Background: Although Ki-67 is a commonly used proliferation marker in breast cancer (BC), its prognostic value after neoadjuvant chemotherapy (NACT) remains unclear. This study aims to investigate the prognostic implications of Ki-67 dynamics during NACT. Methods: Patients with invasive BC treated with NACT (2007–2020) were identified through the National Breast Cancer Register (NBCR). Associations between Ki-67 dynamics with survival outcomes were studied (spline-based Cox regression). The prognostic value of Ki-67 in the Neo-Bioscore model was examined and optimal cut-off values for relative change of Ki-67 ((post-NACT–pre-NACT Ki-67)/pre-NACT Ki-67) were explored (minimum p-value approach). Findings: Among 2494 patients, median pre-NACT Ki-67 was 40% (IQR:28–65%). Median post-NACT Ki-67 in patients with residual disease (n = 1826) was 12% (IQR:5–35%). Lower post-NACT Ki-67 was associated with better breast cancer specific survival (BCSS) in the whole cohort (p < 0.0001), in ER+/HER2− (p = 0.0001) and TNBC (p = 0.0007), but not in HER2+ BC (p = 0.8223). Post-NACT Ki-67 improved the Neo-Bioscore prognostic model increasing the C-index from 0.758 to 0.802. Post-NACT Ki-67, as well as absolute and relative change of Ki-67 were strongly correlated with each other and were prognostic for long-term outcomes. Optimal cut-off values for relative change of Ki-67 identified prognostic subgroups for ER+/HER2− BC (n = 730, p < 0.0001), and TNBC (n = 279, p < 0.0001). The results were validated in an external TNBC cohort of 221 patients (p = 0.00073). Notably, the identified low-risk patients with residual disease and at least 48% reduction of Ki-67 after NACT, had comparable survival to those with pathological complete response (pCR) (p = 0.13). Interpretation: Relative change of Ki-67 was independently prognostic for patient risk stratification. Ki-67 in residual disease warrants for further investigation when exploring post-neoadjuvant treatment strategies. Funding: Cancerfonden, Vetenskapsrådet, Cancerföreningen i Stockholm and Region Stockholm.
Prognostic significance of tumour Ki-67 dynamics during neoadjuvant treatment in patients with breast cancer: a population-based cohort study
Massa, Davide;Lando, Stefania;Guarneri, Valentina;Dieci, Maria Vittoria;
2025
Abstract
Background: Although Ki-67 is a commonly used proliferation marker in breast cancer (BC), its prognostic value after neoadjuvant chemotherapy (NACT) remains unclear. This study aims to investigate the prognostic implications of Ki-67 dynamics during NACT. Methods: Patients with invasive BC treated with NACT (2007–2020) were identified through the National Breast Cancer Register (NBCR). Associations between Ki-67 dynamics with survival outcomes were studied (spline-based Cox regression). The prognostic value of Ki-67 in the Neo-Bioscore model was examined and optimal cut-off values for relative change of Ki-67 ((post-NACT–pre-NACT Ki-67)/pre-NACT Ki-67) were explored (minimum p-value approach). Findings: Among 2494 patients, median pre-NACT Ki-67 was 40% (IQR:28–65%). Median post-NACT Ki-67 in patients with residual disease (n = 1826) was 12% (IQR:5–35%). Lower post-NACT Ki-67 was associated with better breast cancer specific survival (BCSS) in the whole cohort (p < 0.0001), in ER+/HER2− (p = 0.0001) and TNBC (p = 0.0007), but not in HER2+ BC (p = 0.8223). Post-NACT Ki-67 improved the Neo-Bioscore prognostic model increasing the C-index from 0.758 to 0.802. Post-NACT Ki-67, as well as absolute and relative change of Ki-67 were strongly correlated with each other and were prognostic for long-term outcomes. Optimal cut-off values for relative change of Ki-67 identified prognostic subgroups for ER+/HER2− BC (n = 730, p < 0.0001), and TNBC (n = 279, p < 0.0001). The results were validated in an external TNBC cohort of 221 patients (p = 0.00073). Notably, the identified low-risk patients with residual disease and at least 48% reduction of Ki-67 after NACT, had comparable survival to those with pathological complete response (pCR) (p = 0.13). Interpretation: Relative change of Ki-67 was independently prognostic for patient risk stratification. Ki-67 in residual disease warrants for further investigation when exploring post-neoadjuvant treatment strategies. Funding: Cancerfonden, Vetenskapsrådet, Cancerföreningen i Stockholm and Region Stockholm.
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