Introduction
Breast cancer (BC) is the most common malignancy in
women worldwide. Despite a decrease in BC specific mortality, it is one of the leading causes of cancer death
among women.[] Age is a dominant risk factor in the
development of BC. According to the SEER database,
the median age at the time of BC diagnosis is 62 years. [] Approximately less than 4% of women diagnosed
with BC are younger than 35 years.[] Definition of
young age in BC has been controversial; in some studies,
the cut-off points at different years have been identified
according to the poor survival status compared to
older counterparts. In many series, patients at 35 year
or younger showed poor prognosis and increased risk
of local-regional recurrence (LRR) and distant recurrence
(DR).[,] This could partly be explained by BC
at a young age is associated with more advanced stage
and more biologically aggressive disease.[-] These
aggressive biological features of BC in young patients
include higher grade, higher proliferation rate, more
lymphovascular invasion (LVI), more absence of hormone
receptors, and higher prevalence of human epidermal
factor receptor-2 (HER2) positive or triple negative
disease.[,,,-] It is controversial whether
these adverse prognostic factors mainly explain the
poor outcome of young patients or the young age all
by itself has an adverse prognostic significance.[,]
On the other hand, since young age in BC is generally
thought to be an adverse prognostic factor, these patients
receive more aggressive treatments than elderly
patients.[,]
One-third of all BCs occur in patients aged over 70
years.[] BC in elderly patients has been reported relatively
indolent in despite of the younger counterparts
in several studies.[] The biological characteristics of
their tumors are more favorable. They represent higher
estrogen receptor (ER) and progesterone receptor (PR)
expression, less LVI, less HER2 expression, and lower
proliferative rates.[-] Nonetheless, some studies
suggest that older women generally have poor prognosis.[,] This is mostly explained by delayed diagnosis
or lack of routine mammographic screening.[]
Moreover, the co-morbidities of elderly patients often
limit therapeutic options and patients" compliance.[]
They receive less aggressive surgery and less frequent
use of radiotherapy and chemotherapy even in patients
with good performance status.[,,]
Since two distinct age spectrum of women are underrepresented
in the clinical trials, the exact reasons
for poor outcomes remain unclear. Few studies have
assessed whether very young or elderly patients have
different patterns of LRR and DR. It is speculated that
young patients receive more intensive therapy; therefore,
they might have better survival after LRR or DM,
despite a shorter disease-free survival.[] This study
aimed to evaluate the pathological characteristics,
treatment approaches, recurrence patterns, and survival
outcomes of very young and elderly patients.
Methods
The patients treated for BC in nine Radiation Oncology
Departments between 2000 and 2013 were retrospectively
reviewed. The inclusion criteria were patients
≤35 years old and ≥70 years old and patients with invasive
BC who received radiotherapy after breast-conserving
surgery or mastectomy. The exclusion criteria
were stage IV disease, bilateral BC, male gender, patients
aged between 36 and 69 years, and patients with
other malignancies except basal cell carcinoma of the
skin and carcinoma in situ of cervix. The local ethics
committee approved the study, and informed consent
was obtained from the patients.
Patients" medical history, co-morbidities, family
history, tumor features, staging, initial treatment, and
clinical outcomes were obtained from hospital databases.
Pathological assessment included the evaluation
of primary tumor size, histological type, tumor grade,
LVI, perineural invasion (PNI), surgical margin, lymph
node status, extranodal extension, ER, PR, HER2 expression,
and Ki-67 labeling index status. Tumor staging
was performed according to 2002 American Joint
Committee on Cancer guidelines.[] The status of
ER, PR, and HER2 were determined by immunohistochemistry.
ER or PR positivity was determined if at
least 1% of the tumor cells had positive nuclear staining.
Hormone receptor positivity was defined as ER(+)/
PR(+), ER(+)/PR(-) or ER(-)/PR(+). HER2 positivity
was defined as an immunohistochemical score of 3+
or 2+ with positive gene amplification by using fluorescent
in situ hybridization or chromogenic in situ
hybridization.
The last date of follow-up and the date of first recurrences
or death were recorded. End points were
calculated as the interval between definitive surgery
and event of the interest. We evaluated the recurrence
patterns, the 5- and 10-year locoregional recurrencefree
survival (LRFS), distant recurrence-free survival,
breast cancer specific survival (BCSS), and overall
survival (OS). LRR was defined as the first relapse in
the ipsilateral breast, chest wall, or overlying skin and
nodal regions. The contralateral BC was considered as
new event. Any other site of recurrence was defined as
DR. LRFS was defined as time from definitive surgery
to any locoregional recurrence or last follow-up/death.
DRFS was defined as time from definitive surgery to
any DR or last follow-up/death. BCSS was defined as
time from definitive surgery to death from BC or last
follow-up/death. OS was defined as time from surgery
to death from any causes or last follow-up/death.
Statistical Analysis
All analyses were performed using the SPSS software,
version 20 (SPSS Inc, Chicago, IL). The patients were
categorized by age into two groups. Descriptive statistics
were generated for all variables and were summarized
with frequencies and percentages. The significance of
differences in categorical variables such as patient and
tumor characteristics, treatment features, and recurrence
patterns were compared across age groups using
Pearson"s chi-squared or Fischer exact test if necessary.
Survival and recurrence data were analyzed using the
Kaplan?Meier estimated method, and the survival/
recurrence curves were compared using the log-rank
test. Multivariate analyses were conducted using Cox's
proportional hazard regression modeling. The value of
p≤0.05 was considered as statistically significant.
Results
Patient Characteristics
A total of 779 patients who were treated in nine centers
were evaluated. Among them, 49% of patients (n=384)
were young and 51% of patients (n=395) were elder. The
median age of young and elder patients was 30 (19?35)
and 74 (70?87) years, respectively. The co-morbidities
were higher in the elderly (10% vs. 62%, p<0.001). The
number of patients who had family history of BC was
higher in the young patients (21% vs. 12%, p=0.002).
The young patients presented with higher incidence
of clinical stage II and III (79% vs. 70%, p=0.011), grade
3 tumors (48% vs. 30%, p<0.0001), positive lymphovascular
space invasion (LVI) (64% vs. 51%, p<0.001), ?15%
Ki-67 status (86% vs. 51.5%, p<0.002), negative hormone
receptor (ER/PR) (27% vs. 15%, p<0.0001), positive
c-erb-B2 (34% vs. 26%, p=0.015), and triple negative
subtype (18% vs. 8%, p<0.001). No difference was found
between the groups regarding pathologic tumor stage,
pathologic PNI, histopathological subtypes, and surgical
margins. The clinical and pathological characterizations
of the patients are summarized in Table 1.
Table 1: The clinical and pathological characterizations of the patients
Young patients had more breast-conserving surgeries
(42% vs. 34%, p=0.02) and axillary dissection
after positive sentinel lymph node biopsy (20% vs.
7%, p=0.0001). The percentage of young patients who
receive chemotherapy was also higher (96% vs. 66%,
p=0.0001). Although young patients were more likely
to be treated with neoadjuvant chemotherapy (22% vs.
13 %), elderly patients were more likely to be treated
with adjuvant chemotherapy (78% vs. 87%, p=0.0001).
Young patients were more likely to receive doxorubicin,
taxane, and doxorubicin + taxane chemotherapy regimens
(p<0.0001). The number of patients who receive hormone-therapy was higher in elderly (p=0.012),
while no difference was found between two groups
in terms of anti-HER2 treatment. All patients in this
retrospective study received adjuvant radiotherapy after
mastectomy or breast-conserving surgery. The rate
of application only tangential fields to breast or chest
wall alone was found similar between the groups (30%
vs. 30%). The comprehensive lymphatic irradiation
(included axilla, supraclavicular fossa, internal mammary
lymph nodes) ratio was found higher in young
patients (29% vs. 15%; p=0.0001). In addition, young
patients had more likely received boost (49% vs. 28%,
p=0.0001). No difference was found in terms of median
RT dose to the breast or chest wall and boost dose
across the two patient groups (p=0.0001). The treatment
features of the patients are shown in Table 2.
Table 2: The treatment features of the patients
Survival Analysis
The median follow-up time for young and elderly patients
was 67.5 (5-193) months and 54 (5-188) months,
respectively. The 5- and 10-year LRFS rates were 96%
and 93% for young patients and 97% and 97% for elderly
patients (p=0.211) (Figure 1a). The 5- and 10-
year DRFS rates were 77% and 67% for young patients
and 85% and 85% for elderly patients (p<0.0001) (Figure
1b). The 5- and 10-year BCSS rates were 91% and
79% for young patients, and 92% and 87% for elderly.
Although the difference in 10-year BCSS rate was 8%
between the groups, it did not reach a statistical significance
(p=0.243) (Figure 1c). The 5- and 10-year OS
rates were 92% and 78% for young patients and 78%
and 63% for elderly (p=0.0001) (Figure 1d).
Fig 1: The LRFS (a), DRFS (b), BCSS (c), and OS (d) of very young women and elderly women diagnosed with breast cancer.
Based on multivariate survival analysis, age was the
significant prognostic factor for DRFS and OS. In addition
to younger age, higher pathologic tumor stage
and positive pathologic lymph node were negatively
related to DRFS. Higher pathologic tumor stage and
tumor grade and presence of lymphovascular space
invasion were negatively related to LRFS. Higher clinical
and pathological tumor stage, positive pathological
lymph node, and higher tumor grade were found as
significant negative prognostic factors on BCSS. Elder
age, higher clinical stage, and tumor grade were negative
prognostic factors on OS. The multivariate survival
analysis results are shown in Table 3.
Table 3: Multi-variant analyses of disease free survival, breast cancer specific survival and overall survival
Recurrence Patterns
At the last follow-up, 98 (26%) patients in young patients
had recurrences. Most common recurrence pattern
was DM (86%). Fourteen of the young patients
(5%) developed contralateral BC. At the last follow-up,
55 (15%) patients died from BC, and 4 (1%) patients
died from other causes not related to BC. In the elderly, 46 (13%) patients had recurrences. Most recurrence
pattern was DM (85%). Ten (4.5%) elderly patients had
contralateral BC. At the last follow-up, 35 (8.5%) patients
died from BC, and 60 (16.5%) patients died from
other causes not related to BC. The recurrence patterns
and survival status of the patients are shown in Table 4.
Table 4: The recurrence patterns and survival status of the patients
Discussion
Several prognostic factors have been identified in the
literature for recurrences or death from BC. The strongest
prognostic factors are age at diagnosis, co-morbidity,
tumor size, histological grade, and number of involved lymph nodes.[,] Some studies showed that the risk
of BC recurrence is higher in the younger age. In five
NSABP trials among 10,709 women, the 12-year incidence
of ipsilateral breast tumor recurrences for women
aged 49 years or younger, 50-59 years, and 60 years or
older were 9.6%, 5.8%, and 5.6%, respectively.[] Rudra
et al examined the recurrence patterns in patients with
BC. Women aged less than 40 years had higher rates of
LRR (20% vs. 7, p=0.004) and DR (18% vs. 5%, p=0.003)
compared to patients aged above 70 years.[] Although
young age at diagnosis was shown to be associated
with an increased risk of recurrence and poorer survival
[,,], the exact reason for this poor prognosis remains unclear. Numerous publications revealed that
the adverse tumor features at young age are related to
poor outcome. Similar to previous reports [,,,,],
our study showed that the BC in young patients younger
than ≤35 years is characterized by a higher frequency of
aggressive pathological features.
These unfavorable tumor characteristics and the
disparity in treatment approaches might contribute to
higher recurrence rates in younger patients. We found
that the young patients were two times more likely to
have recurrence rate than elderly. However, the recurrence
patterns did not differ between the groups. The
recurrences were mostly appeared in DR. The 5- and
10-year cumulative incidence of DR were significantly
higher in the young patients, justifying more intensive
chemotherapy following surgery in these age groups
of patients. The St Gallen 1998 consensus identified
diagnosis at 35 years or younger as a poor prognostic
factor, and they recommended adjuvant chemotherapy
regardless of tumor features.[] However, this recommendation
was not based on strong evidence. Now,
the systemic chemotherapy decision is predominantly
based on not only patient age but also patients" comorbidities
and performance status and tumor stage
and other clinical and molecular prognostic factors. In
literature, it has been shown that elderly patients less
likely received chemotherapy for their BC [], and
when they received chemotherapy, most of them were
treated with non-cardiotoxic agents.[] Similar to
numerous reports [-], our study revealed that the
number of young patients whom received chemotherapy
was higher than elderly, and they mostly received
neoadjuvant chemotherapy because of higher incidence
of advanced clinical stage. Their chemotherapy
regimens contained mainly anthracycline and taxane.
The incidence of HER2 positivity in young patients was
significantly higher compared to the elderly, but there
was no significant difference in terms of anti-HER2
treatment in both groups. The reason for this may be
the nature of the retrospective study with unbalanced
data set or because most of our patients were treated
before anti-HER2 treatment era. Therefore, no conclusion
can be drawn for the contributing effect of this
agent to improve distant metastasis control.
The 5- and 10-year cumulative incidences of LRR
were not found significantly different between the
groups, though young patients had significantly more
adverse tumor features and significantly higher clinical
and pathological stage of the disease. The reason for the
similarity between the age groups in terms of LRR might
be that the young patients received more comprehensive
lymphatic irradiation and tumor bed boost that has been
shown to reduce LRR.[] On the other hand, we found that the LRR in our series was quite lower compared to
older series. Beadle et al reported a 10-year LRR rate of
16% after breast-conserving therapy and 12.5% after
mastectomy in a cohort of 652 women aged 35 years or
younger.[] Voogd et al reported 10-year LRR rate of
35% after breast-conserving therapy in women aged 35
years or younger.[] Patients with ?35 years of age in
our series showed 6% isolated locoregional recurrence
and 8% LRR and DR with a median follow-up time of
67.5 months. In more recent series, the 5- and 10-year
cumulative incidences of LRR were 1% and 4% after
breast-conserving therapy; 3.5% and 8.7% after mastectomy
in women aged 40 years or younger, which was
quite similar to our results.[]
Historically, young patients had worse survival than
older counterparts. Cancello et al reported that for the
patients aged <35 years, the risk of death rose by 5% for
every 1-year reduction in age, whereas there was no significant
change in death risk with age in patients aged
35?50 years.[] It is speculated that younger age have
a higher risk of death compared to older counterparts
even if they are diagnosed early and receive more intensive
treatment.[] Prognosis in BC has dramatically
improved over the past decades. According to 2017 data
from the American Cancer Society, overall BC death
rates increased by 0.4% per year from 1975 to 1989, but
since then the death rates have decreased rapidly, for
a total decline of 39% through 2015. This decrease after
1989 occurred in both younger and older women.
[] The differences related to age may be narrowing as
the treatment of patients with BC improves. The better
preoperative staging, margin assessment, new systemic
agents, and modern radiotherapy techniques may contribute
better local-regional control and survival.[]
In one of the recent studies, no significant difference in
5-year survival was found between the patients aged 35
years or younger and the patients aged 65 years or older
in despite of lower 5-year RFS in patients with young
age.[] Similar to this study, we found no significant
difference in terms of BCSS between the groups though
the difference in 10-year BCSS rate was 8%. This can
be explained by more intensive treatments that young
patients have received because of better performance
status and tolerability, which compensate the negative
impact of young age on BCSS.
It is not surprising to find that the 5- and 10-year
OS rates were significantly lower in the elderly. Since
these women had more likely to have co-morbidities
and many of them died because of other reasons than
that of BC.
The strengths of our study can be summarized as
having two distinct age groups, which were underrepresented
populations and fall out of screening programs.
The patient data were reviewed in terms of pathological
features and treatment approaches as well as recurrence
patterns and survival. In contrast to most studies in literature,
the treatment and recurrence patterns were represented
in detail. However, several limitations should also
be mentioned. First, the nature of the retrospective study
made unbalanced data set, and some lost information
of patients and treatment characteristics was inevitable.
Second, there is a selection bias in terms of treatment,
since all patients received radiotherapy, and we do not
know the consequence of patients without RT.
Conclusion
In conclusion, similar to previous reports, we have
demonstrated that the younger patients had more aggressive
pathological features and advanced stage. The
LRFS between two distinct age groups was found similar
in spite of the presence of adverse tumor features.
The reason of this can be explained by more comprehensive
lymphatic irradiation and tumor bed boost that
the young patients received, justifying more aggressive
RT in this age groups of patients. The DRFS rates were
significantly lower in the young patients even though
they received more intensive chemotherapy. Future
studies are needed for more effective systemic regimens
to decrease DR in young patients.
Peer-review: Externally peer-reviewed.
Conflict of Interest: There is no conflict of interest.
Ethics Committee Approval: The local ethics committee
approved the study.
Financial Support: There is no financial sport.
Authorship contributions: Concept - Ö.P.E., C.Ö.; Design
- Ö.P.E., F.Y., M.G., C.Ö.; Supervision - Ö.P.E.; Materials ?
Ö.P.E., S.Y.S., Ş.A.E., B.A., B.A., M.G., D.Ç.Ö., Z.A., C.Ö.,
B.G., M.A., G.Ö., İ.B.G., F.Y.; Data collection &/or processing
- Ö.P.E., S.Y.S., Ş.A.E., B.A., B.A., M.G., D.Ç.Ö., Z.A., C.Ö.,
B.G., M.A., G.Ö., İ.B.G., F.Y.; Analysis and/or interpretation
- Ö.P.E., F.Y.; Literature search - Ö.P.E., M.G.; Writing -
Ö.P.E., M.G.; Critical review - Ö.P.E., F.Y., M.G., C.Ö.
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