Blog Navigating ER+ HER2- Early Breast Cancer Webinar Series

Tailoring Treatment for Premenopausal Patients – Is there Still a Role for Gene-Expression Testing?

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Presenters:

Michalis Kontos, Professor of Breast and General Surgery, National and Kapodistrian University of Athens and PD Dr. med Evelyn Klein, Klinik und Polyklinik für Frauenheilkunde der Technischen Universität München.

 

Abstract:

Breast cancer, particularly early-stage hormone receptor-positive (HR+), HER2-negative disease, shows significant biological heterogeneity. In premenopausal patients, treatment decisions are influenced by both oncological factors and individual life circumstances. Molecular risk stratification using the EPclin score, which combines a 12-gene molecular profile with clinical parameters, supports personalized treatment planning. Recent studies have demonstrated that many premenopausal patients classified as EPclin low-risk have excellent outcomes without chemotherapy. A prospective study from the Technical University of Munich further confirmed EPclin’s prognostic value, showing a significant benefit of chemotherapy in high-risk patients. Moreover, EPclin provided more accurate prognostic information than traditional markers such as Ki-67 and tumor grade. Overall, EPclin remains a key tool for optimizing adjuvant therapy in HR+/HER2- premenopausal breast cancer patients, balancing treatment intensity with quality of life.

 

Introduction:

Breast cancer is a biologically heterogeneous disease, particularly in the subtype of early-stage hormone receptor-positive (HR+), HER2-negative breast cancer. Although ER+/Her2- Breast Cancer has an overall better prognosis than Her2-enriched or TNBC, there are still molecular subtypes differing significantly in their prognosis¹.

 

Case presentation:

PD Dr. Klein showed a case of a 41-year-old premenopausal woman presented in July 2013 with a 13 mm lesion in the left breast, detected during routine sonographic screening. Imaging (mammography, and sonography) showed a lesion near the pectoralis muscle in the upper outer quadrant without clinical or sonographic evidence of axillary lymph node involvement.

Core biopsy revealed an invasive ductal carcinoma, grade 2, with hormone receptor positivity (ER 100%, PR 80%) and a Ki-67 of 18%. The patient underwent breast-conserving surgery with sentinel lymph node biopsy. Histology showed extensive DCIS and involved margins, prompting two re-excisions (cranial and caudal), which still failed to achieve clear margins. A subcutaneous mastectomy with implant-based reconstruction was then performed.

Final pathology revealed a multifocal, grade 2 invasive carcinoma with extensive DCIS, clear margins, and micro-metastasis in one of three sentinel nodes (pN0(mi 1/3)). Receptor status updated to ER 100%, PR 70%, HER2 1+, and Ki-67 25%.

An EndoPredict (EPclin) test yielded a low-risk score of 2.2, corresponding to a 4% 10-year distant recurrence risk with endocrine therapy alone. Based on these findings, the multidisciplinary tumor board recommended endocrine therapy with tamoxifen for five years.

The patient adhered to tamoxifen for slightly over five years and, as of the latest follow-up in summer 2023, remains disease-free ten years after initial diagnosis.

 

Case discussion:

Professor Kontos and PD Klein did discussed the addition of ovarian function suppression (OFS) in cases like the one presented. In 2013 the SOFT and TEXT data have not been published yet², which was the reason for the Tamoxifen use only. Due to the clinical intermediate risk profile of this patient the addition of OFS would have been at least discussed today.

Scientific evidence for gene-expression testing in premenopausal women:

Professor Kontos explained, in premenopausal patients, therapy decisions are influenced not only by oncological factors but also by individual life circumstances – including fertility desires, family responsibilities, the impact of chemotherapy on physical appearance and overall well-being, career interruptions, and social interactions. Often, chemotherapy is perceived as more burdensome than surgery.

Molecular risk stratification using gene-expression assays, especially using the EPclin score (a combination of a 12-Gene Molecular Score and clinical parameters), has become an important tool for personalized treatment planning. International clinical guidelines like ESMO3 or NCCN4 acknowledge that premenopausal patients, even with N1 disease can be low risk and thus eventually omit chemotherapy in addition to tamoxifen (TAM) or aromatase inhibitor (AI) plus ovarian function suppression (OFS). In addition to clinical-pathological factors, genomic signatures like EndoPredict are recommended to determine individual risk of recurrence.^5,6

In a study by Constantinidou et al. (2022), 65% of premenopausal patients were classified as EPclin low-risk. This group had a significantly lower 10-year distant recurrence rate (3%) compared to the high-risk group (24%), even without receiving chemotherapy. An exploratory analysis also indicated a potential benefit of ovarian function suppression (OFS) only in EPclin high risk patients.⁷

Further confirmation comes from a Mexican cohort study which supported the predictive power of the EPclin score8. Similarly, the GEICAM/9906 study demonstrated consistent results between pre- and postmenopausal patients, even in node-positive disease⁹, reinforcing the utility of EPclin-guided treatment decisions.

A prospective study conducted at the Technical University of Munich further validated these findings in routine clinical practice¹⁰. Among 368 HR+/HER2- patients (33% premenopausal), the median follow-up was 8.2 years. The five-year distant metastasis-free survival (DMFS) was 96.6% in the EPclin low-risk group versus 85.5% in the high-risk group (Hazard Ratio 2.21; p = 0.005). Notably, 67% of high-risk patients received adjuvant chemotherapy, which allows to analyze the prospective Chemo-benefit in this study. Five-year disease-free survival rate (DFS) in EPclin high-risk patients with chemotherapy was 89.1% compared with EPclin high risk patients not receiving Chemo with a DFS of only 68.9% (HR= 0.46; p=0.036). The investigators also evaluated the correlation between EPclin risk class and tumor grade, Ki-67 distribution, tumor size, and nodal status as well. They found that there was only a weak correlation with tumor grade (r = 0.348), Ki-67 (r = 0.287), and tumor size (r = 0.381) and a moderate correlation (r=0.465) with nodal status. The authors concluded that, in this cohort, the EPclin based low-risk classification was significantly associated with improved DFS in both Ki-67 subtypes, indicating that EndoPredict provides a more exact estimation of prognosis than that provided by Ki-67 subtypes. The study confirmed the prognostic value of EPclin in both pre- and postmenopausal subgroups¹⁰.

 

Discussion with the audience:

PD Dr. Klein emphasized once again the notably unselected patient population included in her real-world evidence (RWE) study. This broad inclusion allowed for a direct comparison of the prognostic value of tumor grading and Ki-67 with that of the genomic assay.

 

• What is the challenge in withholding chemotherapy in premenopausal patients?
• Why are some physicians still reluctant to omit chemotherapy in these patients?

This reluctance likely stems from persisting uncertainty. Until just a few years ago, a premenopausal status alone often implied a clear indication for chemotherapy. Additionally, PD Dr. Klein pointed out that, based on clinical experience, premenopausal patients frequently present with more aggressive tumor biology. Given their long life-expectancy, the prevailing mindset was to treat them with every available option. However, the paradigm is gradually shifting toward a more balanced approach—considering treatment intensity in the context of maintaining optimal quality of life.

During the discussion, an audience member raised the question of how reliable gene expression assays are in premenopausal patients with lymph node involvement. Specifically, they asked whether the experts would trust a low-risk result in a pT2 tumor with three positive lymph nodes.

PD Dr. Klein responded that she had tested many premenopausal, node-positive patients but had never encountered an EPclin low-risk result in a case with N=3. However, in patients with only one positive lymph node (N=1), she would fully trust a low-risk result. In contrast, the discussion turned to whether chemotherapy should still be recommended for a clinically low- to intermediate-risk patient if the genomic test indicates high risk. PD Dr. Klein stated that she would, in any case, follow the genomic assay, as she has repeatedly observed that a personalized molecular profile provides a more accurate prognostic assessment than clinical-pathological factors alone.

Conclusion:

In conclusion, the EPclin score remains a crucial component in tailoring adjuvant therapy for premenopausal women with HR+/HER2- early breast cancer. It enables better identification of those who may benefit from intensified treatment—including chemotherapy and OFS—while helping to avoid overtreatment in low-risk patients. Nevertheless, beyond molecular findings, individual patient preferences and quality of life considerations must always be taken into account.

To get even more information on this topic from the exciting discussion of our experts, please watch the recording of the webinar.

Tailoring treatment for premenopausal patients: Is there still a role for gene expression testing?​

 

References:

1. Pagani O, et al. J. of Clin Oncol. 2023 Prabhu et al.: Dissecting the Biological Heterogeneity within Hormone Receptor Positive HER2 Negative Breast Cancer by Gene Expression Markers Identifies Indolent Tumors within Late Stage Disease. Translational Oncology. 2017.
2. Pagani et al.: Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023.
3. Loibl S. et al.: Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 2023
4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer r V.3.2025 ©National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed [July 17, 2025]. To view the most recent and complete version of the guideline, go online to NCCN.org.
5. Filipits M. 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
6. Filipits et al.: Prediction of Distant Recurrence using EndoPredict among Women with ER+, HER2- Node- Positive and Node-Negative Breast Cancer Treated with Endocrine Therapy Only. Clin Cancer Res. 2019
7. Constantinidou A. et al.: Clinical Validation of EndoPredict in Pre-Menopausal Women with ER-Positive, HER2-Negative Primary Breast Cancer. Clin. Cancer Res. 2022
8. Vázquez-Juarez D. et al.: Follow-up of prospective cohort of Mexican premenopausal women with breast cancer who received guidedadjuvant treatment with the EndoPredict assay. Cancer Res 2022
9. Martin M. et al.: Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2− reast cancer patients: results from the GEICAM 9906 trial. Breast Cancer Res. 2014
10. Klein, E. et al.: Long-term outcome data using EndoPredict as risk stratification and hemotherapy decision biomarker in hormone receptor positive, HER2-negative early breast cancer. Breast Cancer Res Treat. 2024