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Kathleen D. Danenberg Response Genetics, Inc. . Predictive and Prognostic Markers for Gastric Cancer. ERCC1. Why would a predictive test for platinum efficacy be desirable?. Non- platin and platin therapy have similar outcomes.

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kathleen d danenberg response genetics inc
Kathleen D. Danenberg

Response Genetics, Inc.

Predictive and Prognostic Markers for Gastric Cancer

slide4

Non-platin and platin therapy have

similar outcomes

IF (n=170): irinotecan, folinic acid 5-fluorouracil;

CF (n=163): cisplatin and 5-fluorouracil

Median TTP

IF: 5.0 months

CF: 4.2 months

Median OS:

IF: 9.0 months

CF: 8.7 months

Dank et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Annals of Oncology. 2008; 19:1450-1457.

but non platin treatment is less toxic comparative toxicity profiles of cf and if
…but non-platin treatment is less toxic: Comparative toxicity profiles of CF and IF

Dank et al. Annals of Oncology. 2008; 19:1450-1457.

slide6

Conclusions

Dank et al. Annals of Oncology. 2008; 19:1450-1457.

“… Irinotecan/5-fluorouracil (IF) is a platinum-free regimen that has similar efficacy to cisplatin/5-fluorouracil (CF) but with improved tolerance.

As such, IF could represent a potential platinum-free alternative backbone to be combined with new targeted agents to be explored for the treatment of metastatic gastric cancer.

pre clinical studies show ercc1 to be a direct determinant of cisplatin efficacy
Pre-clinical studies showERCC1 to be a direct determinant of cisplatinefficacy

ERCC1 small interfering RNA expression reduces ERCC1 expression and sensitizes the cells to platinum-containing chemotherapeutic agents.

Youn et al. Oncogenic H-Ras Up-Regulates Expression of ERCC1 to Protect Cells from Platinum-Based Anticancer Agents Cancer Res 2004:64, 4849-4857.

ercc1 gene expression in gastric cancer cells negatively correlates with sensitivity to cisplatin
ERCC1 gene expression in gastric cancer cells negatively correlates with sensitivity to cisplatin.

ERCC1 mRNA expression levels and sensitivity to cisplatin in cells from malignant effusions collected from untreated gastric cancer patients(P= 0.014, r = 0.685).

Wang et al. ERCC1 and BRCA1 mRNA expression levels in metastatic malignant effusions is associated with chemosensitivity to cisplatin and/or docetaxel. BMC Cancer 2008;8:97.

slide11

ERCC1 thresholds and benefit of low

ERCC1 from platin therapy

ercc1 mrna levels and response in gastric cancer patients receiving fp
ERCC1 mRNA levels and response in gastric cancer patients receiving FP

20

16

12

8

4

0

p=0.004 by Kruskal-Wallis test.

ERCC1 Expression

Response

No Response

Metzger R, et al. J ClinOncol. 1998;16:309-316.

ercc1 mrna levels and survival of advanced gastric cancer patients treated with a folfox regimen
ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a FOLFOX regimen

Wei J et al. Br J Cancer. 2008;98:1398-402.

p<0.0001

Conclusion: “In patients with high mRNA levels of ERCC1, alternative chemotherapy regimens should be considered.”

slide14

Effect of ERCC1 protein expression on survival in FOLFOX chemotherapy of advanced gastric cancer

ERCC1 was the only significant independent prognostic factor impacted on OS (hazard ratio 1.91, P = 0.037).

Kwon et al. Ann Oncol. 2007;18:504-9.

Overall survival curve according to ERCC1 expression measured by IHC (P = 0.0396).

slide15

Prediction of survival by ERCC1 expression in gastric cancer treated with surgery followed by FOLFOX or receiving surgery alone.

Median RFS

Median OS

Yiu et al. ASCO 2010 abstract 29

slide16

ERCC1 expression and activity of PELF regimen as first-line treatment of metastatic gastric cancer.

PELF = cisplatin (P), epirubicin (E), leucovorin (L), 5-fluorouracil (F)

Conclusion: “IHC studies for ERCC1 might be useful to predict the clinical outcome in MGC patients treated with PELF regimen.”

Natoliet al. J ClinOncol 28, 2010 (suppl; abstr e14603)

slide17

ERCC1expression and outcomes of advanced gastric cancer patients treated with cisplatin and S-1.

Matsubara et al.

Br J Cancer. 2008; 98: 832–839.

slide18

1.0

0.8

0.6

0.4

0.2

0.0

0

12

24

36

48

60

72

84

96

Impact of low ERCC1 and DPD on the outcomes of advanced gastric cancer.

Low ERCC1 and low DPD expression:

median survival time, 15.5 months

Any high expression:

median survival time, 10.2 months

Probability of survival

log-rank P < .001

Months since start of 1st-line chemotherapy

Matsubara et al.

Br J Cancer. 2008; 98: 832–839.

slide19

SWOG proposed prospective trial using ERCC1to select CPT11/docetaxel or FOLFOX

High ERCC1: CPT11/docetaxel

ASSIGNMENT

ASSIGNMENT

RANDOM

High ERCC1:

FOLFOX

Genotypic Arm: ERCC1 Selection

RANDOM

Low ERCC1:

CPT11/docetaxel

Low ERCC1:

FOLFOX

n=200, Endpoints: feasibility and increase of PFS

chemotherapy with egfr targeted agents kras and egfr mutations are rare in gastric adenocarcinoma
Chemotherapy with EGFR-targeted agents: KRAS and EGFR mutations are rare in gastric adenocarcinoma
  • These findings suggest a priori that:
  • due to lack of EGFR mutations, gastric tumors will not be very sensitive to EGFR-directed TKI’s (e.g., gefitinib and erlotinib)
  • b) however, due to the lack of KRAS mutations, they may be sensitive to EGFR-directed antibodies
  • Mammano E etal. Anticancer Res. 2006;26:3547-50.
    • in 49 gastric adenocarcinomas, no specific EGFR gene mutations were detected.
  • S.W. Han et al. Br J Cancer 2009;100:298-304.
    • In 38 gastric patients, no EGFR amplification or K-ras mutations were observed.
egfr tyrosine kinase inhibitors phase ii adenocarcinoma
EGFR Tyrosine Kinase Inhibitors: Phase II, Adenocarcinoma

Doi 1036 Proc ASCO 22, 2003; Ferry Clin Can Res 132:5869; 2007 Janmaat JCO 24: 1612; 2006;Tew GI ASCO 2005; Dragovich JCO 24: 4922; 2006

bouche o et al j clin oncol 2004 22 4319 4328
Bouche O et al. J ClinOncol 2004;22:4319-4328.

PFS and OS with “classical chemotherapy”

Abbreviations: LV5FU2), leucovorin-5-FU; OS, overall survival; PFS, progression-free survival

slide24

PFS and OS are increased by addition of

cetuximab

Bouche et al.. J ClinOncol 2004;22:4319-4328

Moehleret al.. Ann Oncol. 2010 Nov 30.

Moehleret al.. Ann Oncol. 2010 Nov 30.: Patients with a complete response (CR) or partial response (PR) had significantly longer OS times and PFS times than patients with SD or PD.

predicting cetuximab activity
Predicting cetuximab activity

Since KRAS mutations and EGFR mutations are rare in gastric tumors, can EGFR expression levels predict response to cetuximab?

slide26

Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advancedgastric cancer.

-For EGFR (+) patients, both TTP (median 7.2 vs 5.0 months, P=0.020) and OS (not reached vs 7.6 months, P=0.013) were significantly longer after adjusting for clinical factors.

S.W. Han et al Br J Cancer. 2009;100:298-304.

slide27

Cetuximab with irinotecan, folinic acid and 5-FU as first-line treatment in advanced gastroesophagealcancer: a prospective multi-center biomarker-oriented phase II study.

-but tumor EGFR expression did not correlate with PFS

(log-rank P = 0.567) or OS (log-rank P = 0.663).

Moehler et al. Ann Oncol. 2010 Nov 30.

slide28

Phase II study of cetuximab plus FOLFIRI in patients with untreated advanced gastric or GE junction adenocarcinoma (FOLCETUX study).

-EGFR expression did not significantly correlate with ORR

Pinto et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 2007;18:510-517.

her2 inhibitors trastuzumab and lapatinib in gastric cancer
HER2 inhibitors trastuzumaband lapatinib in gastric cancer

ASCO 2008, Abstr 4526, Bang, et al.

Analysis of 2484 gastric cancer samples from the Ph III ToGA trial

21.9% HER2 positivity

ASCO 2009, Abstr LBA 4509, ToGA Trial

Rand Ph III, HER2+ gastric cancer

5-FU/capecitabine + cisplatin +/- trastuzumab

RR 47.3 vs. 34.5%, OS 13.5 vs. 11.1 mo (p = 0.0048)

HR 0.74 (0.60-0.91)

Practice changing!!!

LOGIC Trial

Rand Ph III, HER 2+ gastric cancer

Capecitabine + oxaliplatin +/- lapatinib

the toga trial primary end point os
The ToGAtrial: Primary end point- OS

MedianOS

13.811.1

1.0

Event

Events

167182

HR

0.74

95% CI

0.60, 0.91

p value

0.0046

0.9

FC + T

0.8

FC

0.7

0.6

0.5

0.4

0.3

0.2

11.1

13.8

0.1

0.0

12

16

36

0

2

4

6

8

10

14

18

20

22

24

26

28

30

32

34

Time (months)

No. at risk

294

290

113

90

246

223

209

185

173

143

147

117

90

64

71

47

56

32

43

24

30

16

21

14

13

7

12

6

6

5

4

0

1

0

0

0

T, trastuzumab

r schoff et al virchows arch 2010 457 299 307
Rüschoff et al. Virchows Arch. 2010 457:299-307.

HER2 assay by IHC for gastric cancer required a different set of guidelines than for breast

sources of her2 testing variation with ihc
Sources of HER2 Testing Variation with IHC

Pre-analytic

    Time to fixation

    Method of tissue processing

    Time of fixation

    Type of fixation

Analytic

    Assay validation

    Equipment calibration

    Use of standardized laboratory procedures

    Training and competency assessment of staff

    Type of antigen retrieval

    Test reagents

    Use of standardized control materials

    Use of automated laboratory methods

Post-analytic

    Interpretation criteria

    Use of image analysis

    Reporting elements

    Quality assurance procedures

        Laboratory accreditation

        Proficiency testing

        Pathologist competency assessment

Wolff et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J ClinOncol. 2007;25:118-45.

slide35

Press et al. HER-2 Gene Amplification, HER-2 and Epidermal Growth Factor Receptor mRNA and Protein Expression, and Lapatinib Efficacy in Women with Metastatic Breast Cancer. Clin Cancer Res 2008; 14: 7861

HER-2 mRNA expression by PCR correlates with HER-2 FISH (r=0.83) and IHC (r=0.72)

slide36

Comparison of HER2 expression and amplification in primary breast tumors (T) and corresponding lymph node metastases (N) determined with IHC, FISH, and quantitative RT-PCR

IHC

HER2 expression scored as 0 and 1+ (=negative) or 2+ and 3+ (=positive) is indicated.

FISH analysis:

red, HER2 signals; green, centromere 17 signals. +, specimens harboring a HER2 amplification; −, nonamplified specimens.

Quantitative RT-PCR:

red line, the cutoff between high (scored as HER2 positive) and low relative expressions of HER2.

Vinatzeret al. Clin Cancer Res 2005;11:8348-8357

slide37

PCR quantitation of HER2 expression gives the same clinical information as IHC and FISH

Quantitative RT-PCR:

-simple, cost-effective,

-rapidly produces quantitative, numerical, and reproducible results.

-easily amenable to standardization, insensitive to inter-observer variability

-results are a number, which can be either above or below a predetermined threshold.

IHC

-interpretation of IHC results is inherently difficult and time-consuming, requires experienced pathologists

-is influenced by use of different antibodies, fixatives, staining protocols, and inter-observer variability.

FISH

-is quantitative and reproducible but results are more difficult to interpret than those of quantitative RT-PCR.

-time-consuming, and requires specialized expertise and equipment.

Vinatzeret al. Clin Cancer Res 2005;11:8348-8357

slide38
Her2 gene expression associated with OS in patients with metastatic gastric cancer treated with lapatinib

Chang H et al,Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4647

summary and conclusions
Summary and conclusions

ERCC1 mRNA expression appears to be a viable predictive marker for platin therapy.

The jury is still out on EGFR expression as a predictive marker for cetuximab therapy.

The IHC and FISH-based assay of HER2 has many issues so PCR should be investigated as an additional tool or as an alternative.