Association of statin use with pathological complete response in postmenopausal patients with hormone receptor–positive breast cancer

Abstract

Hormone receptor-positive, HER2-negative breast cancer represents a significant subset of patients who often exhibit suboptimal responses to neoadjuvant chemotherapy (NACT). Identifying strategies to enhance chemosensitivity in this population is a clinical priority. In this study, we investigated the potential contribution of statin therapy to the efficacy of NACT. We retrospectively analyzed 60 patients treated between 2014 and 2025, comprising 22 statin users and 38 non-users. While the overall cohort analysis did not demonstrate a statistically significant difference in pCR rates, an exploratory postmenopausal subgroup analysis (performed because all statin users were postmenopausal) showed a higher pCR rate among statin users; this finding is hypothesis-generating and should be interpreted cautiously (31.8 vs. 5.0%, p = 0.047). In an exploratory multivariable logistic regression analysis limited by sparse events in the postmenopausal subgroup, statin use was associated with pCR after adjustment for Ki-67 proliferation index and clinical T stage; however, the estimate was imprecise and should be interpreted cautiously. Although pCR is not a validated surrogate for long-term survival in this specific subtype, our findings suggest that statins may biologically enhance short-term chemosensitivity, potentially through mevalonate pathway inhibition and modulation of the tumor microenvironment. These preliminary results support the need for larger prospective studies to further elucidate the role of statins as adjunctive agents in breast cancer management.

Introduction

Breast cancer is the most commonly diagnosed malignancy among women worldwide, and a substantial proportion of patients are candidates for neoadjuvant chemotherapy (NACT)¹. Among these, hormone receptor–positive, HER2-negative tumors represent the largest subgroup; however, they typically demonstrate lower rates of pathological complete response (pCR) compared with HER2-positive or triple-negative breast cancers^2,3. As a result, identifying factors that may enhance treatment sensitivity in this population remains an important clinical challenge⁴.

Statins, widely prescribed for cardiovascular disease prevention, have been increasingly investigated for their potential anti-cancer properties⁵. Although large randomized trials have not demonstrated a consistent reduction in overall cancer incidence or mortality with statin use, accumulating evidence suggests that statins may exert tumor-specific effects, particularly in breast cancer^6,7. Several observational studies and meta-analyses have reported associations between statin use and reduced recurrence or improved survival outcomes in breast cancer patients^8–10. These findings suggest that statins may influence tumor biology beyond lipid lowering, potentially through modulation of cholesterol metabolism, cell signaling pathways, and the tumor microenvironment.

In this context, the present study aimed to explore the association between statin use and pathological complete response (pCR) in patients with hormone receptor–positive, HER2-negative breast cancer receiving neoadjuvant chemotherapy. While pCR is not considered a validated surrogate for long-term survival in this subtype, it remains a clinically relevant indicator of short-term chemosensitivity and biological response to systemic therapy¹¹. Accordingly, our analysis focuses on the potential relationship between statin exposure and treatment response rather than on survival outcomes.

By examining this association, we aim to contribute to a better understanding of the potential biological and therapeutic relevance of statins in hormone receptor–positive breast cancer and to generate hypotheses for future prospective studies evaluating their role as adjunctive agents in systemic treatment strategies.

Methods

Study population

This retrospective study included adult patients (≥ 18 years) diagnosed with hormone receptor–positive, HER2-negative breast cancer who received NACT at Kütahya Evliya Çelebi Training and Research Hospital and Kütahya City Hospital between 2014 and 2025.

Eligible patients were required to have complete clinical, pathological, and treatment-related data available in institutional medical records. Patients were included if they received all components of their neoadjuvant treatment and subsequent surgery at the study centers.

Patients were excluded from the study if they had HER2-positive disease, evidence of metastatic disease at diagnosis, inflammatory breast cancer, or had received prior systemic therapy for breast cancer. In addition, patients with incomplete clinical or pathological data, those who did not complete neoadjuvant treatment followed by surgery at the study institutions, and those whose medical records lacked sufficient information for response assessment were excluded from the analysis. Patients receiving statin therapy initiated after the start of neoadjuvant chemotherapy were also excluded to avoid potential confounding related to treatment timing.

Patients were categorized according to statin exposure at the time of initiation of neoadjuvant chemotherapy. Importantly, statin therapy was not initiated for study purposes; all statin users had been receiving treatment prior to cancer diagnosis.

Pathological and clinical assessment

Tumor characteristics including histologic grade, estrogen receptor (ER), progesterone receptor (PR), HER2 status, and Ki-67 proliferation index were assessed using pretreatment core biopsy specimens by institutional pathologists.

ER and PR expression were categorized as < 1%, 1–9%, or ≥ 10%. HER2 status was determined according to standard immunohistochemical criteria, with equivocal (2+) cases undergoing fluorescence in situ hybridization (FISH). The Ki-67 index was classified into predefined ranges (0–2.7%, 2.8–7.3%, 7.4–19.7%, 19.8–53.1%, and > 53.2%).

Radiologic and response assessment

Baseline clinical staging was performed using physical examination and imaging modalities including ultrasonography, computed tomography, and positron emission tomography–computed tomography, as clinically indicated.

Treatment response was evaluated based on changes in tumor size and categorized as complete response, partial response, stable disease, or progressive disease. pCR was defined as the absence of residual invasive tumor in both the breast and axillary lymph nodes.

Statistical analysis

All statistical analyses were performed using IBM SPSS Statistics (version 25.0; IBM Corp., Armonk, NY, USA). Continuous variables were summarized as means with standard deviations or medians, while categorical variables were expressed as frequencies and percentages.

Comparisons between categorical variables were performed using the chi-square test or Fisher’s exact test, as appropriate. For contingency tables with small expected cell counts or tables larger than 2 × 2, the Fisher–Freeman–Halton exact test was applied to ensure accurate estimation of statistical significance.

To evaluate factors associated with pathological complete response (pCR), an exploratory multivariable logistic regression analysis was conducted. The model included clinically relevant variables (statin use, Ki-67 index, and clinical T stage). Given the limited number of events, the multivariable analysis was considered exploratory, and results were interpreted with caution. In the postmenopausal subgroup, only eight pCR events were observed; therefore, the events-per-variable ratio was low and the model was susceptible to overfitting and sparse-data bias. To mitigate this risk, we limited the model to a small number of a priori clinically relevant predictors and interpret the adjusted estimates as hypothesis-generating rather than confirmatory.

All tests were two-sided and p-values are reported; given the exploratory nature, p-values were interpreted descriptively alongside effect sizes and 95% confidence intervals.

Results

Patient characteristics and comparison according to statin use

A total of 60 patients with hormone receptor–positive, HER2-negative breast cancer who received neoadjuvant chemotherapy were included in the analysis. Among these, 22 patients (36.7%) were receiving statin therapy at the time of treatment initiation, while 38 patients (63.3%) were not. The majority of patients were postmenopausal (70.0%), and most had an Eastern cooperative oncology group (ECOG) performance status of 0. Baseline demographic and clinicopathologic characteristics are summarized in Table 1.

Table 1.

Clinical characteristics of the study population.

Characteristic	Number	Percentage (%)
Menopausal status
Premenopausal	18	30
Postmenopausal	42	70
ECOG performance status
0	52	86.6
1	8	13.4
Tumor grade
1	17	28.3
2	25	41.6
3	18	30
Ki-67
0-2.7	8	13.3
2.8–7.3	24	40
7.4–19.7	16	26.6
19.8–53.1	10	16.6
> 53.2	2	3.3
Clinical lymph node
Negative	8	13.3
Positive	52	86.6
Clinical T stage
T1	5	8.3
T2	35	58.3
T3	15	25
T4	5	8.3
Clinical N stage
N0	6	10
N1	25	41.6
N2	27	45
N3	2	3.3
Estrogen receptor
1–9%	17	27.9
≥ 10%	44	72.1
Progesteron receptor
Negative	10	16.6
1–9%	12	20
≥ 10%	38	63.3
Treatments received
AC + Taxane	46	76.7
TC	14	23.3
Statin
Receiving	22	36.7
Not receiving	38	63.3

Values are presented as number (percentage).

ECOG: Eastern Cooperative Oncology Group; AC: Adriamycin + Cyclophosphamide; TC: Docetaxel + Cyclophosphamide.

Regarding tumor characteristics, 28.3% of patients had grade 1 disease, 41.6% had grade 2 disease, and 30.0% had grade 3 disease. Lymph node involvement was observed in 86.6% of patients, and 58.3% had T2-stage tumors. Estrogen receptor expression ≥ 10% was present in 72.1% of cases, and progesterone receptor expression ≥ 10% in 63.3%.

When comparing patients receiving statin therapy with those not receiving statins, no statistically significant differences were observed in baseline clinicopathologic characteristics, including tumor grade, Ki-67 index, clinical T stage, nodal status, or hormone receptor expression (Table 2). Because this is a small retrospective cohort, the absence of statistically significant differences in baseline characteristics should not be interpreted as evidence of clinical equivalence between groups; residual imbalance in prognostic factors may remain.

Table 2.

Clinical characteristics of patients receiving and not receiving statin therapy.

Characteristic	Receiving (N-%)	Not receiving (N-%)	p value
Grade			0.38
1	6 (27.2%)	6 (15.7%)
2	11 (50%)	19 (50%)
3	5 (22.7%)	13 (34.2%)
Ki-67			0.11
0-2.7	5 (22.7%)	3 (7.8%)
2.8–7.3	11 (50%)	13 (34.2%)
7.4–19.7	4 (18.2%)	14(36.8%)
19.8–53.1	2 (9%)	6 (15.7%)
≥ 53.2	0 (0%)	2 (5.2%)
Clinical T stage			0.29
T1	3 (13.6%)	3 (7.9%)
T2	7 (31.8%)	23 (60.5%)
T3	11 (50%)	8 (21%)
T4	1(4.5%)	4 (10.5%)
Clinical N stage			0.27
N0	1 (4.5%)	6 (15.7%)
N1	6 (27.2%)	18 (47.3%)
N2	14 (63.6%)	13 (34.2%)
N3	1 (4.5%)	1 (2.6%)
Estrogen receptor			0.22
1–9%	4 (18.2%)	13 (34.2%)
≥ 10%	18 (81.8%)	25 (65.8%)
Progesterone receptor			0.41
Negative	5 (22.7%)	15 (39.4%)
1–9%	5 (22.7%)	7 (18.4%)
≥ 10%	12 (54.5%)	16 (42.1%)

Values are presented as number (percentage).

Comparisons between groups were performed using the chi-square test or Fisher–Freeman–Halton exact test, as appropriate.

P-values are reported and should be interpreted descriptively given the exploratory nature and small sample size.

Radiologic and pathologic response

Radiologic response rates are summarized in Table 3. Among patients receiving statin therapy, 5 achieved a complete response, 14 a partial response, and 3 had stable disease. In the non-statin group, 10 patients achieved a complete response, 24 a partial response, and 4 had stable disease. No statistically significant difference in radiologic response was observed between groups (p = 0.910).

Table 3.

Comparison of Radiologic response rates between patients receiving and not receiving statin therapy.

Statin	Radiologic response			p value
	Complete response	Partial response	Stable disease
Receiving	5	14	3	0.910
Not receiving	10	24	4

Values are presented as number.

Because of small expected cell counts in some categories, the Fisher–Freeman–Halton exact test was used to compare radiologic response between groups.

P-values are reported and should be interpreted descriptively given the exploratory nature and small sample size.

Pathological complete response rates are presented in Table 4. A pCR was observed in 7 of 22 patients (31.8%) receiving statins and in 6 of 38 patients (15.8%) not receiving statins. Although this difference did not reach statistical significance in the overall cohort (p = 0.197), a numerically higher pCR rate was observed among statin users. Thus, the primary overall-cohort analysis was not statistically significant, and any subgroup findings should be interpreted as exploratory and hypothesis-generating.

Table 4.

Comparison of pathological complete response rates between patients receiving and not receiving statin therapy.

Statin	Pathologic Complete response		p value
	Present	Absent
Receiving	7	15	0.197
Not receiving	6	32

Values are presented as number.

Comparisons between groups were performed using Fisher’s exact test.

P-values are reported and should be interpreted descriptively given the exploratory nature and small sample size.

Postmenopausal subgroup analysis

Because all patients receiving statins were postmenopausal, subgroup analyses were performed within this population. As shown in Table 5, pCR occurred in 7 of 22 statin users (31.8%) compared with 1 of 20 non-users (5.0%), yielding a nominal p-value of 0.047.

Table 5.

Comparison of pathological complete response rates in postmenopausal patients receiving and not receiving statin therapy.

Statin	Pathologic complete response		p value
	Present	Absent
Receiving	7	15	0.047
Not receiving	1	19

Values are presented as number.

Due to small sample size, Fisher’s exact test was used for all comparisons.

P-values are reported and should be interpreted descriptively given the exploratory nature and small sample size.

However, given the limited sample size and the exploratory nature of this subgroup analysis, these findings should be interpreted with caution. The observed association does not establish causality but suggests a potential relationship between statin use and enhanced treatment response in postmenopausal patients, which warrants further investigation in larger, prospectively designed studies.

Multivariable analysis

To further explore factors associated with pathological complete response, an exploratory multivariable logistic regression analysis was performed in the postmenopausal subgroup. Given the small number of pCR events, this model was considered hypothesis-generating and the effect estimates were expected to be imprecise. As shown in Table 6, statin use was associated with pCR after adjustment for Ki-67 index and clinical T stage (odds ratio 11.7, 95% confidence interval 1.03–132.2; p = 0.047). However, the confidence interval spans more than two orders of magnitude, indicating substantial imprecision and uncertainty in the magnitude of the association; therefore, these results should not be used to infer a precise or clinically actionable effect size.

Table 6.

Multivariable logistic regression analysis for pathological complete response in postmenopausal patients.

Variable	Adjusted OR	95% CI	p #
Statin use (Yes vs. No)	11.7	1.03–132.2	0.047
Ki-67 (continuous)	1.03	0.99–1.07	0.112
Clinical T stage (T3–4 vs. T1–2)	0.42	0.06–2.91	0.386

Multivariable logistic regression analysis was performed to evaluate factors associated with pathological complete response.

The model included statin use, Ki-67 index, and clinical T stage.

Given the limited number of events, the analysis was considered exploratory.

Odds ratios (ORs) are presented with 95% confidence intervals (CIs).

Interpretation should be cautious due to the small number of pCR events in the postmenopausal subgroup, which may result in unstable estimates and wide confidence intervals.

Discussion

In this retrospective cohort, we evaluated the association between statin use and response to neoadjuvant chemotherapy in patients with hormone receptor–positive, HER2-negative breast cancer. The primary overall-cohort analysis did not demonstrate a statistically significant difference in pCR rates between statin users and non-users, although pCR rates were numerically higher among statin users. Because all statin users in this dataset were postmenopausal, the postmenopausal comparison represents an exploratory, hypothesis-generating subgroup analysis rather than confirmatory evidence. Given the small sample size, sparse events, and potential residual confounding related to menopausal and metabolic factors, the observed subgroup signal should be interpreted cautiously and warrants validation in larger, prospectively designed studies. Importantly, although the adjusted odds ratio appears large, the very wide confidence interval indicates substantial imprecision and uncertainty in the magnitude of the association; therefore, these results should not be used to infer a precise or clinically actionable effect size.

It is important to emphasize that pCR is not a validated surrogate endpoint for long-term outcomes in hormone receptor–positive breast cancer. Nevertheless, pCR remains a valuable indicator of chemosensitivity and early treatment response¹¹. The observed association between statin use and increased pCR in postmenopausal patients may therefore reflect enhanced tumor responsiveness rather than a direct survival benefit.

Given the exploratory nature of our analyses and the substantial statistical uncertainty, the following mechanistic considerations are provided as supportive biological context rather than confirmatory evidence. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase within the mevalonate pathway, reducing cholesterol synthesis and downstream intermediates involved in membrane biology and intracellular signaling¹². Through effects on protein prenylation, statins may influence oncogenic pathways (e.g., Ras/Rho GTPases) and have been reported to modulate apoptosis, angiogenesis, and inflammatory signaling, which could plausibly affect chemosensitivity^13,14.

Cholesterol and lipid metabolism are increasingly recognized as relevant in hormone receptor–positive breast cancer, where dysregulated lipid availability may support tumor growth and endocrine resistance^15–18. From this perspective, modulation of cholesterol-dependent signaling and the tumor microenvironment provides a biologically plausible rationale for an association between statin exposure and treatment responsiveness, while acknowledging that clinical evidence remains mixed and context-dependent.

Menopause-related metabolic and hormonal changes may further influence tumor reliance on lipid pathways and systemic inflammatory milieu¹⁹. Therefore, the exploratory signal observed in postmenopausal patients is biologically plausible, but it remains uncertain and should be validated in larger prospective studies with adequate event numbers and more detailed characterization of metabolic factors and statin exposure^20–22. However, because the subgroup p-value was borderline and event counts were small, this association is statistically fragile and may be sensitive to minor changes in event counts. Overall, these results should be considered hypothesis-generating.

Limitations

Several limitations should be acknowledged. First, the retrospective design and relatively small sample size limit the statistical power of the study and preclude causal inference. Second, statin exposure was not randomized, and residual confounding related to comorbidities, metabolic status, or concurrent medications cannot be excluded. In particular, in small observational cohorts, non-significant baseline comparisons do not confirm covariate balance, and numerical differences in prognostic factors (e.g., disease burden and proliferative indices) may still influence pathological complete response (pCR). Moreover, all statin users in our dataset were postmenopausal, creating a structural overlap between statin exposure and menopausal status that complicates causal interpretation; menopausal biology and related metabolic or comorbidity factors, as well as healthcare utilization patterns, may partially account for the observed exploratory subgroup association. Third, information regarding the duration, dose, and specific type of statin was not uniformly available, limiting more granular analyses. Additionally, the study population was derived from two tertiary care centers, which may limit the generalizability of the findings to broader or more diverse populations. Moreover, given the exploratory nature of the postmenopausal subgroup analyses and the possibility of multiple testing, the observed associations should be interpreted with caution. In addition, the subgroup result is statistically fragile given the small number of pCR events and the borderline p-value, and it may be sensitive to minor changes in event counts. Finally, although a multivariable analysis was performed, the limited number of events necessitates cautious interpretation of the results.

Conclusion

In conclusion, in this small retrospective cohort of patients with hormone receptor–positive, HER2-negative breast cancer receiving neoadjuvant chemotherapy (NACT), the primary overall-cohort analysis did not demonstrate a statistically significant association between statin use and pathological complete response (pCR). Nevertheless, pCR rates were numerically higher among statin users, and an exploratory signal in postmenopausal patients suggests that statin exposure may merit further investigation in relation to response to NACT. This subgroup observation should be regarded as hypothesis-generating given the limited number of events, wide confidence intervals, and the structural overlap between statin exposure and postmenopausal status, with potential residual confounding. Moreover, pCR is an imperfect surrogate endpoint in this subtype, further limiting definitive clinical inference. Overall, these findings provide preliminary clinical data supporting future prospective evaluation of statin exposure as a potential modifier of response to NACT in postmenopausal patients. Larger, prospectively designed studies with adequate event numbers and more robust control of confounding are required to determine whether statin exposure is meaningfully associated with response to NACT in this setting.

Interpretation should be cautious due to the small number of pCR events in the postmenopausal subgroup, which may result in unstable estimates and wide confidence intervals.

Abbreviations

AC

Adriamycin (doxorubicin) and cyclophosphamide

CI

Confidence interval

ECOG

Eastern cooperative oncology group

ER

Estrogen receptor

HER2

Human epidermal growth factor receptor 2

HMG-CoA

3-hydroxy-3-methylglutaryl–coenzyme A

NACT

Neoadjuvant chemotherapy

OR

Odds ratio

pCR

Pathological complete response

PR

Progesterone receptor

TME

Tumor microenvironment

Author contributions

ME: Conceptualized the study, collected data, designed the data analysis, drafted the initial manuscript, and approved the final version for publication.

Data availability

All data from this study have been stored in a database and are available from the corresponding author, Dr. Mustafa Ersoy, upon request.

Declarations

Competing interests

The authors declare no competing interests.

Ethical considerations

This retrospective study was reviewed and approved by the Non-Interventional Research Ethics Committee of Kütahya University of Health Sciences, and all procedures were conducted in accordance with the principles outlined in the Declaration of Helsinki.

Informed consent

Due to the retrospective nature of the study, the requirement for written informed consent was waived by the Non-Interventional Research Ethics Committee of Kütahya University of Health Sciences.