Combination chemotherapy and hormone therapy in patients with hormone receptor positive and HER2 negative metastatic breast cancer

Abstract

There is sparse data on the outcomes of combined chemotherapy and hormonal therapy (CHT) in patients with metastatic breast cancer (MBC). This retrospective analysis of HR-positive, HER2-negative MBC patients treated between January 2015 and December 2020 with a combination of chemotherapy (capecitabine or oral cyclophosphamide) and hormonal therapy evaluated their progression-free survival (PFS) and overall survival (OS).The study included 224 patients with a median age of 53 (26–91) years, a median of 3 (0–12) prior treatment lines and a median follow-up of 21.2 (1.7–87.0) months. There were 195 (87.1%) PFS events and 154 (68.8%) deaths, with a median PFS of 8.8 (95% CI 7.0-10.6) months and a median OS of 16.7 (95% CI 13.5–19.9) months. In univariable analyses, ECOG PS (≤ 1 vs. ≥ 2, PFS 14.9 vs. 6.0 months, HR 0.32, 95% CI 0.23–0.44, p < 0.001; OS 36.2 vs. 11.0 months, HR 0.29, 95% CI 0.20–0.42, p < 0.001) and duration of most recent endocrine therapy (> 12 vs. ≤ 12 months, PFS 11.7 vs. 6.9 months, HR 0.32, 95% CI 0.23–0.44, p = 0.023; OS 21.9 vs. 15.0 months, HR 0.70, 95% CI 0.49–0.99, p = 0.047) were significantly associated with survival. In multivariable Cox analyses, better ECOG PS (HR 0.29, 95% CI 0.19-0.43, p<0.001) and capecitabine-based chemotherapy (HR 0.60, 95% CI 0.37-0.99, p=0.043) were significantly associated with higher OS. The chemo-hormonal therapy regimens were well tolerated, with 21 (9.4%) patients experiencing any grade ≥3 toxicity. Chemo-hormonal therapy is an effective treatment in heavily pre-treated MBC patients, including those with visceral metastases.

Trial registration: CTRI/2022/01/039242

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-025-12419-3.

Introduction

Estrogen receptor (ER) and/or progesterone receptor (PR) positive tumors comprise 33–70% of all breast cancers,¹ and around 50–70% of metastatic breast cancer (MBC) cases. Patients with ER and/or PR-positive tumors have a better prognosis compared with those who have triple-negative breast cancer (TNBC) or Human Epidermal Growth Factor Receptor 2 (HER-2) positive disease.² A higher proportion of Indian patients (30–60%) are diagnosed in an advanced stage, leading to increased mortality.³.

The outcome of advanced hormone receptor-positive (HR-positive) breast cancer is relatively better due to its inherent disease biology and availability of several hormone therapy and targeted therapy options, with a median overall survival of more than 5 years in the first-line metastatic setting.⁴ However, new treatment approaches are required in patients with multiple prior treatments who acquire resistance to treatment.⁵ Treatment for metastatic disease aims to prolong survival and improve quality of life.⁶ Guidelines recommend sequential endocrine therapy in metastatic breast cancer, suggesting chemotherapy for endocrine-resistant disease or for patients in visceral crisis.⁷ The CDK 4/6 inhibitors, such as palbociclib^8,9 and ribociclib,^10,11 in combination with endocrine therapy, have a role in the first- and second-line treatment. Abemaciclib has demonstrated efficacy even after progression on palbociclib,¹² and a few case reports have indicated its efficacy even after 5–6 lines of treatment.¹³.

Although various combinations of chemo-hormonal therapy (CHT) have been explored in endocrine-sensitive and endocrine-resistant metastatic breast cancer, this remains an understudied question, especially the combination of oral chemotherapy agents and endocrine therapy. Cytotoxic agents have been found to have endocrine effects in premenopausal women with active ovarian function. Tamoxifen has been found to have an antagonistic effect on chemotherapy¹⁴ in in vitro studies, but other endocrine agents like fulvestrant have shown synergistic effects with chemotherapy agents like doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-FU.¹⁵.

In the neoadjuvant and adjuvant settings, variable outcomes have been observed with combination chemo-hormonal therapy. The GEICAM-9401 and SWOG-8814 studies showed a trend to inferior survival outcomes with concurrent tamoxifen and chemotherapy, but the results were not statistically significant in either study.^16,17 An Italian randomized trial evaluated concurrent or sequential tamoxifen administration with anthracycline-based adjuvant chemotherapy and suggested that survival outcomes were similar in both arms.¹⁸ The addition of letrozole to neoadjuvant chemotherapy increased clinical and pathological complete response in postmenopausal patients with hormone receptor-positive tumors in another randomized trial.¹⁹ In an old meta-analysis of metastatic breast cancer patients, comprising 3606 patients in 25 trials, the use of chemotherapy plus endocrine therapy increased the response rates (OR 1.56, 95%CI 1.36–1.80), but there was no difference in overall survival (HR 0.99, 95%CI 0.92–1.07).²⁰ However, most patients in these studies were young with dominant visceral disease, and they often had hormone receptor-negative or hormone receptor-unconfirmed disease. In the studies included in the meta-analysis, such as the Australian and New Zealand Breast Cancer Trialist Group study, hormone receptor status was known in only about 25% of patients.²¹ A small randomized study showed that combination chemo-hormonal therapy increased survival compared with hormone therapy alone in patients with estrogen receptor-rich tumours.²² Interestingly, metronomic chemotherapy acts by altering the microenvironment and angiogenesis.²³ In vitro studies have shown that low-dose oral fluoropyrimidines can induce the ER pathway and exhibit synergism when combined with hormone therapy.²⁴ Retrospective and early-phase studies in neoadjuvant and metastatic settings have shown benefits with hormone therapy and metronomic chemotherapy.²⁵ However, these studies were limited by small sample sizes. Several retrospective and prospective studies have also demonstrated that combination CHT is well tolerated and has low discontinuation rates (Table S1).^25–34 The current study aims to explore the treatment patterns and survival outcomes of women with MBC treated with combined chemotherapy and endocrine therapy.

Methods

Patients and treatment

This study was approved by the Institutional Ethics Committee of Tata Memorial Centre. All study-related procedures were performed in accordance with relevant guidelines and regulations, including the Declaration of Helsinki, and in adherence to ethical standards for research involving human participants. The Institutional Ethics Committee of Tata Memorial Centre approved the waiver of informed consent from patients, except for those who were required to be telephonically contacted for follow-up information, in whom telephonic consent was obtained to record their follow-up.

This was a retrospective analysis of patients with HR-positive, HER2-negative tumors and locally recurrent or metastatic breast cancer who received a combination of oral chemotherapy (capecitabine or oral cyclophosphamide) and hormonal therapy (tamoxifen or an aromatase inhibitor or fulvestrant or megestrol acetate) for recurrent/metastatic disease in any line of treatment for advanced breast cancer, between January 2015 and December 2020 in a single centre in India. All patients with metastatic breast cancer who had HR-positive, HER2-negative breast cancer and who received any duration of combined chemotherapy and endocrine therapy were included in the study. The data were abstracted from the institutional electronic prescription database and electronic pathology database, and the patients were consecutive.

Patients received oral cyclophosphamide in a dose of 50 mg/m2 on days 1–21 every 28 days or oral capecitabine either in a dose of 1000 mg/m2 on days 1–14 every 21 days³⁵ or in a dose of 750 mg/m2 on days 1–21 every 28 days. The latter, a lower daily capecitabine dose for a longer duration of 21 days in each cycle, was used in patients who wished to visit the hospital every 28 days instead of every 21 days. The patients received simultaneous continuous hormone therapy with one of the following drugs: tamoxifen 20 mg once per day, letrozole 2.5 mg once per day, exemestane 25 mg once per day, anastrozole 1 mg per day, fulvestrant 500 mg intramuscular once every 28 days, or megestrol acetate 80–160 mg per day. Blood tests, including complete blood counts and serum chemistries, were done per routine clinical practice. Imaging (either CT scans or PET-CT scans) was also done as per routine clinical practice, usually once every 3–4 cycles of chemotherapy or as clinically indicated.

Patients were classified as having primary or secondary endocrine resistance as per the 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC-5).³⁶ Briefly, primary resistance was defined as relapse during the first two years of adjuvant endocrine therapy or progressive disease within the first six months of first-line endocrine therapy for advanced breast cancer, while secondary resistance was defined as relapse while on adjuvant endocrine therapy after the first two years, or relapse within 12 months of completing adjuvant endocrine therapy, or progressive disease ≥ 6 months after initiating endocrine therapy for advanced breast cancer.

Data collection and outcomes

Response evaluation and assessment for disease progression were done based on RECIST principles. Clinical, laboratory, pathology, radiology and follow-up information were collected from the electronic medical record in a predefined case record form.

The main outcomes were progression-free survival (PFS), overall survival (OS), and treatment-related toxicities. Progression-free survival was defined as the duration from the first dose of chemo-hormone therapy to the date of first confirmed disease progression or death due to any cause, whichever was earlier. Patients who were progression-free on the data cutoff date were censored. Overall survival was defined as the time (in months) from the start of CHT to death due to any cause. Patients who were not known to have died as of the data cut-off date were censored on the date that they were last known to be alive. Treatment-related toxicity was collected from the medical records and evaluated as per CTCAE 4.03 when available in that format.

Statistical analysis

The data cut-off was in May 2022. Demographic variables and toxicities were descriptively reported using the median and interquartile range for continuous variables and frequency and proportion for categorical data. Survival outcomes were analyzed using the Kaplan-Meier method, and comparisons were performed with the log-rank test. Data was analyzed using IBM SPSS Statistics version 23. The univariate Cox method was used to estimate the hazard ratios with their 95% confidence intervals (CI) to assess the association of various factors with PFS and OS. Missing data was not imputed. The proportional hazards assumption was evaluated by the log-minus-log graphical method and, if required, using time-dependent covariates. Statistical significance was defined as a two-sided p-value of less than 0.05, and no correction was made for multiple testing.

The results of this analysis were presented in part at the European Society of Medical Oncology (ESMO) Asia Congress 2022 on December 3, 2022, as a poster presentation [Ann Oncol. 2022;33(Suppl 9):S1439. Abstract 23P, presented at the ESMO Asia Congress 2022; 2–4 December 2022; Singapore. https://doi.org/10.1016/j.annonc.2022.10.032].

Results

Patient characteristics

The study included a total of 224 patients with ER and/or PR-positive, HER2-negative metastatic breast cancer with a median age of 53 (26–91) years. Most patients were postmenopausal (205, 91.5%) and had an ECOG performance status of 1 (206, 92.0%). The ER Allred score was 3–6/8 in 40 (17.9%) and 7–8/8 in 184 (82.1%) patients, while the PR score was 3–6/8 in 133 (59.4%) and 7–8/8 in 91 (40.6%) patients. Most patients (213, 95.1%) had invasive ductal carcinoma, while 11 (4.9%) had invasive lobular carcinoma. The patterns of metastatic disease were varied, with 28 (12.5%) patients having bone-only metastasis, 19 (8.0%) having bone and nodal metastasis, 145 (64.7%) having bone, lymph nodes, and visceral metastasis, 21 (9.4%) having bone, nodes, visceral, and brain metastasis, 6 (2.7%) having brain-only metastasis, and 5 (2.2%) having lymph node-only metastasis. The baseline characteristics are shown in Table 1.

Table 1.

Baseline characteristics.

Baseline characteristics	(n = 224)
Age (years)
Median	53
IQR* Range	26–91
Menopausal status
Post-menopausal	205 (91.5%)
Pre-menopausal	19 (8.5%)
ECOG PS±
1	206 (92.0%)
2–3	18 (8.0%)
ERπ allred score
3–6	40 (17.9%)
7–8	184 (82.1%)
PRϯallred score
3–6	133 (59.4%)
7–8	91 (40.6%)
Histopathology
Invasive ductal carcinoma	213 (95.1%)
Invasive lobular carcinoma	11 (4.9%)
Metastasis site
Bone only	28 (12.5%)
Bone + nodal	19 (8.0%)
Bone + nodal + visceral	145 (64.7%)
Bone + nodal + visceral + brain	21 (9.4%)
Brain only	6 (2.7%)
Nodal only	5 (2.2%)
Endocrine resistance
Primary (adjuvant setting)	18 (8.0%)
Primary (metastatic setting)	55 (24.6%)
Secondary (adjuvant setting)	21 (9.4%)
Secondary (metastatic setting)	108 (48.2%)
Unknown	22 (9.8%)

*Interquartile range.

± Eastern Cooperative Oncology Group Performance status.

Π Estrogen Receptor.

^ϯ Progesterone receptor.

Regarding prior adjuvant treatment, 121 (54.0%) patients had received adjuvant chemotherapy, and the median duration of adjuvant hormone therapy was 36.0 (1-120) months. In the entire cohort, primary endocrine resistance was observed in 18 (8.0%) patients in the adjuvant and 55 (24.6%) patients in the metastatic setting. Secondary endocrine resistance was seen in 21 (9.4%) patients in adjuvant and 108 (48.2%) patients in metastatic settings. The endocrine resistance status was unknown in 22 (9.8%) patients.

Prior treatment before chemo-hormonal therapy (CHT)

The patients included in this study received a median of 3 (0–12) previous treatment lines of treatment. As part of the first-line treatment of the 224 patients, 101 (45.1%) had received endocrine therapy, 99 (44.2%) had received chemotherapy, and 24 (10.7%) had received only palliative radiation. Second-line treatment was received by 144 (64.3%) patients, of whom 86 (38.4%) had received endocrine therapy, and 56 (38.9%) had received chemotherapy, third-line treatment was received by 92 (41.1%) patients, of whom 60 (26.8%) received endocrine therapy and 32 (14.3%) received chemotherapy, fourth-line treatment by 57 (25.4%) patients, of whom 26 (11.6%) received chemotherapy and 31 (13.8%) received endocrine therapy.

Chemo-hormonal therapy (CHT)

Of the 224 patients who received chemo-hormonal therapy, the majority (197 patients, 87.9%) received capecitabine-based combinations, while a smaller proportion (27 patients, 12.1%) received cyclophosphamide-based combinations. Among the patients on capecitabine, the endocrine partner drug was tamoxifen in 67 (29.9%), letrozole in 51 (22.8%), exemestane in 45 (20.0%), fulvestrant in 26 (11.6%), and megestrol acetate in 8 (3.6%) patients. The chemo-hormone therapy regimens used are shown in Table 2.

Table 2.

Combination chemo-hormonal therapies used.

Regimen name	(n = 224)
Capecitabine + Tamoxifen	67 (29.9%)
Capecitabine + Letrozole	51 (22.8%)
Capecitabine + Fulvestrant	26 (11.6%)
Capecitabine + Exemestane	45 (20.0%)
Capecitabine + Megestrol	8 (3.6%)
Cyclo*+Tamoxifen	10 (4.5%)
Cyclo + Letrozole/Anastrozole	7 (3.1%)
Cyclo + Fulvestrant	3 (1.3%)
Cyclo + Exemestane	6 (2.7%)
Cyclo + Megestrol	1 (0.4%)

* Cyclophosphamide.

Survival analysis

At a median follow-up of 21.2 (1.7–87.0) months after starting chemo-hormonal therapy, 195 (87.1%) patients had experienced disease progression and 154 (68.8%) patients had died, with a median PFS of 8.8 (95% CI 7.0-10.6) months and median OS of 16.7 (95% CI 13.5–19.9) months (Figs. 1 and 2). The 6-month and 12-month PFS were 65.5% (95% CI 59.2–71.8%) and 36.5% (95% CI 29.8–43.2%), and the 6-month and 12-month OS were 81.1% (95% CI 76.0-86.2%) and 63.3% (95% CI 56.8–69.8%), respectively.

Fig. 1.

Kaplan-Meier estimates of PFS in the full population.

Fig. 2.

Kaplan-Meier estimates of OS in the full population.

Factors affecting PFS and OS

In univariable analyses, ECOG PS (≤ 1 vs. ≥ 2) was significantly associated with PFS (14.9 vs. 6.0 months, HR 0.32, 95% CI 0.23–0.44, p < 0.001) and OS (36.2 vs. 11.0 months, HR 0.29, 95% CI 0.20–0.42, p < 0.001). The duration of recent HT (> 12 vs. ≤ 12 months) was also significantly associated with PFS (11.7 vs. 6.9 months, HR 0.32, 95% CI 0.23–0.44, p = 0.023) and OS (21.9 months vs. 15.0 months, HR 0.70, 95% CI 0.49–0.99, p = 0.047).

The number of prior lines (≤ 3 vs. ≥ 4) was not significantly associated with PFS (9.2 vs. 6.9 months, HR 0.76, 95% CI 0.57–1.02, p = 0.065) and OS (18.3 vs. 16.5 months, HR 1.02, 95% CI 0.73–1.42, p = 0.904). Similarly, the presence of visceral metastases (no vs. yes) was not significantly associated with PFS (10.2 vs. 8.2 months, HR 1.00, 95% CI 0.73–1.38, p = 0.99) and OS (21.4 vs. 15.3 months, HR 0.70, 95% CI 0.47–1.03, p = 0.065). The type of chemotherapy (capecitabine vs. cyclophosphamide) was not significantly associated with PFS (9.0 vs. 7.0 months, HR 0.87, 95% CI 0.55–1.37, p = 0.54) and OS (18.4 vs. 13.7 months, HR 0.68, 95% CI 0.43–1.09, p = 0.10) (Table 3).

Table 3.

Univariable and multivariable analysis for PFS and OS.

Univariate analysis for PFS and OS							Multivariable analysis for PFS and OS
Variable	PFS HR	PFS 95% CI	p value PFS	OS HR	OS 95% CI HR	p value OS	Variable	PFS HR	PFS 95% CI	p value PFS	OS HR	OS 95% CI HR	p value OS
ECOG PS*							ECOG PS*
≤ 1	0.32	(0.23–0.44)	< 0.001	0.29	(0.20–0.42)	< 0.001	≤ 1	0.33	(0.24–0.47)	0.000	0.29	(0.19–0.43)	0.000
≥ 2	1						≥ 2	1
Duration of recent HT±							Duration of recent HT±
> 12 months	0.32	(0.23–0.44)	0.023	0.70	(0.49–0.99)	0.047	> 12 months	0.76	(0.55–1.06)	0.110	0.78	(0.63–1.30)	0.595
< 12 months	1						< 12 months	1
Prior treatment							Prior treatment
≤ 3	0.76	(0.57–1.02)	0.065	1.02	(0.73–1.42)	0.904	≤ 3	0.63	(0.46–0.88)	0.006	0.90	(0.63–1.30)	0.595
≥ 4	1						≥ 4	1
Visceral metastasis							Visceral metastasis
No	1.00	(0.73–1.38)	0.990	0.70	(0.47–1.03)	0.065	No	0.95	(0.67–1.35)	0.780	0.68	(0.45–1.04)	0.074
Yes	1						Yes	1
Type of CHTπ							Type of CHTπ
Capeµ	0.87	(0.55–1.37)	0.543	0.68	(0.43–1.09)	0.10	Capeµ	1.05	(0.62–1.63)	0.983	0.60	(0.37–0.99)	0.043
Cyclo£	1						Cyclo£	1

*Eastern Cooperative Oncology Group Performance status.

± Hormonal therapy.

π Chemo-hormonal therapy.

µ Capecitabine.

£Cyclophosphamide.

Significant values are in bold.

In multivariable Cox analysis, two factors were significantly associated with progression-free survival (PFS) - better ECOG PS (HR 0.33, 95% CI 0.24–0.47, p < 0.001) and fewer prior treatment lines (HR 0.63, 95% CI 0.46–0.88, p = 0.006). Better ECOG PS (HR 0.29, 95% CI 0.19–0.43, p < 0.001) and capecitabine-based regimens (HR 0.60, 95% CI 0.37–0.99, p = 0.043) were significantly associated with overall survival (OS) (Table 3).

Toxicities of chemo-hormonal therapy:

Chemo-hormonal therapy was well tolerated with grade 3 or higher toxicities in 21 (9.4%) patients, of whom 15 (6.1%) had grade ≥ 3 hand-foot syndrome, 2 (0.08%) had grade 3 diarrhoea, and none had febrile neutropenia. The toxicities are shown in Table S2.

Discussion

To our knowledge, this study encompasses one of the largest datasets of heavily pre-treated metastatic breast cancer patients with HR-positive, HER2-negative breast cancer who have been treated with chemo-hormonal therapy. The median PFS of 8.8 months and median OS of 16.7 months in this cohort are comparable to outcomes in contemporary cohorts of heavily pretreated patients. For example, in the SOLAR-1 study of fulvestrant and alpelisib in the first- or second-line settings, the median PFS was 11.0 months.³⁷ The 6-month PFS (65.5%) and 6-month OS (81.1%) in our cohort of patients who had received a median of three previous lines of systemic therapy compare favorably with the 6-month PFS and OS of 40.8% and 93.0%, respectively, in the EMERALD study³⁸ wherein elacestrant was used in a patient population who had received up to two previous lines of endocrine therapy and one previous line of chemotherapy. Given these results, one of the combinations of chemo-hormonal therapy used in our cohort could be considered a reasonable treatment option in heavily pretreated patients.

Other previous studies have found similar results. In a retrospective Chinese study by Shi et al.,²⁸ patients who received a combination of oral capecitabine with aromatase inhibitors had significantly longer PFS (22.0 vs. 14.0 months, p = 0.002) and OS (66.0 vs. 49.0 months, p = 0.003) compared to those receiving single-agent aromatase inhibitors. In a single-centre retrospective analysis by Alvarado-Miranda et al., the combination of capecitabine and aromatase inhibitors in first-line treatment led to an improvement in median PFS compared with aromatase inhibitors alone (29.37 vs. 20.04 months).²⁶ Several prospective studies have also reported similar findings. In the phase II study by Rashad et al.,³⁴ there was a median PFS of 10 months, OS of 23.3 months and an objective response rate of 60% in 40 patients of HR-positive MBC treated with capecitabine and tamoxifen/letrozole as first-line treatment.

An interesting result in our study is the better overall survival outcome with capecitabine compared with oral cyclophosphamide-based chemo-hormonal therapy regimens. This is in concordance with the known efficacy of capecitabine in patients with HR-positive, HER2-negative metastatic breast cancer.³⁹ However, because our analysis involves a retrospective cohort, this result must be interpreted cautiously.

Chemo-hormonal therapy was well tolerated in our patient cohort, with 9.4% of patients experiencing grade 3 or higher toxicity. A combination of oral capecitabine with aromatase inhibitors showed good tolerance, efficacy, and acceptable toxicity in a similar phase II study by Li et al.³¹.

Our study has important implications beyond its immediate relevance. The dogma of not using simultaneous chemotherapy and endocrine therapy in hormone receptor-positive breast cancer has been accepted based on evidence of a deleterious interaction between anthracycline-based chemotherapy and tamoxifen. It is possible that similar interactions may not exist between other kinds of chemotherapy and endocrine therapy regimens, and there may be additive or synergistic efficacy between these two classes of drugs. In this context, it is pertinent to point out that chemo-hormonal therapy is a standard treatment in metastatic prostate cancer.⁴⁰.

Our study has some limitations, including its retrospective design, relatively small sample size, potential bias in patient selection, heterogeneous patient population and assessment of toxicity. The major limitation is its uncontrolled design, which does not allow an assessment of whether sequential single-agent chemotherapy and hormone therapy, in either sequence, would have resulted in similar outcomes. The patient population is heterogeneous in terms of number and types of prior treatments and the chemo-hormonal treatments being evaluated as the study question, which makes it challenging to extrapolate the results of specific treatment subgroups to larger patient populations. Moreover, the retrospective design and physician choice of chemo-hormonal therapy could have biased the patient selection for specific treatments.

However, we believe that our study’s overarching message that combined chemo-hormonal therapy is worthy of being considered as a therapeutic option in heavily pretreated HR-positive/HER2-negative breast cancer patients, in addition to existing treatment options,⁴¹ remains valid. Given the promising survival results in this heavily pre-treated population, it is worth planning a randomized controlled trial in HR-positive/HER2-negative metastatic breast cancer patients who have received one prior line of treatment for advanced disease, comparing the current standard options [e.g. a selective estrogen receptor degrader (SERD) paired with a pathway-targeted agent such as a phosphatidylinositol-3-kinase-alpha (PI3Kα) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, or a protein kinase B (AKT) inhibitor] to chemo-hormonal therapy (e.g. fulvestrant plus capecitabine). Further, the results of our study should be interpreted cautiously but can be used to counsel patients regarding expected safety and efficacy outcomes.

In conclusion, combination chemo-hormonal therapy using capecitabine with either fulvestrant or an aromatase inhibitor is a valid treatment option in heavily pre-treated patients with hormone receptor-positive, HER2-negative metastatic breast cancer.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

SuG conceptualized and designed the study. KB and SR wrote the first draft. SuG, KB, SR, DV, and PPa contributed to data acquisition and performed the data analyses. KB, SR, DV, PPa, SwR and SuG were responsible for the interpretation of data, drafting the manuscript, editing the manuscript, and project administration. All the authors read and approved the final version of the manuscript.

Funding

Open access funding provided by Department of Atomic Energy. Article processing charges were supported by the Department of Atomic Energy, Government of India. There was no other funding support for this study.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available as they require the Institutional Ethics Committee (IEC) approval before being shared. However, de-identified data will be made available upon reasonable request to the corresponding author, subject to obtaining the necessary permissions from the IEC.

Declarations

Competing interests

The authors declare no competing interests.

Ethics statement

This study was approved by the Institutional Ethics Committee of Tata Memorial Centre. All study-related procedures were performed in accordance with relevant guidelines and regulations, including the Declaration of Helsinki, and in adherence to ethical standards for research involving human participants.

Informed consent

The Institutional Ethics Committee of Tata Memorial Centre approved the study with a waiver of informed consent from patients, except for those who were required to be telephonically contacted for follow-up information, in whom telephonic consent was obtained to record their follow-up.