Clinical trial NCT00066573: Exemestane or Anastrozole in Treating Postmenopausal Women Who Have Undergone Surgery for Primary Breast Cancer
Official title: A Randomized Phase III Trial Of Exemestane Versus Anastrozole In Postmenopausal Women With Receptor Positive Primary Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage IIIA breast cancer
stage I breast cancer
stage II breast cancer
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: North Central Cancer Treatment Group
name: Cancer and Leukemia Group B
name: Eastern Cooperative Oncology Group
name: SWOG Cancer Research Network
name: ETOP IBCSG Partners Foundation
First posted: 2003-08-07
Enrollment: 7576
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy, using exemestane or anastrozole, may fight breast cancer by reducing the production of estrogen. It is not yet known whether exemestane is more effective than anastrozole in preventing the recurrence of breast cancer.

PURPOSE: This randomized phase III trial is studying exemestane to see how well it works compared to anastrozole in preventing cancer recurrence in postmenopausal women who have undergone surgery for primary breast cancer.

Detailed description: OBJECTIVES:

Primary

* Compare the event-free survival of postmenopausal women with receptor-positive primary breast cancer when treated with exemestane vs anastrozole.

Secondary

* Compare the overall survival of patients treated with these regimens.
* Compare the time to distant recurrence in patients treated with these regimens.
* Compare the incidence of new primary contralateral breast cancer in patients treated with these regimens.
* Compare the incidence of all clinical fractures, specifically hip and vertebral fractures, in patients treated with these regimens.
* Compare cardiovascular morbidity and mortality (i.e., significant coronary heart disease, which includes myocardial infarctions and angina requiring percutaneous transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal strokes, and all vascular deaths) in patients treated with these regimens.
* Correlate therapy induced changes in breast density with plasma hormones and growth factors, drug levels of exemestane and anastrozole, genetic variation and breast cancer recurrence or contralateral events in patients treated with these regimens.
* Compare the toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to lymph node status at diagnosis (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), and herceptin use (yes vs no). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral exemestane (25 mg) once daily for 5 years.
* Arm II: Patients receive oral anastrozole (1 mg) once daily for 5 years. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 6 months during the first year of study participation and annually thereafter.

PROJECTED ACCRUAL: A total of 6,840 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed invasive breast cancer

  * pT1-3; pNX, pN0-2 or pN3\*; M0
  * Neoadjuvant patients are eligible no earlier than 3 weeks or later than 3 months after excisional surgery, provided both the clinical-diagnostic staging of cancer and postsurgical resection-pathologic staging of cancer meet the requirements for primary tumor, regional lymph nodes, and distant metastasis classification NOTE: \*Only when the sole basis for this classification is the presence of 10 or more involved axillary lymph nodes
* Completely resected disease

  * Primary surgery performed at least 3 weeks but no more than 3 months before study entry (if no chemotherapy was given)

    * Primary surgery is defined as the last surgery at which histologic evidence of invasive or in situ disease was present in the pathology specimen
  * Patients with positive sentinel lymph node biopsy are eligible provided they have had a subsequent axillary lymph node dissection
* No metachronous breast cancer
* Bilateral mammogram within the past 12 months unless initial surgery was a total mastectomy, in which case only a mammogram of the remaining breast is required
* No metastases confirmed by 1 of the following methods:

  * Bone scan\* (required only if alkaline phosphatase is at least 2 times normal and/or there are symptoms of metastatic disease)
  * Abdominal ultrasound or CT scan (required only if AST/ALT or alkaline phosphatase is at least 2 times normal, unless the elevation is in the bone fraction)
  * Chest x-ray NOTE: \*Confirmatory x-ray, CT scan, or MRI required if the bone scan results are questionable
* No locally recurrent disease
* No prior or concurrent carcinoma in situ of the contralateral breast treated with partial mastectomy and/or hormonal therapy

  * Patients with prior or concurrent carcinoma in situ of the ipsilateral breast are eligible provided the tumor was completely excised AND they have not received prior hormonal therapy
* Hormone receptor status:

  * Estrogen receptor- and/or progesterone receptor-positive by immunohistochemistry or tumor receptor content ≥ 10 fmol/mg protein

PATIENT CHARACTERISTICS:

Age

* Postmenopausal

Sex

* Female

Menopausal status

* Postmenopausal prior to chemotherapy, defined as 1 of the following:

  * Over 60 years of age
  * Age 45-59 with spontaneous cessation of menses for more than 1 year prior to study entry
  * Age 45-59 with menses ceasing (secondary to hysterectomy or spontaneously) within the past year AND a follicle-stimulating hormone (FSH) level prior to study entry in the postmenopausal range\*
  * Age 45-59, previously on hormone replacement therapy (HRT) and have discontinued HRT upon diagnosis of this malignancy AND has an FSH level prior to study entry in the postmenopausal range\*
  * Has undergone bilateral oophorectomy NOTE: \*By institutional standards OR \> 34.4 IU/L if institutional range is not available)

Performance status

* ECOG 0-2

Life expectancy

* At least 5 years

Hematopoietic

* WBC at least 3,000/mm\^3 OR
* Granulocyte count at least 1,500/mm\^3 AND
* Platelet count at least 100,000/mm\^3

Hepatic

* See Disease Characteristics
* AST and/or ALT less than 2 times upper limit of normal (ULN)\*
* Alkaline phosphatase less than 2 times ULN\* NOTE: \*Unless imaging examinations have ruled out metastatic disease

Renal

* Not specified

Other

* Able to swallow study medication and have adequate unassisted oral intake in order to maintain reasonable nutrition status
* No other non-breast malignancy within the past 5 years except adequately treated nonmelanoma skin cancer, curatively treated carcinoma in situ of the cervix, or other curatively treated solid tumors with no evidence of disease for at least 5 years
* No other concurrent medical or psychiatric condition that would preclude study participation and/or interfere with results

PRIOR CONCURRENT THERAPY:

Biologic therapy

* Prior and concurrent trastuzumab (Herceptin®) allowed

Chemotherapy

* See Disease Characteristics
* At least 3 weeks but no more than 3 months since prior chemotherapy
* Prior adjuvant chemotherapy allowed

Endocrine therapy

* See Disease Characteristics
* No prior aromatase inhibitor
* No prior tamoxifen or other selective estrogen receptor modulators (SERMs) except raloxifene

  * At least 3 weeks since prior raloxifene
* At least 3 weeks since prior and no concurrent over-the-counter products or supplements considered to have an estrogenic effect, including any of the following:

  * Ginseng
  * Ginkgo biloba
  * Black cohosh
  * Dong quai
  * Fortified soy supplements (e.g., phytoestrogen preparations)
* At least 3 weeks since other prior hormonal therapy or steroids considered to have an estrogenic effect
* No concurrent estrogens, progesterones, androgens, or SERMs

  * Concurrent intermittent vaginal estrogens (e.g., vagifem, estrogen vaginal cream, testosterone, estradiol vaginal gel, or Estring) allowed if other local measures for intractable vaginal atrophy are insufficient
* No other concurrent therapy that would have an estrogenic effect, including endocrine therapy, hormonal therapy, or steroid therapy

Radiotherapy

* See Disease Characteristics
* Prior adjuvant radiotherapy allowed
* Concurrent radiotherapy allowed

Surgery

* See Disease Characteristics

Primary outcomes:
measure: Event-free Survival
timeFrame: 5 years
Secondary outcomes:
measure: Overall Survival: Percentage of Participants Alive at 5 Years
timeFrame: 5 years
measure: Distant Disease-free Survival: Number of Participants Without Documented Distant Recurrence
timeFrame: 5 years
measure: Clinical Fracture Rate: Number of Participants With Bone Fractures.
timeFrame: 8 years
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Lethbridge
country: Canada
facility: Lethbridge Cancer Centre
state: Alberta
city: Kelowna
country: Canada
facility: BCCA - Cancer Centre for the Southern Interior
state: British Columbia
city: Penticton
country: Canada
facility: Penticton Regional Hospital
state: British Columbia
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Victoria
country: Canada
facility: BCCA - Vancouver Island Cancer Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Moncton
country: Canada
facility: The Moncton Hospital
state: New Brunswick
city: Moncton
country: Canada
facility: The Vitalite Health Network - Dr. Leon Richard
state: New Brunswick
city: Saint John
country: Canada
facility: Atlantic Health Sciences Corporation
state: New Brunswick
city: St. John's
country: Canada
facility: Dr. H. Bliss Murphy Cancer Centre
state: Newfoundland and Labrador
city: Belleville
country: Canada
facility: Quinte Healthcare Corporation
state: Ontario
city: Cambridge
country: Canada
facility: Cambridge Memorial Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston
state: Ontario
city: Kitchener
country: Canada
facility: Grand River Regional Cancer Centre
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Mississauga
country: Canada
facility: Credit Valley Hospital
state: Ontario
city: Newmarket
country: Canada
facility: Stronach Regional Health Centre at Southlake
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
state: Ontario
city: Sudbury
country: Canada
facility: Regional Cancer Program of the Hopital Regional
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: Univ. Health Network-Princess Margaret Hospital
state: Ontario
city: Toronto
country: Canada
facility: Trillium Health Centre - West Toronto
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Cancer Centre
state: Ontario
city: Charlottetown
country: Canada
facility: PEI Cancer Treatment Centre,Queen Elizabeth Hospital
state: Prince Edward Island
city: Gatineau
country: Canada
facility: Centre de Sante et de services sociaux de Gatineau
state: Quebec
city: Greenfield Park
country: Canada
facility: Hopital Charles LeMoyne
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Hopital Notre-Dame
state: Quebec
city: Quebec City
country: Canada
facility: CHA-Hopital Du St-Sacrement
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre hospitalier universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
Study officials:
affiliation: Massachusetts General Hospital
name: Paul E. Goss, MD, PhD
role: STUDY_CHAIR
affiliation: Mayo Clinic
name: James N. Ingle, MD
role: STUDY_CHAIR
affiliation: Washington University Siteman Cancer Center
name: Matthew J. Ellis, MD, PhD, FRCP
role: STUDY_CHAIR
affiliation: Indiana University Melvin and Bren Simon Cancer Center
name: George W. Sledge, MD
role: STUDY_CHAIR
affiliation: The Cleveland Clinic
name: George T. Budd, MD
role: STUDY_CHAIR
affiliation: Insel Gruppe AG, University Hospital Bern
name: Manuela Rabaglio, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Moy B, Elliott CR, Chapman J-AW, et al.: NCIC CTG MA.27: menopausal symptoms of ethnic minority women. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-3059, S144, 2006.
citation: Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. doi: 10.1200/JCO.2012.44.7805. Epub 2013 Jan 28.
citation: 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.
citation: Strasser-Weippl K, Higgins MJ, Chapman JW, Ingle JN, Sledge GW, Budd GT, Ellis MJ, Pritchard KI, Clemons MJ, Badovinac-Crnjevic T, Han L, Gelmon KA, Rabaglio M, Elliott C, Shepherd LE, Goss PE. Effects of Celecoxib and Low-dose Aspirin on Outcomes in Adjuvant Aromatase Inhibitor-Treated Patients: CCTG MA.27. J Natl Cancer Inst. 2018 Sep 1;110(9):1003-1008. doi: 10.1093/jnci/djy017.
citation: Strasser-Weippl K, Sudan G, Ramjeesingh R, Shepherd LE, O'Shaughnessy J, Parulekar WR, Liedke PER, Chen BE, Goss PE. Outcomes in women with invasive ductal or invasive lobular early stage breast cancer treated with anastrozole or exemestane in CCTG (NCIC CTG) MA.27. Eur J Cancer. 2018 Feb;90:19-25. doi: 10.1016/j.ejca.2017.11.014. Epub 2017 Dec 20.
citation: Yerushalmi R, Dong B, Chapman JW, Goss PE, Pollak MN, Burnell MJ, Levine MN, Bramwell VHC, Pritchard KI, Whelan TJ, Ingle JN, Shepherd LE, Parulekar WR, Han L, Ding K, Gelmon KA. Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials. Ann Oncol. 2017 Jul 1;28(7):1560-1568. doi: 10.1093/annonc/mdx152.
citation: Stearns V, Chapman JA, Ma CX, Ellis MJ, Ingle JN, Pritchard KI, Budd GT, Rabaglio M, Sledge GW, Le Maitre A, Kundapur J, Liedke PE, Shepherd LE, Goss PE. Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial. J Clin Oncol. 2015 Jan 20;33(3):265-71. doi: 10.1200/JCO.2014.57.6926. Epub 2014 Dec 15.
citation: Goetz MP, Schaid DJ, Wickerham DL, Safgren S, Mushiroda T, Kubo M, Batzler A, Costantino JP, Vogel VG, Paik S, Carlson EE, Flockhart DA, Wolmark N, Nakamura Y, Weinshilboum RM, Ingle JN, Ames MM. Evaluation of CYP2D6 and efficacy of tamoxifen and raloxifene in women treated for breast cancer chemoprevention: results from the NSABP P1 and P2 clinical trials. Clin Cancer Res. 2011 Nov 1;17(21):6944-51. doi: 10.1158/1078-0432.CCR-11-0860. Epub 2011 Aug 31.