1 / 25

Relative Survival for Colorectal Carcinoma by Race/Ethnicity, SEER 1992-1999

Genetic polymorphisms, toxicity, & response rate in African Americans (AA) with metastatic colorectal cancer compared to Caucasians (C) treated with IFL, FOLFOX or IROX in Intergroup N9741.

clover
Download Presentation

Relative Survival for Colorectal Carcinoma by Race/Ethnicity, SEER 1992-1999

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Genetic polymorphisms, toxicity, & response rate in African Americans (AA) with metastatic colorectal cancer compared to Caucasians (C) treated with IFL, FOLFOX or IROX in Intergroup N9741 R. M. Goldberg, H. L. McLeod, D. J. Sargent, R. F. Morton, E. M. Green, C. Fuchs, R. K. Ramanathan, S. K. Williamson, B. P. Findlay, H. C. Pitot, S. R. Alberts

  2. 100 80 White, non-Hispanic 60 Hispanic Asian/Pacific Islander Survival (%) 40 Black/African American 20 1 2 3 4 5 Years afterDiagnosis Relative Survival for Colorectal Carcinoma by Race/Ethnicity, SEER 1992-1999

  3. Potential Explanations:Societal • Socioeconomic Issues • Hypothesis: AA have less access to medical care • Corollary: AA are diagnosed at later stage • Hypothesis: AA often are of lower socioeconomic status • Corollary: AA have poorer access to ideal care

  4. Potential Explanations:Biological • Tumor Biology • Hypothesis: AA have more aggressive disease • Corollary: AA have a worse outcome regardless of access • Host Biology • Hypothesis: AA respond differently to chemotherapy • Corollary: AA should have different treatment algorithms and may benefit from the use of different drugs or different drug doses

  5. Specific Aims • Compare AA to C patients enrolled in N9741 • RR, TTP, and OS • Chemotherapy toxicities • Prevalence of polymorphisms in key genes coding for enzymes involved in drug metabolism • Correlate clinical endpoints & polymorphisms

  6. N9741: Schema 1412 stage IV patients 486 with pharmacogenetic data RANDOMI ZAT ION IFL: Irinotecan + 5-FU/LV FOLFOX: Oxaliplatin + 5-FU/LV IROX: Irinotecan + oxaliplatin

  7. Number of Patients by Race: Self Reported

  8. Response Rate:Overall and By Arm

  9. Median TTP:Overall and By Arm *Log-rank test p-value

  10. Median OS:Overall and By Arm *Log-rank test p-value

  11. Median OS:95% Confidence Intervals

  12. Toxicity :All Arms Combined

  13. IFL Toxicity

  14. FOLFOX Toxicity

  15. IROX Toxicity

  16. Irinotecan Pathway CPT-11 cell membrane ABCB1 CPT-11 APC CYP3A4 CES1 CPT-11 NPC CYP3A5 CES2 CES1 CES2 SN-38 UGT1A1 SN-38 SN-38G ABCB1 ABCG2 ABCC1 ABCC2 SN-38 TOP1 ADPRT XRCC1 TDP1 NFKB1 CDC45L Cell Death

  17. Controls Irinotecan and SN-38 Efflux from Cells

  18. CYP3A: Prevents Activation to SN-38

  19. Polymorphisms inUGT1A1 do not predict diarrhea or overall toxicity

  20. Oxaliplatin Pathway cell membrane Oxaliplatin Detoxify ABCG2 ABCC2 Oxaliplatin GSTM1 NQO1 GSTP1 SLC31A1 MPO Oxaliplatin SOD1 ATP7A Translesional replication POLB Oxaliplatin POLH Oxaliplatin HMG1 Damage recognition ERCC1 XRCC1 ERCC2 Excision repair Cell Death

  21. ERCC Genes Repair Oxaliplatin Adducts

  22. GST Genes Detoxify Oxaliplatin

  23. Conclusions: Among the Patients in This Trial • AA have a significantly lower RR • No differences in TTP were observed • Differences in OS were inconsistent between AA and C • AA have significantly less severe toxicity, mainly less severe diarrhea • AA and C have significantly different frequencies of polymorphisms in candidate genes coding for key enzymes involved in drug activation, metabolism, and disposition

  24. Implications • FOLFOX remains the preferred regimen in AA & C • Dose escalation may be possible in some AAs • Caution: Correlation of polymorphisms with response and toxicity may not be causal • More research in bigger populations is indicated • FOCUS (2135 pts) and CALGB/SWOG 80405 (2380 pts) have/are collecting germline DNA for pharmacogenetics

  25. Thanks for your attention

More Related