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Clinical translation of the cancer genome atlas signature for ovarian cancer survival
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Abstracts / Gynecologic Oncology 125 (2012) S3–S167
99 Clinical outcome of Serous Tubal Intraepithelial Carcinomas (STIC) S. Wethington, K. Park, R. Soslow, N. Kauff, C. Brown, Y. Sonoda, N. Abu-Rustum, R. Barakat, D. Levine, G. Gardner. Memorial SloanKettering Cancer Center, New York, NY. Objective: Women with germline mutations in BRCA1/2 have a 20-40% lifetime risk of ovarian carcinoma and are therefore recommended to undergo risk-reducing salpingo-oophorectomy (RRSO). Serous tubal intraepithelial carcinoma (STIC) has been recently described as a pathologic finding in RRSO specimens. The purpose of this study is to identify the clinical outcome of patients with STIC at RRSO. Methods: Institutional databases were queried to identify patients with documented BRCA1/2 mutation or high risk personal or family history of ovarian cancer who underwent RRSO between January 2006 and June 2011. All patients were assessed using a sectioning and extensively examining the fimbria (SEE-FIM) protocol, with IHC to confirm lesions seen on routine H&E. To develop a pure cohort for analysis, p53 signature lesions and secretory cell outgrowths (SCOUT) were excluded. Medical records were reviewed for BRCA status, pre-operative testing, surgical staging, treatment, and clinical outcome. Results: Of 608 patients who underwent RRSO, 13 (2%) were found to have STIC. Median age was 53 years (range, 38–76). Five (39%) patients were BRCA1 positive, 6 (46%) BRCA2 positive, and 2 (15%) had high risk family history without genetic testing. Preoperatively, all patients had normal testing with CA-125 and/or pelvic imaging. At the time of RRSO, all patients had peritoneal washings (1 positive for malignancy) and 10 (77%) a D&C (all benign). Nine (69%) women underwent a staging procedure, 3 (23%) were offered staging and declined, and 1 (8%) was not offered staging. Details regarding subsequent staging procedures were available for 7 patients, all of whom underwent a hysterectomy and omentectomy. Six (46%) patients had pelvic node dissection and 5 (39%) paraaortic node dissection. With the exception of positive peritoneal washings in 1 patient, no invasive or metastatic disease was identified. No patient received adjuvant chemotherapy. At median follow-up of 12 months (range 2–30), no recurrences have been identified. Conclusions: For STIC identified at RRSO, the yield of subsequent surgical staging is low, and short-term clinical outcomes are favorable. Considering the limited available data regarding longterm outcome, surgical staging for patients with STIC should be considered until additional clinical outcome data becomes available. Molecular characterization of STIC may yield additional information regarding the management of these lesions and the putative relevance of STIC in the process of carcinogenesis.
was performed using the Illumina Whole Genome DASL assay. In the 43 banked cases Affymetrix U133A expression data also was available from frozen tissue. DASL probes were mapped to Affymetrix probes by gene symbol after removing probes that failed quality control. For each Affymetrix probe that matched one or more DASL probes, we calculated the median expression across the DASL probes. Results: The TCGA survival signature is comprised of 193 genes (85 good survival, 108 poor survival). We identified 276 Affymetrix probes representing 166 unique genes that matched a gene in the TCGA gene set, and 68 of the genes were represented by more than one probe. Linear correlations between the DASL and Affymetrix gene expression estimates in the 43 paired samples ranged from −0.417 to 0.709 (mean = 0.209). The correlation between the DASL and Affymetrix based estimates of the survival signature was 0.775. The DASL version of the TCGA signature was highly predictive of survival in advanced stage high grade serous ovarian cancers from the population-based study. When cases were divided into two groups based on whether their TCGA survival signature scores were above (n=54) or below (n=53) the median score, the median survival of the two groups was 34 months versus 60 months (Figure 1). In a Cox proportional hazards model the estimated hazard ratio for death was 2.18 (p=0.0014). Conclusions: Although individual probe estimates of the genes in the TCGA signature were only weakly correlated between expression data derived from paraffin embedded and frozen samples, linear combinations of those probes have a robust ability to predict survival. This suggests that it will be possible to use FFPE derived signatures in the future for prognostic and predictive purposes as we seek to improve and individualize the treatment of women with ovarian cancer.
doi:10.1016/j.ygyno.2011.12.100
100 Clinical translation of the cancer genome atlas signature for ovarian cancer survival G. Sfakianos, E. Iversen, W. Lowery, R. Whitaker, L. Akushevich, J. Schildkraut, J. Marks, A. Berchuck. Duke University Medical Center, Durham, NC. Objective: A gene expression signature for survival in high grade serous ovarian cancer was developed in the Cancer Genome Atlas (TCGA) project using frozen tissues (Nature 2011;474:609–15). Since frozen tissue usually is not available in most practice settings, we explored whether the TCGA survival signature could be adapted to paraffin embedded tissue blocks to facilitate clinical translation. Methods: Subjects were 150 invasive advanced stage high grade serous ovarian cancers, including 43 cases from an internal bank and 107 from a population-based study. RNA was extracted from sections of paraffin embedded specimens and expression analysis
doi:10.1016/j.ygyno.2011.12.101
Abstracts / Gynecologic Oncology 125 (2012) S3–S167
99 Clinical outcome of Serous Tubal Intraepithelial Carcinomas (STIC) S. Wethington, K. Park, R. Soslow, N. Kauff, C. Brown, Y. Sonoda, N. Abu-Rustum, R. Barakat, D. Levine, G. Gardner. Memorial SloanKettering Cancer Center, New York, NY. Objective: Women with germline mutations in BRCA1/2 have a 20-40% lifetime risk of ovarian carcinoma and are therefore recommended to undergo risk-reducing salpingo-oophorectomy (RRSO). Serous tubal intraepithelial carcinoma (STIC) has been recently described as a pathologic finding in RRSO specimens. The purpose of this study is to identify the clinical outcome of patients with STIC at RRSO. Methods: Institutional databases were queried to identify patients with documented BRCA1/2 mutation or high risk personal or family history of ovarian cancer who underwent RRSO between January 2006 and June 2011. All patients were assessed using a sectioning and extensively examining the fimbria (SEE-FIM) protocol, with IHC to confirm lesions seen on routine H&E. To develop a pure cohort for analysis, p53 signature lesions and secretory cell outgrowths (SCOUT) were excluded. Medical records were reviewed for BRCA status, pre-operative testing, surgical staging, treatment, and clinical outcome. Results: Of 608 patients who underwent RRSO, 13 (2%) were found to have STIC. Median age was 53 years (range, 38–76). Five (39%) patients were BRCA1 positive, 6 (46%) BRCA2 positive, and 2 (15%) had high risk family history without genetic testing. Preoperatively, all patients had normal testing with CA-125 and/or pelvic imaging. At the time of RRSO, all patients had peritoneal washings (1 positive for malignancy) and 10 (77%) a D&C (all benign). Nine (69%) women underwent a staging procedure, 3 (23%) were offered staging and declined, and 1 (8%) was not offered staging. Details regarding subsequent staging procedures were available for 7 patients, all of whom underwent a hysterectomy and omentectomy. Six (46%) patients had pelvic node dissection and 5 (39%) paraaortic node dissection. With the exception of positive peritoneal washings in 1 patient, no invasive or metastatic disease was identified. No patient received adjuvant chemotherapy. At median follow-up of 12 months (range 2–30), no recurrences have been identified. Conclusions: For STIC identified at RRSO, the yield of subsequent surgical staging is low, and short-term clinical outcomes are favorable. Considering the limited available data regarding longterm outcome, surgical staging for patients with STIC should be considered until additional clinical outcome data becomes available. Molecular characterization of STIC may yield additional information regarding the management of these lesions and the putative relevance of STIC in the process of carcinogenesis.
was performed using the Illumina Whole Genome DASL assay. In the 43 banked cases Affymetrix U133A expression data also was available from frozen tissue. DASL probes were mapped to Affymetrix probes by gene symbol after removing probes that failed quality control. For each Affymetrix probe that matched one or more DASL probes, we calculated the median expression across the DASL probes. Results: The TCGA survival signature is comprised of 193 genes (85 good survival, 108 poor survival). We identified 276 Affymetrix probes representing 166 unique genes that matched a gene in the TCGA gene set, and 68 of the genes were represented by more than one probe. Linear correlations between the DASL and Affymetrix gene expression estimates in the 43 paired samples ranged from −0.417 to 0.709 (mean = 0.209). The correlation between the DASL and Affymetrix based estimates of the survival signature was 0.775. The DASL version of the TCGA signature was highly predictive of survival in advanced stage high grade serous ovarian cancers from the population-based study. When cases were divided into two groups based on whether their TCGA survival signature scores were above (n=54) or below (n=53) the median score, the median survival of the two groups was 34 months versus 60 months (Figure 1). In a Cox proportional hazards model the estimated hazard ratio for death was 2.18 (p=0.0014). Conclusions: Although individual probe estimates of the genes in the TCGA signature were only weakly correlated between expression data derived from paraffin embedded and frozen samples, linear combinations of those probes have a robust ability to predict survival. This suggests that it will be possible to use FFPE derived signatures in the future for prognostic and predictive purposes as we seek to improve and individualize the treatment of women with ovarian cancer.
doi:10.1016/j.ygyno.2011.12.100
100 Clinical translation of the cancer genome atlas signature for ovarian cancer survival G. Sfakianos, E. Iversen, W. Lowery, R. Whitaker, L. Akushevich, J. Schildkraut, J. Marks, A. Berchuck. Duke University Medical Center, Durham, NC. Objective: A gene expression signature for survival in high grade serous ovarian cancer was developed in the Cancer Genome Atlas (TCGA) project using frozen tissues (Nature 2011;474:609–15). Since frozen tissue usually is not available in most practice settings, we explored whether the TCGA survival signature could be adapted to paraffin embedded tissue blocks to facilitate clinical translation. Methods: Subjects were 150 invasive advanced stage high grade serous ovarian cancers, including 43 cases from an internal bank and 107 from a population-based study. RNA was extracted from sections of paraffin embedded specimens and expression analysis
doi:10.1016/j.ygyno.2011.12.101