CORRELATION OF MARKER WITH RESPONSE TO CHEMOTHERAPY

University Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): The two most effective classes of chemotherapeutic drugs in breast cancer are the anthracyclines and the taxanes. These drugs differ in mechanisms of action and mechanisms of resistance. Recent studies suggest that anthracycline sensitivity is strongly affected by tumor cell growth and proliferation, and specifically that the receptor tyrosine kinase HER-2 has an effect on response to anthracyclines. In contrast, taxanes appear to cause tumor cell death largely through apoptosis, and the ability of the cell to avoid apoptosis may mediate response to this class of drug. In preclinical and clinical studies, the HER-2 -targeting biologic agent trastuzumab synergistically augments taxane-induced cell killing, and this drug is now commonly added to taxanes in advanced breast cancer. In this prospective cohort of 120 breast cancer patients who will receive neoadjuvant anthracycline-based and taxane-based chemotherapy, tumor samples will be obtained specifically for research purposes at three time points: 1) prior to any chemotherapy, 2) following treatment with an anthracycline-containing regimen but before beginning a taxane-containing regimen (with or without trastuzumab), and 3) after all chemotherapy. These samples will be analyzed for several well characterized predictive markers for responsiveness to the two regimens (anthracycline-based, taxane-based) and will also be analyzed using cDNA microarray analysis to determine the molecular profiles of the tumors before and after each form of treatment. The aims of the study are: Specific Aim 1: To collect serial samples from primary breast cancers prior to, during and after conclusion of neoadjuvant chemotherapy with an anthracycline followed by a taxane with or without trastuzumab; Specific Aim 2: To obtain pre- and post-chemotherapy axillary lymph node tissue to allow correlation of lymph node markers with primary tumor and with chemoresponsiveness; Specific Aim 3: To evaluate predictive markers of anthracycline or taxane chemotherapy response, focusing on two biologic axes: genetic stability/proliferation and survival signals/apoptosis; Specific Aim 4: To determine the gene expression profiles of the tumor samples collected in Specific Aim 1 (see Project 6); Specific Aim 5: To develop and validate promising new predictive markers that use DNA or RNA isolated from frozen specimens or formalin-fixed, paraffin-embedded samples including the analysis of anti-apoptotic molecule NF-kB and related and regulated molecules (see Project 7); Specific Aim 6: To expand this study in a proposed InterSPORE collaboration with four other institutions. This InterSPORE collaboration will be submitted separately as a supplemental grant. The design of this study is novel in the ability to measure responsiveness in primary breast cancer tissue and possibly in involved lymph nodes in the same patient during different regimens. The profiling of tumor markers and gene expression before and after specific noncross-resistant drugs will allow us to identify markers and patterns for targeting of specific forms of therapy to those patients likely to most benefit.