In the present study we have examined the cytogenetic landscape (CNV – Copy Number Variation) of breast cancer prior to and following neoadjuvant therapy (NAC) and the associated tumor landscape alteration with chemotherapy efficiency as well as metastasis-free survival.
Breast cancer patients (n = 30) with stage IIA to IIIB received four cycles of systemic anthracycline-based NAC. To study CNVs in pre- and post-NAC tumor tissues microarray analysis was performed using the Affymetrix (USA) CytoScan HD Array.
The obtained data indicate a direct correlation between CNV frequency alteration during NAC and tumor response to therapy (R = 0.71, p = 0.000011). We showed that the number of cytobands bearing mosaic CNV was decreased after chemotherapy in 43% patients (13/30). The analysis of all CNV, including amplifications and deletions demonstrated that NAC do not influence CNV frequency in 27% of patients (8/30). For 30% (9/30) of patients the appearance of new CNV was detected after chemotherapy. The origin of new clones with amplifications was revealed in 6 cases of 9. The new clones with amplifications in such loci as 5p, 6p, 7q, 8q, 9p, 10p, 10q22.1, 13q, 16p, 19p were detected. All these patients demonstrated distant metastasis where in 5 cases metastases were manifested within 2 years of follow up, excluding 1 patient surviving more than 4 years without metastases. All other patients (n = 24) who have not acquired the new tumor clones with Gain function after NAC did not manifest distant metastasis in 5-year follow-up (Kaplan-Meier, p = 0.00000 Log-rank test). In accordance with these findings amplified tumor clones (loci 5p, 6p, 7q, 8q, 9p, 10p, 10q22.1, 13q, 16p, 19p) could be considered as potential metastatic clones (named as seeds) which are able to go out from primary tumor sites in blood vessels with subsequent penetration to distant metastatic sites and in the case that prometastatic conditions exist in the microevironment they are able to give rise to metastases.
Our study results demonstrate that the clonal evolution of tumors under the exposure to NAC can stimulate tumor metastatic potential. Data obtained dictate a very intelligent approach to treatment with NAC to avoid metastasis stimulation.
Clinical trial identification
Legal entity responsible for the study
Tomsk Cancer Research Institute
Russian Foundation for Basic Research (project 15-04-03091)and Tomsk State University Competitiveness Improvement Program
All authors have declared no conflicts of interest.