Table 3. Predictive and prognostic value of Ki-67 with different cut-off values.
| Study (year) | Ref. | Sample size and NACT regimens | Subtypes | Cut-off value | Biomarker | Predictive/prognostic value | ||
|---|---|---|---|---|---|---|---|---|
| Penault-Llorca et al. (2008) | [33] | Total (n = 710) | All | 1% | Baseline Ki-67 expression | Positive Ki-67 status was associated with objective clinical response (p = 1.3×10−2) and higher pCR rates (p = 2×10−2). | ||
| - CT only | HR+: n = 363 | Pre-treatment Ki-67 was not prognostic. | ||||||
| HR−: n = 240 | Post-treatment Ki-67 status | Ki-67 was not prognostic with cutoff of 1%, 10% and 20% in this study. | ||||||
| Botero et al. (2016) | [44] | Total (n = 357) | All | 15% | Ki67 expression decrease (from > 15% into ≤ 15%) vs. Ki-67 expression stable > 15% | Ki-67 expression decrease independently predicted LRR (p = 0.03) | ||
| - CT only n = 278 | Ki-67 expression decrease revealed better prognosis: | |||||||
| - CT + H: n = 79 | DFS: p = 0.0001 | |||||||
| OS: p = 0.0016 | ||||||||
| Keam et al. (2011) | [34] | Total (n = 105) | TNBC | 10% | Baseline Ki-67 expression high vs. low | pCR rate: 18.2% vs. 0.0%, p = 0.019 | ||
| - CT only | High Ki-67 expression worse | |||||||
| RFS: p = 0.005 | ||||||||
| OS: p = 0.019 | ||||||||
| RD with high Ki-67 vs. RD with low Ki-67 expression vs. pCR with high Ki-67 | RD with high Ki-67 the worst | |||||||
| RFS: p = 0.0013 | ||||||||
| Sueta et al. (2014) | [36] | Total (n = 121) | All | 35% | Baseline Ki-67 expression | High Ki-67 was significantly related with improved pCR in ER-positive, HER2-negative BC (OR, 6.24; 95% CI, 1.40–27.7; p = 0.016) | ||
| - CT only: n = 91 | Luminal: n = 56 | Median Ki-67 value: 43% vs. 29% (in patients achieved pCR vs. not achieved pCR) | ||||||
| - CT + H: n = 30 | Luminal-HER2: n = 17 | |||||||
| HER2+: n = 22 | ||||||||
| TNBC: n = 26 | ||||||||
| Chen et al. (2018) | [35] | Total (n = 1,010) | All | 14% | Baseline Ki-67 expression | Patients with greater Ki-67 level (≥ 14%) had better clinical and pathological response (p < 0.001) | ||
| - CT only n = 999 | The pretreatment Ki-67 could be used as a predictor of NACT only in luminal subtypes (25.5% is ideal cut-off to differentiate clinical response from non-clinical response) | |||||||
| - CT + H: n = 11 | Ki-67 changes | Statistically significant correlation between Ki-67 decrease and clinical response only existed in luminal (p < 0.001) and luminal-HER2 patients (p = 0.048) | ||||||
| Alba et al. (2016) | [37] | Total (n = 262) | All | 50% | Baseline Ki-67 expression > 50% vs. ≤ 50% | In total: pCR rate: 40% vs. 19%, p = 0.0004 | ||
| - CT only | In ER−/HER2− patients: 42% vs. 15%, p = 0.0337 | |||||||
| - CT + H: most of HER2+ patients | In ER−/HER2+ patients: 64% vs. 45%, p = 0.3238 | |||||||
| Montagna et al. (2014) | [45] | Total (n = 904) | All | 20% | Ki-67 expression decrease (from > 20% into < 20%) versus Ki-67 expression stable > 20% | Ki67 expression decrease revealed better prognosis: | ||
| : All the patients did not achieve pCR | DFS: p < 0.0001 | |||||||
| OS: p < 0.0001 | ||||||||
| Guarner et al. 2009) | [42] | Total (n = 221) | All | 15% | Post-NACT Ki-67 ≥ 15% vs. < 15% | DFS (5-year): 50.2% vs. 77.2%, p = 0.0001 | ||
| - CT only | OS (5-year): 73.1% vs. 87.8%, p = 0.0078 | |||||||
| Baseline Ki67 expression ≥ 15% vs. < 15% | DFS (5-year): 60.5% vs. 83.4%, p = 0.048 | |||||||
| No correlation between baseline Ki67 and OS | ||||||||
| Post-NACT nodes negative + Ki-67 < 15% (low risk) vs. nodes positivity or Ki-67 ≥ 15% (intermediate risk) vs. nodes positive and Ki-67 ≥ 15% (high risk) | Intermediate-risk group vs. Low-risk group: | |||||||
| Hazard ratio for recurrence: 3.1, p = 0.0001 | ||||||||
| Hazard ratio for death: 2.4, p = 0.042 | ||||||||
| High-risk group vs. Low-risk group: | ||||||||
| Hazard ratio for recurrence: 9.3, p = 0.0001 | ||||||||
| Hazard ratio for death: 6.5, p = 0.042 | ||||||||
| von Minckwitz et al. (2013) | [40] | Total (n = 1,151) | All | 0–15%: low-level | post-NACT Ki-67 level | High vs. Intermediate vs. Low: | ||
| - CT only | 15.1–35%: intermediate-level | High-level group showed higher risk (disease relapse: p < 0.0001; death: p < 0.0001) | ||||||
| > 35%: high-level | The prognostic efficacy was more obvious for HR+/HER2-negative and TNBC. | |||||||
| RD with low Ki-67 had comparable outcome to pCR | ||||||||
| Addition of post-treatment Ki-67 to pCR provided better prognostic information than pCR alone in HR+ patients. | ||||||||
NACT = neoadjuvant chemotherapy; CT = chemotherapy (chemotherapy in these studies were based on trastuzumab, taxanes, 5-fluorouracil, epirubicin, cyclophosphamide and adriamycin); HR = hormone receptor; pCR = pathological complete response; H = trastuzumab; LRR = locoregional recurrence; DFS = disease free survival; OS = overall survival; RFS = recurrence-free survival; TNBC = triple-negative breast cancer; RD = residual disease; OR = odds ratio; CI = confidence interval; HER2 = human epidermal growth factor receptor 2; ER = estrogen receptor.