Although trastuzumab-deruxtecan (T-DXd) has demonstrated significant efficacy in advanced breast cancer, treatment discontinuation due to adverse events occurs in ∼20% of patients. Pharmacogenetic variants in uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) increase the toxicity risk for other antibody-drug conjugates using topoisomerase I inhibitors, but they remain unexplored for T-DXd. The PROCURE Project is a translational study involving 26 Spanish institutions, investigating the association of germline pharmacogenomic variants with T-DXd toxicity for patients with HER2-positive or HER2-low advanced breast cancer. UGT1A1∗28 genotypes were determined in blood samples, and pharmacogenomic analyses were performed using the clinical data and adverse events extracted from the medical records of the patients. Additionally, stratified Cox models were used to quantify the risk of treatment discontinuation in the different UGT1A1 genotypes. Between July 2022 and March 2024, a total of 292 patients with genetic and clinical information were enrolled in the study. At data cutoff, the median treatment duration with T-DXd was 12.0 months [95% confidence interval (CI) 10.5-14.1]. UGT1A1 genotype distribution among patients was 43.2% wild-type (∗1/∗1), 46.2% heterozygous (∗1/∗28), and 10.3% homozygous (∗28/∗28). No association was observed between UGT1A1 genotypes and the most common T-DXd adverse events. However, poor metabolizers (∗28/∗28) compared with extensive and intermediate metabolizers (∗1/∗1 and ∗1/∗28, respectively) showed a trend toward higher incidence of neutropenia (13.3% versus <6%), as well as a higher incidence of grade ≥3 gastrointestinal toxicity (diarrhea and vomiting). The incidence of drug-induced pneumonitis/interstitial lung disease (ILD) was 11.0% (32/292). No association was observed between UGT1A1 variants and the incidence of pneumonitis/ILD. Patients carrying UGT1A1∗28/∗28 genotype showed a longer treatment duration (HR 0.47, 95% CI 0.23-0.93, P = 0.03) compared with UGT1A1 wild-type patients. In the PROCURE Project, UGT1A1 variants, including the ∗28/∗28 genotype, were not predictive of T-DXd–related adverse events in advanced breast cancer. The project highlights the need to identify alternative biomarkers to optimize toxicity risk stratification and guide personalized treatment strategies.

PURPOSE: A substantial proportion of patients receiving genomically matched therapies do not achieve clinical benefit, underscoring the influence of nongenetic factors on cancer outcomes. High-Definition Oncology (HDO) proposes integrating longitudinal, multimodal patient data—spanning clinical, molecular, physiological, and behavioral domains—to enable truly individualized cancer care. This manuscript describes the HDO study design, framework, and feasibility results in women with metastatic cancer. METHODS: We initiated a prospective, multicenter observational study (HDO study; ClinicalTrials.gov identifier: NCT06590506 ) enrolling 300 female patients with newly diagnosed metastatic breast, lung, or colorectal cancer. Here, we report the study design, standardized workflows, prespecified feasibility criteria, and early internal pilot results. Eleven data modalities are collected longitudinally, including tumor and germline genomics, germline epigenomics, gut microbiome, blood and stool metabolomics and proteomics, exposome characterization, wearable-derived physiological monitoring, digital footprint assessment, medical imaging, and patient-reported outcomes. Standardized workflows govern clinical procedures, data acquisition, biospecimen processing, and quality control across all participating sites. RESULTS: Feasibility was evaluated in the first 30 participants (10% of planned accrual). Patients completed 100% of scheduled clinical visits, 97.4% of planned plasma collections, 80.7% of stool samples, and all tumor biopsies. Wearable devices captured activity, heart rate, sleep, and blood oxygen saturation data during 95.0%, 84.2%, 90.6%, and 70.7% of total patient-days, respectively. Biospecimens met predefined quality control metrics across all molecular modalities. Engagement with mobile applications for pain and emotion reporting exceeded 80%. CONCLUSION: The HDO study demonstrates the feasibility of comprehensive, longitudinal, multimodal data collection in women with metastatic cancer. This internal pilot establishes an integrated framework for future analyses aimed at characterizing disease trajectories, defining molecular and physiological determinants of outcomes, and developing patient-specific computational models.

Aging is a major risk factor for numerous diseases [1,2], and amongst the largest risk factors for cancer [3]. As women age, their risk of developing breast cancer increases substantially, with inc...

Trastuzumab deruxtecan (T-DXd) has demonstrated substantial clinical benefit in patients with advanced human epidermal growth factor receptor 2 (HER2)-positive and HER2-low breast cancer. However, treatment-related adverse events-particularly interstitial lung disease (ILD) or pneumonitis-represent a clinically relevant limitation. While UGT1A1 polymorphisms influence toxicity with other topoisomerase I inhibitor-based therapies, their role in T-DXd-related toxicity appears limited. The PROCURE project aimed to investigate germline pharmacogenetic variants beyond UGT1A1 associated with T-DXd-induced ILD. The PROCURE project is a multicenter translational study conducted across 26 Spanish institutions. Germline DNA from patients with advanced HER2-positive or HER2-low breast cancer treated with T-DXd was genotyped using the Infinium Global Diversity Array enriched for pharmacogenomic variants. A candidate gene approach was applied to 14 genes involved in drug metabolism, transport, pharmacodynamics, and immune-mediated drug hypersensitivity. Logistic regression models were used to evaluate associations with ILD/pneumonitis. A total of 290 patients with clinical and genotyping data were included in the analysis. The median age was 58 years (range, 34-94 years). After a median follow-up of 18.3 months [95% confidence interval (CI): 15.4-20.5], the cohort registered 33 ILD cases (incidence of 11.4%). The strongest association signals mapped to variants within the human leukocyte antigen (HLA) region, with the top single nucleotide polymorphism near HLA-F (rs9258213; OR 6.8, 95% CI 2.6-17.9, P = 9.5 × 10^-5). Additional associations were observed in SLCO1B1 and CYP3A4, genes involved in T-DXd transport and metabolism. This study identifies host genetic variation within the HLA locus and drug pharmacokinetic pathways as potential contributors to T-DXd-induced ILD in patients with advanced breast cancer. Although no definitive pharmacogenomic predictor was identified, these findings provide insights into the biological mechanisms underlying this toxicity and support further investigation of pharmacogenomic biomarkers to improve risk stratification and guide personalized T-DXd therapy.

Background/Objectives: Few large cohorts with relatively uniform treatment approaches and long-term follow-up are available for assessing clinical outcomes for breast cancer (BC) patients. The Institut Català d’Oncologia (ICO) Breast Cancer Cohort was designed to well characterize treatment patterns and overall survival outcomes at 5 and 10 years, with a particular focus on patients < 40 and ≥70 years old, age groups often underrepresented in clinical trials. Methods: In this retrospective, observational study, we included all pathologically confirmed invasive BC patients diagnosed and treated between 2010 and 2014 at ICO, a Spanish reference cancer center, with a follow-up until November 2023. We collected comprehensive real-world data on clinicopathologic characteristics and treatment modalities. Overall survival (OS) was estimated using the Kaplan–Meier technique and was reported stratified by prognostic factors for the age groups of ≤40, 41–69 and ≥70. The Multivariate Cox model was used to estimate the risk of death for subgroups of age, adjusting for subtype, stage and grade. Results: Overall, 3451 patients with stage I to IV BC were diagnosed and treated, with a mean age of 58 years (range 19–98); 371 (10.8%) were diagnosed ≤40 years, and 756 (21.9%) were ≥70 years. With a mean follow-up of 9.9 years (SD = 3.5), the 5- and 10-year OS were 89% (95% CI: 86–92%) and 85% (95% CI: 81–88%) for patients ≤ 40, respectively; for those aged 41–69 years, 91% (95% CI: 90–92%) and 85% (95% CI: 83–86%), respectively; and 70% (95% CI: 66–73%) and 50% (95% CI: 47–54%) for those ≥70 years, respectively. The 5- and 10-year relative survival (RS) were 92% and 88% for patients < 70 years, respectively, and 82% and 77% for those ≥70 years, respectively. The Multivariate Cox model identified a HR of 4.90 (95% CI: 3.44–6.97, p < 0.001) for patients ≥ 70 years compared to those between 41 and 69 years. Conclusions: The ICO Breast Cancer Cohort, as far as we know, the largest in Spain with long-term follow-up, underscores the critical role of age and subtype in determining overall survival outcomes in patients with breast cancer.