INTRODUCTION
Breast cancer is the most common malignancy among women worldwide and survival has improved steadily with advances in screening and systemic therapy [1]. Establishing an optimal treatment strategy remains crucial for further improving outcomes. In South Korea, the incidence of breast cancer has risen markedly—from approximately 20 cases per 100,000 population in the year 2000 to >50 cases per 100,000 population in 2021 [2]. Unlike Western cohorts in which the median age at diagnosis is in the early 60s, Korean women are typically diagnosed in their early 50s—nearly a decade younger [3]. Hormone receptor–positive (HR+) tumors account for approximately 70% of all breast cancers globally and represent the predominant subtype among premenopausal patients [4]. In premenopausal women, circulating estradiol levels remain substantially higher than in postmenopausal women because of intact ovarian function. Ovarian estrogen production frequently recovers following chemotherapy, particularly in younger individuals, thereby maintaining estrogenic stimulation that may contribute to recurrence [5].
Endocrine therapy constitutes the cornerstone of adjuvant management for HR+ breast cancer. For decades, 5 to 10 years of tamoxifen (TAM) monotherapy has been the standard regimen [6]. However, growing evidence indicates that residual ovarian estrogen production can continue to activate hormone driven tumor pathways despite TAM’s antagonistic action [7]. This biological insight, coupled with clinical trial findings, has established ovarian function suppression (OFS) as an essential component of adjuvant endocrine therapy in selected premenopausal women. The 2016 American Society of Clinical Oncology guidelines therefore recommended gonadotropin-releasing-hormone agonist (GnRHa)–mediated OFS in combination with either TAM or an aromatase inhibitor (AI) for patients with high-risk HR+ disease [8].
The Addition of Ovarian Suppression to TAM in Young Women with Hormone-sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA; ClinicalTrials.gov identifier: NCT00912548), SOFT (Suppression of Ovarian Function Trial) and TEXT (TAM and Exemestane Trial) have confirmed the benefit of adding OFS to endocrine therapy in appropriate premenopausal populations [9,10]. Nevertheless, considerable heterogeneity persists in how OFS is applied in real-world clinical settings. Unresolved questions remain regarding optimal duration, candidate selection, and the balance between therapeutic benefit and toxicity. Clinicians frequently extend OFS use beyond guideline indications, particularly among younger patients even when recurrence risk is low.
To clarify these contemporary patterns, we analyzed a nationwide survey conducted among members of the Korean Breast Cancer Society (KBCS), evaluating how clinicians incorporate OFS across diverse clinical and genomic risk contexts.
METHODS
Survey design and population
A nationwide, web-based survey was conducted among members of the KBCS to explore real-world practice patterns in the adjuvant management of premenopausal women with HR+, human epidermal growth factor receptor 2-negative (HER2-) or HER2+ early breast cancer. The questionnaire focused on decision-making regarding OFS and associated systemic therapy across diverse clinical scenarios. Eligible respondents were practicing physicians who routinely manage breast cancer patients in South Korea, including breast surgeons and medical oncologists affiliated with academic centers, general hospitals, or specialized clinics. Participation was voluntary, and survey invitations were distributed via e-mail to the official KBCS membership list. Completion of the survey implied informed consent.
Questionnaire development
The questionnaire consisted of 28 multiple-choice questions designed by a multidisciplinary panel of breast surgeons and oncologists. Questions addressed both physician demographics and therapeutic preferences in common clinical settings related to the initiation and extension of adjuvant endocrine therapy.
Demographic variables included gender, specialty, years of clinical experience, type of institution, and annual surgical volume. Practice-related information—such as direct involvement in systemic chemotherapy administration—was also collected to characterize respondent profiles.
Clinical scenarios
Nine major clinical vignettes were developed to reflect real-world decision complexity. Each scenario modified a single variable (e.g., age, tumor size, nodal burden, genomic risk, or treatment response) while holding other factors consistent. Respondents were asked to select their preferred adjuvant endocrine regimen in each situation.
1. Effect of age on OFS decision: Three cases (ages 30, 35, 40) with pT1cN0, HR+, HER2-, grade 1, Ki-67 14%, Oncotype DX recurrence score (RS) 15.
2. Effect of tumor size on OFS decision: pT1a → pT1b → pT1cN0 in a 37-year-old patient, HR+, HER2-, Grade 1, Ki-67 14%, oncotype DX RS 15.
3. Effect of nodal status on OFS decision: 1 → 3 → ≥ 5 positive nodes in a 37-year-old patient, HR+, HER2-, Grade1, Ki-67 14%, oncotype DX RS 15.
4. Effect of nodal status on extended endocrine therapy decision in low-genomic risk disease: Evaluation of preferred regimens for years 6–10 according to nodal involvement (1 → 3 → ≥ 5 positive nodes) in a 37-year-old patient, HR+, HER2-, Grade1, Ki-67 14%, oncotype DX RS 15.
5. High risk biology (tumor size): pT1a → pT1b → pT1cN0 in 37 year old female, HR+, HER2-, Grade 3, Ki-67 30%, oncotype DX RS 31.
6. High-risk biology (nodal burden): (1 node-> 3 nodes -> 5 nodes) in 37-year-old female, HR+, HER2-, Grade 1, Ki-67 30%, oncotype DX RS 31.
7. Extended therapy in high-risk disease: (nodal burden): (1 node -> 3 nodes -> 5 nodes) in 37-year-old female, HR+, HER2-, Grade 3, Ki-67 30%, oncotype DX RS 31.
8. HER2-positive settings: Impact of nodal status and neoadjuvant response [pathologic complete response (pCR) vs. non-pCR)] on endocrine selection after chemotherapy±anti-HER2 therapy.
9. Post-neoadjuvant residual disease: ypN0 → ypN1 → ypN2 after neoadjuvant chemotherapy (NAC) in 37-year old female, HR+, HER2-, Grade 3, Ki-67 30%, after NAC.
Complete survey items and response options are provided in Appendix 1.
Data collection and timeline
The questionnaire was accessible online between August 21 and October 30, 2025. Responses were automatically captured through a secure electronic platform and anonymized for analysis. Duplicate entries were excluded.
Statistical analysis
Descriptive statistics were used to summarize respondent characteristics and treatment preferences. Continuous variables were reported as medians with interquartile ranges, and categorical variables as frequencies and percentages. Trends in therapy selection were evaluated across ordered clinical variables (age, tumor size, nodal category, genomic risk). Graphical summaries (Figures 1–9) and detailed distributions (Supplementary Tables 1–9) were generated to visualize response patterns. All analyses were conducted using IBM SPSS Statistics, v.28.0 software (IBM Corp., Armonk, NY, USA).
RESULTS
Study participants
Seventy breast-cancer specialists from institutions across Korea completed the survey. The cohort was highly experienced comprising 97.1% surgical oncologists and 1.45% medical oncologists. Most participants (75.7%) practiced in university-affiliated hospitals. Nearly three-quarters had more than 15 years of clinical experience, and over half performed more than 100 breast operations annually (Table 1).
Overview of treatment preferences
Scenario 1 – Effect of age on OFS decision in low genomic risk disease
These three scenarios examined treatment preferences for initial adjuvant endocrine therapy (years 0–5) in premenopausal women with HR+, HER2-, node-negative, low genomic risk (RS 15) early breast cancer, varying only by age (30, 35, and 40 years) (Figure 1). Across all cases, the majority of respondents favored OFS-based therapy, although the intensity and duration of OFS decreased progressively with increasing age.
In scenario 1-1 (30-year-old patient), the most frequent regimen was GnRHa for 5 years plus TAM for 5 years (38.6%, n=27), followed by GnRHa for 5 years plus AI (22.9%), GnRHa for 2 years plus TAM (21.4%), and TAM alone (17.1%). This suggests that clinicians perceive age itself as a high-risk feature, regardless of favorable pathology or genomic profile.
In scenario 1-2 (35-year-old patient), the proportion of OFS-based regimens remained high (81.4%), but the preferred duration of OFS was shorter. GnRHa for 5 years plus TAM for 5 years became the most common choice (38.6%, n=27), while GnRHa for 2 years plus TAM and GnRHa for 5 years plus AI were chosen by 21.4% and 21.4%, respectively. TAM alone accounted for 18.6%.
In scenario 1-3 (40-year-old patient), a clear trend toward de-escalation was observed, with TAM monotherapy increasing up to 22.9%, while OFS-based regimens dropped to 75.7%. Compared to younger age groups, there was a gradual decline in AI-based OFS and an increased acceptance of TAM alone, reflecting reduced concern for ovarian function recovery and recurrence in older premenopausal women. Across increasing age (from 30 to 35 and 40 years), the overall use of OFS-based endocrine therapy remained high (up to 80%), whereas its duration and intensity decreased. Clinicians strongly favored long-term OFS (5 years) in women <35, whereas shorter OFS duration (2 years) or TAM alone became more acceptable by age 40. These findings highlight a clear age-adapted treatment pattern in low-risk, node-negative premenopausal breast cancer patients—where young age alone remains a decisive factor driving endocrine intensification, despite favorable clinical and genomic features.
Scenario 2 – Effect of tumor size on OFS decision in low genomic risk disease
For all three scenarios — 37-year-old premenopausal women with HR+, HER2-, node-negative, low genomic risk (RS 15) but varying tumor sizes (pT1a/b/c) — the preferred adjuvant endocrine therapy patterns exhibited a clear, tumor-size–dependent escalation in treatment intensity (Figure 2).
In scenario 2-1, TAM alone for 5 years was the most frequently selected regimen (54.3%, n=38). Combination endocrine therapies incorporating OFS were also commonly chosen, including GnRHa for 2 years plus TAM for 5 years in 21.4% (n=15), GnRHa for 5 years plus TAM for 5 years in 15.7% (n=11), and GnRHa for 5 years plus AI for 5 years in 8.6% (n=6). Overall, nearly half of the respondents (47%) preferred TAM monotherapy, whereas approximately half (49%) incorporated OFS with either TAM or an AI, indicating a substantial tendency toward using OFS even in a low-risk genomic and clinical setting.
In scenario 2-2, the use of OFS-based therapy increased modestly, with GnRHa for 5 years plus TAM for 5 years (25.7%) and TAM alone for 5 years was the most frequently selected regimen (44.3%, n=31). In scenario 2-3, a substantial shift toward OFS was observed. GnRHa for 5 years plus TAM for 5 years was the most common choice (37.1%, n=26), followed by TAM alone (22.9%) and GnRHa for 5 years plus AI for 5 years (18.6%).
The treatment pattern demonstrates a risk-adapted escalation of endocrine therapy intensity. For smaller, node-negative tumors (pT1a/b), TAM monotherapy was the preferred regimen, whereas for larger tumors (pT1c), most clinicians favored OFS-based combination therapy (either GnRHa plus TAM or GnRHa plus AI). This suggests that, even within a low-RS population, tumor size strongly influences the perceived need for ovarian suppression in adjuvant endocrine management among KBCS members.
Scenario 3 – Effect of nodal status on OFS decision in low genomic risk disease
For all three scenarios — 37-year-old premenopausal women with HR+, HER2-, low genomic risk (RS 15) but different nodal burdens (pN1 with 1+ node, pN1 with 3+ nodes, and pN2 with ≥5 nodes), the treatment preference progressively shifted toward combined chemotherapy and endocrine therapy as nodal involvement increased (Figure 3).
In scenario 3-1 (pT1N1, 1 positive node), treatment opinions were divided. Half of the respondents (50.0%, n=35) chose chemotherapy (anthracycline and cyclophosphamide [AC] followed by taxane) plus GnRHa for 5 years plus endocrine therapy, while the other half preferred endocrine therapy alone, most commonly GnRHa plus TAM or GnRHa plus AI. This reflects clinical equipoise regarding the need for chemotherapy when only a single lymph node is involved despite of low RS.
In scenario 3-2 (pT1N1, 3 positive nodes), the majority (75.7%, n=53) selected chemotherapy (AC followed by taxane) combined with GnRHa for 5 years and endocrine therapy, while only 24.3% chose endocrine-only regimens. This marked a clear shift toward incorporating chemotherapy once multiple nodal metastases were present, even with a low genomic score.
In scenario 3-3 (pT1N2, ≥5 positive nodes), an overwhelming 94.3% (n=66) of respondents preferred chemotherapy plus GnRHa plus endocrine therapy, leaving only 5.7% opting for endocrine therapy alone. This indicates that extensive nodal disease warrants systemic chemotherapy regardless of genomic assay results. While endocrine-only strategies were still considered for patients with limited nodal disease (1 node), combined chemo-endocrine regimens became the standard for those with >3 positive nodes. These findings underscore that, despite low RS (15), clinical risk factors such as nodal involvement remain the primary driver of adjuvant treatment intensity in real-world decision-making among Korean breast cancer specialists.
Scenario 4 – Effect of nodal status on extended endocrine therapy decision in low genomic risk disease
These questions evaluated treatment preferences for extended adjuvant endocrine therapy (years 6–10) in 37-year-old premenopausal women with HR+, HER2-, low genomic risk (RS 15) and varying degrees of nodal involvement (pN1 with 1+ node, pN1 with 3+ nodes, and pN2 with ≥5 nodes) (Figure 4). Across all scenarios, most respondents favored TAM monotherapy, while the proportion selecting OFS-based extended therapy gradually increased with nodal burden.
In scenario 4-1 (pT1N1, 1 positive node), the majority (72.9%, n=51) chose TAM alone for an additional 5 years, while GnRHa plus TAM and GnRHa plus AI were selected by 10.0% and 2.9%, respectively. Only 14.3% of respondents chose no further endocrine therapy. This suggests that most clinicians consider TAM 10 years as sufficient for low-risk, limited-node disease.
In scenario 4-2 (pT1N1, 3 positive nodes), similar patterns were observed, with TAM alone for an additional 5 years remaining dominant (72.9%, n=51). However, the proportion favoring OFS-based therapy (either GnRHa plus AI or GnRHa plus TAM) increased slightly up to 22.9%, reflecting a mild intensification of approach with higher nodal burden. Only 4.3% opted for no extended therapy.
In scenario 4-3 (pT1N2, ≥5 positive nodes), the majority still preferred TAM alone for an additional 5 years (68.6%, n=48), whereas OFS-based therapy was selected by 31.4% (including GnRHa plus AI in 24.3% and GnRHa plus TAM in 7.1%). No respondents chose to omit extended therapy entirely. Despite frequent OFS use in the first 5 years, extended therapy beyond year 5 shifted overwhelmingly to TAM monotherapy, reflecting concerns regarding long-term toxicity, quality of life, adherence, reimbursement, and access issues.
Scenario 5 – Effect of tumor size on OFS decision in high genomic risk disease
These three questions explored physicians’ preferences for initial adjuvant endocrine therapy (years 0–5) in 37-year-old premenopausal women with HR+, HER2-, node negative, high genomic risk (RS 31) and high-grade (G3) tumors, but with differing primary tumor sizes (pT1a, pT1b, and pT1c) (Figure 5). Across all scenarios, nearly all respondent recommended OFS-based endocrine therapy, with the use of OFS plus AI increasing in frequency as tumor size increased.
In scenario 5-1 (pT1aN0), the most frequently selected regimen was GnRHa for 5 years plus AI for 5 years (51.4%, n=36), followed by GnRHa for 5 years plus TAM for 5 years (27.2%) and GnRHa for 2 years plus TAM for 5 years (11.4%). Only 8.6% chose TAM alone for 5 years. These results suggest a strong tendency toward endocrine therapy intensification with OFS even in small, node-negative tumors when the genomic risk is high.
In scenario 5-2 (pT1bN0), similarly, GnRHa for 5 years plus AI for 5 years was the most preferred regimen (58.6%, n=41), followed by GnRHa for 5 years plus TAM (25.7%) and GnRHa for 2 years plus TAM (11.4%). TAM alone was rarely selected (4.3%). This reflects the maintenance of a high-intensity endocrine approach in intermediate-size tumors, consistent with the aggressive nature implied by high RS and grade 3 pathology.
In scenario 5-3 (pT1cN0), the preference for GnRHa plus AI further increased, becoming the predominant regimen (62.9%, n=44), followed by GnRHa for 5 years plus TAM for 5 years (27.1%) and GnRHa for 2 years plus TAM for 5 years (8.6%). TAM alone was selected by only 1.4% of respondents.
These findings demonstrate an incremental increase in OFS plus AI selection corresponding with tumor size. Across all three tumor sizes (T1a → T1b → T1c), the preference for OFS-based therapy remained nearly universal, with a progressive shift toward OFS plus AI as tumor burden increased. While TAM monotherapy was minimal (<10%), GnRHa plus AI emerged as the favored strategy across all subgroups, highlighting a strong consensus among clinicians to escalate endocrine therapy intensity in premenopausal women with high genomic risk (RS 31) regardless of tumor size. This trend reflects the integration of both genomic and clinical aggressiveness into treatment decision-making, emphasizing that high RS supersedes small tumor size in guiding the need for intensive endocrine suppression.
Scenario 6 – Effect of nodal status on OFS decision in high genomic risk disease
These three questions examined preferences for initial adjuvant endocrine therapy (years 0–5) in 37-year-old premenopausal women with HR+, HER2-, high genomic risk (RS 31), high-grade (G3) tumors, and varying nodal involvement (pN1 with 1+ node, pN1 with 3+ nodes, and pN2 with ≥5 nodes) (Figure 6).
Across all scenarios, nearly all respondents recommended OFS-based endocrine therapy, with a clear progressive increase in the use of OFS plus AI as nodal burden increased.
In scenario 6-1 (pT1N1, 1 positive node), the majority of respondents (80.0%, n=56) selected GnRHa for 5 years plus AI for 5 years, while GnRHa for 5 years plus TAM for 5 years and GnRHa for 2 years plus TAM for 5 years were chosen by 14.3% and 5.7%, respectively. No respondents selected TAM monotherapy. This indicates a strong preference for OFS plus AI even in limited-node, high-genomic-risk disease.
In scenario 6-2 (pT1N1, 3 positive nodes), the dominance of OFS plus AI became even more pronounced, with 87.1% (n=61) choosing GnRHa plus AI and 10.0% opting for GnRHa for 5 years plus TAM. GnRHa for 2 years plus TAM was selected by 2.9%.
In scenario 6-3 (pT1N2, ≥5 positive nodes), nearly all respondents (85.7%, n=60) chose GnRHa plus AI, while GnRHa for 5 years plus TAM for 5 years and GnRHa for 2 years plus TAM for 5 years were selected by 7.5% and 1.4%, respectively. Only 1.4% selected TAM alone.
Across increasing nodal burden, there was a progressive shift toward OFS plus AI dominance in endocrine therapy selection, rising from 80% at pN1 to nearly 85% at pN2. TAM -based regimens (either alone or combined with OFS) became increasingly uncommon, collectively accounting for approximately 10% in pN2 disease. These results illustrate that, among premenopausal women with high genomic and clinical risk, clinicians strongly favor intensive ovarian suppression with an AI, underscoring the prevailing perception that clinical risk—particularly nodal involvement—amplifies the necessity for maximal endocrine suppression, even when chemotherapy has already been administered.
Scenario 7 – Effect of nodal status on extended endocrine therapy decision in high genomic risk disease
These three questions investigated preferences for extended adjuvant endocrine therapy (years 6–10) in 37-year-old premenopausal women with HR+, HER2-, high genomic risk (RS 31) and increasing nodal burden (pN1 with 1+ node, pN1 with 3+ nodes, and pN2 with ≥5 nodes) (Figure 7). Across all scenarios, most respondents preferred continuation of TAM monotherapy, although the proportion of OFS-based extended therapy increased modestly with higher nodal involvement.
In scenario 7-1 (pT1N1, 1 positive node), the majority (67.1%, n=47) selected TAM alone for an additional 5 years, while GnRHa plus AI and GnRHa plus TAM were chosen by 20.0% and 8.6%, respectively. Only 2.9% opted to discontinue endocrine therapy. These findings suggest that most clinicians view TAM 10 years as sufficient for high-genomic-risk patients with limited nodal disease.
In scenario 7-2 (pT1N1, 3 positive nodes), similar trends were observed, with TAM alone for an additional 5 years remaining dominant (70.0%, n=49). However, OFS-based regimens were used slightly more often, with GnRHa plus AI chosen by 21.4% and GnRHa plus TAM by 8.6%. None opted for no extended therapy, indicating broader agreement on the need for prolonged endocrine suppression in multiple nodal burden circumstances.
In scenario 7-3 (pT1N2, ≥5 positive nodes), although TAM alone remained the most common choice (61.4%, n=43), the use of GnRHa plus AI increased markedly up to 30.0%, with GnRHa plus TAM at 7.1%. None of the respondents omitted extended therapy. This pattern indicates a shift toward OFS-based extended regimens with higher nodal burden.
Across all three nodal categories, TAM monotherapy was the preferred extended endocrine therapy, reflecting a generally conservative approach beyond 5 years, even in high genomic-risk disease. However, as nodal burden increased (from pN1 to pN2), the use of OFS plus + AI rose from 17% to 30%, suggesting that clinical factors—especially the extent of nodal involvement—continue to guide the decision to intensify extended endocrine therapy. These findings imply that, in real world clinical practice, physicians balance treatment burden, late toxicity, reimbursement, and access issues against residual recurrence risk, favoring TAM continuation for most, but selectively intensifying therapy in patients with multiple positive nodes.
Scenario 8 – OFS decision in HR+, HER2+ disease
These four scenarios evaluated preferences for initial adjuvant endocrine therapy (years 0–5) in 37-year-old premenopausal women with HR+, HER2+ breast cancer following chemotherapy and anti-HER2 targeted therapy, under varying clinical contexts (tumor stage, nodal involvement, and response to NAC) (Figure 8). Across all settings, the majority of respondents selected OFS-based endocrine therapy, with GnRHa plus AI consistently emerging as the predominant regimen, especially in patients with residual disease or greater nodal burden.
In scenario 8-1 (pT1cN0, HR+, HER2+, post-adjuvant chemotherapy), responses were relatively distributed among OFS-based regimens, with GnRHa for 5 years plus TAM for 5 years most commonly selected (31.4%, n=22), followed by GnRHa for 5 years plus AI (31.4%), GnRHa for 2 years plus TAM (17.1%), and TAM alone (17.1%). This pattern suggests that in HER2+, node-negative disease after full systemic therapy, clinicians remain divided between TAM-based and AI-based OFS regimens, reflecting variability in perceived residual risk.
In scenario 8-2 (cT1cN1, 2 positive nodes, HER2+, pCR after NAC plus anti-HER2 therapy), GnRHa for 5 years plus AI for 5 years was the most preferred regimen (41.4%, n=29), followed by GnRHa for 5 years plus TAM for 5 years (28.6%) and GnRHa for 2 years plus TAM (12.9%). TAM alone was chosen by 17.1%. Despite achieving pCR, nearly 80% of respondents still chose OFS-based therapy, suggesting persistent concern for recurrence in HER2+, premenopausal patients.
In scenario 8-3 (cT1cN1, 2 positive nodes, HER2+, non-pCR, residual cancer burden [RCB]-II), a clear shift toward more aggressive endocrine regimens was observed, with GnRHa for 5 years plus AI selected by 68.6% (n=48), GnRHa for 5 years plus TAM by 18.6%, GnRHa for 2 years plus TAM by 5.7%, and TAM alone by 5.7%. The increase in AI-based therapy reflects clinicians’ tendency to escalate endocrine intensity in the presence of residual disease post-neoadjuvant therapy. In scenario 8-4 (cT1cN2, ≥4 nodes, HER2+, non-pCR, RCB-II), intensification peaked in this scenario, with GnRHa plus AI for 5 years chosen by 77.1% (n=54), GnRHa for 5 years plus TAM by 18.6%, and TAM alone by only 2.9%.
Nearly all respondents (95%) used OFS-based regimens, demonstrating a consensus for maximum endocrine suppression in patients with both high clinical and pathological risk. Across these four HER2+ scenarios, there was a progressive increase in the use of OFS plus AI corresponding with disease burden and treatment response from 33% in node-negative (scenario 8-1) to 70% in node-positive, non-pCR (scenario 8-4) patients. While TAM alone remained an option in low-burden or pCR settings, it was nearly eliminated in residual or multiple nodal burden disease. These findings illustrate a strong, risk-adapted trend among clinicians such as de-escalation to TAM-based OFS in lower-risk or pCR cases or escalation to AI-based OFS in patients with residual or extensive nodal disease. Residual disease (non-pCR) drove a significant escalation toward intensive OFS plus AI, reflecting the widely accepted role of residual disease as a marker of poor prognosis.
Scenario 9 – OFS decision in post-neoadjuvant HR+, HER2− disease
These three scenarios examined physicians’ preferences for initial adjuvant endocrine therapy (years 0–5) in 37-year-old premenopausal women with HR+, HER2-breast cancer who had received NAC, but differed in post-treatment pathologic outcomes differing in residual nodal burden (ypN0, ypN1, ypN2) (Figure 9). Across all three settings, nearly all respondents recommended OFS-based endocrine therapy, with a marked shift toward GnRHa plus AI as residual nodal disease increased.
In scenario 9-1, (ypT1N0), GnRHa for 5 years plus AI for 5 years plus AI for 5 years was the most common regimen (68.6%, n=48), followed by GnRHa for 5 years plus TAM for 5 years (20.0%) and GnRHa for 2 years plus TAM for 5 years (5.7%). TAM alone for 5 years was rarely chosen (4.3%). These results demonstrate a strong preference for maintaining OFS-based therapy even in patients with an excellent post-NAC response, suggesting that genomic and biologic risk outweigh complete pathologic response in endocrine decision-making.
In scenario 9-2 (ypT1N1, residual 1–3 positive nodes), the preference for OFS+AI remained predominant, selected by 80.0% (n=56) of respondents, while GnRHa for 5 years plus TAM was chosen by 14.3%, GnRHa for 2 years plus TAM by 4.3%, and none of the respondents chose TAM alone. This pattern reflects clinicians’ inclination to escalate therapy intensity in the presence of any residual nodal disease, regardless of the initial downstaging effect of NAC.
In scenario 9-3 (ypT1N2, ≥4 positive nodes), intensification was further evident, with GnRHa plus AI selected by 88.6% (n=62), while GnRHa for 5 years plus TAM dropped to 10.0%. Only 1.4% chose less aggressive regimens (GnRHa for 2 years plus TAM or TAM alone).
This adoption of OFS plus AI underscores a clinical consensus that patients with residual multiple nodal disease represent the highest-risk cohort, warranting maximal endocrine suppression. Across all three post-NAC scenarios, OFS-based endocrine therapy was nearly universal, with a progressive dominance of GnRHa plus AI corresponding to residual nodal burden, from 68% (ypN0), 80% (ypN1) and to 88% (ypN2). Conversely, TAM-containing regimens were gradually de-emphasized, particularly as nodal disease persisted. Overall, the results reflect a strong, uniform perception that post-NAC pathology (extent of residual disease) guides the degree of endocrine intensification in premenopausal HR+/HER2− breast cancer patients.
DISCUSSION
This comprehensive survey of treatment decision-making among experienced breast specialists provides important insights into how endocrine therapy is selected for premenopausal women with HR+ breast cancer across a wide spectrum of clinical scenarios. Although the specific details of each vignette varied—ranging from extremely low-risk presentations to biologically and clinically high-risk disease—the decision patterns consistently revealed a set of important principles guiding contemporary real-world practice.
1. OFS is applied broadly during the initial 5 years, even in low-risk disease
Across multiple scenarios involving young women with node-negative, low-grade, low-genomic-risk tumors (RS 15), OFS-based endocrine therapy was selected in >75%–80% of cases. The survey results revealed that OFS plus AI is also frequently used in low-risk young patients, such as those who are N0 (node-negative), have a RS of 15, or are 30 years old. This demonstrates a tendency for OFS to be overused in low-risk, young women, suggesting that OFS is being employed more broadly in real-world clinical practice than supported by evidence-based guidelines. This preference persisted even when TAM alone would be a guideline-supported option. This pattern highlights a widespread perception that young age itself represents an independent risk factor, justifying OFS even in biologically indolent disease. These findings are consistent with SOFT/TEXT trial observations, which demonstrated that the youngest premenopausal women—particularly those <35 years—derive disproportionally greater benefit from OFS, independent of other tumor characteristics. Our survey results suggest that clinicians incorporate this evidence exclusively, often extrapolating it to risk categories where the absolute benefit of OFS is uncertain. Potential reasons for this practice include the specific Korean healthcare environment, anxiety associated with young age at diagnosis, and issues related to insurance or coverage.
2. Tumor size and nodal burden remain dominant clinical drivers
Across all scenarios, traditional pathological factors—tumor size and lymph node involvement—exerted the greatest influence on treatment escalation. OFS use rose from 45% in pT1a tumors to 77% in pT1c, illustrating a stepwise intensification aligned with increasing tumor burden. Even more striking was the effect of nodal status. Chemotherapy plus OFS was selected in 50% of pN1 (1 node) cases, increasing to 76% in pN1 (3 nodes), and reaching >94% in pN2 disease even when genomic risk was low. This demonstrates that, despite increasing reliance on genomic profiling, clinical anatomic staging continues to anchor risk stratification, especially regarding decisions involving OFS and chemotherapy. These data confirm that, in real-world practice, nodal disease consistently outweighs genomic risk in determining endocrine therapy intensity.
3. Genomic risk (oncotype DX RS 31) amplifies, but does not displace, clinical risk factors
In scenarios involving high genomic risk (RS 31), clinicians escalated therapy as expected, frequently selecting OFS plus AI or OFS plus chemotherapy. However, the magnitude of escalation was lower than that observed with increasing nodal burden. For example, RS 31 increased OFS use in node-negative disease, but node-positive disease (regardless of RS) was met with far more aggressive treatment. This finding echoes previous observations from TAILORx and MINDACT trial results in which genomic risk refines but does not replace clinical judgment, particularly in young and node-positive populations [11,12]. Our results further indicate that clinicians intuitively prioritize nodal involvement and residual disease over genomic assays when selecting endocrine intensity.
4. Residual disease (Non-pCR) strongly influences OFS plus AI selection, especially in HER2+ tumors
Among HER2+ disease, the distinction between pCR and non-pCR after neoadjuvant therapy produced profound differences in endocrine treatment selection. While OFS plus AI remained common even after pCR, residual disease resulted in the overwhelming adoption of OFS plus AI (67%–77%), particularly in node-positive settings. This trend mirrors the clinical reality that non-pCR in HER2+ disease is a well-established surrogate of aggressive biology, motivating clinicians to intensify endocrine therapy despite the patient’s HER2-targeted therapy responsiveness.
5. Extended endocrine therapy (years 6–10) is characterized by de-escalation to TAM alone
Across all nodal and genomic strata—including RS 31 and pN2 disease— TAM alone was the predominant choice (61%–73%) for extended endocrine therapy. OFS-based extended treatment was selected in only 10%–30%. This consistent de-escalation demonstrates how significantly quality-of-life considerations, OFS-related toxicities, and long-term treatment burden influence recommendations in years 6–10. Even in high-risk biology cases, clinicians opt for strategies they consider tolerable, sustainable, and aligned with long-term survivorship. These findings align with prior studies demonstrating substantial discontinuation rates for OFS-based therapy due to vasomotor symptoms, sexual dysfunction, bone loss, and psychosocial distress. Our survey confirms that these real-world tolerability issues shape clinical decisions at least as strongly as oncologic risk.
6. Divergence between initial and extended therapy reflects a survivorship-centered approach
The contrast between aggressive OFS use during years 0–5 and conservative choices during years 6–10 illustrates nuanced therapeutic principles such as minimizing early recurrence risk through aggressive initial suppression, then reduce treatment burden to preserve survivorship quality and long-term adherence. This “front-loaded intensity followed by de-escalation” aligns with contemporary endocrine therapy guidelines but also highlights gaps in long-term OFS data. The lack of strong evidence supporting OFS beyond 5 years likely contributes to clinician reluctance for prolonged suppression.
7. Clinical factors dominate decisions in the highest-risk disease
In scenarios combining the most adverse features (e.g., HER2-, post-neoadjuvant ypN2, RS 31, young age), OFS plus AI was used in 88% of cases. This pattern underscores that clinicians rely primarily on clinical cues—nodal burden, residual disease, high Ki-67—when making high-stakes treatment decisions.
8. Strengths and implications of these findings
This study provides a detailed overview of how clinicians optimize endocrine therapy decision-making in premenopausal breast cancer. The scenarios capture a broad clinical spectrum, enabling nuanced pattern recognition such as OFS is widely used earlier and selectively continued later. Residual disease and high nodal burden induce maximal endocrine escalation. Survivorship concerns strongly influence extended therapy decisions. These results may inform development of risk-adapted OFS algorithms and identify areas where prospective trials are needed, particularly regarding appropriate OFS duration and integration with genomic biomarkers.
9. Limitations
First, this study relied on survey data, which reflects perceived best practice rather than actual treatment delivered. Second, this study was based on responses from 70 participants, which represents a limited proportion of the total membership of the KBCS. Therefore, caution is warranted when generalizing these findings to fully represent nationwide treatment patterns in Korea. Furthermore, the sample represents mainly Korean breast specialists, potentially limiting generalizability to other practice environments. Future studies involving a larger cohort are needed to validate these results. Nonetheless, the consistency of patterns across diverse scenarios suggests robust underlying clinical principles.
10. Future directions
More precise biomarkers are needed to guide OFS candidates, optimal OFS duration, optimal endocrine therapy partners, extended therapy strategies, risk stratification using integrated clinical and genomic biomarkers, and survivorship-sensitive endocrine regimens. Large prospective datasets incorporating ovarian recovery dynamics, patient-reported outcomes, and genomic-based prediction models may help resolve current uncertainties.
11. Conclusion
Across all nine scenarios, several consistent themes emerged. First, OFS is used aggressively in the first 5 years, driven primarily by young age, tumor size, nodal burden, high genomic risk (RS 31), and residual disease (non-pCR). Second, extended endocrine therapy (years 6–10) showed a pronounced shift toward TAM monotherapy, even for high-risk patients. Third, nodal burden was the strongest clinical driver of escalating endocrine therapy intensity. Fourth, residual disease after NAC had the most dramatic effect on increasing OFS plus AI use, particularly in HER2+ tumors. Lastly, clinicians consistently balanced efficacy with survivorship considerations, whereas early therapy tended toward intensification and extended therapy favored de-escalation.
Literature review
OFS represents a critical component in the management of HR+ breast cancer among premenopausal women. Estrogen is the primary mitogenic driver in HR+ disease, and the suppression of ovarian estrogen production induces a state of biochemical menopause that deprives hormone-dependent tumors of proliferative stimuli. In premenopausal women, circulating estradiol concentrations are significantly higher than in postmenopausal women, produced directly by functioning ovaries [13]. Blocking ovarian estrogen production results in biochemical menopause, depriving HR+ tumors of proliferative signals. Because ovarian function often recovers following cytotoxic chemotherapy—particularly in younger women—the addition of OFS provides a biologically and clinically rational strategy to maintain endocrine suppression.
The efficacy of OFS has been consistently demonstrated in randomized clinical trials. The ASTRRA trial established that adding 2 years of OFS to TAM therapy significantly improved disease-free survival (DFS) among women who remained or resumed menstruation after chemotherapy [9]. In the SOFT and TEXT trials, the combination of an AI, exemestane, with OFS produced superior DFS and distant recurrence–free interval compared with TAM plus OFS only, with the greatest benefit observed in patients at higher clinical risk [14,15]. Long-term follow-up analyses, with a median of 13 years, confirmed durable reductions in recurrence and a significant overall survival advantage for high-risk patients treated with exemestane plus OFS [16,17].
Findings from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis further corroborate that OFS reduces recurrence risk in premenopausal HR+ disease, with the most pronounced benefit in high-risk subgroups [18]. However, the optimal duration of OFS remains undefined—5 years in SOFT/TEXT versus two years in ASTRRA—and data supporting prolonged therapy beyond 5 years are lacking. Current National Comprehensive Cancer Network, St. Gallen consensus, and European Society for Medical Oncology guideline recommendations endorse 2 to 5 years of OFS combined with endocrine therapy for premenopausal women at high clinical risk, such as those of younger age, with high-grade tumors or nodal involvement [19-21]. At the St Gallen International Breast Cancer Consensus conference, the panel was more inclined to recommend OFS in younger women, while also noting the importance of patient preferences here as OFS carries more substantial patient-reported side effects [22].
For premenopausal women who meet the criteria for adjuvant chemotherapy for ER-positive cancers, the panel also recommended OFS. Consistent with our results, the panel favored OFS in stage II or higher breast cancer, particularly among women younger than 40 years of age, and those with higher grade, higher Ki-67, or higher risk genomic signatures, emphasizing that patient preference should play a critical role given the symptomatic burden of induced menopause.
Despite clear efficacy, predictive biomarkers to guide patient selection for OFS remain unavailable. Established genomic assays—such as Oncotype DX, MammaPrint, EndoPredict and PAM50 ROR—are prognostic and predictive for chemotherapy benefit but have not been validated to predict OFS responses [23]. Notably, the Breast Cancer Index (BCI) has demonstrated that premenopausal patients with a low BCI score may derive greater benefit from more intensive endocrine therapy—specially adjuvant exemestane or TAM combined with OFS— compared with TAM alone, as validated in the combined TEXT and SOFT cohort [24]. This finding suggests that genomic markers may help refine patient selection for intensified endocrine strategies in premenopausal HR+ disease.
The integration of OFS with endocrine therapy in HR+, HER2+ disease remains controversial. Subgroup analyses from SOFT suggested greater benefit from OFS with AI among patients with HR+, HER2+ subtype than HR+, HER2-disease [25]. In contrast, the EBCTCG patient-level meta-analysis showed a trend favoring TAM plus OFS over AI plus OFS in premenopausal women with HER2+ subtype. Using AI rather than TAM in premenopausal women receiving OFS reduces the risk of breast cancer recurrence by up to 21%. Reduction in distant recurrence up to 17% was shown regardless of lymph node status, but with more significant benefit in lymph node-positive and age <45 years. There was no increase in non-breast cancer deaths but more fractures in women receiving AI [26]. The meta-analysis provides further evidence for differential benefit from upfront AI versus TAM treatment between HER2+ and HER2-in HR+ premenopausal early breast cancer patients. These results reflect biological heterogeneity and underscore the need for further investigation to optimize endocrine strategies involving this subset.
In conclusion, OFS remains a cornerstone of adjuvant endocrine therapy for premenopausal women with HR+ breast cancer, particularly those at elevated risk of recurrence. The combination of endocrine therapy plus OFS provides the most robust evidence for recurrence reduction, although the optimal duration, optimal endocrine therapy partner, and patient selection criteria warrant further refinement. Future research should focus on integrating genomic and clinical predictors to personalize OFS, maximize benefits, and mitigate treatment-related toxicity.
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