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Pharmacogenetic Profiling in High-Risk Soft Tissue Sarcomas Treated with Neoadjuvant Chemotherapy.

ABSTRACT: Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are substantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chemotherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (ABCB1, ABCC2, NQO1, CBR3, and SLC22A16) and in ifosfamide catabolism (ALDH1A1) in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: ABCC2 and ALDH1A1. In patients treated with anthracyclines, ABCC2 rs3740066 was associated with risk of febrile neutropenia (p = 0.031), and with decreased overall survival (OS) (p = 0.024). ABCC2 rs2273697 was associated with recurrence-free survival (RFS) (p = 0.024). In patients treated with ifosfamide, ALDH1A1 rs3764435 was associated with RFS (p = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to establish their clinical utility.

SUBMITTER: Virgili Manrique AC

PROVIDER: S-EPMC9024670 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Pharmacogenetic Profiling in High-Risk Soft Tissue Sarcomas Treated with Neoadjuvant Chemotherapy.

Virgili Manrique Anna C AC Salazar Juliana J Arranz María Jesús MJ Bagué Silvia S Orellana Ruth R López-Pousa Antonio A Cerdà Paula P Gracia Isidre I Majercakova Katarina K Peiró Ana A Trullols Laura L Fernández Manuel M Valverde Sandra S Quintana María Jesús MJ Bell Olga O Artigas-Baleri Alícia A Sebio Ana A

Journal of personalized medicine 20220411 4

Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are substantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chemotherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS pat ...[more]

PMID: 35455734

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Project description:BackgroundNeoadjuvant radiotherapy (RT) and chemotherapy are applied to large, high-grade extremity soft tissue sarcomas to treat metastatic disease earlier and sterilize margins to perform R0 surgery. However, preoperative RT increases wound complication rates (rWC), delaying adjuvant chemotherapy or preventing it from being administered altogether. Hypofractionated neoadjuvant RT can be offered in this situation, concomitant to chemotherapy, allowing patients to receive chemotherapy as a preoperative treatment in less time with an acceptable rWC.ObjectiveThe objectives of this protocol are to maintain low rates of morbidity and mortality compared to literature data, improving survival rates and avoiding poor responders from receiving unnecessary adjuvant chemotherapy.MethodsThis noncontrolled, single-arm, phase 2 clinical trial recruited patients aged over 18 years with high-grade soft tissue sarcomas in the girdles or extremities. Three neoadjuvant chemotherapy (ifosfamide and doxorubicin) cycles were administered with 5 days of hypofractionated RT (25 Gy in 5 fractions) in the second cycle of doxorubicin only. Viable cell counts in the surgical specimen were measured, and patients in whom this value was less than 30% continued to receive an additional 3 full chemotherapy cycles as adjuvant treatment.ResultsPrimary endpoint will be disease-specific survival measured by the evaluation of local and distant recurrence after neoadjuvant treatment. The secondary endpoints will be wound complication and amputation rates and chemotherapy toxicity. We also will record the viable cell rates after the schema and correlate this with survival.ConclusionsAs seems with other solid tumors, hypofractionated RT has comparable efficacy and safety as conventional fractionation. This modality of treatment combined with chemotherapy could increase the pathological response rates and improve the outcomes of select patients.Trial registrationClinicalTrials.gov NCT02812654; https://clinicaltrials.gov/ct2/show/NCT02812654 (Archived by WebCite at http://www.webcitation.org/6qC3puBOy).

Project description:PurposeNumerous preclinical studies have demonstrated that angiogenesis inhibitors can increase the efficacy of radiotherapy (RT). We sought to examine the safety and efficacy of bevacizumab (BV) and RT in soft tissue sarcomas and explore biomarkers to help determine the treatment response.Methods and materialsPatients with ≥5 cm, intermediate- or high-grade soft tissue sarcomas at significant risk of local recurrence received neoadjuvant BV alone followed by BV plus RT before surgical resection. Correlative science studies included analysis of the serial blood and tumor samples and serial perfusion computed tomography scans.ResultsThe 20 patients had a median tumor size of 8.25 cm, with 13 extremity, 1 trunk, and 6 retroperitoneal/pelvis tumors. The neoadjuvant treatment was well tolerated, with only 4 patients having Grade 3 toxicities (hypertension, liver function test elevation). BV plus RT resulted in ≥80% pathologic necrosis in 9 (45%) of 20 tumors, more than double the historical rate seen with RT alone. Three patients had a complete pathologic response. The median microvessel density decreased 53% after BV alone (p <.05). After combination therapy, the median tumor cell proliferation decreased by 73%, apoptosis increased 10.4-fold, and the blood flow, blood volume, and permeability surface area decreased by 62-72% (p <.05). Analysis of gene expression microarrays of untreated tumors identified a 24-gene signature for treatment response. The microvessel density and circulating progenitor cells at baseline and the reduction in microvessel density and plasma soluble c-KIT with BV therapy also correlated with a good pathologic response (p <.05). After a median follow-up of 20 months, only 1 patient had developed local recurrence.ConclusionsThe results from the present exploratory study indicated that BV increases the efficacy of RT against soft tissue sarcomas and might reduce the incidence of local recurrence. Thus, this regimen warrants additional investigation. Gene expression profiles and other tissue and circulating biomarkers showed promising correlations with treatment response.

Dataset Information

Pharmacogenetic Profiling in High-Risk Soft Tissue Sarcomas Treated with Neoadjuvant Chemotherapy.

Publications

Pharmacogenetic Profiling in High-Risk Soft Tissue Sarcomas Treated with Neoadjuvant Chemotherapy.

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