{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:55Z","timestamp":1787027815285,"version":"build-2736575974"},"reference-count":25,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009045","name":"Jagiellonian University\u2014Medical College","doi-asserted-by":"crossref","award":["N41\/DBS\/000706."],"award-info":[{"award-number":["N41\/DBS\/000706."]}],"id":[{"id":"10.13039\/100009045","id-type":"DOI","asserted-by":"crossref"}]},{"award":["N41\/DBS\/000706."],"award-info":[{"award-number":["N41\/DBS\/000706."]}],"id":[{"id":"https:\/\/ror.org\/03bqmcz70","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Metronomic chemo-endocrine therapy combining fulvestrant with metronomic VEC (vinorelbine, cyclophosphamide, and capecitabine)\u2014the FulVEC regimen\u2014demonstrated promising activity in an initial cohort of 38 patients with advanced ER+\/HER2\u2212 breast cancer (JCM 2023). Here, we present an extended analysis of 72 consecutive patients, with a focus on a novel hypothesis: that treatment-emergent adverse events (AEs) requiring dose modification serve as a surrogate for sufficient pharmacological exposure in metronomic combination chemotherapy. Methods: Retrospective analysis of 72 consecutive patients with metastatic ER+\/HER2\u2212 breast cancer treated with FulVEC at Jagiellonian University Hospital between 2018 and 2024. Efficacy endpoints included progression-free survival (PFS), overall survival (OS), and biochemical response, as assessed by CA15-3 dynamics. Patients were stratified by AE severity requiring intervention (grade 0: no modification; grade 1: dose reduction; and grade 2: treatment delay). The association between AE grade and efficacy outcomes was assessed using Spearman\u2019s correlation, the log-rank test, and the chi-square test. Results: The median PFS was 8.5 months, and the median OS was 18.0 months. The biochemical benefit rate (any CA15-3 decline) was 81.6%. No statistically significant differences in efficacy were observed according to prior exposure to CDK4\/6 inhibitors, fulvestrant, or cytotoxic components of the FulVEC regimen. A monotonic dose\u2013response relationship was observed across AE grade categories: non-progression rates increased from 73.2% (grade 0) to 84.2% (grade 1) and 91.7% (grade 2); biochemical benefit rates from 68.4% to 90.9% and 100.0%; and median CA15-3 reduction deepened from \u221234% to \u221244% and \u221252%, respectively (Spearman r = 0.258 and p = 0.043 for AE grade vs. treatment duration). Formal log-rank comparisons of PFS and OS across the three AE-grade categories did not reach statistical significance (p = 0.583 and p = 0.743, respectively), reflecting the limited size of the treatment-delay subgroup (n = 12); the dose\u2013response signal should, therefore, be regarded as exploratory. No patient required permanent treatment discontinuation due to toxicity. Conclusions: The extended FulVEC cohort confirms durable activity and a reproducible, manageable safety profile in a heavily pretreated population, including CDK4\/6i-refractory patients. The exploratory, hypothesis-generating observation of a dose\u2013response gradient between AE severity and clinical outcomes raises the possibility that treatment-emergent AEs may, in some patients, reflect adequate pharmacological exposure to the metronomic regimen. Given confounding by treatment duration and survivor bias, and the absence of pharmacokinetic data, this hypothesis requires prospective validation and does not, at this stage, support any change to current treatment practice.<\/jats:p>","DOI":"10.3390\/cancers18142303","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:00:52Z","timestamp":1784278852000},"page":"2303","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Adverse Events as a Surrogate of Sufficient Pharmacological Exposure in Metronomic Combination Chemotherapy: Extended Real-World Cohort Analysis of the FulVEC Regimen in Metastatic ER+\/HER2\u2212 Breast Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8598-2850","authenticated-orcid":false,"given":"Anna","family":"Buda-Nowak","sequence":"first","affiliation":[{"name":"Department of Oncology, Jagiellonian University-Medical College, 31-501 Krakow, Poland"},{"name":"Department of Oncology, University Hospital in Krakow, 31-501 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Luba\u015b","sequence":"additional","affiliation":[{"name":"Department of Oncology, University Hospital in Krakow, 31-501 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1141-3479","authenticated-orcid":false,"given":"Micha\u0142","family":"Jurczyk","sequence":"additional","affiliation":[{"name":"Department of Oncology, University Hospital in Krakow, 31-501 Krakow, Poland"},{"name":"Department of Pathophysiology, Jagiellonian University-Medical College, 31-008 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0141ukasz","family":"Kwinta","sequence":"additional","affiliation":[{"name":"Department of Oncology, Jagiellonian University-Medical College, 31-501 Krakow, Poland"},{"name":"Department of Oncology, University Hospital in Krakow, 31-501 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Micha\u0142owska-Kaczmarczyk","sequence":"additional","affiliation":[{"name":"Department of Oncology, Jagiellonian University-Medical College, 31-501 Krakow, Poland"},{"name":"Department of Oncology, University Hospital in Krakow, 31-501 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Przywara-Sikora","sequence":"additional","affiliation":[{"name":"Department of Oncology, Jagiellonian University-Medical College, 31-501 Krakow, Poland"},{"name":"Department of Oncology, University Hospital in Krakow, 31-501 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamil","family":"Konopka","sequence":"additional","affiliation":[{"name":"Department of Oncology, Jagiellonian University-Medical College, 31-501 Krakow, Poland"},{"name":"Department of Oncology, University Hospital in Krakow, 31-501 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Koniewski","sequence":"additional","affiliation":[{"name":"Institute of Sociology, Jagiellonian University, 31-007 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Kad\u0142uczka","sequence":"additional","affiliation":[{"name":"Student Scientific Society, Jagiellonian University-Medical College, 31-008 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Szczerbak","sequence":"additional","affiliation":[{"name":"Student Scientific Society, Jagiellonian University-Medical College, 31-008 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4003-5278","authenticated-orcid":false,"given":"Piotr J.","family":"Wysocki","sequence":"additional","affiliation":[{"name":"Department of Oncology, Jagiellonian University-Medical College, 31-501 Krakow, Poland"},{"name":"Department of Oncology, University Hospital in Krakow, 31-501 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1200\/JCO.23.01940","article-title":"PACE: A randomized phase II study of fulvestrant, palbociclib, and avelumab after progression on CDK4\/6 inhibitor and aromatase inhibitor for HR+\/HER2\u2212 metastatic breast cancer","volume":"42","author":"Mayer","year":"2024","journal-title":"J. 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