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Ubiquitin-Specific Protease 14 is a Biomarker for Recurrence in Early-Stage Endometrial Adenocarcinoma and Potential Therapeutic Target
Abstracts / Gynecologic Oncology 143 (2016) 194–223
Complete Pathologic Response at Interval Debulking Surgery Following Neoadjuvant Chemotherapy Predicts Improved Survival in Women with Advanced Epithelial Ovarian Cancer in a Multi-institutional Cohort M. Lianga,b, E. Prendergasta,b, J. Staplesa, C. Holschneiderb, I. Cassa. a Cedars-Sinai Medical Center, Los Angeles, CA, bUniversity of California Los Angeles - Olive View Medical Center, Sylmar, CA Objectives: We sought to determine if pathologic response at the time of interval debulking surgery (IDS) predicts survival in patients undergoing neoadjuvant chemotherapy (NACT) for advanced epithelial ovarian cancer (EOC). Methods: We retrospectively evaluated 57 consecutive EOC patients treated with NACT followed by IDS. Pathologic response was classified as complete with no residual disease (cPR), microscopic (microPR), or macroscopic (macroPR) at the time of IDS. The surgeon’s assessment of residual disease volume after IDS was categorized as resection to no gross residual (R0), optimal (b1 cm), or suboptimal (≥1 cm). Kaplan-Meier analysis was performed to compare progression-free (PFS) and overall survival (OS) between pathologic response groups and based upon cytoreductive status (R0 vs. any residual disease). Results: Patients were triaged to NACT for stage IV disease (n = 31, 54%), radiologically bulky disease deemed not amenable to optimal cytoreduction (n = 32, 56%), venous thromboembolism (n = 4, 7%), and poor performance status (n = 4, 7%). No baseline differences were observed between groups including age, stage, grade, and histology. Median number of NACT cycles was 3 (range, 1–6). cPR was observed in 6 (11%), microPR in 10 (17%), and macroPR in 41 (72%) patients. cPR was associated with improved median PFS compared to any residual disease (micro PR/macro PR) (undefined vs. 11 months, p = 0.02). There was no difference in median OS between patients with cPR and those with any residual disease (undefined vs. 37 months, p = 0.36). A difference in PFS was not observed between microPR and macroPR disease (11 vs. 11 months, p = 0.54). After IDS, 35 (61%) patients underwent R0, 18 (32%) optimal, and 4 (7%) suboptimal cytoreduction. There were no survival differences between patients with R0 resection compared to any residual disease at IDS (PFS 22 vs. 10 months, p = 0.10; OS undefined vs. 35 months, p = 0.27). Stage, grade, and normalization of CA-125 prior to IDS did not affect survival. Conclusion: In our cohort, cPR in patients with advanced EOC undergoing NACT is uncommon (~10% of cases), but appears to be associated with improved PFS. NACT led to R0 cytoreduction in approximately two-thirds of patients at IDS, but this demonstrated no impact on survival.
doi:10.1016/j.ygyno.2016.08.247
Ubiquitin-Specific Protease 14 is a Biomarker for Recurrence in Early-Stage Endometrial Adenocarcinoma and Potential Therapeutic Target T. Pulver, W. Heilmann, J. Richter, M. Shahi, R. Vogel, R. Ghebre, M. Bazzaro. University of Minnesota, Minneapolis, MN Objectives: A subset of early-stage, low-risk endometrial adenocarcinoma (EAC) goes on to recur for reasons that remain unclear. The purpose of this study was to evaluate the debubiquinating enzyme ubiquitin-specific protease 14 (USP14) as a biomarker for recurrence in stage I EAC as well as a potential therapeutic target. Methods: To determine the relationship between USP14 and recurrence, consecutive cases of stage I EAC at a single academic institution were reviewed. Formalin-fixed, paraffin-embedded slides from primary tumors of cases for which at least 36 months of follow-up were
197
available were stained with a polyclonal antibody specific for USP14. A comparison of staining intensity and recurrence was conducted using a multivariate logistic regression model. Primary tumors were additionally stained for Ki-67. Nuclear positivity for Ki67 in areas corresponding to low and high intensity staining for USP14 was quantified and compared. To evaluate USP14 as a potential molecular target for EAC treatment, the EAC cell lines HEC155 and ECC1 were exposed to the USP14 inhibitor VLX-1570 and subjected to a cell viability assay, Western blot analysis, and flow cytometry. Treatment of the cells with carboplatin was used for comparison. Results: A total of 203 cases were included in the IHC portion of the study, of which 12.4% recurred within 36 months. After accounting for other known risk factors for recurrence, namely grade and stage, higher USP14 staining intensity was associated with increased risk of recurrence (p=0.001). A 1-point increase in staining intensity corresponded to a 6.9-fold increase in risk of recurrence (OR = 6.9; 95% CI: 1.6-27.3). Nuclear positivity for Ki67 demonstrated a strong correlation with USP14 intensity by IHC. EAC cell lines exposed to VLX-1570 demonstrated dose-dependent inhibition of cell viability and accumulation of poly-ubiquinated proteins. USP14 inhibition was also found to induce G2-M cell cycle arrest and apoptosis. Conclusion: High expression of USP14 by IHC is associated with an increased likelihood of recurrence among women with stage I EAC, independent of other known risk factors for recurrence. Our results additionally suggest that USP14 inhibition may have a potential therapeutic effect. Further investigation using preclinical models is warranted.
doi:10.1016/j.ygyno.2016.08.248
Updates of the Precision Medicine Program in Gynecologic Oncology Erin E. Brown, Michelle R. Rowland, Kathleen N. Moore, Camille C. Gunderson. University of Oklahoma Health Sciences Center Objectives: The aim of this study was to build upon a previously initiated Precision Medicine project encompassing patients with metastatic or recurrent gynecologic malignancies who were screened for somatic mutations. We sought to obtain patterns of genomic alterations, identify targeted therapies utilized, and analyze associated outcomes. Methods: In 2014, a multi-disciplinary Precision Medicine Board was initiated at our institution in order to apply molecular genetic profiling to high-risk or recalcitrant gynecologic malignancies. The profiles were obtained by sending archival or fresh tumor samples for sequencing at a CLIA approved laboratory. The panel screens for 315 cancer-related genes and reports identified known and potential “matched” therapies. A detailed database was assembled to follow each patient prospectively for treatment use and resultant outcomes. Results: To date, 88 patients have undergone testing (43 ovary, 27 uterine, 12 cervix, and 6 other female genital tract) with mean age of 55.4 years (17-77 years). Fifty-two primary tumors were tested, and 36 were recurrent. Two patients were not included in the analysis due to sample failure. Significant genomic alterations were found in all tumor types, with the most common mutations being TP53 (50.0%), PIK3CA (25.5%) and ARID1A (15.1%). Organized by family, there were 78 DNA repair mutations (TP53, CHK1/2, CDK, BRCA1/2, CCN), 43 PTEN/PIK3/mTOR pathway mutations, 20 KRAS/ AKT/NF1 mutations, 14 ARID1A, and 10 MYC (transcription factor) mutations. Sixty-two patients (72.1%) had a potential matched therapy (approved drug or clinical trial available at our institution) based upon their profiling, and 16 (18.6%) received a matched therapy. When assessing best response, 6 patients on matched therapy had stable disease, 1 had a partial response, and 1 had progressive disease. Four patients had non-assessable response due to toxicities or death. Four
Complete Pathologic Response at Interval Debulking Surgery Following Neoadjuvant Chemotherapy Predicts Improved Survival in Women with Advanced Epithelial Ovarian Cancer in a Multi-institutional Cohort M. Lianga,b, E. Prendergasta,b, J. Staplesa, C. Holschneiderb, I. Cassa. a Cedars-Sinai Medical Center, Los Angeles, CA, bUniversity of California Los Angeles - Olive View Medical Center, Sylmar, CA Objectives: We sought to determine if pathologic response at the time of interval debulking surgery (IDS) predicts survival in patients undergoing neoadjuvant chemotherapy (NACT) for advanced epithelial ovarian cancer (EOC). Methods: We retrospectively evaluated 57 consecutive EOC patients treated with NACT followed by IDS. Pathologic response was classified as complete with no residual disease (cPR), microscopic (microPR), or macroscopic (macroPR) at the time of IDS. The surgeon’s assessment of residual disease volume after IDS was categorized as resection to no gross residual (R0), optimal (b1 cm), or suboptimal (≥1 cm). Kaplan-Meier analysis was performed to compare progression-free (PFS) and overall survival (OS) between pathologic response groups and based upon cytoreductive status (R0 vs. any residual disease). Results: Patients were triaged to NACT for stage IV disease (n = 31, 54%), radiologically bulky disease deemed not amenable to optimal cytoreduction (n = 32, 56%), venous thromboembolism (n = 4, 7%), and poor performance status (n = 4, 7%). No baseline differences were observed between groups including age, stage, grade, and histology. Median number of NACT cycles was 3 (range, 1–6). cPR was observed in 6 (11%), microPR in 10 (17%), and macroPR in 41 (72%) patients. cPR was associated with improved median PFS compared to any residual disease (micro PR/macro PR) (undefined vs. 11 months, p = 0.02). There was no difference in median OS between patients with cPR and those with any residual disease (undefined vs. 37 months, p = 0.36). A difference in PFS was not observed between microPR and macroPR disease (11 vs. 11 months, p = 0.54). After IDS, 35 (61%) patients underwent R0, 18 (32%) optimal, and 4 (7%) suboptimal cytoreduction. There were no survival differences between patients with R0 resection compared to any residual disease at IDS (PFS 22 vs. 10 months, p = 0.10; OS undefined vs. 35 months, p = 0.27). Stage, grade, and normalization of CA-125 prior to IDS did not affect survival. Conclusion: In our cohort, cPR in patients with advanced EOC undergoing NACT is uncommon (~10% of cases), but appears to be associated with improved PFS. NACT led to R0 cytoreduction in approximately two-thirds of patients at IDS, but this demonstrated no impact on survival.
doi:10.1016/j.ygyno.2016.08.247
Ubiquitin-Specific Protease 14 is a Biomarker for Recurrence in Early-Stage Endometrial Adenocarcinoma and Potential Therapeutic Target T. Pulver, W. Heilmann, J. Richter, M. Shahi, R. Vogel, R. Ghebre, M. Bazzaro. University of Minnesota, Minneapolis, MN Objectives: A subset of early-stage, low-risk endometrial adenocarcinoma (EAC) goes on to recur for reasons that remain unclear. The purpose of this study was to evaluate the debubiquinating enzyme ubiquitin-specific protease 14 (USP14) as a biomarker for recurrence in stage I EAC as well as a potential therapeutic target. Methods: To determine the relationship between USP14 and recurrence, consecutive cases of stage I EAC at a single academic institution were reviewed. Formalin-fixed, paraffin-embedded slides from primary tumors of cases for which at least 36 months of follow-up were
197
available were stained with a polyclonal antibody specific for USP14. A comparison of staining intensity and recurrence was conducted using a multivariate logistic regression model. Primary tumors were additionally stained for Ki-67. Nuclear positivity for Ki67 in areas corresponding to low and high intensity staining for USP14 was quantified and compared. To evaluate USP14 as a potential molecular target for EAC treatment, the EAC cell lines HEC155 and ECC1 were exposed to the USP14 inhibitor VLX-1570 and subjected to a cell viability assay, Western blot analysis, and flow cytometry. Treatment of the cells with carboplatin was used for comparison. Results: A total of 203 cases were included in the IHC portion of the study, of which 12.4% recurred within 36 months. After accounting for other known risk factors for recurrence, namely grade and stage, higher USP14 staining intensity was associated with increased risk of recurrence (p=0.001). A 1-point increase in staining intensity corresponded to a 6.9-fold increase in risk of recurrence (OR = 6.9; 95% CI: 1.6-27.3). Nuclear positivity for Ki67 demonstrated a strong correlation with USP14 intensity by IHC. EAC cell lines exposed to VLX-1570 demonstrated dose-dependent inhibition of cell viability and accumulation of poly-ubiquinated proteins. USP14 inhibition was also found to induce G2-M cell cycle arrest and apoptosis. Conclusion: High expression of USP14 by IHC is associated with an increased likelihood of recurrence among women with stage I EAC, independent of other known risk factors for recurrence. Our results additionally suggest that USP14 inhibition may have a potential therapeutic effect. Further investigation using preclinical models is warranted.
doi:10.1016/j.ygyno.2016.08.248
Updates of the Precision Medicine Program in Gynecologic Oncology Erin E. Brown, Michelle R. Rowland, Kathleen N. Moore, Camille C. Gunderson. University of Oklahoma Health Sciences Center Objectives: The aim of this study was to build upon a previously initiated Precision Medicine project encompassing patients with metastatic or recurrent gynecologic malignancies who were screened for somatic mutations. We sought to obtain patterns of genomic alterations, identify targeted therapies utilized, and analyze associated outcomes. Methods: In 2014, a multi-disciplinary Precision Medicine Board was initiated at our institution in order to apply molecular genetic profiling to high-risk or recalcitrant gynecologic malignancies. The profiles were obtained by sending archival or fresh tumor samples for sequencing at a CLIA approved laboratory. The panel screens for 315 cancer-related genes and reports identified known and potential “matched” therapies. A detailed database was assembled to follow each patient prospectively for treatment use and resultant outcomes. Results: To date, 88 patients have undergone testing (43 ovary, 27 uterine, 12 cervix, and 6 other female genital tract) with mean age of 55.4 years (17-77 years). Fifty-two primary tumors were tested, and 36 were recurrent. Two patients were not included in the analysis due to sample failure. Significant genomic alterations were found in all tumor types, with the most common mutations being TP53 (50.0%), PIK3CA (25.5%) and ARID1A (15.1%). Organized by family, there were 78 DNA repair mutations (TP53, CHK1/2, CDK, BRCA1/2, CCN), 43 PTEN/PIK3/mTOR pathway mutations, 20 KRAS/ AKT/NF1 mutations, 14 ARID1A, and 10 MYC (transcription factor) mutations. Sixty-two patients (72.1%) had a potential matched therapy (approved drug or clinical trial available at our institution) based upon their profiling, and 16 (18.6%) received a matched therapy. When assessing best response, 6 patients on matched therapy had stable disease, 1 had a partial response, and 1 had progressive disease. Four patients had non-assessable response due to toxicities or death. Four