Canadian Cancer Trials Group Bulletins

General


MA.17 Accomplishments

Based on our annual review of trials that can be closed to further follow-up, in January 2010 we informed centres of changes regarding our MA.17 trial. Specifically, centres were informed that there is no longer a requirement to follow MA.17 patients who were not entered on MA.17R. Additionally, those centres that were not activated on MA.17R were also informed that they should permanently close the trial, as follow-up of MA.17 patients is no longer required. With the permanent closure of MA.17 (unless related to MA.17R), we would like to take this opportunity to reflect on the impact this trial has had for patient care and for the investigators, CRAs and Group as a whole. MA.17 is an outstanding example of a trial conducted by an academic cooperative group that has had extraordinary implications for health care delivery on an international level.

The MA.17 trial was activated on August 24, 1998. It was a phase III, randomized, double-blind, placebo-controlled trial comparing letrozole with placebo in postmenopausal women with primary breast cancer who had completed five years of adjuvant therapy with tamoxifen. The trial was to test treatment with an additional five years of letrozole. The primary endpoint was disease-free survival, and secondary endpoints included quality of life, overall survival, and long-term safety. A truly international trial, MA.17 was led by the Canadian Cancer Trials Group and included collaboration with SWOG, ECOG, CALGB, NCCTG, EORTC, and IBCSG.

At the time of the first interim analysis in March 2003, a total of 5187 women had been enrolled. The results of a first interim analysis indicated significant improvement in the outcomes of patients allocated to letrozole with estimated four-year disease-free survival rates of 93 percent with letrozole and 87 percent with placebo (P 0.001). Based on these results, the Canadian Cancer Trials Group's DSMC recommended termination of the trial and prompt communication of the results to the participants. These results were published in the New England Journal of Medicine in November, 2003 (PE Goss et al), after first being published on-line and ahead of print.

The Canadian Cancer Trials Group went on to conduct additional analyses. Because additional data had been accrued between the clinical cut-off date for the interim analysis and the date of altering the trial's conduct, an additional final analysis of all patients' outcomes prior to altering the trial was published in the Journal of the National Cancer Institute in September 2005; the same beneficial results were observed (PE Goss et al).

The decision to close MA.17 met with much discussion in the international arena. In order to address some of the issues raised, the Trial Committee went on to conduct two important additional analyses. After the decision to close the trial, unblind patients and continue letrozole in patients allocated to that arm and offer letrozole to those allocated to placebo, a follow-up intention-to-treat analysis conducted almost three years later demonstrated that the benefits of letrozole persisted in the experimental group, even though two-thirds of patients in the control arm had crossed over to letrozole (JN Ingle, Ann Oncol, 2008). Furthermore, while not a randomized sample, a due diligence analysis conducted two years after unblinding demonstrated superior outcomes in those patients allocated to placebo who had crossed over to letrozole as compared with those patients who chose not to take letrozole (PE Goss, J Clin Oncol 2008).

Two companion sub-studies were also included in MA.17 -- MA.17B, which investigated the influence of letrozole on bone mineral density and demonstrated that after five years of adjuvant tamoxifen, subsequent letrozole caused a modest increase in bone resorption and reduction in bone mineral density in the spine and hip compared to placebo; and MA.17L, which found that letrozole does not significantly alter serum lipid concentrations.

MA.17 spawned a s centrally activated in October 2004. This trial was a double-blind re-randomization to letrozole or placebo for women completing five years of adjuvant letrozole in the MA.17 study. It was closed to accrual in May 2009 after reaching its target of 1918 patients.

The results of MA.17 have contributed to changing world‐wide practices, and are prominently cited in provincial, national and international (e.g. ASCO) guidelines for the adjuvant treatment of breast cancer. The publication list associated with MA.17 is indeed impressive. Nineteen research papers have resulted from this trial, and have been published in high impact journals that include the New England Journal of Medicine and the Journal of Clinical Oncology. According to Google Scholar, the primary publication has been cited 1242 times (February 25, 2010). Additionally, 28 abstracts have been presented or published.

With the permanent closure of MA.17, it is important that those responsible for this outstanding accomplishment be recognized. Kathleen Pritchard provided extraordinary leadership as the Breast Site Committee Chair in overseeing the development of this trial, and in formulating the collaborations that resulted in its successful conduct. Dr. Paul Goss was the Study Chair and brought his laboratoryżbased experience and clinical expertise to the forefront in order to both initiate the concept and see it move to a full fledged study. The contributions of our Intergroup partners at NCCTG (led by James Ingle and Vera Suman), SWOG (led by Silvana Martino and William Barlow), ECOG (Nicholas Robert and Robert Gray), CALGB (Hyman Muss and Don Berry), IBCSG (Monica Castiglione and Richard Gelber), and EORTC (Martine Piccart and David McGuiness) and the support of CTEP are deeply appreciated.

A host of Canadian Cancer Trials Group Central Office faculty and staff made MA.17 happen; outstanding leadership, wisdom and long hours of toil were provided by Joe Pater, Lois Shepherd and Dongsheng Tu. Michael Palmer provided exemplary support as the trial's Study Coordinator. Our thanks and congratulations go to each of these trial leaders and the many investigators, clinical research associates, and Central Office staff who have contributed to this outstanding project. Finally, a debt of gratitude is owed to all of the women who participated in the MA.17 trial.

With future closure of Canadian Cancer Trials Group trials, we will continue to make note of those that have been associated with particularly outstanding research accomplishments. Below we list the 'curriculum vitae' of the MA.17 trial.

PUBLICATIONS

Primary Results and Follow-Up

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from Canadian Cancer Trials Group MA.17. J Natl Cancer Inst 97: 1262-71, 2005.

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349: 1793-802, 2003.

Companion Studies

Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP, Shenkier TN, Tozer RG, Palmer MJ, Shepherd LE, Liu S, Tu D, Goss PE. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to Canadian Cancer Trials Group MA.17 (MA.17D). J Clin Oncol 24: 3629-35, 2006.

Wasan KM, Goss PE, Pritchard PH, Shepherd L, Palmer MJ, Liu S, Tu D, Ingle JN, Heath M, DeAngelis D, Perez EA. The influence of letrozole on serum lipid concent ave completed 5 years of adjuvant tamoxifen (Canadian Cancer Trials Group MA.17L). Ann Oncol 16: 707-15, 2005.

Secondary Endpoints

Muss HB, Tu D, Ingle JN, Martino S, Robert NJ, Pater JL, Whelan TJ, Palmer MJ, Piccart MJ, Shepherd LE, Pritchard KI, He Z, Goss PE. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: Canadian Cancer Trials Group intergroup trial MA.17. J Clin Oncol 26: 1956-64, 2008.

Whelan TJ, Goss PE, Ingle JN, Pater JL, Tu D, Pritchard K, Liu S, Shepherd LE, Palmer M, Robert NJ, Martino S, Muss HB. Assessment of quality of life in MA.17: A randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 23: 6931-40, 2005.

Subsets and Special Analyses

Ingle JN, Tu D, Pater JL, Muss HB, Martino S, Robert NJ, Piccart MJ, Castiglione M, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Goss PE. Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: Canadian Cancer Trials Group MA.17. Ann Oncol 19: 877-82, 2008.

Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Tu D. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol 26: 1948-55, 2008.

Chapman J-AW, Meng D, Shepherd L, Parulekar W, Ingle JN, Muss HB, Palmer M, Yu C, Goss PE. Competing causes of death from a randomized trial of extended adjuvant endocrine therapy for breast cancer. J Natl Cancer Inst 100: 252-60, 2008.

Moy B, Tu D, Pater JL, Ingle JN, Shepherd LE, Whelan TJ, Goss PE. Clinical outcomes of ethnic minority women in MA.17: a trial of letrozole after 5 years of tamoxifen in postmenopausal women with early stage breast cancer. Ann Oncol 17: 1637-43, 2006.

Ingle JN, Tu D, Pater JL, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Goss PE. Duration of letrozole treatment and outcomes in the placebo-controlled Canadian Cancer Trials Group MA.17 extended adjuvant therapy trial. Breast Cancer Res Treat 99: 295-300, 2006.

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. Obstetrical & Gynecological Survey 59: 201-3, 2004.

Correlative Biology

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL. Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Cancer Institute of Canada Clinical Trials Group MA.17. J Clin Oncol 25: 2006-11, 2007.

General

Bradbury P, Meyer R, Pater J, Tu D, Seymour L, Shepherd L, Eisenhauer E. Stopping a trial early in oncology: for patients or for industry? (letter to the editor). Ann Oncol 20: 395-6, 2009.

Pater J, Tu D, Shepherd L, Ingle JN, Goss PE. Decision making in adjuvant trials in breast cancer: the Canadian Cancer Trials Group MA.17 trial as an example. Breast Cancer Res Treat 108: 265-9, 2008.

Booth CM, Pater JL, Goss PE. Identifying breast cancer patients most likely to benefit from aromatase inhibitor therapy after adjuvant tamoxifen (Correspondence). Cancer 109: 1927-8, 2007.

Whelan TJ, Goss PE, Ingle JN, Tu D, Shepherd L, Pater JL. Quality o ol 24: 4038-9, 2006.

Tu D, Pater JL, Ingle JN, Goss PE. Randomized trial of letrozle following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from Canadian Cancer Trials Group MA.17. (Canadian Cancer Trials Group Response to Correspondence by Luc Vakaet). J Natl Cancer Inst 98: 1162-3, 2006.

Pater J, Goss P, Ingle J, Shelley W, Shepherd L. The ethics of early stopping rules (letter to the editor). J Clin Oncol 23: 2862-3, 2005.

ABSTRACTS

Primary Results and Follow-Up

Robert NJ, Goss PE, Ingle JN, Tu D, Shepherd L, Palmer M, Pater J. Updated analysis of Canadian Cancer Trials Group MA.17 (letrozole vs placebo to letrozole vs placebo) post unblinding. Proc Am Soc Clin Oncol 24[18S Part 1], 15. 2006. (Abstract)

Goss PE, Ingle JN, Palmer MJ, Shepherd LE, Tu D. Updated analysis of Canadian Cancer Trials Group MA.17 (letrozole vs placebo to letrozole vs placebo) post unblinding. Breast Cancer Res Treat 94[Suppl 1], S10. 2005. (Abstract)

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pater JL. Randomized placebo-controlled trial of letrozole in postmenopausal women with early breast cancer completing 5 years of tamoxifen. Breast Cancer Res Treat 85[2], 180. 2004. (Abstract)

Goss P, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione MM, Tu D, Shepherd LE, Pater JL. Updated analysis of the Canadian Cancer Trials Group MA.17 randomized placebo controlled trial of letrozole after five years of tamoxifen in postmenopausal women with early stage breast cancer. Proc Am Soc Clin Oncol 23, 87. 2004. (Abstract)

Secondary Endpoints

Maunsell E, Au H, Palmer M, Tu D, Whelan TJ, Goss PE, Davis A. Health-related quality of life in breast cancer survivors after 5 years of adjuvant tamoxifen. Quality of Life Research 14[9], 2092. 2005. (Abstract)

Whelan T, Goss P, Ingle J, Pater J, Shepherd L, Palmer M, Tu D, Robert NJ, Martino S, Muss H. Assessment of quality of life in MA.17, a randomized placebo-controlled trial of letrozole in postmenopausal women following five years of tamoxifen. Proc Am Soc Clin Oncol 23, 6. 2004. (Abstract)

Subsets and Special Analyses

Goss PE, Ingle JN, Martino S, Robert N, Muss H, Shepherd L, Pritchard KI, Livingston RB, Davidson N, Perez EA, Cameron D, Whelan T, Palmer M, Tu D. Outcomes of women who were premenopausal at diagnosis of early stage breast cancer in the Canadian Cancer Trials Group MA17 trial. Cancer Research 69[24 Suppl], 487s. 2009. (Abstract)

Goss PE, Mamounas EP, Jakesz R, Markopoulos C, Dowsett M, Peto R, Godwin J, Davies C. Aromatase inhibitors (AIs) versus not (placebo/observation) as late extended adjuvant therapy for postmenopausal women with early stage breast cancer: overviews of randomized trials of AIs after ~ 5years of tamoxifen. Cancer Research 69[24 Suppl], 733s. 2009. (Abstract)

Chapman JW, Meng D, Shepherd L, Parulekar W, Ingle JN, Muss HB, Palmer M, Yu C, Goss PE. Competing causes of death from a randomized trial of extended adjuvant endocrine therapy for breast cancer: Canadian Cancer Trials Group MA.17. EHRLICH II - 2nd World Conference on Magic Bullets, A-53. 2008. (Abstract)

Chapman JW, Meng D, Shepherd L, Parulekar W, Ingle J, Muss H, Palmer M, Yu C, Goss P. Competing causes of death in breast cancer extended adjuvant endocrine therapy: Canadian Cancer Trials Group MA.17. ASCO Breast Cancer Symposium . 2007. (Abstract)

Chapman J, Meng D, Shepherd L, Parulekar W, Ingle JN, Muss HB, Palmer M, Yu C, Goss PE. Competing causes of death in Canadian Cancer Trials Group MA.17, a placebo-controlled trial of letrozole as extended adjuvant therapy for breast cancer patients. Best of ASCO 25[18s Part 1], 12s. 2007. (Abstract)

Chapman J, Meng D, Shepherd L, Parulekar W, Ingle JN, Muss HB, Palmer M, Yu C, Goss PE. Competing causes of death in Canadian Cancer Trials Group MA.17, a placebo-controlled trial of letrozole as extended adjuvant therapy for breast cancer patients. Proc Am Soc Clin Oncol 25[18s Part 1], 12s. 2007. (Abstract)

Chapman J-A, Meng D, Shepherd L, Parulekar W, Ingle J, Muss H, Palmer M, Yu C, Goss P. Competing causes of death in breast cancer extended adjuvant endocrine therapy: Canadian Cancer Trials Group MA.17. Making Connections: A Canadian Cancer Research Conference Celebrating NCIC's 60th Anniversary , 46-47. 2007. (Abstract)

Muss HB, Tu D, Ingle JN, Martino S, Robert NJ, Pater JL, Whelan T, Palmer MJ, Piccart MJ, Shepherd LE, Pritchard KI, He Z, Goss PE. The benefits of letrozole in postmenopausal women with early stage breast cancer who have had five years of tamoxifen are independent of age. Breast Cancer Res Treat 100[Suppl 1], S23. 2006. (Abstract)

Moy B, Tu D, Shepherd LE, Pater JL, Whelan TJ, Ingle JN, Goss PE. Canadian Cancer Trials Group MA.17: Tolerability of letrozole among ethnic minority women. Proc Am Soc Clin Oncol 24[18S Part 1], 305. 2006. (Abstract)

Meng D, Chapman J-A, Shepherd L, Parulekar W, Ingle J, Goss P, Li D. Competing causes of death in MA.17, a placebo controlled trial of letrozole as extended adjuvant therapy for breast cancer patients. ENAR Int Biometric Soc. 2006. (Abstract)

Ingle J, Tu D, Shepherd L, Palmer M, Pater J, Goss P. Canadian Cancer Trials Group MA.17: Intent to treat analysis of randomized patients after a median follow-up of 54 months. Proc Am Soc Clin Oncol 24[18S Part 1], 15. 2006. (Abstract)

Ingle JN, Goss PE, Tu D. Analysis of duration of letrozole extended adjuvant therapy as measured by hazard ratios of disease recurrence over time for patients on Canadian Cancer Trials Group MA.17. Breast Cancer Res Treat 94[Suppl 1], S11. 2005. (Abstract)

Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP, Shenkier TN, Tozer RG, Palmer MJ, Shepherd LE, Tu D, Goss PE. Effect of letrozole versus placebo on bone mineral density in women completing > 5 years of adjuvant tamoxifen: Canadian Cancer Trials Group MA.17b. Breast Cancer Res Treat 88[Suppl 1], S36. 2004. (Abstract)

Correlative Biology

Moy B, Tu D, Shepherd LE, Palmer MJ, Ingle JN, Goss PE. Canadian Cancer Trials Group MA.17: hormone receptor expression of in-breast recurrences and contralateral primary breast cancers arising on aromatase inhibitors. Cancer Research 69[Suppl 2], 145s. 2008. (Abstract)

Goss PE, Ingle J, Tu D, Shepherd L, Pater J. Canadian Cancer Trials Group MA17: Disease free survival according to estrogen receptor and progesterone receptor status of the primary tumor. Breast Cancer Res Treat 94[Suppl 1], S98. 2005. (Abstract)

General

Pater JL, Tu D, Ingle JN, Shepherd LE, Goss PE. An evaluation of the early termination of MA.17 extended adjuvant therapy trial. Breast Cancer Res Treat 100[Suppl 1], S107. 2006. (Abstract)

Luk C, Goss P, Pritchard K, Whelan TJ, Liu S, Shepherd L, Pater J. Determinants of preferences for starting extended adjuvant letrozole in postmenopausal women following five years of tamoxifen. Proc Am Soc Clin Oncol 23[16S Part 1], 39s. 2005. (Abstract)

Goss PE, Ingle JN, Pater JL. Letrozole in breast cancer (author's reply to letter to the editor). N Engl J Med 350[7], 728-729. 2004. (Abstract) Palmer M, Broekhoven M, Pater J. Drug supply issues in a multinational, intergroup phase III trial. Controlled Clin Trials 24[3S], 67S. 2003. (Abstract)

Palmer M, Broekhoven M, Garrah A, Tu D. CTASSIST: A computer program for patient randomization and tracking of drug distribution. Controlled Clin Trials 21[2S], 110s. 2000. (Abstract)

Goss P, Olivotto I, Poljicak M, Pritchard K, Whelan T, Williams CKO, Shepherd L, Tu D, Djurfeldt M, Palmer M. A phase III randomized double-blind study of letrozole versus placebo in women with primary breast cancer completing five or more years of adjuvant tamoxifen. Reasons for Hope Conference. 1999. (Abstract)

Other

Chen Y. Long-term quality of life assessment in post-menopausal women with primary breast cancer (Thesis). 2005. Queen's University, Dept of Community Health & Epidemiology. (Thesis/Dissertation)