Breast Cancer
Conditions
Keywords
stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer
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. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving letrozole together with lapatinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This randomized phase II trial is studying how well giving letrozole together with lapatinib works in treating postmenopausal women with stage I, stage II, or stage III breast cancer that can be removed by surgery.
Detailed description
OBJECTIVES: Primary * To determine the pathological complete response in patients with HER2-positive and hormone receptor-positive operable stage I-III breast cancer. Secondary * To determine tumor cell apoptosis in situ as measured by TUNEL analysis of tumor sections from fresh frozen or paraffin-embedded core biopsies. (Parts 1 and 2) * To determine whether EGFR, P-EGFR, P-HER2, Ser118 P-ERα, P-Akt, and P-MAPK (by IHC using fresh frozen or paraffin-embedded core biopsies) predict the inhibition of proliferation in situ (Ki67) and/or induction of cell death (TUNEL). (Parts 1 and 2) * To determine the safety profile of neoadjuvant letrozole and lapatinib. (Part 2) * To evaluate tumor response to treatment as measured by ultrasound. (Part 2) * To evaluate the rate of breast conservation surgery. (Part 2) * To determine the inhibition in cell proliferation in situ in response to letrozole and lapatinib as measured by the change in percentage of Ki67-positive tumor cells (determined by IHC using tumor sections from fresh frozen or paraffin-embedded surgical material). (Part 2) OUTLINE: This is a randomized, double-blind, placebo-controlled, two-part study. * Part 1: Patients are randomized to treatment arm. * Patients receive lapatinib and letrozole once daily for 2 weeks. * Patients receive letrozole and placebo once daily for 2 weeks. Patients then proceed to part 2. * Part 2: All patients receive lapatinib and letrozole once daily for 14 weeks. Patients then undergo surgical resection of disease. Patients undergo tissue sample collection at baseline, at 2 weeks, and then at the time of surgery for biomarker and laboratory studies. Samples are analyzed by IHC and TUNEL.
Interventions
DRUGlapatinib ditosylate
Given once daily, 1500mg, for 2 weeks; Given once daily, 1500mg, for 14 weeks in Arm II
DRUGletrozole
Given once daily, 2.5mg, for 2 weeks; Given once daily, 2.5mg, for 14 weeks
OTHERplacebo
Given once daily for 2 weeks
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: Inclusion Criteria: * Clinical stage I, II, or III operable invasive mammary carcinoma, confirmed by histological analysis * Measurable residual tumor at the primary site * Measurable disease is defined as any mass that can be reproducibly measured by physical examination, mammogram, and/or ultrasound and can be accurately measured in at least one dimension (longest diameter to be recorded) as 10 mm (1 cm) * Available core biopsies from the time of diagnosis * May include sections of paraffin-embedded material * Scheduled to undergo surgical treatment with either segmental resection or total mastectomy * Prior history of contralateral breast cancer allowed if patient has no evidence of recurrence of their initial primary breast cancer within the last 5 years * HER2-positive by Herceptest (3+) or FISH * ER-positive and/or PR-positive by IHC
Exclusion criteria
* Locally recurrent breast cancer * Evidence of distant metastatic disease (i.e., lung, liver, bone, or brain metastases) PATIENT CHARACTERISTICS: Inclusion Criteria: * Female * Postmenopausal, as defined by any of the following: * At least 55 years of age * Under 55 years of age and amenorrheic for at least 12 months OR follicle-stimulating hormone (FSH) values ≥ 40 IU/L and estradiol levels ≤ 20 IU/L * Prior bilateral oophorectomy or prior radiation castration with amenorrhea for at least 6 months * ECOG performance status 0-1 * ANC ≥ 1,000/mm³ * Platelet count ≥ 100,000/mm³ * Creatinine ≤ 1.5 times upper limit of normal (ULN) * Bilirubin ≤ 1.5 times ULN * AST and ALT ≤ 1.5 times ULN * Able to swallow and retain oral medication * Cardiac ejection fraction normal by echocardiogram (or MUGA scan if an echocardiogram cannot be performed or is inconclusive)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Pathological Complete Response | at 14 weeks | Progressive disease (PD): \>=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): \>=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. |
Countries
United States
Participant flow
Recruitment details
This study was open from 07/12/2007 through 12/09/2010.
Pre-assignment details
This is a two-part study. Part I consists of two arms: investigational drug plus Letrozole or placebo and Letrozole. Part II is Letrozole plus Lapatinib. Six patients signed consent. Two patients had toxicity or relapse, thus withdrew from the study.
Participants by arm
| Arm | Count |
|---|---|
| Lapatinib + Letrozole, Then Lapatinib + Letrozole Part I: Some participants received Lapatinib 1500mg + Letrozole 2.5mg once daily (QD) for 2 weeks. Participants then underwent ultrasound imaging for tumor measurement, a core biopsy for molecular markers, and an optional FDG-PET/CT scan. Part II, participants received Lapatinib 1500mg + Letrozole 2.5mg QD for 14 weeks. | 4 |
| Placebo + Letrozole, Then Lapatinib + Letrozole Part I: some participants received Placebo + Letrozole 2.5mg once daily (QD) for 2 weeks. Participants then underwent ultrasound imaging for tumor measurement, a core biopsy for molecular markers, and an optional. FDG-PET/CT scan. Part II: participants received Lapatinib 1500mg + Letrozole 2.5mg QD for 14 weeks | 2 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | disease progression | 0 | 1 |
| Overall Study | toxicity | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo + Letrozole, Then Lapatinib + Letrozole | Lapatinib + Letrozole, Then Lapatinib + Letrozole | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 3 Participants | 3 Participants |
| Age Continuous | 74 years STANDARD_DEVIATION 1 | 56.5 years STANDARD_DEVIATION 1 | 62 years STANDARD_DEVIATION 1 |
| Region of Enrollment United States | 2 participants | 4 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 2 / 2 |
| serious Total, serious adverse events | 0 / 4 | 1 / 2 |
Outcome results
Primary
Number of Participants With a Pathological Complete Response
Progressive disease (PD): \>=20% increase in sum of longest diameter (LD) of target lesion(s), taking as reference smallest sum LD recorded since treatment started. Complete response (CR): disappearance of all target lesions. Partial response (PR): \>=30% decrease in sum of LD of target lesion(s), taking as reference baseline sum LD. Stable disease (SD): neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD.
Time frame: at 14 weeks
Population: Participants who were available for measurement of response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part I and Part II Letrozole Plus Laptinab | Number of Participants With a Pathological Complete Response | 1 participants |
| Part 1: Letrozole Plus Placebo Part II Letrozole Plus Laptinab | Number of Participants With a Pathological Complete Response | 0 participants |