This study aimed to identify associations between germline polymorphisms and risk of high-grade osteosarcoma (HGOS) development, event-free survival (EFS) and toxicity in HGOS patients treated with neo-adjuvant chemotherapy and surgery.Germline polymorphisms of 31 genes known to be relevant for transport or metabolism of all four drugs used in HGOS chemotherapy (methotrexate, doxorubicin, cisplatin and ifosfamide) were genotyped in 196 patients with HGOS and in 470 healthy age and gender-matched controls. Of these 196 HGOS patients, a homogeneously treated group of 126 patients was considered for survival analyses (survival cohort). For 57 of these, treatment-related toxicity data were available (toxicity cohort).Eleven polymorphisms were associated with increased risk of developing HGOS (p < 0.05). The distribution of polymorphisms in patients was characterized by a higher Shannon entropy. In the survival cohort (n = 126, median follow-up = 126 months), genotypes of ABCC2_1249A/G, GGH_452T/C, TP53_IVS2+38G/C and CYP2B6*6 were associated with EFS (p < 0.05). In the toxicity cohort (n = 57), genotypes of ABCB1_1236T/C, ABCC2_1249A/G, ABCC2_3972A/G, ERCC1_8092T/G, XPD_23591A/G, XRCC3_18067T/C, MTHFR_1298A/C and GGH_16T/C were associated with elevated risk for toxicity development (p < 0.05).The results obtained in this retrospective study indicate that the aforementioned germline polymorphisms significantly impact on the risk of HGOS development, EFS and the occurrence of chemotherapy-related toxicity. These findings should be prospectively validated with the aim of optimizing and tailoring HGOS treatment in the near future.
Pre-therapeutic DPYD pharmacogenetic test to prevent fluoropyrimidines (FL)-related toxicities is not yet common practice in medical oncology. We aimed at investigating the clinical validity of DPYD genetic analysis in a large series of oncological patients. Six hundred three cancer patients, treated with FL, have been retrospectively tested for eight DPYD polymorphisms (DPYD-rs3918290, DPYD-rs55886062, DPYD-rs67376798, DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYDrs1801159, DPYD-rs17376848) for association with Grade 3 toxicity, developed within the first three cycles of therapy. DPYD-rs3918290 and DPYD-rs67376798 were associated to Grade 3 toxicity after bootstrap validation and Bonferroni correction (p 5 0.003, p 5 0.048). DPYD-rs55886062 was not significant likely due to its low allelic frequency, nonetheless one out of two heterozygous patients (compound heterozygous with DPYD-rs3918290) died from toxicity after one cycle. Test specificity for the analysis of DPYD-rs3918290, DPYD-rs55886062 and DPYD-rs67376798 was assessed to 99%. Among the seven patients carrying one variant DPYD-rs3918290, DPYD-rs55886062 or DPYD-rs67376798 allele, not developing Grade 3 toxicity, 57% needed a FL dose or schedule modification for moderate chronic toxicity. No other DPYD polymorphism was associated with Grade 3 toxicity. Our data demonstrate the clinical validity and specificity of the DPYD-rs3918290, DPYDrs55886062, DPYD-rs67376798 genotyping test to prevent FL-related Grade 3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice.The identification of the genetic bases of inter-individual variability in terms of response or toxicity to pharmacological treatments is a key point in the field of personalized therapy. Specifically, in the oncological setting the high variability observed in the tumor response to treatment and in the severity of toxicity emphasizes the importance of improving the knowledge on the clinical validity of the pharmacogenetic tests.Fluoropyrimidines (FL) are listed among the drugs with pharmacogenetic warnings. 1 Despite the acknowledged efficacy of these drugs in the treatment of different solid tumors, 2 the FL treatment remains challenging as a result of a considerable inter-patient variability in terms of efficacy and toxicity. 3,4 The pharmacogenetic research, aimed at defining predictive markers of FL response, mainly focused on the dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of FL catabolic pathway. Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug...
Next-generation sequencing (NGS) technology has advanced knowledge of the genomic landscape of ovarian cancer, leading to an innovative molecular classification of the disease. However, patient survival and response to platinum-based treatments are still not predictable based on the tumor genetic profile. This retrospective study characterized the repertoire of somatic mutations in advanced ovarian cancer to identify tumor genetic markers predictive of platinum chemo-resistance and prognosis. Using targeted NGS, 79 primary advanced (III–IV stage, tumor grade G2-3) ovarian cancer tumors, including 64 high-grade serous ovarian cancers (HGSOCs), were screened with a 26 cancer-genes panel. Patients, enrolled between 1995 and 2011, underwent primary debulking surgery (PDS) with optimal residual disease (RD < 1 cm) and platinum-based chemotherapy as first-line treatment. We found a heterogeneous mutational landscape in some uncommon ovarian histotypes and in HGSOC tumor samples with relevance in predicting platinum sensitivity. In particular, we identified a poor prognostic signature in patients with HGSOC harboring concurrent mutations in two driver actionable genes of the panel. The tumor heterogeneity described, sheds light on the translational potential of targeted NGS approach for the identification of subgroups of patients with distinct therapeutic vulnerabilities, that are modulated by the specific mutational profile expressed by the ovarian tumor.
Lack of information on the clinical utility of preemptive DPYD screening before fluoropyrimidine treatment is a major barrier preventing its use in clinical practice. This study aimed to define the association between DPYD variants and fluoropyrimidine-related toxicity management costs. A cost analysis was conducted on the toxicities experienced by 550 patients with colorectal cancer treated with fluoropyrimidine-based chemotherapy. Genotyping for DPYD*2A, DPYD*13, DPYDc. 2846A>T, DPYD-HapB3, and UGT1A1*28 was done retrospectively and did not affect patients' treatments. Carriers of at least one DPYD variant experienced higher toxicity management costs (€2,972; 95% confidence interval (CI), €2,456-€3,505) than noncarriers (€825; 95% CI, €785-€864) (P < 0.0001) and had a higher risk for toxicity requiring hospitalization (odds ratio, 4.14; 95% CI, 1.87-9.14). In patients receiving fluoropyrimidine/irinotecan, the incremental cost between DPYD variant and UGT1A1*28/*28 carriers and noncarriers was €2,975. This study suggests that the toxicity management costs during fluoropyrimidine-based therapy are associated with DPYD and UGT1A1*28 variants and supports the utility of genotyping.
Palbociclib, ribociclib, and abemaciclib belong to the third generation of cyclin-dependent kinases inhibitors (CDKis), an established therapeutic class for advanced and metastatic breast cancer. Interindividual variability in the therapeutic response of CDKis has been reported and some individuals may experience increased and unexpected toxicity. This narrative review aims at identifying the factors potentially concurring at this variability for driving the most appropriate and tailored use of CDKis in the clinic. Specifically, concomitant medications, pharmacogenetic profile, and pathophysiological conditions could influence absorption, distribution, metabolism, and elimination pharmacokinetics. A personalized therapeutic approach taking into consideration all factors potentially contributing to an altered pharmacokinetic/pharmacodynamic profile could better drive safe and effective clinical use.
Great research effort has been focused on elucidating the contribution of host genetic variability on pharmacological outcomes in cancer. Nuclear receptors have emerged as mediators between environmental stimuli and drug pharmacokinetics and pharmacodynamics. The pregnane X receptor, constitutive androstane receptor and hepatocyte nuclear factors have been reported to regulate transcription of genes that encode drug metabolizing enzymes and transporters. Altered nuclear receptor expression has been shown to affect the metabolism and pharmacological profile of traditional chemotherapeutics and targeted agents. Accordingly, polymorphic variants in these genes have been studied as pharmacogenetic markers of outcome variability. This review summarizes the state of knowledge about the roles played by pregnane X receptor, constitutive androstane receptor and hepatocyte nuclear factor expression and genetics as predictive markers of anticancer drug toxicity and efficacy, which can improve cancer precision medicine.
The adoption of a preemptive UGT1A1*28 genotyping to increase irinotecan safety in clinical practice is still limited. This is the first actual study of costs associated with the management of irinotecan-related toxicities, and their association with UGT1A1*28 genotype. A retrospective analysis of the cost of toxicity management was conducted on 243 metastatic colorectal cancer patients enrolled in a clinical trial and treated with standard of care FOLFIRI (5-fluorouracil combined with irinotecan). The mean predicted cost per patient was higher for *28/*28 (€4,886), vs. *1/*1 (€812), (regression coefficient 1.79, 95% confidence interval (CI) = 1.31-2.28; P < 0.001) and for *1/*28 (€1,119) vs. *1/*1 (regression coefficient 0.32, 95% CI = 0.04-0.60; P = 0.024). This is consistent with a different grade 4 toxicity profile among the three genotypes, and a higher frequency of costly interventions like hospitalization among patients with the *28 allele. A differential toxicity management cost by *28 genotype is herein demonstrated, representing a first step towards the demonstration of the test clinical utility.
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