• Inhibition in cell proliferation in situ in response to letrozole with or without lapatinib as measured by the change in percentage of Ki67-positive tumor cells (Part 1) [ Designated as safety issue: No ]
  
• Pathological complete response (Part 2) [ Designated as safety issue: No ]
  

• 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) [ Designated as safety issue: No ]
  
• Identification of predictive surrogate biomarkers (EGFR, P-EGFR, Ser118 P-ERα, P-Akt, P-MAPK) in tumors that are particularly susceptible to letrozole and lapatinib (Parts 1 and 2) [ Designated as safety issue: No ]
  
• Safety profile of neoadjuvant letrozole and lapatinib (Part 2) [ Designated as safety issue: Yes ]
  
• Tumor response to treatment as measured by ultrasound (Part 2) [ Designated as safety issue: No ]
  
• Rate of breast conservation surgery (Part 2) [ Designated as safety issue: No ]
  
• Inhibition in cell proliferation in situ in response to letrozole and lapatinib as measured by the change in percentage of Ki67-positive tumor cells (Part 2) [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• To determine the inhibition in cell proliferation in situ in response to letrozole with or without 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 core biopsies). (Part 1)
• To determine the pathological complete response in patients with HER2-positive and hormone receptor-positive operable stage I-III breast cancer. (Part 2)

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 1 of 2 treatment arms.

  • Arm I: Patients receive lapatinib and letrozole once daily for 2 weeks.
  • Arm II: Patients receive letrozole and placebo once daily for 2 weeks. Patients in both arms 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.

DISEASE CHARACTERISTICS:

Inclusion

• 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

• Locally recurrent breast cancer
• Evidence of distant metastatic disease (i.e., lung, liver, bone, or brain metastases)

PATIENT CHARACTERISTICS:

Inclusion

• 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)

Exclusion

• Premenopausal breast cancer, pregnant, or lactating
• Serious medical illness, that in the judgment of the treating physician, places the patient at high risk of operative mortality
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel
• Ulcerative colitis

• History of other malignancy

  • Patients who have been disease-free for 5 years, or patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinomas are eligible
• Active or uncontrolled infection
• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent
• Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure

PRIOR CONCURRENT THERAPY:

Exclusion

• Prior chemotherapy for primary breast cancer
• Tamoxifen or raloxifene as a preventive agent within the past 21 days
• Hormone replacement therapy (e.g., conjugated estrogens tablets [Premarin]) within the past month
• Prior therapy with anthracyclines
• Investigational drug within the past 30 days or 5 half-lives, whichever is longer
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, or any other biologic therapy) other than letrozole
• Concurrent treatment with an investigational agent