Prediction of Resistance and Sensitivity to HER2 Targeted Therapy in the Neoadjuvant Setting

Women with breast cancers that overexpress HER2 are at greater risk for disease progression and death than women whose tumors do not overexpress HER2. Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular domain of the HER2 protein blocks downstream signaling of HER2 and substantially improves the efficacy of chemotherapy in women with metastatic and early-stage HER2-positive breast cancers. Because resistance to trastuzumab eventually results in progressive disease in the metastatic setting and contributes to recurrence following adjuvant trastuzumab-based therapy, it is important to develop agents other than trastuzumab that target HER2 signaling through different mechanisms of action. Lapatinib is an oral, small molecule, dual tyrosine kinase inhibitor of HER2 and EGFR. Lapatinib has shown a lack of cross-resistance with trastuzumab in preclinical studies and activity in women with HER2-positive, metastatic breast cancer that has progressed during trastuzumab treatment. Trastuzumab blocks the downstream signaling of HER2 by binding to the extracellular domain of the receptor. Lapatinib binds to the intracellular domains of HER2 and EGFR and prevents activation of downstream signaling pathways. Because of this different mechanism of action, lapatinib may be effective in trastuzumab-resistant disease. The study will also provide important safety information on trastuzumab and lapatinib combinations immediately following anthracycline exposure, and also provide an initial direct comparison of cardiac effects of trastuzumab and lapatinib when incorporated into a standard sequential adriamycin and cyclophosphamide (AC) followed by weekly paclitaxel neoadjuvant regimen. Availability of a second agent that can interrupt HER2-signaling pathways through completely different mechanisms than those of trastuzumab offers the potential for further improvement in the management of patients with HER2-overexpressing breast cancer in both the adjuvant and metastatic setting. Co-administration of both trastuzumab and lapatinib with chemotherapy may be important in improving outcomes in subsets of HER2-positive breast cancers. However, use of two inhibitors of the HER2 pathway will increase costs and may increase toxicity, so it will be important to identify the subsets of patients who would benefit from the dual therapy. Inhibition of HER2 with a single agent clearly is sufficient for many patients as evidenced by the results of the trastuzumab trials. Therefore, co-administration to unselected populations of women with HER2-positive breast cancers would not represent an optimal approach. Given the activity of lapatinib, it is likely that it will also be sufficiently active in inhibiting HER2-pathway activation in some patients to allow for its use as the sole inhibitor of the HER2 pathway. Different populations may also derive greater benefit from one of the HER2-blocking agents relative to the other. Identification of potential predictive factors for pathologic complete response to the combination or to either agent administered alone in neoadjuvant trials would provide important information for adjuvant trials designed to definitively address these important issues. This study will compare 3 combined chemotherapy regimens: AC followed by paclitaxel plus trastuzumab and lapatinib, AC followed by paclitaxel plus lapatinib, and AC followed by paclitaxel plus trastuzumab given before surgery to patients with HER2-positive breast cancer.Tumor samples were collected prior to and post-treatment, and RNA sequencing was performed with this version. ]]>
Inclusion Criteria:Female 18 years or older ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1 Primary breast tumor palpable and measures greater than or equal to 2.0 cm by physical exam Diagnosis of invasive adenocarcinoma made by core needle biopsy Breast cancer determined to be HER2-positive LVEF (Left Ventricular Ejection Fraction) assessment by MUGA (Multi-gated Acquisition) scan or ECG (Electrocardiogram) within 3 months prior to randomization Blood counts must meet the following criteria: ANC (Absolute Neutrophil Count) greater than or equal to 1200/mm3 Platelet count greater than or equal to 100,000/mm3 Hemoglobin greater than or equal to 10 g/dL Serum creatinine less than or equal to upper limit of normal (ULN) for the lab Adequate hepatic function by these criteria: Total bilirubin less than or equal to the ULN for the lab unless the patient has a bilirubin elevation greater than ULN to 1.5 x ULN resulting from Gilbert's disease or similar syndrome due to slow conjugation of bilirubin; and Alkaline phosphatase less than or equal to 2.5 x ULN; and Aspartate transaminase (AST) less than or equal to 1.5 x ULN for the lab. If skeletal pain present or alkaline phosphatase greater than ULN, but less than or equal to 2.5 x ULN, bone scan or positron emission tomography (PET) scan must not demonstrate metastatic disease If AST or alkaline phosphatase greater than ULN, liver imaging [Computed tomography (CT),Magnetic resonance imaging (MRI) or PET scan] must not demonstrate definitive metastatic disease and the requirements in criterion for hepatic function must be met Able to swallow oral medications ]]>