The History of the NSABP
The Early Years
The long history of NSABP clinical trials began at a meeting in 1957 of 23 surgeons determined to better understand the nature of breast cancer.Our first patient was randomly assigned on April 4, 1958, to a clinical trial designed to determine the effectiveness of adjuvant therapy for women with operable breast cancer.That trial, and others that followed, provided the first evidence that chemotherapy given in the adjuvant setting could decrease the rate of early recurrence in some patients and showed that patients with 1-3 positive nodes had a more favorable result then those with 4 or more positive nodes, planting the seed for a landmark study that would begin much later in 1999.It also demonstrated that large randomized clinical research studies, following rigid criteria, could be carried out effectively at multiple sites across the country.
In 1967, one of the original founding surgeons of the committee, Bernard Fisher, MD, who was based at the University of Pittsburgh, became chairman of the NSABP.The 1960's were a time of growth for the University of Pittsburgh, and in 1970 the medical school welcomed the NSABP, now an NIH-sponsored clinical trial program, to the Pitt campus, where the group's Operations Center remained for almost a quarter of a century.
The NSABP Establishes Its Reputation
The years following resulted in significant scientific advancement by the group, findings that changed the treatment of breast cancer and established a standard of care worldwide for this disease.
In the 1970's, questions about the effectiveness of new chemotherapy agents were beginning to be asked. The NSABP conducted a number of studies in this arena, using the then-current standard treatment as the control group, evaluating the most promising new compounds available, and moving forward in a step-wise fashion.At about the same time, questions were being posed about the effectiveness of radical mastectomy.Was the disfiguring surgery more effective than the breast-conserving procedures being proposed by some surgeons?The trials that ultimately answered this question were begun in 1971 with NSABP B-04, which, after 25 years of follow-up, continued to demonstrate no difference in recurrence or survival among patients with operable breast cancer treated with either breast-conserving procedures or radical mastectomy.The results of the B-04 trial were so significant that in 1979 the NIH Consensus Conference announced that mastectomy and axillary dissection should be considered the standard treatment for early breast cancer, resulting in the rapid decline in radical mastectomy.Succeeding clinical trials gave even more credence to the hypothesis that breast-conserving surgery results were at least as good as those for the more radical procedure.
In 1977 the NSABP began to develop studies in colorectal cancer.Findings from these early trials made a significant contribution to the treatment of stages II and III of this disease: C-03, after 10 years of follow-up, demonstrated a 10% survival rate in patients who had received 5-FU + leucovorin, which continued to be the standard into the new century, when the group's C-07 trial showed that the addition of oxaliplatin to the regimen improved disease-free survival.C-08, which followed, added a new type of agent, a monoclonal antibody (bevacizumab), to the drug that had positive results in C-07.However, the C-08 trial demonstrated that bevacizumab did not improve patient outcome.
During the 1980's, mammography became widely used, making it possible for physicians to diagnose very small tumors.NSABP B-17 was developed to determine if ductal carcinomas in situ, tumors too small to be felt, could be treated using tissue-conserving techniques.Lumpectomy alone was compared to lumpectomy plus radiation in patients with localized disease.The results of this landmark study demonstrated that radiation therapy significantly reduced the incidence of cancer in the opposite breast, marking another step forward by the NSABP in a decade that was memorable for advancements in breast cancer research.
Changes and the Chemoprevention Trials
In the early 90's, a Canadian surgeon who was participating in NSABP studies falsified patient information and entered the data into several of our trial records.After the falsification was identified, a full re-analysis of the studies showed that the data in question had no effect on the research results.However, the incident caused substantial public concern that led to Congressional hearings and the retirement of Dr. Fisher as NSABP chairman.
The group maintained its focus during this difficult period, and its first chemoprevention study, the first breast cancer chemoprevention trial ever conducted, was launched in 1992.In P-1, more than 13,000 well women, determined to be at increased risk of developing breast cancer, were randomly assigned to tamoxifen or a placebo.After 5 years, there was a 49% reduction in invasive breast cancer in the group taking tamoxifen. In the P-2 study (STAR), a trial of nearly 20,000 women, that opened at the end of the decade, tamoxifen and raloxifene were shown to be equally effective in reducing the risk of invasive breast cancer, with fewer cardiovascular side effects in those women taking raloxifene.
In 1994 Norman Wolmark, MD, became chairman of the NSABP, and after agreement was reached to award the Operations Center NCI funding to Allegheny University of the Health Sciences, the NSABP moved to the campus of Allegheny General Hospital. The Biostatistical Center remained at the University of Pittsburgh. At the group's first national meeting following Dr. Wolmark's appointment, NSABP member investigators made it clear they were ready and eager to move forward.
In July of 1998, Allegheny University became part of the Allegheny Health, Education and Research Foundation (AHERF) bankruptcy.After careful consideration and in consultation with the NCI, the NSABP board of directors gave unanimous approval to management's proposal that the NSABP Foundation, which had been incorporated in 1995 as a 501(c) (3), be awarded the NCI grant.This occurred February 1, 1999.
Collaboration With Industry
At the beginning of the new century, the NSABP Foundation was the only one of the eight NCI-designated National Clinical Trials Groups to become an independent grantee.In the 15 years that followed, the results of the NSABP's B-31 and B-32 trials changed the way breast cancer was treated and established a new standard of care.B-31 demonstrated that the addition of 52 weeks of Herceptin to standard therapy reduced mortality by 39%, findings that excited the oncology community worldwide.B-32 resolved a question that had been asked for many years:Could results from sentinel node resection equal those from conventional axillary dissection in clinically node-negative breast cancer patients?After more than10 years of follow-up, there continues to be no significant difference in overall survival or in disease-free survival for the study patients, making it possible for them to avoid a more extensive surgical procedure with its associated increased risks.
The NSABP also reported important results in colorectal cancer:in our C-07 trial,oxaliplatin added to the standard treatment, resulted in a significant increase in disease-free survival.This was the first advance in a decade in the treatment of colon cancer.
As these and other studies were being developed, it became clear that the NCI was encountering funding issues, and the problem looked likely to worsen in the future.This realization resulted in a decision to work in partnership with pharmaceutical and biotechnology companies to assure adequate funding for our large NCI-sponsored phase III studies.The STAR trial had already set the precedent. Since that time we have had contractual arrangements with pharmaceutical companies for financial support to cover a portion of our sites' unmet costs.
The relationships with our pharmaceutical partners expanded, and in 2008 we opened the BETH study.In collaboration with Genentech, the sole funding source, our physicians developed the protocol, and we managed the North American sites and held the IND for this study.BETH was a global trial conducted in almost 50 countries.Sites in the rest of the world were managed by TRIO, a group associated with UCLA, and Roche Pharmaceutical.Since that time, we have participated in five additional phase III industry-sponsored studies.In mid-2015, we opened ARGO, a large phase III colon trial study for which the Foundation assumed full leadership responsibility, and what may well become a global study sponsored totally by Bayer Pharmaceutical.In this most recent trial our biostatistical center is providing professional direction and managing the database.Our relationships with industry have provided income that has made support for our members possible and has given us the opportunity to offer clinical scientists at the sites new and interesting agents for their patients.
Like any credible business organization, we have continued to grow, and in the past few years we have made significant changes in the structure and direction of the Foundation.In 2014, under the NCI mandate to reduce the number of National Clinical Trials groups, the NSABP joined with the Radiation Therapy Oncology Group (RTOG) and Gynecological Oncology Group (GOG), to create a new corporation qualified to become the federal grantee.Government-sponsored breast and colon studies led by the NSABP are now developed and managed within the NRG Oncology Foundation, Inc.Because federal funding for prevention studies was no longer available and because fewer breast and colon treatment studies were being approved by the NCI, it became clear that another structural change to our organization would be necessary. Thus we began plans to develop as an Academic Research Organization (ARO), which would design and manage industry-only sponsored research.
In the first quarter of 2014, the NSABP Foundation amended its bylaws and articles of incorporation to be consistent with its new mission.Members of the smaller nine-member board of directors are in place and functioning as is the new department and committee structure.
The number of industry-sponsored trials open and in development has increased, as have the numerous laboratory projects associated with the increased clinical activity.Three phase III breast studies are active; these are global trials for which we have responsibility in the U.S.Four additional phase IIIs are planned, two of which will open in the first quarter of 2018. As noted, our phase III colon study, opened in 2016, gave us the opportunity to be the global sponsor and assume full leadership of the project.
The direction of our phase II studies has changed to become more nimble and targeted and to enable the program to broaden its perspectives.At this time, eleven (11) early studies, Phase 1B and Phase II, are in development.Three early trials are accruing with three additional studies in follow-up. Collaborative work between NSABP laboratory scientists and the physician scientists interested in early-phase clinical research has added a new dimension to our efforts, and the combined capabilities of such collaborations have sparked the interest of a number of commercial and academic organizations who have joined our endeavors.
The NSABP is unique among the research entities that were formerly the cooperative groups in operating an active research laboratory.The Pennsylvania Tobacco Fund, the core support for our preclinical activity, has been seriously reduced and may disappear in the next two years.In 2015, with the retirement of Soon Paik, MD, our long term Director, the Foundation began a careful search to identify Dr. Paik's successor.In the Fall of the next year, Peter Lucas, MD, PhD, joined the Foundation as Director of Laboratory services.A tenured Associate Professor of Medicine in the Department of Pathology, Dr. Lucas shares his research time between our lab and his University responsibilities.This collaboration opened new opportunities to encourage and develop synergies between the two research facilities.
The establishment of NRG Oncology and the redirection of the NSABP Foundation have made it clear that there are very real differences between operational requirements and the day-to-day management of federally funded studies vs those funded by pharmaceutical companies.Our challenge lies in understanding and developing creative responses to the expectations of these two very disparate management cultures.Studies with industry pose new timeline and operational requirements that need to be met and resolved expeditiously in ways that will not disturb the organization's equilibrium, a demanding task, but one we are confident we can accomplish.
We must plan carefully for the scientific and corporate growth of the Foundation by assuring strong leadership. Promising directions in cancer research, particularly in genetics and immunology, offer great opportunity for lifesaving gains for those organizations prepared to meet the challenges of the ever-changing horizon. With the reputation the NSABP has established as one of the most accomplished research groups in the world, we plan to be in the vanguard of this work.