Вы находитесь на странице: 1из 12

Breast Cancer Res Treat

DOI 10.1007/s10549-017-4333-2

EPIDEMIOLOGY

The prognostic effect of estrogen receptor status differs


for younger versus older breast cancer patients
Victoria Sopik1 • Ping Sun1 • Steven A. Narod1

Received: 17 April 2017 / Accepted: 7 June 2017


Ó Springer Science+Business Media, LLC 2017

Abstract diagnosed before age 40, breast cancer-specific survival at


Purpose To estimate the prognostic impact of estrogen 15 years was worse for those with ER-positive breast
receptor (ER)-status among women with primary invasive cancer than for those with ER-negative breast cancer (55
breast cancer, according to age at diagnosis. vs. 61%; adjusted HR = 0.90; 95% CI 0.57–1.41;
Methods We studied 1910 women with primary invasive p = 0.64). In contrast, among 1697 women diagnosed
breast cancer (stages I–III) who were treated at Women’s between ages 40 and 75, breast cancer-specific survival at
College Hospital between 1987 and 2000. For each patient, 15 years was better for those with ER-positive breast
we obtained information on age at diagnosis, tumour size, cancer than for those with ER-negative breast cancer (78
lymph node status, ER-status, treatments received (radio- vs. 72%; adjusted HR = 0.60; 95% CI 0.47–0.76;
therapy, chemotherapy and tamoxifen) and dates and cau- p \ 0.0001).
ses of death. Patients were followed from the date of Conclusions Positive ER-status is a favourable prognostic
diagnosis until the date of death from breast cancer or the factor among women diagnosed with breast cancer at or
date of last follow-up. We used the Kaplan–Meier method above age 40, but not among women diagnosed before
to estimate the 15-year actuarial rates of breast cancer- age 40.
specific survival for women with ER-positive and ER-
negative breast cancer, according to age at diagnosis (cat- Keywords Breast cancer  ER-positive  Survival  Age at
egories). We used the Cox proportional hazards model to diagnosis  Prognosis
estimate the adjusted hazard ratios for death from breast
cancer associated with positive ER-status (compared to
negative ER-status), stratified by age at diagnosis. Introduction
Results We identified 1347 women with ER-positive
breast cancer (70.5%) and 563 women with ER-negative Young women with breast cancer have relatively poor
breast cancer (29.5%). Among all 1910 women in the survival compared to older women [1–3]. The exact rea-
cohort, the actuarial rate of breast cancer-specific survival sons for this are unclear. Breast cancers in young women
at 15 years was 77% for those with ER-positive breast tend to have unfavourable biological features, including
cancer compared to 70% for those with ER-negative breast large tumour size, high tumour grade, lymphovascular
cancer (adjusted HR = 0.69; 95% CI 0.56–0.85; invasion, increased expression of HER2 and lower
p = 0.0006). The prognostic impact of ER-status differed expression of the estrogen receptor (ER) and progesterone
according to age at diagnosis. Among 213 women receptor (PR) [4, 5]. However, even after correction for
these features, young age at diagnosis (less than 40)
remains a significant adverse predictor of breast cancer
& Steven A. Narod death [4–8]. The inferior survival of young women with
steven.narod@wchospital.ca
breast cancer may be due to a more aggressive biology
1
Women’s College Research Institute, 76 Grenville Street, which is not captured by the traditional prognostic factors.
Toronto, ON M5S 1B2, Canada Young women may differ from older women with respect

123
Breast Cancer Res Treat

to the prognostic effects of the canonical tumour markers Results


(e.g. ER-status). Young women may also differ from older
women with respect to the treatments they receive and/or Of the 1910 women in the cohort, 1347 (70.5%) had ER-
their response to these treatments. positive breast cancer and 563 (29.5%) had ER-negative
The prevalence of ER-positive tumours increases with breast cancer (compared in Table 1). Compared to patients
age at diagnosis [4], and the relatively low incidence of with ER-negative breast cancer, patients with ER-positive
ER-positive tumours in young women is often cited as an breast cancer were on average, older (mean age at diag-
explanation for the inferior survival of young women [9]; nosis 55.2 vs. 50.8; p \ 0.0001) and had smaller breast
however, after adjusting for ER-status, young age is still tumours (mean tumour size 21.4 mm vs. 28.6 mm;
associated with worse outcomes [8]. Breast cancer patients p \ 0.0001). Women with ER-positive breast cancer were
with tumours that are estrogen receptor (ER)-positive more likely to take tamoxifen (58.9 vs. 25.9%; p \ 0.0001)
generally have lower risks of mortality compared to and were less likely to receive chemotherapy (28.9 vs.
women with ER-negative tumours [10, 11]. However, 46.2%; p \ 0.0001), compared to patients with ER-nega-
positive ER-status does not invariably correlate with a tive breast cancer. The proportion of ER-positive patients
favourable prognosis. For example, among BRCA2 muta- increased from 52.6% in patients diagnosed before age
tion carriers with breast cancer, positive ER-status is an 40–79.2% in patients from 60 to 75 years (Table 1). After
adverse prognostic factor [12]. Generally, ER-positive a mean follow-up 15 years, a total of 408 women (21.4%)
tumours are considered to be less aggressive than ER- had died of breast cancer, including 27.7% of all ER-
negative tumours, but it is not clear if this holds true for negative breast patients and 18.7% of all ER-positive breast
young patients; i.e. It is unclear if the prognostic effect of cancer patients.
ER-positivity varies with age. In this study, we evaluated Among all patients, the 15-year actuarial breast cancer-
the prognostic effects of ER-status in primary breast can- specific survival rate was 70% for those with ER-negative
cer, according to age at diagnosis. breast cancer and was 77% for those with ER-positive
breast cancer (p \ 0.0001) (Fig. 1). After adjusting for age
of diagnosis, tumour size, lymph node status, use of
Methods chemotherapy and use of tamoxifen, the hazard ratio for
death from breast cancer associated with positive ER-status
We studied a cohort of 1910 women with primary invasive (vs. negative ER-status) was 0.69 (95% CI 0.56–0.85;
breast cancer who were treated at the Henrietta Banting p = 0.0006).
Breast Center at Women’s College Hospital between 1987 Among all patients, breast cancer-specific survival at
and 2009. For each patient, we abstracted information on 15 years was 57.9% for women diagnosed before age 40
age at diagnosis, tumour size, lymph node status, ER status, and was 76.6% for women diagnosed between ages 40 and
treatments received (surgery, radiotherapy, chemotherapy, 75 (p \ 0.0001). In a multivariable analysis, the hazard
hormone therapy) and dates and causes of death. Women ratio for death from breast cancer associated with early age
diagnosed above age 75 and women with unknown ER- at diagnosis (\40 years vs. 40–75 years) was 1.58 (95% CI
status were excluded from the analysis. We compared the 0.21–2.05; p = 0.0006).
women with ER-positive and ER-negative breast cancer for We examined the impact of ER-status on breast cancer
several variables, using the Student t test. survival according to age at diagnosis (Fig. 2). Among 213
We classified women into four groups, according to age women diagnosed before age 40, breast cancer-specific
at diagnosis (younger than 40 years, 40–49 years, survival at 15 years was 61.3% for ER-negative patients
50–59 years and 60–75 years). We evaluated the impact of and was 54.9% for ER-positive patients (p = 0.90)
ER status on survival, according to age at diagnosis. (Fig. 2a). Among 557 women diagnosed between ages 40
Patients were followed for death from breast cancer from and 49, breast cancer-specific survival at 15 years was
the date of diagnosis to death from breast cancer, death 67.4% for ER-negative patients and was 74.4% for ER-
from another cause or date of last-follow-up. The Kaplan– positive patients (p = 0.0006) (Fig. 2b). Among 533
Meier method was used to generate univariable survival women diagnosed between ages 50 and 59, breast cancer-
curves and the log-rank test was used to estimating p-val- specific survival at 15 years was 73.3% for ER-negative
ues. Adjusted hazard ratios were estimated using the Cox patients and was 78.4% for ER-positive patients (p = 0.04)
proportional hazards model. In the multivariable model, the (Fig. 2c). Among 607 women diagnosed between ages 60
hazard ratio was adjusted for age at diagnosis, tumour size, and 75, breast cancer-specific survival at 15 years was
lymph node status (positive/negative), tamoxifen (no/yes) 77.9% for ER-negative patients and was 81.8% for ER-
and chemotherapy (no/yes). positive patients (p = 0.06) (Fig. 2d).

123
Breast Cancer Res Treat

Table 1 Comparison of
Variables ER-negative ER-positive p value
baseline characteristics,
N = 563 (29.5%) N = 1347 (70.5%)
according to ER status (percent
is for row) Date of birth 1942.7 (1914–69) 1938.8 (1912–70) \0.0001
Year at diagnosis 1993.4 (1987–00) 1994.0 (1987–00) 0.004
Age at diagnosis
\40 101 (47.4%) 112 (52.6%)
40–49 185 (33.2%) 372 (66.8%)
50–59 151 (28.3%) 382 (71.7%) \0.0001
60–75 126 (20.8%) 481 (79.2%)
Mean 50.8 (24–75) 55.2 (24–75) \0.0001
Tumour size
B10 132 (29.4%) 317 (70.6%)
11–20 170 (24.4%) 527 (75.6%)
21–50 222 (33.5%) 440 (66.5%) 0.001
50? 33 (36.3%) 58 (63.7%)
Mean (mm) 28.6 (1–102) 21.4 (0–130) 0.009
Lymph node status
Negative 332 (32.3%) 693 (67.6%)
Positive 203 (28.2%) 517 (71.8%) 0.06
Tamoxifen
No 417 (43.0%) 553 (57.0%)
Yes 146 (15.5%) 794 (84.5%) \0.0001
Radiotherapy
No 181 (30.1%) 421 (69.9%)
Yes 377 (29.2%) 916 (70.8%) 0.69
Surgery
Mastectomy 138 (34.5%) 262 (65.5%)
Lumpectomy 425 (28.2%) 1085 (71.9%) 0.01
Chemotherapy
No 298 (23.8%) 952 (76.2%)
Yes 260 (40.1%) 389 (59.5%) \0.0001
Survival of BC
No BC death 407 (27.1%) 1095 (72.9%)
BC death 156 (38.2%) 252 (61.8%) \0.0001

In a multivariable model, the hazard ratio for death from patients (Fig. 3), there was a gradual decline in breast
breast cancer associated with positive ER-status (vs. neg- cancer-specific survival with decreasing age at diagnosis.
ative ER-status) was 0.90 for women diagnosed before age In contrast, among ER-positive patients (Fig. 4a), there
40 (95% CI 0.57–1.41; p = 0.64) and was 0.60 for women was an abrupt decline in 15-year survival for women
diagnosed between ages 40 and 75 (95% CI 0.47–0.76; diagnosed before age 40 (54.9%) compared to women
p \ 0.0001). diagnosed between ages 40 and 49 (74.5%), 50 and 59
The protection offered by positive ER-status was tran- (78.4%) or 60 and 75 (81.1%). Among patients with ER-
sient in all age groups. Among women who were alive five positive breast cancer who did not take tamoxifen, a
years after diagnosis, the adjusted hazard ratio for death similar trend was observed (Fig. 5). In a multivariate
from breast cancer (in years 5–15) associated with positive model, young age at diagnosis (\40 years vs.
ER-status was 2.24 for women diagnosed before age 40 40–75 years) was associated with a much greater increase
(95% CI 0.93–5.40) and was 1.15 for women diagnosed in the risk of death from breast cancer among ER-positive
between ages 40 and 75 (95% CI 0.79–1.69). patients (HR = 2.12; 95% CI 1.50–2.99; p \ 0.0001)
We next examined the impact of age at diagnosis on than among ER-negative patients (HR = 1.18; 95% CI
survival, according to ER-status. Among ER-negative 0.80–1.76; p = 0.40).

123
Breast Cancer Res Treat

Fig. 1 Fifteen-year breast


cancer-specific survival for all
patients in the cohort, according
to ER status

Next, we compared the impact of tamoxifen use on (95% CI 0.47–0.76; p \ 0.0001) and was 0.90 for women
survival among women with ER-positive breast cancer, diagnosed before age 40 (95% CI 0.57–1.41; p = 0.64).
according to age at diagnosis. The proportion of ER- From this, we conclude that prognostic effect of ER-
positive patients who took tamoxifen was only 25% status is less for younger (\40 years) than for older women
among women diagnosed before age 40, compared to (40–75 years). The differential effect of ER-status across
62% among women diagnosed between ages 40 and 75. age is due in large part to the relatively poor survival of
Among women with ER-positive breast cancer diagnosed young women with ER-positive tumours, compared to
before age 40 (Fig. 6), breast cancer-specific survival at older women with ER-positive tumours (55 vs. 78%;
15 years was 50.4% for those who did not take tamoxifen adjusted HR = 2.12; 95% CI 1.50–2.99; p \ 0.0001). In
and was 68.1% for those who took tamoxifen (p = 0.05). contrast, the adverse effect of young age at diagnosis was
Characteristics of the who did and did not take tamoxifen much less pronounced among women with ER-negative
are presented in Table 2. After adjusting for the various tumours (15-year survival 61 vs. 72%; adjusted
factors, the hazard ratio for death from breast cancer HR = 1.18; 95% CI 0.80–1.76; p = 0.40).
associated with tamoxifen use in young women was 0.42 The effect of ER-status on the risk of death from breast
(95% CI 0.17–1.03; p = 0.06). For ER-positive patients cancer is non-proportional (i.e. the hazard ratio associated
diagnosed between ages 40 and 75, the adjusted hazard with ER-status is not constant over time from diagnosis).
ratio associated with tamoxifen use was 0.71 (95% CI The hazard rate is initially higher for ER-negative tumours
0.52–0.96; p = 0.03). and at some point following diagnosis there is a switch—
the hazard rate becomes higher for ER-positive tumours.
Among all women in our cohort, this switch occurred
Discussion around the five year mark (Fig. 1); however, among
women diagnosed before age 40, the switch occurred much
In this analysis of 1910 women with stage I–III breast earlier, around 2.5 years post-diagnosis, and by 8 years the
cancer, positive ER-status was associated with superior actuarial survival curves converged (Fig. 2a). Among
15-year survival (compared to negative ER-status) among women who are alive five years after diagnosis, positive
women diagnosed at or above age 40 (78 vs. 72%; ER-status is a strong adverse prognostic factor for years
p \ 0.0001) but not among women diagnosed before age 5-15 among women diagnosed before age 40 (adjusted
40 (55 vs. 61%; p = 0.90). After adjusting for other HR = 2.24; 95% CI 0.93–5.40; p = 0.07) and is less
prognostic factors and for treatment, the hazard ratio for strong among women diagnosed between ages 40 and 75
death from breast cancer associated with positive ER-status (adjusted HR = 1.15; 95% CI 0.79–1.69; p = 0.46). These
was 0.60 for women diagnosed between ages 40 and 75 data support the position that positive ER-status is not a

123
Breast Cancer Res Treat

Fig. 2 a. Fifteen-year breast


cancer-specific survival
according to ER status for
patients diagnosed a before age
40, b between ages 40 and 49,
c between ages 50 and 59,
d between ages 60 and 75

canonical indicator of good prognosis—the notable found four studies reporting similar or inferior survival
exceptions being women diagnosed under 40, women who rates associated with positive ER-status in young women
have survived for five years and women with BRCA2 (diagnosed before age 35 or 40) [13–16] and two studies
mutations [12]. reporting superior survival associated with positive ER-
Our results are generally consistent with those of pre- status in young women (diagnosed before age 40) [17, 18].
vious studies which have examined the interaction between In virtually all studies, the risk of death prior to five years
age at diagnosis and ER-status. Few studies have evaluated was greater for patients with ER-negative tumours and
the prognostic effects of ER-status according to age, after five years was greater for patients with ER-positive
whereas several studies have evaluated the prognostic tumours. We also found several studies which report an
effects of age at diagnosis according to ER-status. We adverse effect of young age at diagnosis in ER-positive

123
Breast Cancer Res Treat

Fig. 2 continued

tumours but not in ER-negative tumours, consistent with tumours (p \ 0.001). Young age at diagnosis (\35 years
our results [6, 8, 13, 14, 17, 19, 20]. vs. 35–50 years) was a significant predictor of worse
In an analysis of 3700 premenopausal patients in the overall survival at ten years for patients with ER-positive
International Breast Cancer Study Group (IBCSG) trials, tumours (HR = 1.98; 95% CI 1.56–2.51; p \ 0.001) but
among women diagnosed before age 35, ten-year overall not for patients with ER-negative tumours (HR = 1.07;
survival was 39% for those with ER-positive tumours 95% CI 0.81–0.42; p = 0.62).
compared to 56% for those with ER-negative tumours In a study of 9885 breast cancer patients ages 50 and
(p = 0.12) [13]. Among women ages 35–50, ten-year below from Korea, among 1444 patients diagnosed before
overall survival was 63% for those with ER-positive age 35, breast cancer survival at ten years was 65% for
tumours compared to 58% for those with ER-negative those with hormone receptor (HR)-positive breast cancer

123
Breast Cancer Res Treat

Fig. 3 Fifteen-year breast


cancer-specific survival,
according to age at diagnosis,
for women with ER-negative
breast cancer

Fig. 4 Fifteen-year breast


cancer-specific survival,
according to age at diagnosis,
for women with ER-positive
breast cancer

and was 75% for those with HR-negative breast cancer Not all studies show the same effect. In an analysis of
[14]. Among patients ages 35–50, breast cancer survival at 111,993 breast cancer patients diagnosed between 1990
ten years was 85% for those with HR-positive breast cancer and 2003 in the Surveillance, Epidemiology and End-Re-
and was 75% for those with HR-negative breast cancer. sults (SEER) database, the prognostic impact of ER-status
Among HR-positive patients, young women (\35 years) was much greater for women ages 40–74 compared to
had significantly increased risk of death from breast cancer women younger than age 40 [17]. Among 10,459 women
at ten years compared with older women (multivariate diagnosed before age 40, ten-year breast cancer-specific
HR = 2.1; 95% CI 1.70–2.71), but not among those with survival was 77.4% for those with ER-positive tumours
HR-negative breast cancer (multivariate HR = 0.9; 95% compared with 72.2% for those with ER-negative tumours.
CI 0.74–1.26). The hazard rate decreased over time; at five years, breast

123
Breast Cancer Res Treat

Fig. 5 Fifteen-year breast


cancer-specific survival,
according to age at diagnosis,
for women with ER-positive
breast cancer who did not take
tamoxifen

Fig. 6 Fifteen-year breast


cancer-specific survival for ER-
positive patients diagnosed
before age 40, according to the
use of tamoxifen

cancer-specific survival was 89.7% for women with ER- tumours ranged from 74.1 to 76.2%. The adjusted hazard
positive breast cancer and was 77.9% for women with ER- ratios for death from breast cancer in older age groups
negative breast cancer. The adjusted hazard ratio for death associated with negative ER-status overall ranged from
from breast cancer associated with negative ER-status 1.72 to 1.98, and for years 5–10 ranged from 0.71 to 0.97.
overall (0–10 years) was 1.37 (95% CI 1.25–1.50). For Younger patients with ER-positive tumours had an
years 5–10, the adjusted hazard ratio for death associated approximately two-fold higher risk of death from breast
with negative ER-status was 0.43 (95% CI 0.35–0.52). In cancer compared with older patients.
contrast, for all other age groups, ten-year breast cancer- The inferior survival of younger versus older women
specific survival for those with ER-positive tumours ranged with ER-positive breast cancer observed here may in part
from 87.4 to 88.8% and for those with ER-negative be due to differences in the distributions of prognostic

123
Breast Cancer Res Treat

Table 2 Comparison of ER-


Variables No tamoxifen Tamoxifen p value
positive patients diagnosed
N = 84 (75.0%) N = 28 (25.0%)
before age 40 who did and who
did not take tamoxifen Date of birth 1958.1 (1948–70) 1959.1 (1948–70) 0.38
Year at diagnosis 1993.4 (1987–99) 1995.5 (1987–99) 0.01
Age at diagnosis (years) 35.3 (24–39) 36.4 (28–39) 0.18
Tumour size
B10 11 (13.3%) 4 (14.3%) 0.24
11–20 25 (30.1%) 12 (42.9%)
21–50 41 (49.4%) 8 (28.6%)
50? 6 (7.2%) 4 (14.3%)
Mean (mm) 27.0 (0–100) 29.9 (0–100) 0.53
Lymph node status
Negative 32 (40.0%) 15 (53.6%) 0.21
Positive 48 (60.0%) 13 (46.4%)
Radiotherapy
No 32 (39.0%) 7 (25.0%) 0.18
Yes 50 (61.0%) 21 (75.0%)
Surgery
Mastectomy 29 (34.5%) 8 (28.6%) 0.56
Lumpectomy 55 (65.5%) 20 (71.4%)
Chemotherapy
No 27 (32.1%) 14 (50.0%) 0.09
Yes 57 (67.9%) 14 (50.0%)
Survival of BC
No BC death 45 (53.6%) 21 (75.0%) 0.05
BC death 39 (46.4%) 7 (25.0%)

factors that we have not accounted for, such as grade, PR ‘‘luminal A-like’’ tumours (i.e. ER-positive/PR-negative,
status, HER2 status or Ki67 status. Our analysis may ER-positive/HER2-positive, or ER-positive/Ki-67 ‘‘high’’)
therefore not have sufficient resolution; recent studies [22].
indicate that ER-positive breast cancer consists of two (or Young women with ER-positive breast cancer have a
more) prognostic subgroups [21], the distribution of higher proportion of the luminal B (poor-prognosis) sub-
which might differ for young versus older women. The type compared to older women with ER-positive breast
two main subtypes are luminal A (good-prognosis) and cancer [1, 8, 23–25]; however, it is not clear if the differ-
luminal B (poor-prognosis). Compared to the luminal A ence is sufficient to account for the differences in prog-
subtype, luminal B tumours often have low expression of nosis. Several studies have found that even among patients
ER or estrogen-regulated genes, low PR expression, with luminal A or luminal B breast cancer, young age
higher tumour grade, higher expression of proliferation- (\40 years) is still associated with inferior survival
related genes and activation of growth factor receptor [1, 8, 23, 24]. Furthermore, in studies adjusting for
signaling pathways [21]. Luminal B tumours are also molecular subtype, young age was still a significant pre-
considered to have lower sensitivity to endocrine treat- dictor of worse prognosis [1, 8, 23].
ment and higher sensitivity to chemotherapy than luminal Liedtke et al. studied 3089 breast cancer patients from
A tumours [21]. These molecular subtypes can be defined 40 publically available gene expression datasets [23].
by genetic array testing or approximations to this classi- Among 1502 patients with luminal (ER-positive) breast
fication using immunohistochemistry. Subtypes defined by cancer, young women (diagnosed before age 40) had
immunohistochemistry markers are similar to, but not inferior 12-year event-free survival compared to older
identical to intrinsic subtypes. The proposed surrogate women (42 vs. 60%; p = 0.001). Young women with
definition classifies ER-positive breast cancer as ‘‘luminal luminal breast cancer were more likely to have luminal B
A-like’’ if it is ER-positive, PR-positive, HER2-negative (vs. luminal A) tumours compared to older women with
and Ki-67 ‘‘low’’. ‘‘Luminal B-like’’ disease comprises luminal breast cancer (64 vs. 49%). However, even after
those ER-positive cases which lack the characteristics of stratifying for luminal A vs. luminal B subtype, the trend of

123
Breast Cancer Res Treat

worse prognosis for young women compared to older In our study, tamoxifen use was associated with a
women remained. reduced risk of death among women diagnosed before age
Fredholm et al. studied a population-based cohort of 40 (adjusted HR = 0.42; 95% CI 0.17–1.03; p = 0.06) and
1120 women with stage I-III breast cancer, diagnosed from among women diagnosed between ages 40 and 75 (adjusted
1992 to 2005 in Sweden [1]. Among 544 women with HR = 0.71; 95% CI 0.52–0.96; p = 0.03). The hazard
luminal, HER2-negative breast cancer, young women ratio of 0.42 for women under 40 is perhaps more extreme
(n = 248) were more likely have luminal B (ER?/PR?/ than expected, but it is consistent with previous reports. In
HER2-/Ki67 high) versus luminal A (ER?/PR?/HER2-/ the 2005 overview of the Early Breast Cancer Trialists’
Ki67 low) subtype compared to older women (80 vs. 66%). Collaborative Group (EBCTCG), the relative reduction in
However, in a multivariable analysis adjusting for subtype the risk of breast cancer-mortality associated with tamox-
(luminal A vs B) and other prognostic factors, young age ifen use was 37% for women under 40, 24% for women
was still a significant predictor of distant disease-free sur- ages 40–59, 35% for women ages 60–69 and 37% for
vival (HR = 1.87; 95% CI 1.03–3.44; p = 0.042). women ages 70 and above [30]. Despite that tamoxifen
Taken together, these data suggest that the inferior appears to be highly effective in young women with ER-
survival of young women with ER-positive breast cancer positive breast cancer, and despite that young women with
can to some extent be explained by an increased frequency ER-positive breast cancer have a particularly poor prog-
of the luminal B subtype (which carries a worse prognosis nosis, it is concerning to us that only 25% of the ER-
than the luminal A subtype), but that even after adjustment positive patients under 40 in this cohort took tamoxifen
for subtype, an adverse prognostic effect of young age [31]. According to current guidelines, all women with ER-
remains. More research is required to identify prognostic positive breast cancer are recommended to receive adju-
markers which can explain the worse prognosis of young vant endocrine therapy. It is not clear why so many young
women with ER-positive breast cancer. women do not take tamoxifen, but perhaps they perceive
Several prognostic gene signatures have been developed to having an ER-positive tumour to be an indication of ‘‘better
improve breast cancer prognostication, such as the 21-gene prognosis’’, which is then weighed in the decision between
signature Oncotype Dx and the 70-gene signature Mam- potential benefits and costs of treatment. Young women are
maPrint. These gene signatures are associated with an overall often concerned about the risks of infertility associated
recurrence score which is a continuous predictor of the risk of with extended use of tamoxifen [32], but the great majority
distant recurrence. The distribution of these prognostic gene of women under 40 will still be fertile after treatment [33].
expression signatures differs for younger versus older women Focusing on this potential risk when discussing treatment
with breast cancer, such that young women are more likely to options with young women may have negative conse-
have poor-prognosis signatures [26–29]. Most studies which quences for the patient’s survival.
adjust for both the prognostic gene signature and age at For patients with node-negative, ER-positive breast
diagnosis tend to report a significant prognostic impact of the cancer, current guidelines recommend the use of online
recurrence score but not of age [26–28]. However, in these prognostic programmes such as Adjuvant! Online and
studies, women under age 40 account for only 10–20% of all PREDICT to aid clinicians in predicting patient prognosis
patients, and age was typically evaluated as a binary variable and determining which patients may benefit from
for women under 50 versus over 50, with no data being pro- chemotherapy [34]. However, it is not clear if these tools
vided on the comparative analysis using other age thresholds accurately predict the risks of mortality in young women
[26–28]. Notably, age less than 35 was the cutoff in the and further studies are needed. For example, Adjuvant!
IBCSG trial analysis [13]. In a recent study of 1406 patients Online does not consider age in the basic model, but it
with lymph node-negative, hormone receptor-positive, includes a statement that patients diagnosed at or before age
HER2-negative breast cancer and an Oncotype DX score of 35 carry an additional increased risk of death by a factor of
less than 18 (i.e. low recurrence risk) [29], after a median 1.5 if the tumour is ER-positive, and users have the option
follow-up of 46 months, 4.8% of 63 patients diagnosed before to include this in the estimation of survival [35]. This
age 40 developed distant metastases, compared to only 0.2% adjustment improves prediction capability in young women
of 1343 patients age 40 and older [29]. The seven-year but not completely [35]. Our analyses indicate that women
actuarial rate of distant metastases was 10% for women under diagnosed before age 40 have an approximately two-fold
40 compared to 2% for women ages 40 and above. This increased risk of death if the tumour is ER-positive. Future
suggests that young age (\40 years) may be a negative prognostic programmes should consider the impact of age
prognostic factor, even in patients with a low 21-gene more carefully. Future studies are required to determine to
expression assay score. Further research on these scores in what extent chemotherapy is effective in young women
young women (\40 years) is required. with node-negative, ER-positive breast cancer.

123
Breast Cancer Res Treat

Compliance with Ethical Standards women aged 18–40 years at diagnosis: the POSH study. J Natl
Cancer Inst 105:978–988
Conflicts of interest The authors declare that they have no conflicts 16. van der Hage JA, Mieog JS, van de Vijver MJ et al (2007)
of interest. Efficacy of adjuvant chemotherapy according to hormone
receptor status in young patients with breast cancer: a pooled
Ethical approval All procedures performed in studies involving analysis. Breast Cancer Res 9:R70
human participants were in accordance with the ethical standards of 17. Yu KD, Wu J, Shen ZZ, Shao ZM (2012) Hazard of breast
the institutional and/or national research committee and with the 1964 cancer-specific mortality among women with estrogen receptor-
Helsinki declaration and its later amendments or comparable ethical positive breast cancer after five years from diagnosis: implication
standards. for extended endocrine therapy. J Clin Endocrinol Metab
97:E2201–E2209
Informed consent Informed consent was obtained from all individ- 18. De Lima Vazquez F, Silva TB, Da Costa Vieira RA et al (2016)
ual participants included in the study. Retrospective analysis of breast cancer prognosis among young
and older women in a Brazilian cohort of 738 patients,
1985–2002. Oncol Lett 12:4911–4924
19. Goldhirsch A, Gelber RD, Yothers G et al (2001) Adjuvant
References therapy for very young women with breast cancer: need for tai-
lored treatments. J Natl Cancer Inst Monogr 30:44–51
1. Fredholm H, Magnusson K, Lindström LS et al (2016) Long-term 20. Liu YR, Jiang YZ, Yu KD, Shao ZM (2015) Different patterns in
outcome in young women with breast cancer: a population-based the prognostic value of age for breast cancer-specific mortality
study. Breast Cancer Res Treat 160:131–143 depending on hormone receptor status: a SEER population-based
2. Maggard MA, O’Connell JB, Lane KE et al (2003) Do young analysis. Ann Surg Oncol 22:1102–1110
breast cancer patients have worse outcomes? J Surg Res 21. Wirapati P, Sotiriou C, Kunkel S et al (2008) Meta-analysis of
113:109–113 gene expression profiles in breast cancer: toward a unified
3. Chung M, Chang HR, Bland KI et al (1996) Younger women understanding of breast cancer subtyping and prognosis signa-
with breast carcinoma have a poorer prognosis than older women. tures. Breast Cancer Res 10:R65
Cancer 77:97–103 22. Goldhirsch A, Winer EP, Coates AS et al (2013) Personalizing
4. Nixon AJ, Neuberg D, Hayes DF, Gelman R, Connolly JK et al the treatment of women with early breast cancer: highlights of the
(1994) Relationship of patient age to pathologic features of the St Gallen International Expert Consensus on the Primary Therapy
tumor and prognosis for patients with stage I or II breast cancer. of Early Breast Cancer 2013. Ann Oncol 24:2206–2223
J Clin Oncol 12:888–894 23. Liedtke C, Rody A, Gluz O et al (2015) The prognostic impact of
5. Bharat A, Aft RL, Gao F, Margenthaler JA (2009) Patient and age in different molecular subtypes of breast cancer. Breast
tumor characteristics associated with increased mortality in Cancer Res Treat 152:667–673
young women (\or = 40 years) with breast cancer. J Surg Oncol 24. Johnson R, Hu P, Fan C, Anders CK (2015) Gene expression in
100:248–251 ‘‘young adult type’’ breast cancer: a retrospective analysis.
6. Fredholm H, Eaker S, Frisell J, Holmberg L, Fredriksson I, Oncotarget 6:13688–13702
Lindman H (2009) Breast cancer in young women: poor survival 25. Jenkins E, Deal A, Anders CK et al (2014) Age-specific changes
despite intensive treatment. PLoS ONE 4:e7695 in intrinsic breast cancer subtypes: a focus on older women.
7. Narod SA (2012) Breast cancer in young women. Nat Rev Clin Oncologist 19:1076–1083
Oncol 9:460–470 26. van de Vijver MJ, He YD, van’t Veer LJ et al (2002) A gene-
8. Azim HA Jr, Michiels S, Bedard PL et al (2012) Elucidating expression signature as a predictor of survival in breast cancer.
prognosis and biology of breast cancer arising in young women N Engl J Med 347:1999–2009
using gene expression profiling. Clin Cancer Res 18:1341–1351 27. Buyse M, Loi S, van’t Veer L L et al (2006) Validation and
9. Paluch-Shimon S, Pagani O, Partridge AH et al (2016) Second clinical utility of a 70-gene prognostic signature for women with
international consensus guidelines for breast cancer in young node-negative breast cancer. J Natl Cancer Inst 98:1183–1192
women (BCY2). Breast 26:87–99 28. Paik S, Shak S, Tang G et al (2004) A multigene assay to predict
10. Parl FF, Schmidt BP, Dupont WD, Wagner RK (1984) Prognostic recurrence of tamoxifen-treated, node-negative breast cancer.
significance of estrogen receptor status in breast cancer in relation N Engl J Med 351:2817–2826
to tumor stage, axillary node metastasis, and histopathologic 29. Wen H, Krystel-Whittemore M, Patil S et al (2017) Breast car-
grading. Cancer 54:2237–2242 cinoma with an Oncotype Dx recurrence score \18: rate of dis-
11. Crowe JP, Gordon NH, Hubay CA et al (1991) Estrogen receptor tant metastases in a large series with clinical follow-up. Cancer
determination and long term survival of patients with carcinoma 123:131–137
of the breast. Surg Gynecol Obstet 173:273–278 30. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
12. Jonasson JG, Stefansson OA, Johannsson OT et al (2016) (2005) Effects of chemotherapy and hormonal therapy for early
Oestrogen receptor status, treatment and breast cancer prognosis breast cancer on recurrence and 15-year survival: an overview of
in Icelandic BRCA2 mutation carriers. Br J Cancer 115:776–783 the randomised trials. Lancet 365:1687–1717
13. Aebi S, Gelber S, Castiglione-Gertsch M et al (2000) Is 31. Narod SA, Sopik V, Sun P (2017) Which women decide to take
chemotherapy alone adequate for young women with oestrogen- tamoxifen? Breast Cancer Res Treat. doi:10.1007/s10549-017-
receptor-positive breast cancer? Lancet 355:1869–1874 4226-4
14. Ahn SH, Son BH, Kim SW et al (2007) Poor outcome of hormone 32. Gorman JR, Usita PM, Madlensky L, Pierce JP (2011) Young
receptor-positive breast cancer at very young age is due to breast cancer survivors: their perspectives on treatment decisions
tamoxifen resistance: nationwide survival data in Korea–a report and fertility concerns. Cancer Nurs 34:32–40
from the Korean Breast Cancer Society. J Clin Oncol 33. Jacobson MH, Mertens AC, Spencer JB, Manatunga AK,
25:2360–2368 Howards PP (2016) Menses resumption after cancer treatment-
15. Copson E, Eccles B, Maishman T et al (2013) Prospective induced amenorrhea occurs early or not at all. Fertil Steril
observational study of breast cancer treatment outcomes for UK 105(765–72):e4

123
Breast Cancer Res Treat

34. Eisen A, Fletcher GG, Gandhi S et al (2015) Optimal systemic 35. Olivotto IA, Bajdik CD, Ravdin PM et al (2005) Population-
therapy for early breast cancer in women: a clinical practice based validation of the prognostic model ADJUVANT! for early
guideline. Curr Oncol 22:S67–S81 breast cancer. J Clin Oncol 23:2716–2725

123