Prognostic Markers for Response and and Overall Survival in Patients with Adenocarcinoma

Treated with Neoadjuvant TherapyJ.M. Leers2, G. Lurje1, A. Oezcelik2,,W. Zhang1, D. Yang1, J.A. Hagen2, S.R. DeMeester2, T.R. DeMeester2, and H.J. Lenz1

1Department of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA2Department of Surgery, University Hospital, University of Southern California, Los Angeles, CA

Methods

We investigated tissue samples of 104 patients (94 males and 10 females) with a median age of 60 years (range: 29-86) with localized esophageal adenocarcinoma treated with 5-FU based neoadjuvant therapy at USC. A panel of ten genes involved in DNA repairs and 5-FU metabolism were selected. DNA was isolated from formalin-fixed paraffin-embedded normal esophageal tissue samples and germline polymorphisms were analyzed using PCR-RFLP and 5´-end [γ-33P] ATP-labeled PCR methods. Fisher’s exact test was used to examine the associations between polymorphism and complete pathological response. Kaplan-Meier curves, log-rank test and Cox proportional hazards model were used for their associations with overall survival.

Neoadjuvant therapy has been introduced to improve survival in patients with localized esophageal adenocarcinoma (EA). Yet, the benefit of neoadjuvant therapy for patients with EA is still under debate as only about one third of treated patients respond to therapy. The identification of molecular markers that predict response will be critical to tailor the appropriate therapy for these patients. With ERCC1 118, XPD 156 and XRCC 1 399 we investigated polymorphisms of genes involved in DNA repair.

Introduction

This data supports the role of functional ERCC-1 polymorphism as a predictive marker for response and may therefore be applied as a marker for tailored therapy. Further, XPD 156 and XRCC1 399 were identified as independent prognostic markers in localized EA treated with neoadjuvant therapy.

Conclusions

Results

31 out of 104 patients (30%) had complete pathological response. The median overall survival was 18.5 months (95% CI: 13.5-25.7). Single nucleotide polymorphism ERCC1 118T CC (p-value = 0.031, Fisher’s exact test) was identified as an adverse prognostic marker for response in univariate analysis. None of 11 carriers showed evidence of response.

Genomic polymorphisms and clinical outcome in patients with resected esophageal cancer

Complete Response Overall Survival

Genotype N Yes No P value *Median overall survival, mos (95% CI)

Hazard ratio (95% CI) P value *

ERCC1 3’UTR 1.00 0.89

C/C 69 20 (29%) 49 (71%) 17.4 (13.2, 25.7) 1 (Reference)

C/A 23 6 (26%) 17 (74%) 20.1 (9.0, 110.3+) 0.93 (0.49, 1.76)

A/A 6 2 (33%) 4 (67%) 38.4 (2.6, 38.4) 0.77 (0.24, 2.48)

ERCC1 118T 0.067 0.11

T/T 31 10 (32%) 21 (68%) 16.5 (12.1, 34.8) 1 (Reference)

T/C 62 21 (34%) 41 (66%) 20.1 (13.5, 31.0) 0.79 (0.46, 1.35)

C/C 11 0 (0%) 11 (100%) 10.7 (2.4, 37.9) 1.72 (0.75, 3.94)

MTHFR 677 C/T 0.16 0.51

C/C 40 16 (40%) 24 (60%) 25.4 (10.7, 58.4) 1 (Reference)

C/T 54 12 (22%) 42 (78%) 15.2 (12.9, 24.9) 1.28 (0.77, 2.13)

T/T 10 3 (30%) 7 (70%) 21.8 (0.3, 114.0+) 0.87 (0.33, 2.29)

MTHFR 1298 0.29 0.76

A/A 50 15 (30%) 35 (70%) 15.8 (13.2, 25.7) 1 (Reference)

A/C 47 12 (26%) 35 (74%) 19.6 (12.4, 38.8) 0.83 (0.50, 1.38)

C/C 7 4 (57%) 3 (43%) 28.6 (7.4, 34.8) 0.94 (0.37, 2.41)

XPD 156 0.41 0.043

C/C 30 12 (40%) 18 (60%) 24.9 (12.1, 95.5+) 1 (Reference)

C/A 54 15 (28%) 39 (72%) 21.8 (12.9, 37.9) 1.23 (0.67, 2.26)

A/A 17 4 (24%) 13 (76%) 13.2 (2.8, 18.5) 2.35 (1.13, 4.90)

XPD 751 0.11 0.33

A/A 34 13 (38%) 21 (62%) 13.5 (7.4, 34.8) 1 (Reference)

A/C 59 13 (22%) 46 (78%) 24.9 (16.3, 31.0) 0.69 (0.41, 1.17)

C/C 11 5 (45%) 6 (55%) 11.5 (2.4, 84.4+) 0.99 (0.40, 2.43)

XRCC1 399 0.94 0.11

G/G 21 7 (33%) 14 (67%) 13.5 (9.8, 21.8) 1 (Reference)

G/A 72 21 (29%) 51 (71%) 19.6 (13.5, 34.8) 0.58 (0.33, 1.02)

A/A 10 3 (30%) 7 (70%) 64.1 (1.8, 74.5+) 0.49 (0.18, 1.34)

TS 3’ UTR 0.84 0.13

+/+ 37 10 (27%) 27 (73%) 16.5 (11.5, 31.0) 1 (Reference)

+/- 50 17 (34%) 33 (66%) 23.2 (13.2, 110.3) 0.74 (0.43, 1.28)

-/- 14 4 (29%) 10 (71%) 10.4 (3.5, 26.3) 1.45 (0.72, 2.90)

TS 5’ UTR 0.35 0.86

3R/3R 33 8 (24%) 25 (76%) 19.6 (9.8, 38.4) 1 (Reference)

3R/2R 55 18 (33%) 37 (67%) 18.5 (12.9, 34.8) 1.05 (0.60, 1.81)

2R/2R 8 4 (50%) 4 (50%) 12.4 (6.4, 44.9+) 1.29 (0.52, 3.22)

TS 5’ UTR SNP 0.91 0.60

3G/3G 13 4 (31%) 9 (69%) 31.0 (6.4, 95.5+) 1 (Reference)

3G/3C 24 6 (25%) 18 (75%) 16.3 (11.5, 28.6) 1.59 (0.66, 3.83)

2G/3G 22 7 (32%) 15 (68%) 23.2 (2.8, 114.0+) 1.25 (0.49, 3.17)

2G/3C 30 10 (33%) 20 (67%) 16.5 (10.7, 58.4) 1.42 (0.60, 3.38)

2G/2G 7 3 (43%) 4 (57%) 12.4 (6.4, 25.4) 2.29 (0.76, 6.90)

* P values were based on Fisher’s exact test for tumor response to 5-FU based neoadjuvant therapy and the log-rank test for overall survival.

Table 2 Genomic polymorphisms and clinical outcome in patients with resected esophageal cancer* P values were based on Fisher’s exact test for tumor response to 5-FU based neoadjuvant therapy and the log-rank test for overall survival.

Table 3 Genomic polymorphisms and clinical outcome in patients with resected esophageal cancer* P values were based on Fisher’s exact test for tumor response to 5-FU based neoadjuvant therapy and Wald test in Cox proportional hazards regression model for overall survival adjusting T, N, and M.

Results

In Cox regression analysis adjusting for TNM category, patients carrying XPD 156 A/A (p=0.01) and XRCC 1 399 G/G (p=0.03) had shorter survival compared to patients with XPD 156 C/C or C/A and XRCC 1 399 G/A or A/A, respectively.

XRCC 1 399 G>A Adjusted p-value 0.03 XPD 156 C>A Adjusted p-value 0.01