PhII Neo-Adjuvant Letrozole & Lapatinib in Pts w/HER2+ & Hormone Receptor+ Operable Breast CA SPORE

• 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)
• Pathological complete response (Part 2)

• 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)
• 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)
• Safety profile of neoadjuvant letrozole and lapatinib (Part 2)
• Tumor response to treatment as measured by ultrasound (Part 2)
• Rate of breast conservation surgery (Part 2)
• 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)

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.

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.

• Drug: lapatinib ditosylate
  Given once daily, 1500mg, for 2 weeks; Given once daily, 1500mg, for 14 weeks in Arm II
  Other Name: GW572016
• Drug: letrozole
  Given once daily, 2.5mg, for 2 weeks; Given once daily, 2.5mg, for 14 weeks
  Other Name: Femara
• Other: placebo
  Given once daily for 2 weeks
  Other Name: placebo

• Experimental: Arm I
  Patients receive Lapatinib and Letrozole once daily for two weeks, following tumor measurement patients receive Lapatinib and Letrozole once daily for 14 weeks.
  Interventions:

  • Drug: lapatinib ditosylate
  • Drug: letrozole
• Experimental: Arm II
  Patients receive Letrozole and placebo once daily for 2 weeks, following tumor measurement patients receive Letrozole and Lapatinib once daily for 14 weeks.
  Interventions:

  • Drug: lapatinib ditosylate
  • Drug: letrozole
  • Other: placebo

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)

Exclusion Criteria:

• 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 Criteria:

• 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