Fig. 4: This schematic model illustrates the putative effect of neoadjuvant chemotherapy on Ki67 proliferation index (PI) and tumor regression.

Each pair of bars represents the Ki67 PI prior to neoadjuvant chemotherapy (light blue; expected value) and post-chemotherapy (dark blue; measured value). Ki67 high index (KiH), Ki67 low index (KiL), the difference (KiD) between KiH/KiL and tumor mass reduction were specified for each bar. Two main effects were observed (left). The decline in the KiH is interpreted as a result of the cytotoxic effect chemotherapy has on proliferating, chemo-sensitive subclones. The incline in the KiL can be attributed to selection pressure exerted by neoadjuvant chemotherapy on clonal diversity. Prior to neoadjuvant chemotherapy, chemo-resistant subclones were inhibited in their growth by better adapted (“fitter”), chemo-sensitive subclones. Following selection caused by neoadjuvant therapy, the surviving (chemo-resistant) subclones were able to exploit their growth advantage (increase in proliferation). Both effects were observed in tumor blocks with a large reduction of tumor mass (right; responder). Chemo-sensitive subclones perished with chemo-resistant subclones being selected through neoadjuvant chemotherapy. In contrast, in tumor blocks where chemo-resistant subclones accounted for a large proportion of the tumor mass (non-responder), only minor changes in KiH and KiL were observed.