Clinical trial NCT00265759: Exemestane, Letrozole, or Anastrozole in Treating Postmenopausal Women Who Are Undergoing Surgery for Stage II or Stage III Breast Cancer
Official title: A Randomized Phase III Trial Comparing 16 to 18 Weeks of Neoadjuvant Exemestane (25 mg Daily), Letrozole (2.5 mg), or Anastrozole (1 mg) in Postmenopausal Women With Clinical Stage II and III Estrogen Receptor Positive Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
estrogen receptor-positive breast cancer
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Cancer and Leukemia Group B
First posted: 2005-12-15
Enrollment: 622
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using exemestane, letrozole, or anastrozole, may fight breast cancer by lowering the amount of estrogen the body makes. Giving exemestane, letrozole, or anastrozole before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether exemestane, letrozole, or anastrozole is more effective in treating breast cancer.

PURPOSE: This randomized phase III trial is studying exemestane, letrozole, and anastrozole to compare how well they work in treating postmenopausal women who are undergoing surgery for stage II or stage III breast cancer.

Detailed description: OBJECTIVES:

Primary

* Determine whether anastrozole, exemestane, or letrozole administered for 16 to 18 weeks as neoadjuvant endocrine treatment for postmenopausal patients with stage II or stage III estrogen receptor (ER)-positive breast cancer should be chosen as the aromatase inhibitor arm of a future study that will compare neoadjuvant aromatase inhibitor (AI) treatment with neoadjuvant chemotherapy. (Cohort A)
* To determine whether patients who have a high Ki-67 value (\> 10%) after 2 weeks of neoadjuvant AI treatment experience a higher than expected pathological response rate to neoadjuvant chemotherapy (20%) than would be typically observed for postmenopausal patients with unselected ER+ rich tumors (estimated to be 5%), indicating that an early assessment of proliferation is a useful approach to the identification of a chemotherapy sensitive subgroup of ER+ tumors. (Cohort B \[patients enrolled after the 375th patient\])

Secondary

* Compare the neoadjuvant treatment regimens relative to the rates of improvement in surgical outcome for patients considered marginal for Breast Conservation Surgery prior to therapy. (Cohort A)
* Compare the neoadjuvant treatment regimens relative to the rates of improvement in surgical outcome for patients designated as candidates for Mastectomy prior to therapy. (Cohort A)
* Compare the relative safety of the neoadjuvant treatment regimens in terms of reported adverse events. (Cohort A)
* To compare the tumor pathologic size between the neoadjuvant treatment regimens, to compare the rates of pathological complete response. (Cohort A)
* To compare the tumor pathologic size between the neoadjuvant treatment regimens, to compare the rates of down-staging to stage I. (Cohort A)
* Compare the incidence of metastatic lymph node involvement on the three arms of the study in patients who have a lymph node dissection at the end of neoadjuvant treatment. (Cohort A)
* Compare the neoadjuvant treatment regimens relative to clinical response rate. (Cohort B)
* Compare the neoadjuvant treatment regimens relative to progression-free survival. (Cohort A and B)
* Compare the neoadjuvant treatment regimens relative to overall survival. (Cohort A and B)

OUTLINE: This is a multicenter study comprising cohort A (phase III study) and cohort B (phase II study). Once cohort A accrual is met (375 patients), subsequent patients are enrolled to cohort B. Patients in both cohorts are stratified according to T stage (T2 vs T3 vs T4), and randomized to 1 of 3 aromatase inhibition (AI) treatment arms.

* Arm I: Patients receive oral exemestane once daily for 16-18 weeks.
* Arm II: Patients receive oral letrozole once daily for 16-18 weeks.
* Arm III: Patients receive oral anastrozole once daily for 16-18 weeks. Patients in cohort B undergo breast biopsy after 2-4 weeks of AI treatment for analysis of Ki-67 levels. Patients with Ki-67 level ≤ 10% continue AI treatment. Patients with Ki-67 level \> 10% (high) are given the option to switch to neoadjuvant chemotherapy or undergo immediate breast surgery.

After completion of AI therapy, all patients undergo partial or radical mastectomy or lumpectomy with or without lymph node dissection.

After surgery, patients are followed up periodically for 10 years.

PROJECTED ACCRUAL: A total of 610 patients (375 for cohort A and 235 for cohort B) will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of breast cancer

  * T2-T4c, any N, M0 disease
* Clinically staged, as documented by the treating physician, as 1 of the following:

  * T4a-c disease for which modified radical mastectomy with negative margins is the goal
  * T2 or T3 disease for which conversion from needing mastectomy to breast conservation is the goal
  * T2 disease for which lumpectomy at first attempt is the goal
* Primary tumor must be palpable and measure \> 2 cm by tape, ruler, or caliper measurements in at least one dimension
* Must agree to undergo mastectomy or lumpectomy after neoadjuvant aromatase inhibitor therapy
* No inflammatory breast cancer, defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or peau d'orange without erythema)
* No distant metastasis (M1)

  * Isolated ipsilateral supraclavicular node involvement allowed
* No diagnosis that was established by incisional biopsy
* Must have estrogen receptor (ER) positive tumor with an Allred score of 6, 7 or 8

  * Patients with \> 66.66% (two-thirds) of cells staining positive and have a minimum Allred score of 6 are eligible

PATIENT CHARACTERISTICS:

* ECOG/Zubrod performance status of ≤ 2
* Female
* Patient must be postmenopausal, verified by 1 of the following:

  * Bilateral surgical oophorectomy
  * No spontaneous menses ≥ 1 year
  * No menses for \< 1 year with FSH and estradiol levels in postmenopausal range
* No other malignancies within the past 5 years, except for successfully treated cervical carcinoma in situ; lobular carcinoma in situ of the breast; contralateral ductal carcinoma in situ that was treated with mastectomy or lumpectomy with radiotherapy (without tamoxifen); or non-melanoma skin cancer with no evidence of recurrence

  * Must have undergone potentially curative therapy for all prior malignancies AND deemed to be at low risk for recurrence, according to the treating physician

PRIOR CONCURRENT THERAPY:

* No prior treatment for invasive breast cancer, including radiotherapy, endocrine therapy, chemotherapy, or investigational agents
* No prior sentinel lymph node biopsy (cohort B only)
* At least 1 week since prior agents with estrogenic or putatively estrogenic properties, including herbal preparations
* At least 1 week since prior hormone replacement therapy of any type, megestrol acetate, or raloxifene
* No concurrent enrollment in another neoadjuvant clinical trial for treatment of the existing breast cancer
* No other concurrent anti-neoplastic therapy, including chemotherapy or radiotherapy
* No concurrent agents or herbal products that alter ER function

Primary outcomes:
measure: Clinical Response (Complete or Partial Response) Rate (Cohort A)
timeFrame: Up to 18 weeks
measure: Anti-tumor Effect in Terms of Pathologic CR (pCR) Rate to Neoadjuvant Chemotherapy (Cohort B)
timeFrame: Up to 18 weeks
Secondary outcomes:
measure: Toxicity (Cohort A)
timeFrame: Up to 30 days after drug therapy
measure: Disease-free Survival (DFS) (Cohort A and B)
timeFrame: 5 years
measure: Rate of Improved Surgical Outcome for Patients Considered Marginal for Breast Conservation Surgery Prior to Therapy (Cohort A)
timeFrame: At time of surgery up to 18 weeks
measure: Rate of Downstaging to Stage I Determined by Sentinel Node Evaluation (Cohort A)
timeFrame: At time of surgery up to 18 weeks
measure: Rate of Lymph Node Involvement (LNI) (Cohort A)
timeFrame: At time of surgery up to 18 weeks
measure: The Pathologic Complete Response (pCR) Rate (Cohort A)
timeFrame: At time of surgery up to 18 weeks
measure: Clinical Response Rate (Cohort B)
timeFrame: Up to 18 weeks
measure: Rate of Improved Surgical Outcome for Patients Designated as Candidates for Mastectomy Prior to Therapy (Cohort A)
timeFrame: At time of surgery up to 18 weeks
measure: Percentage of Participants With Overall Survival (Cohort A and B)
timeFrame: 5 years
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
state: Missouri
city: Houston
country: United States
facility: M. D. Anderson Cancer Center at University of Texas
state: Texas
city: Laredo
country: United States
facility: Doctor's Hospital of Laredo
state: Texas
Study officials:
affiliation: Washington University Siteman Cancer Center
name: Matthew J. Ellis, MD, PhD, FRCP
role: STUDY_CHAIR
References:
citation: Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol. 2011 Jun 10;29(17):2342-9. doi: 10.1200/JCO.2010.31.6950. Epub 2011 May 9.
citation: Ellis MJ, Suman VJ, Hoog J, Goncalves R, Sanati S, Creighton CJ, DeSchryver K, Crouch E, Brink A, Watson M, Luo J, Tao Y, Barnes M, Dowsett M, Budd GT, Winer E, Silverman P, Esserman L, Carey L, Ma CX, Unzeitig G, Pluard T, Whitworth P, Babiera G, Guenther JM, Dayao Z, Ota D, Leitch M, Olson JA Jr, Allred DC, Hunt K. Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J Clin Oncol. 2017 Apr 1;35(10):1061-1069. doi: 10.1200/JCO.2016.69.4406. Epub 2017 Jan 3.
citation: Punturi NB, Seker S, Devarakonda V, Mazumder A, Kalra R, Chen CH, Li S, Primeau T, Ellis MJ, Kavuri SM, Haricharan S. Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer. Nat Commun. 2021 May 19;12(1):2940. doi: 10.1038/s41467-021-23271-0.