Oral Drug S-1 Linked to Longer Survival Than Capecitabine in Metastatic Breast Cancer Study

For patients with hormone receptor-positive, HER2-negative metastatic breast cancer, the treatment landscape has been transformed over the past decade by cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, targeted drugs that halt tumor cell division by blocking key enzymes of the cell cycle. Yet chemotherapy remains an unavoidable reality: when endocrine therapy and targeted combinations eventually fail, most patients move on to cytotoxic regimens, and the oral fluoropyrimidines capecitabine and S-1 are among the most widely used options. A new retrospective cohort study from the Cancer Institute Hospital of the Japanese Foundation for Cancer Research in Tokyo, published in BMC Cancer, now offers one of the clearest real-world comparisons of these two drugs in the modern CDK4/6 inhibitor era, and its headline finding is striking: while both drugs controlled the disease for a similar length of time, patients treated with S-1 lived substantially longer overall.

The study, led by Takayuki Kobayashi and colleagues in the Department of Breast Medical Oncology, enrolled 123 patients with hormone receptor-positive, HER2-negative metastatic breast cancer who received either capecitabine or S-1 as their first-line chemotherapy between 2015 and 2023. This window is significant, because it captures the period in which CDK4/6 inhibitors became the standard of care, meaning most patients in the cohort had already been exposed to these targeted agents before starting chemotherapy. The researchers analyzed progression-free survival, the time patients remained on treatment without their disease worsening, and overall survival, the time from the start of chemotherapy until death, using Kaplan-Meier curves and Cox proportional hazards models, the standard statistical tools for comparing survival between groups while accounting for the passage of time and other influencing factors.

Across the entire cohort, the median progression-free survival was 7.6 months and the median overall survival was 34.7 months, figures that demonstrate that oral fluoropyrimidines remain genuinely effective first-line chemotherapy even after the widespread adoption of CDK4/6 inhibitors. This is an important reassurance, because a persistent question in the field has been whether tumors that have progressed after CDK4/6 inhibition behave differently, perhaps more aggressively or with altered drug sensitivity, when they finally encounter chemotherapy. The retrospective design means the data reflect everyday clinical practice rather than the carefully controlled conditions of a randomized trial, which is precisely what makes them valuable for understanding how these drugs perform in the heterogeneous patient populations oncologists actually treat.

The question of prior CDK4/6 inhibitor exposure was central to the analysis. Eighty-five of the 123 patients, or 69 percent, had received a CDK4/6 inhibitor before starting chemotherapy. When the researchers compared these patients with the 38 who had never received the targeted drugs, the differences were not statistically significant. Median progression-free survival was 7.3 months in the previously exposed group versus 10.1 months in the unexposed group, a numerical gap that did not reach significance with a p-value of 0.64. Median overall survival was nearly identical, at 34.8 versus 34.7 months, with a p-value of 0.59. In other words, prior exposure to CDK4/6 inhibitors did not adversely affect survival outcomes once patients began oral fluoropyrimidine chemotherapy, a finding that challenges the assumption that the biology of post-CDK4/6 disease necessarily erodes the effectiveness of subsequent chemotherapy.

The pharmacological background helps explain why this comparison matters. Both capecitabine and S-1 are oral prodrugs that are converted in the body to 5-fluorouracil, a fluoropyrimidine that interferes with DNA synthesis by inhibiting thymidylate synthase, thereby killing rapidly dividing cells. Capecitabine relies on a three-step enzymatic activation, with the final step mediated by thymidine phosphorylase, an enzyme that is relatively enriched in tumor tissue. S-1 combines tegafur, another 5-fluorouracil prodrug, with two modulating compounds: gimeracil, which inhibits dihydropyrimidine dehydrogenase, the enzyme responsible for degrading 5-fluorouracil, thereby prolonging and intensifying drug exposure, and oteracil, which reduces gastrointestinal toxicity by limiting activation of the drug in the gut. These mechanistic differences translate into distinct toxicity profiles and dosing schedules, and they have long fueled debate about which agent offers the better balance of efficacy and tolerability.

When the two regimens were compared head to head, the results diverged in an unexpected way. Eighty patients received S-1 and 43 received capecitabine. Progression-free survival was similar between the groups, at 8.7 months for S-1 versus 6.7 months for capecitabine, a difference that did not reach statistical significance with a p-value of 0.19. Overall survival, however, told a different story: patients treated with S-1 had a median overall survival of 40.1 months compared with 24.0 months for those treated with capecitabine, a difference that was statistically significant at p equal to 0.010. The authors emphasize that this survival gap emerged despite similar disease control during treatment, which raises intriguing questions about what happens after the drugs stop working.

To test whether the survival advantage of S-1 was genuine rather than an artifact of differences between the patient groups, the researchers performed multivariate analysis, a statistical technique that adjusts for multiple clinical variables simultaneously. The result was unambiguous: treatment with S-1 remained an independent favorable prognostic factor for overall survival, with a hazard ratio of 0.39 and a 95 percent confidence interval of 0.24 to 0.66, and a p-value below 0.001. A hazard ratio below 1 indicates a reduced risk of death; in this case, patients on S-1 experienced roughly a 61 percent lower hazard of death compared with those on capecitabine after adjustment for other factors. Tolerability, meanwhile, appeared comparable, as the rates of treatment discontinuation due to adverse events were similar between the two regimens, suggesting that the survival difference was not simply a consequence of patients tolerating one drug better than the other.

The authors are careful about interpretation, and appropriately so. As a retrospective, single-institution cohort study, the analysis cannot exclude the possibility of selection bias: physicians may have chosen S-1 for patients with particular clinical characteristics that themselves predict longer survival, and no amount of multivariate adjustment can fully eliminate such confounding. The imbalance in group sizes, with nearly twice as many patients receiving S-1, also reflects real-world prescribing patterns rather than randomization. The authors explicitly state that these findings necessitate further investigation to elucidate the mechanisms underlying the observed survival difference, and a prospective randomized trial would be the definitive way to establish whether S-1 truly extends life or whether the association reflects deeper differences in the populations treated.

Nevertheless, the study carries practical weight for clinicians and patients navigating a disease that remains incurable once it has spread. The demonstration that prior CDK4/6 inhibitor exposure does not compromise survival on subsequent chemotherapy is reassuring for the growing population of patients whose tumors progress after targeted therapy, and it suggests that the sequencing strategy of endocrine therapy with CDK4/6 inhibition followed by fluoropyrimidine chemotherapy does not foreclose meaningful benefit from cytotoxic treatment. At the same time, the overall survival signal favoring S-1, if confirmed, could influence drug selection in settings where both agents are available, particularly in Japan and other Asian countries where S-1 is widely approved. The study received no external funding, was approved by the institutional review board of the Cancer Institute Hospital with the requirement for informed consent waived, and the authors declared no competing interests, strengthening the credibility of the observational data.

Published on 7 October 2026 as an open-access article in BMC Cancer, the study adds a meaningful piece to the evolving puzzle of how best to sequence therapy for hormone receptor-positive, HER2-negative metastatic breast cancer. It documents that in the CDK4/6 inhibitor era, first-line oral fluoropyrimidines continue to deliver median overall survival approaching three years, that the legacy of targeted therapy does not diminish the value of chemotherapy, and that two drugs long considered interchangeable may not be equivalent after all. Whether the survival advantage of S-1 reflects its pharmacological design, its tolerability profile, or the biology of the patients who receive it remains an open question, but it is now a question with a concrete clinical signal attached, and one that the oncology community will be pressed to answer with prospective evidence.

Subject of Research: Comparative effectiveness of S-1 versus capecitabine as first-line chemotherapy for hormone receptor-positive, HER2-negative metastatic breast cancer in the CDK4/6 inhibitor era

Article Title: S-1 versus capecitabine as first-line chemotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer in the era of cyclin-dependent kinase 4/6 inhibitors: a retrospective cohort study

Article References: Kobayashi, T., Nishimura, M., Aoyama, Y., Kuno, M., Hosonaga, M., Kurata, M., Inagaki, L., Masuda, J., Ozaki, Y., Takano, T., & Ueno, T. (2026). S-1 versus capecitabine as first-line chemotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer in the era of cyclin-dependent kinase 4/6 inhibitors: a retrospective cohort study. BMC Cancer. https://doi.org/10.1186/s12885-026-17102-y

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17102-y

Keywords: metastatic breast cancer, S-1, capecitabine, fluoropyrimidine, CDK4/6 inhibitors, hormone receptor-positive, HER2-negative, progression-free survival, overall survival, retrospective cohort study, chemotherapy, oncology