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Cost-effectiveness of homologous recombination defect testing to target PARP inhibitor use in platinum-sensitive recurrent ovarian cancer
S92
Abstracts / Gynecologic Oncology 125 (2012) S3–S167
Table Table 1(continued) (continued) 1 Ovary (N = 122) Surgery Bowel Splenectomy Diaphragm Liver Lymphadenectomy Platinum and Taxol Radiotherapy
Uterus (N = 41)
P
Table Outcomes from the study. (BI: Bowel involvement; DFS: Disease free survival; OS: Overall survival; OPCR: Optimal cytoreduction; NAC: Neoadjuvant Chemotherapy) Table 1 A: Outcomes from the study
14/120 2/121 3/121 1/121 51/122 105/121 1/121
11.7 1.7 2.5 0.8 41.8 86.8 0.8
3/40 1/40 0/41 0/41 29/41 11/41 15/37
7.5 2.5 0.0 0.0 70.7 26.8 40.5
0.4 0.7 0.3 0.5 0.03 b 0.001 b 0.001
Values for continuous measurements are means, unless otherwise specified.
doi:10.1016/j.ygyno.2011.12.221
221 The significance of bowel involvement in advanced epithelial ovarian cancer S. Saha, A. Tesfaye, M. Kanaan, D. Wiese, D. Wilson, N. Dutt, S. Nagpal, M. Arora, D. Eilender, T. Singh. McLaren Regional Medical Center, Flint, MI. Objective: Epithelial Ovarian cancer (OvCa) commonly presents in advanced stages (stage IIIC and IV). Bowel involvement (BI) doesn't have a direct role in the current FIGO staging system, which uses peritoneal metastases size to subclassify stage III. A study was undertaken to identify the prognostic significance of BI and its surgical resection, on the recurrence rate and overall survival. Methods: Retrospective review of ovarian cancer database (1999– 2008) for Stage IIIC and IV patients (Pts) undergoing radical debulking surgery was done. Data collected included with demographics, operative procedure, pathology and follow up data. Pts were grouped into Group (Gp) A with BI and Gp B with no BI. Pts were treated by the same oncologic surgeon with GYN and GI expertise. All Pts received Platinum based chemotherapy. The primary outcome was overall survival. Secondary outcome was disease free survival. Results: Of 177 Pts with OvCa, 101 (57%) had advanced stages (IIIC and IV). Gp A had 58 (57%) and Gp B had 43 (43%) pts. The median CA125 level for Gps A & B was 490 & 205 respectively. The rectosigmoid was most commonly resected bowel (57%). Bowel continuity was maintained in 82.7% of Gp A Pts. Optimum cytoreduction (OPCR) was achieved in 77% & 85% of Gps A & B Pts respectively (P = 0.2). Neoadjuvant chemotherapy (NAC) was given to 61.4% & 52.4% of Gps A & B pts respectively. In Gp A, OPCR was achieved in 88% of Pts who received NAC & 67% of those who didn't (p= 0.07). In Gp B, OPCR was achieved in 95.7% of Pts who received NAC & 72.2% those who didn't (p= 0.047). The median disease free survival (DFS) was 17.8 mon in Gp A and 22.8 mon in Gp B (p= 0.7). The rate of disease recurrence was 66.7% in Gp A and 68% in Gp B (p= 0.5). The 2 years overall survival was 51.7% for Gp A & 83.3% for Gp B (p= 0.0032). Among those with OPCR, the 2 years overall survival was 57.1% for Gp A & 82.9% for Gp B (p= 0.013). Conclusions: NAC was associated with much higher rate of OPCR in both groups. Pts with BI had earlier recurrence but the rate of disease recurrence was similar in both groups. Even when treated with radical bowel resection and chemotherapy, pts with BI had significantly shorter overall survival than similarly staged patients without BI in advanced OvCa. Despite OPCR, BI dictates poor overall survival. Further studies are needed to see role of BI in further substaging of patients with advanced disease.
Variable Stage
IIIC IV
Recurrence Median DFS (months) 2 yrs OS 2 yrs OS in pts with OPCR
Group A (n = 58) BI
Group B (n = 43) No BI
P value
47 (81%) 11 (19%) 38(66.7%) 17.8
35 (81%) 8 (19%) 28(68%) 22.8
0.5 0.7
51.70% 57.1% (n = 42)
83.30% 82.9% (n = 35)
0.0032 0.013
NeoAdjuvant Chemotherapy
No NeoAdjuvant Chemotherapy
P value
87.5% 95.7%
67% 72.2%
0.07 0.047
Table 1 B: Rates of OPCR vs NAC
Group A Group B
doi:10.1016/j.ygyno.2011.12.222
222 Cost-effectiveness of homologous recombination defect testing to target PARP inhibitor use in platinum-sensitive recurrent ovarian cancer A. Alvarez-Secord1, J. Barnett2, J. Ledermann3, B. Peterson1, E. Myers1, L. Havrilesky1. 1Duke University Medical Center, Durham, NC, 2Brooke Army Medical Center, Fort Sam Houston, TX, 3UCL Cancer Institute, London, United Kingdom. Objective: (1) To determine whether use of a PARP inhibitor is potentially cost-effective for maintenance treatment of platinumsensitive recurrent high-grade serous ovarian cancer (HGSC) following response to chemotherapy; (2) To determine whether a test for homologous recombination (HR) defects is potentially cost-effective in the same population. Methods: A modified Markov decision analysis compared 3 strategies for the management of women with recurrent platinum-sensitive HGSC following clinical response: (1) Observe ; (2) Olaparib to progression; (3) HR defect testing; treat positives with olaparib to progression. Time horizon was 12 months; progression-free survival (PFS) and rates of adverse events (AEs) were derived from previously presented results of a phase III randomized controlled trial. Key assumptions: (1) 50% of patients harbor an HR defect; (2) PFS of individuals with an HR defect is 12 months on olaparib (versus 9 months if HR status unknown). Costs derived from national data were assigned to treatments, AEs, and HR test. Costs of marketed, oral targeted therapeutics were used to approximate a monthly cost of olaparib ($6356); the cost of BRCA testing ($3340) approximated the cost of HR testing; all estimates were varied for sensitivity analysis. Results: Global olaparib was the most effective strategy, followed by HR defect testing and no olaparib. Neither global olaparib nor HR defect testing was cost-effective compared to no olaparib, with incremental cost-effectiveness ratios (ICERs) of $233,847 and $213,166/progression-free year of life saved (PF-YLS), respectively. In sensitivity analysis, strategies (2) and (3) became cost-effective, with ICERs under $50,000 per PF-YLS compared to no olaparib, when the cost of olaparib was $1,500 to $1,750/month. When strategy (1) was removed from the analysis, HR testing preferred and the ICER of global olaparib compared to HR testing was $271,682/PF-YLS. At a
Abstracts / Gynecologic Oncology 125 (2012) S3–S167
lower olaparib cost of $2,000 per month, global olaparib became preferred over HR defect testing, with an ICER of $47,042/PF-YLS. Conclusions: Strategies that incorporate oral olaparib as maintenance following a response to platinum-based relapse therapy for recurrent platinum-sensitive HGSC are potentially cost-effective if the monthly cost of olaparib is under $1,750. When compared only to global use of olaparib and at more realistic drug cost expectations, homologous recombination defect testing is a preferred strategy.
S93
High-risk Imaging
Low-risk Imaging
OVA1 cutoff
% Malignant
Odds ratio
% Malignant
Odds ratio
4.4 5.0 6.0 7.0 8.0 9.0
50.5 51.7 66.1 79.5 82.5 84.8
8.8 4.9 8.4 13.4 12.0 10.9
16.7 16.3 24.4 31.6 50.0 100.0
5.2 3.3 4.9 5.4 10.6 NC
doi:10.1016/j.ygyno.2011.12.224
224 Insulin-like growth factor binding protein-4 (IGFBP-4) tumor and serum levels are increased across all stages of epithelial ovarian cancer R. Mosig1, M. Lobl1, S. Cohen1, E. Chudin2, R. Fruscio3, S. Marchini3, M. D'Incalci3, R. Sachidanandam1, P. Dottino4, J. Martignetti1. 1Mount Sinai School of Medicine, New York, NY, 2Prognosys Bioscience, Inc, La Jolla, CA, 3Mario Negri Gynecological Oncology Group MaNGO, Milan, Italy, 4The Group for Women, New York, NY.
Fig. 1. Two way sensitivity analysis on the cost of olaparib and homologous recombination (HR) defect testing.
doi:10.1016/j.ygyno.2011.12.223
223 Combing imaging and OVA1 to predict the likelihood of malignancy for an ovarian tumor F. Ueland1, S. Goodrich2, J. Santoso3, C. DeSimone2, R. Ware Miller2, I. Podzielinski2, A. Smith4, Z. Zhang5, J. Van Nagell2. 1University of Kentucky Medical Center, Lexington, KY, 2University of Kentucky, Lexington, KY, 3West Clinic, Memphis, TN, 4Applied Clinical Intelligence, Bala Cynwyd, PA, 5Johns Hopkins Medical Institutions, Baltimore, MD. Objective: Imaging helps determine the malignant risk of ovarian tumors and OVA1 is a sensitive ovarian tumor biomarker. Our aim was to evaluate the combination of imaging and OVA1 in estimating the likelihood of malignancy for an ovarian tumor. Methods: In a prospective, multi-institutional trial, 524 women had ovarian imaging, biomarker analysis, and surgery for an ovarian tumor. Imaging included ultrasound, CT scan, or MRI and was classified as high risk (solid or papillary morphology, ascites, metastatic) or low risk (not high risk). Biomarker and imaging results were correlated with pathology and menopausal status. Odds ratios, sensitivity, specificity, and predictive values were calculated. Results: There were 363 benign tumors and 161 malignancies. An increasing OVA1 score correlated with a rising likelihood of malignancy and the % malignant were consistently higher for high versus low risk imaging. The sensitivity for predicting malignancy was 98% for imaging "or" OVA1; 83% for imaging "and" OVA1. Only 3.7% of ovarian tumors were malignant when both imaging and OVA1 were low risk (odds ratio = 0.07). Conclusions: Combining imaging with OVA1 offers useful clinical guidance for predicting ovarian malignancy.
Objective: The recent application of massively parallel sequencing technologies to cancer genomes and transcriptomes has allowed for unbiased and complete view of the global changes associated with tumor development. We therefore hypothesized that analysis of the complete transcriptomes of early and late stage papillary serous tumors could be used to provide a unique catalogue of transcripts encoding tumor-secreted proteins. In this manner, novel candidate serum biomarkers for the detection and surveillance of both early and late stage EOC could be identified. Methods: RNA-Seq was used to quantify papillary serous ovarian cancer transcriptomes. Paired end sequencing of 22 flash frozen tumors was performed. Sequence alignments were processed with the program ELAND, expression levels with ERANGE and then bioinformatically screened for secreted protein signatures. Serum samples from women with benign and malignant pelvic masses and serial samples from women during chemotherapy regimens were measured for IGFBP-4 by ELISA. Student's t Test, ANOVA, and ROC curves were used for statistical analysis. Results: A number of transcripts predicted to be present in serum were identified based on our bioinformatic filter and criteria of being expressed within the top 7.5% of genes in all tumor samples and the availability of antibodies for serum detection. Of these, IGFBP-4 was one of the top candidates identified. In a discovery set of 21 samples, IGFBP-4 protein levels were found to be elevated in patients, including those with early stage disease and normal CA125 levels. In a larger and independent validation set (87 controls, 106 cases), IGFBP-4 levels were significantly increased (pb5x10-5). IGFBP-4 levels were ~ 3x greater in women with malignant pelvic masses compared to women with benign masses. ROC sensitivity was 73% at 93% specificity (AUC 0.816). In women receiving chemotherapy, average IGFBP-4 levels were below the ROC-determined threshold and lower in NED patients compared to AWD patients. Conclusions: This study, the first to our knowledge to use RNA-Seq for biomarker discovery, identified IGFBP-4 as overexpressed in EOC patients. Beyond this, these studies identified two additional intriguing findings. First, IGFBP-4 can be elevated in early stage disease without elevated CA125. Second, IGFBP-4 levels are significantly elevated with malignant versus benign disease. These findings provide the rationale for future validation studies of IGFBP-4 and continued evaluation of additional candidates.
Abstracts / Gynecologic Oncology 125 (2012) S3–S167
Table Table 1(continued) (continued) 1 Ovary (N = 122) Surgery Bowel Splenectomy Diaphragm Liver Lymphadenectomy Platinum and Taxol Radiotherapy
Uterus (N = 41)
P
Table Outcomes from the study. (BI: Bowel involvement; DFS: Disease free survival; OS: Overall survival; OPCR: Optimal cytoreduction; NAC: Neoadjuvant Chemotherapy) Table 1 A: Outcomes from the study
14/120 2/121 3/121 1/121 51/122 105/121 1/121
11.7 1.7 2.5 0.8 41.8 86.8 0.8
3/40 1/40 0/41 0/41 29/41 11/41 15/37
7.5 2.5 0.0 0.0 70.7 26.8 40.5
0.4 0.7 0.3 0.5 0.03 b 0.001 b 0.001
Values for continuous measurements are means, unless otherwise specified.
doi:10.1016/j.ygyno.2011.12.221
221 The significance of bowel involvement in advanced epithelial ovarian cancer S. Saha, A. Tesfaye, M. Kanaan, D. Wiese, D. Wilson, N. Dutt, S. Nagpal, M. Arora, D. Eilender, T. Singh. McLaren Regional Medical Center, Flint, MI. Objective: Epithelial Ovarian cancer (OvCa) commonly presents in advanced stages (stage IIIC and IV). Bowel involvement (BI) doesn't have a direct role in the current FIGO staging system, which uses peritoneal metastases size to subclassify stage III. A study was undertaken to identify the prognostic significance of BI and its surgical resection, on the recurrence rate and overall survival. Methods: Retrospective review of ovarian cancer database (1999– 2008) for Stage IIIC and IV patients (Pts) undergoing radical debulking surgery was done. Data collected included with demographics, operative procedure, pathology and follow up data. Pts were grouped into Group (Gp) A with BI and Gp B with no BI. Pts were treated by the same oncologic surgeon with GYN and GI expertise. All Pts received Platinum based chemotherapy. The primary outcome was overall survival. Secondary outcome was disease free survival. Results: Of 177 Pts with OvCa, 101 (57%) had advanced stages (IIIC and IV). Gp A had 58 (57%) and Gp B had 43 (43%) pts. The median CA125 level for Gps A & B was 490 & 205 respectively. The rectosigmoid was most commonly resected bowel (57%). Bowel continuity was maintained in 82.7% of Gp A Pts. Optimum cytoreduction (OPCR) was achieved in 77% & 85% of Gps A & B Pts respectively (P = 0.2). Neoadjuvant chemotherapy (NAC) was given to 61.4% & 52.4% of Gps A & B pts respectively. In Gp A, OPCR was achieved in 88% of Pts who received NAC & 67% of those who didn't (p= 0.07). In Gp B, OPCR was achieved in 95.7% of Pts who received NAC & 72.2% those who didn't (p= 0.047). The median disease free survival (DFS) was 17.8 mon in Gp A and 22.8 mon in Gp B (p= 0.7). The rate of disease recurrence was 66.7% in Gp A and 68% in Gp B (p= 0.5). The 2 years overall survival was 51.7% for Gp A & 83.3% for Gp B (p= 0.0032). Among those with OPCR, the 2 years overall survival was 57.1% for Gp A & 82.9% for Gp B (p= 0.013). Conclusions: NAC was associated with much higher rate of OPCR in both groups. Pts with BI had earlier recurrence but the rate of disease recurrence was similar in both groups. Even when treated with radical bowel resection and chemotherapy, pts with BI had significantly shorter overall survival than similarly staged patients without BI in advanced OvCa. Despite OPCR, BI dictates poor overall survival. Further studies are needed to see role of BI in further substaging of patients with advanced disease.
Variable Stage
IIIC IV
Recurrence Median DFS (months) 2 yrs OS 2 yrs OS in pts with OPCR
Group A (n = 58) BI
Group B (n = 43) No BI
P value
47 (81%) 11 (19%) 38(66.7%) 17.8
35 (81%) 8 (19%) 28(68%) 22.8
0.5 0.7
51.70% 57.1% (n = 42)
83.30% 82.9% (n = 35)
0.0032 0.013
NeoAdjuvant Chemotherapy
No NeoAdjuvant Chemotherapy
P value
87.5% 95.7%
67% 72.2%
0.07 0.047
Table 1 B: Rates of OPCR vs NAC
Group A Group B
doi:10.1016/j.ygyno.2011.12.222
222 Cost-effectiveness of homologous recombination defect testing to target PARP inhibitor use in platinum-sensitive recurrent ovarian cancer A. Alvarez-Secord1, J. Barnett2, J. Ledermann3, B. Peterson1, E. Myers1, L. Havrilesky1. 1Duke University Medical Center, Durham, NC, 2Brooke Army Medical Center, Fort Sam Houston, TX, 3UCL Cancer Institute, London, United Kingdom. Objective: (1) To determine whether use of a PARP inhibitor is potentially cost-effective for maintenance treatment of platinumsensitive recurrent high-grade serous ovarian cancer (HGSC) following response to chemotherapy; (2) To determine whether a test for homologous recombination (HR) defects is potentially cost-effective in the same population. Methods: A modified Markov decision analysis compared 3 strategies for the management of women with recurrent platinum-sensitive HGSC following clinical response: (1) Observe ; (2) Olaparib to progression; (3) HR defect testing; treat positives with olaparib to progression. Time horizon was 12 months; progression-free survival (PFS) and rates of adverse events (AEs) were derived from previously presented results of a phase III randomized controlled trial. Key assumptions: (1) 50% of patients harbor an HR defect; (2) PFS of individuals with an HR defect is 12 months on olaparib (versus 9 months if HR status unknown). Costs derived from national data were assigned to treatments, AEs, and HR test. Costs of marketed, oral targeted therapeutics were used to approximate a monthly cost of olaparib ($6356); the cost of BRCA testing ($3340) approximated the cost of HR testing; all estimates were varied for sensitivity analysis. Results: Global olaparib was the most effective strategy, followed by HR defect testing and no olaparib. Neither global olaparib nor HR defect testing was cost-effective compared to no olaparib, with incremental cost-effectiveness ratios (ICERs) of $233,847 and $213,166/progression-free year of life saved (PF-YLS), respectively. In sensitivity analysis, strategies (2) and (3) became cost-effective, with ICERs under $50,000 per PF-YLS compared to no olaparib, when the cost of olaparib was $1,500 to $1,750/month. When strategy (1) was removed from the analysis, HR testing preferred and the ICER of global olaparib compared to HR testing was $271,682/PF-YLS. At a
Abstracts / Gynecologic Oncology 125 (2012) S3–S167
lower olaparib cost of $2,000 per month, global olaparib became preferred over HR defect testing, with an ICER of $47,042/PF-YLS. Conclusions: Strategies that incorporate oral olaparib as maintenance following a response to platinum-based relapse therapy for recurrent platinum-sensitive HGSC are potentially cost-effective if the monthly cost of olaparib is under $1,750. When compared only to global use of olaparib and at more realistic drug cost expectations, homologous recombination defect testing is a preferred strategy.
S93
High-risk Imaging
Low-risk Imaging
OVA1 cutoff
% Malignant
Odds ratio
% Malignant
Odds ratio
4.4 5.0 6.0 7.0 8.0 9.0
50.5 51.7 66.1 79.5 82.5 84.8
8.8 4.9 8.4 13.4 12.0 10.9
16.7 16.3 24.4 31.6 50.0 100.0
5.2 3.3 4.9 5.4 10.6 NC
doi:10.1016/j.ygyno.2011.12.224
224 Insulin-like growth factor binding protein-4 (IGFBP-4) tumor and serum levels are increased across all stages of epithelial ovarian cancer R. Mosig1, M. Lobl1, S. Cohen1, E. Chudin2, R. Fruscio3, S. Marchini3, M. D'Incalci3, R. Sachidanandam1, P. Dottino4, J. Martignetti1. 1Mount Sinai School of Medicine, New York, NY, 2Prognosys Bioscience, Inc, La Jolla, CA, 3Mario Negri Gynecological Oncology Group MaNGO, Milan, Italy, 4The Group for Women, New York, NY.
Fig. 1. Two way sensitivity analysis on the cost of olaparib and homologous recombination (HR) defect testing.
doi:10.1016/j.ygyno.2011.12.223
223 Combing imaging and OVA1 to predict the likelihood of malignancy for an ovarian tumor F. Ueland1, S. Goodrich2, J. Santoso3, C. DeSimone2, R. Ware Miller2, I. Podzielinski2, A. Smith4, Z. Zhang5, J. Van Nagell2. 1University of Kentucky Medical Center, Lexington, KY, 2University of Kentucky, Lexington, KY, 3West Clinic, Memphis, TN, 4Applied Clinical Intelligence, Bala Cynwyd, PA, 5Johns Hopkins Medical Institutions, Baltimore, MD. Objective: Imaging helps determine the malignant risk of ovarian tumors and OVA1 is a sensitive ovarian tumor biomarker. Our aim was to evaluate the combination of imaging and OVA1 in estimating the likelihood of malignancy for an ovarian tumor. Methods: In a prospective, multi-institutional trial, 524 women had ovarian imaging, biomarker analysis, and surgery for an ovarian tumor. Imaging included ultrasound, CT scan, or MRI and was classified as high risk (solid or papillary morphology, ascites, metastatic) or low risk (not high risk). Biomarker and imaging results were correlated with pathology and menopausal status. Odds ratios, sensitivity, specificity, and predictive values were calculated. Results: There were 363 benign tumors and 161 malignancies. An increasing OVA1 score correlated with a rising likelihood of malignancy and the % malignant were consistently higher for high versus low risk imaging. The sensitivity for predicting malignancy was 98% for imaging "or" OVA1; 83% for imaging "and" OVA1. Only 3.7% of ovarian tumors were malignant when both imaging and OVA1 were low risk (odds ratio = 0.07). Conclusions: Combining imaging with OVA1 offers useful clinical guidance for predicting ovarian malignancy.
Objective: The recent application of massively parallel sequencing technologies to cancer genomes and transcriptomes has allowed for unbiased and complete view of the global changes associated with tumor development. We therefore hypothesized that analysis of the complete transcriptomes of early and late stage papillary serous tumors could be used to provide a unique catalogue of transcripts encoding tumor-secreted proteins. In this manner, novel candidate serum biomarkers for the detection and surveillance of both early and late stage EOC could be identified. Methods: RNA-Seq was used to quantify papillary serous ovarian cancer transcriptomes. Paired end sequencing of 22 flash frozen tumors was performed. Sequence alignments were processed with the program ELAND, expression levels with ERANGE and then bioinformatically screened for secreted protein signatures. Serum samples from women with benign and malignant pelvic masses and serial samples from women during chemotherapy regimens were measured for IGFBP-4 by ELISA. Student's t Test, ANOVA, and ROC curves were used for statistical analysis. Results: A number of transcripts predicted to be present in serum were identified based on our bioinformatic filter and criteria of being expressed within the top 7.5% of genes in all tumor samples and the availability of antibodies for serum detection. Of these, IGFBP-4 was one of the top candidates identified. In a discovery set of 21 samples, IGFBP-4 protein levels were found to be elevated in patients, including those with early stage disease and normal CA125 levels. In a larger and independent validation set (87 controls, 106 cases), IGFBP-4 levels were significantly increased (pb5x10-5). IGFBP-4 levels were ~ 3x greater in women with malignant pelvic masses compared to women with benign masses. ROC sensitivity was 73% at 93% specificity (AUC 0.816). In women receiving chemotherapy, average IGFBP-4 levels were below the ROC-determined threshold and lower in NED patients compared to AWD patients. Conclusions: This study, the first to our knowledge to use RNA-Seq for biomarker discovery, identified IGFBP-4 as overexpressed in EOC patients. Beyond this, these studies identified two additional intriguing findings. First, IGFBP-4 can be elevated in early stage disease without elevated CA125. Second, IGFBP-4 levels are significantly elevated with malignant versus benign disease. These findings provide the rationale for future validation studies of IGFBP-4 and continued evaluation of additional candidates.