Age, endocrine therapy persistence, and recurrence risk in hormone receptor-positive early breast cancer: clarifying a long-standing clinical question

Hormone receptor-positive (HR-positive) early breast cancer (eBC) has long been considered a therapeutic success story, largely because endocrine therapy (ET) substantially reduces recurrence risk when taken consistently and over many years (1-3). This remarkable improvement in survival rates has made ET a mainstay in HR-positive eBC (4,5). Yet within this broad success lies a persistent and troubling paradox: young women with HR-positive tumors continue to experience significantly poorer outcomes than their older counterparts, even when treated according to guidelines. This phenomenon has been observed across numerous Western and Asian cohorts, and although various explanations have been proposed—including biological aggressiveness, treatment tolerance, social context, and long-term adherence—the relative contributions of these factors have remained difficult to quantify (6-9). The nationwide cohort study by Dumas et al. provides a valuable opportunity to clarify one component of this disparity by examining the specific influence of ET persistence or discontinuation on disease-free survival (DFS) across age groups using a methodological approach designed to approximate causal inference (10). Discontinuation was defined based on dispensing gaps accounting for surplus medication; treatment switches were not classified as discontinuation. Their work offers one of the most rigorous examinations to date of a long-standing clinical question and helps illuminate why young women with HR-positive disease continue to face a disproportionate risk of recurrence.

Previous observational studies have consistently shown that women under 40 years with HR-positive breast cancer have higher recurrence and mortality risk than older women, whereas no comparable age gradient exists in HR-negative disease (11-13). The health insurance system database (SNDS) cohort analyzed by Dumas et al. confirms this pattern at an unprecedented national scale: women aged ≤34 years had a 5-year DFS of only 74.5%, compared with 88.4% in women aged 45–49 years. After 50 years old, DFS ranged from 88.2% for patients age 55–59 years to 89.8% for patients age 50–54 years. These findings reinforce that HR-positive disease in young women is biologically distinct and clinically more aggressive (14). Younger women are more likely to present with luminal B–like tumors, higher proliferation indices, and molecular signatures associated with relative endocrine resistance (15,16). They also face unique life-stage stressors—including fertility concerns, heavy symptom burden, psychological distress, and competing responsibilities—that frequently compromise sustained adherence to ET (17-19). Together, these biological and psychosocial factors create an environment in which younger patients are more vulnerable both to incomplete endocrine treatment and to the clinical consequences of missing it (15,18,20).

The most innovative feature of the Dumas et al. study is the use of target trial emulation, a causal inference framework increasingly applied within epidemiology to align observational data with the structure of a randomized controlled trial (21). Using a target trial emulation framework, the investigators structured their observational cohort to mirror the key elements of a randomized trial—defining a uniform time zero, assigning patients to hypothetical treatment strategies, censoring them when they deviated from these strategies, and weighting for time-varying confounding. This approach mitigates immortal-time and adherence biases and allows a more causally interpretable estimate of the effect of ET persistence than traditional observational analyses (22). Because adherence research is notoriously susceptible to confounding and immortal time bias, traditional analyses often overestimate or misattribute treatment effects. By establishing a clear time zero, employing cloning and censoring strategies, and weighting patients to balance covariates across emulated arms, the authors substantially reduce these biases (10). This allows them not only to measure the association between ET persistence and outcomes but to estimate the magnitude of benefit that might be achievable if ET were taken consistently without prolonged interruptions. However, persistence was inferred from dispensing records and therefore assumes medication intake, which may lead to misclassification if dispensed medication is not taken. This would likely attenuate the observed association, suggesting that the true impact of sustained adherence may be underestimated. In addition, DFS events were algorithmically derived from claims data and may be subject to misclassification.

The results are clinically insightful. In general, younger patients with HR-positive tumors had shorter DFS compared with older age. In addition, the authors described an increase in 5-year ET persistence proportions with age, peaking in the 55–59 years age group. When emulating a strategy in which gaps in ET do not exceed 30 days, the authors report under the emulated sustained persistence strategy, the projected 5-year DFS difference is a 4.3% improvement in 5-year DFS for women aged ≤34 years with HR-positive eBC. Women aged 35–39 years experience a more modest but still meaningful improvement of 2.6%. Importantly, compared with gaps of up to 30 days, gaps of up to 90 days reduced the DFS benefit from 4.3 to 1.3 percentage points. The DFS benefit was further reduced to 1.0 percentage point when gaps of up to 180 days were allowed (10). The observed gradient in DFS benefit with increasing allowable gaps should be interpreted as illustrating the sensitivity of outcomes to treatment interruptions rather than defining a universal operational threshold. These findings should primarily inform the design of prospective adherence interventions and pragmatic clinical studies. Interestingly, after 50 years of age, DFS benefit never exceeded 1.9 percentage points. In contrast, DFS proportions were less variable across all age groups both before and after age 50 years in patients with HR-negative tumors. This steep age gradient, particularly in young women with HR-positive disease, suggests that the biological and clinical consequences of endocrine-therapy interruption are substantially more pronounced in younger patients. These observations are biologically plausible and consistent with prior literature, including higher endogenous estrogen levels and more proliferative tumor biology in younger patients; however, these mechanisms remain hypothesis-generating and require further validation. Premenopausal women have markedly higher endogenous estrogen levels, such that lapses in ET can rapidly re-establish estrogenic stimulation of residual microscopic disease (23). Younger women also more frequently develop luminal tumors with higher proliferative activity and gene-expression signatures associated with endocrine resistance, amplifying the potential impact of even brief treatment interruptions (15). Large population-based analyses further show that the adverse prognostic effect of young age is most pronounced within HR-positive and luminal subtypes, reinforcing the biological sensitivity of this disease context (6,11). In contrast, postmenopausal women exhibit lower baseline estrogen levels and less proliferative luminal biology, which may attenuate the effect of temporary lapses in therapy.

Notably, Dumas et al. also demonstrate that even perfect adherence does not eliminate the survival gap between younger and older women. Under the strictest emulated persistence scenario, the DFS of women ≤34 years remains several points lower than that of older cohorts. This residual disparity highlights that adherence is a key contributor but not the sole explanation for the poor prognosis of the youngest women. Biological factors likely play an important role: young women disproportionately present with higher genomic risk scores, more aggressive proliferation-related signatures, and endocrine-resistant phenotypes that persist regardless of adherence (15). Additionally, chemotherapy-induced ovarian suppression—a well-established predictor of improved outcomes in premenopausal women with HR-positive breast cancer—is achieved less reliably in the youngest patients. Multiple studies have demonstrated that chemotherapy-induced amenorrhea is associated with significantly better disease-free and overall survival in this setting, underscoring its biological relevance (24,25). Yet the likelihood of achieving permanent ovarian suppression is strongly age-dependent: younger women have a substantially lower incidence of chemotherapy-induced amenorrhea than women approaching natural menopause, largely due to greater ovarian reserve and more rapid post-treatment endocrine recovery (26,27). This age-related variation further contributes to the heightened vulnerability of young HR-positive patients, for whom incomplete endocrine suppression may compound the adverse impact of interruptions in adjuvant ET. These considerations underscore that adherence interventions, while essential, must be complemented by continued research into tumor biology and tailored endocrine or ovarian suppression strategies.

Still, the immediate clinical implications of the study are clear and consequential. Among young women, ET interruptions longer than 30 days appear clinically meaningful. Importantly, these findings should be interpreted as projected differences under an emulated sustained persistence strategy rather than as evidence for a fixed clinical threshold. Nevertheless, the magnitude of the effect—an absolute 5-year DFS difference of approximately 4.3% in women aged ≤34 years—suggests that even relatively short interruptions may be clinically relevant in this population. This finding challenges the comforting assumption that brief gaps in ET are clinically innocuous. That reassurance may be more defensible in predominantly postmenopausal populations, in whom baseline estradiol levels are very low and sex-steroid dynamics are relatively stable (28,29) and in whom primary breast cancers more often display less proliferative, biologically indolent profiles than in younger women (30,31). In contrast, young premenopausal women with HR-positive disease more frequently harbour highly proliferative, genomically distinct luminal tumours, and young age confers a particularly pronounced survival disadvantage within the HR-positive/human epidermal growth factor receptor 2 (HER2)-negative subtype (6,15,32). Against this biological background, interruptions of ET in younger patients are likely to be more consequential, and clinicians should adopt a proactive strategy to prevent, anticipate, and manage treatment gaps—especially given robust evidence that non-adherence and early discontinuation of adjuvant ET are associated with increased recurrence and mortality (33,34). This includes early and aggressive management of vasomotor symptoms, sexual dysfunction, and musculoskeletal side effects; structured fertility counseling before treatment initiation; close follow-up during the first 2 years when adherence typically declines; and integrated psychosocial support to address the emotional and practical challenges of long-term therapy adherence (17,18).

At a population level, the relevance of this work extends beyond France. In China and many other Asian countries, breast cancer occurs at a younger median age than in Western nations, with a significant proportion of cases diagnosed before age 40 years (13,35,36). The proportion of patients for whom ET persistence is most crucial is therefore larger, and the potential public health impact of improved adherence is correspondingly greater. The methodological framework showcased by Dumas et al. offers a compelling model for leveraging national health databases in Asia to assess adherence patterns, quantify survival loss attributable to interruptions, and design targeted interventions at scale. As survivorship programs expand throughout the region, integrating adherence support—whether through digital health tools, community-based counseling, or multidisciplinary survivorship clinics—could represent a high-value investment.

Taken together, the findings of this study point toward a more nuanced understanding of young-onset HR-positive breast cancer. ET persistence is a modifiable factor that contributes meaningfully to outcomes, especially for the youngest women. However, persistence alone cannot resolve all of the age-related disparities observed in this disease. Progress will require a multi-pronged approach, combining biological insights, optimized endocrine regimens, ovarian suppression strategies, comprehensive toxicity management, psychosocial support, and health system-level interventions that minimize the risk of treatment interruption.

Ultimately, the work by Dumas et al. strengthens a principle that is both intuitive and often underappreciated: patients benefit from therapies they can and do take consistently. However, residual confounding cannot be excluded, particularly for psychosocial and behavioral factors such as symptom burden, treatment tolerance, social support, and fertility considerations, which may influence both persistence and outcomes but are not fully captured in claims data. For young women facing HR-positive eBC, long-term adherence to ET represents both a challenge and an opportunity. Addressing the barriers to persistence is not merely a matter of supporting adherence—it is a matter of improving survival. By quantifying the impact of treatment interruptions and highlighting the age groups for whom persistence matters most, this study offers a roadmap for clinicians, researchers, and health systems to better support the patients whose risk is greatest and whose potential benefit is highest.

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-2025-1-183/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-1-183/coif). M.S. reports grants and personal fees from Pierre-Fabre, Astra-Zeneca, and Eisai; grants, personal fees and non-financial support from Roche, Pfizer, Novartis, Pantarhei Bioscience, and BioNTech; personal fees from EuroBio, Lilly, Gilead, Daiichi Sankyo, and Menarini Stemline; grants from Genentech; and personal fees and non-financial support from MSD, outside the submitted work. In addition, he is also listed as an inventor on patents EP 2390370 B1 and EP 2951317 B1. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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.

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