Dr. Himisha Beltran is a core member of the genitourinary (GU) correlative sciences committee and serves on the GU committee of the Alliance for Clinical Trials in Oncology, one of the five main National Cancer Institute (NCI)-sponsored cooperative groups.
Last year, she was awarded an Alliance Scholar Award in honor of Dr. Emil “Tom” Frei for her proposal to examine molecular data in samples from CALGB 90203. This clinical trial is also known as “PUNCH” = Preoperative Use of Neoadjuvant ChemoHormonal Therapy.
This clinical trial enrolled 788 men with high-risk prostate cancer who were randomized to undergo either surgery alone or in conjunction with 6 cycles of docetaxel chemotherapy and androgen deprivation therapy. Neoadjuvant refers to giving patients chemotherapy or another intervention to first try to shrink a tumor before the main treatment, which in this clinical trial was surgery to remove the prostate. This docetaxel (taxane) chemotherapy combination has demonstrated unprecedented survival advantages when these drugs are used early on in treatment. Large clinical trials, commonly referred to as CHAARTED and STAMPEDE, have shown a much larger improvement in prostate cancer survival using this approach compared with any other treatment that has been studied in the modern era.
We are still awaiting the overall PUNCH clinical trial results based on the main endpoint or outcome (in this study it was the relapse of PSA levels). But, regardless of the results, this study serves as an invaluable resource to analyze biology and mechanisms of response and resistance to chemohormonal therapy because all patients on the study had tissue samples sent for research after prostatectomy.
It is through the commitment of these men and their willingness to further the field of research in the search for a prostate cancer cure that we are able to determine which men had an especially aggressive type of non-androgen receptor (AR) driven prostate cancer. We often refer to this as neuroendocrine prostate cancer or NEPC. We at Weill Cornell Medicine, our Alliance partners and other institutions have already published a wealth of data from men with advanced NEPC. However, some of the molecular changes that make the prostate cancer so aggressive may happen much earlier in the disease spectrum than was previously realized.
At this year’s annual Alliance meeting from May 12-14, Dr. Beltran and collaborators presented on the use of novel technology to analyze gene expression pre- and post-treatment using tissue samples from patients treated on the PUNCH clinical trial.
This technology is called Nanostring and allows us to use a targeted panel of ribonucleic acid (RNA) and get reliable results using samples that have not been processed in any special way (for example, frozen or exposed to specific chemicals). It also allows us to glean insights from tissues that only have a very small amount of tumor left after treatment. In the past this had only been possible using DNA.
DNA and RNA tell us different types of information. DNA offers a biological instruction manual for the body and creates RNA. RNA helps carry out these instructions and creates proteins. The RNA (or transcriptome) is what is actually expressed by genes, so while it is harder to use, it can tell us more information about what is happening at that time. Both DNA and RNA can change after treatment, so the largest amount of information about a specific tumor is gained by combining the information we glean from each of these sources. We can go even deeper in our search for information with additional analyses at the level of the epigenome or metabolome.
In addition to proving that this approach is feasible using very small tissue samples, Dr. Beltran showed that gene expression clustered into different groups based upon AR signaling and neuroendocrine genes. This lends insight into the early development of resistance and offers a window into the mechanisms behind the resistance. Based upon these impressive results, the committee has granted approval to expand the analysis dataset with an additional 100 patient samples and an increased number of genes.
We look forward to continuing to update you on this important research project and keeping you apprised of the results.