels.
At the AACR Meeting, Chinnaiyan discussed the genomic analysis of the first 150 patients from this cohort, which identified actionable tumor mutations in ~90% of cases. Most prevalent were alterations in the AR pathway, found in 63% of mCRPC cases. Alterations in other pathways were identified in 65% of cases. AR pathway alterations included amplification of the AR gene, mutations in AR that cause hyper-activation, and mutations in other genes that are in the AR pathway such as deletions of the AR-inhibiting genesNCOR1/2 and ZBTB16. The development of mutations that boost the AR pathway are known resistance mechanisms to ADT and contribute to the development of mCRPC. However, the presence of AR mutations indicate that these tumors may still be reliant on AR for their growth and survival, and might be sensitive to the more powerful AR pathway-targeting drugs abiraterone (Zytiga®) or enzalutamide (Xtandi®). Future results from the Dream Team’s studies will determine whether actionable AR pathway mutations predict sensitivity to these drugs in mCRPC patients.
Another paradigm-changing finding was that ~23% of mCRPC tumors harbored alterations in genes that participate in the repair of damaged DNA. Loss of both copies of the BRCA2 gene was the most prevalent of these alterations, while mutations in another six DNA-repair genes includingBRCA1 and ATM were identified. Breast and ovarian tumors with alterations in BRCA1/2 are particularly susceptible to treatment with olaparib (Lynparza®), a therapy that targets PARP1, another DNA-repair enzyme. These results led to the recent FDA-approval of olaparib for advanced ovarian cancer patients with BRCA1/2 alterations in their tumors. A Phase II clinical trial called TO-PARP, run in conjunction with the Dream Team project, is testing the efficacy of olaparib in prostate cancer patients with vs. without mutations in DNA-repair genes. Interim results from the trial indicated a highly promising efficacy of olaparib specifically in prostate cancer patients with mutations in BRCA1 and BRCA2 as well as several other DNA-repair genes, including ATM. TO-PARP trial results were presented in more detail at the AACR Meeting by Dr. Joaquin Mateo of the Institute for Cancer Research in the UK, and have prompted the planning of Phase III clinical trials of olaparib in prostate cancer patients. “Olaparib is likely to be the first precision medicine therapy approved for prostate cancer—an accomplishment that on its own, makes the investment in the Dream Team worthwhile,” commented Dr. Philip Kantoff, Leader of the Dana-Farber/Harvard Cancer Center Prostate Cancer Program and Senior Advisor to PCF.
Other actionable mutations were identified in oncogene pathways including the PI3K pathway, RAF kinase pathway, CDK inhibitor pathway and the WNT pathway. Each of these mutations may cause tumors to be sensitive to inhibitors of that pathway, which are being tested in various cancer clinical trials. For instance, PI3K-inhibitors are being tested in prostate cancer clinical trials and potentially promising early Phase I results were presented at AACR by Dr. Johann de Bono (Institute for Cancer Research, UK).
In addition, this study provides great insight into what genes contribute to prostate tumor biology overall. “Driver” mutations are mutations in oncogenes or tumor suppressor genes that respectively activate or deactivate their function and drive prostate cancer development. Potential driver mutations were identified in 99% of the mCRPC cases, including 63% of patients with AR mutations. At least 60% of patients had gene fusions in putative driver oncogenes. In these genomic alterations, the part of a chromosome near an oncogene breaks and re-fuses to another chromosomal region, changing the control factors to increase oncogene expression.
Finally, Chinnaiyan’s study identified hereditary mutations that may increase the risk for prostate cancer in 8% of patients, most prevalently in the BRCA2 gene. This vital information will allow individuals with a family history of prostate cancer to determine if they carry risk-associated genetic mutations and should consider earlier and more aggressive screening and intervention.
These findings are already being used to match patients with the therapies most likely to benefit them in clinical trials, and the Dream Team’s continuing genomic and clinical studies are carving out a whole new way to treat prostate cancer patients – with precision.
Read more about this study in the University of Michigan’s Press Release.
