Impact of extended endocrine therapy for patients with risk factors for late recurrence in estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after 5 years of endocrine therapy

doi:10.21203/rs.3.rs-4960309/v1

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Research Article

Impact of extended endocrine therapy for patients with risk factors for late recurrence in estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after 5 years of endocrine therapy

https://doi.org/10.21203/rs.3.rs-4960309/v1

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Journal Publication

published 17 Oct, 2024

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Purpose

Extended endocrine therapy shows promise for reducing the recurrence of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, its benefits for patients with high-risk factors for late recurrence remain unclear, particularly for premenopausal patients. This study aimed to explore the impact of extended endocrine therapy on patients with risk factors for late recurrence of postmenopausal and premenopausal ER-positive, HER2-negative breast cancer.

Methods

We retrospectively analyzed data from patients with ER-positive, HER2-negative breast cancer at Tohoku Kosai Hospital who were disease-free after 5 years of adjuvant endocrine therapy. The patients were classified as high risk based on lymph node positivity, tumor size > 2 cm, or high tumor grade. The high-risk group was further divided into the extended and stop therapy groups. Propensity score matching was applied to balance the baseline characteristics. Disease-free survival (DFS) was the primary endpoint.

Results

Among the 1,474 eligible patients, 224 received extended endocrine therapy and 1,250 stopped the therapy. After propensity score matching, the high-risk group comprised 348 patients (174 patients in each group). The extended therapy group had significantly higher 10-year DFS and distant DFS rates than did the stop group. The multivariate Cox model indicated a 69% reduction in recurrence risk for the extended therapy group.

Conclusions

Extended endocrine therapy significantly improves DFS in patients with high-risk ER-positive, HER2-negative breast cancer, especially in those with large tumors, lymph node involvement, and high tumor grade. These findings support personalized treatment strategies for enhancing long-term outcomes.

breast neoplasms

receptors

estrogen

risk factors

recurrence

Breast cancer is a heterogeneous disease, with hormone receptor-positive subtypes accounting for approximately 70–80% of all cases. Five years of tamoxifen treatment reduces the risk of recurrence by approximately 40% and breast cancer-related mortality by 30% up to 15 years post-diagnosis in estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer[1]. In postmenopausal women, compared with tamoxifen, aromatase inhibitors (AIs) reduce recurrence rates by approximately 30%. Five years of treatment with an AI reduces 10-year breast cancer mortality rates by approximately 15% compared with 5 years of tamoxifen treatment and hence by approximately 40% compared with no endocrine treatment[2]. However, despite the initial effectiveness of these treatments, at least half of all recurrences occur after 5 years of endocrine therapy. In a meta-analysis of 88 trials that included 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, the risk of distant recurrence steadily continued for at least 20 years and strongly correlated with the original lymph node status, tumor size, and grade[3]. Extended adjuvant endocrine therapy with either tamoxifen or AIs is effective in reducing the risk of distant recurrence and new primary breast cancer[4–6]. In the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, in which approximately 90% were postmenopausal women, 10 years of tamoxifen treatment reduced the risk of recurrence (relative risk, 0.75; 95% confidence interval [CI], 0.62–0.90) and breast cancer mortality (absolute mortality reduction, 2.8%), especially after 10 years[4]. In the MA17 trial, extended AI (letrozole) after tamoxifen was associated with an improvement in disease-free survival (DFS) (hazard ratio [HR], 0.52; 95% CI, 0.45–0.61) and overall survival (HR, 0.61; 95% CI, 0.52–0.71)[5–7]. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial, extended AI (exemestane) after 5 years of tamoxifen treatment resulted in an improvement in relapse-free survival (relative risk, 0.44)[8]. The MA17R and AERAS trials have also confirmed DFS benefits by extending AI treatment for an additional 5 years in postmenopausal patients who were disease-free after the initial AI treatment[9, 10]. Despite the improved DFS outcomes observed in these trials, results from other trials (the DATA and IDEAL trials) have not confirmed this benefit[11, 12].

Various clinical trials have shown the efficacy of extended endocrine therapy; however, it remains unclear which patients benefit the most from extended endocrine therapy and whether the benefits of extended endocrine therapy outweigh the toxic risks of reduced bone density, joint pain, uterine cancer development, and thrombosis. In addition, the benefits of extended endocrine therapy in patients with risk factors for late recurrence, such as large tumor size, lymph node metastasis, and high-grade disease, remain unclear. Furthermore, most previous trials have either focused on postmenopausal breast cancer or included a few premenopausal breast cancer cases; therefore, the effect of extended endocrine therapy on premenopausal breast cancer is not well understood.

This study aimed to explore the impact of extended endocrine therapy on patients with risk factors for late recurrence of postmenopausal and premenopausal ER-positive, HER2-negative breast cancer by evaluating its potential to enhance survival and reduce the incidence of late-stage relapse.

Study population

We retrospectively analyzed data from patients with breast cancer who underwent curative surgery at Tohoku Kosai Hospital between 2004 and 2015. We identified patients with ER-positive, HER2-negative invasive breast cancer without recurrence after 5 years of adjuvant endocrine therapy. We performed a landmark analysis in which only patients without recurrence until the landmark time were included in the analysis of data from these time points. The landmark time was 5 years after the initiation of endocrine treatment. Patients with ER-negative, HER2-positive breast cancer, noninvasive ductal carcinoma, or recurrence within 5 years were excluded. Patients with positive lymph nodes, tumor size > 2 cm, and a high tumor grade were classified into the high-risk group for late recurrence. The high-risk group was divided into an “extended group” that continued endocrine therapy and a “stop group” that discontinued the endocrine therapy. Regarding postoperative endocrine therapy, premenopausal patients received tamoxifen for 5 years, then continued tamoxifen, or switched to an AI, such as exemestane, letrozole, or anastrozole, when menopausal. Postmenopausal patients received tamoxifen, toremifene, and AIs for > 5 years. ER and progesterone receptor (PR) expressions were defined as positive when the positivity rate was ≥ 1%; positivity was classified as either 1–10% or ≥ 10%. HER2 negativity was defined as a score of 0 or 1. A score of 2 plus was confirmed as negative by fluorescence in situ hybridization. Tumor size and lymph node metastasis were defined based on the Union for International Cancer Control, 8th Edition. This study was approved by the institutional review board of our hospitals, and all enrolled patients provided informed consent.

Main outcomes

The primary endpoint was DFS, which was defined as the duration from surgical resection of the primary breast tumor to the first report of recurrence. The DFS events included recurrence (conserved breast recurrence, locoregional recurrence, and distant organ metastasis), secondary primary cancers (contralateral breast cancer and new invasive cancers of other organs), and death from any cause.

Statistical analyses

The distribution of continuous variables across groups was evaluated using the Mann–Whitney U test. The distribution of categorical variables across groups was evaluated by applying the chi-squared test (χ²). In the high-risk group, a propensity score matching approach was applied to control for selection bias. True confounders were isolated among variables that were not equally distributed between the extended and stop groups; potential confounders were selected among those variables potentially affecting the primary outcome (DFS), possibly affecting the treatment assignment in clinical decision-making, or both. Among the available variables, age, menopausal status, tumor size, lymph node involvement, tumor grade, surgery type, radiotherapy, chemotherapy, and endocrine therapy type were selected for matching. To reduce bias owing to these potential confounding factors, 1:1 matching of the two groups was performed using the nearest neighbor method with a caliper width of 0.20 of the standard deviation of the logit of the propensity scores. DFS was estimated using the Kaplan–Meier method, and differences between survival curves were assessed using the log-rank test. A Cox regression model was used to calculate the HRs and 95% CIs. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R 2.13.0 (R Foundation for Statistical Computing, Vienna, Austria)[13]. All reported P values were two-sided, and < 0.05 was considered statistically significant.

A flow diagram of the study is shown in Fig. 1. A total of 4,359 patients underwent curative surgery between 2004 and 2015. Of these, 1,474 patients were eligible for this study and were disease-free after completing a 5-year endocrine therapy. A total of 1,250 patients stopped endocrine therapy, and 224 patients received extended endocrine therapy. The high-risk group comprised 615 patients.

Propensity-score matched high-risk populations

Table 1 summarizes the baseline characteristics of the high-risk group before and after propensity score matching. The extended group was younger and had a higher proportion of premenopausal patients than did the stop group. After matching, the baseline characteristics of the two groups were balanced with no significant differences in age, body mass index (BMI), menopausal status, tumor size, lymph node involvement, tumor grade, PR status, surgery type, radiotherapy, and chemotherapy. After matching the 348 selected patients, the stop and extended groups comprised 174 patients each. The prevalences of premenopausal breast cancer were 53.4% and 56.3% in the stop and extended groups, respectively.

Table 1

Characteristics of patients before and after propensity score matching Abbreviations: BMI, body mass index; ET, endocrine therapy; SERM, selective estrogen receptor modulator; AI, aromatase inhibitor.
Characteristics	All-patient population			Propensity-matched population
Characteristics	Stop group (n = 431)	Extended group (n = 184)	P-value	Stop group (n = 174)	Extended group (n = 174)	P-value
Age, median (range)	56.0(27–86)	49.0 (30–86)	< 0.001	51.5(27–85)	50.0 (30–86)	0.602
BMI, median (range)	22.5(14–46)	22.5(15–41)	0.826	22.1(14–46)	22.6(15–41)	0.604
Menopausal status			< 0.001			0.667
Premenopausal	180 (41.8%)	109 (59.2%)		93 (53.4%)	98 (56.3%)
Postmenopausal	251 (58.2%)	75 (40.8%)		81 (46.6%)	76 (43.7%)
Tumor size, mm			0.126			0.290
≤ 10	37 (8.6%)	20 (10.9%)		14 (8.0%)	19 (10.9%)
11–20	200 (46.4%)	84 (45.7%)		74 (42.5%)	80 (46.0%)
21–50	184 (42.7%)	69 (37.5%)		80 (46.0%)	64 (36.8%)
≥ 51	10 (2.3%)	11 (5.9%)		6 (3.4%)	11 (6.3%)
Lymph node involvement			0.001			0.677
0	142 (32.9%)	33 (17.9%)		34 (19.5%)	34(19.5%)
1–3	243 (56.4%)	122 (66.3%)		107(61.5%)	115(66.1%)
4–9	36 (8.4%)	22 (12.0%)		25 (14.4%)	20(11.5%)
≥ 10	10 (2.3%)	7 (3.8%)		8 (4.6%)	5 (2.9%)
Grade			0.139			0.488
1	126 (29.2%)	50 (27.2%)		46 (26.4%)	49 (28.2%)
2	223 (51.7%)	100 (54.3%)		101(58.0%)	91 (52.3%)
3	82 (19.0%)	34 (18.5%)		27 (15.5%)	34 (19.5%)
PR			0.672			0.857
+	382 (88.6%)	166 (90.2%)		18 (10.3%)	16(9.2%)
–	49 (11.4%)	18 (9.8%)		156(89.7%)	158(90.8%)
Surgery type			0.036			0.642
Lumpectomy	170 (39.4%)	56 (30.4%)		51(29.3%)	56(32.2%)
Mastectomy	261 (60.6%)	128 (69.6%)		123(70.7%)	118(67.8%)
Radiotherapy			0.022			0.731
Yes	262 (60.8%)	130 (70.7%)		120(69.0%)	120(69.0%)
No	169 (39.2%)	54 (29.3%)		54(31.0%)	54(31.0%)
Chemotherapy			< 0.001			1.000
Yes	118 (27.4%)	106 (57.6%)		92 (52.9%)	93 (53.4%)
No	313 (72.6%)	78 (42.4%)		82 (47.1%)	81 (46.6%)
Type of ET			0.026			0.662
SERM	230 (53.4%)	116 (63.4%)		101(58.0%)	106(60.9%)
AI	201 (46.6%)	67 (36.6%)		73 (42.0%)	68 (39.1%)
Duration of ET, month
60	426 (100%)	-		174(100%)	-
61–84	-	8 (4.2%)		-	7 (4.0%)
85–120	-	181 (95.8%)		-	167(96.0%)

Disease-free survival in the high-risk groups before and after propensity score matching

Table 2 shows the first recurrence events in the extended and stop groups. There were 46 events in the 615 patients included in the DFS analysis. The total numbers of first events were 36 (20.7%) and 10 (5.7%) in the stop and extended groups, respectively. Distant recurrence was the most common event in both groups. In the overall population of patients who were disease-free after 5 years of endocrine therapy (N = 1474), the 10-year DFS rate was not significantly different between the extended and stop groups (94.4% [95% CI, 0.900–0.969] and 92.2% [95% CI, 0.905–0937], respectively; P = 0.200; Fig. 2a). Before propensity score matching, the 10-year distant DFS rate was higher in the extended group than in the stop group (94.1% [95% CI, 0.891–0.968] and 84.3% [95% CI, 0.802–0875], respectively; P < 0.001; Fig. 2b). After propensity score matching, the 10-year DFS rate in the high-risk group was higher in the extended group than in the stop group (94.2% [95% CI, 0.889–0.970) and 82.8% [95% CI, 0.762–0877], respectively; P < 0.001; Fig. 2c). The 10-year DFS rate in the high-risk group after propensity score matching was higher in the extended group than in the stop group (96.7% [95% CI, 0.919–0.986] and 85.1% [95% CI, 0.786–0898], respectively; P < 0.001; Fig. 2d). The multivariate Cox proportional hazards model to predict DFS after propensity score matching indicated that, compared with 5-year endocrine therapy, the extended endocrine therapy reduced the risk of recurrence in high-risk populations (HR, 0.31; 95% CI, 0.15–0.62; P = 0.001) (Table 3).

Table 2

First event of recurrence
First event	Stop group (N = 174) No. (%)	Extended group (N = 174) No. (%)
Ipsilateral breast tumor recurrence	2 (1.1)	0 (0)
Contralateral breast cancer	1 (0.6)	3 (1.7)
Local chest wall recurrence	0 (0)	2 (1.1)
Regional node recurrence	4 (2.3)	0 (0)
Distant recurrence	27 (15.5)	5 (2.9)
Second primary cancer	1 (0.6)	0 (0)
Death	1 (0.6)	0 (0)
Total first events	36 (20.7)	10 (5.7)
Alive, event-free	138 (79.3)	164 (94.3)

Table 3

Multivariate Cox proportional hazards models for predicting disease-free survival after propensity score matching
Characteristics	Multivariate analysis
Characteristics	HR (95% CI)	P-value
Extended ET	0.31 (0.15–0.62)		0.001
Postmenopausal	1.77 (0.97–3.22)		0.063
Tumor size > 2 cm	1.54 (0.81–2.90)		0.185
Lymph node involvement	1.05 (0.46–2.36)		0.915
High grade	1.74 (0.83–3.66)		0.146
Chemotherapy	1.66(0.87–3.16)		0.126
HR, hazard ratio; ET, endocrine therapy; CI, confidence interval.

Subgroup analysis

Figure 3 presents a subgroup analysis of DFS. Compared with the stop group, the extended group consistently showed better outcomes across various subgroups, including age, menopausal status, BMI, pT stage, pN stage, tumor grade, prior chemotherapy, and type of surgery. Compared with the stop group, the HRs indicated a significant reduction in the risk of recurrence in the extended group across most subgroups. Premenopausal patients with breast cancer showed a trend toward a higher benefit from extended endocrine therapy, but this was not significant.

This study investigated the impact of extended endocrine therapy on postmenopausal and premenopausal patients with ER-positive, HER2-negative breast cancer who completed 5 years of initial endocrine therapy. Our findings suggest significant benefits of extended endocrine therapy in reducing recurrence risk, particularly for those with high-risk factors, such as larger tumor size, lymph node involvement, and high tumor grade.

Propensity score-matched analysis demonstrated that patients who received extended endocrine therapy had significantly higher DFS rates than did those who stopped therapy after 5 years. Specifically, the 10-year DFS rate was notably higher in the extended group (94.2%) compared with that in the stop group (82.8%), with an HR of 0.31, indicating a 69% reduction in the risk of recurrence in the extended therapy group. This benefit was consistent across various subgroups according to age, menopausal status, and other clinical characteristics. Extended endocrine therapy is particularly beneficial for high-risk patients defined by factors, such as positive lymph node status, larger tumor size, and high tumor grade. Conversely, in patients without high-risk factors, the benefits of extended endocrine therapy are less pronounced. In the overall population who were disease-free after 5 years of initial endocrine therapy (n = 1,474 patients), the 10-year DFS rates were not significantly different between the extended and stop groups (94.4% vs. 92.2%, P = 0.200), indicating a limited additional benefit from extended therapy in this cohort. This suggests that extended endocrine therapy may not be necessary for patients without significant risk factors for late recurrence because their baseline risk of recurrence is already low.

Our results are consistent with those of previous trials that highlighted the efficacy of extended endocrine therapy[4–6, 8–10]. However, many studies have focused predominantly on postmenopausal women. Clinical trials studying premenopausal breast cancer include the NSABP B-14[14], ATLAS[15], and aTTom trials[16], all of which compared extended tamoxifen administration after 5 years of tamoxifen administration. In the NSABP B-14 trial, which included 25% premenopausal women, through 7 years of follow-up after rerandomization, there was no additional benefit from tamoxifen administration beyond 5 years[14]. In the ATLAS and aTTom trials, premenopausal breast cancer was present in only 8% and 3% of patients, respectively[15–17]. In the ATLAS trial, 10 years of tamoxifen significantly reduced risk of recurrence (21.4 vs. 25.1%, P = 0.002) and breast cancer mortality (12.2 vs. 15.0%, P = 0.01) during the second decade after diagnosis[15]. Although the aTTom trial has not yet been published, a pooled analysis of the aTTom and ATLAS trials (n = 17,477 patients) reported that breast cancer mortality was reduced with an additional 5 years of tamoxifen treatment (relative risk, 0.85; 95% CI, 0.77–0.94; P = 0.001)[18]. Our study included 53.4% of premenopausal patients in the stop group and 56.3% in the extended group, which provides critical insights into the efficacy of extended therapy in this subgroup that has been underrepresented in earlier trials. Notably, our findings from the subgroup analysis suggest a potential trend toward a higher benefit from extended therapy in premenopausal women, although this was not statistically significant. However, our study also emphasizes the importance of patient selection for extended therapy, given the associated risks, such as bone density reduction, joint pain, and the potential development of secondary conditions, such as uterine cancer and thrombosis. Therefore, the balance between the benefits and risks should be carefully considered, particularly in patients with significant risk factors for late recurrence. The American Society of Clinical Oncology clinical practice guidelines recommend extended endocrine therapy for patients with node-positive breast cancer[19]. Lymph node metastasis, large tumor size, and high histological grade are established risk factors for late recurrence[3]. Combining these high-risk factors with age, the Clinical Treatment Score post-5 years (CTS5) was designed to show the risk of recurrence 5 years after postoperative endocrine therapy[20]. Based on two large clinical trials, the Arimidex, Tamoxifen, Alone, or in Combination (ATAC) trial and Breast International Group 1–98 (BIG1-98) trials, CTS5 had a significant prognostic value for distant recurrence, but only in postmenopausal women[20]. Therefore, the role of CTS5 in premenopausal women remains unclear. The Breast Cancer Index (BCI) is primarily used to assess the risk of distant recurrence in patients with hormone receptor-positive breast cancer and to help determine the potential benefit of extended endocrine therapy[21, 22]. The guidelines of both the National Cancer Center Network and American Society of Clinical Oncology provide weak recommendations that BCI may be used to inform decisions regarding extended endocrine therapy with tamoxifen, an AI, or the sequence of tamoxifen followed by an AI[23, 24]. However, there are few cases in premenopausal patients, and its applicability to premenopausal patients has not been as extensively validated as that for postmenopausal patients. Therefore, caution should be exercised when interpreting the BCI results in premenopausal women, and additional clinical judgments and context-specific factors should be considered.

These findings emphasize the importance of personalized treatment strategies for managing ER-positive, HER2-negative breast cancer. Extended endocrine therapy should be considered for patients with high-risk factors for late recurrence to balance the benefits of prolonged DFS with the potential side effects. Our study provides robust evidence supporting extended endocrine therapy in selected high-risk patients, potentially guiding clinical decision-making to improve long-term patient outcomes.

This study has limitations, including its retrospective design and the potential for selection bias, despite the use of propensity score matching. Further prospective randomized trials are warranted to validate these findings and to optimize the criteria for patient selection for extended endocrine therapy.

In conclusion, extended endocrine therapy offers significant DFS benefits for patients with high-risk breast cancer beyond the initial 5 years of treatment. These results advocate a tailored approach to the management of breast cancer survivors aimed at reducing late recurrences and improving long-term outcomes.

ER estrogen receptor

HER2 human epidermal growth factor receptor 2

DFS disease-free survival

ATLAS Adjuvant Tamoxifen: Longer Against Shorter

CI confidence interval

PR progesterone receptor

BMI body mass index

Funding

This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgments

We would like to thank Editage (www.editage.jp) for English language editing.

Competing interests

The authors have no relevant financial or non-financial interest to disclose.

Author contributions

Masahiro Ito drafted the manuscript. Shigehira Saji contributed to finalizing the manuscript and provided the final approval of the article. All the authors have read and approved the final version of the manuscript.

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to no approval from the Ethics Committee for sharing data.

Ethics approval

This study was approved by the institutional review board of our hospitals.

Consent to participate

All enrolled patients provided informed consent.

Consent to publish

All study participants consent for publication of this study.

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No competing interests reported.

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Impact of extended endocrine therapy for patients with risk factors for late recurrence in estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after 5 years of endocrine therapy

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Abstract

Purpose

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Results

Conclusions

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Introduction

Patients and methods

Study population

Main outcomes

Statistical analyses

Results

Propensity-score matched high-risk populations

Disease-free survival in the high-risk groups before and after propensity score matching

Subgroup analysis

Discussion

Abbreviations

Declarations

References

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