Mammographic Density Reduction is Associated to the Prognosis in Asian Breast Cancer Patients Receiving Hormone Therapy

Abstract

Introduction

Using mammographic density as a significant biomarker for predicting prognosis in adjuvant hormone therapy patients is controversial due to the conflicting results of recent studies. This study aimed to evaluate hormone therapy-induced mammographic density reduction and its association with prognosis in Taiwanese patients.

Methods

In this retrospective study, 1941 patients with breast cancer were screened, and 399 patients with estrogen receptor-positive breast cancer who received adjuvant hormone therapy were enrolled. The mammographic density was measured using a fully automatic estimation procedure based on full-field digital mammography. The prognosis included relapse and metastasis during treatment follow-up. The Kaplan-Meier method and Cox proportional hazards model were used for disease-free survival analysis.

Results

A mammographic density reduction rate >20.8%, measured preoperatively and after receiving hormone therapy from 12-18 months, was a significant threshold for predicting prognosis in patients with breast cancer. The disease-free survival rate was significantly higher in patients whose mammographic density reduction rate was >20.8% (P = .048).

Conclusion

This study’s findings could help estimate the prognosis for patients with breast cancer and may improve the quality of adjuvant hormone therapy after enlarging the study cohort in the future.

Keywords

breast density breast cancer tamoxifen aromatase inhibitor estrogen receptor

Introduction

Previous studies have revealed that high mammographic density (MD) is strongly associated with susceptibility to breast cancer. Females with high MD may have a 4-6-fold greater risk of developing cancer than those with a low MD.¹ In addition, a high percentage of MD is a significant risk factor for breast cancer than the absolute dense area.² A natural conjecture is whether utilizing breast density as a biomarker is feasible. Moreover, determining whether mammography can reduce the incidence and mortality of breast cancer by MD estimation is necessary.³ Adjuvant hormone therapy (HT) effectively inhibits the growth of hormone-sensitive tumors in breast cancer and may decrease MD during treatment.⁴ Several studies^5,6 have revealed that MD reduction (MDR) during therapy is associated with decreased risk of breast cancer progression. However, the mechanisms underlying MD decrease during HT are not entirely understood. It is generally believed to be related to endogenous and exogenous factors.^7,8

Previous studies have revealed that tamoxifen is associated with reduced MD.^6,9 MDR can be a specific prognostic marker to predict endocrine resistance. However, this finding is inconsistent with the aromatase inhibitor (AI) treatment. The effect of AIs on MD varies from none¹⁰ to an average decrease of 5.9%⁶ based on previous findings. Studies have also revealed that MD did not decrease significantly in small or large study cohorts compared to control groups of postmenopausal women treated with AIs.^10-12 Despite the differing views on this issue, a study¹³ revealed that the overall aromatase expression was higher in tissue cores from dense regions than in those from sparse regions of healthy females' breasts, and the investigators could not rule out the possible influence of AI on MD density.

Due to the conflicting results of these studies, this is a controversial issue. A systemic review from Cochrane in 2021 is the most comprehensive systematic meta-analysis to date.⁴ This review stated that quantitative meta-analyses are challenging due to the significant heterogeneity among studies. These factors include differences in cohort size, population, treatment type (tamoxifen or AIs), MD measurement procedure, and body mass index (BMI) consideration and adjustment. Overall, there is only low/very low-quality evidence supporting the hypothesis that changes in MD after endocrine therapy are prognostic biomarkers for treatment or prevention. Tamoxifen may have a more significant effect; nonetheless, the evidence is limited.

This study aimed to evaluate the feasibility of utilizing MDR as a predictor of response to adjuvant HT in Taiwanese patients with breast cancer. The novelty of this study is that we attempted to combine the effects of two common adjuvant HTs (tamoxifen and AIs). Furthermore, adjuvant hormonal therapy is a long-term process; therefore, patients may face the challenge of therapy change due to menopause or other factors.

Methods

This retrospective study was approved by the Institutional Review Board of the institution (approval no. 171217). The requirement for informed consent from the patients was waived owing to the study’s retrospective nature. Additionally, the data were anonymized. All experimental methods were supervised by the ethics committee and conducted in accordance with the relevant guidelines and the Declaration of Helsinki. This study was reported following the strengthening the reporting of observational studies in epidemiology (STROBE) guidelines.¹⁴

This study used existing medical records and raw mammographic data from the Institute between January 2011 and December 2015. Patient age, BMI (kg/m²), tumor size, grade, and stage, lymph node status, estrogen receptor (ER)/progesterone receptor/human epidermal growth factor receptor 2 (HER2) status, and MD grade before HT were obtained from the medical records. In total, 1941 ER-positive patients were screened. The participants were selected based on the predefined inclusion and exclusion criteria. The inclusion criteria were:¹ patients aged 35-75 years with ER-positive breast cancer,² patients administered adjuvant HT treatment, and³ patients with available complete records of mammographic examination during adjuvant HT treatment. The exclusion criteria were:¹ patients with ER-negative breast cancer,² patients who were not administered or rejected HT after a confirmed diagnosis,³ patients who received neoadjuvant chemotherapy or no surgery after a confirmed diagnosis,⁴ patients who had bilateral or occult breast cancer or any other condition that was inappropriate for evaluation, and⁵ patients who underwent HT for <48 months. Through comparison with the Cochrane review,⁴ our study cohort also met the criteria of minimum dose in AI treatment, and the target population was postmenopausal females at treatment initiation. For cohorts treated with selective estrogen receptor modulators (SERM), tamoxifen and fulvestrant were the SERMs used. Moreso, most patients were premenopausal, with only a few who were postmenopausal. Women who were temporarily menopausal owing to gonadotropin-releasing hormone analogs (GnRH) were also excluded. All the patients were first diagnosed and did not receive any SERM or AI prior to treatment.

The adjuvant HT treatment strategy is generally based on institutional guidelines. The standard duration of treatment with tamoxifen is 5 years; postmenopausal women are treated with AIs for up to 5 years postoperatively or after 2-3 years of tamoxifen. The AIs administered in this study included anastrozole, letrozole, and exemestane, which include reversible nonsteroidal agents and irreversible steroidal inhibitors. To prevent subgroups that were too small, these AIs were clustered into one group because only slight differences existed in their clinical use. After comparing the treatment guidelines between institutes, the medication and dosing criteria were consistent with the interventions listed in the Cochrane review.⁴

To prevent overestimation of tamoxifen on MDR, patients with DCIS/T0/Tis stage disease based on TNM classification were also excluded. Patients who received HT and anti-HER2 combination therapy still met the inclusion criteria because no previous studies have demonstrated that anti-HER2 therapy significantly affects MD. A flowchart describing the patient selection process is illustrated in Figure 1.

Figure 1.

Flowchart of the patient enrollment.

The MD measurements in previous studies were based on computer-aided quantitative assessments (such as semi-automatic mammographic density measurement¹⁵). This study used fully automated volumetric mammographic MD measurements based on raw full-field digital mammography (FFDM) to minimize human effort and potential bias. Standard two-dimensional digital mammograms of all the participants were obtained using three mainstream FFDM systems: Senographe Essential/Senographe DS (GE Medical Systems, Milwaukee, WI, USA), Mammomat Inspiration (Siemens AG Healthcare, Erlangen, Germany), and Selenia Dimensions Systems (Hologic Inc., Bedford, MA, USA).

The MD grade measurements (including volpara density grade (VDG), overall dense breast volume (DV, in cm³), total breast volume (in cm³), and volumetric breast density (VBD, in percentage) were estimated and quantified using Volpara software (version 1.5.1; Volpara Health Technologies, Wellington, New Zealand), which uses a specific algorithm to model X-ray physics.¹⁶ The VBD was obtained by dividing the DV by the total breast volume and multiplying by 100. In this study, the DV and VBD were estimated by averaging the left and right sides. The VBD in this study was estimated only from the healthy side of the breast to minimize the effect of surgery and radiotherapy on breast/fibroglandular volume estimations and obtain more accurate results. All the participants underwent the same procedure and four-view digital mammograms for each examination at the institute.

MDR was calculated based on the MD difference between both digital mammograms. The first MD was determined from the mammogram obtained preoperatively and before the adjuvant HT (pre-MD). The second was determined from the mammogram obtained 12-18 months after adjuvant HT initiation (post-MD). The formula below defines MDR as the difference between both mammographic images (expressed as a percentage):

M D R (%) = \frac{p r e M D - p o s t M D}{100}

(1)

A positive MDR value indicated that the patient’s MD reduced after receiving adjuvant HT for 12-18 months (1-1.5 years); otherwise, the MDR was negative (indicating that MD increased after treatment).

When MDR was considered a biomarker and tested for its association with prognosis, it was essential to treat MDR change as a continuous variable and test its association with DFS or find an appropriate threshold value that differentiates the cohorts into two categories and calculates their DFS rates separately. In this study, the patients were grouped according to a fixed MD threshold. The MDR cut-off point selection was obtained using Youden’s index¹⁷ after the diagnostic test. The receiver operating characteristic (ROC) curve was plotted. It represented the sensitivity and specificity of the enrolled cohort to disease events (relapse, metastasis, and death). The performance and accuracy of the threshold value were estimated using the area under the ROC curve analysis and compared with DeLong’s nonparametric test.¹⁸

Statistical Analysis

Multivariate logistic regression analysis was used to estimate the association between MDR and its related factors. DFS was estimated using the Kaplan–Meier estimator¹⁹ with the log-rank test²⁰ and Cox’s proportional hazard regression model²¹ with the hazard ratio (HR). In the overall model fit estimation of the Cox regression model, the Chi-square test was used to assess the relationship between time and all the covariates in the model to ensure that the proportional hazard assumption was satisfied. No missing data for any analysis factor or follow-up time satisfied the inclusion criteria. Statistical P-value <.05 was considered significant. Statistical analyses were conducted using MedCalc for Windows (Version 19.5.3, MedCalc Software, Ostend, Belgium).

Results

Patients’ Characteristics

After screening all eligible patients, 399 patients with ER-positive breast cancer who were first diagnosed between 2011 and 2015 and had received adjuvant HT were recruited. The mean age (standard deviation [SD]) of the enrolled patients was 53.16 (11.44) years. Each patient had complete mammographic records during the entire follow-up, and the follow-up days were converted to years for the time scale in the Kaplan–Meier curve analysis and Cox regression. The average follow-up was 5.11 (1.64) years. The follow-up from adjuvant HT initiation to the last mammogram among the patients was 5.2 (1.55) years. The mean interval between the pre- and post-MD groups in this study cohort was 445 days (14.83 months; 95% confidence interval [CI], 430.57-459.56 days).

Fifty-eight (14.54%) patients had tumor recurrence (N = 23) or metastasis (N = 35), and 53 (13.28%) became lymph node metastasis-positive during the follow-up. Regarding the chemotherapy regimen the entire study cohort received, 215 (53.88%) patients did not receive chemotherapy postoperatively or before HT. Among the remaining patients, 48 (22.33%) received combined anti-HER2 targeted therapy and anthracycline-based chemotherapy regimen, and 167 (77.67%) received only the anthracycline-based regimen chemotherapy. In the study cohort, 213 patients experienced HER2 overexpression. Table 1 summarizes the participants’ details.

Table 1.

Clinicopathologic characteristics of patients The mammographic density grade was estimated in the VDG using the Volpara method. The primary tumor stage is listed based on the pathologic status. The T stage was based on the TNM grading system.

Associated variable	Total (N = 399)	MDR >20.8% (N = 103)	MDR <20.8% (N = 296)
Age (years), mean±SD	53.16 ± 11.44	50.15 ± 10.97	54.20 ± 11.42
Follow-up (days), median (95% CI)	1883 (1838.0-1940.3)	1896.0 (1827.2-2107.5)	1879.0 (1829.0-1934.9)
BMI (kg/m²), mean±SD	24.57 ± 4.27	24.34 ± 4.51	24.65 ± 4.19
Menopausal
Premenopausal	179	62	117
Postmenopausal	220	41	179
Hormone therapy
TAM only	208	65	143
AIs only	105	17	88
TAM/AIs combination	86	21	65
Chemotherapy
Y	217	52	166
N	182	51	130
Radiotherapy
Y	240	66	174
N	159	37	122
Mammographic density grade
a	0	0	0
b	57	9	48
c	177	33	144
d	165	61	104
Primary tumor stage
T1 (a/b/c)	201	57	144
T2	179	41	138
T3/T4 (a/b/c)	19	5	14
Lymph node status
Negative	237	67	170
Positive	53	32	121
HER2
Negative	186	45	141
Positive	213	58	155
Histologic grade
1/2	356	91	265
3	40	11	29
Metastasis
Y	35	11	24
N	364	92	272
Recurrence
Y	23	2	11
N	386	101	285

VDG, Volpara density grade; MDR, mammographic density reduction; SD, standard deviation; CI, confidence interval; BMI, body mass index; TAM, tamoxifen; AI, aromatase inhibitor; Y, yes; N, no; HER2, human epidermal growth factor receptor 2.

When measuring the MDR before and after surgery and HT during the 12-18 months follow-up, MDR = 20.8% was of optimal sensitivity and specificity in the disease-free prediction. When the cut-off MDR value was 20.8% in the enrolled group, the sensitivity and specificity of disease-free prediction were 80.0% and 80.5%, respectively. Figure 2 presents the DFS rates of the MDR >20.8% group and the MDR <20.8% group, based on Kaplan–Meier curves (P = .041 in log-rank test).

Figure 2.

Cumulative disease-free survival curves for patients with breast cancer administrated HT with and without MDR >20.8%.

Table 2 presents the mean VBD and MDR of the entire study cohort, based on an MDR >20.8% or <20.8%, treatment type, and menopausal status. The VBD in this table was determined preoperatively and after adjuvant HT administration. The mean MDR of the study cohort was 3.03%. In contrast, the mean MDR was 32.4% in the MDR >20.8% group and 31.7%–34.1% in each subdivision group. The mean MDR was −7.2% in the MDR <20.8% group and between −3.89% and −13.9% in each subdivision group.

Table 2.

The MD/MDR distribution of the study cohort.

	Total (N = 399)			MDR >20.8% (N = 103)			MDR <20.8% (N = 296)
Mean VBD (in %±SD)	13.92±7.03			17.41±7.55			12.71±6.43
Mean MDR (in %±SD)	3.03±.27			32.4±.09			−7.2±.23
Treatment Group	TAM (N = 208)	AI (N = 105)	TAM and AI (N = 86)	TAM (N = 65)	AI (N = 17)	TAM and AI (N = 21)	TAM (N = 143)	AI (N = 88)	TAM and AI (N = 65)
Mean VBD (in %±SD)	16.01 ± 7.40	10.98 ± 5.06	12.44 ± 6.57	18.71 ± 7.58	12.76 ± 5.56	17.13 ± 7.62	14.79 ± 7.01	10.64±4.92	10.93 ± 5.44
Mean MDR (in %±SD)	6.23 ± .25	.95± .24	−2.18 ± .33	31.7 ± .07	33.1 ± .09	34.1 ± .09	−5.35 ± .21	−5.25 ± .01	−13.9 ± .29
Menopausal Status	Premenopausal (N = 179)		Postmenopausal (N = 220)	Premenopausal (N = 62)		Postmenopausal (N = 41)	Premenopausal (N = 117)		Postmenopausal (N = 179)
Mean VBD (in %±SD)	17.46 ± 7.03		11.35 ± 5.82	19.44 ± 6.96		14.79 ± 7.54	16.41 ± 6.87		10.51 ± 5.01
Mean MDR (in %±SD)	8.56 ± .25		−1.47 ± .28	32.0 ± .09		33.0±.09	−3.89 ± .21		−9.36 ± .24

Abbreviations: AI, aromatase inhibitor; MDR, mammographic density reduction; SD, standard deviation; TAM, tamoxifen; VBD, volumetric breast density percentage.

Factors considered in the MDR association analysis were age (years), BMI (kg/m²), tumor size (which were continuous variables), mammographic density grade before adjuvant HT (fatty/scattered or dense/extremely dense), adjuvant HT group (tamoxifen, AIs, or a combination of both), pre-MD (percentages, continuous variable), HER2-positivity status, radiotherapy (yes or no), and menopausal status (age >50 years). The significant factors after the test were density grade before surgery and adjuvant HT; “dense” or “extremely dense” (OR = 2.56, P = .002), adjuvant HT group is AIs (OR = .42, P = .005), pre-MD (OR = 1.10, P < .0001), and menopause (OR = .5, P = .009). The results of the analysis of the factors associated with MDR are presented in Table 3.

Table 3.

Factors associated with the MDR in multivariate logistic regression analysis.

Variable	Odds ratio (95% CI)	P-value
Age, years (continuous)	.998 (.964-1.035)	.951
BMI, kg/m² (continuous)	1.056 (.991-1.126)	.097
Density grade before adjuvant HT
Fatty/Scattered	1.000
Dense/extremely dense	2.562 (1.430-4.589)	.002**
Treatment group
Tamoxifen	1.000
AIs	.4250 (.2341-.7716)	.005**
Combination	.7108 (.4009-1.2602)	.243
Pre-MD, %	1.0989 (1.0632-1.1358)	<.0001
Chemotherapy status
No	1.000
Yes	.768 (.4901-1.2038)	.249
HER2 status
Negative	1.000
Positive	.776 (.469-1.282)	.323
Radiotherapy
No	1.000
Yes	1.2507 (.7861-1.9898)	.345
Menopausal status
No	1.000
Yes	.501 (.296-.845)	.009**

Abbreviations: MDR, mammographic density reduction; CI, confidence interval; BMI, body mass index; HT, hormone therapy; AI, aromatase inhibitor; MD, mammographic density; HER2, human epidermal growth factor receptor 2; *P < , 05 and **P < ; 01.

Table 4 summarizes the effects of various factors on the association between MDR and recurrence-free survival in the study group. In multivariate analyses, after adjusting for several prognostic factors (such as age, BMI, tumor size, histologic grade status, pathologic stage status, menopausal status, lymph node status, and HER2 status), MDR positivity was an independent predictor of total recurrence-free survival (HR = .881; P = .032). Pathologic stage 3 (HR = 2.812, P = .004) or tumor size >2 cm (HR = 5.212, P = .016) were also significantly associated with a lower DFS rate. Menopausal status was not significant (P = .056); however, it was close to the threshold. An analysis of pre- and postmenopausal females may help detect more related factors.

Table 4.

Predictive impact of mammographic density reduction on disease-free survival.

Variable	Hazard ratio (95% CI)	P-value
MDR >20.8%	.881 (.400-1.938)	.032*
Age, years (continuous)	1.008 (.979-1.037)	.582
BMI, kg/m² (continuous)	.996 (.918-1.081)	.926
High histologic grade (Grade 3)	1.246 (.656-2.367)	.502
High pathologic stage (stage >3)	2.812 (1.402-5.639)	.004**
Tumor size, >2 cm	5.212 (1.362-19.953)	.016*
Menopausal	1.153 (.374-3.556)	.056
Lymph node metastasis	2.108 (.885-5.019)	.092
HER2-positive	1.453 (.821-2.573)	.199

Abbreviations: CI, confidence interval; MDR, mammographic density reduction; BMI, body mass index; HER2, human epidermal growth factor receptor 2; *P < , 05 and **P < ; 01.

Multivariate analysis findings for postmenopausal females are also provided in this paper. Table 5 summarizes the findings in the postmenopausal group (age >50 years) after adjusting for prognostic factors, similar to those in Table 4 (except menopausal status). MDR-positivity was also a significant predictor of recurrence in this group (hazard ratio [HR] = .881, P = .045). High pathologic stage (HR = 2.812, P = .004) and tumor size >2 cm (HR = 5.212, P = .016) were significantly associated with a lower DFS rate in the postmenopausal group.

Table 5.

Predictive impact of mammographic density reduction on disease-free survival in postmenopausal patients.

Variable	Hazard ratio (95% CI)	P-value
MDR >20.8%	.903 (.335-2.435)	.045*
Age, years (continuous)	1.004 (.960-1.051)	.856
BMI, kg/m² (continuous)	.981 (.895-1.075)	.675
High histologic grade (Grade 3)	1.159 (.529-2.539)	.712
High pathologic stage (stage >3)	3.176 (1.311-7.695)	.011*
Tumor size >2 cm	10.158 (.736-139.730)	.031*
Lymph node metastasis	2.181 (.795-5.987)	.13
HER2-positive	1.959 (.978-3.927)	.058

Abbreviations: MDR, mammographic density reduction; BMI, body mass index; HER2, human epidermal growth factor receptor 2; *P < , 05.

Discussion

No clear definition of a clinically meaningful MDR threshold exists in related studies to date. In this study, we assessed the association between MDR and recurrence-free survival by measuring changes in mammographic breast density in Taiwanese patients with ER-positive breast cancer before and after HT. Based on the study cohort’s data, we observed an MDR threshold (MDR >20.8%). Based on Kaplan–Meier survival curves, we confirmed it as an independent prognostic factor of recurrence-free survival. This result is comparable to a Cochrane review that estimated relative reductions in dense regions (>20%) using automated methods as a prognostic biomarker for breast cancer mortality. In this study, however, the endpoint of the event was a relapse, metastasis, or death (disease-free); nonetheless, differences in nature remained. Previous studies in Caucasian females have indicated an MDR threshold of 10% as the cut-off to reduce recurrence risk in breast cancer.^22,23 However, MD measurements in these studies were based on semi-automated measurement (CUMULUS software,²⁴) and not entirely on the FFDM. This creates methodological heterogeneity in this study; therefore, direct comparisons are inappropriate. In addition, the breast volume and density distribution between Asian and Caucasian females also display some differences.²⁵

The reason why MD varies among individuals remains unknown. Another potential reason for the higher breast cancer risk with high MD is extracellular matrix-producing stromal cell proliferation.²⁶ This density-cancer association is also supported by findings from collagen crosslinking studies in mice because it may promote tumorigenesis.^27-29 However, the molecular basis linking MD and increased cancer risk in humans remains unclear.

BMI and body size³⁰ are usually higher in Caucasian than in Asian females. The trend of MD decrease between pre- and postmenopausal patients after HT seems to be a contributing factor. Several population-based studies, including Caucasian and Korean participants, have demonstrated that the MD grade estimated before HT, menopause status, and HER2 status are associated with MDR.²² This study, with the exception that HER2 status was not associated with MDR, revealed similar results. Larger BMI had a higher association with MDR in this study (OR = 1.056, 95% CI, .991-1.126, Table 3); however, it was not significant (P = .097). Therefore, we did not adjust other factors using BMI in further analysis. BMI was also not significantly associated with DFS (HR = .996 in all cohorts, P = .926; HR = .981 in the postmenopausal cohort, P = .675; Tables 4 and 5). These conclusions are broadly consistent with previous studies.^31,32

A previous analysis of MD in tamoxifen- and AI-treated patients in a Caucasian-based study revealed that patients who were postmenopausal and underwent AI treatment had the greatest MDR,³³ which is inconsistent with the findings of our study cohort. In Table 2, after combining the data according to menopausal status and treatment group, the mean MDR was 1.5% and .3% in postmenopausal tamoxifen-treated and AI-treated patients. This confirmed that MD reduction in postmenopausal AI-treated patients was less than in the postmenopausal tamoxifen-treated patients. MD was significantly reduced in the tamoxifen and the premenopausal groups than in the AI and the postmenopausal groups. The analysis of factors associated with MDR, as detailed in Table 3, also supports this. In the treatment group analysis, compared to the tamoxifen group, the AI treatment group displayed a lower association with MDR (OR = .425 in the AI group, P < .005).

A significant limitation of this study was that approximately 80% of the participants were excluded during the screening process (1941 participants were screened initially, and 399 were finally enrolled). This factor may have raised bias and patient selection issues. The main reason was that most participants did not meet the follow-up duration criteria of this study. Medical resources are highly accessible in Taiwan; therefore, adjuvant HT can be performed in two or more hospitals. Thus, few patients completed all their treatments at the same institute. This is a common challenge of these studies. As such, the progress this study can provide is limited as regards the common conclusions of similar previous studies presented in recent guidelines. Future studies should include collecting an expanded sample of patient data from multiple institutions and conducting a meta-analysis of relevant past studies. This study did not collaborate with other institutions; therefore, the sources and analysis of the reported data were based on the experience of only one hospital. This is the most significant limitation and disadvantage of this study. This issue may be addressed in the future by enrolling more participants and collaborating with other institutions.

Conclusion

In conclusion, this study’s findings help estimate the prognosis for patients with breast cancer and may improve the quality of adjuvant HT treatment after enlarging the study cohort in the future. This study considered patients treated with AIs and tamoxifen and conducted a survival analysis based on MDR correlation. Therefore, for researchers trying to use MDR to observe the survival of HT patients, especially for Asian patients who switch from tamoxifen treatment to AIs due to menopause or other factors in the long-term treatment process, the results of this study provide a reference value.

Footnotes

Acknowledgments

The authors would like to thank the Hung-Tin Lin of the Cancer Research Center, Sing-Yin Chen, and Wen-Ting Shen of the Molecular Medicine Laboratory, Changhua Christian Hospital for their help in collecting and checking the clinical data of the enrolled patients.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by The Changhua Christian Hospital, Taiwan, funded this study. Grant number: 111-CCH-HCR-142. Changhua Christian Hospital, Taiwan, funded APC.

Ethical Approval

This retrospective study was approved by the Institutional Review Board of the institution (approval no. 171217). All experimental methods were supervised by the ethics committee and conducted in accordance with the relevant guidelines and the Declaration of Helsinki.

Informed Consent

The requirement for informed consent from the patients was waived owing to the study’s retrospective nature.

ORCID iDs

Wei-Chung Shia

Dar-Ren Chen

Appendix

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