Systematic Review

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The predictive value of Ki-67 before

neoadjuvant chemotherapy for breast
cancer: a systematic review and
meta-analysis
Xianyu Chen1, Chao He1, Dongdong Han2, Meirong Zhou1, Quan Wang3, Jinhui Tian4,
Lun Li*,1, Feng Xu1, Enxiang Zhou1 & Kehu Yang4

Aim: To review the predictive values of Ki-67 before neoadjuvant chemotherapy (NAC) for
breast cancer patients. Methods: PubMed and EMBASE were searched. Random-effect model
meta-analysis was conducted using Revman software. Results: High Ki-67 was associated
with more pathological complete responses (pCRs) events (odds ratio: 3.10; 95% CI: 2.52–3.81;
53 studies, 10,848 patients) regardless of HR+, HER2+ and triple-negative breast cancer types,
the definitions of pCR and cut-off points for Ki-67. Ki-67 could predict pCR in those who
received anthracyclines plus taxanes, and anthracyclines only, and those from Asia and
Europe. Conclusion: High Ki-67 before NAC was a predictor for pCR in neoadjuvant setting
for breast cancer patients.

First draft submitted: 19 September 2016; Accepted for publication: 6 December 2016;
Published online: 11 January 2017

Neoadjuvant chemotherapy (NAC), an approach whereby patients receive chemotherapy before Keywords 
surgery, has been a standard treatment strategy for patients with not only local advanced but also • Ki-67 • neoadjuvant
operable breast cancer [1–3] . Giving NAC to patients could increase the possibility of surgery with chemotherapy
negative margins by downsizing the tumor and further increase the probability of achieving patho- • pathological complete
logic complete response (pCR) [2,4] . Recent meta-analyses showed that patients who achieved pCR response
after NAC may have longer survival than those who did not [5,6] . However, a high proportion of
patients still fail to respond to NAC and have risks of relapse and death. Therefore, it is important
to predict the response to NAC and identify patients who might benefit from NAC [3] .
In order to select patients most likely to respond to NAC and avoid unnecessary treatments for
patients most likely not to respond, molecular markers for the prediction of response to NAC are
required [7] . However, no reliable molecular markers that can predict which patients might benefit
from NAC were available [8] . Ki-67, a marker of cell proliferation, is a specific nuclear antigen
expressed in all phases of the cell cycle, except G0 [7] . Some guidelines and international groups
concluded that measurement of Ki-67 could be important both in standard clinical practice and
within clinical trials [9,10] .
A number of studies have addressed the predictive significance of Ki-67 in neoadjuvant setting,
but Ki-67 served as a predictive marker was controversial [2–3,8] . Several studies showed that high
Ki-67 was not associated with more pCR events than low Ki-67 [4,11–17] , but some other stud-
ies [18–23] found that Ki-67 might be an independent predictor for pCR. Due to small sample size
1
Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
2
Department of Urology, the Second Hospital of Lanzhou University, Lanzhou, China
3
Department of Gastrointestinal Surgery, Xijing Hospital of Digestive Diseases, Xijing Hospital, Four Military Medical University, Xi’an,
Shaanxi, China
4
Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
*Author for correspondence: guo19880101@163.com part of

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Systematic Review Chen, He, Han et al.
of available studies [24] and inconsonant results
across studies, the consensus on the predictive
values of Ki-67 by pCR in neoadjuvant setting
has not been established yet [25] . We conducted
this systematic review and meta-analysis of big
data in order to review the predictive value of
Ki-67 before NAC for breast cancer patients.
Our team reviewed the predictive and prog-
nostic values of Ki-67 before or after NAC, and
the change of Ki-67 in neoadjuvant setting for
breast cancer patients. And this is the part I of
the whole project which only focused on the
predictive values of Ki-67 before NAC and the
change of Ki-67, and the second article is part II
which focused on the prognostic values of Ki-67
before or after NAC, and the change of Ki-67 in
neoadjuvant setting for breast cancer patients.
Methods
●●Search strategy
PubMed and EMBASE were searched using
the search strategy developed by Jinhui Tian
and Lun Li (Supplementary Material) . Briefly, the
search strategy consisted of four parts: disease
(breast cancer), factor (Ki-67), setting (NAC)
and outcomes (response, among others). We
added subject heading terms in the searches if
possible. Reference lists from identified studies
were reviewed to identify further relevant stud-
ies. Two reviewers (Lun Li and Jinhui Tian)
independently searched in March 2016 without
language restrictions, and updated in 30 June
2016.
●●Inclusion criteria & study selection
We included studies that have to meet the fol-
lowing criteria: published studies in English;
exposure factor was Ki-67 before NAC; and
breast cancer patients who received NAC (chem-
otherapy prior to breast cancer surgery). The
outcome we assessed was pCR defined according
to the original studies. Three most commonly
used pCR definitions were used: ypT0 ypN0
(absence of invasive cancer and in situ cancer
in the breast and axillary nodes), ypT0/is ypN0
(absence of invasive cancer in the breast and
axillary nodes, irrespective of ductal carcinoma
in situ) and ypT0/is (absence of invasive cancer
in the breast irrespective of ductal carcinoma
in situ or nodal involvement) [6] . A study may
publish more than one article, so that the most
comprehensive data were used.
The retrieved citations were screened by
two reviewers (Lun Li and Dongdong Han),
10.2217/fon-2016-0420 Future Oncol. (Epub ahead of print)
and included potential studies based on titles,
abstracts and full-texts. If there were some
inconsistencies, they were resolved by a third
reviewer (Kehu Yang).
●●Data abstraction
The following information was abstracted using
excel by two authors (Lun Li and Quan Wang):
the first author, publication year, age, stage,
NAC regimens, sample size, the details of Ki-67
and pCR. If there were any disagreements, they
were resolved by discussion.
●●Data analysis
Random-effect meta-analyses were conducted
by Revman software version 5.30. Data were
expressed using odds ratio (OR) and its 95% CI.
I2 test was used to test the percentage of vari-
ability across trials attributable to heterogene-
ity. Subgroup analyses were conducted accord-
ing to data types (unadjusted vs adjusted data),
molecular subtypes (hormone receptor positive
[HR+] vs HER2 + vs triple negative), cut-off
points (<15% vs 15% vs 20% vs 21–49% vs
≥50%), pCR definitions (ypT0 ypN0 vs ypT0/is
ypN0 vs ypT0/is), NAC regimes (anthracyclines
and/or taxanes vs anthracyclines plus taxanes vs
anthracyclines only vs taxanes only) and popula-
tion of origins (Asian vs European vs other). The
funnel plot was used to assess the publication
bias, and the Egger’s linear regression test was
used to evaluate the small-study effect. It was
thought to be significant when the p-value was
less than 0.05.
Results
●●Search results
After systematic search, 1274 citations were
retrieved, and 1144 records were excluded based
on screening titles and abstracts. And further
we excluded studies that were not about pCR
(n = 34), not about Ki-67 (n = 21), reviews
(n = 12), and others (n = 10). Finally, 53 studies
[1–4,7–55] were included for systematic review and
44 studies [2–4,8–14,16–18,20–28,31–34,36,38–40,42–55]
were included for meta-analysis as they classi-
fied Ki-67 into high and low levels and provided
enough information (Figure 1) .
●●Characteristics of included studies
Most studies were from China (n = 10), Japan
(n = 9), Italy (n = 7), Germany (n = 7), Korea
(n = 5), France (n = 5), Spain (n = 3) and USA
(n = 2). The sample size of the included studies
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 Ki-67 & pCR in neoadjuvant setting for breast cancer Systematic Review

PubMed (n = 516);
EMBASE (n = 640);
Reference tracking (n = 118)

Records after duplicates removed (n = 842)

Records excluded (n = 717)

Not about ki67 (n = 327)
Not about neoadjuant chemotherapy (n = 304)
Others cancers (n = 86)

Full-text articles assessed (n = 125)

Full-text articles excluded (n = 72)

Reviews (n = 12)
Not about ki67 (n = 21)
Others (n = 10)
Not about pCR (n = 29)

Studies included for systematic review (53 studies)

Studies included for meta-analysis (44 studies)

Figure 1. The process of study selection.

for systematic review ranged from 24 to 1166
with a total number of 10,848 (median 119).
The pCR rate varied from 4.27 to 65.12%
(median 15.54%). And other details of patients,
NAC regimens and Ki-67 were presented in
Supplementary Table 1.
●●Systematic review
The study conducted by Kurozumi et al. [33]
showed a highest pCR rate (65.12%) for
HER2 + breast cancer patients receiving taxanes
followed by fluorouracil, epirubicin and cyclo-
phosphamide concomitant with trastuzumab.
Saracchini et al. [34] observed a similar pCR
(49%) among HER2+ breast cancer patients who
received liposome-encapsulated doxorubicin
plus cyclophosphamide followed by trastuzumab
plus docetaxel. However, for those HER2+ breast
cancer patients who received NAC without
trastuzumab, a lower pCR (12.39%) rate was
found [17] . Five studies [17,24,33–34,42] analyzed
the relationship between Ki-67 and pCR among
HER2 + breast cancer patients, but three of
them [24,33–34] showed Ki-67 might be a predic-
tor for pCR by univariate analysis. Two studies
conducted multivariate analysis [24,33] , and only
the study conducted by Zhang et al. [24] found
that high Ki-67 index was associated with more
pCR events independently (p = 0.028). Another
three studies [20,22,49] conducted subgroup analy-
ses for HER2 + breast cancer patients, and only
one study [22] showed Ki-67 might predict pCR.
Although these studies failed to show consist-
ent relationships between Ki-67 and pCR, most
studies showed high Ki-67 might be associated
with higher pCR rate than low Ki-67.
For triple-negative breast cancer, seven stud-
ies were available [10,12,16,28,38,40,50] , and the pCR
ranged from 13.33 [12] to 42.00% [10] . For triple-
negative breast cancer, the Ki-67 expression is
high, even using 57.5% as a cut-off point, the
percentage of patients with high Ki-67 was

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Systematic Review Chen, He, Han et al.
50% [38] . This might explain why patients
with triple-negative breast cancer experienced
a worse survival than other molecular types.
Among these studies, three [38,40,50] found that
Ki-67 might predict pCR by univariate analysis.
But only one study [38] revealed that Ki-67 was
an independent predictor for pCR. Although
statistical significances were not found in most
studies, high Ki-67 seemed to be associated with
more pCR events than low Ki-67.
Five studies [14,20,22,39,49,52] analyzed the rela-
tionship between Ki-67 and pCR in HR+ breast
cancer patients, but only two studies [39,52]
showed Ki-67 could predict the pCR in HR+
breast cancer patients. Two studies [2,52] ana-
lyzed the relationship between Ki-67 and pCR
in estrogen receptor negative (ER-) breast cancer
patients; however, neither found a positive sta-
tistical significance. Tan et al. [2] classified Ki-67
expression into three categories: low (<14%),
intermediate (14–30%) and high (>30%),
and found Ki-67 was a predictive marker for
pCR. Four studies [1,7,29,35] found Ki-67 could
be an independent predictor for pCR as a con-
tinuous variable. Colleoni et al. [21] found that
+10% increase of Ki-67 might predict pCR,
but Jones et al. [37] showed that Ki-67 per 2.7-
fold increase might not be a predictor for pCR.
Qin et al. [41] analyzed the association between
the decrease of Ki-67 and pCR, and showed
the possibility of pCR in patients with Ki-67
decrease was higher than those without.
In total, 53 studies reported the relationship
between Ki-67 expression and pCR, 18 stud-
ies [4,8,10–17,25,28,30,32,42,45,51,54] did not find any
positive relationships between Ki-67 expression
and pCR by univariate analysis, the rest showed
Ki-67 might be a predictor for pCR. However,
nine studies [7,19,21,31,34,44,47,53,55] did not conduct
further analysis, and six studies [3,26,33,37,46,50]
failed to show positive relationships between
high Ki-67 expression and pCR by multivariate
analyses.
●●Meta-analysis
29 studies [2,4,8,10–14,17,18,20–21,25–28,31,32,34,39,40,
42,44–47,51,53–55] provided unadjusted data and 14
studies [3,9,16,22–24,33,36,38,43,48–50,52] provided mul-
tivariate data. There was a statistical difference
in pCR between high and low Ki-67 expression
(n = 43; OR: 3.10; 95% CI: 2.52–3.81; I2 = 17%)
(Figure 2) . The results were similar when pool-
ing the univariate data (n = 29; OR: 3.13;
95% CI: 2.35–4.18; I2 = 27%) and multivariate
10.2217/fon-2016-0420 Future Oncol. (Epub ahead of print)
data (n = 14; OR: 2.94; 95% CI: 2.20–3.93;
I2 = 0%). Ki-67 could also predict pCR in HR+
(n = 7; OR: 2.51; 95% CI: 1.24–5.07; I2 = 30%),
HER2+ (n = 9; OR: 2.76; 95% CI: 1.78–4.27;
I2 = 0%) and triple-negative breast cancer patients
(n = 10: OR: 2.77; 95% CI: 1.67–4.59; I2 = 2%)
(Figure 3) . For those using the cut-off points that
were less than 15% (n = 10; OR: 2.50; 95% CI:
1.72–3.62; I2 = 19%), 15% (n = 5; OR: 4.92;
95% CI: 2.64–9.20; I2 = 13%), 20% (n = 15;
OR: 3.60; 95% CI: 2.51–5.15; I2 = 8%), 21–49%
(n = 10; OR: 3.01; 95% CI: 2.18–4.16; I2 = 0%)
and 50% or more (n = 6; OR: 2.72; 95% CI:
1.70–4.36; I2 = 0%), the pooled results were
still statistically significant (Figure 4) . High Ki-67
was associated with more ypT0/is ypN0 (n = 29;
OR: 3.17; 95% CI: 2.51–3.98; I2 = 5%), ypT0
ypN0 (n = 7; OR: 3.97; 95% CI: 1.86–8.44;
I2 = 38%) and ypT0/is (n = 7; OR: 2.19; 95% CI:
1.47–3.27; I2 = 0%) (Figure 5) .
Ki-67 could predict pCR in breast cancer
patients who received NAC containing anthra-
cyclines and/or taxanes, (n = 13; OR: 2.90;
95% CI: 2.14–3.93; I2 = 0%), anthracyclines
plus taxanes (n = 22; OR: 3.15; 95% CI:
2.23–4.43; I2 = 35%) and anthracyclines (n = 5;
OR: 4.67; 95% CI: 2.70–8.05; I2 = 0%), except
taxanes (n = 3; OR: 1.29; 95% CI: 0.36–4.67;
I2 = 14%) (Figure 6) . Ki-67 could also predict
pCR in Asian (n = 19; OR: 2.38; 95% CI:
1.83–3.09; I 2 = 9%), and European (n = 23;
OR: 4.23; 95% CI: 3.26–5.48; I2 = 0%) breast
cancer patients, but not in American (n = 1;
OR: 4.14; 95% CI: 0.20–84.63) breast cancer
patients (Figure 7) .
●●Publication bias
There seemed to be no publication bias, and
Egger’s regression showed that there were no
statistical significance (p = 0.95).
Discussion
Although variations could be found in NAC
regimens, molecular subtypes of breast cancers,
cut-off points of Ki-67 and pCR definitions,
high Ki-67 expression before NAC seemed to
be associated with higher pCR rate than low
Ki-67 in breast cancer patients receiving NAC.
In our study, the highest pCR was found in
HER2 + breast cancer patients [33] , which might
reflect that NAC containing trastuzumab could
bring higher pCR rate in addition to traditional
NAC for HER2 + breast cancer patients. This
was confirmed by a previous meta-analysis of
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 Ki-67 & pCR in neoadjuvant setting for breast cancer Systematic Review

Odds ratio Odds ratio

Study or subgroup Log [odds ratio] SE Weight (%) IV, random (95% CI) IV, random (95% CI)
1.1.1 unadjusted
Bria (2015) 2.56 1.71 0.4 12.94 (0.45–369.27)
Colleoni (2008) 2.16 0.73 1.8 8.67 (2.07–36.26)
Colleoni (2010) 1.47 0.47 3.7 4.35 (1.73–10.93)
Colleoni (2010) 0.63 1.12 0.8 1.88 (0.21–16.86)
Denkert (2013) 1.78 0.28 7.1 5.93 (3.43–10.27)
Elnemr (2016) 0.69 0.6 2.5 1.99 (0.62–6.46)
Estevez (2003) 0.19 0.98 1.1 1.21 (0.18–8.25)
Guarneri 2009) 1.35 1.05 0.9 3.86 (0.49–30.20)
Huang (2013) 1.44 0.79 1.6 4.22 [0.90–19.85)
Humbert (2015) 1.5 0.86 1.4 4.48 (0.83–24.18)
Ingolf (2014) 0.62 0.63 2.3 1.86 (0.54–6.39)
Jin (2013) 0.34 0.57 2.8 1.40 (0.46–4.29)
Keam (2011) 2.57 1.46 0.5 13.07 (0.75–228.50)
Kraus (2012) 1.42 1.54 0.5 4.14 (0.20–84.63)
Lee (2008) -0.09 1.58 0.4 0.91 (0.04–20.22)
Li (2011) (1) 0.71 0.54 3.0 2.03 (0.71–5.86)
Li (2013) 0.44 0.37 5.2 1.55 (0.75–3.21)
Lin (2013) 2.5 1.47 0.5 12.18 (0.68–217.27)
Lips (2012) -1.24 1.17 0.8 0.29 (0.03–2.87)
Masuda (2011) 1.7 0.89 1.3 5.47 (0.96–31.32)
Miyoshi (2008) -0.34 0.82 1.5 0.71 (0.14–3.55)
Montagna (2010) 1.4 0.41 4.5 4.06 (1.82–9.06)
Petit (2004) 1.8 0.67 2.1 6.05 (1.63–22.49)
Petit (2010) 2.31 1.06 0.9 10.07 (1.26–80.44)
Saracchini (2013) 2.35 1.13 0.8 10.49 (1.14–96.04]
Schmid (2005) 3.38 1.5 0.5 29.37 (1.55–555.54)
Tan (2014) 0.67 0.45 4.0 1.95 (0.81–4.72)
Vincent-Salomon (2004) 1.42 0.67 2.1 4.14 (1.11–15.38)
Wang (2016) 1.74 0.42 4.4 5.70 (2.50–12.98)
Zhou (2008) 0.24 0.54 3.0 1.27 (0.44–3.66)
Subtotal (95% CI) 62.2 3.13 (2.35–4.18)
Heterogeneity: Tau2 = 0.15; Chi2 = 39.51, df = 29 (p = 0.09); I2 = 27%
Test for overall effect: Z = 7.80 (p < 0.00001)
1.1.2 adjusted
Alba (2016) 1.09 0.43 4.2 2.97 (1.28– 6.91)
Darb-Esfahani (2009) 2.34 1.06 0.9 10.38 (1.30–82.89)
Fasching (2011) 1.26 0.5 3.4 3.53 (1.32–9.39)
GRIM (2012) 2.35 1.08 0.9 10.49 (1.26–87.07)
Hashimoto (2014) 1.82 1.11 0.8 6.17 (0.70–54.36)
Kim (2014) 2.14 1.08 0.9 8.50 (1.02–70.58)
Kim (2015 0.07 0.56 2.8 1.07 (0.36–3.21)
Kurozumi (2015) 0.86 0.47 3.7 2.36 (0.94–5.94)
Li (2011) (2) 0.32 0.52 3.2 1.38 (0.50–3.82)
Miyashita (2014) 1.74 0.61 2.5 5.70 (1.72–18.83)
Ohno (2013) 1 0.36 5.4 2.72 (1.34–5.50)
Sanchez-Muñoz (2013) 1.7 0.69 2.0 5.47 (1.42–21.17)
Sueta (2014) 1.29 0.56 2.8 3.63 (1.21–10.89)
Zhang (2012) 0.95 0.43 4.2 2.59 (1.11–6.01)
Subtotal (95% CI) 37.8 2.94 (2.20–3.93)
Heterogeneity: Tau2 = 0.00; Chi2 = 12.20, df = 13 (p = 0.51); I2 = 0%
Test for overall effect: Z = 7.26 (p < 0.00001)

Total (95% CI) 100.0 3.10 (2.52–3.81)

Heterogeneity: Tau2 = 0.08; Chi2 = 51.97, df = 43 (p = 0.16); I2 = 17%
Test for overall effect: Z = 10.75 (p < 0.00001) 0.01 0.1 1 10 100
Test for subgroup differences: Chi2 = 0.10, df = 1 (p = 0.76); I2 = 0%

Figure 2. Meta-analysis of the relationship between Ki-67 before neoadjuvant chemotherapy and pathologic complete response.

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Systematic Review Chen, He, Han et al.

Odds ratio Odds ratio

Study or subgroup Log [odds ratio] SE Weight (%) IV, random (95% CI) IV, random (95% CI)
1.2.1 HR+
Alba (2016) 0.72 0.64 19.3 2.05 (0.59–7.20)
Fasching (2011) 1.08 0.58 21.7 2.94 (0.94–9.18)
Kim (2014) 1.95 1.54 4.9 7.03 (0.34–143.79)
Lips (2012) -1.24 1.17 7.9 0.29 (0.03–2.87)
Montagna (2010) 0.23 0.59 21.3 1.26 (0.40–4.00)
Petit (2010) 2.31 1.06 9.4 10.07 (1.26–80.44)
Sueta (2014) 1.83 0.76 15.5 6.23 (1.41–27.65)
Subtotal (95% CI) 100.0 2.51 (1.24–5.07)
Heterogeneity: Tau2 = 0.26; Chi2 = 8.54, df = 6 (p = 0.20); I2 = 30%
Test for overall effect: Z = 2.55 (p = 0.01)
1.2.2 HER2+
Alba (2016) 0.53 0.48 21.5 1.70 (0.66–4.35)
Bria (2015) 2.56 1.71 1.7 12.94 (0.45–369.27)
Fasching (2011) 1.56 0.79 7.9 4.76 (1.01–22.38)
Huang (2013) 1.44 0.79 7.9 4.22 (0.90–19.85)
Kim (2014) 1.72 1.14 3.8 5.58 (0.60–52.16)
Kurozumi (2015) 0.86 0.47 22.4 2.36 (0.94–5.94)
Montagna (2010) 0.39 1.1 4.1 1.48 (0.17–12.76)
Saracchini (2013) 2.35 1.13 3.9 10.49 (1.14–96.04)
Zhang (2012) 0.95 0.43 26.8 2.59 (1.11–6.01)
Subtotal (95% CI) 100.0 2.76 (1.78–4.27)
Heterogeneity: Tau2 = 0.00; Chi2 = 4.84, df = 8 (p = 0.78); I2 = 0%
Test for overall effect: Z = 4.56 (p < 0.00001)
1.2.3 Triple negative
Fasching (2011) 1.76 1.09 5.5 5.81 (0.69–49.22)
Hashimoto (2014) 1.82 1.11 5.3 6.17 (0.70–54.36)
Humbert (2015) 1.5 0.86 8.8 4.48 (0.83–24.18)
Keam (2011) 2.57 1.46 3.1 13.07 (0.75–228.50)
Kim (2015) 0.07 0.56 20.3 1.07 (0.36–3.21)
Kraus (2012) 1.42 1.54 2.8 4.14 (0.20–84.63)
Li (2011) (2) 0.32 0.52 23.4 1.38 (0.50–3.82)
Masuda (2011) 1.7 0.89 8.3 5.47 (0.96–31.32)
Miyashita (2014) 1.74 0.61 17.2 5.70 (1.72–18.83)
Montagna (2010) 0.8 1.12 5.2 2.23 (0.25–19.99)
Subtotal (95% CI) 100.0 2.77 (1.67–4.59)
Heterogeneity: Tau2 = 0.01; Chi2 = 9.19, df = 9 (p = 0.42); I2 = 2%
Test for overall effect: Z = 3.94 (p < 0.0001)
Test for subgroup differences: Chi2 = 0.06; df = 2 (p = 0.97); I2 = 0%
0.01 0.1 1 10 100

Figure 3. Subgroup analysis for different breast cancer molecular types.

five trials (515 patients), which showed tras-
tuzumab could bring higher pCR probability
in addition to NAC (risk ratio: 1.85; 95% CI:
1.39–2.46) [56] . Based on our meta-analysis,
Ki-67 could predict the response for HER2 +
breast cancer, and this might suggest that
patients with high Ki-67 might be sensitive
to NAC containing trastuzumab. For triple-
negative breast cancer patients and HR+, Ki-67
could also predict the effectiveness of NAC.
Those triple-negative breast cancer patients
always were with high Ki-67 expression and
high pCR probability [53] . For HR+ breast can-
cer patients, our meta-analysis showed Ki-67
could predict pCR, but our systematic review
did not find any support evidence for positive
relationships for ER- breast cancer patients.
In our study, the meta-analysis showed that
Ki-67 might be a predictor for pCR, regardless
of data types (univariate and multivariate data).
High levels of Ki-67 before NAC demonstrated
that tumors with high Ki-67 have a better

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 Ki-67 & pCR in neoadjuvant setting for breast cancer Systematic Review

Odds ratio Odds ratio

Study or subgroup Log [odds ratio] SE Weight (%) IV, random (95% CI) IV, Random (95% CI)
1.3.1 <15%
Elnemr (2016) 0.69 0.6 8.5 1.99 (0.62–6.46)
Fasching (2011) 1.26 0.5 11.4 3.53 (1.32–9.39)
Hashimoto (2014) 1.82 1.11 2.8 6.17 (0.70–54.36)
Keam (2011) 2.57 1.46 1.6 13.07 (0.75–228.50)
Kim (2015) 0.07 0.56 9.5 1.07 (0.36–3.21)
Lee (2008) -0.09 1.58 1.4 0.91 (0.04–20.22)
Li (2013) 0.44 0.37 17.8 1.55 (0.75–3.21)
Ohno (2013) 1 0.36 18.5 2.72 (1.34–5.50)
Tan (2014) 0.67 0.45 13.5 1.95 (0.81–4.72)
Wang (2016) 1.74 0.42 14.9 5.70 (2.50–12.98)
Subtotal (95% CI) 100.0 2.50 (1.72–3.62)
Heterogeneity: Tau2 = 0.07; Chi2 = 11.11, df = 9 (p = 0.27); I2 = 19%
Test for overall effect: Z = 4.81 (p < 0.00001)
1.3.2 15%
Bria (2015) 2.56 1.71 3.4 12.94 (0.45–369.27)
Denkert (2013) 1.78 0.28 62.6 5.93 (3.43–10.27)
Guarneri (2009) 1.35 1.05 8.6 3.86 (0.49–30.20)
Ingolf (2014) 0.62 0.63 21.1 1.86 (0.54–6.39)
Schmid (2005) 3.38 1.5 4.4 29.37 (1.55–555.54)
Subtotal (95% CI) 100.0 4.92 [2.64–9.20)
Heterogeneity: Tau2 = 0.08; Chi2 = 4.58, df = 4 (p = 0.33); I2 = 13%
Test for overall effect: Z = 5.00 (p < 0.00001)
1.3.4 20%
Colleoni (2008) 2.16 0.73 5.8 8.67 (2.07–36.26)
Colleoni (2010) 1.47 0.47 12.6 4.35 (1.73–10.93)
Colleoni (2010) 0.63 1.12 2.6 1.88 (0.21–16.86)
Darb-Esfahani (2009) 2.34 1.06 2.9 10.38 (1.30–82.89)
Estevez (2003) 0.19 0.98 3.3 1.21 (0.18–8.25)
GRIM (2012) 2.35 1.08 2.8 10.49 (1.26–87.07)
Huang (2013) 1.44 0.79 5.0 4.22 (0.90–19.85)
Jin (2013) 0.34 0.57 9.1 1.40 (0.46–4.29)
Li (2011) (1) 0.71 0.54 10.0 2.03 (0.71–5.86)
Lin (2013) 2.5 1.47 1.5 12.18 (0.68–217.27)
Montagna (2010) 1.4 0.41 15.8 4.06 (1.82–9.06)
Petit (2004) 1.8 0.67 6.8 6.05 (1.63–22.49)
Petit (2010) 2.31 1.06 2.9 10.07 (1.26–80.04)
Sanchez-Muñoz (2013) 1.7 0.69 6.4 5.47 (1.42–21.17)
Saracchini (2013) 2.35 1.13 2.5 10.49 (1.14–96.04)
Zhou (2008) 0.24 0.54 10.0 1.27 (0.44–3.66)
Subtotal (95% CI) 100.0 3.60 (2.51–5.15)
Heterogeneity: Tau = 0.04; Chi = 16.34, df = 15 (p = 0.36); I = 8%
2 2 2

Test for overall effect: Z = 7.00 (p < 0.00001)

1.3.5 21% – 49%
Colleoni (2004) 1.18 0.32 26.3 3.25 (1.74–6.09)
Kim (2014) 2.14 1.08 2.3 8.50 (1.02–70.58)
Kraus (2012) 1.42 1.54 1.1 4.14 (0.20–84.63)
Kurozumi (2015) 0.86 0.47 12.2 2.36 (0.94–5.94)
Miyoshi (2008) -0.34 0.82 4.0 0.71 (0.14–3.55)
Petit (2010) 1.41 0.61 7.2 4.10 (1.24–13.54)
Sueta (2014) 1.29 0.56 8.6 3.63 (1.21–10.89)
Tan (2014) 1.13 0.39 17.7 3.10 (1.44–6.65)
Vincent-Salomon (2004) 1.42 0.67 6.0 4.14 (1.11–15.38)
Zhang (2012) 0.95 0.43 14.6 2.59 (1.11–6.01)
Subtotal (95% CI) 100.0 3.01 (2.18–4.16)
Heterogeneity: Tau2 = 0.00; Chi2 = 5.11, df = 9 (p = 0.82); I2 = 0%
Test for overall effect: Z = 6.72 (p < 0.00001)
1.3.6 ≥50%
Alba (2016) 1.09 0.43 31.3 2.97 (1.28–6.91)
Humbert (2015) 1.5 0.86 7.8 4.48 (0.83–24.18)
Ingolf (2014) 0.48 0.59 16.6 1.62 (0.51–5.14)
Li (2011) (2) 0.32 0.52 21.4 1.38 (0.50–3.82)
Masuda (2011) 1.7 0.89 7.3 5.47 (0.96–31.32)
Miyashita (2014) 1.74 0.61 15.6 5.70 (1.72–18.83)
Subtotal (95% CI) 100.0 2.72 (1.70–4.36)
Heterogeneity: Tau = 0.00; Chi = 4.96, df = 5 (p = 0.42); I = 0%
2 2 2

Test for overall effect: Z = 4.16 (p < 0.0001)

Test for subgroup differences: Chi2 = 4.39, df = 4 (p = 0.36); I2 = 9.0%
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Figure 4. Subgroup analysis for different cut-off points for Ki-67.

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Systematic Review Chen, He, Han et al.

Odds ratio Odds ratio

Study or subgroup Log [odds ratio] SE Weight (%) IV, random (95% CI) IV, random (95% CI)
1.5.1 ypT0/is ypN0
Alba (2016) 1.09 0.43 6.8 2.97 (1.28–6.91)
Bria (2015) 2.56 1.71 0.5 12.94 (0.45–369.27)
Colleoni (2008) 2.16 0.73 2.5 8.67 (2.07–36.26)
Colleoni (2010) 1.47 0.47 5.8 4.35 (1.73–10.93)
Colleoni (2010) 0.63 1.12 1.1 1.88 (0.21–16.86)
Elnemr (2016) 0.69 0.6 3.6 1.99 (0.62–6.46)
Estevez (2003) 0.19 0.98 1.4 1.21 (0.18–8.25)
Guarneri (2009) 1.35 1.05 1.2 3.86 (0.49–30.20)
Hashimoto (2014) 1.82 1.11 1.1 6.17 (0.70–54.36)
Humbert (2015) 1.5 0.86 1.8 4.48 (0.83–24.18)
Keam (2011) 2.57 1.46 0.6 13.07 (0.75–228.50)
Kim (2014) 2.14 1.08 1.2 8.50 (1.02–70.58)
Kim (2015) 0.07 0.56 4.1 1.07 (0.36–3.21)
Kurozumi (2015) 0.86 0.47 5.8 2.36 (0.94–5.94)
Lee (2008) -0.09 1.58 0.5 0.91 (0.04–20.22)
Li (2011) (1) 0.71 0.54 4.4 2.03 (0.71–5.86)
Li (2011) (2) 0.32 0.52 4.8 1.38 (0.50–3.82)
Lips (2012) -1.24 1.17 1.0 0.29 (0.03–2.87)
Miyashita (2014) 1.74 0.61 3.5 5.70 (1.72–18.83)
Montagna (2010) 1.4 0.41 7.4 4.06 (1.82–9.06)
Ohno (2013) 1 0.36 9.3 2.72 (1.34–5.50)
Petit (2004) 1.8 0.67 2.9 6.05 (1.63–22.49)
Petit (2010) 2.31 1.06 1.2 10.07 (1.26–80.44)
Sanchez-Muñoz (2013) 1.7 0.69 2.8 5.47 (1.42–21.17)
Saracchini (2013) 2.35 1.13 1.1 10.49 (1.14–96.04)
Schmid (2005) 3.38 1.5 0.6 29.37 (1.55–555.54)
Tan (2014) 0.67 0.45 6.2 1.95 (0.81–4.72)
Vincent-Salomon (2004) 1.42 0.67 2.9 4.14 (1.11–15.38)
Wang (2016) 1.74 0.42 7.1 5.70 (2.50–12.98)
Zhang (2012) 0.95 0.43 6.8 2.59 (1.11–6.01)
Subtotal (95% CI) 100.0 3.17 (2.51–3.98)
Heterogeneity: Tau2 = 0.02; Chi2 = 30.38, df = 29 (p = 0.40); I2 = 5%
Test for overall effect: Z = 9.82 (p < 0.00001)
1.5.2 ypT0 ypN0
Darb-Esfahani (2009) 2.34 1.06 10.1 10.38 (1.30–82.89)
Denkert (2013) 1.78 0.28 34.5 5.93 (3.43–10.27)
Grim (2012) 2.35 1.08 9.8 10.49 (1.26–87.07)
Ignolf (2014) 0.62 0.63 19.8 1.86 (0.54–6.39)
Kraus (2012) 1.42 1.54 5.5 4.14 (0.20–84.63)
Lin (2013) 2.5 1.47 5.9 12.18 (0.68–217.27)
Miyoshi (2008) -0.34 0.82 14.5 0.71 (0.14–3.55)
Subtotal (95% CI) 100.0 3.97 (1.86–8.44)
Heterogeneity: Tau2 = 0.35; Chi2 = 9.68, df = 6 (p = 0.14); I2 = 38%
Test for overall effect: Z = 3.58 (p = 0.0003)
1.5.3 ypT0/is
Fasching (2011) 1.26 0.5 16.8 3.53 (1.32–9.39)
Huang (2013) 1.44 0.79 6.7 4.22 (0.90–19.85)
Jin (2013) 0.34 0.57 12.9 1.40 (0.46–4.29)
Li (2013) 0.44 0.37 30.6 1.55 (0.75–3.21)
Masuda (2011) 1.7 0.89 5.3 5.47 (0.96–31.32)
Sueta (2014) 1.29 0.56 13.4 3.63 (1.21–10.89)
Zhou (2008) 0.24 0.54 14.4 1.27 (0.44–3.66)
Subtotal (95% CI) 100.0 2.19 (1.47–3.27)
Heterogeneity: Tau2 = 0.00; Chi2 = 5.96, df = 6 (p = 0.43); I2 = 0%
Test for overall effect: Z = 3.83 (p = 0.0001)
Test for subgroup differences: Chi2 = 3.08, df = 2 (p = 0.21); I2 = 35.0%
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Figure 5. Subgroup analysis for different definitions for pathologic complete response.

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 Ki-67 & pCR in neoadjuvant setting for breast cancer Systematic Review

Odds ratio Odds ratio

Study or subgroup Log [odds ratio] SE Weight (%) IV, random (95% CI) IV, random (95% CI)
1.8.1 anthracyclines and/or taxanes
Alba (2016) 1.09 0.43 13.1 2.97 (1.28–6.91)
Colleoni (2008) 2.16 0.73 4.6 8.67 (2.07–36.26)
Colleoni (2010) 1.47 0.47 11.0 4.35 (1.73–10.93)
Colleoni (2010) 0.63 1.12 1.9 1.88 (0.21–16.86)
Elnemr (2016) 0.69 0.6 6.7 1.99 (0.62–6.46)
Fasching (2011) 1.26 0.5 9.7 3.53 (1.32–9.39)
Guarneri (2009) 1.35 1.05 2.2 3.86 (0.49–30.20)
Ingolf (2014) 0.62 0.63 6.1 1.86 (0.54–6.39)
Jin (2013) 0.34 0.57 7.5 1.40 (0.46–4.29)
Kim (2014) 2.14 1.08 2.1 8.50 (1.02–70.58)
Kim (2015) 0.07 0.56 7.7 1.07 (0.36–3.21)
Miyashita (2014) 1.17 0.61 6.5 5.70 (1.72–18.83)
Sueta (2014) 1.29 0.56 7.7 3.63 (1.21–10.89)
Zhang (2012) 0.95 0.43 13.1 2.59 (1.11–6.01)
Subtotal (95% CI) 100.0 2.90 (2.14–3.93)
Heterogeneity: Tau2 = 0.00; Chi2 = 11.49, df = 13 (p = 0.57); I2 = 0%
Test for overall effect: Z = 6.83 (p < 0.00001)
1.8.2 anthracyclines and taxanes
Darb-Esfahani (2009) 2.34 1.06 2.3 10.38 (1.30–82.89)
Denkert (2013) 1.78 0.28 11.1 5.93 (3.43–10.27)
Grim (2012) 2.35 1.08 2.2 10.49 (1.26–87.07)
Hashimoto (2014) 1.82 1.11 2.1 6.17 (0.70–54.36)
Humbert (2015) 1.5 0.86 3.3 4.48 (0.83–24.18)
Keam (2011) 2.57 1.46 1.3 13.07 (0.75–228.50)
Kraus (2012) 1.42 1.54 1.2 4.14 (0.20–84.63)
Kurozumi (2015) 0.86 0.47 7.3 2.36 (0.94–5.94)
Lee (2008) -0.09 1.58 1.1 0.91 (0.04–20.22)
Li (2011) (1) 0.71 0.54 6.3 2.03 (0.71–5.86)
Li (2011) (2) 0.32 0.52 6.6 1.38 (0.50–3.82)
Li (2013) 0.44 0.37 9.2 1.55 (0.75–3.21)
Lin (2013) 2.5 1.47 1.3 12.18 (0.68–217.27)
Lips (2012) -1.24 1.17 2.0 0.29 (0.03–2.87)
Masuda (2011) 1.7 0.89 3.1 5.47 (0.96–31.32)
Ohno (2013) 1 0.36 9.4 2.72 (1.34–5.50)
Sanchez-Muñoz (2013) 1.7 0.69 4.6 5.47 (1.42–21.17)
Saracchini (2013) 2.35 1.13 2.1 10.49 (1.14–96.04)
Schmid (2005) 3.38 1.5 1.3 29.37 (1.55–555.54)
Tan (2014) 0.67 0.45 7.7 1.95 (0.81–4.72)
Wang (2016) 1.74 0.42 8.2 5.70 (2.50–12.98)
Zhou (2008) 0.24 0.54 6.3 1.27 (0.44–3.66)
Subtotal (95% CI) 100.0 3.15 (2.23–4.43)
Heterogeneity: Tau2 = 0.20; Chi2 = 32.45, df = 21 (p = 0.05); I2 = 35%
Test for overall effect: Z = 6.54 (p < 0.00001)
1.8.3 anthracyclines only
Huang (2013) 1.44 0.79 12.4 4.22 (0.90–19.85)
Montagna (2010) 1.4 0.41 46.1 4.06 (1.82–9.06)
Petit (2004) 1.8 0.67 17.3 6.05 (1.63–22.49)
Petit (2010) 2.31 1.06 6.9 10.07 (1.26–80.44)
Vincent-Salomon (2004) 1.42 0.67 17.3 4.14 (1.11–15.38)
Subtotal (95% CI) 100.0 4.67 (2.70–8.05)
Heterogeneity: Tau2 = 0.00; Chi2 = 0.84, df = 4 (p = 0.93); I2 = 0%
Test for overall effect: Z = 5.53 (p < 0.00001)
1.8.4 taxanes only
Bria (2015) 2.56 1.71 13.8 12.94 (0.45–369.27)
Estevez (2003) 0.19 0.98 37.0 1.21 (0.18–8.25)
Miyoshi (2008) -0.34 0.82 49.2 0.71 (0.14–3.55)
Subtotal (95% CI) 100.0 1.29 (0.36–4.67)
Heterogeneity: Tau2 = 0.20; Chi2 = 2.34, df = 2 (p = 0.31); I2 = 14%
Test for overall effect: Z = 0.39 (p = 0.70)
Test for subgroup differences: Chi2 = 4.12, df = 3 (p = 0.25); I2 = 27.2%

0.01 0.1 1 10 100

Figure 6. Subgroup analysis for different neoadjuvant chemotherapy regimens.

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Systematic Review Chen, He, Han et al.

Odds ratio Odds ratio

Study or subgroup Log [odds ratio] SE Weight (%) IV, random (95% CI) IV, random (95% CI)
1.4.1 Asain
Elnemr (2016) 0.69 0.6 4.6 1.99 (0.62–6.46)
Huang (2013) 1.44 0.79 2.7 4.22 (0.90–19.85)
Kim (2014) 2.14 1.08 1.5 8.50 (1.02–70.58)
Kim (2015) 0.07 0.56 5.2 1.07 (0.36–3.21)
Kurozumi (2015) 0.86 0.47 7.1 2.36 (0.94–5.94)
Lee (2008) -0.09 1.58 0.7 0.91 (0.04–20.22)
Li (2011) (1) 0.71 0.54 5.5 2.03 (0.71–5.86)
Li (2011) (2) 0.32 0.52 5.9 1.38 (0.50–3.82)
Li (2013) 0.44 0.37 10.6 1.55 (0.75–3.21)
Lin (2013) 2.5 1.47 0.8 12.18 (0.68–217.27)
Masuda (2011) 1.7 0.89 2.2 5.47 (0.96–31.32)
Miyashita (2014) 1.74 0.61 4.4 5.70 (1.72–18.83)
Miyoshi (2008) -0.34 0.82 2.5 0.71 (0.14–3.55)
Ohno (2013) 1 0.36 11.1 2.72 (1.34–5.50)
Sueta (2014) 1.29 0.56 5.2 3.63 (1.21–10.89)
Tan (2014) 0.67 0.45 7.6 1.95 (0.81–4.72)
Wang (2016) 1.74 0.42 8.6 5.70 (2.50–12.98)
Zhang (2012) 0.95 0.43 8.3 2.59 (1.11–6.01)
Zhou (2008) 0.24 0.54 5.5 1.27 (0.44–3.66)
Subtotal (95% CI) 100.0 2.38 (1.83–3.09)
Heterogeneity: Tau2 = 0.03; Chi2 = 19.85, df = 18 (p = 0.34); I2 = 9%
Test for overall effect: Z = 6.49 (p < 0.00001)
1.4.2 European
Alba (2016) 1.09 0.43 9.5 2.97 (1.28–6.91)
Bria (2015) 2.56 1.71 0.6 12.94 (0.45–369.27)
Colleoni (2008) 2.16 0.73 3.3 8.67 (2.07–36.26)
Colleoni (2010) 1.47 0.47 7.9 4.35 (1.73–10.93)
)
Colleoni (2010) 0.63 1.12 1.4 1.88 (0.21–16.86)
Darb-Esfahani (2009) 2.34 1.06 1.6 10.38 (1.30–82.89)
Denkert (2013) 1.78 0.28 22.4 5.93 (3.43–10.27)
Estevez (2003) 0.19 0.98 1.8 1.21 (0.18–8.25)
Fasching (2011) 1.26 0.5 7.0 3.53 (1.32–9.39)
GRIM 2012) 2.35 1.08 1.5 10.49 (1.26–87.07)
Guarneri (2009) 1.35 1.05 1.6 3.86 (0.49–30.20)
Hashimoto (2014) 1.82 1.11 1.4 6.17 (0.70–54.36)
Humbert (2015 1.5 0.86 2.4 4.48 (0.83–24.18)
Ingolf (2014) 0.62 0.63 4.4 1.86 (0.54–6.39)
Jin (2013) 0.34 0.57 5.4 1.40 (0.46–4.29)
Keam (2011) 2.57 1.46 0.8 13.07 (0.75–228.50)
Lips (2012) -1.24 1.17 1.3 0.29 (0.03–2.87)
Montagna (2010) 1.4 0.41 10.4 4.06 (1.82–9.06)
Petit (2004) 1.8 0.67 3.9 6.05 (1.63–22.49)
Petit (2010) 2.31 1.06 1.6 10.07 (1.26–80.44)
Sanchez-Muñoz (2013) 1.7 0.69 3.7 5.47 (1.42–21.17]
Saracchini (2013) 2.35 1.13 1.4 10.49 (1.14–96.04)
Schmid (2005) 3.38 1.5 0.8 29.37 (1.55–555.54)
Vincent-Salomon (2004) 1.42 0.67 3.9 4.14 (1.11–15.38)
Subtotal (95% CI) 100.0 4.23 (3.26–5.48)
Heterogeneity: Tau2 = 0.00; Chi2 = 22.08, df = 23 (p = 0.52); I2 = 0%
Test for overall effect: Z = 10.88 (p < 0.00001)
1.4.3 other
Kraus (2012) 1.42 1.54 100.0 4.14 (0.20–84.63)
Subtotal (95% CI) 100.0 4.14 (0.20–84.63)
Heterogeneity: Not applicable
Test for overall effect: Z = 0.92 (p = 0.36)

Test for subgroup differences: Chi2 = 9.35. df = 2 (p = 0.009); I2 = 78.6%

0.01 0.1 1 10 100

Figure 7. Subgroup analysis for different ethnic origins.

10.2217/fon-2016-0420 Future Oncol. (Epub ahead of print) future science group

 Ki-67 & pCR in neoadjuvant setting for breast cancer
chance to respond to NAC, which may seem
to be a logical consequence of the administra-
tion of cytostatics, targeted on rapidly dividing
cells [1,48] . Ki-67 is expressed in the G1, S, G2
and M phase of the cell cycle, but not in rest-
ing cells in G0 [7] , so Ki-67 could be evaluated
to assess tumor proliferation [54] . High Ki-67
represents high tumor proliferation and rapid
dividing cells, so NAC usually target on divid-
ing cells and further kill or destroy tumor cells.
However, in some studies, Ki-67 did not predict
pCR, probably due to heterogeneous patient
populations, small sample size, poor repre-
sentativeness of the tumor tissues derived from
core biopsies and different NAC regimens [12] .
Even though, the pooled results of univariate
and multivariate data did not vary too much,
which suggest that Ki-67 might be not only
a predictor for pCR, but also an independent
­predictor for pCR.
No consensus achieved on the standard val-
ues for classifying Ki-67 as high or low, so lots
of cut-off points were used, seven studies used
cut-off values that were lower than 14%, five
used 14%, three used 15%, 13 used 20%, four
used 25%, five used the cut-off points that were
more than 25%, less than 50%, and four used
the cut-off points that were more than 50%.
There were also some studies which categorized
Ki-67 into low, median and high levels. We
used <15%, 15%, 20%, 21–49%, ≥50% and
the pooled results of different cut-off points
showed Ki-67 could predict pCR. In order to
find the best cut-off point, several studies were
conducted. Kim et al. [49] identified 25% as
the optimal cut-off value by receiver operating
characteristic (ROC) curve analysis. However,
another study conducted by Alba et al. showed
that the Ki-67 cut-off points with the highest
combined sensitivity and specificity values was
50% [55] . But Denkert et al. [18] found a wide
range of Ki-67 cut-off points between 3 and
94% for pCR was significant using the stand-
ardized cut-off finder algorithm for pCR. The
best cut-off point might be different among
different molecular types. Fasching et al. [22]
showed that the optimal cut-off points were
between 30 and 40% for triple-negative breast
cancer, between 36 and 40% for HR+, HER2-
breast cancer, between 17 and 20% for HER2 +
breast cancer based on empirical cut-off calcu-
lations. Sueta et al. [52] showed that the opti-
mal cut-off of Ki-67 level in ER- breast cancer
using ROC analysis was 35%. Horimoto et al.
future science group
Systematic Review
showed that the most effective cut-off Ki-67
value for predicting pCR was 35%, and the
ROC plot with 35% as the Ki-67 cut-off value
was closest to the perfect classification for
HER2- breast cancer [57] . All available studies
used data-derived ‘optimal’ cut-points, which
can result in serious bias due to different patient
populations [58] . Meanwhile, we could see that
the optimal cut-off points might vary across
different molecular types. Based on our study,
we found 15 and 20% could be good cut-off
points, which were due to highest OR values
and consistent results across studies and low
statistical heterogeneity. However, we could not
conclude whether these two were the best.
Four studies analyzed the relationship
between Ki-67 and pCR using continuous data,
even some of them were of few pCR events,
but all these studies showed that Ki-67 was
an independent predictor for pCR. This not
only strengthens the conclusion that Ki-67
might be a predictor for pCR, but also requires
researchers to establish a rational criterion for
the cut-off value in order to predict the pCR,
because Ki-67 as a continuous variable did not
help guide NAC decisions. However, some
researchers believed that Ki-67 was a continu-
ous marker, as Ki-67 reflects the percentage
of proliferating cells in the tumor, which can
reach any value between 0 and 100% from a
tumor biological point of view. And they stated
that the optimal cut-off point for Ki-67 might
not exist [54] . Meanwhile, transforming con-
tinuous variables into two categories can lead
to a loss of power and a statistical model with
continuous values could provide more informa-
tion [58] . But it is less suitable to consider Ki-67
as a continuous marker with respect to clinical
decisions [54] . As sometimes treatment recom-
mendations depend on an accurate diagnosis
with Ki-67, some other researchers appealed to
develop accepted cut-off points [59] . The 2009
St Gallen Consensus has recommended using
markers of proliferation, such as Ki-67, in deter-
mining the optimum treatment for early breast
cancer [9] .
●●Strength & limitations
This was the first systematic review and meta-
analysis which focused on the predictive value
of Ki-67 before NAC based on 53 studies and
10,848 breast cancer patients. However, our
study has its own limitations: first, only English
studies were included, which might introduce
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Systematic Review Chen, He, Han et al.

selective bias, although no publication bias was
found. Second, there might be clinical hetero-
geneity among studies, such as different NAC,
baselines of populations, methods of detecting
of Ki-67 and different cut-off points, so we used
random effect model in order to incorporate the
influence of heterogeneity. Third, the clinical
stage of breast cancer might affect the meta-
analysis, as some studies even included stage
IV breast cancer patients. This means for any-
one surgery was possible if they were suitable
for surgery after NAC and NAC did not have
any special requirements for clinical stages for
breast cancer patients. But due to limited data,
we could not conduct further analysis. Fourth:
the level of quality of evidence was not high,
most of them were of low quality and some were
of very low quality (Supplementary Table 2) .
●●Implications to future practice & research
Based on our study, Ki-67 before NAC might
be a predictor for pCR. Ki-67 before NAC
could predict response to NAC in order to
induce a better response [7] . Ki-67 was a feasi-
ble marker for development of individualized
treatment options for breast cancer patients.
So the routine detection of the Ki-67 prolif-
eration marker before NAC should be recom-
mended. The use of Ki-67 in neoadjuvant
setting could be helpful in deciding whether
to give NAC based on judging the potential
benefits and the possibility of achieving pCR.
Those patients whose tumors have high Ki-67
before NAC might benefit from NAC and
have a high probability of achieving pCR,
and further increase the overall survival and
recurrence-free survival. Those patients whose
tumors have relatively low Ki-67 at diagnosis
are unlikely to benefit from additional therapy,
even if it were predicted to work, because of
their excellent prognosis [10] .
Although lots of studies were available,
the proper Ki-67 cut-off values could not be
defined until now. Although there were several
studies trying to find a proper cut-off for high
Ki-67, no consensus was achieved, and no other
studies validated those cut-off points. In this
condition, it was suggested to set Ki-67 at a
higher level to allow prediction of the chemo-
therapy response, at least 15% [22] . Although
most included studies were >100, due to the
low incidence of pCR, most studies did not
conduct multivariate analysis, and most studies
analyzed the pCR rate between high and low
Ki-67 by univariate analyses without adjust-
ing other factors including other independent
biomarkers [32] . This means that the influ-
ences of other factors, which might affect the
effectiveness of NAC, were not adjusted. So in
the future, the multivariate analysis should be
conducted and the results should be presented
if possible.
Conclusion
Based on our study, we could conclude that
Ki-67 might predict the response by pCR and
detection of pretreatment Ki-67 could iden-
tify patients most likely to benefit from NAC.
The use of Ki-67 in breast cancers could be a
routine part of pathology practice before NAC
but efforts should be made to develop accepted
cut-off points.

Executive summary
●● This systematic review of 53 studies (10,848 patients) showed there was a statistical difference in pathologic complete
response (pCR) between high and low Ki-67 expression for breast cancer patients who received neoadjuvant
chemotherapy (NAC).
●● The variations in Ki-67 cut-off points and pCR definitions did not change the statistical difference in pCR between high
and low Ki-67 expression.
●● Ki-67 could also predict pCR in HR+, HER2+ and triple-negative breast cancer patients, those who received NAC
containing plus taxanes and anthracyclines only, and those from Asia and Europe, but not in ER- breast cancer patients,
those who received taxanes only and those from America.
●● No consensus achieved on the standard values for classifying Ki-67 as high or low, we found 15 and 20% might
be good cut-off points, which were due to highest odds ratio values and consistent results across studies and low
statistical heterogeneity.
●● We could conclude that Ki-67 might predict the response by pCR and detection of pretreatment Ki-67 could identify
patients most likely to benefit from NAC.

10.2217/fon-2016-0420 Future Oncol. (Epub ahead of print) future science group

 Ki-67 & pCR in neoadjuvant setting for breast cancer
Supplementary data
To view the supplementary data that accompany this paper
please visit the journal website at: http://www.futuremedi-
cine.com/doi/full/10.2217/fon-2016-0420
Author contributions
The study design was done by L Li, C He, D Han, M
Zhou, Q Wang, J Tian, X Chen, F Xu , E Zhou, K Yang.
The literature search was done by L Li, J Tian. The study
selection was done by L Li, D Han, K Yang. The data
extraction/preparation was done by L Li, Q Wang. The
Data analyses were done by L Li, J Tian, K Yang. The
data interpretation was done by L Li, C He, D Han, M
Zhou, Q Wang, J Tian, X Chen, F Xu, E Zhou, K Yang.
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Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan-
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or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
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