Pharmacogenetic Assessment of Toxicity and Outcome After Platinum Plus Taxane Chemotherapy in Ovarian Cancer: The Scottish Randomised Trial in Ovarian Cancer

Abstract

There are no clear candidates for taxane/platinum pharmacogenetic markers. This study highlights the need for validation of putative genetic markers in large, well-defined clinical sample sets.

Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma

“…The former showed no association in >1000 ovarian and colorectal cancer patients, but the latter was in concordance with previous reports of increased gastrointestinal toxicity in cisplatin-treated nonsmall cell lung cancer. 5,19,39 One study in osteosarcoma reported no association of ERCC1 c.354T>C p.Asn 118 Asn with cisplatin-induced hearing loss but did not investigate other chemotherapy toxicities. 23 Myelosuppression was increased in variants of GSTP1 c.313A>G p.Ile 105 Val, the same genotype implicated in poor histological response and PFS.…”

“…The influence of NER and GST polymorphisms are well described in solid and hematological malignancies. 5,9,[18][19][20][21] Increased lung relapse and improved overall survival in GSTM1 null and GSTT1 null patients, respectively, was recently reported in 80 osteosarcoma patients. 22 A further small study reported an association between excision repair cross-complementation group 2 (ERCC2) c.2251A>C p.Lys 751 Gln, poor histological response, and inferior survival.…”

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

“…25 Contradictory results have been obtained regarding the effect of genetic variation on paclitaxel neurotoxicity. 15,28,29 A large study by Marsh et al 29 did not find evidence of associations with neurotoxicity for important polymorph- Figure 2 Kaplan-Meier comparisons of cumulative dose of paclitaxel up to the development of grade 2 neurotoxicity, by genotype at SNPs in CYP2C8 and CYP3A5. Patients with: (a) CYP2C8*3 alleles had a significantly higher risk to encounter neurotoxicity; (b) CYP2C8 haplotype C alleles and (c) CYP3A5*3 alleles were associated with protection against neurotoxicity.…”

“…However, a more recent study by Green et al 15 found a statistically significant association for CYP2C8*3 allele with increased neurotoxicity risk, which is coincident with our findings. The differences among these studies could be caused by the different experimental designs: on the one hand, Green et al 15 included a reduced number of patients but neurotoxicity was the primary endpoint of the study; 15,28 and on the other hand, Marsh et al 29 included a large number of patients recruited into a phase III randomized trial but the cumulative dose of paclitaxel at neurotoxicity onset was not taken into account. In addition, the study by Sissung et al 28 focused on ABCB1 polymorphisms, could not find significant differences in 22 patients evaluated for neurotoxicity.…”

“…So far, three studies addressing this hypothesis and using different strategies have produced contradictory results. One study found higher neurotoxicity for an allele variant of CYP2C8, 15 whereas Sissung et al 28 and Marsh et al 29 did not find significant associations for the genes studied. However, two studies had recruited less than 25 patients, and the latter did not take into account the dose-dependent nature of paclitaxel neurotoxicity.…”