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

Genetic polymorphisms, Genetic polymorphisms, toxicity, & response rate toxicity, & response rate

in in African Americans (AA) African Americans (AA)

with metastatic colorectal with metastatic colorectal cancer compared to Caucasians cancer compared to Caucasians

(C) (C) treated with IFL, FOLFOX or treated with IFL, FOLFOX or

IROX IROX

in Intergroup N9741in Intergroup N9741 R. M. Goldberg, H. L. McLeod, D. J. R. M. Goldberg, H. L. McLeod, D. J. Sargent, R. F. Morton, E. M. Green, C. Sargent, R. F. Morton, E. M. Green, C.

Fuchs, R. K. Ramanathan, S. K. Fuchs, R. K. Ramanathan, S. K. Williamson, B. P. Findlay, H. C. Williamson, B. P. Findlay, H. C.

Pitot, S. R. AlbertsPitot, S. R. Alberts

Relative Survival for Colorectal Carcinoma by Race/Ethnicity,

SEER 1992-1999

Years after Diagnosis

20

40

60

80

100

1 2 3 4 5

Su

rviv

al (

%)

White, non-Hispanic

Black/African American

Asian/Pacific Islander

Hispanic

Potential Explanations:Potential Explanations:SocietalSocietal

Socioeconomic IssuesSocioeconomic Issues Hypothesis: AA have less access to Hypothesis: AA have less access to

medical caremedical care Corollary: AA are diagnosed at later stageCorollary: AA are diagnosed at later stage

Hypothesis: AA often are of lower Hypothesis: AA often are of lower socioeconomic statussocioeconomic status

Corollary: AA have poorer access to ideal Corollary: AA have poorer access to ideal carecare

Potential Explanations:Potential Explanations:BiologicalBiological

Tumor BiologyTumor Biology Hypothesis: AA have more aggressive Hypothesis: AA have more aggressive

diseasedisease Corollary: AA have a worse outcome regardless Corollary: AA have a worse outcome regardless

of access of access Host BiologyHost Biology

Hypothesis: AA respond differently to Hypothesis: AA respond differently to chemotherapychemotherapy

Corollary: AA should have different treatment Corollary: AA should have different treatment algorithms and may benefit from the use of algorithms and may benefit from the use of different drugs or different drug dosesdifferent drugs or different drug doses

Specific AimsSpecific Aims

Compare AA to C patients enrolled in Compare AA to C patients enrolled in N9741N9741 RR, TTP, and OSRR, TTP, and OS Chemotherapy toxicitiesChemotherapy toxicities Prevalence of polymorphisms in key genes Prevalence of polymorphisms in key genes

coding for enzymes involved in drug coding for enzymes involved in drug metabolismmetabolism

Correlate clinical endpoints & Correlate clinical endpoints & polymorphismspolymorphisms

1412 stage IV patients 1412 stage IV patients

486 with 486 with pharmacogenetic datapharmacogenetic data

1412 stage IV patients 1412 stage IV patients

486 with 486 with pharmacogenetic datapharmacogenetic data

IFL:IFL:Irinotecan + Irinotecan +

5-FU/LV5-FU/LV

IFL:IFL:Irinotecan + Irinotecan +

5-FU/LV5-FU/LV

IROX: IROX: Irinotecan + Irinotecan + ooxaliplatinxaliplatin

IROX: IROX: Irinotecan + Irinotecan + ooxaliplatinxaliplatin

FOLFOX: FOLFOX: Oxaliplatin + Oxaliplatin +

5-FU/LV 5-FU/LV

FOLFOX: FOLFOX: Oxaliplatin + Oxaliplatin +

5-FU/LV 5-FU/LV

RRAANNDDOOMMIIZZAATTIIOONN

RRAANNDDOOMMIIZZAATTIIOONN

N9741: SchemaN9741: Schema

Number of Patients by Race: Number of Patients by Race: Self Reported Self Reported

AAAA CCCC TotalTotal

AllAll 117 (8%)117 (8%) 12971297 14141414

IFLIFL 40 (10%)40 (10%) 372372 412412

FOLFOX4FOLFOX4 50 (8%)50 (8%) 590590 640640

IROXIROX 27 (7%)27 (7%) 335335 362362

Response Rate:Response Rate:Overall and By ArmOverall and By Arm

AAAA CC P-ValueP-Value

AllAll 31%31% 41%41% 0.0150.015

IFLIFL 28%28% 34%34% 0.440.44

FOLFOX4FOLFOX4 34%34% 49%49% 0.0470.047

IROXIROX 26%26% 38%38% 0.220.22

Median TTP:Median TTP:Overall and By ArmOverall and By Arm

AAAA CC P-Value*P-Value*

AllAll 7.3 mo7.3 mo 8.2 mo8.2 mo 0.560.56

IFLIFL 5.5 mo5.5 mo 6.9 mo6.9 mo 0.130.13

FOLFOX4FOLFOX4 11.0 mo11.0 mo 9.3 mo9.3 mo 0.980.98

IROXIROX 6.7 mo6.7 mo 7.3 mo7.3 mo 0.620.62

*Log-rank test p-value

Median OS:Median OS:Overall and By ArmOverall and By Arm

AAAA CC P-Value*P-Value*

AllAll 16.3 mo16.3 mo 17.9 mo17.9 mo 0.440.44

IFLIFL 12 mo12 mo 15.2 mo15.2 mo 0.0160.016

FOLFOX4FOLFOX4 16.9 mo16.9 mo 19.6 mo19.6 mo 0.470.47

IROXIROX 22 mo22 mo 16.7 mo16.7 mo 0.0660.066

*Log-rank test p-value

Median OS:Median OS:95% Confidence Intervals95% Confidence Intervals

AAAA CC P-ValueP-Value

AllAll 16.3 mo16.3 mo

13.6-2013.6-2017.9 mo17.9 mo

17-18.817-18.80.440.44

IFLIFL 12 mo12 mo

10.7-16.310.7-16.315.2 mo15.2 mo

13.5-17.413.5-17.40.0160.016

FOLFOX4FOLFOX4 16.9 mo16.9 mo

13.8-21.713.8-21.719.6 mo19.6 mo

18.7-21.318.7-21.30.470.47

IROXIROX 22 mo22 mo

11.4-28.911.4-28.916.7 mo16.7 mo

15.5-18.715.5-18.70.0660.066

Toxicity :Toxicity :All Arms CombinedAll Arms Combined

AA AA n=42n=42

C C n=472n=472

P-valueP-value

Any grade Any grade >> 33

34%34% 48%48% 0.0040.004

G4 G4 NeutropeniaNeutropenia

9%9% 8%8% 0.930.93

G4 DiarrheaG4 Diarrhea 5%5% 17%17% <0.001<0.001

ParesthesiasParesthesias 9%9% 8%8% 0.730.73

VomitingVomiting 6%6% 4%4% 0.430.43

IFL ToxicityIFL Toxicity

AA AA n=42n=42

C C n=472n=472

P-valueP-value


28%28% 45%45% 0.0350.035


10%10% 5%5% 0.240.24

G4 DiarrheaG4 Diarrhea 8%8% 23%23% 0.0240.024



FOLFOX ToxicityFOLFOX Toxicity

AA AA n=50n=50

C C n=590n=590

P-valueP-value


36%36% 46%46% 0.160.16


8%8% 12%12% 0.380.38


ParesthesiasParesthesias 1616 14%14% 0.710.71


IROX ToxicityIROX Toxicity

AA AA n=27n=27

C C n=335n=335

P-valueP-value

Any grade Any grade >> 3 3 41%41% 55%55% 0.160.16


7%7% 5%5% 0.550.55




Irinotecan PathwayCPT-11

cell membrane

CPT-11

CPT-11

SN-38

SN-38

SN-38TOP1

Cell Death

APC

SN-38G

ABCB1

CYP3A4CYP3A5

CES1CES2

UGT1A1

CES1CES2

ABCC2ABCG2

ABCC1

ADPRT

TDP1

CDC45L

XRCC1

NFKB1

NPC

ABCB1

Controls Irinotecan and Controls Irinotecan and SN-38 Efflux from CellsSN-38 Efflux from Cells

AAAA CC p valuep value

abcb1_3435abcb1_3435 <0.000<0.00011

C/CC/C 51%51% 18%18%

Other Other 49%49% 82%82%

abcg2abcg2 0.020.02

G/T or T/TG/T or T/T 3%3% 22%22%

G/GG/G 97%97% 78%78%

abcc2_3abcc2_3 0.050.05

A/AA/A 5%5% 22%22%

OtherOther 95%95% 78%78%

CYP3A: Prevents Activation CYP3A: Prevents Activation to SN-38 to SN-38 AAAA CC P-valueP-value

CYP3A4CYP3A4 < 0.0001< 0.0001 A/A G/G T/CA/A G/G T/C 89%89% 7%7% A/A & T/TA/A & T/T 11%11% 93%93%

CYP3A5CYP3A5 <0.0001<0.0001 C/C & T/TC/C & T/T 86%86% 11%11% C/CC/C 14%14% 89%89%

Polymorphisms inPolymorphisms inUGT1A1 do not predict UGT1A1 do not predict

diarrhea or overall toxicitydiarrhea or overall toxicity

AAAA CC P-valueP-value

UGT1A1UGT1A1 .008.008

6/66/6 17%17% 47%47%

6/76/7 63%63% 44%44%

7/77/7 21%21% 9%9%

UGT1a13UGT1a13 0.410.41

T/TT/T 12%12% 8%8%


Oxaliplatin

Detoxify

GSTP1GSTM1

SOD1 MPONQO1

POLH POLBTranslesional

replication

Damagerecognition

HMG1

Excisionrepair

Cell Death

ERCC2

ERCC1

XRCC1

cell membrane

Oxaliplatin

Oxaliplatin

ATP7A

SLC31A1

ABCG2ABCC2

Oxaliplatin

Oxaliplatin

Oxaliplatin Pathway

ERCC Genes Repair ERCC Genes Repair Oxaliplatin AdductsOxaliplatin Adducts


Ercc1_nErcc1_n 0.00010.0001

A/AA/A 5%5% 22%22%


Ercc2_dErcc2_d 0.00020.0002

A/AA/A 4%4% 22%22%

A/BA/B 29%29% 50%50%

B/BB/B 70%70% 28%28%

GST Genes Detoxify GST Genes Detoxify OxaliplatinOxaliplatin


Gstp1_I10Gstp1_I1055

0.070.07

T/TT/T 26%26% 44%44%

C/TC/T 53%53% 45%45%

C/CC/C 21%21% 11%11%

GSTM1_0GSTM1_0 0.00010.0001

AbsentAbsent 3%3% 51%51%

PresentPresent 97%97% 49%49%

Conclusions: Among the Conclusions: Among the Patients in This TrialPatients in This Trial

AA have a significantly lower RRAA have a significantly lower RR No differences in TTP were observedNo differences in TTP were observed Differences in OS were inconsistent Differences in OS were inconsistent

between AA and Cbetween AA and C AA have significantly less severe toxicity, AA have significantly less severe toxicity,

mainly less severe diarrhea mainly less severe diarrhea AA and C have significantly different AA and C have significantly different

frequencies of polymorphisms in candidate frequencies of polymorphisms in candidate genes coding for key enzymes involved in genes coding for key enzymes involved in drug activation, metabolism, and drug activation, metabolism, and disposition disposition

ImplicationsImplications

FOLFOX remains the preferred regimen in AA FOLFOX remains the preferred regimen in AA & C& C

Dose escalation may be possible in some AAs Dose escalation may be possible in some AAs Caution: Correlation of polymorphisms with Caution: Correlation of polymorphisms with

response and toxicity may not be causalresponse and toxicity may not be causal More research in bigger populations is More research in bigger populations is

indicatedindicated FOCUS (2135 pts) and CALGB/SWOG 80405 (2380 FOCUS (2135 pts) and CALGB/SWOG 80405 (2380

pts) have/are collecting germline DNA for pts) have/are collecting germline DNA for pharmacogeneticspharmacogenetics

Thanks for your attentionThanks for your attention