Yekedüz E., Saad E., Machaalani M., Simsek B., Steiner C., Semaan K., ...Daha Fazla
JOURNAL OF CLINICAL ONCOLOGY, cilt.43, sa.16_suppl, ss.1, 2025 (SCI-Expanded, Scopus)
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Yayın Türü:
Makale / Tam Makale
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Cilt numarası:
43
Sayı:
16_suppl
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Basım Tarihi:
2025
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Doi Numarası:
10.1200/jco.2025.43.16_suppl.12125
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Dergi Adı:
JOURNAL OF CLINICAL ONCOLOGY
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Derginin Tarandığı İndeksler:
Science Citation Index Expanded (SCI-EXPANDED), Scopus, PASCAL, CAB Abstracts, CINAHL, Gender Studies Database, International Pharmaceutical Abstracts, Veterinary Science Database, Nature Index
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Sayfa Sayıları:
ss.1
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Ankara Üniversitesi Adresli:
Evet
Özet
12125
Background:
Antibody-drug conjugates (ADCs) are now essential in the treatment of solid and hematologic cancers. While effective, ADCs can cause adverse events (AEs) requiring careful management. Pneumonitis, a potentially severe AE, may result in treatment discontinuation or mortality. However, its risk factors and underlying mechanisms remain poorly understood.
Methods:
Patients (pts) with solid or hematologic malignancies treated with ADCs at Dana-Farber Cancer Institute up to August 1, 2024, were screened. Only those with available genomic data were included. Pneumonitis was evaluated based on the Common Terminology Criteria for AEs v4.03. A total of 18 candidate single nucleotide polymorphisms (SNPs) linked to drug-related AEs and implicated in ADC metabolism pathways were identified using PharmGKB. SNPs were inferred from targeted panel sequencing using the STITCH pipeline, with 3 SNPs that could not be successfully imputed. The association between the SNPs, as probabilistic dosages, and occurrence of pneumonitis was tested using a multivariable Cox regression model, adjusting for age, sex, race, cancer type, and sequencing panel version. Pts were censored at the end of treatment or death. P-values were adjusted using the Bonferroni correction.
Results:
The study included 1,184 pts with cancer treated with ADCs, encompassing a total of 1,465 ADC treatments, as some pts received multiple lines of ADCs. The median age at treatment initiation was 60 years (interquartile range: 20). Most pts were female (80.7%). Breast cancer was the most common cancer (54.6%), followed by urothelial (13.3%), and ovarian (11.6%) cancers. The most frequently administered ADCs included trastuzumab deruxtecan (33.1%), sacituzumab govitecan (25.1%), and enfortumab vedotin (11.3%). A total of 92 pneumonitis events were observed in 89 pts (Table), among which 54 (58.6%) were grade 2 or higher. The prevalence of pts carrying the minor alleles (intermediate or poor metabolizers) of rs4646437 (CYP3A4) and rs776746 (CYP3A5) was 16.8% and 15.6%, respectively. Multivariable analysis revealed that carriers of the minor allele of rs4646437 (Hazard Ratio [HR]: 3.03, 95% Confidence Interval [CI]: 1.73–5.29, P= 0.001) or rs776746 (HR: 2.43, 95% CI: 1.56–3.81, P= 0.001) had a significantly higher risk of developing pneumonitis, after adjusting for age, sex, race, cancer type, and sequencing panel version.
Conclusions:
Our findings highlight the potential role of inherited genetic factors in modulating treatment-related toxicities of ADCs. Understanding these associations can provide valuable insights into personalized treatment strategies and inform risk assessment to optimize the safety and efficacy of ADCs.
Rates of pneumonitis.
% per Group
N
Trastuzumab Deruxtecan
13.1
64
Mirvetuximab Soravtansine
8.4
10
Tisotumab Vedotin
5.0
1
Enfortumab Vedotin
3.6
6
Trastuzumab Emtansine
3.3
6
Sacituzumab Govitecan
1.3
5