A A A

NCIC CTG MA 17 clinical trial case study

A case study methodology was employed and the Canadian Cancer Society results chain framework was used to assess the long-term impacts of the MA 17 clinical trial, which assessed the use of a new aromatase inhibitor sequentially with tamoxifen to reduce breast cancer recurrence in post menopausal women with hormone receptor positive (HR+) breast cancer. This trial was led by the NCIC Clinical Trials Group (CTG), which receives its core funding through a peer-reviewed grant from CCSRI.

The purpose of the case study was twofold: (a) to assess trial impacts and document pathways from research to knowledge translation and impact; and (b) to provide insight regarding the mission effectiveness of providing infrastructure funding for this type of large scale research initiative.

The results of the MA 17 clinical trial case study have provided insight into the value of funding clinical trials, how to effectively tell research stories and demonstrate impact, and have helped identify gaps in the tracking of the actual take-up and use of Canadian Cancer Society funded research. Regarding the last point, the CCSRI is now working on ways to better track research impacts, and the results of this case study are providing new insights on how best to do this.

Key findings:

  • The MA 17 clinical trial led to immediate and traceable changes in world-wide standard of care practices and is responsible for thousands of disease free years in women worldwide.
  • The success of the MA 17 clinical trial was facilitated by the credibility of the CTG and its Breast Disease Site Committee, its ability to attract high impact investigators, and its capacity to act as an independent broker among the various interests and potential biases surrounding cancer treatment at the time.
  • The CCS’s long history of funding endocrine-related breast cancer research contributed to the scientific knowledge base and research capacity that informed the trial, which points to the value of investing in discovery-based basic and translational cancer research.
  • The CTG is a valuable asset for the CCS, as it has built an international reputation, networks clinical trial centres and oncologists across the country, provides researchers with access to wide regional trial opportunities and clinical samples, and has world class management expertise.

Overview

Up until the early 2000s, the standard for adjuvant treatment of post-menopausal women with early stage, hormone receptor-positive (HR+) breast cancer was the prescription of a drug named tamoxifen. A selective estrogen receptor modulator, tamoxifen works by binding to the estrogen receptor thus keeping cells from making or using estrogen. While tamoxifen was shown to be effective at reducing cancer recurrence risk for the first few years after surgery, research demonstrated that continuing tamoxifen therapy for longer than five years did not improve recurrence-free or overall survival and could actually be harmful. There were no widely accepted treatments available beyond five years, yet research showed that a significant risk of recurrence for breast cancer still remained. Oncologist and cancer researcher Dr Paul Goss, currently of the Massachusetts General Hospital Cancer Center, had preliminary research findings which suggested that the administration of an aromatase inhibitor, a class of drugs that, unlike tamoxifen, actually suppress the synthesis of estrogen, could be an effective adjuvant therapy for postmenopausal women with HR+ breast cancer. He approached the Canadian Cancer Society funded NCIC CTG, a cooperative oncology network based at Queen’s University, with the idea for a clinical trial using an aromatase inhibitor sequentially with tamoxifen to reduce breast cancer recurrence in post menopausal women with HR+ breast cancer. Dr Goss eventually led a group that would test this hypothesis by conducting the MA 17 clinical trial. The MA 17 clinical trial was activated in August 24, 1998 and met patient accrual by mid-2002. The trial was organized and coordinated across two continents, six distinct institutional groups, nine countries and 416 sites by the CTG. An interim analysis of the planned five year study demonstrated results that were so convincing that CTG leadership, in consultation with the data and safety monitoring committee (DSMC), decided to terminate the trial early and unblind the study in October, 2003 in order to disseminate the remarkable preliminary results. In November 2003, CTG published the findings in the New England Journal of Medicine, showing that the use of the aromatase inhibitor letrozole significantly reduced the risk of breast cancer recurrence in the extended adjuvant setting. This led to a virtually immediate and traceable change in treatment practices.

Outcomes and impacts

The MA 17 trial advanced the availability of an effective therapy in a clinical setting where there had not been one before. Under the strong leadership of principal investigator Dr Goss, and with the engaged support of a diverse set of researchers, the CTG delivered persuasive evidence that has had a global impact on preventing disease recurrence in women surviving HR+ breast cancer. This reach was facilitated by the ability of the CTG to attract of a strong group of prestigious international researchers and institutions to the trial. Upon study unblinding, there was a widely distributed press release, followed by a number of highly-cited publications. Post trial market research conducted by the pharmaceutical company that participated in the trial suggested that prescribing physicians recalled the name of the trial (MA 17), the name of the principal investigator (Dr Goss) and the coordinating centre of the trial (CTG) in an essentially unprecedented fashion, suggesting that the trial directly influenced their prescribing patterns.

The MA 17 clinical trial had a profound impact on a number of different areas, both directly in the form of follow-on related clinical trials, and indirectly by encouraging an increased research focus on late to extended adjuvant breast cancer therapy and increasing the use of aromatase inhibitors in all (early, late and extended) adjuvant settings. The results of the MA 17 trial have contributed to changing world-wide standard of care practices and are cited prominently in provincial, national and international guidelines for the adjuvant treatment of breast cancer. Most importantly, the MA 17 clinical trial was responsible for hundreds and possibly thousands of disease free years for Canadian women. It has almost certainly created thousands of disease free years worldwide.

The prospective implications of this successful clinical trial are many. The scientific implications continue today, and go beyond the scope of this case study. From a management perspective, the value of the MA 17 trial is that it demonstrated wide and heterogeneous reach. The CTG offered a clinical trial infrastructure which provided investigators access to international expertise, wide regional and international trial sites and "independent" guidance. The guidance and leadership CTG demonstrated was critical, as it allowed for the coordination of several groups with different primary interests to work towards the same common goal. This was facilitated by the credibility of the CTG investigators and the perception that it was not tied too closely to any specific scientific interests. As such, this case study shows that there is an important place in the cancer research and clinical trial environments for a high quality, widely connected and independent group such as the CTG. Furthermore, when such a group is driven by a clear mission it will overcome institutional biases and barriers to achieve its goals.

Last modified on: February 26, 2016