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

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ClinicalTrials.gov Identifier: NCT00754845

Recruitment Status : Completed

First Posted : September 18, 2008

Results First Posted : November 19, 2018

Last Update Posted : August 25, 2023

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Sponsor:

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

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Breast Cancer
Interventions	Drug: letrozole Other: placebo
Enrollment	1918

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Letrozole	Placebo
Arm/Group Description	Patients receive oral letrozole onc...	Patients receive oral placebo once ...
Arm/Group Description	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. letrozole: Given orally	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. placebo: Given orally
Period Title: Overall Study
Started	959	959
Completed	959	959
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Letrozole	Placebo	Total
Arm/Group Description		Patients receive oral letrozole onc...	Patients receive oral placebo once ...	Total of all reporting groups
Arm/Group Description		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. letrozole: Given orally	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. placebo: Given orally	Total of all reporting groups
Overall Number of Baseline Participants		959	959	1918
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Median (Full Range) Unit of measure: Years
	Number Analyzed	959 participants	959 participants	1918 participants
		65.6 (43 to 92.2)	64.8 (43.4 to 89.9)	65.1 (43 to 92.2)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	959 participants	959 participants	1918 participants
	Female	959 100.0%	959 100.0%	1918 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	959 participants	959 participants	1918 participants
	Hispanic or Latino	11 1.1%	13 1.4%	24 1.3%
	Not Hispanic or Latino	940 98.0%	939 97.9%	1879 98.0%
	Unknown or Not Reported	8 0.8%	7 0.7%	15 0.8%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	959 participants	959 participants	1918 participants
Canada		276 28.8%	285 29.7%	561 29.2%
United States		683 71.2%	674 70.3%	1357 70.8%
ECOG Performance Status ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	959 participants	959 participants	1918 participants
	Grade 0	852 88.8%	856 89.3%	1708 89.1%
	Grade 1	100 10.4%	95 9.9%	195 10.2%
	Grade 2	7 0.7%	8 0.8%	15 0.8%
		[1] Measure Description: ECOG Performance Status Grade 0: Fully active, able to carry on all pre-disease performance without restriction Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work Grade 2: Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours

Outcome Measures

1.Primary Outcome


Title	Disease-free Survival (DFS)
Description	It is defined as the months from the day of randomization to the earli...
Description	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.
Time Frame	Unitil the end of study with a median follow up of 75 months

Outcome Measure Data

Analysis Population Description

All women randomized were included in the analysis based on treatment arm they were randomized.


Arm/Group Title	Letrozole	Placebo
Arm/Group Description:	Patients receive oral letrozole onc...	Patients receive oral placebo once ...
Arm/Group Description:	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. letrozole: Given orally	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. placebo: Given orally
Overall Number of Participants Analyzed	959	959
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: probability of DFS at 5 years
	0.95 (0.93 to 0.96)	0.91 (0.89 to 0.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letrozole, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.01
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Stratified by the stratification factors at randomization

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95% 0.48 to 0.91
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Incidence of Contralateral Breast Cancer
Description	The annual incidence rate was estimated based on the time to the devel...
Description	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
Time Frame	10 years

Outcome Measure Data

Analysis Population Description

All women randomized


Arm/Group Title	Letrozole	Placebo
Arm/Group Description:	Patients receive oral letrozole onc...	Patients receive oral placebo once ...
Arm/Group Description:	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. letrozole: Given orally	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. placebo: Given orally
Overall Number of Participants Analyzed	959	959
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Number of new case per 1000 person years
	2.1 (1.0 to 3.2)	4.9 (3.2 to 6.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letrozole, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.007
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

3.Secondary Outcome


Title	Overall Survival (OS)
Description	For subjects who died, overall survival was calculated in months from ...
Description	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.
Time Frame	Until the end of study with a median follow-up of 75 months

Outcome Measure Data

Analysis Population Description

All women randomized


Arm/Group Title	Arm I	Arm II
Arm/Group Description:	Patients receive oral letrozole onc...	Patients receive oral placebo once ...
Arm/Group Description:	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. letrozole: Given orally	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. placebo: Given orally
Overall Number of Participants Analyzed	959	959
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: probability of OS at 5 years
	0.93 (0.92 to 0.95)	0.94 (0.92 to 0.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.83
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95% 0.73 to 1.28
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Change From Baseline in Role Function- Physical Scale on SF(Short Form)-36 Health Survey
Description	Difference between post baseline scores and baseline score of role fun...
Description	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).
Time Frame	8 years

Outcome Measure Data

Analysis Population Description

All randomized patients.


Arm/Group Title	Letrozole	Placebo
Arm/Group Description:	Patients receive oral letrozole onc...	Patients receive oral placebo once ...
Arm/Group Description:	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. letrozole: Given orally	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. placebo: Given orally
Overall Number of Participants Analyzed	959	959
Least Squares Mean (Standard Error) Unit of Measure: score on a scale
	-7.74 (1.09)	-6.28 (1.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Letrozole, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.01
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Adverse Events

Time Frame	During protocol treatment of 5 years
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Arm I	Arm II
Arm/Group Description	Patients receive oral letrozole onc...	Patients receive oral placebo once ...
Arm/Group Description	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. letrozole: Given orally	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. placebo: Given orally
All-Cause Mortality
	Arm I	Arm II
	Affected / at Risk (%)	Affected / at Risk (%)
Total	100/959 (10.43%)	100/954 (10.48%)
Serious Adverse Events Serious Adverse Events
	Arm I	Arm II
	Affected / at Risk (%)	Affected / at Risk (%)
Total	15/959 (1.56%)	19/954 (1.99%)
Blood and lymphatic system disorders
CNS hemorrhage/bleeding ^† 2	0/959 (0.00%)	1/954 (0.10%)
Melena/GI bleeding ^† 2	1/959 (0.10%)	0/954 (0.00%)
Rectal bleeding/ hematochezia ^† 2	1/959 (0.10%)	0/954 (0.00%)
Cardiac disorders
Cardiac troponin I (cTnI) ^† 1	0/959 (0.00%)	1/954 (0.10%)
Thrombosis/embolism ^† 2	0/959 (0.00%)	1/954 (0.10%)
Ventricular arrhythmia (PVCs/bigeminy/trigeminy/ ventricular tachycardia) ^† 2	1/959 (0.10%)	1/954 (0.10%)
Edema ^† 2	1/959 (0.10%)	0/954 (0.00%)
Cardiac left ventricular function ^† 2	1/959 (0.10%)	1/954 (0.10%)
Cardiac-ischemia/infarction ^† 2	2/959 (0.21%)	4/954 (0.42%)
Supraventricular arrhythmias (SVT/atrial fibrillation/ flutter) ^† 2	1/959 (0.10%)	0/954 (0.00%)
Cardiovascular/ General - Other ^† 2	1/959 (0.10%)	0/954 (0.00%)
General disorders
Fatigue ^† 2	1/959 (0.10%)	0/954 (0.00%)
Constitutional Symptoms - Other ^† 2	0/959 (0.00%)	1/954 (0.10%)
Sudden death ^† 2	4/959 (0.42%)	1/954 (0.10%)
Hepatobiliary disorders
Liver dysfunction/ failure (clinical) ^† 2	1/959 (0.10%)	0/954 (0.00%)
Hepatic - Other ^† 2	1/959 (0.10%)	0/954 (0.00%)
Infections and infestations
Infection without neutropenia ^† 2	2/959 (0.21%)	3/954 (0.31%)
Infection with unknown ANC ^† 2	0/959 (0.00%)	1/954 (0.10%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Second malignacy ^† 2	3/959 (0.31%)	3/954 (0.31%)
Nervous system disorders
CNS cerebrovascular ischemia ^† 2	0/959 (0.00%)	3/954 (0.31%)
Neuropathy-motor ^† 2	0/959 (0.00%)	1/954 (0.10%)
Renal and urinary disorders
Creatinine ^† 2	0/959 (0.00%)	1/954 (0.10%)
Renal failure ^† 2	3/959 (0.31%)	2/954 (0.21%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion (non-malignant) ^† 2	0/959 (0.00%)	1/954 (0.10%)
Hypoxia ^† 2	1/959 (0.10%)	1/954 (0.10%)
Pulmonary - Other ^† 2	0/959 (0.00%)	2/954 (0.21%)
Pneumonitis/pulmonary infiltrates ^† 2	0/959 (0.00%)	1/954 (0.10%)
Dyspnea (shortness of breath) ^† 2	0/959 (0.00%)	1/954 (0.10%)
1 Term from vocabulary, Common Toxicity Crit 2 Term from vocabulary, CTCAE (2.0) † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Arm I	Arm II
	Affected / at Risk (%)	Affected / at Risk (%)
Total	863/959 (89.99%)	841/954 (88.16%)
Cardiac disorders
Edema ^† 1	158/959 (16.48%)	136/954 (14.26%)
Hypertension ^† 1	157/959 (16.37%)	145/954 (15.20%)
Endocrine disorders
Hot flashes/ flushes ^† 2	360/959 (37.54%)	354/954 (37.11%)
Gastrointestinal disorders
Anorexia ^† 2	46/959 (4.80%)	52/954 (5.45%)
Constipation ^† 2	117/959 (12.20%)	140/954 (14.68%)
Diarrhea ^† 2	105/959 (10.95%)	81/954 (8.49%)
Dyspepsia/heartburn ^† 2	86/959 (8.97%)	79/954 (8.28%)
Nausea ^† 2	69/959 (7.19%)	76/954 (7.97%)
General disorders
Fatigue ^† 2	346/959 (36.08%)	355/954 (37.21%)
Sweating ^† 2	176/959 (18.35%)	175/954 (18.34%)
Abdominal pain ^† 2	51/959 (5.32%)	38/954 (3.98%)
Headache ^† 2	151/959 (15.75%)	138/954 (14.47%)
Arthralgia ^† 2	513/959 (53.49%)	475/954 (49.79%)
Myalgia ^† 2	268/959 (27.95%)	240/954 (25.16%)
Bone pain ^† 2	174/959 (18.14%)	133/954 (13.94%)
Pain-Other ^† 2	73/959 (7.61%)	77/954 (8.07%)
Infections and infestations
Infection w/o neutropenia ^† 2	81/959 (8.45%)	82/954 (8.60%)
Metabolism and nutrition disorders
Hypercholesterolemia ^† 2	203/959 (21.17%)	184/954 (19.29%)
Hyperglycemia ^† 2	56/959 (5.84%)	66/954 (6.92%)
Musculoskeletal and connective tissue disorders
Arthritis ^† 2	317/959 (33.06%)	288/954 (30.19%)
Nervous system disorders
Anxiety ^† 2	54/959 (5.63%)	56/954 (5.87%)
Dizziness ^† 2	145/959 (15.12%)	139/954 (14.57%)
Insomnia ^† 2	269/959 (28.05%)	243/954 (25.47%)
Depression ^† 2	152/959 (15.85%)	150/954 (15.72%)
Neuropathy-sensory ^† 2	110/959 (11.47%)	107/954 (11.22%)
Reproductive system and breast disorders
Vaginal dryness ^† 2	102/959 (10.64%)	96/954 (10.06%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 2	63/959 (6.57%)	69/954 (7.23%)
Dyspnea ^† 2	148/959 (15.43%)	165/954 (17.30%)
Skin and subcutaneous tissue disorders
Alopecia ^† 2	61/959 (6.36%)	64/954 (6.71%)
1 Term from vocabulary, Common Toxicity Crit 2 Term from vocabulary, CTCAE (2.0) † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Senior Biostatistician
Organization:	Canadian Cancer Trials Group
Phone:	6135336430
EMail:	dtu@ctg.queensu.ca

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Layout table for additonal information

Responsible Party:	Canadian Cancer Trials Group
ClinicalTrials.gov Identifier:	NCT00754845
Other Study ID Numbers:	MA17R CAN-NCIC-MA17R ( Registry Identifier: NCI US - Physician Data Query ) CDR0000614819 ( Other Identifier: PDQ )
First Submitted:	September 17, 2008
First Posted:	September 18, 2008
Results First Submitted:	February 23, 2017
Results First Posted:	November 19, 2018
Last Update Posted:	August 25, 2023

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