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Abstract

BACKGROUND:

The 21-gene recurrence score (RS) assay has been validated to predict the risk of disease-free survival in estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer patients. However, its relation with locoregional recurrence (LRR) risk is unclear.

OBJECTIVE:

This study aimed to explore the ability of RS to predict LRR risk.

METHODS:

Consecutive ER-positive, HER2-negative, pT1, pN0-1, and M0 early breast cancer patients were analyzed retrospectively. According to RS, patients were divided into low- (RS $<$ 18), intermediate- (RS 18–30), and high-risk (RS $\geqslant$ 31) groups. The primary endpoint was LRR. Subgroup analysis was conducted according to different nodal statuses and surgery types.

RESULTS:

A total of 1558 patients were enrolled: 354 (22.7%), 788 (50.6%), and 416 (26.7%) patients in the low-, intermediate-, and high-risk groups, respectively. The median follow-up time was 53 months, and 2, 8, and 14 LRR events were observed in the low-, intermediate-, and high-risk groups, respectively ( $P=$ 0.004). Both univariate ( $P=$ 0.009) and multivariate ( $P=$ 0.010) analyses demonstrated that 21-gene RS was correlated with LRR. Compared to low-risk patients, high-risk patients were at greater risk of LRR (HR 5.75, 95% CI 1.30–25.31, $P=$ 0.021). Among pN0 ( $P=$ 0.033), pN1 ( $P=$ 0.049) and postmastectomy patients ( $P=$ 0.012), 21-gene RS remained predictive of the risk of LRR.

CONCLUSION:

The 21-gene RS assay was significantly associated with the risk of LRR in ER-positive, HER2-negative early breast cancer patients. Among patients with different nodal statuses and patients receiving mastectomy, RS remained predictive of the risk of LRR.

Keywords

21-gene RS assay breast cancer locoregional recurrence mastectomy breast-conserving surgery

Abbreviations

RS	Recurrence score
IDC	Invasive ductal carcinoma
ER	Estrogen receptor
PR	Progesterone receptor

HER2	Human epidermal growth factor
	receptor-2
LRR	Locoregional recurrence
DFS	Disease-free survival
BCFI	Breast cancer-free interval
BCSS	Breast cancer-specific survival
IBTR	Ipsilateral breast tumor recurrence

1. Introduction

Breast cancer is a group of heterogeneous diseases that has various biological and clinical characteristics. Therefore, identifying early breast cancer patients with a high risk of recurrence and selecting the optimal therapy are of great importance [1]. Currently, the treatment decision-making of early breast cancer patients still relies largely on traditional clinical and pathological characteristics. While personalized treatment is increasingly emphasized, integrating multigene assays into early breast cancer patient care has gained growing research interest.

Among estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer patients, the 21-gene recurrence score (RS) assay has become one of the most commonly used multigene assays [2, 3]. Several studies have demonstrated the predictive value of 21-gene RS for distant metastasis in both lymph node negative and positive patients [4, 5]. RS was recommended by both the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines in the management of ER-positive, HER2-negative early breast cancer patients.

Locoregional recurrence (LRR) is a significant predictor of distant recurrence among breast cancer patients [6, 7]. Currently, the risk of LRR is mainly evaluated according to traditional clinicopathological factors (including patient age, tumor grade, TNM stage, and molecular subtypes). However, the association of LRR and multigene assays remains controversial. Studies exploring the association between RS and LRR risk have reached different conclusions. Several researchers found that RS was a significant predictor of LRR in both node-negative and node-positive patients [8, 9, 10], while some found no significant association between RS and the risk of LRR [11]. And some had found that applying a 21-gene RS assay with different cutoffs could be predictive of LRR [12]. Meanwhile, with the development of comprehensive treatment, the prognosis of breast cancer has been improved a lot in the past decades, including a decrease in the LRR [13, 14].

Based on the above issues, our study aims to evaluate the relationship between 21-gene RS and the risk of LRR among early breast cancer patients that were treated in the modern era and to assess their association in patients with different nodal statuses and breast surgery types.

2. Materials and methods

2.1 Patient population

We retrospectively reviewed consecutive patients treated in Comprehensive Breast Health Center, Ruijin Hospital from January 2009 to December 2017. Female patients with pT1-pT3, pN0-pN1, M0 ER-positive, HER2-negative invasive early breast cancer were included. Other inclusion criteria included receiving either mastectomy or lumpectomy with negative margins and undergoing 21-gene RS assay testing. Patients with bilateral breast cancer, pT4 disease, metastatic breast cancer, previous exposure to systemic therapy, and previous or concurrent malignant disease were excluded from the study. The last follow-up date was 31 ${}^{\text{st}}$ December, 2019. The current study was performed in accordance with the Declaration of Helsinki and was approved by the independent ethics committees of Ruijin Hospital.

2.2 Study design and end points

Traditional clinicopathological factors and follow-up information were retrieved from the database, including age, type of surgery, pathology, grade, pT status, pN status, immunohistochemistry (IHC) expression of ER, progesterone receptor (PR), HER2, Ki67, RS, and date and type of events. ER expression $\geqslant$ 50% and PR expression $\geqslant$ 20% were defined as high expression of receptors according to the 2009 and 2013 St Gallen expert consensus [15, 16]. Luminal A breast cancer was defined as ER-positive, HER2-negative with PR expression $\geqslant$ 20% and Ki67 $<$ 14%, while luminal B was defined as ER-positive, HER2-negative with PR expression $<$ 20%, or Ki67 $\geqslant$ 14% [16]. The 21-gene RS was tested and calculated locally at our center according to previous studies [2, 3, 4, 5, 17, 18, 19, 20, 21, 22]. Based on RS results, patients were stratified into low RS ( $<$ 18), intermediate RS (18–30), and high RS ( $\geqslant$ 31) groups. Regarding adjuvant therapy decision-making, the administration of chemotherapy was guided by guidelines such as St Gallen consensus, NCCN guidelines and clinical trials such as the CALGB 49907 trial [23] and NSABP-B14 trial, where patient characteristics and 21-gene assay results were both taken into account. All patients who underwent lumpectomy were recommended to receive adjuvant radiotherapy, and for patients who underwent mastectomy, adjuvant radiotherapy was recommended to patients with nodal metastasis or patients with tumors larger than 5 cm. All enrolled patients had hormonal receptor-positive disease; therefore, adjuvant endocrine therapy was recommended.

The primary endpoint was LRR, defined as the incidence of in-breast, ipsilateral chest wall, or regional nodal recurrence. Second endpoints included breast cancer-free interval (BCFI) and breast cancer-specific survival (BCSS). BCFI was defined as the time from surgery to contralateral breast cancer, any recurrence, any metastasis, and death from breast cancer. BCSS was defined as the time from surgery to death caused by breast cancer [24].

2.3 Statistical analysis

Log-rank tests were performed to assess the relationship between RS and the risk of LRR, BCFI, and BCSS. Kaplan-Meier estimates were conducted to demonstrate the cumulative incidence rates of LRR, BCFI, and BCSS events. Log-rank tests and Kaplan-Meier estimates were also conducted in subgroup analyses. Cox regression models were conducted to examine the prognostic value of RS and other clinicopathological factors. All statistical analyses were performed by SPSS version 18.0 (SPSS, Inc., Chicago, IL). A $P$ value less than 0.05 was considered statistically significant.

3. Results

3.1 Patient and tumor characteristics

Overall, 1558 patients with ER-positive, HER2-negative disease were enrolled in this study (Fig. S1). Table 1 provides detailed information on the patient and tumor characteristics. At the time of diagnosis, 1070 patients (68.7%) were over 50 years old. Eight hundred ninety-seven patients (57.6%) received mastectomy, and 661 patients (42.4%) received lumpectomy. There were 1085 patients (69.6%) diagnosed with pT1 tumors and 1324 patients (85.0%) with pN0 disease. High ER and PR expression was found in 1434 patients (92.0%) and 1045 (67.1%) patients, respectively. Meanwhile, 788 patients (50.6%) had Ki-67 $\geqslant$ 14%. There were 524 (33.6%) and 788 patients (50.6%) with luminal A or luminal B breast cancer, respectively. According to the 21-gene RS results, 354 (22.7%), 788 (50.6%), and 416 (26.7%) patients were categorized into low, intermediate, or high RS groups, respectively. Eventually, 796 (51.1%), 725 (46.5%), and 1511 (97.0%) patients received adjuvant chemotherapy, radiotherapy, and endocrine therapy, respectively. The administration of adjuvant treatment in patients with different RS is shown in Table S1. Among patients receiving lumpectomy, 599 (90.6%) underwent adjuvant radiotherapy, while 126 (14.0%) patients who received mastectomy underwent adjuvant radiotherapy (data not shown).

Table 1
Patient characteristics

Characteristics	No. (%)
Total	1558	(100.0%)
Age (years)
$<$ 50	488	(31.3%)
$\geqslant$ 50	1070	(68.7%)
Surgery type
Mastectomy	897	(57.6%)
Lumpectomy	661	(42.4%)
Tumor size
T1	1085	(69.6%)
T2-3	469	(30.1%)
Tx	4	(0.3%)
Nodal status
0	1324	(85.0%)
1	234	(15.0%)
Pathology type
IDC	1352	(86.8%)
ILC	74	(4.7%)
Others	132	(8.5%)
Tumor grade
I–II	1029	(66.0%)
III	317	(20.3%)
N/A	212	(13.6%)
ER expression
$<$ 50%	124	(8.0%)
$\geqslant$ 50%	1434	(92.0%)
PR expression
$<$ 20%	513	(32.9%)
$\geqslant$ 20%	1045	(67.1%)
Ki-67
$<$ 14%	769	(49.4%)
$\geqslant$ 14%	788	(50.6%)
N/A	1	(0.1%)
Molecular subtype
Luminal A	524	(33.6%)
Luminal B	1033	(66.3%)
N/A	1	(0.1%)
RS
Low	354	(22.7%)
Intermediate	788	(50.6%)
High	416	(26.7%)
Adjuvant chemotherapy
No	762	(48.9%)
Yes	796	(51.1%)
Adjuvant radiotherapy
No	833	(53.5%)
Yes	725	(46.5%)
Adjuvant endocrine therapy
No	47	(3.0%)
Yes	1511	(97.0%)

Abbreviations: RS, recurrence score; ER, estrogen receptor; PR, progesterone receptor; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma.

3.2 Events of LRR

With a median follow-up time of 53 months, 24 LRR events were eventually observed among enrolled patients. Table S2 provides the detailed event type of LRR according to the 21-gene RS category. Two patients (0.6%) with low RS risk experienced LRR, while 8 (1.0%) and 14 (3.4%) patients with intermediate and high RS experienced LRR, respectively. Among the high-risk RS patients who experienced LRR, 6, 5, and 3 patients experienced local recurrence, regional recurrence, and both local and regional recurrences, respectively.

3.3 Association between 21-gene RS and LRR

Among the 1558 patients, RS was significantly associated with the risk of LRR ( $P=$ 0.004, Fig. 1). The univariate Cox regression model showed that RS was significantly correlated with LRR ( $P=$ 0.009, Table S3). Multivariate Cox regression demonstrated that RS remained independently predictive of LRR ( $P=$ 0.010, Table 2). Compared to low RS patients, high RS patients were at greater risk of LRR (HR 5.75, 95% CI 1.30–25.31, $P=$ 0.021).

Table 2
Multivariate Cox regression analysis of predictors of locoregional recurrence

Variable	HR (95% CI)	$P$
T2-3 vs. T1	2.28 (1.02–5.08)	0.044
RS		0.010
Intermediate vs. low	1.97 (0.42–9.30)	0.391
High vs. low	5.75 (1.30–25.31)	0.021

Abbreviation: RS, recurrence score.

Figure 1.

Locoregional recurrence (LRR) by 21-gene recurrence score (RS).

Figure 2.

Locoregional recurrence (LRR) by 21-gene recurrence score (RS) in A) patients with pN0 disease; B) patients with pN1 disease; C) patients receiving mastectomy; D) patients receiving lumpectomy.

Figure 3.

Cumulative incidence of A) breast cancer-free interval (BCFI) and B) breast cancer-specific survival (BCSS) events by 21-gene recurrence score (RS).

The associations between RS and LRR according to different nodal statuses and breast surgery types are listed in Fig. 2. In node-negative patients, there were 2 (0.6%), 7 (1.1%), and 11 (3.0%) LRR events in the low-, intermediate-, and high-risk RS groups, respectively ( $P=$ 0.033). In node-positive patients, 1 (0.7%) and 3 LRR events (5.5%) were found in the intermediate and high RS group patients, and RS groups remained significantly associated with the risk of LRR ( $P=$ 0.049). Regarding patients receiving mastectomy, 1 (0.4%), 6 (1.4%), and 10 (4.3%) LRR events were observed in the low-, intermediate-, and high-risk groups, respectively ( $P=$ 0.012). For patients receiving lumpectomy, 1 (0.8%), 2 (0.6%), and 4 (2.2%) patients with low, intermediate, and high RS experienced LRR ( $P=$ 0.107).

3.4 Association between 21-gene RS and BCFI, BCSS

Eventually, a total of 80 patients experienced BCFI (breast cancer-free interval, defined as the time from surgery to contralateral breast cancer, any recurrence, any metastasis, and death from breast cancer) events, and 14 patients experienced BCSS (breast cancer-specific survival, defined as the time from surgery to death caused by breast cancer) events (Fig. 3). The cumulative incidence rate of BCFI was 3.7%, 3.9%, and 8.7% for low, intermediate, and high RS patients, respectively ( $P=$ 0.006, Fig. 3A). In univariate analysis, RS was significantly related to BCFI ( $P=$ 0.007, Table S4) and remained independently associated with BCFI in multivariate analysis ( $P=$ 0.022, Table S5). Regarding BCSS, the cumulative incidence rates were 0.3%, 0.1%, and 2.9% for low, intermediate, and high RS patients, respectively ( $P<$ 0.001, Fig. 3B). RS was significantly associated with BCSS in univariate analysis ( $P=$ 0.006, Table S6) and remained a predictor of BCSS in multivariate analysis ( $P=$ 0.038, Table S7).

4. Discussion

Our study, including 1558 consecutive patients with 21-gene RS results, demonstrated that 21-gene RS was significantly correlated with the risk of LRR among ER-positive, HER2-negative early breast cancer patients. Patients with high RS were at greater risk of LRR than patients with low RS. Moreover, among pN0 or pN1 patients and patients receiving mastectomy, RS remained associated with LRR.

While early breast cancer patient care requires increasing individualization, adjuvant treatment decision-making has been increasingly guided by tumor biological characteristics. Since 21-gene RS has been proven to predict distant recurrences, researchers have explored the association between RS and LRR. Mamounas et al. first found that RS could predict the risk of LRR in node-negative patients [8]. Subsequently, they confirmed a similar association between RS and LRR in node-positive patients [9]. In contrast, Solin et al. found that RS failed to predict LRR in the whole cohort but was related to the risk of LRR when RS was calculated as a continuous variable among the hormonal receptor-positive subgroup [11]. Moreover, Jegadeesh et al.’s study demonstrated that 21-gene RS $>$ 24, instead of $>$ 25, was significantly related to a higher risk of LRR [12]. After exploring the relationship between RS and LRR in 1588 consecutive patients, our study found that RS was significantly correlated with the risk of LRR. Patients with low or intermediate risk of RS had a lower risk of LRR, indicating that RS may be used as a predictor of LRR among ER-positive, HER2-negative patients.

Currently, the value of postmastectomy radiotherapy (PMRT) among pN1 patients is still controversial [9, 25]. Russell et al. pointed out that although the survival benefit from additional PMRT had been confirmed in some studies [26], the development of effective systemic therapy had improved the outcome of pN1 disease and reduced the magnitude of PMRT’s value [27]. Current studies have come to various conclusions in terms of PMRT in pN1 patients [13, 28, 29, 30]. Therefore, further subgroup analyses were conducted in different node or breast surgery subgroups. In both pN0 ( $P=$ 0.033, Fig. 2A) and pN1 ( $P=$ 0.049, Fig. 2B) patients, we found that 21-gene RS can predict the risk of LRR; moreover, among patients receiving mastectomy, RS was also significantly related to LRR ( $P=$ 0.012, Fig. 2C). The number of LRR events according to different RS groups and treatment subgroups is presented in Table S8. This discovery may suggest that among pN0, pN1 and postmastectomy patients with low RS, the risk of LRR could be adequately low. However, these results need to be interpreted with caution since certain $P$ values of the subgroup analysis were close to 0.05 and the number of events was limited. Moreover, due to the limited number of events, further analysis among pN1 patients who received mastectomy was not suitable. Nevertheless, we believe future analysis focusing on this cohort is warranted, as the findings might guide PMRT selection in patients with pN1 disease. In further exploratory analysis among patients under the age of 50 years, a total of 7 LRR events were observed (Table S9). However, probably due to limited number of events among patients under 50 years, survival analysis among them did not reach a statistical significance ( $P=$ 0.956, Fig. S2).

The overall incidence rate of LRR was 1.5% in our study, which was relatively low compared with previous studies. One reason may be the relatively short follow-up time, which may be considered a limitation of our study. However, the 2005 EBCTCG overview demonstrated that approximately three-quarters of the LRRs occurred in the first 5 years after randomization [26]. The 25-year follow-up analysis of the NSABP B-04 trial showed that 81.6% and 89.5% of LRRs occurred during the first 5 years for pN0 and pN1 patients receiving mastectomy, respectively [31]. Another possible explanation for the low LRR incidence rate might be the late surgery year (2009–2017) compared with previous studies, such as Mamounas’s study, which enrolled patients treated in the 1980s and 1990s. During our study period, adjuvant treatment, including chemotherapy such as anthracycline or taxane, radiotherapy, and endocrine therapy such as aromatase inhibitor, was well developed, and effective systemic therapy was standardly administered in our center. Modern treatment advances have been proved to improved disease outcome including LRR. McBride et al. found that PMRT reduced the rate of LRR in patients treated in the early era (1978–1997), while failed to benefit patients treated in the later era (2000–2007) [14]. As Mamounas’s study was derived from the NSABP B-14 and B-20 trials, patients who received different treatment strategies were included (chemotherapy plus tamoxifen, tamoxifen alone, or placebo alone), leading to a high overall incidence of LRR (8.4%) compared with our study, where enrolled patients were treated with endocrine therapy plus chemotherapy when appropriate. As the effectiveness of local and systemic treatment increases, better LRR control has been achieved; thus, it is important to accurately weigh the absolute benefit from excess local treatment against potential toxicity. Finally, the retrospective study design and single-center patient cohort may be considered other limitations of this study.

In conclusion, this study demonstrated that RS was significantly associated with the risk of LRR for ER-positive, HER2-negative early breast cancer patients, and among patients with different nodal statuses and patients receiving mastectomy, RS remained predictive of the risk of LRR, which may be used to guide future individualized local therapy.

Author contributions

Conception: XC, KS and YZ.

Interpretation or analysis of data: YZ, WG and XC.

Preparation of the manuscript: YZ and WG.

Revision for important intellectual content: YZ, WG, XC and KS.

Supervision: XC and KS.

Supplementary data

The supplementary files are available to download from http://dx.doi.org/10.3233/CBM-210274.

sj-docx-1-cbm-10.3233_CBM-210274.docx - Supplemental material

Supplemental material, sj-docx-1-cbm-10.3233_CBM-210274.docx

Footnotes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81772797); Shanghai Municipal Education Commission – Gaofeng Clinical Medicine Grant Support (No. 20172007); and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine – “Guangci Excellent Youth Training Program” (No. GCQN-2017-A18). The funders had no role in the study design, data collection, data analysis, article writing, or article submission.

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Association of 21-gene recurrence score and locoregional recurrence in early breast cancer patients

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

Abbreviations

1. Introduction

2. Materials and methods

2.1 Patient population

2.2 Study design and end points

2.3 Statistical analysis

3. Results

3.1 Patient and tumor characteristics

Table 1 Patient characteristics

3.3 Association between 21-gene RS and LRR

Table 2 Multivariate Cox regression analysis of predictors of locoregional recurrence

4. Discussion

Author contributions

Supplementary data

sj-docx-1-cbm-10.3233_CBM-210274.docx - Supplemental material

Footnotes

Acknowledgments

References

Table 1
Patient characteristics

Table 2
Multivariate Cox regression analysis of predictors of locoregional recurrence