Clinical trial NCT00963729: Chemotherapy or Letrozole Before Surgery in Treating Postmenopausal Women With Breast Cancer That Can Be Removed By Surgery
Official title: A Neoadjuvant Study of Chemotherapy Versus Endocrine Therapy in Postmenopausal Patients With Primary Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: estrogen receptor-positive breast cancer
recurrent breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2009-08-21
Enrollment: 756
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by reducing the production of estrogen. It is not yet known whether giving more than one drug (combination chemotherapy) or giving letrozole before surgery is more effective in treating women with breast cancer.

PURPOSE: This randomized phase III trial is studying giving combination chemotherapy before surgery to see how well it works compared with letrozole given before surgery in treating postmenopausal women with breast cancer that can be removed by surgery.

Detailed description: OBJECTIVES:

* To compare the efficacy and tolerability of cytotoxic chemotherapy versus aromatase inhibition for the down-staging of strongly ER+ primary breast cancer in postmenopausal women.
* To identify biological predictors of response to these two treatment modalities.

OUTLINE: This is a multicenter pilot, feasibility study followed by a randomized study. In the pilot study, a record of all patients screened and invited to participate in the study is compiled. Reasons for failure to recruit will be recorded. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive fluorouracil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients who do not achieve at least partial response after 3 courses receive docetaxel IV on day 1 of 3-week courses for an additional 3 courses.
* Arm II: Patients receive oral letrozole daily for 18-23 weeks until day of surgery.

Patients in both arms undergo surgery at week 18-23. Most patients then receive adjuvant therapy.

Quality of life is assessed at baseline, periodically during study treatment, and then during follow up.

Blood is collected pre-treatment, at mid-treatment, and before surgery. Blood is then collected every 6 months for 2 years. Blood samples and preserved tumor samples are used for correlative studies.

After completion of surgery, patients are followed up at least annually for 10 years.

PROJECTED ACCRUAL: A total of 40 patients for the pilot study and 716 patients for the phase III study will be accrued.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically proven primary invasive breast cancer that is thought to be suitable for neoadjuvant treatment

  * No cytological proof of malignancy only
  * T2 tumor or greater (≥ 20 mm by ultrasound) or any T stage with nodal disease ≥ 20 mm diameter on ultrasound assessment
  * No evidence of distant metastatic disease as disclosed by bone scan, liver, and chest imaging
* Definite indication for neoadjuvant and adjuvant chemotherapy
* Primary tumor amenable to biopsy
* No inoperable disease that is judged very unlikely to be rendered operable by neoadjuvant treatment
* No inflammatory breast cancer
* No bilateral invasive breast cancer
* HER-2 positivity is NOT an exclusion criterion in the feasibility (pilot) study
* Estrogen receptor (ER) positive tumor

  * No ER-poor disease as defined locally (e.g., H-score \< 100, Allred 3/4/5)
  * Allred 6/7/8, H-score H ≥100 allowed

PATIENT CHARACTERISTICS:

* Postmenopausal, meeting 1 of the following criteria:

  * Over 12 months since last menstrual period
  * Postmenopausal gonadotrophin levels (luteinizing hormone or follicle-stimulating hormone levels above local criteria)
  * Postmenopausal estradiol levels below local criteria
  * Prior bilateral oophorectomy
  * Menopause induced by gonadotrophin-releasing hormone not allowed
* WHO performance status 0 or 1
* WBC ≥ 3.0 × 10\^9/L
* ANC ≥ 1.5 × 10\^9/L
* Platelets ≥ 100 × 10\^9/L
* Hemoglobin \> 9 g/dL
* AST/ALT ≤ 1.5 times upper limit of normal (ULN)
* Serum bilirubin ≤ 1.5 times ULN
* Alkaline phosphatase ≤ 1.5 times ULN
* Serum creatinine ≤ 1.5 times ULN
* No active, uncontrolled infection
* No malignancy within the past 10 years except for basal cell carcinoma or cervical carcinoma in situ

  * Treatment for previous malignancy confined to resection alone
* No concomitant medical, psychiatric, or geographic problems that might prevent completion of treatment or follow-up
* No known severe hypersensitivity to aromatase inhibitors
* No contraindication to receiving aromatase inhibitors (clinical evidence or recorded history of osteoporosis)
* No other serious illness or medical condition including any of the following:

  * Congestive heart failure or unstable angina pectoris
  * Myocardial infarction within the past year
  * Uncontrolled hypertension or high-risk uncontrolled arrhythmias
  * History of significant neurologic or psychiatric disorders, including psychotic disorders, dementia, or seizures, that would prohibit the understanding and giving of informed consent
  * Active peptic ulcer
  * Unstable diabetes mellitus
* No definite contraindications for the use of corticosteroids
* No contraindication to receiving combination anthracycline/taxane chemotherapy
* Willing to undergo repeat biopsies

PRIOR CONCURRENT THERAPY:

* No hormone replacement therapy within 4 weeks of starting treatment
* No chronic oral treatment with corticosteroids unless initiated \> 6 months prior to study entry and at low dose (≤ 20 mg methylprednisolone or equivalent)
* No concurrent warfarin or heparin therapy

Primary outcomes:
measure: Feasibility of patient recruitment (pilot)
measure: Feasibility of tissue collection (pilot)
measure: Ultrasound (or mammogram) response rate
Secondary outcomes:
measure: Clinical response rate
measure: Radiologic response rate by ultrasound (pilot)
measure: Quality of life
measure: Pathological complete response rate (pCR) defined as no residual invasive or pre-invasive carcinoma in breast or axilla (pilot)
measure: Plasma DNA changes in relation to treatment response
measure: Rate of conservation surgery
measure: Degree of pathological response
measure: Ki-67 changes and its relationship to treatment response
measure: Length of time to maximum response within the treatment period
measure: Tolerability of the various treatments
measure: Disease-free survival
measure: Overall survival
measure: MRI response
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center - University of Ulsan College of Medicine
city: Isleworth
country: United Kingdom
facility: West Middlesex University Hospital
state: England
city: London
country: United Kingdom
facility: Guy's Hospital
state: England
city: London
country: United Kingdom
facility: St. Mary's Hospital
state: England
city: London
country: United Kingdom
facility: Charing Cross Hospital
state: England
Study officials:
affiliation: Charing Cross Hospital
name: R. Charles Coombes, MD, MRCP, FRCP, PhD, FMedSci
role: STUDY_CHAIR
References: