Abstract
Background
Estrogen receptor (ER)-negative early breast cancer (eBC) generally derives greater benefit from adjuvant chemotherapy than ER-positive disease, but the predictive role of ER expression levels for dose-dense (DD) chemotherapy remains uncertain. This exploratory analysis of the GIM2 phase III trial evaluated whether ER expression influences the efficacy of DD chemotherapy in node-positive eBC.
Methods
In the GIM2 trial, patients with node-positive eBC were randomized to receive anthracycline-based chemotherapy followed by paclitaxel, administered either in a DD or standard-interval schedule. ER expression was categorized as ER 0, ER-low (1–10%), ER-intermediate (11–50%), and ER-high (>50%). Associations between ER levels and invasive disease-free survival (iDFS) and overall survival (OS) were evaluated using multivariable Cox models. Treatment effects across the continuum of ER expression were explored using STEPP.
Results
Among 1709 eligible patients, 150 (9%) had ER 0, 78 (4%) ER-low, 283 (17%) ER-intermediate, and 1198 (70%) ER-high tumors. After a median follow-up of 15 years (IQR 8–16), 15-year iDFS rates were 48%, 59%, 56%, and 59%, respectively (p = 0.001). Corresponding 15-year OS rates were 72%, 71%, 68%, and 75% (p < 0.001). ER expression was independently associated with both iDFS and OS; however, no significant interaction was observed between ER levels and treatment effect for either endpoint. STEPP analyses demonstrated a consistent benefit of DD chemotherapy across the spectrum of ER expression.
Conclusions
ER expression levels were prognostic, but quantitative ER expression did not identify a subgroup with a clearly differential benefit from DD chemotherapy. Given the exploratory nature of this analysis and the small size of the ER-0 and ER-low subgroups, these hypothesis-generating findings are consistent with DD chemotherapy remaining an effective adjuvant treatment option for patients with node-positive eBC across the range of ER expression.
Keywords: Breast cancer, Dose-dense chemotherapy, Hormone receptor positive, Estrogen receptor levels
Graphical abstract
Highlights
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Over 1700 patients with early breast cancer were followed for 15 years.
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Estrogen receptor expression was prognostic for long-term survival.
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Dose-dense chemotherapy benefit was consistent across all ER levels.
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No ER cut-off predicted greater benefit from dose-dense chemotherapy.
1. Introduction
Breast cancer is a biologically heterogeneous disease comprising multiple molecular subtypes that differ in their natural history, prognosis, and response to systemic therapies. In patients with early-stage breast cancer, treatment decisions are guided by a comprehensive risk stratification process that integrates tumor- and patient-related characteristics. Key prognostic and predictive factors include tumor size, histological grade, lymph node involvement, hormone receptor status (including estrogen receptor [ER] and progesterone receptor [PgR]), HER2 status, proliferation markers, and multigene expression assays. These parameters help estimate the individual risk of recurrence and guide the selection of optimal adjuvant or neoadjuvant systemic treatments according to current international clinical practice guidelines [1,2], balancing therapeutic benefits with potential toxicity.
Chemotherapy remains the cornerstone of adjuvant treatment for patients deemed at high clinical or genomic risk of recurrence. Among chemotherapy strategies, dose-dense chemotherapy, defined by shortened intervals between treatment cycles, has emerged as a superior approach compared to standard-schedule regimens. The rationale for dose-dense therapy is based on mathematical models of tumor cell kinetics, suggesting that shorter treatment intervals may limit tumor cell regrowth between cycles and enhance the cytotoxic efficacy. A landmark individual patient-level meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), involving 37,298 patients across 26 randomized clinical trials, demonstrated that dose-intensified regimens, either through shortened intervals (every two weeks vs. every three weeks) or sequential administration of chemotherapy agents, were associated with significant reductions in breast cancer recurrence and mortality, without an increase in non-breast cancer-related deaths [3]. Importantly, the proportional benefits of dose-dense chemotherapy appeared consistent across the ER-positive and ER-negative subgroups, although the absolute benefit was slightly greater in ER-negative disease.
Despite these findings, the impact of dose-dense chemotherapy in relation to levels of ER expression remains unclear. Growing evidence indicates that low ER expression (1–10%) [4] may represent a distinct biological subgroup, with clinical behavior and treatment responsiveness more similar to ER-negative tumors than to strongly ER-positive tumors. However, most trials to date have not stratified outcomes by ER expression levels beyond the conventional positive/negative dichotomy.
To address this knowledge gap, the present study aimed to investigate the effects of dose-dense chemotherapy compared to standard-interval chemotherapy according to ER expression categories, with a particular focus on invasive disease-free survival (iDFS) and overall survival (OS). This analysis was conducted within the context of the Gruppo Italiano Mammella 2 (GIM2) randomized phase III trial, which evaluated the efficacy of dose-dense versus standard-schedule adjuvant chemotherapy in patients with high-risk, early-stage breast cancer [5]. By examining outcomes across quantitative ER expression categories in a large, randomized trial with 15 years of follow-up, this study aims to determine whether quantitative ER expression level represents a predictive biomarker for dose-dense chemotherapy benefit, thereby contributing to the refinement of patient selection for this treatment approach.
2. Patients and methods
2.1. Study design and procedures
The GIM2 trial, which has been described in detail previously [5], was a multicenter, open-label, randomized phase III trial that enrolled patients with invasive early breast cancer and at least one axillary lymph node metastasis. The primary objective of this study was to determine whether the fluorouracil, epirubicin, and cyclophosphamide (FEC) regimen followed by paclitaxel (FEC-P) would improve disease-free survival (DFS) compared to the same regimen without fluorouracil (EC-P), and whether a dose dense every 2 weeks (DD) schedule would improve DFS compared to standard every 3 weeks (SI) schedule. Eligible participants were randomly assigned to one of the following adjuvant chemotherapy regimens: (1) SI FEC-P, (2) SI EC-P, (3) DD FEC-P, or (4) DD EC-P. Following the completion of chemotherapy, patients with HR-positive breast cancer received endocrine therapy according to local guidelines. HR-positive tumors were defined locally by the presence of at least 10% of tumor cells exhibiting positive staining for either estrogen receptor (ER) or PgR through immunohistochemical analysis. In accordance with the criteria universally adopted at the time, HER2 overexpression was defined as either the presence of at least 10% of tumor cells exhibiting positive staining for HER2 protein via immunohistochemistry (IHC) or the presence of ERBB2 gene amplification documented by in situ hybridization assay [6].
2.2. Objectives and endpoints
This exploratory analysis aimed to assess whether the degree of ER positivity assessed by IHC was associated with different proportional benefits of DD chemotherapy. For this purpose, patients were categorized into four groups according to ER expression level: ER staining 0% (negative, ER-0), ER staining 1-10% (ER-low), ER staining 11-50% (ER-intermediate), and ER staining > 50% (ER-high). The iDFS and OS were the main and secondary endpoints of this exploratory analysis, respectively. iDFS was calculated from the date of randomization to the date of local recurrence, distant metastases, contralateral or ipsilateral invasive breast tumor (excluding ductal carcinoma in situ), second primary malignancy, or death from any cause, whichever occurred first. OS was calculated from the date of randomization to the date of death from any cause.
2.3. Statistical analysis
The statistical assumptions of the GIM2 primary objective have been described elsewhere [5]. The present analysis was not planned in the trial protocol, and the statistical power was not pre-specified. Accordingly, no formal sample size or power calculation was defined a priori for the comparisons across the four ER-expression categories, and no post-hoc power calculation was performed, since its interpretation would depend on assumptions regarding an effect size that had not been prespecified. For this analysis, we compared the two DD arms with the two SI arms, regardless of the receipt of fluorouracil. iDFS and OS were calculated as in the main GIM2 trial [5,7].
The association between variables was evaluated using Kruskal-Wallis test in continuous variables and Pearson's Chi-Squares test in categorical variables. The reverse Kaplan-Meier method was used to estimate the median follow-up and interquartile range (IQR). iDFS and OS probabilities were estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival probabilities. The survival probabilities of the ER-negative, ER-low, ER-intermediate, and ER-high cohorts were first compared overall and then separately to compare patients allocated to the SI and DD arms. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CI) were calculated using the Cox proportional hazards regression model. The results were fitted to a multivariable model that accounted for age, body mass index (BMI), type of surgery, histology, HER2 status, tumor grade, nodal status, and treatment. This covariate set was prespecified before any examination of the results, based on the established clinical and prognostic relevance of these variables in early breast cancer and on consistency with the adjustment set used in the primary analysis of the trial. Menopausal status and tumor size were available in the dataset but were not part of the prespecified covariate set; their exclusion was therefore driven neither by missing data nor by inspection of their association with the outcomes or with ER expression. To assess the difference in DD efficacy between cohorts, an interaction term was introduced in each survival model (iDFS and OS), accounting for the modification of the magnitude of the treatment effect between the ER-negative, ER-low, ER-intermediate, and ER-high cohorts. All statistical analyses were conducted on the intention-to-treat population. Treatment effect according to continuous ER levels was evaluated using Subpopulation Treatment Effect Pattern Plots (STEPP) [8]. Statistical significance of HRs was assessed using the likelihood ratio test. All statistical tests were two-sided and p-values < 0.05 were considered statistically significant. All analyses were performed using STATA 17 (Stata-Corp. 2017. Stata Statistical Software: Release 17. College Station, TX: StataCorp LP) and R version 4.3.1.
3. Results
3.1. Patient characteristics
Of the 2091 patients randomized in the GIM2 trial, 88 patients enrolled in five centers that provided only the standard-interval schedule were not included in the intention-to-treat population for the comparison of dose-dense versus standard-interval chemotherapy, leaving 2003 patients (1002 assigned to dose-dense and 1001 to standard-interval chemotherapy). Of these, 294 patients (14.7%) had unknown ER status and could not be classified according to the ER-expression categories investigated in the present analysis; the final analytical population therefore comprised 1709 patients (Fig. 1). A comparison of baseline characteristics performed in the whole population of 2003 patients, including ER-unknown as a separate category, yielded results broadly consistent with those observed in the 1709 patients included here, suggesting that the exclusion of patients with unknown ER status did not substantially alter the distribution of baseline characteristics across ER-expression categories.
Fig. 1.
CONSORT diagram of the present exploratory analysis of the GIM2 trial.
In this analysis of 1709 breast cancer patients from the GIM2 trial, patients were stratified according to ER expression into four groups: ER-negative (ER-0), ER-low (1–10%), ER-intermediate (11–50%), and ER-high (>50%). Among these patients, 150 (8.8%) had ER-negative tumors, 78 (4.6%) had ER-low tumors (1–10%), 283 (16.6%) had ER-intermediate tumors (11–50%), and 1198 (70.1%) had ER-high tumors (>50%). The distribution of patients and tumor characteristics in the four cohorts is described in Table 1. The median age at diagnosis was 51.8 years (IQR: 44.0–59.3), with a lower median age observed in patients with ER-intermediate tumors. Overall, 49.3% of patients were premenopausal, with a higher proportion of premenopausal patients in the ER-intermediate group (60.8%; p < 0.001). The body mass index (BMI) distribution did not significantly differ among the ER groups (p = 0.844). Most patients underwent lumpectomy (61.4%), although mastectomy was more frequent in the ER-intermediate group (44.5%; p = 0.063). Most tumors were of ductal histology (79.8%) and HER2-negative (66.8%); however, HER2 positivity was significantly more common in the ER-negative and ER-low groups (p < 0.001). Tumor size and nodal status were similarly distributed across groups, whereas high-grade tumors (G3) were predominantly found in ER-negative cases (80.0%; p < 0.001). Adjuvant endocrine therapy was administered most frequently to patients with higher ER expression. Tamoxifen and aromatase inhibitors were the most frequently used agents in the ER-positive subgroups. Supplementary Table S1 provides a detailed comparison of the clinicopathological characteristics between ER-0 and ER-low breast cancers. No statistically significant differences were observed in the age at diagnosis, menopausal status, BMI, type of surgery, tumor size, or nodal status. However, ER-low tumors demonstrated a higher prevalence of lobular histology (p = 0.023) and a lower proportion of high-grade (p = 0.002) and HER2-positive (p = 0.041) tumors than ER-negative tumors. As expected, 82.0% of ER-0 patients received no endocrine therapy, whereas most ER-low patients were treated with tamoxifen and/or aromatase inhibitors. Among the 27 ER-0 patients who received endocrine therapy, 77.8% were PgR-positive.
Table 1.
Clinicopathological characteristics of the overall cohort of patients.
| All patientsa N = 1709 (%) |
ER-0 N = 150 (%) |
ER-low (1-10%) N = 78 (%) |
ER-intermediate (11-50%) N = 283 (%) |
ER-high (>50%) N = 1198 (%) |
p | |
|---|---|---|---|---|---|---|
| Median age at diagnosis (years, IQR) | 51.8 (44.0 - 59.3) | 52.7 (42.1 - 59.3) | 49.4 (42.9 - 56.6) | 48.4 (41.8 - 57.0) | 52.7 (45.2 - 60.0) | <0.001 |
| Menopausal status | <0.001 | |||||
| Premenopausal | 842 (49.3) | 70 (46.7) | 42 (53.9) | 172 (60.8) | 558 (46.6) | |
| Postmenopausal | 867 (50.7) | 80 (53.3) | 36 (46.2) | 111 (39.2) | 640 (53.4) | |
| Unknown | 0 | 0 | 0 | 0 | 0 | |
| BMI | 0.84 | |||||
| Underweight (<18.5) | 27 (1.6) | 2 (1.3) | 1 (1.3) | 4 (1.4) | 20 (1.7) | |
| Normal weight (18.5 - 24.9) | 782 (45.8) | 64 (42.7) | 30 (38.5) | 133 (47.0) | 555 (46.3) | |
| Overweight (25.0 - 29.9) | 537 (31.4) | 50 (33.3) | 32 (41.0) | 93 (32.9) | 362 (30.2) | |
| Obese (≥30) | 326 (19.1) | 29 (19.3) | 13 (16.7) | 47 (16.6) | 237 (19.8) | |
| Unknown | 37 (2.2) | 5 (3.3) | 2 (2.6) | 6 (2.1) | 24 (2.0) | |
| Surgery | 0.06 | |||||
| Mastectomy | 659 (38.6) | 48 (32.0) | 28 (35.9) | 126 (44.5) | 457 (38.2) | |
| Lumpectomy | 1050 (61.4) | 102 (68.0) | 50 (64.1) | 157 (55.5) | 741 (61.9) | |
| Histologic type | 0.001 | |||||
| Ductal | 1364 (79.8) | 130 (86.7) | 66 (84.6) | 230 (81.3) | 938 (78.3) | |
| Lobular | 236 (13.8) | 7 (4.7) | 10 (12.8) | 32 (11.3) | 187 (15.6) | |
| Other | 109 (6.4) | 13 (8.7) | 2 (2.6) | 21 (7.4) | 73 (6.1) | |
| Unknown | 0 | 0 | 0 | 0 | 0 | |
| HER2 status | <0.001 | |||||
| Negative | 1142 (66.8) | 80 (53.3) | 39 (50.0) | 174 (61.5) | 849 (70.9) | |
| Positive | 362 (21.2) | 63 (42.0) | 28 (35.9) | 81 (28.6) | 190 (15.9) | |
| unknown | 205 (12.0) | 7 (4.7) | 11 (14.1) | 28 (9.9) | 159 (13.3) | |
| Tumor size (T) | 0.08 | |||||
| pT1 | 891 (52.1) | 80 (53.3) | 41 (52.6) | 124 (43.8) | 646 (53.9) | |
| pT2 | 693 (40.6) | 61 (40.7) | 30 (39.5) | 132 (46.6) | 470 (39.2) | |
| pT3/4 | 119 (7.0) | 9 (6.0) | 6 (7.7) | 27 (9.5) | 77 (6.4) | |
| Unknown | 6 (0.4) | 0 (0.0) | 1 (1.3) | 0 (0.0) | 5 (0.4) | |
| Nodal status (N) | 0.62 | |||||
| N1 | 1039 (60.8) | 88 (58.7) | 43 (55.1) | 167 (59.0) | 741 (61.9) | |
| N2 | 424 (24.8) | 39 (26.0) | 26 (33.3) | 71 (25.1) | 288 (24.0) | |
| N3 | 246 (14.4) | 23 (15.3) | 9 (11.5) | 45 (15.9) | 169 (14.1) | |
| Unknown | 0 | 0 | 0 | 0 | 0 | |
| Tumor grading (G) | <0.001 | |||||
| G1 | 112 (6.6) | 1 (0.7) | 5 (6.4) | 21 (7.4) | 85 (7.1) | |
| G2 | 811 (47.5) | 26 (17.3) | 25 (32.1) | 118 (41.7) | 642 (53.6) | |
| G3 | 739 (43.2) | 120 (80.0) | 46 (59.0) | 136 (48.1) | 437 (36.5) | |
| Unknown | 47 (2.8) | 3 (2.0) | 2 (2.6) | 8 (2.8) | 34 (2.8) | |
| Treatment received | NA | |||||
| Standard-interval chemotherapy | 847 (49.6) | 76 (50.7) | 38 (48.7) | 139 (49.1) | 594 (49.6) | |
| Dose-dense chemotherapy | 862 (50.4) | 74 (49.3) | 40 (51.3) | 144 (50.9) | 604 (50.4) | |
| Adjuvant endocrine therapy | NA | |||||
| None | 213 (12.5) | 123 (82.0) | 18 (23.1) | 15 (5.3) | 57 (4.8) | |
| Tamoxifen only | 686 (40.1) | 16 (10.7) | 21 (26.9) | 139 (49.1) | 510 (42.6) | |
| Aromatase inhibitors | 401 (23.5) | 5 (3.3) | 26 (33.3) | 71 (25.1) | 299 (25.0) | |
| Tamoxifen → aromatase inhibitors | 409 (23.9) | 6 (4.0) | 13 (16.7) | 58 (20.5) | 332 (27.7) | |
| Unknown | 0 | 0 | 0 | 0 | 0 |
Abbreviations: HER2, human epidermal growth factor receptor 2; IQR, interquartile range; p, p-value derived from Kruskal-Wallis test in continuous variables and Pearson's Chi-Squared in categorical variables. Patients with ER 0 tumors who received adjuvant endocrine therapy exhibited positive progesterone receptor expression.
From the 2091 patients enrolled in the GIM2 trial: 88 patients randomized in 5 centers providing only standard interval chemo and 294 patients with ER status missing were excluded from the present analysis.
3.2. Invasive disease-free survival
At a median follow-up of 15.0 years, iDFS outcomes differed significantly according to ER expression level (p = 0.001; Supplementary Fig. S1, Supplementary Table S2). Patients with ER-high tumors demonstrated the most favorable long-term iDFS, with 7- and 15-year iDFS rates of 78.8% and 59.3%, respectively. In contrast, ER-negative patients had the poorest outcomes, with corresponding iDFS rates of 61.4% and 48.1%, respectively. ER-low tumors showed intermediate outcomes, with 7- and 15-year iDFS rates of 75.3% and 58.8%, respectively. The cumulative incidence of iDFS events was highest for distant recurrences, accounting for 21.0% of all events, followed by second primary non-breast malignancies (3.7%) and local recurrences (3.4%), respectively (Supplementary Table S3). Notably, ER-low and ER-high tumors demonstrated a significantly reduced risk of developing an iDFS event compared to ER-negative cases (aHR: 0.61; 95% CI: 0.39–0.95 and aHR: 0.61; 95% CI: 0.47–0.79, respectively) (Table 2).
Table 2.
Multivariable Cox regression analyses for iDFS and OS.
| Variable | iDFS HR | iDFS 95% CI | p | OS HR | OS 95% CI | p |
|---|---|---|---|---|---|---|
| ER categories | ||||||
| ER-0 | Ref. | |||||
| ER-low | 0.61 | 0.39 – 0.95 | 0.002 | 0.97 | 0.56 – 1.69 | 0.02 |
| ER-intermediate | 0.78 | 0.57 – 1.05 | 1.08 | 0.72 – 1.62 | ||
| ER-high | 0.61 | 0.47 – 0.79 | 0.73 | 0.51 – 1.05 | ||
Abbreviations: iDFS, invasive disease-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval. Model adjusted for: ER group, age, BMI, surgery type, histology, HER2 status, tumor grade, nodal status, treatment.
3.3. Overall survival
Overall survival (OS) varied significantly according to the ER expression levels (Supplementary Fig. S2, Supplementary Table S2). Patients with ER-high tumors had the most favorable prognosis, with a 15-year OS of 74.9% (95% CI: 71.8–77.7) and a significantly reduced risk of death compared with ER-negative patients (aHR: 0.73; 95% CI: 0.51–1.05). In contrast, patients with ER-low tumors exhibited 15-year OS rates (71.5%; 95% CI: 58.2–81.3) comparable to those of ER-negative patients (72.3%; 95% CI: 63.8–79.2), with no significant difference in hazard ratio (aHR: 0.97; 95% CI: 0.56–1.69) (Table 2).
3.4. Effect of chemotherapy schedule by ER expression
No significant interaction was observed between ER levels and treatment effect for either iDFS (p for interaction = 0.380) or OS (p for interaction = 0.440), suggesting a consistent treatment benefit across ER subgroups (Table 3). However, the subgroup-specific hazard ratios revealed differential trends. For iDFS, patients with ER-negative (HR, 0.70; 95% CI, 0.44–1.12) and ER-low (HR, 0.60; 95% CI, 0.28–1.28) tumors appeared to derive more benefit from the dose-dense regimen than those with higher ER expression (ER-intermediate: HR, 1.05; 95% CI, 0.73–1.51; ER-high: HR, 0.77; 95% CI, 0.63–0.93). Similar patterns were observed for OS. Indeed, the benefit of dose-dense chemotherapy appeared more pronounced in ER-negative (HR: 0.65; 95% CI: 0.34–1.25) and ER-low patients (HR: 0.46; 95% CI: 0.19–1.12), while limited benefit was observed in ER-positive subgroups with intermediate (HR: 0.98; 95% CI: 0.62–1.54) and high ER expression (HR: 0.75; 95% CI: 0.58–0.97). These findings suggest a potential trend toward greater benefits from dose-dense chemotherapy in tumors with lower ER expression, although no statistically significant interaction was detected. A STEPP analysis was further performed to evaluate the impact of chemotherapy schedule (dose-dense versus standard-interval) on iDFS and OS across different levels of ER expression. For iDFS (Fig. 2), 15-year iDFS rates were consistently higher in the dose-dense arm across all overlapping subpopulations, with hazard ratios oscillating around 0.7–0.8 throughout the ER spectrum and remaining below 1.0 across virtually all subpopulations. A broadly similar pattern was observed for OS (Fig. 3), with dose-dense survival rates consistently at or above those of the standard arm. Confidence intervals widened at the extremes of the ER distribution, reflecting smaller subpopulation sizes, but no threshold effect or systematic inflection point was identifiable at any specific level of ER expression in either analysis.
Table 3.
Effect of dose-dense versus standard-interval chemotherapy on iDFS and OS according to ER expression category.
| ER category | iDFS HR | iDFS 95% CI | iDFS interaction p∗ | OS HR | OS 95% CI | OS interaction pa |
|---|---|---|---|---|---|---|
| ER-0 | 0.70 | 0.44 – 1.12 | 0.38 | 0.65 | 0.34 – 1.25 | 0.44 |
| ER-low | 0.60 | 0.28 – 1.28 | 0.46 | 0.19 – 1.12 | ||
| ER-intermediate | 1.05 | 0.73 – 1.51 | 0.98 | 0.62 – 1.54 | ||
| ER-high | 0.77 | 0.63 – 0.93 | 0.75 | 0.58 – 0.97 |
Abbreviations: iDFS, invasive disease-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; ER, estrogen receptor.
Interaction p-value from multivariable Cox model testing the differential treatment effect across ER categories. HR < 1.0 favors dose-dense chemotherapy.
Fig. 2.
STEPP analysis of the effect of dose-dense versus standard-interval adjuvant chemotherapy on invasive disease-free survival (iDFS) across the continuum of ER expression. A) 15-year iDFS rates for the dose-dense (green) and standard-interval (yellow) arms across overlapping subpopulations ordered by median ER expression. B) Hazard ratios (dose-dense vs standard) with 95% confidence intervals across the same subpopulations. A hazard ratio below 1.0 favors dose-dense chemotherapy. The interaction p-value for ER expression and treatment effect was 0.38 for iDFS. Abbreviations: iDFS, invasive disease-free survival; ER, estrogen receptor; HR, hazard ratio; CI, confidence interval.
Fig. 3.
STEPP analysis of the effect of dose-dense versus standard-interval adjuvant chemotherapy on overall survival (OS) across the continuum of ER expression. A) 15-year OS rates for the dose-dense (green) and standard-interval (yellow) arms across overlapping subpopulations ordered by median ER expression. B) Hazard ratios (dose-dense vs standard) with 95% confidence intervals across the same subpopulations. A hazard ratio below 1.0 favors dose-dense chemotherapy. The interaction p-value for ER expression and treatment effect was 0.44 for OS. Abbreviations: OS, overall survival; ER, estrogen receptor; HR, hazard ratio; CI, confidence interval.
4. Discussion
In this exploratory analysis of the GIM2 trial, to our knowledge the largest randomized study to date evaluating quantitative ER expression as a predictive biomarker for dose-dense chemotherapy, we provide three main findings after a median follow-up of 15 years, the longest reported in this setting. First, ER expression measured by IHC remains a strong prognostic factor for both iDFS and OS, with ER-negative tumors showing the worst and ER-high tumors the most favorable long-term outcomes. Second, ER expression levels, analyzed both as categorical subgroups and as a continuous variable through STEPP, did not significantly influence the benefit of dose-dense scheduling (interaction p = 0.38 for iDFS and 0.44 for OS). Third, ER-low tumors displayed a distinctive clinical pattern, with iDFS rates similar to ER-high tumors but OS rates closer to ER-negative disease; given the small size of this subgroup, this observation should be regarded as hypothesis-generating.
The question of whether ER status affects the benefit of dose-dense chemotherapy has been debated for many years. Early meta-analyses suggested that the advantage of dose-dense scheduling might be restricted to ER-negative disease. For example, Bonilla et al. [9] reported a DFS advantage confined to receptor-negative patients, and Petrelli et al. [10] found an OS benefit only in ER-negative disease. In contrast, several randomized trials [[11], [12], [13], [14], [15]] did not confirm this interaction. More recently, the EBCTCG individual patient-level meta-analysis [3], showed that the proportional benefits of dose-intensified regimens were similar in ER-positive and ER-negative subgroups. Likewise, the 12-year update of the CALGB 9741 trial [16] confirmed the sustained long-term benefit of dose-dense chemotherapy regardless of ER status.
Our analysis aligns with this latter body of evidence and extends it by evaluating ER expression as a continuous quantitative variable with a 15-year follow-up. We found no clear evidence that the benefit of dose-dense chemotherapy varies across the full spectrum of ER expression, helping to clarify earlier conflicting results.
The directional pattern of hazard ratios across ER categories, showing a numerically greater benefit in ER-negative and ER-low tumors, is biologically consistent with the Norton–Simon Gompertzian model. This framework predicts that fast-growing tumors are more sensitive to shorter inter-cycle chemotherapy intervals, owing to reduced opportunity for cytotoxic-induced regrowth between cycles. However, this numerical trend did not reach statistical significance, and the results in the ER-intermediate group do not fully fit this model. These observations suggest that quantitative ER expression, as assessed by routine IHC, does not fully capture the biology relevant to treatment response.
The divergence between iDFS and OS observed in ER-low patients deserves attention. Although iDFS at 15 years was numerically comparable to ER-high disease (58.8% vs 59.3%), OS overlapped that of ER-negative patients (71.5% vs 72.3%), raising the hypothesis that recurrences in this subgroup may have a more aggressive biology, which the present analysis cannot demonstrate directly, as cause-specific mortality was not available. This observation is consistent with the expanding body of evidence showing that ER-low tumors behave more like ER-negative than ER-positive disease, including similar response rates and molecular features [[17], [18], [19], [20]]. In our analysis the dose-dense schedule produced the numerically largest OS benefit in ER-low patients (HR 0.46; 95% CI 0.19–1.12); this estimate, however, is based on only 78 patients and is imprecise, and should therefore be considered hypothesis-generating rather than evidence of a preferential benefit of intensified chemotherapy in this subgroup, in which endocrine therapy may be less effective.
Our finding that quantitative ER expression by IHC, whether categorical or continuous, does not predict differential benefit from dose-dense chemotherapy has important implications. A recent biomarker analysis of the C9741 [16] showed that several common biomarkers including ER status by IHC, PAM50 intrinsic subtypes, and risk of recurrence score (ROR-PT) score fail to predict dose-dense benefit. In contrast, the SETER/PR index, a measure of endocrine transcriptional activity, identifies a subgroup of ER-positive patients (SETER/PR < 0.75) who derive substantial OS benefit from dose-dense scheduling (interaction p = 0.030), whereas those with high endocrine transcriptional activity do not. Preliminary results from the GEICAM/9906 sub-study using the related SET2,3 index in the context of dose-dense paclitaxel [21] point in the same direction. Together with our data, these observations suggest that the biologically relevant axis of prediction is not how much ER protein is present, but how transcriptionally active the ER signaling pathway is within the tumor. Prospective validation of SETER/PR, ideally integrated with contemporary prognostic tools and dynamic biomarkers, is warranted and may ultimately refine patient selection for dose-dense chemotherapy in ER-positive disease.
Our results complement and extend two prior exploratory analyses of the GIM2 trial. Conte et al. [22] observed a numerically more pronounced dose-dense benefit in IHC-defined luminal B-like tumors (unadjusted DFS HR 0.72, 95% CI 0.54–0.96) than in luminal A-like disease (HR 0.89), without a statistically significant interaction. Puglisi et al. [23] demonstrated that the absolute benefit of dose-dense scheduling varied substantially with composite prognostic risk, with a number needed to treat as low as 6 in the highest-risk quartile. Taken together, these analyses suggest that the proportional benefit of dose-dense chemotherapy is broadly consistent across molecular and ER subgroups, whereas the absolute benefit scales with overall disease risk underscoring the importance of integrating multiple clinical and pathological factors when individualizing treatment decisions.
HER2-positive tumors accounted for 21.2% of the present cohort, and the GIM2 trial was conducted across the period in which adjuvant trastuzumab was introduced into clinical practice. In a previous exploratory analysis of the trial [24], among the 452 patients with HER2-positive breast cancer, 320 received chemotherapy alone and 132 received chemotherapy followed by trastuzumab. No significant interaction between HER2 status, trastuzumab use and chemotherapy schedule was observed for either DFS (p = 0.698) or OS (p = 0.708), although no apparent benefit of dose-dense chemotherapy was seen in HER2-positive patients who received adjuvant trastuzumab (DFS: HR 0.99, 95% CI 0.52–1.89; OS: HR 0.95, 95% CI 0.37–2.41). Since HER2-positive tumors were more frequent in the ER-0 and ER-low categories, the heterogeneous use of anti-HER2 therapy over time should be taken into account when interpreting the subgroup-specific estimates reported here.
Several limitations should be acknowledged. This was an unplanned exploratory analysis; all findings should therefore be considered hypothesis-generating. No formal power calculation was performed for the four ER-expression categories, and the analysis was not powered to detect an interaction between ER expression and treatment effect. ER expression was assessed locally rather than through central pathology review, introducing potential variability in quantification. In addition, 294 of the 2003 patients (14.7%) included in the dose-dense versus standard-interval comparison had unknown ER status and were excluded from the present analysis; although the distribution of baseline characteristics was broadly comparable, a potential selection bias related to missing ER information cannot be excluded and may limit the generalizability of our findings. The small sample sizes in the ER-negative (n = 150) and ER-low (n = 78) subgroups limit the precision of subgroup-specific estimates, and the absence of a significant ER-by-treatment interaction should not be interpreted as strict equivalence. Finally, the GIM2 trial predated the use of CDK4/6 inhibitors, although the question of chemotherapy scheduling remains relevant in the current clinical practice.
In conclusion, this 15-year exploratory analysis of the GIM2 trial shows that quantitative ER expression retains prognostic relevance but did not identify a subgroup with a clearly differential benefit from dose-dense adjuvant chemotherapy in node-positive early breast cancer. From a clinical standpoint, these hypothesis-generating findings are consistent with the use of a dose-dense schedule across the range of ER expression, including the biologically distinct ER-low subgroup, although the estimates in the smallest ER categories are imprecise and do not establish a preferential benefit in any subgroup. From a research standpoint, our results reinforce the need to move beyond IHC-based ER quantification towards biomarkers that capture endocrine transcriptional activity, to be evaluated in prospective studies.
CRediT authorship contribution statement
Carmine De Angelis: Writing – review & editing, Writing – original draft, Visualization, Methodology, Investigation, Data curation, Conceptualization. Alessandra Rosa: Writing – review & editing, Methodology, Formal analysis, Data curation. Virginia Delucchi: Writing – review & editing, Methodology, Formal analysis, Data curation. Francesca Poggio: Writing – review & editing, Data curation. Mario Giuliano: Writing – review & editing, Methodology. Michelino De Laurentiis: Writing – review & editing, Methodology. Anita Rimanti: Writing – review & editing. Anna Turletti: Writing – review & editing. Angela Vaccaro: Writing – review & editing. Alessandra Fabi: Writing – review & editing. Simona Gasparro: Writing – review & editing. Ornella Garrone: Writing – review & editing. Fabio Puglisi: Writing – review & editing. Barbara Cardinali: Writing – review & editing. Piero Fregatti: Writing – review & editing. Matteo Lambertini: Writing – review & editing. Luca Boni: Writing – review & editing, Methodology, Data curation. Eva Blondeaux: Writing – review & editing, Visualization, Validation, Software, Methodology, Formal analysis, Data curation. Lucia Del Mastro: Writing – review & editing, Supervision, Resources.
Ethics declaration
The authors have NOT obtained informed consent from participants or their legal representatives. This is a retrospective, exploratory analysis of previously collected, de-identified data from patients enrolled in the GIM2 trial. As no new data collection, patient contact, or intervention was involved, additional ethics committee approval was not required.
This study was performed in compliance with relevant laws, regulatory frameworks and guidelines where the research took place. Ethics committee approval was not required under relevant laws and institutional guidelines.
Data availability statement
The data that support the findings of this study are available on reasonable request to the Corresponding author, CDA.
Funding
No external funding was received to conduct this analysis.
Declaration of competing interest
CDA reports advisory role for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Gilead, Daiichi Sankyo, Menarini, Exact Sciences, and MSD and speaker honoraria from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Gilead, Daiichi Sankyo, Menarini, Exact Sciences, and MSD; Travel Grants from Gilead, Pfizer, Roche and research support (to the Institution) from Novartis, Gilead, and Daiichi Sankyo outside the submitted work. EB reports speaker fee from Eli Lilly and AstraZeneca, funding (to the institution) from Gilead Science. MdL reported stock and other Ownership Interests from Arvinas; honoraria from Roche, Novartis, Pfizer, Lilly, Pierre Fabre, AstraZeneca, MSD, Seagen, Gilead Sciences, Ipsen, Exact Sciences, TOMA Biosciences, Daiichi Sankyo Europe GmbH, Veracyte; consulting or Advisory Role from Roche, Novartis, Pfizer, Lilly, AstraZeneca, MSD, Pierre Fabre, Seagen, Gilead Sciences, Ipsen, Daiichi Sankyo Europe GmbH; speakers’ bureau from Novartis Research Funding: Novartis (Inst), Roche (Inst), Lilly, Pfizer (Inst), Daiichi Sankyo (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Genzyme (Inst), AstraZeneca (Inst). FPo reports advisory role for Pfizer and Roche, speaker honoraria from Eli Lilly, Novartis, AstraZeneca, Daichii Sankyo, Menarini, and Exact Sciences; travel grants from Novartis, Roche, Daichii Sankyo and Takeda. FP reported honoraria for advisory boards, activities as a speaker, travel grants, research grants from Astrazeneca, Bayer, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, Ipsen, Italfarmaco, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen. Research funding from Astrazeneca, Eisai, Roche. LDM reports advisory role for Lilly, Novartis, AstraZeneca, Pfizer, Gilead, Daiichi Sankyo, Menarini Stemline, Exact Sciences, Olema, Roche and MSD; speaker honoraria from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Gilead, Daiichi Sankyo, Menarini Stemline, Exact Sciences, and MSD; travel grants from Gilead, Roche, Daichii Sankyo, Menarini Stemline and AstraZeneca; research support (to the Institution) from Pfizer, Gilead and Roche outside the submitted work. MG reports advisory role for Lilly, Novartis, AstraZeneca, Pfizer, Gilead, Daiichi Sankyo, Menarini Stemline, Exact Sciences, Istituto Gentili and MSD; speaker honoraria from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Gilead, Daiichi Sankyo, Menarini Stemline, Exact Sciences, and MSD; travel grants from Gilead, Pfizer, Roche, Novartis, Daichii Sankyo and AstraZeneca; research support (to the Institution) from Daiichi Sankyo outside the submitted work. ML reports advisory role for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Gilead, MSD, Pierre Fabre, Menarini, Nordic Pharma, Bayer, Ipsen, Daiichi Sankyo; receiving speaker honoraria from Roche, Lilly, Novartis, Pfizer, AstraZeneca, Takeda, Ipsen, Sandoz, Libbs, Daiichi Sankyo, Gilead, Menarini; receiving travel grants from Gilead, Roche, Daiichi Sankyo; receiving research funding (to his institution) from Gilead; having other financial interests as JCO Consultant Editor, Chair of the ESO Certificate of Competence in Breast Cancer, all outside the submitted work. PF has received honoraria for lectures, advisory board participation, and/or consultancy from AstraZeneca, Merit Medical, MSD, Novartis, Polytech, and Sysmex. OG reports advisory role for Lilly, Exact Sciences, MSD, Daiichi-Sankyo, AstraZeneca, Gentili, Gilead; honoraria from Novartis, Pfizer, Lilly, Daiichi-Sankyo, Gilead; Travel grants from Daiichi-Sankyo, Novartis, Gilead, MSD; research support (to the Institution) from Gilead outside the submitted work. The other authors reported no conflict of interest.
Acknowledgements
The authors thank patients, physicians, nurses, and trial coordinators who participated in the GIM2 trial. We acknowledge Giovanni Cucchiara and Carlo Panzano of Clinical Research Technology, Salerno, Italy, for clinical record online management. The GIM group received financial support for trial conduct from Bristol-Myers Squibb and Pharmacia. Bristol-Myers Squibb provided paclitaxel and Dompè Biotech, Italy provided filgrastim. The funder did not play a role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.breast.2026.104942.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available on reasonable request to the Corresponding author, CDA.