Metronomic capecitabine plus aromatase inhibitor as initial therapy in HR-positive HER2-negative metastatic breast cancer: a low-cost and easily implementable option

The treatment of advanced hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer has seen significant progress with a clear impact on overall survival (OS) and progression-free survival (PFS) (1). Current therapeutic strategies increasingly focus on personalization, where the identification of biomarkers allows for tailored treatment selection following progression on CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) (2-5). However, in many regions worldwide, access to CDK4/6i remains a substantial barrier (6). Therefore, studies evaluating more cost-effective and accessible strategies are needed to improve global care for resource-limited communities or even create alternative treatment options in resource-rich communities.

Conventional chemotherapy is typically delivered at the maximum tolerated dose (MTD) followed by rest periods, aiming for maximal cytotoxicity but often limited by toxicity and potential resistance during treatment-free intervals. In contrast, metronomic chemotherapy involves the continuous administration of low-dose cytotoxic agents without extended breaks, exerting both antiangiogenic and immunomodulatory effects. Metronomic chemotherapy is currently considered an effective alternative for patients experiencing resistance or toxicity from prior treatments (7-9).

Retrospective evidence supporting the use of chemotherapy as a first-line option has long existed. A US-led real-world analysis showed 63% of patients received single-agent chemotherapy, mainly capecitabine or paclitaxel, following National Comprehensive Cancer Network (NCCN) guidelines (10). A national study in Denmark also reported the efficacy of first-line capecitabine, although outcomes were inferior to modern alternatives (11).

The MECCA trial provides the first prospective evidence evaluating metronomic capecitabine in combination with ET compared to ET alone as first-line therapy for HR+ HER2-negative breast cancer. The primary endpoint was PFS, with OS, disease control rate, and safety as secondary endpoints. Median PFS was 20.9 months in the combination group versus 11.9 months in the aromatase inhibitor (AI) group [hazard ratio (HR) =0.58; 95% confidence interval (CI): 0.43–0.76]. Median OS was not reached in the combination group and was 45.1 months in the AI group (HR =0.58; 95% CI: 0.37–0.93) (12). By comparison, median PFS in MONALEESA-2 was 25.3 months with ribociclib + ET vs. 16.0 months with ET alone (HR =0.56) (13). In MONARCH-3, median PFS was 28.2 months with abemaciclib + ET vs. 14.8 months with ET alone (HR =0.54) (14). Median OS follows suit, with MONALEESA-2 demonstrating a median OS 63.9 vs. 51.4 months for ribociclib + ET vs. ET alone, respectively (HR =0.76) (13). The median OS for abemaciclib + ET in MONARCH-3 was 66.8 vs. 53.7 months with ET alone (HR =0.84), a difference which did not meet statistical significance (14). However, such cross-trial comparisons should be interpreted with great caution. Differences in study design, inclusion criteria, and baseline patient characteristics, as well as variations in data completeness, limit the validity of direct numerical comparisons across trials (15).

Beyond MECCA, two phase III trials compared ET plus CDK4/6 inhibition with capecitabine. In the PEARL trial, palbociclib plus ET showed similar PFS to capecitabine in postmenopausal HR+/HER2– metastatic breast cancer resistant to AIs but had fewer discontinuations and better quality of life (QoL) outcomes. The Young-PEARL trial reported longer PFS with palbociclib plus exemestane and ovarian suppression versus capecitabine in premenopausal women, without an OS benefit (16,17).

QoL represents a pivotal dimension in treatment decision-making for advanced breast cancer, given that treatment-related side effects that compromise QoL are of critical importance in routine clinical care (18). Optimizing tolerability through adequate dosing and toxicity management is crucial in advanced breast cancer. A recent phase III trial supports a fixed 7/7 capecitabine schedule (1,500 mg twice daily) to reduce toxicity while maintaining efficacy, with fewer grade 2–4 events and discontinuations versus the 14/7 regimen (19). For CDK4/6 inhibitors, proactive dose adjustment is equally important, as moderate, protocol-driven reductions do not compromise efficacy, emphasizing individualized dosing to balance safety and benefit (20,21).

Safety and toxicity remain key factors influencing adherence and discontinuation. In MECCA, the most common adverse events (AEs) were hand-foot syndrome (29.4%) and peripheral neuropathy (8.7%); 15.1% experienced grade 3 AEs, mostly palmar-plantar erythrodysesthesia. Treatment discontinuation due to AEs was 16.7% (12). Comparable rates were reported for CDK4/6i (14.6% in MONALEESA-2/3/7; 19.6% in MONARCH-2) (22,23). Both regimens show manageable toxicities, enabling therapy personalization based on AE profiles. Notably, a 2019 meta-analysis found 40% of capecitabine AEs occurred within 30 days, underscoring the value of early toxicity monitoring (24). With CDK4/6i, there have been multiple attempts to prioritize need. For example, the SONIA study suggests that some patients may be ideal candidates for initiating therapy with ET alone (25). Here, patients received either first-line CDK4/6 inhibitors followed by ET alone, or ET first then CDK4/6i at progression. After 37.3 months, PFS2 did not differ significantly, and grade ≥3 AEs were lower when CDK4/6i was deferred. Cross-over occurred in 78% and 86% of patients, respectively, emphasizing thoughtful first-line selection. Similar proportions required chemotherapy (10% vs. 5%) or did not start second-line therapy (9% vs. 7%). This scenario will be a question for MECCA as well—which patients need metronomic capecitabine in combination with ET as a first-line therapy, rather than capecitabine on progression after ET alone?

Real-world data show heterogeneous outcomes and access to therapy. In a cohort of 2,771 patients, first-line CDK4/6 inhibitor use was linked to longer time to next therapy and chemotherapy than ET alone, despite similar unadjusted OS (26,27).

The efficacy of abemaciclib and ribociclib in patients at high-risk of recurrence is shifting CDK4/6i use to the adjuvant setting, raising key questions about optimal sequencing in metastatic disease (27,28). While some data exists for CDK4/6i after CDK4/6i, the number of patients extending CDK4/6i from the adjuvant to metastatic was quite low, and effective, independent alternatives to extending CDK4/6i are needed (28-30).

Attempts to define which populations of patients with HR+ breast cancer might benefit from CDK4/6i have been unsuccessful. SONIA demonstrated no difference for patients who received first line vs. second line CDK4/6i when considering PFS2 (median, 31.0 versus 26.8 months, respectively; HR =0.87) (25). The trial has been criticized for having ET-alone in the second-line, when there are second-line agents targeting ESR1, mTOR, or PI3K-pathway. Notably, no trials have clearly identified which subgroups might benefit from which approach. With all subgroups appearing comparable, SONIA established first-line ET alone as a non-inferior option that maintained health-related QoL with better health economics.

Attempts to predict disease burden or disease distribution would predict subpopulations that most benefit from CDK4/6i or doublet therapies, but SONIA and MECCA demonstrate similar populations with visceral and bone-only disease (12,25). Conversely, the RIGHT CHOICE trial included approximately 4% of patients with bone-only disease, and 13% of the patients were described as having “symptomatic non-visceral disease” (31). Yet the pragmatic inclusion criteria of the MECCA trial allowed significantly elevated AST/ALT in the setting of liver metastases, similar to the RIGHT CHOICE trial. In RIGHT CHOICE, the median PFS for ribociclib + ET was 21.8 months compared to combination CT, with capecitabine in two of the combinations, which had a median PFS of 12.8 months (HR =0.061). This variability in bone-only disease, eligibility criteria, and the framing of the trials—particularly when considering the mPFS across studies—suggests these first-line trials may not be as far apart as imagined. This creates space for clinical trialists to continue to explore wide eligibility criteria that are more uniform across studies.

Beyond clinical characteristics, we turn to genomic classifications to personalize treatment. Resistance mechanisms to CDK4/6i have been identified, such as mutations in BRCA or P53, as well as loss of Rb function, acquired CDK6 amplifications, changes in cyclin E/CDK2 activity, c-Myc alterations, and PI3K/AKT/mTOR signaling pathway alterations. Identifying these genomic markers may will further support the appeal of this therapeutic alternative in mutation carriers (32-34).

In HER2-low disease, trastuzumab deruxtecan (T-Dxd) has emerged as an effective option in later lines after multiple progressions (35). Although it carries specific toxicities such as interstitial lung disease and nausea, these events are often manageable with appropriate monitoring and supportive care. Nevertheless, its high cost and the need for specialized management highlight the importance of developing earlier-line strategies that are effective, well tolerated, and broadly accessible (36,37).

Brain metastases occur in approximately 15% of patients with HR+ HER2 breast cancer, and treatment options with effective intracranial activity are limited (38). Among iCDKs, only abemaciclib has subgroup data supporting central nervous system (CNS) activity, although a non-randomized phase II trial did not meet its prespecified endpoint, with an intracranial clinical benefit rate of 24% (14,39). Capecitabine has shown intracranial efficacy, with an intracranial response rate of 38% in one series (40). This difference in intracranial efficacy may be a distinguishing factor in selecting MECCA as an approach in small populations of patients.

Safety considerations include the DPYD genotype, linked to severe capecitabine toxicities whose prevalence varies across ethnicities, underscoring the need for broader pharmacogenomic studies (41). As MECCA was conducted exclusively in China, population diversity was limited. Similar concerns arose with CREATE-X, which reported higher fluoropyrimidine toxicity in Asian vs. non-Asian patients. In contrast, the CaRe study in non-Asian populations showed lower discontinuation rates (10.4% vs. 25.4%) (42,43). Extended DPYD genotyping is highly cost-effective in high-income settings, increasing QALYs at lower costs by preventing severe toxicities and hospitalizations (44). Although implementation in LMICs is constrained by limited resources, integrating pharmacogenetic screening could enhance patient safety.

Finally, metronomic capecitabine is a low-cost drug with demonstrated efficacy in patients with hormone receptor–positive, HER2-negative metastatic breast cancer. According to the ESMO International Consortium, this combination is considered a cost-effective option for low- and middle-income countries (LMICs) (6). Affordable care remains a primary concern in global oncology, and continued advances utilizing low-cost therapies in novel combinations would advance global health.

The MECCA trial demonstrated its efficacy and safety, offering a practical alternative to CDK4/6 inhibitors for both LMICs and high-income settings seeking tolerable, accessible therapies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-82/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-82/coif). S.L.G. reports stock ownership (current, self): HCA Healthcare; consulting (all relationships ended, self): Pfizer, SeaGen, AstraZeneca, DaiichiSankyo, Gilead Sciences, Menarini Stemline, Genentech, Novartis, and Lilly/Loxo@Lilly; research funding (all funds to institution): AstraZeneca, Novartis, Daiichi Sankyo, Lilly, Hoffmann-La Roche/Genentech, and Menarini (Stemline) Group; honoraria: MJH Life Sciences, Wolters Kluwer, and ASCO Advantage; and unpaid leadership/board; Dempsey Center. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rugo HS, Bardia A, Gradishar WJ, et al. Expert consensus on treating HR+/HER2- metastatic breast cancer based on real-world practice patterns observed in the RETRACT survey of US oncologists. Breast. 2025;82:104485. [Crossref] [PubMed]
2. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2023;388:2058-70. [Crossref] [PubMed]
3. Juric D, Kalinsky K, Im SA, et al. INAVO121: Phase III study of inavolisib (INAVO) + fulvestrant (FUL) vs. alpelisib (ALP) + FUL in patients (pts) with hormone receptor-positive, HER2-negative (HR+, HER2–) PIK3CA -mutated (mut) locally advanced or metastatic breast cancer (LA/mBC). J Clin Oncol 2023;41:TPS1123. [Crossref]
4. Beaver JA, Park BH. The BOLERO-2 trial: the addition of everolimus to exemestane in the treatment of postmenopausal hormone receptor-positive advanced breast cancer. Future Oncol 2012;8:651-7. [Crossref] [PubMed]
5. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. N Engl J Med 2025;392:1189-202. [Crossref] [PubMed]
6. Cherny NI, Trapani D, Galotti M, et al. ESMO Global Consortium Study on the availability, out-of-pocket costs, and accessibility of cancer medicines: 2023 update. Ann Oncol 2025;36:247-62. [Crossref] [PubMed]
7. Cazzaniga ME, Capici S, Cordani N, et al. Metronomic Chemotherapy for Metastatic Breast Cancer Treatment: Clinical and Preclinical Data between Lights and Shadows. J Clin Med 2022;11:4710. [Crossref] [PubMed]
8. Larsson K F, Adra J, Klint L, et al. Metronomic chemotherapy using capecitabine and cyclophosphamide in metastatic breast cancer - efficacy, tolerability and quality of life results from the phase II METRO trial. Breast 2024;78:103795. [Crossref] [PubMed]
9. Banys-Paluchowski M, Schütz F, Ruckhäberle E, et al. Metronomic Chemotherapy for Metastatic Breast Cancer - a Systematic Review of the Literature. Geburtshilfe Frauenheilkd 2016;76:525-34. [Crossref] [PubMed]
10. Tolaney SM, Punie K, Carey LA, et al. Real-world treatment patterns and outcomes in patients with HR+/HER2- metastatic breast cancer treated with chemotherapy in the United States. ESMO Open 2024;9:103691. [Crossref] [PubMed]
11. Celik A, Berg T, Gibson M, et al. Capecitabine monotherapy as first-line treatment in advanced HER2-normal breast cancer - a nationwide, retrospective study. Acta Oncol 2024;63:494-502. [Crossref] [PubMed]
12. Hong RX, Xu F, Xia W, et al. Metronomic Capecitabine Plus Aromatase Inhibitor as Initial Therapy in Patients With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: The Phase III MECCA Trial. J Clin Oncol 2025;43:1314-24. [Crossref] [PubMed]
13. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med 2022;386:942-50. [Crossref] [PubMed]
14. Goetz MP, Toi M, Huober J, et al. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3. Ann Oncol 2024;35:718-27. [Crossref] [PubMed]
15. Sullivan KM, Keyes-Elstein L. Cross-trial comparisons in reviews: proceed with caution. Nat Rev Rheumatol 2020;16:663-4. [Crossref] [PubMed]
16. Martín M, Zielinski C, Ruiz-Borrego M, et al. Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study. Eur J Cancer 2022;168:12-24. [Crossref] [PubMed]
17. Ahn HK, Kim JY, Lee KH, et al. Palbociclib plus endocrine therapy versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (Young-PEARL): overall survival analysis of a randomised, open-label, phase 2 study. Lancet Oncol 2025;26:343-54. [Crossref] [PubMed]
18. Cardoso F, Rihani J, Harmer V, et al. Quality of Life and Treatment-Related Side Effects in Patients With HR+/HER2- Advanced Breast Cancer: Findings From a Multicountry Survey. Oncologist 2023;28:856-65. [Crossref] [PubMed]
19. Khan QJ, Bohnenkamp C, Monson TE, et al. Randomized Trial of Fixed-Dose Capecitabine Compared With Standard-Dose Capecitabine in Metastatic Breast Cancer: X-7/7 Trial. JCO Oncol Adv 2025;2:e2400068. [Crossref] [PubMed]
20. Bjerrum A, Henriksen AF, Knoop AS, et al. Overall survival after CDK4/6 inhibitor dose reduction in women with metastatic breast cancer. BJC Rep 2024;2:82. [Crossref] [PubMed]
21. Goetz MP, Cicin I, Testa L, et al. Impact of dose reductions on adjuvant abemaciclib efficacy for patients with high-risk early breast cancer: analyses from the monarchE study. NPJ Breast Cancer 2024;10:34. [Crossref] [PubMed]
22. Burris HA, Chan A, Bardia A, et al. Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer. Br J Cancer 2021;125:679-86. [Crossref] [PubMed]
23. Slamon DJ, Diéras V, Rugo HS, et al. Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer. J Clin Oncol 2024;42:994-1000. [Crossref] [PubMed]
24. Xu D, Chen X, Li X, et al. Addition of Capecitabine in Breast Cancer First-line Chemotherapy Improves Survival of Breast Cancer Patients. J Cancer 2019;10:418-29. [Crossref] [PubMed]
25. Sonke GS, van Ommen-Nijhof A, Wortelboer N, et al. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature 2024;636:474-80. [Crossref] [PubMed]
26. Kimmick G, Pilehvari A, You W, et al. First- vs second-line CDK 4/6 inhibitor use for patients with hormone receptor positive, human epidermal growth-factor receptor-2 negative, metastatic breast cancer in the real world setting. Breast Cancer Res Treat 2024;208:263-73. [Crossref] [PubMed]
27. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol 2020;38:3987-98. [Crossref] [PubMed]
28. Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med 2024;390:1080-91. [Crossref] [PubMed]
29. Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial. J Clin Oncol 2025;43:1101-12. [Crossref] [PubMed]
30. Giordano A, Lin NU, Tolaney SM, et al. Is there a role for continuation of CDK4/6 inhibition after progression on a prior CDK4/6 inhibitor in HR+/HER2- metastatic breast cancer? Ann Oncol 2024;35:10-4. [Crossref] [PubMed]
31. Lu YS, Mahidin EIBM, Azim H, et al. Final Results of RIGHT Choice: Ribociclib Plus Endocrine Therapy Versus Combination Chemotherapy in Premenopausal Women With Clinically Aggressive Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer. J Clin Oncol 2024;42:2812-21. [Crossref] [PubMed]
32. Collins JM, Nordstrom BL, McLaurin KK, et al. A Real-World Evidence Study of CDK4/6 Inhibitor Treatment Patterns and Outcomes in Metastatic Breast Cancer by Germline BRCA Mutation Status. Oncol Ther 2021;9:575-89. [Crossref] [PubMed]
33. Marvalim C, Datta A, Lee SC. Role of p53 in breast cancer progression: An insight into p53 targeted therapy. Theranostics 2023;13:1421-42. [Crossref] [PubMed]
34. Glaviano A, Wander SA, Baird RD, et al. Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment. Drug Resist Updat 2024;76:101103. [Crossref] [PubMed]
35. Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med 2022;387:9-20. [Crossref] [PubMed]
36. Perachino M, Blondeaux E, Molinelli C, et al. Adverse events and impact on quality of life of antibody-drug conjugates in the treatment of metastatic breast cancer: A systematic review and meta-analysis. Eur J Clin Invest 2025;55:e70001. [Crossref] [PubMed]
37. Kahan Z, Gil-Gil M, Ruiz-Borrego M, et al. Health-related quality of life with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive metastatic breast cancer: Patient-reported outcomes in the PEARL study. Eur J Cancer 2021;156:70-82. [Crossref] [PubMed]
38. Aversa C, Rossi V, Geuna E, et al. Metastatic breast cancer subtypes and central nervous system metastases. Breast 2014;23:623-8. [Crossref] [PubMed]
39. Tolaney SM, Sahebjam S, Le Rhun E, et al. A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor-Positive Breast Cancer. Clin Cancer Res 2020;26:5310-9. [Crossref] [PubMed]
40. Gouveia MC, Hidalgo Filho CM, Moreno RA, et al. Activity of capecitabine for central nervous system metastases from breast cancer. Ecancermedicalscience 2023;17:1638. [PubMed]
41. White C, Scott RJ, Paul C, et al. Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature. Pharmgenomics Pers Med 2021;14:1603-17. [Crossref] [PubMed]
42. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 2017;376:2147-59. [Crossref] [PubMed]
43. Di Lisa FS, Krasniqi E, Pizzuti L, et al. Adjuvant capecitabine in triple negative breast cancer patients with residual disease after neoadjuvant treatment: real-world evidence from CaRe, a multicentric, observational study. Front Oncol 2023;13:1152123. [Crossref] [PubMed]
44. Koleva-Kolarova R, Vellekoop H, Huygens S, et al. Cost-effectiveness of extended DPYD testing before fluoropyrimidine chemotherapy in metastatic breast cancer in the UK. Per Med 2023;20:339-55. [Crossref] [PubMed]