Tag: Research

Cancer Alliances: Making an Impact

Beltran_Alliance Meeting 2016_1Dr. 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.

Aligned with Cancer Cures in Mind

Cancer CureThrough clinical trials, we are able to develop safe and more effective ways to detect, diagnose and treat cancer. All clinical trials have a sponsor, which means there is an organization or person involved in the design and support of the study. The sponsor is usually a pharmaceutical company, academic institution or government body. In the United States, there has been a fairly recent increase in the number of government-sponsored studies.

The majority of cancer clinical trials are led by the National Cancer Institute (NCI)-sponsored cooperative groups. This means that cancer specialists across hospitals, medical centers and community clinics can more easily collaborate with one another through a formalized group. One major advantage of NCI-funded cooperative group clinical trials is the ability to study diseases and/or treatments that may be less interesting or practical for pharmaceutical companies or individual academic centers.

Following a series of recommendations leading to mergers, there are now five main groups in the US that form the NCI Clinical Trials Network (NCTN). One of these main groups, the Alliance for Clinical Trials in Oncology, was formed in 2011 after the merger of Cancer and Leukemia Group B (CALGB), North Central Cancer Treatment Group (NCCTG) and the American College of Surgeons Oncology Group (ACOSOG). These mergers streamlined many research efforts that were previously happening on parallel or competing trajectories.

Weill Cornell Medicine (WCM) has investigators involved in all five of the major cooperative groups, but is most heavily involved in the leadership of the Alliance. Dr. Scott Tagawa, Medical Director of the Genitourinary (GU) Oncology Program, serves as Weill Cornell Medicine’s Principal Investigator for the Alliance and a member of the Board of Directors. Dr. John Leonard serves as Chair of the lymphoma committee and member of other leadership committees.

There are many WCM investigators currently leading studies within the Alliance group. The GU committee has a high level of involvement by our medical oncologists, Drs. Tagawa, Beltran, Molina, Nanus, and Faltas. Additionally, Dr. Barbieri and other urologists from our team have recently become more involved in the Alliance.

We have a long history of participation in the GU oncology studies through CALGB and the Alliance, most recently with completed studies in early stage prostate cancer. These include testing:

  • Dietary intervention in men with low risk disease who are on active surveillance (Clinical Trial ID: 70807)
  • Chemohormonal therapy prior to surgery in men with high risk disease (90203)
  • The addition of antiangiogenic therapy in addition to chemotherapy for advanced urothelial carcinoma (90601)
  • Testing the impact of targeted oral therapies in curbing the spread of cancer in patients with intermediate to high risk, advanced renal cell carcinoma (RCC) (A031203)

Through our cooperative groups, we are currently accruing to studies in advanced prostate cancer and early stage bladder cancer with additional new clinical trials in the works.

Prostate cancer:

Bladder cancer:

The Alliance for Clinical Trials in Oncology is committed to reducing the impact of cancer on people by uniting nearly 10,000 scientists and clinicians across the United States and Canada, from many disciplines, hospitals, medical centers and community clinics. Together we’re discovering, creating, validating and implementing new, more effective strategies to prevent and treat cancer; we’re proud to be part of it!

Dying from Prostate Cancer: Lessons Learned from the PLCO Trial

Screening for any disease, including prostate cancer remains imperfect. One study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, was a National Cancer Institute (NCI) sponsored study that took place between 1993-2001. The goal of the trial was to investigate the impact cancer screening had on dying from these four common tumor types. There were 76,693 men evaluated in the prostate cancer portion of the study.

While some aspects of this randomized trial remain controversial, including the impact that screening had on dying from prostate cancer, it remains a rich prospective dataset for further analysis, as it is one of the largest longitudinal studies ever conducted of men with prostate cancer.

In the “intervention” arm of the PLCO Screening Trial in which men were randomized to be screened for prostate cancer with annual prostate specific antigen (PSA) blood tests and digital prostate exams, there was still an unfortunate set of men who died from prostate cancer. Because the goal of the trial was to determine the prostate cancer mortality differences between the two arms, an understanding of who died and how they died is extremely important.

In a study led by Weill Cornell Medicine’s Dr. Chris Barbieri, we examined how men died of prostate cancer. Dr. Sameer Mittal presented the results of the research at an oral podium presentation yesterday at the 2016 American Urological Association annual meeting, with full results simultaneously published in European Urology.

Of 38,340 men in the screening arm, 151 died of prostate cancer. After graphing their oncologic courses of diagnosis and treatment, we noted a few interesting trends. The most prominent were as follows:

  • More than 50% of the men who died (81 men) either were never screened before this test or had their first PSA test result that was positive. These men were older and had higher median PSA (13.7). It’s possible that if these men were actually screened and or screened earlier and treated, their deaths from prostate cancer could have been prevented.
  • A subgroup of men who died despite screening were young and had a low median PSA (2.0). Surprisingly, they died within approximately 1.5 years of diagnosis. To put this in perspective, we expect an average man diagnosed with metastatic prostate cancer to live for 5 years, so this is quite unusual. We know that some subsets of prostate cancer do not secrete high levels of PSA and this is an area that needs more research in order to prevent further deaths. We don’t know for sure if these men had neuroendocrine prostate cancer (NEPC), but their rapid disease course seems consistent with this aggressive prostate cancer sub-type.

Despite what some may believe, some men do die of prostate cancer. We continue to research why this is the case in order to prevent further death and suffering from this common disease. These study insights underscore the importance of developing diagnostic biomarkers to better detect aggressive prostate cancers and to best predict the way the cancer will respond to various treatments.