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Matrix Metalloproteinase-1 Level Is a Potential Serum Biomarker as a Prognostic Factor of Patients With Locally Advanced Cervical Cancer After Chemoradiation Therapy
Volume 90 Number 1S Supplement 2014 0.006). On multivariate analysis, low ATM and low PARP1 status remained significant for worse OS in patients with “high” pre-treatment Hb (> 115 g/L) status, adjusted by stage, ATM: [HR Z 2.6 (1.1-6.3), p Z 0.03]; PARP1: [HR Z 3.0 (1.2-7.6), p Z 0.02]; with a trend to significance in DNA-PKcs tumors [HR Z 2.5 (1.0-6.3), p Z 0.05]. Conclusions: In this cohort of cervical cancer patients treated with radical CRT, low tumor ATM and PARP1 status were independently associated with worse OS in patients with “high” Hb status. Further investigation of the interactions of DNA damage and repair proteins in these tumors is warranted to appreciate the association between inherent genomic instability and radiation sensitivity effects, and to determine better treatment strategies. Author Disclosure: C.K. Ho: None. E. Kornaga: None. A. Klimowicz: None. M. Dean: None. G. Bebb: None. T. Phan: None. P. Ghatage: None. A.M. Magliocco: None. S.P. Lees-Miller: None. C.M. Doll: None.
199 Apolipoprotein C-II/Matrix Metalloproteinase-1 Level Is a Potential Serum Biomarker as a Prognostic Factor of Patients With Locally Advanced Cervical Cancer After Chemoradiation Therapy Y. Harima, K. Ikeda, K. Utsunomiya, A. Komemushi, S. Kanno, T. Shiga, and N. Tanigawa; Kansai Medical University, Moriguchi, Japan Purpose/Objective(s): To assess the usefulness of pretreatment serum protein level as a generally applicable measurement in predicting and estimating chemoradiation therapy outcome of patients with locally advanced squamous cell cervical cancer (CC). Materials/Methods: In this series, a total of 87 patients with CC who underwent definitive chemoradiation therapy between February 2006 and May 2012 were included. Age, tumor size, and pretreatment serum values of SCC, Apolipoprotein C-II (ApoC-II), Matrix metalloproteinase-1 (MMP1), MMP2, and a composite variable of ApoC-II divided by MMP1 (ApoC-II/MMP1) of 49 patients in the good prognosis group and 38 in the poor one were analyzed. The primary endpoint was to estimate correlations between the patient characteristics and overall survival as analyzed by Kaplan-Meier survival rate, log-rank test, univariate and multivariate Cox proportional-hazard model analysis. Results: ROC analysis yielded a cutoff point of 14.8 mg/mL for ApoC-II to predict all-cause mortality. With this cutoff point, the survival time analysis was performed, indicating significant difference between two strata (p < 0.001) using Kaplan-Meier method and the log-rank test. MMP1 and ApoC-II/MMP1 were also significant predictors (p Z 0.009, p Z 0.001). On univariate analysis with Cox proportional-hazard model, ApoC-II, MMP1, SCC, size, and ApoC-II/MMP1 were a significant independent variables to predict overall survival rate (p Z 0.019, p Z 0.017, p Z 0.021, p Z 0.002, and p Z 0.001). On multivariate analysis, ApoC-II/ MMP1 was a significant independent predictor of overall survival rate (p Z 0.017).The specificity and sensitivity of ApoC-II/ MMP1 levels were 70.6% and 58.3%, respectively, as determined using ROC curves. Conclusions: ApoC-II/MMP1 levels correlated with outcome in patients with CC after chemoradiation therapy. ApoC-II/MMP1 could be used as a biomarker for predicting and estimating chemoradiation therapy outcome of patients with CC. Author Disclosure: Y. Harima: None. K. Ikeda: None. K. Utsunomiya: None. A. Komemushi: None. S. Kanno: None. T. Shiga: None. N. Tanigawa: None.
Oral Scientific Sessions
S93
200 On-Treatment Serum Squamous Cell Carcinoma Antigen (SCCA) Predicts Response to Therapy on Posttherapy FDG-PET and Recurrence in Women Treated With Chemoradiation for Squamous Cancer of the Cervix S. Markovina,1 L. Henke,2 S. Pak,3 T.A. DeWees,1 G. Silverman,3 J. Pfeifer,2 and P.W. Grigsby4; 1Washington University, St. Louis, MO, 2 Washington University School of Medicine, St. Louis, MO, 3University of Pittsburgh School of Medicine, Pittsburgh, PA, 4Washington University Medical Center, St. Louis, MO Purpose/Objective(s): Recurrence from cervical cancer is common in women with advanced disease and adverse risk factors. Efforts to risk-stratify patients include [18F]fluorodeoxyglucose emission tomography (FDG-PET) and serum squamous cell carcinoma antigen (SCCA), which are both strongly prognostic for recurrence. SCCA is a serine protease inhibitor that is important for resistance to stress-induced cell death. We hypothesized that on-treatment serum SCCA metrics and in situ pre-treatment protein levels can better stratify patients for treatment response and risk of recurrence and death, and that SCCA plays a cellular role in resistance to radiation therapy. Materials/Methods: Two hundred seventeen patients treated with definitive chemoradiation for cervical squamous carcinoma with serum SCCA measured at diagnosis were included (normal range 0-2.2 ng/mL). Serum SCCA was measured at weekly intervals during chemoradiation in 124 patients (57%). Pre-treatment FDG-PET was performed on all patients and post-treatment FDG-PET was performed on 172 patients (80%). In situ SCCA protein levels were measured by immunohistochemistry on a 102patient tissue microarray. Cervical tumor cell lines were treated with 2, 4, 6, or 8 Gy and cellular SCCA levels measured by ELISA. Chi-squared and Kaplan-Meier with log-rank analyses were used for pair-wise and logistic tests, respectively. Results: We found that serum SCCA > 30 ng/mL at diagnosis is strongly associated with both residual disease on post-treatment FDGPET (p Z 0.02) and with recurrence (p < 0.0001), as is failure of serum SCCA to normalize by the end of treatment (p Z 0.0006 and p < 0.0001, respectively). Failure to normalize was associated with recurrence even if serum SCCA at diagnosis was low (p Z 0.015). A transient increase in serum SCCA after initiation of chemoradiation was seen in 52 patients (42%), and further stratified patients for recurrence (p < 0.0001). Although tumor recurrence almost uniformly resulted in death, high in situ SCCA on pre-treatment specimens was strongly associated with death in this population (p < 0.0001). Preliminary findings in cervical tumor cell lines demonstrate increased SCCA after radiation in relatively radioresistant lines, and increased relative radioresistance with exogenous expression of SCCA. Conclusions: Serum SCCA is an independently powerful prognostic tool in cervical carcinoma. Preliminary data suggest that SCCA may also play a cellular role in mediating resistance to radiation and this may promote recurrence and death in a subset of patients. We are currently investigating this hypothesis. Selected escalation of therapy in these patients could then be considered. Author Disclosure: S. Markovina: None. L. Henke: None. S. Pak: None. T.A. DeWees: None. G. Silverman: None. J. Pfeifer: None. P.W. Grigsby: None.
199 Apolipoprotein C-II/Matrix Metalloproteinase-1 Level Is a Potential Serum Biomarker as a Prognostic Factor of Patients With Locally Advanced Cervical Cancer After Chemoradiation Therapy Y. Harima, K. Ikeda, K. Utsunomiya, A. Komemushi, S. Kanno, T. Shiga, and N. Tanigawa; Kansai Medical University, Moriguchi, Japan Purpose/Objective(s): To assess the usefulness of pretreatment serum protein level as a generally applicable measurement in predicting and estimating chemoradiation therapy outcome of patients with locally advanced squamous cell cervical cancer (CC). Materials/Methods: In this series, a total of 87 patients with CC who underwent definitive chemoradiation therapy between February 2006 and May 2012 were included. Age, tumor size, and pretreatment serum values of SCC, Apolipoprotein C-II (ApoC-II), Matrix metalloproteinase-1 (MMP1), MMP2, and a composite variable of ApoC-II divided by MMP1 (ApoC-II/MMP1) of 49 patients in the good prognosis group and 38 in the poor one were analyzed. The primary endpoint was to estimate correlations between the patient characteristics and overall survival as analyzed by Kaplan-Meier survival rate, log-rank test, univariate and multivariate Cox proportional-hazard model analysis. Results: ROC analysis yielded a cutoff point of 14.8 mg/mL for ApoC-II to predict all-cause mortality. With this cutoff point, the survival time analysis was performed, indicating significant difference between two strata (p < 0.001) using Kaplan-Meier method and the log-rank test. MMP1 and ApoC-II/MMP1 were also significant predictors (p Z 0.009, p Z 0.001). On univariate analysis with Cox proportional-hazard model, ApoC-II, MMP1, SCC, size, and ApoC-II/MMP1 were a significant independent variables to predict overall survival rate (p Z 0.019, p Z 0.017, p Z 0.021, p Z 0.002, and p Z 0.001). On multivariate analysis, ApoC-II/ MMP1 was a significant independent predictor of overall survival rate (p Z 0.017).The specificity and sensitivity of ApoC-II/ MMP1 levels were 70.6% and 58.3%, respectively, as determined using ROC curves. Conclusions: ApoC-II/MMP1 levels correlated with outcome in patients with CC after chemoradiation therapy. ApoC-II/MMP1 could be used as a biomarker for predicting and estimating chemoradiation therapy outcome of patients with CC. Author Disclosure: Y. Harima: None. K. Ikeda: None. K. Utsunomiya: None. A. Komemushi: None. S. Kanno: None. T. Shiga: None. N. Tanigawa: None.
Oral Scientific Sessions
S93
200 On-Treatment Serum Squamous Cell Carcinoma Antigen (SCCA) Predicts Response to Therapy on Posttherapy FDG-PET and Recurrence in Women Treated With Chemoradiation for Squamous Cancer of the Cervix S. Markovina,1 L. Henke,2 S. Pak,3 T.A. DeWees,1 G. Silverman,3 J. Pfeifer,2 and P.W. Grigsby4; 1Washington University, St. Louis, MO, 2 Washington University School of Medicine, St. Louis, MO, 3University of Pittsburgh School of Medicine, Pittsburgh, PA, 4Washington University Medical Center, St. Louis, MO Purpose/Objective(s): Recurrence from cervical cancer is common in women with advanced disease and adverse risk factors. Efforts to risk-stratify patients include [18F]fluorodeoxyglucose emission tomography (FDG-PET) and serum squamous cell carcinoma antigen (SCCA), which are both strongly prognostic for recurrence. SCCA is a serine protease inhibitor that is important for resistance to stress-induced cell death. We hypothesized that on-treatment serum SCCA metrics and in situ pre-treatment protein levels can better stratify patients for treatment response and risk of recurrence and death, and that SCCA plays a cellular role in resistance to radiation therapy. Materials/Methods: Two hundred seventeen patients treated with definitive chemoradiation for cervical squamous carcinoma with serum SCCA measured at diagnosis were included (normal range 0-2.2 ng/mL). Serum SCCA was measured at weekly intervals during chemoradiation in 124 patients (57%). Pre-treatment FDG-PET was performed on all patients and post-treatment FDG-PET was performed on 172 patients (80%). In situ SCCA protein levels were measured by immunohistochemistry on a 102patient tissue microarray. Cervical tumor cell lines were treated with 2, 4, 6, or 8 Gy and cellular SCCA levels measured by ELISA. Chi-squared and Kaplan-Meier with log-rank analyses were used for pair-wise and logistic tests, respectively. Results: We found that serum SCCA > 30 ng/mL at diagnosis is strongly associated with both residual disease on post-treatment FDGPET (p Z 0.02) and with recurrence (p < 0.0001), as is failure of serum SCCA to normalize by the end of treatment (p Z 0.0006 and p < 0.0001, respectively). Failure to normalize was associated with recurrence even if serum SCCA at diagnosis was low (p Z 0.015). A transient increase in serum SCCA after initiation of chemoradiation was seen in 52 patients (42%), and further stratified patients for recurrence (p < 0.0001). Although tumor recurrence almost uniformly resulted in death, high in situ SCCA on pre-treatment specimens was strongly associated with death in this population (p < 0.0001). Preliminary findings in cervical tumor cell lines demonstrate increased SCCA after radiation in relatively radioresistant lines, and increased relative radioresistance with exogenous expression of SCCA. Conclusions: Serum SCCA is an independently powerful prognostic tool in cervical carcinoma. Preliminary data suggest that SCCA may also play a cellular role in mediating resistance to radiation and this may promote recurrence and death in a subset of patients. We are currently investigating this hypothesis. Selected escalation of therapy in these patients could then be considered. Author Disclosure: S. Markovina: None. L. Henke: None. S. Pak: None. T.A. DeWees: None. G. Silverman: None. J. Pfeifer: None. P.W. Grigsby: None.