Letrozole in Breast Cancer Who Have Received 5 Years of Aromatase Inhibitor Therapy

• ClinicalTrials.gov Identifier: NCT00754845
• Recruitment Status: Completed
• First Posted: September 18, 2008
• Results First Posted: November 19, 2018
• Last Update Posted: August 25, 2023
• Sponsor: Canadian Cancer Trials Group
• Collaborators: Eastern Cooperative Oncology Group; North Central Cancer Treatment Group; SWOG Cancer Research Network; Alliance for Clinical Trials in Oncology
• Information provided by (Responsible Party): Canadian Cancer Trials Group

Tracking Information

• First Submitted Date: September 17, 2008
• First Posted Date: September 18, 2008
• Results First Submitted Date: February 23, 2017
• Results First Posted Date: November 19, 2018
• Last Update Posted Date: August 25, 2023
• Actual Study Start Date: November 23, 2004
• Actual Primary Completion Date: December 21, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 14, 2018)

Disease-free Survival (DFS) [ Time Frame: Unitil the end of study with a median follow up of 75 months ]

It is defined as the months from the day of randomization to the earliest date when a recurrence of the primary disease (recurrence in the breast, chest wall and nodal sites or the development of metastatic disease) or a contralateral breast cancer was observed. Subjects who died without recurrence of the primary disease or the development of the contralateral breast cancer were censored at their death date. If a patient has not recurred, developed a contralateral breast cancer, or died, disease-free survival was censored on the date of the last day the patient was known to be alive. Probability of disease free survival at 5 years is estimated and reported.

• Original Primary Outcome Measures (submitted: September 17, 2008): Disease-free survival

Current Secondary Outcome Measures (submitted: November 14, 2018)

• Incidence of Contralateral Breast Cancer [ Time Frame: 10 years ]
  The annual incidence rate was estimated based on the time to the development of contralateral breast cancer, which was calculated in months from the day of randomization to the diagnosis date of contralateral breast cancer for subjects who had developed the contralateral breast cancer, to the time of death for the patient who died, or to the last day the patient was known alive for subjects without contralateral breast cancer
• Overall Survival (OS) [ Time Frame: Until the end of study with a median follow-up of 75 months ]
  For subjects who died, overall survival was calculated in months from the day of randomization to the date of death. Otherwise, survival was censored at the last day the patient was known to be alive. Probability of overall survival at 5 years is estimated and reported.
• Change From Baseline in Role Function- Physical Scale on SF(Short Form)-36 Health Survey [ Time Frame: 8 years ]
  Difference between post baseline scores and baseline score of role function-physical scale on SF-36 Health Survey (scale range between 0 and 100 with higher score indicating better quality of life).

Original Secondary Outcome Measures (submitted: September 17, 2008)

• Incidence of contralateral breast cancer
• Overall survival
• Long-term clinical and laboratory safety of aromatase inhibitor therapy, particularly cardiovascular morbidity and mortality, changes in bone mineral density, incidence of all bone fractures, and common toxicities
• Quality of life (QOL) as assessed by SF-36 Health Survey and the Menopause-Specific QOL Questionnaire (NCIC CTG participating centers)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Letrozole in Breast Cancer Who Have Received 5 Years of Aromatase Inhibitor Therapy
• Official Title: A Double Blind Randomization to Letrozole or Placebo for Women Previously Diagnosed With Primary Breast Cancer Completing Five Years of Adjuvant Aromatase Inhibitor Either as Initial Therapy or After Tamoxifen (Including Those in The MA.17 Study)

Brief Summary

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether letrozole is more effective than a placebo in treating in women with breast cancer who have already received 5 years of aromatase inhibitor therapy.

PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in treating women with primary breast cancer who have received 5 years of aromatase inhibitor therapy.

Detailed Description

OBJECTIVES:

Primary

• To compare the disease-free survival of women with primary breast cancer treated with letrozole vs placebo after completing approximately 5 years (i.e., 4½ - 6 years) of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane).

Secondary

• To compare the effect of these drugs on overall (all cause specific) mortality of these patients.
• To compare the incidence of contralateral breast cancer in patients treated with these drugs.
• To evaluate the long-term clinical and laboratory safety of aromatase inhibitor therapy, particularly cardiovascular morbidity and mortality (e.g., significant coronary artery disease, including myocardial infarction and angina requiring percutaneous transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal strokes, and all vascular deaths); incidence of all bone fractures (with particular emphasis on hip and wrist fractures as indicators of osteoporosis); changes in bone density; and common toxicities.
• To compare overall quality of life (QOL) and menopausal-specific QOL of patients treated with these drugs.

OUTLINE: This is a multicenter study. Patients are stratified according to lymph node status at diagnosis (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), interval between last dose of aromatase inhibitor therapy and study randomization (< 6 months vs 6 months to 2 years), and duration of prior tamoxifen citrate use (0 vs < 2 years vs 2 - 4½ years vs > 4½ years). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
• Arm II: Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.

Patients undergo bone mineral density measurement by DEXA scan at baseline (if not done within 12 months of study entry), at 24 and 48 months during study therapy, and at the completion of study therapy. Some patients also complete quality-of-life questionnaires at baseline and at 12, 24, 36, 48, and 60 months.

After completion of study therapy, patients are followed annually.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: letrozole
  Given orally
  Other Name: femara
• Other: placebo
  Given orally
  Other Name: sugar pill

Study Arms

• Experimental: Letrozole
  Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
  Intervention: Drug: letrozole
• Placebo Comparator: Placebo
  Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
  Intervention: Other: placebo

Publications *

• Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, Gelmon K, Whelan T, Strasser-Weippl K, Rubin S, Sturtz K, Wolff AC, Winer E, Hudis C, Stopeck A, Beck JT, Kaur JS, Whelan K, Tu D, Parulekar WR. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med. 2016 Jul 21;375(3):209-19. doi: 10.1056/NEJMoa1604700. Epub 2016 Jun 5.
• Li Y, Zheng X, Tu D, Ingle JN, Goss PE, Parulekar WR, Qin G. Predicting the clinical outcomes and benefit from letrozole after 5 years of treatment with aromatase inhibitors for early breast cancer: analysis from CCTG MA.17R. Breast Cancer Res Treat. 2022 Feb;191(3):523-533. doi: 10.1007/s10549-021-06448-5. Epub 2021 Nov 26.
• Ethier JL, Anderson GM, Austin PC, Clemons M, Parulekar W, Shepherd L, Summers Trasiewicz L, Tu D, Amir E. Influence of the competing risk of death on estimates of disease recurrence in trials of adjuvant endocrine therapy for early-stage breast cancer: A secondary analysis of MA.27, MA.17 and MA.17R. Eur J Cancer. 2021 May;149:117-127. doi: 10.1016/j.ejca.2021.02.034. Epub 2021 Apr 11.
• Lemieux J, Brundage MD, Parulekar WR, Goss PE, Ingle JN, Pritchard KI, Celano P, Muss H, Gralow J, Strasser-Weippl K, Whelan K, Tu D, Whelan TJ. Quality of Life From Canadian Cancer Trials Group MA.17R: A Randomized Trial of Extending Adjuvant Letrozole to 10 Years. J Clin Oncol. 2018 Feb 20;36(6):563-571. doi: 10.1200/JCO.2017.75.7500. Epub 2018 Jan 12. Erratum In: J Clin Oncol. 2018 May 20;36(15):1540.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 31, 2010): 1918
• Original Estimated Enrollment (submitted: September 17, 2008): 1800
• Actual Study Completion Date: April 19, 2017
• Actual Primary Completion Date: December 21, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Previously diagnosed with primary breast cancer

• Must have received 4½ - 6 years of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane), either as initial therapy or after prior tamoxifen citrate, including treatment received as part of clinical trial CAN-NCIC-MA17

  • Completed aromatase inhibitor therapy ≤ 2 years ago

• No metastatic or recurrent disease, contralateral breast cancer, or ductal carcinoma in situ in either breast, as determined by the following:

  • Clinical examination of the breast area, axillae, and neck within the past 60 days
  • Mammogram within the past 12 months*
  • Chest x-ray within the past 60 days
  • Bone scan, if alkaline phosphatase > 2 times normal and/or there are symptoms of metastatic disease AND confirmatory x-ray, if bone scan results are questionable, within the past 60 days
  • Abdominal ultrasound, liver scan, or CT scan of the abdomen within the past 60 days, if ALT, AST, or alkaline phosphatase > 2 times normal NOTE: *A baseline mammogram is not required for patients who have undergone bilateral complete mastectomy

• Hormone-receptor status:

  • Estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) primary tumor at the time of diagnosis, defined as a tumor receptor content of > 10 fmol/mg protein or receptor positive by immunocytochemical assay (for patients not previously enrolled on clinical trial CAN-NCIC-MA17)
  • ER+ and/or PR+ primary tumor OR hormone receptor status of primary tumor unknown (for patients previously enrolled on clinical trial CAN-NCIC-MA17)

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• ECOG performance status 0-2
• Life expectancy ≥ 5 years
• WBC > 3.0 x 10^9/L OR granulocyte count (polymorphs + bands) ≥ 1.5 times 10^9/L
• Platelet count > 100 x 10^9/L
• AST and/or ALT < 2 times upper limit of normal (ULN)*
• Alkaline phosphatase < 2 times ULN*

• Able (i.e. sufficiently fluent) and willing to complete quality-of-life questionnaires in either English or French (NCIC CTG participating centers)

  • Inability to complete questionnaires due to illiteracy in English or French, loss of sight, or other equivalent reason allowed
• Accessible for treatment and follow-up
• No other prior or concurrent malignancy except adequately treated, superficial squamous cell or basal cell skin cancer, carcinoma in situ of the cervix, or other cancer treated > 5 years ago that is presumed cured NOTE: *Elevated levels allowed provided imaging examinations have ruled out metastatic disease

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No concurrent selective estrogen receptor modulator (e.g., raloxifene, idoxifene)
• No other concurrent anticancer therapy

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 0 Years to 120 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United Kingdom

Administrative Information

• NCT Number: NCT00754845
• Other Study ID Numbers: MA17R; CAN-NCIC-MA17R ( Registry Identifier: NCI US - Physician Data Query ); CDR0000614819 ( Other Identifier: PDQ )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Canadian Cancer Trials Group
• Original Responsible Party: Not Provided
• Current Study Sponsor: Canadian Cancer Trials Group
• Original Study Sponsor: Same as current

Collaborators

• Eastern Cooperative Oncology Group
• North Central Cancer Treatment Group
• SWOG Cancer Research Network
• Alliance for Clinical Trials in Oncology

Investigators

• Study Chair: Paul E. Goss, MD, PhD; Massachusetts General Hospital

• PRS Account: Canadian Cancer Trials Group
• Verification Date: April 2020