H. Lee Moffitt Cancer & Research Institute
“Investigation of BRCE”
Rational/Purpose: The current procedure for identifying positive BRCA status includes full sequencing of the BRCA1 and CRCA2 genes, at a cost of approximately $2800. Many women who might benefit from BRCA testing do not pursue it because of the high cost. Another limitation of current resting methodology is that it cannot identify all mutations. We theorize that serum proteomics analyses could identify characteristic protein patterns associated with BRCA1 mutations and with BRCA2 mutations. If so, more complete ascertainment of BRCA mutation status among tested individuals at a much lower cost may be possible. This would facilitate translation of this advanced technology into clinical practice.
Florida Atlantic University
Vijaya Iragavarapu- Charyulu
“N-TIMP-3 as a Selective Agent”
In this proposal, we will test the effects of wild type TIMP-3 and different N-TIMP-3 mutants, mutated at the amino terminus, on different breast cancer cell lines [DA-3 (murine mammary tumor cells), and MCF-7 (Human breast cancer cell line)] in terms of cell growth and viability. We will determine if the treatment of tumor cells with the N-TIMP-3 mutants results in the selective inhibition of either MMPs or TACE.
University of Miami
“Gene Expression Profiling”
Rationale/Purpose: In order to identify molecular patterns that predict responsiveness to specific treatments, we plan to utilize diagnostic biopsies from breast cancer patients that have been obtained prior to initiation of systemic chemotherapy. Genetic profiles obtained from these biopsies can thus be correlated with response to subsequent chemotherapy.
Although chemotherapy has traditionally been administered following upfront surgical resection of the tumor (adjuvant therapy), there has been increasing interest in neoadjuvant chemotherapy for locally advanced breast cancer (therapy delivered prior to surgical resection to reduce tumor size). Neoadjuvant or primary chemotherapy has become increasingly utilized as standard treatment for patients with locally advanced breast cancer. Locally advanced disease standard treatment for patients with large primary breast tumors, inflammatory breast cancer, and/or palpable axillary lymph node involvement but without distant metastatic disease (Stages IIB, III). The higher stages at diagnosis portend an extremely poor prognosis for these patients and the tumors present technical challenges for complete surgical resection. Benefits of this approach include facilitation of complete surgical removal as well as less extensive surgical procedures. Moreover, chemotherapy administration in the presence of palpable tumor allows immediate evaluation of in vivo sensitivity to therapy, allowing the clinician to identify therapies that are successful and to halt those that are ineffective.
Significantly, the magnitude of tumor response correlates well with prognosis: patients who have a complete pathologic response (no evidence of tumor pathologically in the surgically respected specimen) exhibit excellent long-term survival (85-90% survival at 5 years compared with 50-60% with less than a complete response). Thus, the pathologic response to neoadjuvant chemotherapy has clearly been established as a surrogate marker for overall survival. The overall goal of our program is the development of an advanced molecular assay that would specifically select patients for maximum chemo-responsiveness to a specific regimen and identify patients with primary refractory disease who may benefit from alternative therapies earlier in the course of their treatment.