cancers

Article
Local Recurrence in Young Women with Breast Cancer:
Breast Conserving Therapy vs. Mastectomy Alone
Dang Van Nguyen 1,† , Sang-Won Kim 2,3,† , Young-Taek Oh 3 , O Kyu Noh 3 , Yongsik Jung 4 , Mison Chun 3, *
and Dae Sung Yoon 5, *

1 Department of Oncology, Hanoi Medical University, Hanoi 116001, Vietnam; drdangnguyen@gmail.com

2 Department of Radiation Oncology, Myunggok Medical Research Institute, Konyang University College of
Medicine, Daejeon 35365, Korea; swkim78@kyuh.ac.kr
3 Department of Radiation Oncology, Ajou University School of Medicine, Suwon 16499, Korea;
ohyoung@ajou.ac.kr (Y.-T.O.); okyu.noh@gmail.com (O.K.N.)
4 Department of Surgery, Ajou University School of Medicine, Suwon 16499, Korea; jungys@ajou.ac.kr
5 Department of Surgery, Konyang University College of Medicine, Daejeon 35365, Korea
* Correspondence: chunm@ajou.ac.kr (M.C.); dsyoonmd@kyuh.ac.kr (D.S.Y.);
Tel.: +82-31-219-5884 (M.C.); +82-42-600-9297 (D.S.Y.)
† These authors equally contributed to this study.

Simple Summary: To date, breast conserving therapy has equivalent local control to mastectomy
alone. However, it is not clear whether this finding is equally applied to young women because of
the lack of large scale prospective randomized studies. In this study, we compared the local control
between breast conserving therapy and mastectomy alone for young women with breast cancer. We



found that young women who underwent breast conserving therapy had an approximately 2.5-fold


increased risk of local recurrence compared with those receiving mastectomy alone. The prognosis
Citation: Nguyen, D.V.; Kim, S.-W.; of young women who had local recurrence after breast conserving therapy were poor despite
Oh, Y.-T.; Noh, OK.; Jung, Y.;
the aggressive salvage treatments. Therefore, the development of more effective novel systemic
Chun, M.; Yoon, D.S. Local
treatments is required to improve treatment outcomes in young women with breast cancer receiving
Recurrence in Young Women with
breast conserving therapy.
Breast Cancer: Breast Conserving
Therapy vs. Mastectomy Alone.
Abstract: We compared the cumulative incidence of local recurrence in young patients (≤40 years)
Cancers 2021, 13, 2150. https://
doi.org/10.3390/cancers13092150
with breast cancer between breast conserving therapy (BCT) and mastectomy alone. Among 428
women with early-stage breast cancer who were treated between 2001 and 2012, 311 underwent
Academic Editor: BCT and 117 underwent mastectomy alone. Adjuvant systemic treatments were administered to
Kwok-Leung Cheung 409 patients (95.6%). We compared the cumulative incidence of LR and survival rates between two
groups. During a median follow-up period of 91 months, the 10-year cumulative incidence of LR
Received: 18 March 2021 was 9.3% (median interval of 36.5 months from surgery). Patients treated with BCT tended to have
Accepted: 25 April 2021 a higher risk for local recurrence (11.1% for BCT vs. 4.1% for mastectomy alone, p = 0.078). All
Published: 29 April 2021 patients with isolated LR after BCT (n = 23) underwent salvage mastectomy followed by systemic
treatments. The 5-year distant metastasis-free survival and overall survival of patients with isolated
Publisher’s Note: MDPI stays neutral
LR after BCT were 44.2% and 82.2%, respectively. The BCT group exhibited an approximately 2.5-fold
with regard to jurisdictional claims in
higher risk of LR than mastectomy alone group. Patients with isolated LR after BCT showed poor
published maps and institutional affil-
prognosis despite undergoing aggressive salvage treatments. The development of novel treatments
iations.
should be investigated to reduce LR for improving prognosis and preserving cosmetic outcomes in
young women.

Keywords: breast cancer; breast conservation therapy; total mastectomy; young women; local recurrence
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
1. Introduction
conditions of the Creative Commons
Attribution (CC BY) license (https:// Breast conservation therapy (BCT) is the preferred primary local treatment for early-
creativecommons.org/licenses/by/ stage, invasive breast cancer because of its equivalent survival to that of mastectomy, with
4.0/). the additional advantage of preserving cosmetic outcomes of the involved breast [1,2].

Cancers 2021, 13, 2150. https://doi.org/10.3390/cancers13092150 https://www.mdpi.com/journal/cancers

Cancers 2021, 13, 2150 2 of 9

However, performing BCT in young patients remains challenging. Since young age
has been reported to be an independent risk factor for high local recurrence and poor
prognosis [3–5], more aggressive local treatment such as mastectomy is often considered
for young patients. In addition, including a small number of young patients in early
randomized trials has made it difficult to confirm the efficacy and safety of BCT in young
women [6,7].
Previous studies have been published to address unconfirmed legitimacy of BCT for
young patients [8–23], and consistently demonstrated similar survival between BCT and
mastectomy. However, the majority of these were retrospective studies and could not draw
a definite conclusion. Several studies had problematic study designs, including patients
who received postmastectomy radiation therapy [9–14,16,18,22,23]. In addition, only a few
studies have analyzed treatment outcomes in recently treated patients [18,21,23].
As the preservation of the cosmetic outcomes of the breast is an important goal of BCT,
local control should be seriously concerned before determining definitive local treatment
modality. However, the comparison of local control between BCT and mastectomy has
been of little interest because of similar survival. It has been questioned whether BCT
also shows comparable local control with that of mastectomy because several studies
have demonstrated the superiority of mastectomy in terms of local control [8,12,14,17,
22,23]. Diagnosis with recurrence comes psychologically as a disaster for patients even
though its extent is limited and can be salvaged by mastectomy. Furthermore, as repeated
hospitalization, surgery, and adjuvant treatments are undertaken, additional medical costs
and longer treatment duration can create burdens for patients.
In this study, we compared the incidence of local recurrence (LR) in young women
with breast cancer between BCT and mastectomy alone. In addition, we investigated risk
factors associated with increased LR among patients who underwent BCT.

2. Materials and Methods

The Institutional Review Board of two participating institutions approved this study
with a waiver of informed consent due to its retrospective nature. All procedures per-
formed were in accordance with the ethical standards of the institution and with the 1964
Declaration of Helsinki (and its later amendments).
We reviewed the medical records of all patients with breast cancer aged ≤40 years at
diagnosis who were curatively treated between 2001 and 2012. Patients diagnosed with
inflammatory breast cancer, ductal carcinoma in situ, or malignancies other than carcinoma
were excluded from the analysis, as were those treated with neoadjuvant therapy or
postmastectomy radiation therapy and those who refused radiation therapy after partial
mastectomy.
All patients underwent definitive local treatment with either BCT or total mastectomy
alone. If patients underwent total mastectomy subsequently after partial mastectomy
because of a positive resection margin, local treatment was defined as mastectomy. Local
treatment approaches were determined according to the surgeons’ discretion or patients’
preference. Axillary evaluation was performed with sentinel lymph node biopsy or limited
axillary dissection.
Adjuvant chemotherapy was administered in 323 patients (75.5%). For patients
with negative lymph nodes, the chemotherapeutic drug was either a combination of
cyclophosphamide, methotrexate, and 5-fluorouracil, or an anthracycline-based regimen.
Patients with positive lymph nodes received a taxane-based regimen. Adjuvant hormone
therapy was administered to all patients with positive hormone receptor status for at least
5 years. In total, 406 patients (95.6%) received adjuvant systemic treatments.
Patients treated with BCT received whole-breast irradiation of 45–50 Gy with a con-
ventional fractionation scheme, followed by a boost to the tumor bed with a median dose
of 14 Gy. For patients with multiple lymph nodes, radiation was delivered conventionally
to the supraclavicular area with a total dose of 45–50 Gy.
Cancers 2021, 13, 2150 3 of 9

Categorical variables of clinico-pathological factors were compared between both

treatment groups using the Chi-squared or Fisher’s exact test. Continuous variables,
such as age and primary tumor size, were compared using the Kruskal–Wallis test. We
assessed LR using cumulative incidence analysis (Gray’s test). LR was defined as the
first recurrence occurring at the ipsilateral breast or chest wall. Competing risks included
regional recurrence, distant metastasis, contralateral breast cancer, and intercurrent death.
Competing risk regression was used to identify risk factors for LR. For patients with
isolated LR after BCT, distant metastasis-free survival (DMFS) and overall survival (OS)
were calculated from the date of pathologic confirmation of LR to the event of interest,
using the Kaplan–Meier method. Univariate analysis was conducted using the log-rank
test and multivariate analysis was conducted using Cox proportional hazard analysis.
A two-sided p value less than 0.05 was considered statistically significant. All statistical
analyses were performed with R software ver. 3.3.3.

3. Results
3.1. Patient Characteristics
We identified 428 patients who met our study criteria. Of these, 311 patients (72.7%)
underwent BCT and 117 (27.3%) underwent total mastectomy alone. A comparison of pa-
tient characteristics between both treatment groups is summarized in Table 1. The median
age of entire patients was 37 years (range, 19–40 years). The median tumor size was similar
between both treatment groups (1.7 cm for the BCT group vs. 2.0 cm for the mastectomy
alone group). Among pathological factors, human epidermal growth factor receptor 2
status and the number of positive lymph nodes were significantly different between the
two treatment groups.

Table 1. Patient characteristics.

Variables BCT (n = 311) Mastectomy (n = 117) p Value

Age at diagnosis (years)
Median 36 37 0.041
IQR 33 to 39 34 to 39
Laterality
Left 169 (54.3%) 54 (46.2%) 0.161
Right 142 (45.7%) 63 (53.8%)
Histologic grade
Low to intermediate 136 (46.7%) 53 (50.5%) 0.587
High 155 (53.3%) 52 (49.5%)
Estrogen receptor
Negative 104 (33.4%) 31 (26.7%) 0.226
Positive 207 (66.6%) 85 (73.3%)
Progesterone receptor
Negative 100 (32.2%) 36 (31.0%) 0.917
Positive 211 (67.8%) 80 (69.0%)
HER2
Negative 258 (83.2%) 71 (61.7%) <0.001
Positive 52 (16.8%) 44 (38.3%)
Cancers 2021, 13, 2150 4 of 9

Table 1. Cont.

Variables BCT (n = 311) Mastectomy (n = 117) p Value

Intrinsic subtype
Luminal A 190 (61.3%) 63 (54.8%)
Luminal B 36 (11.6%) 27 (23.5%) <0.001
HER2 16 (5.2%) 17 (14.8%)
Triple negative 68 (21.9%) 8 (7.0%)
Tumor size
≤2 cm 207 (66.6%) 68 (58.1%) 0.131
>2 cm 104 (33.4%) 49 (41.9%)
No. of positive LNs
0 247 (79.4%) 74 (63.2%) 0.001
1–3 64 (20.6%) 43 (36.8%)
AJCC stage
I 176 (56.6%) 49 (41.9%) 0.009
II 135 (43.4%) 68 (58.1%)
Adjuvant chemotherapy
None 75 (24.1%) 30 (25.6%)
CMF 18 (5.8%) 4 (3.4%) 0.013
Anthracycline-based regimen 159 (51.1%) 45 (38.5%)
Taxane-based regimen 59 (19.0%) 38 (32.5%)
Adjuvant endocrine therapy
No 92 (29.6%) 35 (29.9%)
0.523
oral regimen 134 (43.1%) 56 (47.9%)
With LHRH analogues 85 (27.3%) 26 (22.2%)
Adjuvant trastuzumab
Not indicated 259 (83.3%) 73 (62.4%)
<0.001
No 46 (14.8%) 39 (33.3%)
Yes 6 (1.9%) 5 (4.3%)
CMF, combination of cyclophosphamide, methotrexate and 5-fluorouracil; LHRH, luteinizing
hormone-releasing hormone.

3.2. Local Recurrence

The median follow-up period was 91 months for all patients (range, 8–192 months).
The median follow-up period was similar between BCT group and mastectomy group (89
months vs. 95 months, respectively). There were 30 patients (26 patients in the BCT group
and 4 in the total mastectomy alone group) who experienced LR as the first recurrence, with
a median interval of 36.5 months between initial local treatment and the date of pathologic
confirmation. Of these, 25 patients developed isolated LR (23 patients in the BCT group and
2 patients in the total mastectomy alone group). All patients with isolated LR underwent
salvage total mastectomy (BCT group) or wide excision (total mastectomy alone group).
The 10-year cumulative incidence of LR was 9.3% for all patients. Patients who
underwent BCT showed a tendency toward higher cumulative incidence of LR, compared
with those in the total mastectomy alone group (11.1% in the BCT group vs. 4.1% in the
total mastectomy alone group, p = 0.078) (Figure 1). Multivariate competing risk regression
analysis showed that BCT had a tendency toward increased risk of LR (relative risk, 3.182;
95% confidential interval, 0.0921–1.27; p = 0.064). Other factors, including histologic grade
(p = 0.63), estrogen receptor (p = 0.80), progesterone receptor (p = 0.54), HER2 (p = 0.18),
and tumor size (p = 0.31) were not found to be significantly associated with increased risk
of LR.
We investigated to identify factors for increased risk of LR in the BCT group. On uni-
variate analysis, all covariates including histologic grade, estrogen receptor, progesterone
receptor, HER2, biological subtypes and tumor size were not significantly associated with
increased the risk of LR (all p > 0.1).
Cancers 2021, 13, 2150 5 of 9

Figure 1. Graph of cumulative incidence of local recurrence between breast conservation therapy
(black line) and mastectomy alone (red line).

3.3. Survival Rates after Local Recurrence

The estimated 10-year DMFS was 84.7% for all patients. The estimated 10-year DMFS
was not significantly different between two groups (84.4% in the BCT group vs. 85.7%
in the mastectomy alone group, p = 0.533). Patients with LR showed significantly worse
estimated 10-year DMFS than those without LR (47.0% vs. 88.0%; p < 0.001). The 10-year
distant metastasis-free survival rate of patients with LR was similar between two groups
(49.3% in the BCT group vs. 50.0% in the mastectomy group). For 23 patients with isolated
LR after BCT, 7 patients experienced distant metastasis and the estimated 10-year DMFS
rate after LR was 44.2% with a median period of 54 months (Figure 2).

Figure 2. Kaplan-Meier curve of distant metastasis-free survival in patients with isolated local
recurrence after breast conservation therapy.

The estimated 10-year OS was 89.0% for all patients. The 10-year OS was not signifi-
cantly different between two groups (90.3% in the BCT group vs. 85.8% in the mastectomy
Cancers 2021, 13, 2150 6 of 9

alone group, p = 0.433). Patients with LR showed significantly worse estimated 10-year OS
than those without LR (66.5% vs. 91.1%; p < 0.001). For patients with isolated LR after BCT,
the estimated 10-year OS was 51.4% (Figure 3).

Figure 3. Kaplan–Meier curve of overall survival in patients with isolated local recurrence after
breast conservation therapy.

4. Discussion
Previously, the notion that breast cancer arising in young age presents more aggressive
pathological features with advanced stage and young age is associated with increased
risk of recurrence acted as barriers to perform BCT in young patients [3–5]. However, this
concern may be unwarranted as previous studies have reported consistently equivalent
survival between BCT and mastectomy [8–19,21–23]. The treatment outcomes of young
patients undergoing BCT have also improved, owing to better preoperative imaging workups
and advances in adjuvant treatments [18,24,25]. Based on this evidence, BCT is currently
recommended as the first option whenever suitable, even in young patients [26,27].
Despite the evidence showing equivalent survival between BCT and mastectomy,
young patients with breast cancer in the United States are increasingly choosing mastectomy
instead of BCT [28–30]. Several factors may influence this phenomenon, including living
conditions that make it difficult to receive conventional radiation therapy and fear of higher
risk of LR, leading to subsequent repeated surgery [19].
Patients’ fears are not unfounded because several studies have reported higher rates of
LR in young patients treated with BCT [8,12,14,17,22,23]. In this study, patients in the BCT
group had a 2.5-fold higher risk of LR than those in the total mastectomy alone group and
all 23 patients with isolated LR after BCT eventually underwent salvage mastectomy. The
higher cumulative incidence of LR in the BCT group is supported by a recent prospectively
observational cohort study (10-year LR rates of 11.7% in the BCT group vs. 4.9% in the
mastectomy group, p < 0.001) [23].
Interestingly, the cumulative incidence curve in this study indicates that the risk of
LR in the BCT group increased constantly over time, whereas a plateau was reached after
6 years in the total mastectomy alone group. van der Sangen et al. also reported similar
patterns of LR according to the primary local treatments in young women [12]. Due to the
Cancers 2021, 13, 2150 7 of 9

continuous increase of LR in the BCT group, the difference in the incidence of LR between
BCT and total mastectomy alone group will increase over time.
In this study, approximately one-third of patients with isolated LR after BCT suffered
from the development of distant metastasis, even though they underwent aggressive
salvage treatments. Anderson et al. also reported that of 342 patients with isolated LR
after BCT, 127 (37.1%) experienced distant metastases [31]. Given the poor DMFS after
aggressive salvage treatments for isolated LR in the BCT group (44.2% at 5 years), more
effective novel systemic treatments should be investigated. In addition, prediction of LR
using an externally validated nomogram like Dutch INFLUENCE can help to early detect
LR and prevent distant metastasis [32].
The constantly increased incidence of LR and secondary development of distant
metastasis in the BCT group can be dealt with by identifying patients with risk factors
for LR. Therefore, we investigated risk factors associated with increased risk of LR in the
BCT group. However, no clinical or pathological factors were significantly associated with
increased LR. Previously, a few researchers investigated to identify risk factors associated
with LR after BCT and they did not find any relevant factors [12,24,25]. This suggests that
decisions for definitive local treatment approaches should not be solely based on clinical
and/or pathological factors in young women. Further studies are warranted to examine
risk factors at the molecular level.
This study had several limitations including inherent biases due to its retrospective
design. The local treatment approach was determined according to the surgeons’ discretion
or patients’ preference. Therefore, the distribution of some factors was not balanced.
Although we adjusted for all available clinical and pathological factors, other unknown
confounders might influence treatment outcomes. In addition, this study analyzes data
from two institutions, and it is difficult to generalize the results. However, all the details of
local and systemic treatments were performed based on standard procedures. During the
study period, the test for BRCA mutation was not routinely performed at two institutions.
Thus, this study could not evaluate the effect of BRCA mutation. Finally, there were a
limited number of patients receiving adjuvant trastuzumab because it was not reimbursed
for most of study period in Korea.

5. Conclusions
Patients in the BCT group exhibited approximately a 2.5-fold increased risk of LR
compared with those in the mastectomy alone group. The incidence of LR increases contin-
uously in the BCT group in contrast to the mastectomy alone group. Furthermore, one-third
of patients with an isolated LR after BCT experienced distant metastasis despite of aggres-
sive salvage mastectomy followed by systemic treatments. Although BCT had equivalent
OS to total mastectomy alone and it can be recognized as the first local treatment option for
young women with breast cancer, countermeasures are required to improve quality of life
in patients treated with BCT through preservation of breast cosmetic outcomes. To reduce
the risk of distant metastasis and to improve prognosis in patients with isolated LR after
BCT, more effective systemic treatments should be investigated. Ultimately, it is more
important to reduce the incidence of LR by developing novel treatments for improved
prognosis, as well as preserving cosmetic outcomes in young women undergoing BCT.

Author Contributions: Conceptualization, S.-W.K. and M.C.; formal analysis, D.V.N. and S.-W.K.;
investigation, D.V.N. and S.-W.K.; data curation, M.C., Y.-T.O., O.K.N., Y.J. and D.S.Y.; resources,
M.C. and D.S.Y.; writing—original draft preparation, D.V.N.; writing—review and editing, S.-W.K.;
supervision, M.C. and D.S.Y.; All authors have read and agreed to the published version of the
manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Helsinki and approved by the Institutional Review Board of Ajou University School of
Medicine (AJIRB-16-340) and Konyang University College of Medicine (2017-03-011).
Cancers 2021, 13, 2150 8 of 9

Informed Consent Statement: Patient consent was waived due to the following: This research
involves no more than minimal risk; The waiver of informed consent will not adversely affect the
rights and welfare of the subjects; It is not practicable to conduct the research without the waiver or
alteration; Whenever appropriate, participants will be provided with additional pertinent information
after their participation.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author. The data are not publicly available due to privacy and ethical restrictions.
Conflicts of Interest: The authors declare no conflict of interest.

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