The Translational Genomics Research Institute (TGen) hosted the Pediatric Cancer Translational Genomics conference in Scottsdale, AZ on February 6-8. The 180 attendees were described as a “dream team” in pediatric oncology. They represented 29 U.S. states and 11 overseas nations, and their discussions focused on how to translate pediatric genomic data for personalized or precision oncology.
One challenge facing pediatric oncology, as explained by Peter Adamson, MD, chair of the Children’s Oncology Group (COG), is that its funding is currently much more dependent on the federal government than other types of medical oncology. Clinical research in pediatric oncology receives about 99% of its funds from the federal government, while medical oncology receives about 60% of its funds from industry. The business models play out that way because pediatric cancer does not have an economic driver. Pediatric cancer relies on the National Institutes of Health (NIH), which is likely to face a flat or decreased budget in the near future. Increasingly, public-private partnerships and perhaps more collaborative research funding from foundations will be needed to address the funding challenges of pediatric oncology.
The main concerns expressed by speakers and attendees about moving forward with translating genomic data from pediatric oncology were the need for more biopsies and the need for bioinformatics.
Because tumors change over time, they need to be sampled over time. When pediatric oncologists can sample tumors over time through multiple biopsies, they will be able to take advantage of differences at the time of recurrence so the treatment can adapt to the tumor that recurred. Tumors are a moving target, and findings from a biopsy can be game-changing. However, because biopsies pose more than a minimal risk to a child, regulations require that they must have the potential to benefit that child. The research community felt that they need to prove the potential benefits of biopsies to guide treatment decisions for recurrent tumors.
Bioinformatics was another area of concern, including the need to share, organize, store, and annotate information. Four major pediatric sequencing groups were represented: the KIDS (Knowledge Integration & Dynamic-interexchange System) Cloud project, which is a collaboration between TGen, Dell Computers, and the Van Andel Research Institute; the Pediatric Cancer Genome Project, which involves St Jude Children’s Research Hospital and The Genome Institute at Washington University; TARGET (Therapeutically Applicable Research to Generate Effective Treatments) from the National Cancer Institute; and MAGIC (Medulloblastoma Advanced Genetics International Consortium) from Sick Kids Hospital in Toronto, Canada.
“When it comes to access to clinical and pathological data, more is more,” stated Spyro Mousses, PhD, Director of the Center for BioIntelligence at TGen. Data sharing and collaborations were emphasized as a way to move research forward and connect current science with choices for patient treatments. Pediatric oncology includes rare and ultra-rare diseases, and only by pooling resources and data over several years can enough information be developed about these diseases to provide guidance on clinical decisions.
By Kathy Boltz PhD
On the eve of the ASCO GU Symposium, a January 31st Presscast previewed 5 important studies with important clinical ramifications for patients with prostate cancer. Topics covered include a genetic explanation for the ability of vigorous exercise to prevent prostate cancer recurrence and death, comparative data on effectiveness and cost of radiation techniques and prostatectomy, and Phase 3 studies of two promising novel agents with excellent tolerability that extend survival in men with advanced prostate cancer. ASCO GU is jointly sponsored by ASCO (American Society of Clinical Oncology), ASTRO (American Society of Radiation Oncology), and SUO (Society of Urologic Oncology) and will take place February 2-4 in San Francisco.
Value of Vigorous Exercise
June M. Chan, MD, University of California at San Francisco, and co-authors reported that men who exercise vigorously at least 3 hours a week have favorable changes in gene expression patterns in normal prostate tissue. This finding builds on a previous study showing that men with prostate cancer who exercised vigorously more than 3 hours a week were much less likely to have progressive disease or die of prostate cancer, and provides some insight into the mechanisms by which vigorous exercise may be protective against recurrence of prostate cancer.
The study included 70 men diagnosed with low-risk prostate cancer who were treated with active surveillance. These men were previously enrolled in a trial of nutritional supplements and provided biopsy tissue at baseline. In the men who reported vigorous exercise at least 3 times per week (n=23), 184 genes were differently expressed in normal prostate tissue versus those who did not exercise 3 times per week (n=47).
Up-regulated genes included known tumor suppressor genes, BRCA 1 and BRCA 2. Furthermore, gene-set analysis demonstrated that cell cycle and DNA repair pathways were positively modulated in the men who reported vigorous exercise at least 3 times a week versus those who exercised less. A separate analysis found no effect on genes and pathways in men who reported engaging in any type of physical activity (but not vigorous exercise 3 times a week) versus no exercise.
Dr. Chan said that these findings suggest that a certain threshold of intensity or duration of exercise may be important in reducing the risk of prostate recurrence.
Although this is a small sample size, further study is needed. For now, the results suggest that participation in vigorous exercise for at least 3 hours per week may prevent or delay recurrence.
Comparative Effectiveness Studies of Treatment Modalities
A separate study showed that since 2000, use of IMRT has supplanted use of CRT. By 2008, almost zero percent of prostate cancer patients who required radiation were treated with CRT, while almost 100% received IMRT.
IMRT significantly reduced the frequency of bowel effects (mainly rectal bleeding) from 14.7 per 100 person-years of follow-up to 13.7 (P<.001), although the effects on erectile dysfunction were increased in the IMRT-treated group from 5.3 per 100 person-years of follow-up to 5.9 in the IMRT group. However, IMRT provided significantly superior cancer control, as reflected by the need for additional cancer treatment: 3.1 per 100 person-years of follow-up for CRT vs 2.5 in the IMRT group (P<.001).
When IMRT was compared with proton beam therapy (the newest and most expensive type of radiation), proton beam therapy was associated with a significantly increase in bowel side effects (17.8 per 100 person-years of follow-up versus 12.2 for IMRT; P<.001). No significant difference in cancer control was observed between these two types of radiation.
“This type of comparative research is needed, because until now it has been unclear if newer treatments are better than older ones,” stated Ronald Chen, MD, University of North Carolina, Chapel Hill, NC. “This study supports IMRT as current standard radiation for prostate cancer, with fewer side effects and improved cancer control versus the older CRT. Currently, there is no clear evidence that proton therapy is better than IRT.”
A study based on the SEER-Medicare database from 1991 to 2007 that included a total of 137,427 patients diagnosed with prostate cancer at age 65 or older found that the long-term toxicity and cost per patient-year of radical prostatectomy, external beam radiation (EBRT), and brachytherapy differ, with EBRT causing the most toxicity and being the most costly.
After 15 years of follow-up, the cumulative incidence of genitourinary toxicity was significantly higher for EBRT (approaching 20% of patients) than for prostatectomy (about 7%) or brachytherapy (about 5%; P<.001). The cumulative incidence of gastrointestinal toxicity was also significantly higher with EBRT than for prostatectomy or brachytherapy (P<.0001 for both comparisons), although the overall incidence was under 3% for all groups at 15 years.
The cost per patient-year was $6,412.29 for EBRT, $3,205.71 for prostatectomy, and $2557.36 for brachytherapy (P<.0001 for all comparisons). Despite these benefits, only about 12% of patients were treated with brachytherapy, while 44% had radical prostatectomy and 44% had EBRT.
The study was presented by lead author Jay P. Ciezki, MD, The Cleveland Clinic, Cleveland, OH.
Two New Drugs Extend Survival in Advanced Prostate Cancer: Radium-223 and MDV3100
Two important studies to be presented at ASCO GU showed that two new drugs extend the lives of men with castrate-resistant prostate cancer (CRPC). Both drugs are first-in-class: radium-223, an alpha-emitting radiopharmaceutical that homes to bone metastases, and MDV3100, an androgen-receptor-signaling inhibitor.
Final results of the ALSYMPCA trial, reported elsewhere, demonstrated the survival benefit of radium-223 in men with metastatic CRPC) confined to the bone. The Phase 3 study included 922 patients with confirmed CRPC and bone metastases, but no known visceral metastases; all patients were either post-docetaxel or were not candidates for that drug.
Oliver Sartor, MD, Director of the Tulane Cancer Center in New Orleans, LA, said that radium-223 significantly improved survival from a median of 11.2 months with placebo versus 14 months with radium-223 (P=.00185), and also significantly prolonged the time to first skeletal-related event (SRE) from a median of 8.4 months for placebo to a median of 13.6 months (P=.00046). Time to spinal cord compression, pathological bone fracture, and need for RBRT were all significantly prolonged in patients treated with radium-223.
“These effects are clinically meaningful to patients,” Dr. Sartor stated.
This radiopharmaceutical is extremely well tolerated, with an adverse effect profile that appears to be at least as good, if not better for some parameters, as placebo.
Reserving perhaps the biggest news for last, a Phase 3 study showed that the androgen receptor signaling inhibitor MDV3100 prolonged life in men with late-state CRPC. These results of the AFFIRM study were presented by Howard I. Scher, MD, Memorial Sloan-Kettering Cancer Center.
AFFIRM randomized 1100 patients with progressive CRPC who failed docetaxel chemotherapy in a 2:1 ratio to either oral MDV3100 160 mg/day or placebo. MDV3100 significantly prolonged survival by an average of 4.8 months. A significantly higher proportion of patients treated with MDV3100 showed tumor shrinkage by imaging and also had at least a 50% or greater decline in PSA level. The time to progression assessed by imaging and PSA was about 5 months longer in patients treated with the experimental agent.
“These favorable changes [in imaging and PSA] are consistent with the survival benefit observed,” Dr. Scher told listeners.
The adverse event profile of MDV3100 is similar to placebo; in fact, more patients had serious adverse events in the placebo arm (38.6%) than in the MDV3100 arm (33.5%). More Grade 3 or higher adverse events were also reported in the placebo arm (53.1% vs 45.3% in the MDV3100 arm).
“The benefit:risk profile will likely position MDV3100 as the front-line agent post-docetaxel therapy,” Dr. Scher stated.
Press cast moderator, Nicholas Vogelzang, MD, had one comment about the MDV3100 results: “Wow!” Dr. Vogelzang is Chair and Medical Director of the Developmental Therapeutics Committee of US Oncology.
Dr. Vogelzang said that both radium-223 and MDV3100 are likely to gain FDA approval with “no hurdles,” offering patients with CRPC two new options that can extend survival. Although not studied yet, these two agents with distinctive mechanisms of action could be used in combination or sequentially to further boost survival. This will be studied later.
By Alice Goodman