Mutational Biomonitoring of Breast Cancer Chemotherapy Patients Reveals Dichotomy in Bone Marrow Response

Objective. This study was conducted to determine whether there was significant variability in the bone marrow response to standard breast cancer chemotherapy regimen. Background. Cancer is the paradigm for late-onset diseases occurring through a combination of genetic susceptibility and environmental exposure. Traditional firstline cancer chemotherapy is based on genotoxicity; that is, agents that kill cancer cells by damaging their DNA, inducing apoptosis. Variability in response might therefore be due to differences in metabolism of the genotoxic agents or differences in repairing induced DNA damage, which might also affect tumor response. Chemotherapy dose is limited by its effects on normal cell-types, particularly the hematopoietic progenitor cells of the bone marrow, so bone marrow response may also be associated with treatment toxicity and tolerance. Methods. We have developed a fast, simple and inexpensive method of detecting and quantifying bone marrow somatic mutation. The GPA assay enumerates allele loss phenotypes in circulating erythrocytes that arise through somatic mutation in the bone marrow. Results. We applied the GPA assay to 24 breast cancer patients undergoing five types of genotoxic chemotherapy. We found great (20-200 fold) variation in induced mutation between these patients, fully half of whom showed low to no response to their firstline chemotherapy. We are investigating whether our quantitative measure of bone marrow response is associated with clinical parameters of acute toxicity, treatment efficacy and secondary carcinogenesis. Conclusion. Biomonitoring induced bone marrow mutation, if predictive of clinical efficacy, offers the possibility of individually adjusting dose and drug during cancer treatment for optimal effect. Grants. This study was partially funded by a grant from the Pennsylvania Department of Health.