Polymorphisms in epidermal growth factor (EGF) and proteinase activated receptor 1 (PAR-1)
1
Polymorphisms in epidermal growth factor (EGF) and proteinase activated receptor 1 (PAR-1) associated with tumor recurrence in localized adenocarcinoma (EA) of the esophagus treated with surgery alone. G. Lurje 1 , J.M. Leers 2 , A. Pohl 1 , A. Oezcelik 2 , W. Zhang 1 , D. Yang 1 , J.A. Hagen 2 , S.R. DeMeester 2 , T.R. DeMeester 2 , and H.J. Lenz 1 1 Department of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 2 Department of Surgery, University Hospital, University of Southern California, Los Angeles, CA Methods Tissue samples from 239 patients (median age of 64 years; range: 25-91) were obtained at the University of Southern California University Hospital. All patients were diagnosed with locally advanced esophageal adenocarcinoma (pT1-4, pN1- 2, pM0) and were uniformly treated with surgery alone. The median time to recurrence was 2.8 years (95% CI: 1.9-4.2). Within the first 3 years after surgery, 101 out of 114 (89%) patients showed recurrent disease. DNA was isolated from formalin-fixed paraffin-embedded normal esophageal tissue samples and polymorphisms were analyzed using PCR-based protocols. Tumor recurrence after curative resection continues to impose a significant problem in the management of patients with localized esophageal adenocarcinoma (EA). The identification of molecular markers of prognosis is critical in better defining tumor stage- and progression, and may also help to define novel targets, as well surrogate endpoints of disease progression and response to therapy. Proteinase- activated-receptor 1 (PAR-1) and epidermal-growth-factor (EGF) have been shown to mediate the regulation of early-onset angiogenesis and in turn may impact the process of tumor growth and disease progression. Results This study supports the role of functional PAR-1 and EGF polymorphisms as independent prognostic markers in localized EA and may therefore help to identify patient subgroups at high risk for tumor recurrence. As such, the assessment of the patients’ individuals risk may be optimized on the basis of tumor-stage specific genotypes. Larger prospective and biomarker embedded clinical trials Introduction Conclusions PAR-1 -506 ins/del (adjusted p-value = 0.011) and EGF +61 A>G (adjusted p-value = 0.035) showed to be adverse prognostic markers, in both univariate and multivariable analysis (adjusted by type of surgery, T1- and N-category and race). In combined analysis, grouping alleles into favorable vs. non-favorable alleles, high expression variants of PAR-1 -506 ins/del (any insertion allele) and EGF +61 A>G (A/A) were associated with a higher likelihood of developing tumor recurrence (adjusted p-value < 0.001). Tim e to recurrence (TTR ) O verall Survival (O S) n M edian TTR ,yrs (95% C I) R elative risk (95% C I) Probability ± SE*of5-year recurrence P value † M edian O S,yrs (95% C I) R elative risk (95% C I) Probability ± SE*of5- yearsurvival P value † Sex 0.99 0.35 Male 203 2.8 (1.9,4.2) 1 0.60 ± 0.04 2.8 (2.1,3.7) 1 0.34 ± 0.04 Female 36 2.1 (1.7,9.8+) 1.00 (0.61,1.64) 0.67 ± 0.10 5.2 (2.0,8.1) 0.80 (0.50,1.29) 0.52 ± 0.10 Age,years 0.20 < 0.001 < 60 92 3.3 (2.7,11.0+) 1 0.56 ± 0.07 4.6 (3.1,9.0) 1 0.48 ± 0.07 60-69 64 3.2 (1.9,9.8+) 1.01 (0.64,1.61) 0.59 ± 0.07 3.5 (2.4,5.3) 1.30 (0.84,2.00) 0.40 ± 0.07 ≥ 70 83 1.9 (1.3,4.2) 1.42 (0.92,2.18) 0.70 ± 0.07 1.5 (0.9,2.2) 2.16 (1.46,3.21) 0.23 ± 0.06 R ace 0.90 0.60 Caucasian 221 2.7 (1.9,4.2) 1 0.62 ± 0.04 2.8 (2.2,3.7) 1 0.37 ± 0.04 Asian 5 3.2+ (0.1,3.2+) 0.90 (0.22,3.65) 0.20 ± 0.18 3.3+ (0.2,3.3+) 1.25 (0.40,3.93) 0.60 ± 0.24 Hispanic 13 5.5+ (1.0,5.5+) 0.83 (0.36,1.89) 0.50 ± 0.15 4.2 (1.2,5.5+) 0.68 (0.30,1.54) 0.40 ± 0.15 Stage < 0.001 < 0.001 Ib 34 10.3+ 1 0.19 ± 0.08 10.3+ (4.1,10.3+) 1 0.71 ± 0.11 IIa 36 6.2+ (3.3,6.2+) 2.61 (0.90,7.56) 0.44 ± 0.12 6.4 (2.2,14.3+) 2.07 (0.91,4.71) 0.55 ± 0.11 IIb 33 2.4 (1.6,4.4) 5.46 (2.07,14.4) 0.71 ± 0.09 5.0 (1.9,5.9) 2.71 (1.24,5.92) 0.51 ± 0.10 III 136 1.6 (1.0,1.9) 7.33 (3.00,17.9) 0.75 ± 0.05 2.0 (1.4,2.6) 4.58 (2.32,9.02) 0.20 ± 0.04 T-category < 0.001 < 0.001 T1 43 10.3+ 1 0.25 ± 0.08 10.3+ (4.1,10.3+) 1 0.68 ± 0.09 T2 44 4.0 (2.8,6.2) 2.53 (1.15,5.55) 0.64 ± 0.11 5.0 (3.6,6.4) 2.07 (1.06,4.04) 0.55 ± 0.09 T3 ‡ 151 1.7 (1.3,2.1) 4.55 (2.30,9.00) 0.74 ± 0.05 2.0 (1.5,2.6) 3.61 (2.03,6.40) 0.22 ± 0.04 T4 ‡ 1 N-category < 0.001 < 0.001 Negative 69 10.3+ (6.2,10.3+) 1 0.30 ± 0.07 11.6 (4.1,14.3+) 1 0.63 ± 0.08 1-2 positive 48 2.3 (1.4,13.2+) 2.70 (1.43,5.10) 0.57 ± 0.08 3.7 (1.9,13.2+) 1.72 (1.00,2.95) 0.47 ± 0.08 3-7 Positive 55 2.1 (1.0,4.2) 3.58 (1.95,6.56) 0.74 ± 0.08 3.3 (2.0,4.5) 2.42 (1.46,4.01) 0.29 ± 0.07 ≥8 positive 67 1.3 (0.6,1.8) 5.89 (3.25,10.7) 0.94 ± 0.05 1.4 (0.8,1.8) 4.40 (2.69,7.19) 0.08 ± 0.06 D ifferentiation § 0.022 < 0.001 Well/moderate 102 3.5 (2.3,13.2+) 1 0.55 ± 0.06 4.1 (3.1,5.8) 1 0.42 ± 0.06 Poor 135 1.9 (1.4,3.8) 1.54 (1.06,2.25) 0.67 ± 0.05 2.0 (1.4,2.9) 1.79 (1.27,2.53) 0.34 ± 0.05 Type ofsurgery 0.10 0.003 En Bloc 137 3.8 (2.4,6.2) 1 0.58 ± 0.05 4.1 (3.1,5.3) 1 0.45 ± 0.05 Transhiatal 102 1.9 (1.4,3.3) 1.36 (0.94,1.97) 0.66 ± 0.06 2.0 (1.4,2.8) 1.63 (1.18,2.27) 0.26 ± 0.05 *G reenw ood SE;+ Estim ates w ere notreached;† Based on log-rank test;§ Fortw o patients inform ation oftum ordifferentiation w as notavailable ‡ G rouped togetherforthe estim ates ofrelative risk and probability ± SE of5-yearrecurrence and overall survival 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 0 2 4 6 8 10 12 14 Estim ated R ecurrence-Free P robability Years Since Surgery ofLocalized Esophageal Adenocarcinom a PAR -1 -506 ins/del (rs11267092) del/del (n=127) del/ins orins/ins (n=110) Adjusted P value = 0.011 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 0 2 4 6 8 10 12 14 Estim ated Estim ated R ecurrence-Free Probability Years Since Surgery ofLocalized Esophageal Adenocarcinom a EG F +61 A>G (rs 4444903) A/A (n=66) A/G orG /G (n=171) Adjusted P value = 0.035
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Polymorphisms in epidermal growth factor (EGF) and proteinase activated receptor 1 (PAR-1) associated with tumor recurrence in localized adenocarcinoma (EA) of the esophagus treated with surgery alone. - PowerPoint PPT Presentation
Transcript of Polymorphisms in epidermal growth factor (EGF) and proteinase activated receptor 1 (PAR-1)
Polymorphisms in epidermal growth factor (EGF) and proteinase activated receptor 1 (PAR-1) associated with tumor recurrence in localized adenocarcinoma (EA)
of the esophagus treated with surgery alone.
G. Lurje1, J.M. Leers2, A. Pohl1, 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
MethodsTissue samples from 239 patients (median age of 64 years; range: 25-91) were obtained at the University of Southern California University Hospital. All patients were diagnosed with locally advanced esophageal adenocarcinoma (pT1-4, pN1-2, pM0) and were uniformly treated with surgery alone. The median time to recurrence was 2.8 years (95% CI: 1.9-4.2). Within the first 3 years after surgery, 101 out of 114 (89%) patients showed recurrent disease. DNA was isolated from formalin-fixed paraffin-embedded normal esophageal tissue samples and polymorphisms were analyzed using PCR-based protocols.
Tumor recurrence after curative resection continues to impose a significant problem in the management of patients with localized esophageal adenocarcinoma (EA). The identification of molecular markers of prognosis is critical in better defining tumor stage- and progression, and may also help to define novel targets, as well surrogate endpoints of disease progression and response to therapy. Proteinase-activated-receptor 1 (PAR-1) and epidermal-growth-factor (EGF) have been shown to mediate the regulation of early-onset angiogenesis and in turn may impact the process of tumor growth and disease progression.
Results
This study supports the role of functional PAR-1 and EGF polymorphisms as independent prognostic markers in localized EA and may therefore help to identify patient subgroups at high risk for tumor recurrence. As such, the assessment of the patients’ individuals risk may be optimized on the basis of tumor-stage specific genotypes. Larger prospective and biomarker embedded clinical trials are needed to validate these preliminary data.
Introduction
Conclusions
PAR-1 -506 ins/del (adjusted p-value = 0.011) and EGF +61 A>G (adjusted p-value = 0.035) showed to be adverse prognostic markers, in both univariate and multivariable analysis (adjusted by type of surgery, T1- and N-category and race). In combined analysis, grouping alleles into favorable vs. non-favorable alleles, high expression variants of PAR-1 -506 ins/del (any insertion allele) and EGF +61 A>G (A/A) were associated with a higher likelihood of developing tumor recurrence (adjusted p-value < 0.001).
Time to recurrence (TTR) Overall Survival (OS) n Median TTR, yrs
(95% CI) Relative risk (95% CI)
Probability ± SE* of 5-year recurrence
P value † Median OS, yrs (95% CI)
Relative risk (95% CI)
Probability ± SE* of 5-year survival
P value †
Sex 0.99 0.35 Male 203 2.8 (1.9, 4.2) 1 0.60 ± 0.04 2.8 (2.1, 3.7) 1 0.34 ± 0.04 Female 36 2.1 (1.7, 9.8+) 1.00 (0.61, 1.64) 0.67 ± 0.10 5.2 (2.0, 8.1) 0.80 (0.50, 1.29) 0.52 ± 0.10
Age, years 0.20 < 0.001 < 60 92 3.3 (2.7, 11.0+) 1 0.56 ± 0.07 4.6 (3.1, 9.0) 1 0.48 ± 0.07
60-69 64 3.2 (1.9, 9.8+) 1.01 (0.64, 1.61) 0.59 ± 0.07 3.5 (2.4, 5.3) 1.30 (0.84, 2.00) 0.40 ± 0.07 ≥ 70 83 1.9 (1.3, 4.2) 1.42 (0.92, 2.18) 0.70 ± 0.07 1.5 (0.9, 2.2) 2.16 (1.46, 3.21) 0.23 ± 0.06 Race 0.90 0.60 Caucasian 221 2.7 (1.9, 4.2) 1 0.62 ± 0.04 2.8 (2.2, 3.7) 1 0.37 ± 0.04
Asian 5 3.2+ (0.1, 3.2+) 0.90 (0.22, 3.65) 0.20 ± 0.18 3.3+ (0.2, 3.3+) 1.25 (0.40, 3.93) 0.60 ± 0.24 Hispanic 13 5.5+ (1.0, 5.5+) 0.83 (0.36, 1.89) 0.50 ± 0.15 4.2 (1.2, 5.5+) 0.68 (0.30, 1.54) 0.40 ± 0.15
Stage < 0.001 < 0.001 Ib 34 10.3+ 1 0.19 ± 0.08 10.3+ (4.1, 10.3+) 1 0.71 ± 0.11
IIa 36 6.2+ (3.3, 6.2+) 2.61 (0.90, 7.56) 0.44 ± 0.12 6.4 (2.2, 14.3+) 2.07 (0.91, 4.71) 0.55 ± 0.11 IIb 33 2.4 (1.6, 4.4) 5.46 (2.07, 14.4) 0.71 ± 0.09 5.0 (1.9, 5.9) 2.71 (1.24, 5.92) 0.51 ± 0.10
III 136 1.6 (1.0, 1.9) 7.33 (3.00, 17.9) 0.75 ± 0.05 2.0 (1.4, 2.6) 4.58 (2.32, 9.02) 0.20 ± 0.04 T-category < 0.001 < 0.001 T1 43 10.3+ 1 0.25 ± 0.08 10.3+ (4.1, 10.3+) 1 0.68 ± 0.09 T2 44 4.0 (2.8, 6.2) 2.53 (1.15, 5.55) 0.64 ± 0.11 5.0 (3.6, 6.4) 2.07 (1.06, 4.04) 0.55 ± 0.09 T3 ‡ 151 1.7 (1.3, 2.1) 4.55 (2.30, 9.00) 0.74 ± 0.05 2.0 (1.5, 2.6) 3.61 (2.03, 6.40) 0.22 ± 0.04
T4 ‡ 1 N-category < 0.001 < 0.001
Negative 69 10.3+ (6.2, 10.3+) 1 0.30 ± 0.07 11.6 (4.1, 14.3+) 1 0.63 ± 0.08 1-2 positive 48 2.3 (1.4, 13.2+) 2.70 (1.43, 5.10) 0.57 ± 0.08 3.7 (1.9, 13.2+) 1.72 (1.00, 2.95) 0.47 ± 0.08
3-7 Positive 55 2.1 (1.0, 4.2) 3.58 (1.95, 6.56) 0.74 ± 0.08 3.3 (2.0, 4.5) 2.42 (1.46, 4.01) 0.29 ± 0.07 ≥8 positive 67 1.3 (0.6, 1.8) 5.89 (3.25, 10.7) 0.94 ± 0.05 1.4 (0.8, 1.8) 4.40 (2.69, 7.19) 0.08 ± 0.06
Differentiation § 0.022 < 0.001 Well/moderate 102 3.5 (2.3, 13.2+) 1 0.55 ± 0.06 4.1 (3.1, 5.8) 1 0.42 ± 0.06
Poor 135 1.9 (1.4, 3.8) 1.54 (1.06, 2.25) 0.67 ± 0.05 2.0 (1.4, 2.9) 1.79 (1.27, 2.53) 0.34 ± 0.05 Type of surgery 0.10 0.003
En Bloc 137 3.8 (2.4, 6.2) 1 0.58 ± 0.05 4.1 (3.1, 5.3) 1 0.45 ± 0.05 Transhiatal 102 1.9 (1.4, 3.3) 1.36 (0.94, 1.97) 0.66 ± 0.06 2.0 (1.4, 2.8) 1.63 (1.18, 2.27) 0.26 ± 0.05 * Greenwood SE; + Estimates were not reached; † Based on log-rank test ; § For two patients information of tumor differentiation was not available ‡ Grouped together for the estimates of relative risk and probability ± SE of 5-year recurrence and overall survival
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EGF +61 A>G (rs 4444903)
A/A (n=66)
A/G or G/G (n=171)
Adjusted P value = 0.035
