Letrozole After Tamoxifen in Treating Women With Breast Cancer

Breast Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00003140
• Other study ID #: MA17
• Secondary ID: U10CA025224CAN-N
• Status: Completed
• Phase: Phase 3
• Start date: August 24, 1998
• Est. completion date: October 2003

Study information

• Verified date: March 2012
• Source: Canadian Cancer Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by reducing the production of estrogen.

PURPOSE: This randomized phase III trial is studying letrozole to see how well it works in treating women with breast cancer who have received tamoxifen for at least 5 years.

Description:

OBJECTIVES:

Primary

• Compare the disease-free survival and overall survival of postmenopausal women with primary breast cancer who have completed at least five years of adjuvant aromatase inhibitor as initial therapy or after tamoxifen treated with letrozole or placebo.

Secondary

• Compare the incidence of contralateral breast cancer in patients treated with these regimens.

• Evaluate the long-term clinical and laboratory safety of letrozole, in terms of lipid profile, cardiovascular morbidity and mortality, incidence of bone fractures, change in bone density, and common toxic effects, in this patient population.

• Compare the quality of life of patients treated with these regimens. Re-randomization

Primary

• Compare disease-free survival of patients who, after receiving at least 4.5 years of letrozole, are re-randomized to receive an additional 5 years of letrozole vs placebo.

Secondary

• Determine whether common genetic polymorphisms for genes encoding proteins involved in pharmacokinetic and/or pharmacodynamic pathways for letrozole contribute to individual variation in toxicity and efficacy of letrozole therapy.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to receptor status (positive vs unknown), lymph node status (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), interval between last dose of aromatase inhibitor therapy and randomization (< 6 months vs 6 months-2 years), and duration of prior tamoxifen use (0 years vs < 2 years vs 2-4.5 years vs > 4.5 years). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral letrozole once daily.

• Arm II: Patients receive oral placebo once daily. In both arms, treatment continues for 5 years in the absence of disease progression or unacceptable toxicity. Patients in arm II may then be offered oral letrozole once daily for up to 5 years.

Quality of life is assessed at baseline, at 6 months, and then annually for 4.5 years.

• Double-blind, re-randomization:

Patients who complete ≥ 4.5 years of letrozole (arm I) and who did not experience recurrent disease or new primary breast cancer, including ductal carcinoma in situ, may participate in the double-blind, placebo-controlled, re-randomization portion of the study. Patients are stratified according to lymph node status at enrollment (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), and interval between last dose of letrozole and re-randomization (<6 months vs 6 months to 2 years). Common genetic single nucleotide polymorphisms for genes encoding proteins involved in pharmacokinetic and/or pharmacodynamic pathways for letrozole are analyzed in order to determine if these single nucleotide polymorphisms contribute to individual variation in toxicity and efficacy of letrozole therapy.

Quality of life is assessed as during the first randomization.

Patients are followed annually.

PROJECTED ACCRUAL: A total of 4,700 patients will be accrued for this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5187
• Est. completion date: October 2003
• Est. primary completion date: August 22, 2003
• Accepts healthy volunteers: No
• Gender: Female
• Age group: N/A to 120 Years

Eligibility

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed primary invasive breast carcinoma resected at time of original diagnosis

• No ductal carcinoma in situ

• Axillary lymph node negative, positive, or unknown

• No evidence of metastases

• No localized or distant breast cancer recurrence

• Not registered on protocol NCCTG-893052, any other IBCSG protocol, or protocol SWOG-S9623

• Hormone receptor status:

• Estrogen or progesterone receptor positive as defined by tumor receptor content at least 10 fmol/mg protein or receptor positive by ERICA or PgRICA

• Unknown status allowed if effort to determine status has been made by immunocytochemistry

• No contralateral breast cancer

PATIENT CHARACTERISTICS:

Age:

• Postmenopausal

Sex:

• Female

Menopausal status:

• Postmenopausal defined by one of the following:

• Age 50 or over at start of adjuvant tamoxifen

• Under age 50 and considered postmenopausal by treating physician at start of adjuvant tamoxifen

• Under age 50 at start of adjuvant tamoxifen and had bilateral oophorectomy (surgical or radiation)

• Under age 50 and premenopausal at start of adjuvant tamoxifen, but became amenorrheic during tamoxifen and remained amenorrheic for at least 1 year

• Considered postmenopausal by physician with LH/FSH levels under the treatment center's postmenopausal limits

Performance status:

• ECOG 0-2

Life expectancy:

• At least 5 years

Hematopoietic:

• WBC = 3,000/mm^3 OR

• Granulocyte count = 1,500/mm^3

• Platelet count = 100,000/mm^3

Hepatic:

• AST and/or ALT < 2 times upper limit of normal (ULN) (unless imaging examinations have ruled out metastatic disease)

• Alkaline phosphatase < 2 times ULN (unless imaging examinations have ruled out metastatic disease)

Renal:

• Not specified

Other:

• No concurrent medical or psychiatric condition that would preclude study participation

• No other malignancy within the past 5 years except adequately treated superficial squamous cell or basal cell skin cancer or carcinoma in situ of the cervix

• Able to swallow study drug

• Adequate oral intake

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• Prior adjuvant chemotherapy allowed

• No concurrent chemotherapy

Endocrine therapy:

• Completed at least 4.5 but no more than 6 years of adjuvant tamoxifen after resection

• Completed at least 4.5-6 years of adjuvant aromatase inhibitor as initial therapy or after tamoxifen

• No more than 3 months since prior adjuvant tamoxifen

• No concurrent hormone replacement therapy (e.g., megestrol)

• No concurrent selective estrogen-receptor modulators (e.g., raloxifene or idoxifene)

• Concurrent intermittent vaginal estrogens (e.g., Estring) allowed if other local measures for intractable vaginal atrophy are insufficient

• No other concurrent aromatase inhibitors

• No more than 2 years since prior aromatase inhibitor therapy (re-randomization)

Radiotherapy:

• Prior radiotherapy allowed

Surgery:

• See Disease Characteristics

Other:

• At least 1 month since prior investigational drugs

• Prior treatment on a clinical trial for breast cancer allowed if permission has been obtained from the sponsors of the original study for their patient to participate on MA.17/JMA.17/BIG-97-01

• No prior placebo on core protocol

• No concurrent anticancer therapy

• Concurrent thyroid medication, calcium, vitamin D, and bisphosphonates allowed

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• letrozole
Given orally

Other:
• placebo
Given orally

Locations

Country	Name	City	State
Canada	The Royal Victoria Hospital	Barrie	Ontario
Canada	PEI Cancer Treatment Centre,Queen Elizabeth Hospital	Charlottetown	Prince Edward Island
Canada	Centre de Sante et de services sociaux de Gatineau	Gatineau	Quebec
Canada	QEII Health Sciences Center	Halifax	Nova Scotia
Canada	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario
Canada	BCCA - Cancer Centre for the Southern Interior	Kelowna	British Columbia
Canada	Cancer Centre of Southeastern Ontario at Kingston	Kingston	Ontario
Canada	Lethbridge Cancer Centre	Lethbridge	Alberta
Canada	L'Hotel-Dieu de Levis	Levis	Quebec
Canada	London Regional Cancer Program	London	Ontario
Canada	Markham Stouffville Hospital	Markham	Ontario
Canada	Credit Valley Hospital	Mississauga	Ontario
Canada	The Moncton Hospital	Moncton	New Brunswick
Canada	The Vitalite Health Network - Dr. Leon Richard	Moncton	New Brunswick
Canada	CHUM - Hopital Notre-Dame	Montreal	Quebec
Canada	CHUM - Hotel Dieu du Montreal	Montreal	Quebec
Canada	CHUM - Pavillon Saint-Luc	Montreal	Quebec
Canada	Hopital du Sacre-Coeur de Montreal	Montreal	Quebec
Canada	Hopital Maisonneuve-Rosemont	Montreal	Quebec
Canada	McGill University - Dept. Oncology	Montreal	Quebec
Canada	NRGH - Nanaimo Cancer Clinic	Nanaimo	British Columbia
Canada	Stronach Regional Health Centre at Southlake	Newmarket	Ontario
Canada	Lakeridge Health Oshawa	Oshawa	Ontario
Canada	Ottawa Health Research Institute - General Division	Ottawa	Ontario
Canada	Penticton Regional Hospital	Penticton	British Columbia
Canada	Peterborough Regional Health Centre	Peterborough	Ontario
Canada	University Institute of Cardiology and	Quebec
Canada	CHA-Hopital Du St-Sacrement	Quebec City	Quebec
Canada	CHUQ-Pavillon Hotel-Dieu de Quebec	Quebec City	Quebec
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Atlantic Health Sciences Corporation	Saint John	New Brunswick
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Algoma District Cancer Program	Sault Ste. Marie	Ontario
Canada	Centre hospitalier universitaire de Sherbrooke	Sherbrooke	Quebec
Canada	Niagara Health System	St. Catharines	Ontario
Canada	Dr. H. Bliss Murphy Cancer Centre	St. John's	Newfoundland and Labrador
Canada	Regional Cancer Program of the Hopital Regional	Sudbury	Ontario
Canada	BCCA - Fraser Valley Cancer Centre	Surrey	British Columbia
Canada	Thunder Bay Regional Health Science Centre	Thunder Bay	Ontario
Canada	Humber River Regional Hospital	Toronto	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	North York General Hospital	Toronto	Ontario
Canada	Odette Cancer Centre	Toronto	Ontario
Canada	St. Joseph's Health Centre	Toronto	Ontario
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Toronto East General Hospital	Toronto	Ontario
Canada	Trillium Health Centre - West Toronto	Toronto	Ontario
Canada	Univ. Health Network-Princess Margaret Hospital	Toronto	Ontario
Canada	Univ. Health Network-The Toronto General Hospital	Toronto	Ontario
Canada	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia
Canada	BCCA - Vancouver Island Cancer Centre	Victoria	British Columbia
Canada	Windsor Regional Cancer Centre	Windsor	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United Kingdom	The Royal Marsden NHS Foundation Trust	London
United Kingdom	Christie's Hospital NHS Trust	Manchester
United Kingdom	Wythenshawe Hospital	Manchester
United Kingdom	The Royal Marsden NHS Foundation Trust - Sutton	Surrey

Sponsors (8)

Lead Sponsor	Collaborator
NCIC Clinical Trials Group	Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, European Organisation for Research and Treatment of Cancer - EORTC, International Breast Cancer Study Group, National Cancer Institute (NCI), North Central Cancer Treatment Group, Southwest Oncology Group

Countries where clinical trial is conducted

Canada,  United Kingdom, 

References & Publications (31)

Abetz L, Barghout V, Thomas S, et al.: Letrozole did not worsen quality of life relative to placebo in post-menopausal women with early breast cancer: results from the US subjects of the MA-17 study. [Abstract] Breast Cancer Research and Treatment 94 (Sup

Baum M. Adjuvant endocrine therapy in postmenopausal women with early breast cancer: where are we now? Eur J Cancer. 2005 Aug;41(12):1667-77. Review. — View Citation

Baum M. Current status of aromatase inhibitors in the management of breast cancer and critique of the NCIC MA-17 trial. Cancer Control. 2004 Jul-Aug;11(4):217-21. Review. — View Citation

Booth CM, Pater JL, Goss PE. Identifying breast cancer patients most likely to benefit from aromatase inhibitor therapy after adjuvant tamoxifen. Cancer. 2007 May 1;109(9):1927-8; author reply 1928. — View Citation

Buzdar A, Chlebowski R, Cuzick J, Duffy S, Forbes J, Jonat W, Ravdin P. Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer. Curr Med Res Opin. 2006 Aug;22(8):1575-85. Review. — View Citation

Chapman JW, Meng D, Shepherd L, et al.: Competing causes of death in breast cancer extended adjuvant endocrine therapy: NCIC CTG MA.17. [Abstract] American Society of Clinical Oncology 2007 Breast Cancer Symposium, 7-8 September 2007, San Francisco, Calif

Goss P: Breaking the 5-year barrier: results from the MA.17 extended adjuvant trial in women who have completed adjuvant tamoxifen treatment. [Abstract] European Journal of Cancer Supplements 4 (9): 10-5, 2006.

Goss PE, Ingle JN, Martino S, et al.: Outcomes of women who were premenopausal at diagnosis of early stage breast cancer in the NCIC CTG MA17 trial. [Abstract] 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, Texas. A-13,

Goss PE, Ingle JN, Martino S, et al.: Updated analysis of the NCIC CTG MA.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer. [Abstract] J Clin Oncol 22 (Suppl 1

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 — View Citation

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; National Cancer Institute of Canada Clinical Trials G — View Citation

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 wom — View Citation

Goss PE, Ingle JN, Palmer MJ, et al.: Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs placebo) post unblinding. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-16, 2005.

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 impro — View Citation

Goss PE, Ingle JN, Tu D: NCIC CTG MA17: disease free survival according to estrogen receptor and progesterone receptor status of the primary tumor. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-2042, 2005.

Ingle J, Tu D, Shepherd L, et al.: NCIC CTG MA.17: intent to treat analysis (ITT) of randomized patients after a median follow-up of 54 months. [Abstract] J Clin Oncol 24 (Suppl 18): A-549, 2006.

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 NCIC CTG MA.17. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-17, 2005.

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 p — View Citation

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 tr — View Citation

Luk C, Goss P, Pritchard K, et al.: Determinants of preferences for starting extended adjuvant letrozole (L) in postmenopausal women following five years of tamoxifen. [Abstract] J Clin Oncol 23 (Suppl 16): A-642, 39s, 2005.

Moy B, Tu D, Shepherd LE, et al.: NCIC CTG MA.17: tolerability of letrozole among ethnic minority women. [Abstract] J Clin Oncol 24 (Suppl 18): A-6018, 305s, 2006.

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 af — View Citation

Pater JL, Tu D, Ingle JN, et al.: An evaluation of the early termination (ET) of MA.17 extended adjuvant therapy trial. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-2081, S107-8, 2006.

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 yea — View Citation

Robert NJ, Goss PE, Ingle JN, et al.: Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs placebo) post unblinding. [Abstract] J Clin Oncol 24 (Suppl 18): A-550, 2006.

Scott LJ, Keam SJ. Letrozole : in postmenopausal hormone-responsive early-stage breast cancer. Drugs. 2006;66(3):353-62. Review. — View Citation

Vachon CM, Ingle JN, Scott CG, et al.: Pilot study of changes in mammographic density in women treated with letrozole or placebo on NCIC CTG MA17. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-6005, 2005.

Vakaet L. Re: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2006 Aug 16;98(16):1162; author reply 1162-3. — View Citation

Wardley AM. Emerging data on optimal adjuvant endocrine therapy: Breast International Group trial 1-98/MA.17. Clin Breast Cancer. 2006 Feb;6 Suppl 2:S45-50. Review. — View Citation

Whelan T, Goss P, Ingle J, et al.: Assessment of quality of life (QOL) in MA.17, a randomized placebo-controlled trial of letrozole in postmenopausal women following five years of tamoxifen. [Abstract] J Clin Oncol 22 (Suppl 14): A-517, 7s, 2004.

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 postmenopausa — View Citation

* Note: There are 31 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease-free survival		5 years