Abstract
Chemotherapy can alter the makeup of a tumor cell population by exerting selection pressure. We examined the change in Shannon index, a mathematical diversity measure used in ecology, for c-MYC copy number variation (CNV) after neoadjuvant chemotherapy and evaluated its clinical significance in breast cancer. Associations between Shannon indices for c-MYC CNV in pre- and post-neoadjuvant chemotherapy breast cancer samples and clinicopathologic features of tumors as well as patient survival were analyzed in 144 patients. A change in c-MYC amplification and copy number gain status was found in 14.3% and 33.6% with most cases showing positive to negative conversion. The chemo-sensitive group showed a significant decrease in Shannon index after neoadjuvant chemotherapy. However, there was no difference in diversity indices between pre- and post-neoadjuvant chemotherapy specimens in the chemo-resistant group. In survival analyses, high Shannon indices for c-MYC CNV in post-neoadjuvant chemotherapy samples as well as those in pre-neoadjuvant chemotherapy samples were revealed as independent prognostic factors for poor disease-free survival not only in the whole group but also in the chemo-resistant subgroup. These findings suggest that a change in Shannon index for c-MYC CNV after neoadjuvant chemotherapy reflects chemo-responsiveness and that Shannon indices after neoadjuvant chemotherapy have a prognostic value in breast cancer patients who receive neoadjuvant chemotherapy.
Highlights
Intratumoral heterogeneity refers to the presence of phenotypically and/or genetically distinct tumor cell populations within a tumor that may result in tumor progression[1,2] and therapeutic resistance[3]
We examined c-MYC copy number variation (CNV) in two cohorts of invasive breast cancer patients using an ecological diversity index, the Shannon index, and we found that a high Shannon index for c-MYC was a significant poor prognostic factor, which suggests that a diversity index of even a single gene can be a measure of intratumoral heterogeneity and can be used as a prognostic indicator[14]
To evaluate chemo-responsiveness, we adopted the Miller-Payne regression grading system[24], which well matches the design of this study as it is based on the reduction in the proportion of tumor cellularity compared to pre-treatment primary tumor samples
Summary
Intratumoral heterogeneity refers to the presence of phenotypically and/or genetically distinct tumor cell populations within a tumor that may result in tumor progression[1,2] and therapeutic resistance[3]. Almendro et al analyzed cellular heterogeneity with genetic and phenotypic features as well as the spatial distribution of tumor cells in pre- and post-neoadjuvant chemotherapy breast cancer[17] They reported that there was no change in genetic diversity after chemotherapy, contradicting the general concept that chemo-sensitive subclones regress and resistant ones persist after chemotherapy, thereby leading to decreased genetic diversity after treatment. It was a comprehensive study incorporating genetic and phenotypic diversity in breast cancer pre- and post-neoadjuvant chemotherapy, patient survival in relation to cellular diversity after chemotherapy was not evaluated. We focused on the relationship between chemo-responsiveness and the changes in diversity index during chemotherapy using c-MYC which is located at one of the most unstable chromosomal regions (8q24) and frequently harbors copy number gain or amplification in breast cancer regardless of subtype[18,19,20], in an attempt to find the clinicopathologic significance of post-treatment genetic diversity
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