The Impacts of Inclusion in Clinical Trials on Outcomes among Patients with Metastatic Breast Cancer (MBC)
The Impacts of Inclusion in Clinical Trials on Outcomes among Patients with Metastatic Breast Cancer (MBC)
Ji Yun Lee 0 1
Sung Hee Lim 0 1
Min-Young Lee 0 1
Hae Su Kim 0 1
Jin Seok Ahn 0 1
Young-Hyuck Im 0 1
Yeon Hee Park 0 1
0 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , Korea
1 Editor: Shian-Ying Sung, Taipei Medical University , TAIWAN
Metastatic breast cancer (MBC) remains a devastating and incurable disease. Over the past decade, the implementation of clinical trials both with and without molecular targeted therapeutics has impacted the daily clinical treatment of patients with MBC. In this study, we determine whether including MBC patients in clinical trials affects clinical outcomes.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: This research was supported by a grant of
the Korea Health Technology R&D Project through
the Korea Health Industry Development Institute
(KHIDI), funded by the Ministry of Health & Welfare,
Republic of Korea (grant number: HI14C1234).
Competing Interests: The authors have declared
that no competing interests exist.
We retrospectively reviewed data for a total of 863 patients diagnosed with initial or recurrent (after receiving adjuvant systemic treatments following surgery) metastatic disease between January 2000 and December 2013. Data were obtained from the breast cancer database of Samsung Medical Center.
Among the 806 patients selected for inclusion, 188 (23%) had participated in clinical trials. A
total of 185 clinical trials were conducted from 2000 to 2014. When compared with earlier
periods (n = 10 for 2000–2004), clinical trial enrollment significantly increased over time (n = 103
for 2005–2009, P = 0.024; n = 110 for 2010–2014, P = 0.046). Multivariate analyses revealed
that biologic subtype, distant recurrence free interval (DRFI), and clinical trial enrollment were
independent predictors of overall survival. Patients who participated in clinical trials showed
improved survival, with a hazard ratio of 0.75 (95% CI, 0.59–0.95), which was associated with
a 25% reduction in the risk of death. However, subgroup analysis showed that this improved
survival benefit was not maintained in patients with triple negative breast cancer (TNBC).
Although not conclusive, we could speculate that there were differences in the use of newer agents or regimens over time, and these differences appear to be associated with improved survival.
Breast cancer is the most common female cancer and one of the leading causes of death among
women worldwide [
]. It is estimated that 30–50% of patients with early to locally advanced
breast cancer at diagnosis experience relapse despite the use of adjuvant systemic treatment
after surgery . In addition, 5–10% of patients with breast cancer present with metastatic
disease at diagnosis [
]. Patients with metastatic disease at either initial diagnosis or relapse
have traditionally been considered incurable with conventional treatment. However, over the
past decade, the survival of patients with metastatic breast cancer (MBC) has improved slowly
]. Potential explanation for this improvement are early detection of metastatic disease [
new drugs [
], advances in supportive care [
], and palliative surgery or radiotherapy
Over the past decade, a number of trials have demonstrated improved survival in patients
with MBC when treatments with newer hormone agents or chemotherapeutic regimens were
compared with previous standards [
]. In particular, trastuzumab increases the clinical
benefit of first-line chemotherapy in cases of MBC that overexpress human epidermal growth
factor receptor (HER2) [
]. However, it is not clear whether the clinical outcomes of patients
who participate in clinical trials differ from those of patients who receive conventional
treatment without inclusion in clinical trials.
The number of clinical trials exploring treatments for MBC that is refractory to
conventional treatment has increased rapidly in Korea since the year 2000. We explored the impact of
inclusion in clinical trials on survival among patients with MBC, and sought to identify patients
who were the most likely to benefit from clinical trials. We hypothesized that the outcomes of
patients who participate in clinical trials are improved compared to those of patients who
received only conventional treatments.
Materials and Methods
Study Design and Sample
We retrospectively reviewed data for a total of 863 patients with metastatic disease at either
initial diagnosis or recurrence after receiving adjuvant therapy between January 2000 and
December 2013. Data were obtained from the breast cancer database of Samsung Medical Center. We
excluded patients with local and/or contralateral recurrence, patients with double primary
cancer, and patients who participated in clinical trials in neoadjuvant and/or adjuvant settings. A
total of 806 patients were included in this study (Fig 1). This study was performed in
accordance with the Declaration of Helsinki and approved by Institutional Review Board of
Samsung Medical Center. The patient records /information was anonymized and de-identified
prior to analysis.
Clinical data were obtained by review of all patient medical records. Baseline patient
characteristics collected for analysis included age, biological subtype according to the hormone receptor
(HR) status, disease status, year of diagnosis with MBC, and medical treatment. Breast cancer
is a heterogeneous disease that is classified according to biological subtype determined using
immunohistochemistry (IHC) for estrogen receptor (ER), progesterone receptor (PgR), and
human epidermal growth factor receptor type 2 (HER2). We stratified the patients into three
groups: HR + (defined as ER+ and/or PgR+, HER2-), HER2+ (defined as HER2+ regardless of
ER and/or PgR), and triple negative breast cancer (TNBC) (defined as lacking ER, PgR, and
HER2 expression). Patients were divided by disease status at diagnosis with MBC: metastatic
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Fig 1. Summary of inclusion criteria.
disease at initial diagnosis, distant recurrence-free interval (DRFI) < 5 years, and DRFI 5
]. We also divided the patients into groups according to the time period of diagnosis
with MBC: 2000 to 2004, 2005 to 2009, and 2010–2013. The data-cutoff date for the results
presented here was December 16 2014. Given the retrospective nature of study, clinical data of
performance status at diagnosis with MBC was limited to evaluate.
Overall survival (OS) was defined as the interval from the date of diagnosis of distant
metastasis to death from any cause. All patients who remained alive at the date of last analysis were
censored. Patient characteristics were compared using chi-square and Fisher’s exact tests
(categorical variables). Survival probabilities were estimated using the Kaplan-Meier method and
compared for significant differences using log-rank analysis. Multivariate analyses were
performed using the Cox proportional hazards regression model. All analyses were carried out
using SPSS 20.0 (IBM SPSS Statistics, IBM Corp., Armonk, NY, USA) and statistical
significance was set at P 0.05.
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Trends in clinical trials for patients with metastatic breast cancer
Fig 2 shows trends in clinical trials of treatments for MBC from 2000 to 2014. Among 806
patients, 188 (23%) had participated in clinical trials, and 223 clinical trials were conducted
from 2000 to 2014 at SMC. When compared with earlier periods (n = 10 for 2000–2004), a
significant increase in the number of patients who were enrolled on a clinical trial was observed
over time (n = 103 for 2005–2009, P = 0.024; n = 110 for 2010–2014, P = 0.046). The clinical
trials that were received for the treatment of MBC are outlined in S2 Table.
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Fig 2. Trends of participating in clinical trials among patients with MBC from 2000 to 2014.
Survival outcomes and prognostic factors
The median follow-up durations among all patients were 6.2 years (range, 0.9–15.4 years), 6.6
years (range, 0.5–14.5), and 6.9 years (range, 1.4–14.1) for HR+, HER2+, and TNBC,
respectively. The median survival after diagnosis with MBC was 3.8 years (95% CI, 3.4–4.3 years).
Estimated 5-year and 10-year survival rates were 41% and 22%, respectively. Biological subtype
Fig 3. Survival after diagnosis with MBC according to (a) biological subtype and (b) clinical trial enrollment.
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Values in parentheses are 95% confidence intervals. MBC, metastatic breast cancer; DRFI, DRFI, distant recurrence-free interval.
was strongly associated with survival after metastasis (P < 0.001) (Fig 3A). Estimated 5-year
survival rates among patients with HR+, HER2+, and TNBC were 50%, 37%, and 25%,
respectively. The estimated 5-year survival rate was significantly higher for patients who had enrolled
in clinical trials than for patients who had not (50% vs. 38%, P < 0.001) (Fig 3B). Patients with
a longer DRFI ( 5 years) showed significantly better survival outcomes than those with a
shorter DRFI (< 5 years) (S1A Fig). There was a significant improvement in survival for
women with MBC over time (S1B and S1C Fig).
Table 2 shows the hazards ratios (HRs) estimated using the Cox proportional hazards
model. Biological subtype (HER2+ or TNBC), shorter DRFI (< 5 years), and lack of clinicial
trial participation were associated with significantly shorter survival. Patients who were
enrolled in clinical trials showed improved survival with a HR of 0.67 (95% CI, 0.53–0.84),
which was associated with a 33% reduction in the risk of death. Patients diagnosed with MBC
during earlier time periods showed poorer survival than those who were diagnosed during later
time periods (2000–2004 vs. 2010–2013, P = 0.001) in univariate analysis; however, in
multivariate analysis, there was no significant improvement in survival over time (Table 2).
Fig 4 illustrates survival from the time of diagnosis with MBC according to clinical trial
enrollment, stratified by biological subtype. Patients with biological subtype HR+ who were enrolled
in clinical trials experienced survival benefits (P = 0.019, Fig 4A) as did those with subtype
HER2+ (P = 0.027, Fig 4B); however, this was not true of TNBC (P = 0.527, Fig 4C). As shown
in the S2 Fig, survival benefit was consistent across age subgroups. We noted significant
improvements in overall survival associated with clinical trial enrollment among patients with
certain biological subgroups (HR+ or HER2+), shorter DRFI (< 5 years), and certain time
periods of recurrence (2010–2013).
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Fig 4. Survival after diagnosis with MBC according to clinical trial enrollment stratified by biologic subtype: (a) HR+, (b) HER2+, and (c) TNBC.
Recent epidemiological data indicate significant worldwide decreases in breast cancer mortality
over the past few decades [
]. Much of this improvement in outcomes is attributed to
earlier detection strategies, the greater use of adjuvant hormone and cytotoxic treatments, and
more efficacious and numerous treatment options for a patients with MBC [
results of the present study provide further evidence of improvements in survival associated
the better treatment integration of clinical trial.
Consistent with the results of previous studies [
6, 7, 24–26
], our analyses demonstrate
that certain biologic subtypes (HER2+ or TNBC) and short DRFI (< 5 years) are associated
with inferior survival. After adjusting for these variables, a trend toward better survival was
seen among patients who were enrolled in clinical trials (P = 0.021). The impact of clinical
trial enrollment on survival has not broadly translated into improved survival. Subgroup
analysis showed that patients with biological subtype HER2+ and later time period of
recurrence (2005–2009 or 2010–2013) experienced greater benefit from clinical trial enrollment.
This improvement could be explained by the increased availability of effective drugs,
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especially new HER2-targeting agents. In the late 2000s and the early 2010s, several clinical
trials for HER2-targeting agents beyond trastuzumab, including lapatinib [
], and the antibody drug conjugate ado-trastuzumab emtansine or T-DM1 [
established. Furthermore, advances in understanding tumor biology, particularly signaling
pathway, have changed the treatment paradigm for MBC [
]. The combination of the
mTOR inhibitor everolimus with the aromatase inhibitor exemestane has increased efficacy
in patients with ER+ MBC [
]. In the current study, the patients in later time periods had a
more chance to use novel agents or new combination regimens. Patients with shorter DRFI
(< 5 years) also experienced benefits from enrollment in clinical trials. This finding may
reflect the fact that HER2+ disease is associated with early recurrence. It is noteworthy that
patients with TNBC did not show any improvement in survival associated with clinical trial
enrollment. This suggests that there remains a critical need for the development of therapies,
especially those that focus on clinically efficient molecular targets, for patients with MBC.
Previous reports indicated that the period of diagnosis is an independent predictor of
6, 32, 33
]. On the contrary, in the present study, we found that the survival of MBC
patients has improved over time, but the time period of diagnosis with MBC was not related to
prognosis after adjustment for multiple prognostic covariates. Several factors could mediate
time-related bias: changes in radiologic facilities for detection and diagnosis, changes in
diagnostic criteria, evolution of clinical characteristics, and improvement of supportive care. In the
present study, the preponderance of favorable tumor biologies such as HR+, longer DRFI, and
greater enrollment in clinical trials among patients who were diagnosed during later time
periods might explain the improvement in survival over the time that we observed. Nevertheless,
this improvement over time may be mainly due to new advances including the discovery of
oncogenic drivers and therapeutic agents for these driver mutations.
The current study has a number of limitations. This was a retrospective single center cohort
study and therefore, selection bias could be a confounding variable. Most important critical
weakness in this study is that patients enrolled in clinical trials are a highly selected group, and
are not necessarily representative of the general population of patients with MBC. We were
unable to evaluate clinical findings, such as performance status and organ function, that may
be associated with more favorable survival outcomes among patients who were enrolled in
Our findings, although not conclusive, suggest that breast cancer survival is improved by
enrollment in clinical trials. The development of targeted, biologically-based therapies may be
the most promising strategy for prolonging survival among MBC patients. Our results support
the ethical background for conducting clinical trials.
Clinical practice points
The number of clinical trials exploring treatments for MBC that is refractory to conventional
treatment has increased rapidly.
The incorporation of clinical trials improved overall survival among patients with MBC.
Patients with biologic subtype HR+ and HER2+ experienced survival benefits, however, this
was not maintained in patients with triple negative breast cancer.
Our finding suggest that development of targeted therapeutics available for everyday clinical
practice should be needed for MBC patients.
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S1 Fig. Survival curves according to (a) disease status at diagnosis with MBC, (b) time
period of diagnosis with MBC, and (c) time period of clinical trial enrollment.
S2 Fig. Subgroup analysis.
S1 Table. Chemotherapies and hormone therapies prescribed for the treatment of
metastatic breast cancer for the time cohort.
S2 Table. Clinical trials for metastatic breast cancer.
Conceived and designed the experiments: Y.H.P. Performed the experiments: J.Y.L., S.H.L., M.
L., and H.S.K. Analyzed the data: J.Y.L., S.H.L., M.L., and H.S.K. Contributed
reagents/materials/analysis tools: J.Y.L., S.H.L., M.L., J.S.A., Y.I., and Y.H.P. Wrote the paper: J.Y.L., and Y.H.
P. contributed to subsequent drafts and commented and revised on the final draft paper: J.Y.L.,
S.H.L., M.L., H.S.K., J.S.A., Y.I., and Y.H.P.
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