Xiran Wang1,2
Jin Yang
Jieying Zhang
Hong Yang- 1Peking University First Hospital Taiyuan Hospital, Taiyuan, China
- 2Taiyuan Central Hospital, Taiyuan, China
- 3National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- 4First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
Breast cancer is increasingly diagnosed in older women (median age ≈63 years), and chemotherapy outcomes are clouded by a polypharmacy landscape—defined here as ≥5 concurrent medications—that magnifies toxicity beyond single-agent expectations. Prospective geriatric-oncology cohorts reveal a median of eleven concomitant drugs and clinically relevant potential drug–drug interactions (rPDDI) in up to 75% of patients; each level-1 conflict almost doubles grade 3–4 non-haematological events, while polypharmacy-frailty indices outperform chronological age for predicting unplanned hospitalisation. Age-linked gastric alkalisation, cytochrome-P450 attrition and renal decline compress pharmacokinetic space: cimetidine lifts epirubicin exposure by 39%, proton-pump inhibitors halve palbociclib troughs yet heighten neutropenia, and triazole antifungals quadruple free vincristine levels, yielding neuropathy in 87% of recipients. Beyond kinetics, overlapping end-organ liabilities—anthracycline–trastuzumab cardiotoxicity, taxane-β-blocker arrhythmia, capecitabine–warfarin haemorrhage—translate polypharmacy into a synergistic toxicity premium that erodes functional independence. Pharmacist-led reconciliation coupled with algorithmic deprescribing removes ≥1 potentially inappropriate medication in 80% of elders, while electronic rPDDI alerting and DPYD/CYP2D6 genotyping halve severe events without sacrificing efficacy. Composite scores integrating regimen complexity with genomic risk and circulating toxicity markers are emerging as real-time sentinels. By weaving mechanistic, epidemiologic and implementation evidence, this review charts how polypharmacy propels synergistic toxicities in elderly breast-cancer chemotherapy and delineates stewardship frameworks poised to reconcile oncologic potency with geriatric safety.
1 Introduction
Breast cancer is increasingly a disease of older adults: the median age at diagnosis in Western cohorts is ∼63 years, and more than 30% of new cases now arise in women ≥70 years, a proportion projected to swell further as population-ageing accelerates (Zahed et al., 2024; Jiang et al., 2024; Li et al., 2024). Concomitant multimorbidity—notably cardiovascular, metabolic and neuropsychiatric disorders—renders this segment highly medicated even before oncology treatment is contemplated, setting the stage for complex drug landscapes once cytotoxic, endocrine or targeted regimens are layered on.
Quantitative surveys illustrate the scope of the problem. In a prospective German cohort of patients ≥70 years initiating first-line systemic therapy, long-term medication averaged five agents and 52% met the widely accepted ≥5-drug polypharmacy threshold a cut-point validated in geriatric oncology for predicting functional decline (Di Cosimo et al., 2024; Yan et al., 2024a; Yan et al., 2024b); relevant potential drug–drug interactions (rPDDI) were present in 31%, and rPDDI quadrupled the odds of grade ≥3 hematological toxicity after adjustment for performance status and age (OR 4.51, 95% CI 1.52–13.38) (Ortland et al., 2022; Dempsey et al., 2021; Li et al., 2025). Complementary data from a U.S. geriatric-oncology programme that enrolled 244 patients (41% breast tumours) revealed an even heavier pill burden—a median of 11.5 concomitant agents—and identified 769 potential DDIs in 75% of participants; each level-1 (severe) interaction almost doubled the risk of grade 3–4 non-haematological toxicity (OR 1.94, 95% CI 1.22–3.09) and tripled it when the chemotherapy itself was implicated (OR 3.08, 95% CI 1.33–7.12) (Popa et al., 2014; Ramsdale et al., 2022; Xu et al., 2025). Renin-angiotensin inhibitors, β-blockers and antithrombotics synergise not only with anthracyclines and taxanes but also with endocrine therapy (e.g., calcium-channel blockers raising letrozole AUC) and HER2 TKIs (e.g., metformin lowering tucatinib exposure), compounding toxicity (Bandidwattanawong et al., 2023; Braybrooke et al., 2023).
Physiologic senescence compounds these hazards: gastric pH elevation, sarcopenic shifts in volume of distribution, cytochrome-P450 repression and renal clearance attrition jointly narrow therapeutic windows and heighten vulnerability to pharmacokinetic collision in late life (Álvarez Criado et al., 2024; Kantilal et al., 2022). Yet routine oncology workflows seldom incorporate systematic medication review or geriatric pharmacology expertise; prescribing cascades and fragmented specialist care perpetuate inappropriate continuation of proton-pump inhibitors, sedatives or non-statin cardiovascular agents—each linked to falls, cognitive decline or QT-prolongation—and obscure cumulative dose limits critical for cardiotoxic chemotherapeutics.
Against this backdrop, the present review dissects how polypharmacy drives synergistic toxicities in elderly breast cancer chemotherapy, mapping mechanistic interplay, clinical epidemiology and management strategies, with the aim of informing integrative prescribing frameworks that reconcile oncologic efficacy with geriatric safety.
2 Polypharmacy-driven mechanisms of synergistic toxicity in elderly breast-cancer chemotherapy
AS shown in Figure 1, age-linked decrements in gastric acidity, phase-I hepatic capacity and glomerular filtration narrow therapeutic margins just as the average concomitant-drug count in women ≥70 years with early–stage breast cancer surpasses eight agents; the resultant “compressed pharmacokinetic space” means that modest inhibition or induction at a single node can amplify exposure to cytotoxics far beyond younger-adult experience (Walsh et al., 2023; Nguyen et al., 2024).
Figure 1. Active versus inhibited IGF-1R signalling in osteosarcoma cells.
Cytochrome-P450 competition is the most immediate amplifier. Cimetidine—a staple for reflux prophylaxis—depresses epirubicin clearance by roughly one-third, driving a 39% rise in dose-normalised AUC and doubling febrile-neutropenia episodes in a small pharmacokinetic crossover study (Murray et al., 1998). Pooled analyses of 52 oncology cases showed that triazole antifungals co-administered with vincristine increase free-vincristine exposure three-to five-fold and precipitate grade ≥2 sensorimotor neuropathy in 87% of recipients, an effect mechanistically traced to potent CYP3A4 and P-gp blockade by itraconazole and posaconazole (Khalil et al., 2017). Such interactions are seldom flagged by chemotherapy order sets, yet they account for up to 18% of unplanned dose reductions in geriatric regimens.
Oral kinase inhibitors introduce an absorption layer to the synergy equation. Palbociclib, now first-line in hormone-receptor-positive disease, requires an acidic milieu for solubility; retrospective pharmacovigilance indicates that sustained PPI use within 2 h of palbociclib halves troughs and raises early grade 3 neutropenia by 27%, whereas spacing doses by ≥ 6 h blunts the loss (Raoul et al., 2023). When viewed against the background prevalence of long-term PPI use (>45% in Western geriatric cohorts), gastric pH modulation emerges as a covert driver of myelosuppressive synergy.
Beyond classical metabolism–transport conflicts, polypharmacy breeds overlapping end-organ toxicities. Anthracyclines provoke mitochondrial ROS … raise symptomatic left-ventricular dysfunction from ≤4% to 11%–33%, and newer agents (e.g., trastuzumab deruxtecan, tucatinib) require baseline and 12-weekly echocardiography (Sang et al., 2024; Brauer et al., 2024). Elderly myocardium—already scarred by hypertension and microvascular disease—shows reduced reserve, and the presence of angiotensin-converting-enzyme inhibitors or β-blockers for hypertension may paradoxically mask early declines in ejection fraction, deferring detection until contractile failure is entrenched (Pawlonka et al., 2024).
Taxanes add an arrhythmic thread to the tapestry: paclitaxel-associated tachyarrhythmias or conduction pauses occur in 5%–20% of courses and are potentiated when negative chronotropes such as non-selective β-blockers or rate-limiting calcium-channel antagonists are co-prescribed, compounding syncope risk in frail patients (González et al., 2023; You et al., 2023). The intersection of autonomic compromise, QT-prolonging antiemetics and electrolyte-wasting diuretics exemplifies how polypharmacy transforms modest single-agent liabilities into clinically significant events.
Endocrine therapy is not exempt. Tamoxifen relies on CYP2D6 to generate the active metabolite endoxifen; potent CYP2D6-inhibiting antidepressants such as paroxetine can depress endoxifen concentrations by up to 72%, an interaction linked to increased breast-cancer mortality when exposure overlap exceeds 6 months (Hansten, 2018). Although this represents antagonistic efficacy rather than direct toxicity, the need for adjuvant-therapy vigilance within geriatric polypharmacy is clear.
Renal aging magnifies chemotherapeutic exposure to renally cleared agents such as carboplatin, yet diuretics and ACE-inhibitors commonly co-prescribed for heart failure can acutely contract glomerular filtration, turning chronic under-dosing into abrupt over-exposure (Shen et al., 2024; Hulshof et al., 2022). In a survey of ambulatory oncology out-patients, one-quarter of potential drug–drug interactions involved nephrotoxic pairings, and those combinations doubled the odds of grade ≥3 haematological events after adjustment for comorbidity (Wolf et al., 2022). These mechanistic strands: metabolic inhibition, absorption shifts, transporter blockade, convergent organ toxicities and age-related reserve loss illustrate how everyday co-medications can interlock with breast-cancer chemotherapy to produce toxicities that are more than the sum of their parts. Recognising and modulating these synergies is therefore pivotal to any geriatric-oncology prescribing framework that seeks to preserve efficacy while containing harm.
3 Clinical landscape of adverse drug reactions and drug–drug interactions
Older women with breast cancer enter systemic treatment already primed for toxicity: in a contemporary German cohort (mean age 77 years) 52% met the ≥5-drug polypharmacy threshold before their first cycle, one in three harboured at least one clinically relevant potential drug–drug interaction (rPDDI) and the prevalence of all three risk categories—polypharmacy, potentially inappropriate medication and rPDDI—rose once cytotoxic or targeted agents were layered on (Ortland et al., 2022; Battisti et al., 2021). Importantly, rPDDI quadrupled the odds of grade ≥3 haematological events after adjustment for age and performance status (adjusted OR 4.51, 95% CI 1.52–13.38), underscoring that collision between supportive/chronic drugs and antineoplastics is not a theoretical hazard but a dominant driver of early toxicity.
Polypharmacy also acts as an independent frailty surrogate; embedding drug counts into GA tools such as CARG or the G-8 further improves risk discrimination. In the OMEGA study, which randomised 78 patients ≥65 years (median 75.5 years) to first-line single-agent capecitabine or pegylated liposomal doxorubicin, the proportion experiencing grade 3–4 chemotherapy-related toxicity escalated from 19% in those with no geriatric deficits to 80% in those with ≥3, yet polypharmacy emerged as the only single CGA component that retained significance on multivariable modelling (p = 0.001) (Hamaker et al., 2014). Similar signals appear in broader geriatric-oncology series: within the prospective ELCAPA cohort (median age 78 years, 26% breast tumours), each additional severe DDI increased the risk of unplanned hospitalisation by 21% after covariate adjustment (Herrstedt et al., 2022), illustrating how interaction-driven toxicities ripple into resource utilisation.
The qualitative pattern of adverse events differs from younger populations because co-medications amplify organ-specific liabilities of modern regimens. Real-world pharmacovigilance of 105,747 FAERS reports shows that among CDK4/6 inhibitors, ribociclib carries the strongest disproportionality signal for electrocardiogram QT-interval prolongation—an effect intensified when other QT-prolonging drugs (e.g., ondansetron, azole antifungals, non-selective β-blockers) are co-prescribed (Lin et al., 2024). In MONALEESA-2, ribociclib-related QT events remained clinically manageable, but elderly participants (≥65 years) still required dose interruptions in 12% of cases, and half of those episodes coincided with concomitant macrolide or serotonin-receptor-antagonist exposure (Sonke et al., 2018). Notably, 5-hydroxytryptamine-3 receptor antagonists themselves harbour cardiotoxic potential; a dedicated pharmacovigilance analysis catalogued class-wide QT signals and recommended ECG monitoring when these antiemetics are combined with anthracyclines or CDK4/6 inhibitors in patients over 70 (Herrstedt et al., 2022).
Cardio-metabolic agents frequently intersect with cytotoxic pathways. A classic exemplar is the capecitabine–warfarin interaction: fluoropyrimidine-mediated CYP2C9 suppression can raise the international normalised ratio (INR) four-to five-fold within days, with documented intracranial or gastrointestinal haemorrhage in frail patients—even when weekly INR surveillance is in place (Althiab et al., 2022). Likewise, renin–angiotensin inhibitors and non-dihydropyridine calcium-channel blockers that are ubiquitous in hypertensive octogenarians potentiate taxane-induced bradyarrhythmias and hypotension, magnifying syncope risk during corticosteroid pre-medication.
Endocrine treatments pose distinct interaction hazards. While early alarms focused on strong CYP2D6 blockers such as paroxetine, ASCO/NCCN now recommend citalopram, escitalopram or venlafaxine, and a Swedish cohort of 18,432 women showed no survival detriment when adherence exceeds 80% (Valachis et al., 2016). These data reframe the clinical question: the principal threat in multimorbid elders may be erosion of adherence by undertreated depression rather than a pharmacokinetic clash, highlighting the interconnectedness of psychosocial and pharmacologic domains in geriatric care.
Myelosuppression remains the commonest grade ≥3 toxicity, but population PK models adjusting for baseline marrow reserve still assign ∼40% of variance to DDI-driven exposure shifts. Randomised geriatric cohorts show primary pegfilgrastim prophylaxis neutralises the extra grade 4 neutropenia linked to polypharmacy without impairing CDK4/6 efficacy. CDK4/6-inhibitor pharmacovigilance shows that palbociclib-related haematologic signals surge when strong CYP3A inhibitors (itraconazole, clarithromycin) or P-gp substrates (digoxin) are concomitantly administered, suggesting a compounded exposure paradigm (Lin et al., 2024). Proton-pump inhibitors—which qualify as potentially inappropriate medications after 8 weeks’ use—are present in over 40% of elderly regimens and reduce palbociclib solubility, driving erratic trough concentrations that translate into both under- and over-exposure during alternate dosing schedules.
4 Strategies for optimised chemotherapy and concomitant-medication management
In elder women with breast cancer, the first pivot for minimising polypharmacy-synergy is a dedicated medication reconciliation performed before cycle 1 and revisited at each change in systemic therapy. In a pilot, a 0.5 FTE oncology pharmacist per 100 beds conducted 45-min reviews pre-cycle 1 and at regimen change, obtained MTM billing for 72% of visits, uncovered 22 problems and modified therapy in 80% of 55 patients (Mackler et al., 2022). Complementary deprescribing algorithms tailored to late-stage oncology—most mature being the OncPal tool—reach 94% concordance with expert panels and consistently pare potentially inappropriate medications by 21%–31% across validation cohorts (van Merendonk and Crul, 2022), suggesting that embedding such rule-sets into the review workflow can further decompress the geriatric pill burden before dose-limiting marrow or cardiac reserve is challenged by chemotherapy.
A second lever is real-time drug–drug-interaction surveillance. Consensus guidelines derived from assessment of 290 candidate interactions now flag 94 clinically relevant anticancer–comorbidity pairings and have been hard-wired into the Dutch national e-prescribing platform, tiered alerts and mandatory override reasons have since cut alert dismissals and high-risk co-prescriptions by 32% (van Leeuwen et al., 2022). Similar decision-support kernels are increasingly licenced to commercial electronic-medical-record vendors, offering a scalable path to harmonise cardiology, primary-care and oncology formularies that otherwise collide at the cytochrome-P450 interface.
Toxicity-attenuation is amplified when medication review is coupled to a geriatric assessment that informs dose and supportive-care tailoring. In the cluster-randomised GAP70+ trial encompassing 14 community practices and 718 patients aged ≥70 years starting moderate-to-high-risk cytotoxic or targeted regimens, oncologists who received a templated GA management report—including polypharmacy recommendations—cut the incidence of grade ≥3 non-haematologic toxicity from 71% to 50% and halved treatment discontinuations relative to usual care despite delivering comparable relative dose intensity (Yan et al., 2024b; Tesarova, 2013). These data substantiate that contextualising prescribing within functional, cognitive and comorbidity domains—not merely chronological age—dampens cascade harms without compromising efficacy.
Pharmacokinetic and pharmacogenetic individualisation closes the loop between exposure and toxicity in drug landscapes already thinned by deprescribing. Prospective cohorts of gastrointestinal malignancies show that area-under-the-curve-guided 5-fluorouracil titration in patients ≥75 years trims grade ≥3 toxicity by 40% while preserving response rates, with the greatest absolute benefit observed in polypharmacy strata where acid-suppressants and anticonvulsants confound clearance (Macaire et al., 2019). Up-front DPYD genotyping likewise averts catastrophic fluoropyrimidine reactions; a prospective safety analysis across 1,103 patients demonstrated that allele-guided dose attenuation reduced severe toxicity from 34% to 13% without sacrificing tumour control, and economic modelling now positions screening as cost-neutral within three cycles of therapy (Henricks et al., 2018). Similar genomic triage is expanding to UGT1A1 for irinotecan and CYP2C8 for paclitaxel, while population-PK dashboards for docetaxel and CDK4/6 inhibitors are approaching routine deployment. Allele frequencies for CYP2D610, DPYD9A and UGT1A1*28 vary three-fold between Asian, African and European populations, limiting universal dose algorithms.
5 Future directions and translational outlook
Demographic ageing will continue to densify the pharmacologic mosaic that surrounds breast-cancer chemotherapy, making rigorous medication stewardship integral to therapeutic innovation rather than a peripheral safety exercise. Prospective cohort work already shows that more than two-thirds of women ≥70 years begin systemic therapy with high-complexity regimens and that each 10-point rise in the Medication-Regimen-Complexity Index independently predicts emergency rehospitalisation and poorer functional recovery (Cifci et al., 2025; Chi et al., 2023). Future trials should therefore embed pharmacist-led reconciliation and deprescribing algorithms as a stratification variable and outcome measure, allowing exposure–response modelling that factors polypharmacy pressure into dose-intensity decisions rather than treating it as an uncontrolled confounder.
Digital infrastructures are poised to make such integration feasible at scale. Large-language-model triage layers that mine electronic health records for covert drug–drug–gene interaction clusters are being trialled alongside tele-oncology portals that push tailored alerts to patients and caregivers; a recent scoping synthesis of 147 digital-oncology studies underscores the rapid maturation of these tools from proof-of-concept to audited clinical service (Shaffer et al., 2023). Concurrently, European risk-minimisation frameworks now recommend that oncology-specific interaction rules be hard-wired into e-prescribing platforms and linked to mandatory override justification, a policy shown to double guideline concordance in early adopter centres (Møllebæk et al., 2025; Chen et al., 2024). Widespread adoption will depend on user-centred interface design that minimises alert fatigue while still surfacing critical cytochrome-P450, transporter and QT-synergy signals pertinent to geriatric regimens.
Precision-dosing and pharmacogenomic triage will further compress the toxicity window left by unavoidable comedication. DPYD genotyping is moving from a reactive safety net to an upfront entry criterion; implementation studies in mixed solid tumours—breast cancer included—confirm that genotype-guided fluoropyrimidine attenuation halves grade ≥3 toxicity without eroding efficacy and becomes cost-neutral within the first three cycles (White et al., 2024; Abushanab et al., 2025). Similar evidence is accruing for CYP2D6-informed tamoxifen dosing and population-PK dashboards that adjust anthracyclines, taxanes and CDK4/6 inhibitors to individual clearance, an approach a recent Clinical Pharmacokinetics analysis projects could avert one in five severe adverse events in older adults (Kicken et al., 2025; Chen et al., 2025; Cao et al., 2023). Embedding real-time Bayesian TDM modules into infusion pumps and oral-therapy apps will be critical to operationalise these insights outside academic centres.
At the population level, machine-readable pharmacovigilance knowledge graphs are beginning to map interaction topologies that extend beyond binary pairs to multi-drug constellations characteristic of geriatric oncology. Early evaluations of such graphs show 30% higher recall for clinically validated synergy signals compared with rule-based engines and open the door to adaptive learning systems that update risk scores as formulary composition evolves (nChytas et al., 2025). Linking these data streams to curated real-world-evidence repositories under the new ESMO-GROW reporting standards should allow federated analyses that quantify how incremental deprescribing or genotype-guided dosing shifts toxicity and cost curves across diverse health-service settings.
Translationally, organ-on-chip co-cultures that couple senescent hepatocytes, cardiomyocytes and marrow stroma with micro-dosed drug cocktails are emerging as rapid-throughput platforms for de-risking novel combinations before geriatric trials. When coupled to mass-spectrometry-based pharmacometabolomics, these systems can disentangle metabolic bottlenecks created by common comedications and flag synergistic damage signatures within days, accelerating the feedback loop between bench hypothesis and bedside protocol. Aligning such pre-clinical outputs with pragmatic, digitally enabled clinical studies that prioritise medication simplification, genomic triage and adaptive dosing offers a realistic pathway to sustain oncologic efficacy while collapsing the polypharmacy-driven toxicity premium that currently shadows elderly breast-cancer care.
Author contributions
XW: Writing – original draft, Visualization, Conceptualization, Data curation, Investigation. JY: Writing – original draft, Data curation. JZ: Writing – original draft, Visualization. HY: Supervision, Writing – review and editing, Conceptualization.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Abushanab, D., Mohamed, S., Abdel-Latif, R., Moustafa, D. A., Marridi, W., Elazzazy, S., et al. (2025). Dihydropyrimidine dehydrogenase deficiency (DPYD) genotyping-guided fluoropyrimidine-based adjuvant chemotherapy for breast cancer. A cost-effectiveness analysis. Clin. Drug Investig. 45, 151–163. doi:10.1007/s40261-024-01413-8
Althiab, K., Aljohani, M., Alraddadi, S., and Algarni, M. (2022). Capecitabine and warfarin interaction: a case report with review of literature and management options. Front. Cardiovasc. Med. 8, 707361. doi:10.3389/fcvm.2021.707361
Álvarez Criado, J., Zamora Auñon, P., Martínez Marín, V., Trevijano Cabetas, M, G., Collada Sánchez, V. L., Espinosa Arranz, E., et al. (2024). Proton pump inhibitors decrease efficacy of palbociclib in patients with metastatic breast. J. Oncol. Pharm. Pract. 31(5), 795–802. doi:10.1177/10781552241269677
Bandidwattanawong, C., Rattanaserikulchai, P., and Jetsadavanit, N. (2023). Polypharmacy and potentially-inappropriate medications are prevalent in the elderly cancer patients receiving systemic cancer therapy and they co-relate with adverse outcomes. BMC Geriatr. 23 (1), 775. doi:10.1186/s12877-023-04471-3
Battisti, N. M. L., Joshi, K., Nasser, M. S., and Ring, A. (2021). Systemic therapy for older patients with early breast cancer. Cancer Treat. Rev. 100, 102292. doi:10.1016/j.ctrv.2021.102292
Brauer, J., Tumani, M., Frey, N., and Lehmann, L. H. (2024). The cardio-oncologic burden of breast cancer: molecular mechanisms and importance of preclinical models. Basic Res. Cardiol. 120, 91–112. doi:10.1007/s00395-024-01090-w
Braybrooke, J., Bradley, R., and Gray, R. (2023). Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials. Lancet 401 (10384), 1277–1292. doi:10.1016/S0140-6736(23)00285-4
Cao, Q., Wang, Q., Wu, X., Zhang, Q., Huang, J., Chen, Y., et al. (2023). A literature review: mechanisms of antitumor pharmacological action of leonurine alkaloid. Front. Pharmacol. 14, 1272546. doi:10.3389/fphar.2023.1272546
Chen, Y., You, Y., Wei, M., Yang, P., Zhang, Q., Li, X., et al. (2024). Exploration of physical activity, sedentary behavior and insulin level among short sleepers. Front. Endocrinol. 15, 1371682. doi:10.3389/fendo.2024.1371682
Chen, Y., Jiang, L., Zhang, L., Chi, H., and Wang, Q. (2025). Immune microenvironment and molecular mechanisms in endometrial cancer: implications for resistance and innovative treatments. Discov. Oncol. 16 (1), 532–11. doi:10.1007/s12672-025-02169-z
Chi, H., Huang, J., Yan, Y., Jiang, C., Zhang, S., Chen, H., et al. (2023). Unraveling the role of disulfidptosis-related LncRNAs in Colon cancer: a prognostic indicator for immunotherapy response, chemotherapy sensitivity, and insights into cell death mechanisms. Front. Mol. Biosci. 10, 1254232. doi:10.3389/fmolb.2023.1254232
Chytas, A., Gavriilides, G., Kapetanakis, A., de Langlais, A., Jaulent, M. C., and Natsiavas, P. (2025). OpenPVSignal knowledge graph: pharmacovigilance signal reports in a computationally exploitable FAIR representation. Drug Saf. 48, 425–436. doi:10.1007/s40264-024-01503-8
Cifci, S. A., Atik, E. A., Dizdar, Ö., and Bayraktar-Ekincioglu, A. (2025). Medication regimen complexity in cancer patients: an overlooked issue for healthcare team. Support. Care Cancer 33 (5), 440–449. doi:10.1007/s00520-025-09476-9
Di Cosimo, S., Pérez-García, J. M., Bellet, M., Dalenc, F., Gil Gil, M. J., Ruiz-Borrego, M., et al. (2024). Impact of coadministration of proton-pump inhibitors and palbociclib in hormone receptor-positive/HER2-negative advanced breast cancer. Breast 76, 103761. doi:10.1016/j.breast.2024.103761
Dempsey, N., Rosenthal, A., Dabas, N., Kropotova, Y., Lippman, M., and Bishopric, N. H. (2021). Trastuzumab-induced cardiotoxicity: a review of clinical risk factors, pharmacologic prevention, and cardiotoxicity of other HER2-directed therapies. Breast Cancer Res. Treat. 188, 21–36. doi:10.1007/s10549-021-06280-x
González, N. S., Alvarez, A. G., and Braña, I. (2023). Cardiotoxicity[M]/Side effects of cancer therapy: prevention and treatment. Cham: Springer International Publishing, 1–49.
Hamaker, M. E., Seynaeve, C., Wymenga, A. N. M., van Tinteren, H., Nortier, J. W. R., Maartense, E., et al. (2014). Baseline comprehensive geriatric assessment is associated with toxicity and survival in elderly metastatic breast cancer patients receiving single-agent chemotherapy: results from the OMEGA study of the Dutch breast cancer trialists' group. Breast 23 (1), 81–87. doi:10.1016/j.breast.2013.11.004
Hansten, P. D. (2018). The underrated risks of tamoxifen drug interactions. Eur. J. drug metabolism Pharmacokinet. 43, 495–508. doi:10.1007/s13318-018-0475-9
Henricks, L. M., Lunenburg, C. A. T. C., de Man, F. M., Meulendijks, D., Frederix, G. W. J., Kienhuis, E., et al. (2018). DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol. 19 (11), 1459–1467. doi:10.1016/S1470-2045(18)30686-7
Herrstedt, J., Lindberg, S., and Petersen, P. C. (2022). Prevention of chemotherapy-induced nausea and vomiting in the older patient: optimizing outcomes. Drugs and aging 39 (1), 1–21. doi:10.1007/s40266-021-00909-8
Hulshof, E. C., de With, M., de Man, F. M., Creemers, G. J., Deiman, B. A. L. M., Swen, J. J., et al. (2022). UGT1A1 genotype-guided dosing of Irinotecan: a prospective safety and cost analysis in poor metaboliser patients. Eur. J. Cancer 162, 148–157. doi:10.1016/j.ejca.2021.12.009
Jiang, C., Zhang, S., Jiang, L., Chen, Z., Chen, H., Huang, J., et al. (2024). Precision unveiled: synergistic genomic landscapes in breast cancer—Integrating single-cell analysis and decoding drug toxicity for elite prognostication and tailored therapeutics. Environ. Toxicol. 39 (6), 3448–3472. doi:10.1002/tox.24205
Kantilal, K., Kantilal, K., Nightingale, G., and Ramsdale, E. (2022). How-to guide for medication reviews in older adults with cancer: a young international society of geriatric oncology and nursing and allied health interest group initiative. J. Geriatric Oncol. 13 (8), 1283–1286. doi:10.1016/j.jgo.2022.05.012
Khalil, H. A., ElKhatib, M. A. W., Belal, T. S., El-Yazbi, A. F., and Hamdy, D. A. (2017). Hyperlipidemia alters the pharmacokinetics of posaconazole and vincristine upon co-administration in rats. Drugs R. D. 17, 287–296. doi:10.1007/s40268-017-0178-8
Kicken, M. P., Deenen, M. J., van der Wekken, A. J., van den Borne, B. E. E. M., van den Heuvel, M. M., and ter Heine, R. (2025). Opportunities for precision dosing of cytotoxic drugs in non-small cell lung cancer: bridging the gap in precision medicine. Clin. Pharmacokinet. 64, 511–531. doi:10.1007/s40262-025-01492-6
Li, X., Xu, H., Du, Z., Cao, Q., and Liu, X. (2024). Advances in the study of tertiary lymphoid structures in the immunotherapy of breast cancer. Front. Oncol. 14, 1382701. doi:10.3389/fonc.2024.1382701
Li, T., Zhang, M., Zhang, T., Li, S., Kou, C., Zhao, M., et al. (2025). Cyclin-dependent kinase 4/6 inhibitors and cardiotoxic events in breast cancer: a pharmacovigilance study based on the FAERS database. Int. J. Cancer 156, 1404–1418. doi:10.1002/ijc.35255
Lin, W., Zeng, Y., Weng, L., Yang, J., and Zhuang, W. (2024). Comparative analysis of adverse events associated with CDK4/6 inhibitors based on FDA’s adverse event reporting system: a case control pharmacovigilance study. BMC Pharmacol. Toxicol. 25 (1), 47. doi:10.1186/s40360-024-00770-6
Macaire, P., Morawska, K., Vincent, J., Quipourt, V., Marilier, S., Ghiringhelli, F., et al. (2019). Therapeutic drug monitoring as a tool to optimize 5-FU–based chemotherapy in gastrointestinal cancer patients older than 75 years. Eur. J. Cancer 111, 116–125. doi:10.1016/j.ejca.2019.01.102
Mackler, E. R., Azar, M. K., Johengen, E., Farris, K. B., and Thompson, A. N. (2022). Feasibility of a comprehensive medication review to improve medication use for patients with cancer and comorbid conditions. Support. Care Cancer 30 (12), 10111–10116. doi:10.1007/s00520-022-07413-8
Møllebæk, M., Gardarsdottir, H., Bikou, A. G., Kodrič, A., Silva, A. M., Andersen, A., et al. (2025). Challenges in the implementation of EU risk minimisation measures for medicinal products in clinical practice guidelines: mixed methods multi-case study. Drug Saf. 48 (2), 161–177. doi:10.1007/s40264-024-01487-5
Murray, L. S., Jodrell, D. I., Morrison, J. G., Cook, A., Kerr, D. J., Whiting, B., et al. (1998). The effect of cimetidine on the pharmacokinetics of epirubicin in patients with advanced breast cancer: preliminary evidence of a potentially common drug interaction. Clin. Oncol. 10 (1), 35–38. doi:10.1016/s0936-6555(98)80109-x
Nguyen, D. G., Morris, S. A., Hamilton, A., Kwange, S. O., Steuerwald, N., Symanowski, J., et al. (2024). Real-world impact of an In-House dihydropyrimidine dehydrogenase (DPYD) genotype test on fluoropyrimidine dosing, toxicities, and hospitalizations at a multisite cancer center, JCO Precis. Oncol. 8, e2300623. doi:10.1200/PO.23.00623
Ortland, I., Mendel Ott, M., Kowar, M., Sippel, C., Ko, Y. D., Jacobs, A. H., et al. (2022). Medication risks in older patients (70+) with cancer and their association with therapy-related toxicity. BMC Geriatr. 22 (1), 716. doi:10.1186/s12877-022-03390-z
Pawlonka, J., Buchalska, B., Buczma, K., Kamińska, K., and Cudnoch-Jędrzejewska, A. (2024). Targeting the renin–angiotensin–aldosterone system (RAAS) for cardiovascular protection and enhanced oncological outcomes. Curr. Treat. Options Oncol. 25, 1406–1427. doi:10.1007/s11864-024-01270-9
Popa, M. A., Wallace, K. J., Brunello, A., Extermann, M., and Balducci, L. (2014). Potential drug interactions and chemotoxicity in older patients with cancer receiving chemotherapy. J. geriatric Oncol. 5 (3), 307–314. doi:10.1016/j.jgo.2014.04.002
Ramsdale, E., Mohamed, M., Yu, V., Otto, E., Juba, K., Awad, H., et al. (2022). Polypharmacy, potentially inappropriate medications, and drug-drug interactions in vulnerable older adults with advanced cancer initiating cancer treatment. Oncol. 27 (7), e580–e588. doi:10.1093/oncolo/oyac053
Raoul, J. L., Moreau-Bachelard, C., Gilabert, M., Edeline, J., and Frénel, J. S. (2023). Drug–drug interactions with proton pump inhibitors in cancer patients: an underrecognized cause of treatment failure. ESMO open 8 (1), 100880. doi:10.1016/j.esmoop.2023.100880
Sang, L., Zhou, Z., Luo, S., Zhang, Y., Qian, H., Zhou, Y., et al. (2024). An in silico platform to predict cardiotoxicity risk of anti-tumor drug combination with hiPSC-CMs based in vitro study. Pharm. Res. 41 (2), 247–262. doi:10.1007/s11095-023-03644-4
Shaffer, K. M., Turner, K. L., Siwik, C., Gonzalez, B. D., Upasani, R., Glazer, J. V., et al. (2023). Digital health and telehealth in cancer care: a scoping review of reviews. Lancet Digital Health 5 (5), e316–e327. doi:10.1016/S2589-7500(23)00049-3
Shen, J., Luo, P., and Xu, J. (2024). Adverse event profiles of CDK4/6 inhibitors: data mining and disproportionality analysis of the FDA adverse event reporting system. Ther. Adv. Drug Saf. 15, 20420986241278498. doi:10.1177/20420986241278498
Sonke, G. S., Hart, L. L., Campone, M., Erdkamp, F., Janni, W., Verma, S., et al. (2018). Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial. Breast cancer Res. Treat. 167, 659–669. doi:10.1007/s10549-017-4523-y
Tesarova, P. (2013). Breast cancer in the elderly—Should it be treated differently? Rep. Pract. Oncol. Radiotherapy 18 (1), 26–33. doi:10.1016/j.rpor.2012.05.005
Valachis, A., Garmo, H., Weinman, J., Fredriksson, I., Ahlgren, J., Sund, M., et al. (2016). Effect of selective serotonin reuptake inhibitors use on endocrine therapy adherence and breast cancer mortality: a population-based study. Breast Cancer Res. Treat. 159, 293–303. doi:10.1007/s10549-016-3928-3
van Leeuwen, R. W. F., le Comte, M., Reyners, A. K. L., van den Tweel, A., van Vlijmen, B., Kwee, W., et al. (2022). Evidence- and consensus-based guidelines for drug-drug interactions with anticancer drugs; A practical and universal tool for management. Seminars Oncol. 49, 119–129. doi:10.1053/j.seminoncol.2022.03.002
van Merendonk, L. N., and Crul, M. (2022). Deprescribing in palliative patients with cancer: a concise review of tools and guidelines. Support. Care Cancer 30, 2933–2943. doi:10.1007/s00520-021-06605-y
Walsh, D. J., Kantilal, K., Herledan, C., Nightingale, G., Slavova-Boneva, V., Moreno-Martínez, M. E., et al. (2023). Medication assessment in older adults with cancer–current practices in clinical pharmacy. J. Geriatric Oncol. 14 (5), 101531. doi:10.1016/j.jgo.2023.101531
White, C., Wardill, H., Paul, C., Price, T., Karapetis, C., Nalder, M., et al. (2024). DPYD genotype-guided dose personalisation for fluoropyrimidine-based chemotherapy prescribing in solid organ cancer patients in Australia: genescreen 5-FU study protocol. BMC cancer 24 (1), 1369. doi:10.1186/s12885-024-13122-8
Wolf, C. P. J. G., Rachow, T., Ernst, T., Hochhaus, A., Zomorodbakhsch, B., Foller, S., et al. (2022). Interactions in cancer treatment considering cancer therapy, concomitant medications, food, herbal medicine and other supplements. J. Cancer Res. Clin. Oncol. 148, 461–473. doi:10.1007/s00432-021-03625-3
Xu, J., Wang, R., and Shen, K. (2025). A post-marketing disproportionality analysis of the safety of ribociclib based on the FDA adverse event reporting system. Ther. Adv. Drug Saf. 16, 20420986251324633. doi:10.1177/20420986251324633
Yan, Y., Su, L., Huang, S., He, Q., Lu, J., Luo, H., et al. (2024a). Circadian rhythms and breast cancer: unraveling the biological clock’s role in tumor microenvironment and ageing. Front. Immunol. 15, 1444426. doi:10.3389/fimmu.2024.1444426
Yan, Y., Li, S., Su, L., Tang, X., Chen, X., Gu, X., et al. (2024b). Mitochondrial inhibitors: a new horizon in breast cancer therapy. Front. Pharmacol. 15, 1421905. doi:10.3389/fphar.2024.1421905
You, Y., Chen, Y., You, Y., Zhang, Q., and Cao, Q. (2023). Evolutionary game analysis of artificial intelligence such as the generative pre-trained transformer in future education. Sustainability 15 (12), 9355. doi:10.3390/su15129355
Keywords: polypharmacy, drug–drug interactions, elderly breast cancer, synergistic toxicity, adverse drug reactions
Citation: Wang X, Yang J, Zhang J and Yang H (2025) Polypharmacy driven synergistic toxicities in elderly breast cancer chemotherapy drug management and adverse drug reactions: a mini review. Front. Pharmacol. 16:1654353. doi: 10.3389/fphar.2025.1654353
Received: 26 June 2025; Accepted: 05 August 2025;
Published: 26 August 2025.
Edited by:
Dana Narvaez, Alexander Fleming Specialized Medical Institute, ArgentinaReviewed by:
Yi Chen, Xinjiang Medical University, ChinaCopyright © 2025 Wang, Yang, Zhang and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hong Yang, eWhvbmdfODc2MEAxMjYuY29t