Abstract
Purpose
The purpose of this study was to evaluate the treatment outcomes of estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2−) breast cancer according to the risk group using EndoPredict (EP) score.
Patients and Methods
Between 2015 and 2019, 207 patients with ER+/HER2− pN0-N1 early breast cancer who underwent surgery, EP test, and adjuvant radiotherapy were accrued. The EPclin score, which combines the molecular EP score with nodal status and tumor size, was calculated, and patients were divided into EPclin low- or high-risk groups by the cutoff value of 3.3.
Results
There were 154 and 53 patients in the EPclin low- and high-risk groups, respectively. Forty-one patients (81.1%) of the high-risk group received adjuvant chemotherapy, while only 1 (0.6%) of the low-risk group did. With a median follow-up of 54.1 months (range 8.2–76.6), the 5-year disease-free survival rates of low- and high-risk groups were 100% and 88.9%, respectively (p < 0.001).
Conclusions
The EPclin score was associated with recurrences in ER+/HER2− early breast cancer.
Keywords: Breast cancer, EndoPredict, Treatment outcome, Radiotherapy
Introduction
In 2018, approximately 2.1 million women were newly diagnosed with breast cancer worldwide [1]. About 84% of newly diagnosed breast cancer patients had invasive breast cancer in Korea, and 68.4% had estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2−) molecular subtype [2]. In patients with this molecular subtype, the use of endocrine therapy is mandatory [3], and there are previous reports that adjuvant endocrine therapy and the addition of chemotherapy are beneficial to patients with high-risk features [4, 5, 6].
Recently, several multigene expression prognostic assays such as OncotypeDX, MammaPrint, and EndoPredict (EP) have been developed to provide information on the clinical outcomes and adjuvant treatment options such as endocrine therapy alone or endocrine plus chemotherapy for patients with ER+/HER2− early-stage breast cancer. Among these, the EP test is an RNA-based multigene expression assay, and the gene molecular score of this test is combined with the clinical characteristics of the tumor size and lymph node status, providing a risk score, named the clinical EP score (EPclin score) [7].
For patients at higher risk of regional recurrence (RR), regional nodal irradiation (RNI) is often recommended to reduce the risk of regional relapse in node-positive or high-risk node-negative breast cancer. The EPclin score has been reported to predict the likelihood of distant recurrence within 10 years after 5 years of adjuvant endocrine therapy alone [8]. However, the potential benefit of RNI with respect to risk group according to the EPclin score is not well reported yet. In this retrospective study, we evaluated the treatment outcomes of ER+/HER2− early breast cancer according to the risk group using the EPclin score and investigated whether the EPclin score could help identify patients who would potentially benefit from RNI.
Methods and Materials
Between May 2015 and December 2019, ER+/HER2− early breast cancer patients with pN0-N1 who underwent breast surgery and adjuvant radiotherapy (RT) were retrospectively reviewed. Among them, patients who underwent EP test after surgery were included. Resection margin status was defined as negative (over 1 mm), close (less than 1 mm but no ink on tumor), and positive (ink on tumor).
The EP test (Myriad International GmbH, Cologne, Germany) was performed using formalin-fixed paraffin-embedded tissue samples of primary breast tumors by the quantitative real-time polymerase chain reaction technique [8, 9]. The EPclin score was calculated by combining the molecular EP score derived from a 12-gene molecule array with the tumor size and nodal status. The patients were classified into two recurrence risk groups according to the cutoff value of 3.3 for the EPclin score [7] as follows: the low risk (EPclin score ≤3.3) and high risk (EPclin score >3.3). Patients with an estimated risk of distant metastasis (DM) of more than or equal to 10% at 10 years were categorized as high-risk patients.
Patient characteristics and treatment variables were compared between the low- and high-risk groups using t tests for continuous variables and χ2 or Fisher exact tests when appropriate for categorical variables. Survival curves were generated using the Kaplan-Meier method, and a log-rank test was used for univariate analysis and to compare survival between the groups. p values <0.05 were considered to indicate statistical significance. The SPSS statistical software version 18.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analyses.
Results
The patient, tumor, and treatment characteristics are summarized in Table 1. Among 1,702 breast cancer patients who underwent surgery during the study period, 207 (12.2%) patients were included in the current study. The median age was 50 years (range 29–76), and most patients underwent breast-conserving surgery (99.0%, 205/207). The pathological tumor size ranged from 0.1 cm to 4.5 cm (median, 1.4 cm). Totally, 176 patients (85.0%) had T1 tumors, while 31 (15.0%) had T2 tumors, and 7.7% (16/207) had nodal positivity. The histologic grade was 3 in 16 patients (7.7%), and lymphovascular invasion was observed in 27 patients (13.0%).
Table 1.
Patient, tumor, and treatment characteristics
| Variables | EPclin Low risk (n = 154) |
EPclin High risk (n = 53) |
p value | ||
|---|---|---|---|---|---|
| patients, n | % | patients, n | % | ||
| Age, years | |||||
| <60 ≥60 |
124 30 |
(80.5) (19.5) |
45 8 |
(84.9) (15.1) |
0.550 |
|
| |||||
| Pathology | |||||
| IDC ILC Others |
132 14 8 |
(85.7) (9.1) (5.2) |
43 4 6 |
(81.1) (7.5) (11.3) |
0.323 |
|
| |||||
| Pathological T stage | |||||
| T1a T1b T1c T2 Tumor size* |
6 29 107 12 1.3 (0.1–3.4) |
(3.9) (18.8) (69.5) (7.8) |
0 3 31 19 1.7 (0.6–4.5) |
(0.0) (5.7) (58.5) (35.8) |
<0.001 <0.001 |
|
| |||||
| Pathological N stage | |||||
| N0 N1 |
146 8 |
(94.8) (5.2) |
45 8 |
(84.9) (15.1) |
0.033 |
|
| |||||
| Histologic grade | |||||
| I II III |
59 92 3 |
(38.3) (59.7) (1.9) |
9 31 13 |
(17.0) (58.5) (24.5) |
<0.001 |
|
| |||||
| Lymphovascular invasion | |||||
| Absent Present Unknown |
136 18 0 |
(88.3) (11.7) (0.0) |
43 9 1 |
(81.1) (17.0) (1.9) |
0.159 |
|
| |||||
| Resection margin | |||||
| Negative (≥1 mm) Positive Close (<1 mm) |
129 5 20 |
(83.8) (3.2) (13.0) |
42 3 8 |
(79.2) (5.7) (15.1) |
0.663 |
|
| |||||
| ER status | |||||
| Negative Positive |
0 154 |
(0.0) (100.0) |
0 53 |
(0.0) (100.0) |
|
|
| |||||
| PR status | |||||
| Negative Positive |
4 150 |
(2.6) (97.4) |
5 48 |
(9.4) (90.6) |
0.050 |
|
| |||||
| Type of surgery | |||||
| Breast conservation Mastectomy |
153 1 |
(99.4) (0.6) |
52 1 |
(98.1) (1.9) |
0.447 |
|
| |||||
| Chemotherapy | |||||
| No Yes |
153 1 |
(99.4) (0.6) |
10 43 |
(18.9) (81.1) |
<0.001 |
|
| |||||
| Endocrine therapy | |||||
| Tamoxifen only AI only Tamoxifen/AI Other (GnRH agonists) |
79 67 5 3 |
(51.3) (43.5) (3.2) (1.9) |
24 23 1 5 |
(45.3) (43.4) (1.9) (9.4) |
0.118 |
|
| |||||
| Regional nodal irradiation | |||||
| Breast or CW only SCL IMN SCL + IMN EPclin score* |
145 3 6 0 2.7 (1.0–3.3) |
(94.2) (1.9) (3.9) (0.0) |
49 2 1 1 3.8 (3.3–5.1) |
(92.5) (3.8) (1.9) (1.9) |
0.298 <0.001 |
IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; ER, estrogen receptor; PR, progesterone receptor; AI, aromatase inhibitor; GnRH, gonadotropin-releasing hormone; CW, chest wall; SCL, supraclavicular node; IMN, internal mammary node.
Median (range).
In line with the previous study [7], 154 (74.4%) out of 207 patients were classified into the low-risk group and 53 (25.6%) into the high-risk group. The median EPclin score for the low-risk group was 2.7 (range 1.0–3.3) and that for the high-risk group was 3.8 (range 3.3–5.1). The high-risk group was associated with a higher pathological T stage (p < 0.001), a larger tumor size (p < 0.001), nodal positivity (p = 0.033), and a higher histologic grade (p < 0.001) (Table 1).
Out of the 207 patients, 44 (21.3%) patients received adjuvant chemotherapy, and most of these patients (43/44) were in the high-risk group. The chemotherapy regimens included anthracycline and/or taxane in 18 (40.9%) patients and cyclophosphamide, methotrexate, and 5-fluorouracil in 18 (40.9%) patients, while other regimens were used in the remaining eight (18.2%) patients. All patients received endocrine therapy as a part of their adjuvant treatment as follows: tamoxifen (49.8%, 103/207); aromatase inhibitors (43.5%, 90/207); and both tamoxifen and aromatase inhibitors (2.9%, 6/207). Postoperative whole-breast or chest wall RT was delivered to a median dose of 50.4 Gy (range 40.0–50.4 Gy) with 1.8–2.7 Gy per fraction, and the median tumor bed boost dose was 9 Gy (range 8.1–16 Gy). Irradiated volume was the involved breast or chest wall with or without supraclavicular fossa or internal mammary node. Adjuvant RNI was administered in 5.8% (9/145) of the low-risk group and 7.6% (4/50) of the high-risk group.
The median follow-up was 54.1 months (range 8.2–76.6 months), and six (2.9%) patients experienced disease relapse after treatment. Among them, three (1.4%) had local recurrence (LR) alone, and three (1.4%) had DM alone, and most recurrence events (5/6) were observed among patients with an EPclin score >3.3. The interval from surgery to LR was 13–62 months (median, 45 months), and the interval from surgery to DM was 12–35 months (median, 25 months). The overall disease-free survival (DFS) was 97.3% at 5 years, and the 5-year DFS rates were 100% and 88.9% in the EPclin low-risk and high-risk groups, respectively (p < 0.001, Fig. 1). Among clinicopathological factors, pathological T stage, adjuvant chemotherapy, and EPclin score were associated with DFS on univariate analysis (Table 2). No RR was observed in the accrued patients. Further details regarding patterns of failure are given in Table 3.
Fig. 1.
Kaplan-Meier curves of disease-free survival (DFS) according to the EPclin risk group.
Table 2.
Univariate analysis of DFS
| Variables | Patients, n | 5-year DFS, % | p value |
|---|---|---|---|
| Age, years | |||
| <60 | 169 | 96.7 | 0.253 |
| ≥60 | 38 | 100.0 | |
|
| |||
| Pathological T stage | |||
| T1 T2 |
176 31 |
100.0 82.4 |
<0.001 |
|
| |||
| Pathological N stage | |||
| NO | 191 | 97.1 | 0.513 |
| N1 | 16 | 100.0 | |
|
| |||
| Histologic grade | |||
| I or II III |
191 16 |
97.6 93.8 |
0.271 |
|
| |||
| Lymphovascular invasion | |||
| Absent | 179 | 96.9 | 0.370 |
| Present | 27 | 100.0 | |
|
| |||
| Resection margin | |||
| Negative (≥1 mm) | 171 | 97.9 | 0.167 |
| Positive or close (<1 mm) | 36 | 94.1 | |
|
| |||
| Chemotherapy | |||
| No Yes |
163 44 |
100.0 86.7 |
<0.001 |
|
| |||
| Regional nodal irradiation | |||
| No Yes |
194 13 |
97.1 100.0 |
0.478 |
|
| |||
| EPclin score | |||
| Low risk High risk |
154 53 |
100.0 88.9 |
<0.001 |
Table 3.
Summary of disease recurrences
| Recurrence | Age, years | Surgery | PT | pN | Tumor size, cm | HG | LVI | RM | EPclin score | EPclin score class | RT field | CTx | ET | Time to recurrence |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Local | 43 | BCS | 1c | 0 | 1.8 | I | No | (−) | 3.1 | Low risk | Breast only | No | TMX | 62 months |
| Local | 49 | BCS | 2 | 0 | 2.8 | II | No | (−) | 3.5 | High risk | Breast only | CMF #6 | TMX | 45 months |
| Local | 47 | BCS | 2 | 0 | 2.8 | II | No | Close | 3.6 | High risk | Breast only | CMF #6 | TMX | 13 months |
| Distant (bone) | 43 | BCS | 2 | 0 | 2.5 | II | No | (−) | 4.7 | High risk | Breast only | AC #4 | AI | 35 months |
| Distant (contralateral axilla, bone, liver) | 48 | BCS | 2 | 0 | 2.1 | II | No | Close | 4.2 | High risk | Breast only | AC #4 + weekly T #12 | TMX | 25 months |
| Distant (bone) | 54 | BCS | 2 | 0 | 2.1 | III | No | (−) | 4.2 | High risk | Breast only | TC #4 | TMX | 12 months |
HG, histologic grade; LVI, lymphovascular invasion; RM, resection margin; EP, EndoPredict; RT, radiotherapy; CTx, chemotherapy; ET, endocrine therapy; BCS, breast-conserving surgery; CMF, cyclophosphamide, methotrexate, fluorouracil; AC, adriamycin and cyclophosphamide; T, paclitaxel; TC, docetaxel and cyclophosphamide; TMX, tamoxifen; Al, aromatase inhibitor.
Discussion
The present study reported the treatment outcomes of surgery, RT, and systemic therapy for ER+/HER2− early breast cancer according to the EPclin score. The findings showed that LR and DM were observed in only 6 patients, mostly in the EPclin high-risk group, and no RR was observed regardless of the EPclin score.
EPclin score is a significant prognostic factor of DM. Buus et al. [8] reported that the EPclin score was a significant prognostic factor of DM in ER+/HER2− early breast cancer patients who received adjuvant endocrine therapy, and the DM rate was 5.8% in the low-risk group and 28.8% in the high-risk group, respectively. In a study by Dubsky et al. [10], when EPclin groups were divided into early relapse (0–5 years) and late relapse (>5 years after diagnosis), EPclin scores showed a significant association with both early and late distant recurrence. However, in our study, all DM events occurred only in the high-risk group, and the incidence rate of DM was much lower than that reported previously. These different results might be because 81% of patients in the high-risk group received chemotherapy, and the follow-up period was relatively short.
EPclin score also showed an association with LR. In our study, LR occurred in 1.4% of patients, and two out of three LRs occurred in the high-risk group. This finding is in line with recent observations. Fitzal et al. [11] showed that both EP score and EPclin score are effective prognostic tools for predicting local recurrence-free survival, and the risk of LR over a 10-year period among patients in the EP high-risk group was significantly higher than that in patients in the EP low-risk group (10-year local recurrence-free survival, 91.0% vs. 97.5%). In addition to EP, Mamounas et al. [12, 13] showed that locoregional recurrence (LRR) was significantly associated with OncotypeDX recurrence score (RS). Drukker et al. [14] reported the prediction of the LRR risk through MammaPrint, which involved analysis of a 70-gene signature. In their study, the 10-year LRR risk was 12.6% in the high-risk group but 6.1% in the low-risk group. Although it was difficult to observe sufficient LR events in our study because the follow-up period was shorter than that in previous studies, the EPclin score could show a clear prognostic correlation with the risk of LR with longer follow-up.
Even with early breast cancer, it has been reported that the addition of RNI to whole-breast RT reduces the rate of breast cancer recurrence in patients with high-risk node-negative or node-positive disease [15]. Therefore, it may be necessary to identify the subgroup that requires RNI using a multigene panel test. Following a 62-month median follow-up period, Kim et al. [16] evaluated the LRR pattern in 339 patients who underwent RT and the OncotypeDX test. In their study, RR occurred in patients in the high RS group who did not receive RNI, suggesting that RNI may be beneficial in patients with a high RS. Another report showed a significant association between the OncotypeDX RS and the risk for LRR [12]. In our study, 11 out of 16 node-positive patients did not receive RNI, and only two out of eight EPclin high-risk patients received RNI. However, as there was no RR in the present study, it is unclear whether RNI provides any benefit to those with EPclin high-risk scores. Long-term follow-up with a larger number of patients is needed to identify those patients at a higher risk of RR and the subset who might benefit from RNI.
The current study has limitations inherent to any retrospective study. The limited sample size and the low number of recurrence events made it difficult to perform subgroup analyses to identify potential prognostic factors. It will be necessary to increase the number of patients via a multicenter study. The short follow-up period was also associated with a low number of recurrence events, considering the natural course of ER+ breast cancer. A longer follow-up is necessary to accurately estimate the recurrence rates and to assess the benefit of adjuvant systemic chemotherapy or RNI for ER+ breast cancer.
Conclusion
EPclin score was associated with local and/or distant recurrences in ER+/HER2− early breast cancer, and able to identify the low-risk patients who had excellent DFS. While no RR was observed regardless of the EPclin score, longer follow-up with a larger number of patients is needed to identify those patients at a higher risk of RR.
Statement of Ethics
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board (Ewha Womans University Mokdong Hospital; approval no. 2021-06-017). Informed consent was exempted by the Institutional Review Board.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors have no funding sources to declare.
Author Contributions
Kyubo Kim conceived and designed the research. Wonguen Jung analyzed the data and wrote the manuscript with support from Kyubo Kim and Byung-In Moon. Kyubo Kim supervised the findings of this study. All the authors discussed the results and commented on the manuscript.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
Acknowledgments
None of the authors had a personal or financial conflict of interest.
Funding Statement
The authors have no funding sources to declare.
References
- 1.Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68((6)):394–424. doi: 10.3322/caac.21492. [DOI] [PubMed] [Google Scholar]
- 2.Kang SY, Lee SB, Kim YS, Kim Z, Kim HY, Kim HJ, et al. Breast cancer statistics in Korea, 2018. J Breast Cancer. 20182021 Apr;24((2)):123. doi: 10.4048/jbc.2021.24.e22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.National Comprehensive Cancer Network Breast cancer (version 8 2021) Available from: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (accessed September 30, 2021)
- 4.Early Breast Cancer Trialists' Collaborative Group Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomized trials among 28,896 women. N Engl J Med. 1988 Dec 29;319((26)):1681–92. doi: 10.1056/NEJM198812293192601. [DOI] [PubMed] [Google Scholar]
- 5.Early Breast Cancer Trialists' Collaborative Group (EBCTCG) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14–20;365((9472)):1687–717. doi: 10.1016/S0140-6736(05)66544-0. [DOI] [PubMed] [Google Scholar]
- 6.Peto R, Davies C, Godwin J, Gray R, Pan HC, et al. Early Breast Cancer Trialist' Collaborative Group (EBCTCG) Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012 Feb 4;379((9814)):432–44. doi: 10.1016/S0140-6736(11)61625-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res. 2011 Sep 15;17((18)):6012–20. doi: 10.1158/1078-0432.CCR-11-0926. [DOI] [PubMed] [Google Scholar]
- 8.Buus R, Sestak I, Kronenwett R, Denkert C, Dubsky P, Krappmann K, et al. Comparison of EndoPredict and EPclin with oncotype DX recurrence score for prediction of risk of distant recurrence after endocrine therapy. J Natl Cancer Inst. 2016 Nov;108((11)):djw149. doi: 10.1093/jnci/djw149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Sestak I. Risk stratification in early breast cancer in premenopausal and postmenopausal women: integrating genomic assays with clinicopathological features. Curr Opin Oncol. 2019;31((1)):29–34. doi: 10.1097/CCO.0000000000000490. [DOI] [PubMed] [Google Scholar]
- 10.Dubsky P, Brase JC, Jakesz R, Rudas M, Singer CF, Greil R, et al. The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2− breast cancer patients. Br J Cancer. 2013 Dec 10;109((12)):2959–64. doi: 10.1038/bjc.2013.671. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Fitzal F, Filipits M, Rudas M, Greil R, Dietze O, Samonigg H, et al. The genomic expression test EndoPredict is a prognostic tool for identifying risk of local recurrence in postmenopausal endocrine receptor-positive, her2neu-negative breast cancer patients randomised within the prospective ABCSG 8 trial. Br J Cancer. 2015 Apr 14;112((8)):1405–10. doi: 10.1038/bjc.2015.98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Mamounas EP, Tang G, Fisher B, Paik S, Shak S, Costantino JP, et al. Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol. 2010 Apr 1;28((10)):1677–83. doi: 10.1200/JCO.2009.23.7610. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Mamounas EP, Liu Q, Paik S, Baehner FL, Tang G, Jeong JH, et al. 21-Gene recurrence score and locoregional recurrence in node-positive/ER-positive breast cancer treated with chemo-endocrine therapy. J Natl Cancer Inst. 2017 Jan;109((4)):djw259. doi: 10.1093/jnci/djw259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Drukker CA, Elias SG, Nijenhuis MV, Wesseling J, Bartelink H, Elkhuizen P, et al. Gene expression profiling to predict the risk of locoregional recurrence in breast cancer: a pooled analysis. Breast Cancer Res Treat. 2014 Dec;148((3)):599–613. doi: 10.1007/s10549-014-3188-z. [DOI] [PubMed] [Google Scholar]
- 15.Whelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, et al. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015 Jul 23;373((4)):307–16. doi: 10.1056/NEJMoa1415340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kim K, Jung J, Shin KH, Kim JH, Chang JH, Kim SS, et al. Impact of oncotype DX recurrence score on the patterns of locoregional recurrence in breast cancer (Korean radiation oncology group 19-06) J Breast Cancer. 2020 Jun;23((3)):314. doi: 10.4048/jbc.2020.23.e36. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.