Download Prognostic Value of Breast Cancer Subtypes, Ki67 Proliferation

ORIGINAL ARTICLE
Prognostic Value of Breast Cancer Subtypes, Ki-67
Proliferation Index, Age, and Pathologic Tumor
Characteristics on Breast Cancer Survival in
Caucasian Women
N. Lynn Ferguson, MD,*a John Bell, MD,† Robert Heidel, PhD,§
Solomon Lee, DO,* Stuart VanMeter, MD,* Lisa Duncan, MD,*
Barbara Munsey, BS,¶ Timothy Panella, MD,‡ and Amila Orucevic, MD, PhD*
*University of Tennessee Medical Center at Knoxville, Graduate School of Medicine, Department of
Pathology, Knoxville, TN, USA; †University of Tennessee Medical Center at Knoxville, Graduate
School of Medicine, Department of Surgery, Knoxville, TN, USA; ‡University of Tennessee Medical
Center at Knoxville, Graduate School of Medicine, Department of Internal Medicine, Knoxville, TN,
USA; §University of Tennessee Medical Center at Knoxville, Graduate School of Medicine, Knoxville,
TN, USA; ¶University of Tennessee Medical Center at Knoxville, Cancer Center, Knoxville, TN, USA
n
Abstract: Estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) status
are well-established prognostic markers in breast cancer management. The triple negative breast carcinoma subtype (ER-/
PR-/HER2-) has been associated with worse overall prognosis in comparison with other subtypes in study populations consisting of ethnic minorities and young women. We evaluated the prognostic value of breast cancer subtypes, Ki-67 proliferation index (Ki-67PI), and pathologic tumor characteristics on breast cancer survival in Caucasian women in our institution,
where greater than 90% of the total patient population is white. From 628 new invasive breast cancer cases in our data
base (2000-late 2004), 593 (94%) were identified in Caucasian women. ER/PR/HER2 breast cancer subtypes were classified based on St. Gallen International Expert Consensus recommendations from 2011. ER/PR/HER2 status and its effect
on survival were analyzed using a Kaplan–Meier curve. ER/PR/HER2 status, grade, tumor-node-metastasis status (TNM)/
anatomic stage, and age were analyzed in terms of survival in a multivariate fashion using a Cox regression. Ki-67PI was
analyzed between ER/PR/HER2 groups using the Kruskal–Wallis, Mann–Whitney U-tests, and 2 9 5 ANOVA. Our results
showed that patients with stage IIB through stage IV breast carcinomas were 2.1–16 times more likely to die than patients
with stages IA-B and IIA disease, respectively (95% CI 1.17–3.81 through 9.68–28.03, respectively), irrespective of ER/PR/
HER2 subtype. Similar effect was seen with T2, N2/N3, or M1 tumors in comparison with T1, N0/N1, and M0 tumors.
Chances of dying increase approximately 5% for every year increase in age. There was a significant main effect of Ki-67PI
between ER/PR/HER2 subtypes, p < .001, but Ki-67PI could not predict survival. In summary, TNM status/anatomic stage
of breast carcinomas and age are predictive of survival in our patient population of Caucasian women, but breast carcinoma
subtypes and Ki-67 proliferation index are not. n
Key Words: Breast cancer subtypes, Caucasian women, clinicopathologic characteristics of breast carcinoma, Ki-67 proliferation index, overall survival
Address correspondence and reprint requests to: Amila Orucevic, MD,
PhD, The University of Tennessee Medical Center, Department of Pathology, 1924 Alcoa Highway, Knoxville, TN 37920, USA, or e-mail: aorucevic@
utmck.edu.
a
The abstract with partial data from this manuscript received a 2012 The
Breast Journal Award, and Dr. Ferguson received the third place award
upon presentation of our work at the 17th Annual Multidisciplinary Symposium on Breast Disease in Amelia Island, Florida, in February 2012.
DOI: 10.1111/tbj.12059
© 2012 Wiley Periodicals, Inc., 1075-122X/13
The Breast Journal, Volume 19 Number 1, 2013 22–30
INTRODUCTION
B
ased on the American Cancer Society Cancer
Facts and Figures 2012 data for breast cancer (1),
226,870 new cases of invasive breast cancer are anticipated to occur among women in the United States
during 2012. Incidence of breast cancer rates was stable from 2004 to 2008 (most recent available data),
and death rates have progressively decreased in
Breast Cancer Prognostic Markers & Survival • 23
women since 1990, with larger decreases in younger
women. The decrease in breast cancer death rates is
assumed to be a result of earlier detection, improved
treatment, and perhaps decreased incidence (1).
Codification of tumor staging into the TNM system by the American Joint Committee on Cancer
(AJCC) celebrated its 50th anniversary in 2009, and
relevance of TNM staging for breast cancer in the
21st century was questioned by the Breast Cancer
Task Force (2). While T, N, and M still provide value
in establishing the future outcome of breast cancer
patients, determination of estrogen receptor (ER),
progesterone receptor (PR), and epidermal growth
factor receptor 2 (HER2) status has both prognostic
and predictive values in breast cancer management
(3–6), and testing for them is now considered standard of care (7).
The triple negative breast carcinoma subtype
(ER /PR /HER2 ) has been associated with worse
overall prognosis in comparison with other subtypes
in study populations consisting of ethnic minorities
and young women (8–16). Only a few studies tried to
address causes for possible differences in overall prognosis and survival between African-American and
Caucasian women with breast cancer, and relationship of ER/PR/HER2 status/subtype of breast cancer
with socioeconomic influences such as poverty, diet,
body mass index, history of pregnancy, oral contraceptive use, and postmenopausal hormone replacement was discussed with not entirely conclusive
results (10,12,13,17,18). A single study of an allwhite patient population from Scotland suggested that
a higher risk of ER-negative breast cancer is correlated with a lifelong history of poverty (19). Similar
results were reported in the United States in a report
by Gordon (20). The studies mentioned previously
clearly identified the need for more research to better
understand the relationship between race and breast
cancer.
Owing to the geographic location of our institution
in East Tennessee, greater than 90% of the total
patient population is white. More than 95% of breast
cancer patients diagnosed in our institution are also
treated and followed in our institution. We evaluated
the prognostic value of breast cancer subtypes, Ki-67
proliferation index, and pathologic tumor characteristics on breast cancer survival in a large cohort of Caucasian women diagnosed and treated for breast cancer
in our institution.
MATERIALS AND METHODS
Selection and Description of Participants
Our study population is a retrospective cohort
group taken from a prospectively monitored data base
of 593 Caucasian women diagnosed with primary
breast cancer between January 1, 2000 and September
8, 2004, with an age range of 23–98. This time frame
was chosen to assure a minimum of 5 years of followup data. The patients were treated and followed at
our academic institution located in Knoxville, Tennessee, where greater than 90% of the total patient population is Caucasian.
After obtaining Institutional Review Board
approval, we searched our institution’s cancer center
data base for newly diagnosed invasive breast cancer
cases in women, spanning from the year 2000 to
2004. A total of 628 new invasive breast cancer cases
were identified in women. Among those, 593 (94%)
patients were Caucasian, 27 (4.2%) were African
American, and eight (1.2%) were of unknown ethnicity. We chose only the 593 Caucasian women as our
study cohort and analyzed the following clinicopathologic characteristics: age, tumor type, tumor size,
tumor grade, Nottingham score, tumor-node-metastasis status, anatomic stage/prognostic groups, ER/PR/
HER2 status, Ki-67 proliferation index, and overall
survival status.
Determination of Clinicopathologic Tumor
Characteristics, Breast Cancer Subtype, and
KI-67 Proliferation Index
Tumor type was determined based on World
Health Organization classification (21). Tumor size,
Nottingham score, and histologic tumor grade (the
Nottingham combined histologic grade) were evaluated at the time of the pathologic assessment of the
tumors based on established criteria (21–23) and were
extrapolated from the pathology reports.
Tumor-node-metastasis status was assigned based
on the AJCC staging system that was in place at the
time of assessment (24,25) and was restaged in our
study to the newest AJCC staging system (edn 7) (2).
Stages IA and IB were combined in our study.
Estrogen receptor, PR, and HER2 status and Ki-67
proliferation index were determined at the time of the
patient’s cancer assessment by immunohistochemical
24 • lynn ferguson et al.
methods on a selected tumor block of the needle core
biopsy tissue and/or a selected tumor block after final
surgical excision. ER and PR were considered positive
with >1% of the nuclear staining, based on the newest
ASCO/CAP guidelines for immunohistochemical
testing for estrogen and progesterone receptor in
breast cancer (26). HER2 was considered overexpressed with 3+ score positivity by immunocytochemical
methods and negative with 0+ or 1+ immunoreactivity. Tumor blocks with 2+ immunohistochemical
scores were sent for fluorescence in situ hybridization
to an independent reference laboratory, and a ratio of
>2.2 of HER2-neu gene to chromosome 17 was considered positive for HER2 gene overexpression. Ki-67
proliferation index was determined in the area with
highest Ki-67 nuclear labeling. A total of 300 proliferating and nonproliferating cells were counted, and the
percentage of proliferating cells was calculated and
reported as percent proliferating cells.
Patient’s Inclusion into the Study, Treatment
and Survival
Patients with synchronous invasive cancers in both
breasts with different ER/PR/HER2 status, multifocal
cancers in the same breast with different ER/PR/HER2
status, and patients with newly diagnosed breast cancer with synchronous or metachronous malignancies
of other organs were excluded from our study. All of
the patients were diagnosed with stages I to IV primary breast cancer and underwent surgical treatment,
adjuvant chemotherapy, and radiation therapy according to standard treatment protocols at the time of the
diagnosis, based on NCCN guidelines on similar
evidence-based data at the time of diagnosis (27).
ER-positive patients underwent antihormonal treatment and HER2-positive patients received anti-HER2
therapy only when diagnosed with systemic metastatic
disease. Follow-up status and outcome information
were obtained from our cancer registry data base, and
in the case of patients who were still living, the last
date of follow-up was March 11, 2011.
Statistical Analysis
Breast cancer subtypes (ER/PR/HER2 status) and
other clinicopathologic characteristics of invasive
carcinomas were examined using frequency statistics,
after dividing patients into five groups based on their
cancer subtype per the St. Gallen International Expert
Consensus recommendation from 2011 (28) as follows: group 1—luminal A-like subtype = ER and/or
PR positive, HER2 negative, and Ki-67 proliferation
index less than 14% (ER+/PR+/HER2 ; ER+/PR /
HER2 ; and ER /PR+/HER2 ); group 2—luminal
B-/HER2-negative-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index
more than 14% (ER+/PR+/HER2 ; ER+/PR /
HER2 ; and ER /PR+/HER2 ); group 3—luminal
B-/HER2-positive-like subtype = ER and/or PR positive, HER2 positive, and any Ki-67 proliferation index
(ER+/PR+/HER2+; ER+/PR /HER2+; and ER /PR+/
HER2+); group 4—HER2-positive-/nonluminal-like
subtype with ER and PR negative, HER2 positive
(ER /PR /HER2+), and any Ki-67 proliferation
index; and group 5—triple negative subtype = ER and
PR negative and HER2 negative (ER /PR /HER2 ),
and any Ki-67 proliferation index. Totally, 554
patients had complete data on ER/PR/HER2 status
and the following clinicopathologic characteristics:
age, tumor morphology, Nottingham score and overall
grade, tumor status, anatomic stage/prognostic groups,
and survival status. Five hundred and twenty-nine
patients with known ER/PR/HER2 status had known
nodal status, 549 patients had known metastasis status, 541 patients had known tumor size, and 464 had
known Ki-67 proliferation index. However, with ER/
PR/HER2 grouping based on the St. Gallen International Consensus recommendations that included
Ki-67 proliferation index, 493 patients were eligible to
be analyzed in this study.
The Kaplan–Meier curve was used as a univariate
analysis looking at how the five ER/PR/HER2 groups
differed in terms of survival. The Cox regression curve
was used as a multivariate analysis looking at how the
five ER/PR/HER2 groups differed in terms of survival
when controlled for age, grade, tumor status, nodal
status, and metastasis status (extraneous variables), or
when controlled for age, grade, and anatomic stage/
prognostic groups.
The Kruskal–Wallis test was used to test for any
effects in Ki-67 proliferation index between the five
ER/PR/HER2 groups. The Mann–Whitney U-test was
utilized in a post hoc fashion to explain any significant
main effect found. Then, 2 9 5 factorial ANOVA was
employed to test for significant main effects and interactions between the five ER/PR/HER2 groups and
mortality in regard to Ki-67. All analyses were conducted using SPSS Version 19 (SPSS, Chicago, IL), and
statistical significance was assumed at a p < .05 level.
Breast Cancer Prognostic Markers & Survival • 25
Table 1. Clinicopathologic Characteristics of Invasive Carcinomas
ER/PR/HER2 frequency
Age*
Type**
Grade**
Nottingham score*
Size (mm)*
Ki-67 %*
T stage**
N stage**
M stage**
Anatomic stage**
Survival months
Group 1
Group 2
Group 3
Group 4
Group 5
149 = 30.2%
63.07
IDC
1–2
5
18.16
7.62
1
0
0
IA-B
109.6
163 = 33%
59.24
IDC
2
7
23.41
30.08
1
0
0
IA-B
111.3
55 = 11.1%
53.18
IDC
3
7
24.56
31.37
1
0
0
IA-B
117.4
38 = 7.7%
53.68
IDC
3
8
24.2
43.13
1
0
0
IA-B-IIA
107.5
88 = 17.8%
52.82
IDC
3
8
23.08
51.55
1
0
0
IA-B
100.9
*mean value.
**most frequent; IDC = invasive ductal carcinoma.
group 1—luminal A-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index less than 14% (ER+/PR+/HER2 ; ER+/PR /HER2 ; and ER /PR+/HER2 ).
group 2—luminal B-/HER2-negative-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index more than 14% (ER+/PR+/HER2 ; ER+/PR /HER2 ; and ER /
PR+/HER2 ).
group 3—luminal B-/HER2-positive-like subtype = ER and/or PR positive, HER2 positive, and any Ki-67 proliferation index (ER+/PR+/HER2+; ER+/PR /HER2+; and ER /PR+/HER2+).
group 4—HER2-positive-/nonluminal-like subtype = ER and PR negative, HER2 positive (ER /PR /HER2+), and any Ki-67 proliferation index.
group 5—triple negative subtype = ER and PR negative and HER2 negative (ER /PR /HER2 ) and any Ki-67 proliferation index.
RESULTS
Our patient population of 493 Caucasian women
was divided into five groups based on their cancer
subtype per the St. Gallen International Expert Consensus recommendations from 2011 (28): group 1—
luminal A-like subtype = ER and/or PR positive,
HER2 negative, and Ki-67 proliferation index less
than 14% (ER+/PR+/HER2 ; ER+/PR /HER2 ; and
ER /PR+/HER2 ); group 2—luminal B-/HER2-negative-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index more than 14%
(ER+/PR+/HER2 ; ER+/PR /HER2 ; and ER /PR+/
HER2 ); group 3—luminal B-/HER2-positive-like
subtype = ER and/or PR positive, HER2 positive, and
any Ki-67 proliferation index (ER+/PR+/HER2+; ER+/
PR /HER2+; and ER /PR+/HER2+); group 4—
HER2-positive-/nonluminal-like subtype with ER and
PR negative, HER2 positive (ER /PR /HER2+), and
any Ki-67 proliferation index; and group 5—triple
negative subtype = ER and PR negative and HER2
negative (ER /PR /HER2 ), and any Ki-67 proliferation index.
The clinicopathologic characteristics of invasive
carcinomas for each group are summarized in Table 1,
showing that the most frequent prognostic subtype
was luminal B-/HER2-negative-like subtype (group 2),
comprising 33% of the total, immediately followed by
luminal A-like subtype. The youngest patients were in
triple negative carcinoma subtype (mean age 52.82),
and the oldest patients were in luminal A-like subtype
(mean age 63.07). The most frequent tumor type for
all groups was invasive ductal carcinoma. Mean Nottingham score for luminal A-like subtype was 5, luminal B-/HER2-negative-like subtype and luminal B-/
HER2-positive-like subtype was 7, and HER2-positive-/nonluminal-like subtype and triple negative subtype was 8.
The most frequent overall Nottingham grade 3 was
seen in triple negative, HER2-positive-/nonluminal-like
subtype, and luminal B-/HER2-positive-like subtype,
and grades 2 and 1–2 were seen in luminal B-/HER2negative-like subtype and luminal A-like subtype. Of
note, an overall Nottingham grade 1 was not seen in
triple negative carcinoma subtype or in HER2-positive-/nonluminal-like subtype (Table 2).
Table 3 shows frequencies of tumor stage, node
stage, and metastasis stage for each of the five ER/PR/
HER2 groups. The most frequent tumor stage and
node stage were 1 and 0, respectively, for all groups,
while patients from HER2-positive-/nonluminal-like
group had most frequent metastases.
Table 4 shows distribution of anatomic stage/prognostic groups for each of ER/PR/HER2 groups. The
most frequent cancer stage was stages IA-B, while
HER2-positive-/nonluminal-like group had equal distribution of stages IA-B and stage IIA.
Figure 1 shows the Kaplan–Meier curve for cumulative survival in months according to the five ER/PR/
HER2 groups. This curve showed no significant difference in survival, p = .358. It is interesting to note that
5-year survival rate was the best for luminal A-like
group = 77%, followed by luminal B-/HER-negativelike group = 76%, HER2-positive-/nonluminal-like
26 • lynn ferguson et al.
Table 2. Distribution of Overall Nottingham Grade
in Patients Divided into Five Groups Based on
ER/PR/HER2 Carcinoma Subtypes Classified
Based on the St. Gallen International Expert Consensus Recommendations from 2011 (28)
Group
Group
Group
Group
Group
Total
1
2
3
4
5
Grade 1
Grade 2
Grade 3
Total
71
22
9
0
0
102
76
77
22
12
15
202
2
64
24
26
73
189
149
163
55
38
88
493
group 1—luminal A-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index less than 14% (ER+/PR+/HER2-; ER+/PR /HER2 ; and ER /PR+/
HER2 ).
group 2—luminal B-/HER2-negative-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index more than 14% (ER+/PR+/HER2 ; ER+/PR /HER2 ;
and ER /PR+/HER2 ).
group 3—luminal B-/HER2-positive-like subtype = ER and/or PR positive, HER2 positive,
and any Ki-67 proliferation index (ER+/PR+/HER2+; ER+/PR /HER2+; and ER /PR+/
HER2+).
group 4—HER2-positive-/nonluminal-like subtype = ER and PR negative, HER2 positive
(ER /PR /HER2+), and any Ki-67 proliferation index.
group 5—triple negative subtype = ER and PR negative and HER2 negative (ER /PR /
HER2 ) and any Ki-67 proliferation index.
Table 3. Frequencies of Tumor Stage, Nodal
Stage and Metastasis Stage of Invasive Carcinomas in Five ER/PR/HER2 Carcinoma Subtypes
Classified Based on the St. Gallen International
Expert Consensus Recommendations from 2011
(28)
T1
Group
Group
Group
Group
Group
Total
1
2
3
4
5
112 =
92 =
32 =
18 =
46 =
300
T2
75%
56.4%
58.1%
47.3%
52.2
26 =
48 =
11 =
15 =
32 =
132
N0
Group
Group
Group
Group
Group
Total
1
2
3
4
5
100 =
100 =
27 =
20 =
47 =
294
17%
29.4
20%
39.4%
36.3
N1
70.9%
64.5%
50%
57.1%
56.6%
30 =
35 =
20 =
12 =
24 =
121
21.2%
22.5%
37%
34.3%
28.9%
M0
group = 74%, and luminal B-/HER2-positive-like subtype = 67%. The lowest 5-year survival (69%) was
seen in the triple negative group.
When the Cox regression curve for cumulative survival in months according to the five ER/PR/HER2
groups was controlled for anatomic stage/prognostic
groups, tumor grade, and age when predicting for survival, stages IIB through IV and age had significant
effects on survival (Fig. 2 and Table 5), but hormone
receptor status and grade did not within the model.
The results found that the chances of dying increases
4.8% for every year increase in age.
When the Cox regression curve for cumulative survival in months according to the five ER/PR/HER2
groups was controlled for tumor-node-metastasis status, grade, and age in terms of survival, only tumor
stage, node stage, metastasis stage, and age were significant predictors of death, while hormone receptor
status and grade were not significant. The patients
with T2 tumors, N2, N3 tumors and M1 tumors were
1.72 times; 2.79 times, 2.63 times, and 4.0 times more
likely to die than patients with T1, N0/N1 tumors,
and M0 tumors, respectively (95% CI 1.093–2.729
for T2; 1.48–5.25 for N2, 1.17–5.92 for N3; and 1.66
–9.64 for M1; Fig. 3), when controlled for hormone
receptor status.
Figure 4 demonstrates the Ki-67 proliferation index
for each of the five ER/PR/HER2 groups. There was a
significant difference in Ki-67 proliferation index
Group
Group
Group
Group
Group
Total
1
2
3
4
5
141 =
150 =
52 =
34 =
83 =
460
95.3%
9.4%
94.5%
91.9%
94.3%
T3
8=
14 =
6=
0=
8=
36
5.3%
8.5%
10.9%
0%
9%
3=
9=
6=
5=
2=
25
N2
8=
12 =
3=
2=
10 =
35
5.6%
7.7%
55.6%
5.7%
12.0%
M1
7=
10 =
3=
3=
5=
28
4.7%
6.3%
5.5%
8.1%
5.7%
T4
Total
2%
5.5%
10.9%
13.1%
2.2%
149
163
55
38
88
493
N3
Total
3=
8=
4=
1=
2=
18
2.1%
5.2%
7.4%
2.9%
2.4%
141
155
54
35
83
468
Total
148
160
55
37
88
488
group 1—luminal A-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index less than 14% (ER+/PR+/HER2 ; ER+/PR /HER2 ; and ER /PR+/
HER2 ).
group 2—luminal B-/HER2-negative-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index more than 14% (ER+/PR+/HER2 ; ER+/PR /HER2 ;
and ER /PR+/HER2 ).
group 3—luminal B-/HER2-positive-like subtype = ER and/or PR positive, HER2 positive,
and any Ki-67 proliferation index (ER+/PR+/HER2+; ER+/PR /HER2+; and ER /PR+/
HER2+).
group 4—HER2-positive-/nonluminal-like subtype = ER and PR negative, HER2 positive
(ER /PR /HER2+), and any Ki-67 proliferation index.
group 5—triple negative subtype = ER and PR negative and HER2 negative (ER /PR /
HER2 ) and any Ki-67 proliferation index.
values between the five groups with p < .001. Mann–
Whitney U-tests found significant difference in the Ki67 proliferation index between groups 1 and 2, groups
1 and 3, groups 1 and 4, groups 1 and 5, groups 2
and 4, groups 2 and 5, and groups 3 and 5, with
p < .001; groups 3 and 4, p = .003; and groups 4 and
5, p = .043, while no significant effect was seen
between groups 2 and 3, p = .413. The means are presented in Table 1. Despite the significant main effect
and subsequent post hoc findings, when mortality was
accounted for in the 2 9 5 factorial ANOVA, a nonsignificant interaction was found, F(4, 454) = .90,
p = .465, g2 = .01, power = .29, meaning there was
evidence that Ki-67 proliferation index does not have
an impact on survival of patients when divided into
the five ER/PR/HER2 groups.
Breast Cancer Prognostic Markers & Survival • 27
Table 4. Distribution of Anatomic Stage/Prognostic Groups of Invasive Carcinomas in Five ER/PR/
HER2 Carcinoma Subtypes Classified Based on
the St. Gallen International Expert Consensus
Recommendations from 2011 (28)
Group
Group
Group
Group
Group
Total
1
2
3
4
5
IA-B
IIA
IIB
IIIA
IIIB
IIIC
IV
Total
89
79
22
12
37
239
33
33
11
12
15
104
10
18
8
6
17
59
6
13
5
1
12
37
1
3
4
3
1
12
3
6
2
1
1
13
7
10
3
3
5
28
149
162
55
38
88
492
group 1—luminal A-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index less than 14% (ER+/PR+/HER2-; ER+/PR /HER2 ; and ER /PR+/
HER2 ).
group 2—luminal B-/HER2-negative-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index more than 14% (ER+/PR+/HER2 ; ER+/PR /HER2 ;
and ER /PR+/HER2 ).
group 3—luminal B-/HER2-positive-like subtype = ER and/or PR positive, HER2 positive,
and any Ki-67 proliferation index (ER+/PR+/HER2+; ER+/PR /HER2+; and ER /PR+/
HER2+).
group 4—HER2-positive-/nonluminal-like subtype = ER and PR negative, HER2 positive
(ER /PR /HER2+), and any Ki-67 proliferation index.
group 5—triple negative subtype = ER and PR negative and HER2 negative (ER /PR /
HER2 ) and any Ki-67 proliferation index.
Figure 2. Survival for the five ER/PR/HER2 groups classified
based on the St. Gallen International Expert Consensus recommendations from 2011 (28), when controlled for anatomic stage/
prognostic groups, tumor grade, and age. Stage IIB and higher
(IIB-IV), and age were significant predictors of death, but breast
carcinoma subtype and grade were not significant.
Table 5. Cox Regression for Five ER/PR/HER2
Carcinoma Subtypes Classified Based on the St.
Gallen International Expert Consensus Recommendations from 2011 (28) When Controlled for
Grade, Stage, and Age
Significance
(p-value)
Figure 1. The Kaplan–Meier curve for cumulative survival in
months according to the five ER/PR/HER2 groups classified based
on the St. Gallen International Expert Consensus recommendations from 2011 (28). This curve showed no significant difference
in survival, with p = .358.
DISCUSSION
We evaluated the prognostic value of breast cancer
subtypes, Ki-67 proliferation index and pathologic
tumor characteristics on breast cancer survival in Caucasian women in our institution, where greater than
90% of the total patient population is white. The
median follow-up length of time of our patient cohort
was 9 years.
Group 1
Group 2
Group 3
Group 4
Group 5
Grade 1
Grade 2
Grade 3
Stages IA-B
Stage IIA
Stage IIB
Stage IIIA
Stage IIIB
Stage IIIC
Stage IV
Age
.144
.192
.454
.864
.346
.563
.814
.380
.000
.912
.013
.000
.008
.000
.000
.000
Adjusted
odds ratio
95%
CI lower
95%
CI upper
.720
.768
.931
1.367
.439
.384
.412
.714
1.180
1.533
2.106
2.620
1.068
1.353
.615
.688
1.858
2.660
.970
2.115
3.496
3.352
5.856
16.475
1.048
.561
1.172
1.973
1.368
2.651
9.680
1.033
1.674
3.814
6.195
8.212
12.937
28.038
1.064
group 1—luminal A-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index less than 14% (ER+/PR+/HER2-; ER+/PR /HER2 ; and ER /PR+/
HER2 ).
group 2—luminal B-/HER2-negative-like subtype = ER and/or PR positive, HER2 negative, and Ki-67 proliferation index more than 14% (ER+/PR+/HER2 ; ER+/PR /HER2 ;
and ER /PR+/HER2 ).
group 3—luminal B-/HER2-positive-like subtype = ER and/or PR positive, HER2 positive,
and any Ki-67 proliferation index (ER+/PR+/HER2+; ER+/PR /HER2+; and ER /PR+/
HER2+).
group 4—HER2-positive-/nonluminal-like subtype = ER and PR negative, HER2 positive
(ER /PR /HER2+), and any Ki-67 proliferation index.
group 5—triple negative subtype = ER and PR negative and HER2 negative (ER /PR /
HER2 ) and any Ki-67 proliferation index.
28 • lynn ferguson et al.
Figure 3. Survival for the five ER/PR/HER2 groups classified
based on the St. Gallen International Expert Consensus recommendations from 2011 (28), when controlled for tumor-node-metastasis status, tumor grade, and age. T2 tumors, N2 and N3 tumors,
M1 tumors, and age were significant predictors of death, but breast
carcinoma subtype and grade were not significant.
60
50
40
30
Ki-67 PI %
20
10
0
Group Group Group Group Group
1
2
3
4
5
Figure 4. Ki-67 proliferation index (mean values) for the five ER/
PR/HER2 groups classified based on the St. Gallen International
Expert Consensus recommendations from 2011 (28). Ki-67 proliferation index was significantly different between majority of the
groups (p < .001 for groups 1&2, 1&3, 1&4, 1&5, 2&4, 2&5, 3&5;
p = .003 for groups 3&4; p = .043 for groups 4&5).
From our patient population of 593 Caucasian
women, 493 patients had complete data on ER/PR/
HER2 status and corresponding Ki-67 proliferation
index and were divided into five groups according to
their hormone receptor status/subtype based on the
cancer subtype classification per the St. Gallen International Expert Consensus recommendation from
2011 (28). St. Gallen’s recommendations account for
clinicopathologic classification of breast carcinoma
subtypes using immunohistochemical methods and Ki67 proliferation index rather than defining subtypes
by genetic array. Luminal A-like subtype was seen in
30% of our patients, luminal B-/HER2-negative-like
subtype in 33%, luminal B-/HER2-positive-like subtype in 11%, HER2-positive-/nonluminal-like subtype
in 7.7% and triple negative carcinoma subtype in
17.8%. The percent of patients in each group in our
study was similar to previously published data on
breast cancer in Caucasian women when tumors are
divided according to the hormone receptor subtype
(11,12,17,29) with percents for triple negative carcinoma ranging from 15% in O’Brien’s study to 21.8%
in Lund’s study (11,17).
The triple negative carcinoma subtype occurred in
younger patients (mean age 52.82) than the luminal
A-like carcinoma subtype (mean age 62.07) in our
study. This is similar to the data reported by Tawfik
et al. (12) who showed in their study that triple negative patients were significantly younger than nontriple
negative patients.
The most frequent tumor type in our patient
population was invasive ductal carcinoma (72%)
followed by invasive lobular carcinoma (11%),
invasive mammary carcinoma with ductal and lobular
features (10%), and other types (7%). This is in an
expected range for breast cancer (21), and is similar
to the previously published study by Tawfik et al. (12)
in a cohort of 700 patients from University of Kansas
Medical Center, with 83% of patients in their study
population being Caucasians. Interestingly, although,
in Tawfik’s study, 6.1% of triple negative patients had
overall Nottingham grade 1 (well-differentiated)
tumors, in our study, none of our triple negative
patients, nor patients with HER2-positive-/nonluminal-like subtype had well-differentiated tumors.
The Kaplan–Meier curve for cumulative survival in
months for patients divided into the five ER/PR/HER2
subtypes (luminal A-like, luminal B-like/HER2 ,
luminal B-like/HER2+, HER2+/nonluminal like, and
triple negative) showed no significant difference in survival in our study, although some trend was seen in
triple negative patients that had the shortest survival.
Interestingly, though, luminal B-/HER2-positive-like
patients in our study showed the longer survival than
luminal A-like patients. These results are in part concordant with data published by O’Brien et al. (17),
who evaluated influence of breast tumor subtypes,
race and long-term survival in the Carolina Breast
Breast Cancer Prognostic Markers & Survival • 29
Cancer Study on 1149 invasive breast cancer patients,
631 of which were Caucasians and 518 of which were
African American. In their study, triple negative
patients and ER /PR /HER2+ patients had a higher
mortality rate when compared with luminal A and B
subtypes, and mortality of triple negative white
patients was higher than triple negative African-American patients. This led them to conclude that the triple
negative breast cancer subtype was associated with
poor prognosis, but was not a more aggressive disease
in African-American patients than Caucasians, which
was similar to the results published by Tawfik et al.
(12). Results from the molecular phenotypes of tumors
collected between 1976–1997 in the Nurses Health
Study (3) also showed that triple negative tumors
(subdivided to basal like and unclassified), luminal B
and HER2-type tumors had worse prognosis than
luminal A tumor subtype, when tumor subtype was
defined by immunocytochemistry. However, in our
study, the longest surviving group was luminal B-/
HER2-positive like. The latter result could not be
explained by difference in treatment, because luminal
A-like and luminal B-/HER2-negative-like groups
received same hormonal treatment as luminal B-/
HER2-positive patients, and the anti-HER2 therapy
was given to three patients only with luminal B-/
HER2-positive subtype because of stage IV disease
(Table 3). As the triple negative patients in our study had
the shortest survival, followed by patients from HER2positive-/nonluminal-like group, it will be interesting to
find out in our ongoing study whether ER/PR/HER2 subtype had any significant impact on survival in patients
from our institution at a different time interval when antiHER2 treatment was starting to be used in combination
with adjuvant chemotherapy in HER2-positive patients
(year 2005 forward).
The Cox regression curve for cumulative survival in
months for patients divided into the five ER/PR/HER2
subtypes in our study, which controlled for anatomic
stage, grade and age showed that stage IIB through
stage IV, and age had significant effect on survival
(Fig. 2 and Table 5), but breast carcinoma subtype and
grade did not. Similar results were obtained when the
Cox regression curve for cumulative survival in months
according to the five ER/PR/HER2 groups in our study
was controlled for tumor-node-metastasis status, grade,
and age in terms of survival. Only tumor-node-metastasis stage and age were significant predictors of death,
while hormone receptor status was not significant (Fig.
3). Our data support the notion that TNM staging for
breast cancer in the 21st century is still relevant (2) and
that determination of estrogen receptor, progesterone
receptor, and HER2 status as both prognostic and predictive markers in breast cancer management (3–6) is
valid but is probably also influenced by the type of
classification system used for determining the ER/PR/
HER2 subtypes, characteristics of populations studied,
time periods of the study, as well as choice of variables
used in statistical analysis.
Ki-67 proliferation index was highest in the triple
negative breast carcinoma group in our study, followed by HER2-positive-/nonluminal-like group,
luminal B-/HER2-positive-like, luminal B-/HER2-negative-like, and luminal A-like subtypes. It has been
shown that proliferation was the strongest prognosticator in node-negative breast cancer (30). Combined
evaluation of the Ki-67 proliferation index and Oncotype DX recurrence score (the 10-year risk of recurrent distant disease predictive of clinical benefits from
chemotherapy in lymph node-negative, ER-positive
patients who are to receive tamoxifen therapy) (31)
was recently proposed by Gwin et al. (32). The combined evaluation would identify tumors with high
recurrence potential in a low-risk recurrence score
group and consequently identify patients who would
benefit from adjuvant chemotherapy. We evaluated
overall survival in our patients without regard of
node status and divided into five ER/PR/HER2 subtypes per recommendations from St. Gallen panelists
(28), in which classification of two subtypes also
depended on Ki-67 proliferation index. We showed
that in our study population, Ki-67 did not have significant impact on survival. It is possible that Ki-67
proliferation index is strong prognosticator and has a
complementary value only in certain breast cancer
patients, which was addressed in a recent study by
Aleskandarany et al. (33). They showed that Ki-67
proliferation index could separate subgroups of
patients within luminal/hormone receptor-positive
breast cancer with significantly different clinical outcome, but not in HER2-positive-/nonluminal-like or
triple negative patients. It will be interesting to find
out in our ongoing study whether Ki-67 proliferation
index had impact on patients’ survival when breast
carcinoma subtypes were again classified per St. Gallen panelists’ recommendations, but this time using
tumor grade rather than Ki-67 proliferation index
(28). This was recently used in the study by von
Minckwitz et al. (34) because Ki-67 data were not
available for their study cohort. Our ongoing study
30 • lynn ferguson et al.
will hopefully also validate St. Gallen panelists’ recommendations for the use of tumor grade in breast
carcinoma subtype classification in the absence of
Ki-67 proliferation index.
In summary, we evaluated the prognostic value of
breast cancer subtypes, Ki-67 proliferation index, and
pathologic tumor characteristics on breast cancer survival in Caucasian women in our institution, where
greater than 90% of the total patient population is
white. We showed that age and tumor-node-metastasis
status/anatomic stage of breast carcinomas are predictive
of survival in our patient population, but Ki-67 proliferation index, tumor grade, Nottingham score, and breast
carcinoma subtype are not. Our data suggest that prognostic value of breast cancer hormonal status on survival
of Caucasian women warrants more investigations.
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