- Email: [email protected]
Gene expression profiles of high-grade serous ovarian cancers in patients with normal CA-125 levels at the time of recurrence
Abstracts / Gynecologic Oncology 133 (2014) 2–207
81
196 — Poster Session A Gene expression profiles of high-grade serous ovarian cancers in patients with normal CA-125 levels at the time of recurrence V. Broach, F. Dao, D.A. Levine. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
197 — Poster Session A Association of in vitro chemotherapy drug resistance assays in ovarian cancer patients with BRCA1/2 mutations J. Lee, A.W. Menzin, V.S. John, J.L. Lovecchio, J.S. Whyte. Hofstra — North Shore Long Island Jewish School of Medicine, Manhasset, NY, USA.
Objectives: CA-125 is a useful tool for monitoring response to therapy and recurrence in patients with high-grade serous ovarian cancer (HGSOC). However, 15% to 20% of patients have normal levels of CA-125 at the time of recurrence, limiting the prognostic ability of CA-125 in this population. We aimed to determine differences in gene expression profiles of tumors from patients with and without elevated CA-125 levels at the time of recurrence. Methods: Patients with stage IIIC or IV HGSOC who underwent primary surgical cytoreduction and initial platinum-based chemotherapy were identified from The Cancer Genome Atlas (TCGA). All patients had platinum-sensitive, radiographic-confirmed recurrent disease. Patients were stratified into two groups: those with elevated CA-125 (N35 U/mL) and those with normal CA-125 (≤35 U/mL) at time of recurrence. Gene expression profiling was performed using 1 Agilent and 2 Affymetrix expression microarray platforms. Expression data were combined across microarrays using factor analysis for genes present on all array platforms. Gene expression levels for 11,864 genes were analyzed. Mean gene expression was compared using student t-test and significance was defined as P b 0.001. Results: Data were available for 21 patients with normal CA-125 (≤35 U/mL) and 32 patients with elevated CA-125 (N35 U/mL) at the time of recurrence. There were no statistical differences in mean age (56 years, STD 11 years) or median time to recurrence (13 months, range 6–50 months) between the two study groups. Of the 11,864 genes analyzed, 14 showed a statistically significant difference in expression between the two groups (figure); six genes had increased expression and eight genes had decreased expression in patients with normal CA-125 levels at recurrence. The gene functions were consistent with known CA-125/MUC16 biology, including regulation of transcription and DNA binding, which would affect growth, mobility, and invasion. Conclusions: Gene expression profiles vary between advancedstage, platinum-sensitive HGSOC patients who recur with and without elevated CA-125 levels. These findings may indicate inherent differences in tumor biology. Further evaluation of the functional significance of this variable gene expression may lead to better stratification and monitoring approaches based on primary tumor genomics.
Objectives: To evaluate performance of an in vitro chemotherapy drug response assay in BRCA1/2-deficient patients with primary ovarian cancer (OVCA). Methods: Retrospective review of newly diagnosed OVCA patients undergoing primary staging/debulking surgery with performance of commercially available in vitro chemosensitivity assays (CSTA). All patients were offered genetic counseling and testing. Progressionfree survival (PFS) and overall survival (OS) were analyzed. Comparative analysis was performed using Fisher's exact test. PFSs were analyzed using Kaplan–Meier curves. Results: A total of 140 patients met inclusion criteria and had adequate follow-up information. Deleterious mutations in BRCA1 and BRCA2 were found in 8.6% (12/140) and 6.4% (9/140) of patients, respectively, with 25.7% (25/140) patients negative for BRCA mutation. The remaining 59.3% (83/140) declined testing. All patients underwent primary chemotherapy with a platinum agent and a taxane. The mean age at diagnosis was 55 and 61 years in BRCA1/2 mutated and negative/not tested patients (neg/NT). The majority of patients were diagnosed with stage III/IV disease: 71.4% (15/21) BRCA and 80.7% (96/119) neg/NT patients. BRCA1/2 patients had a trend toward improved PFS when compared to PFS in neg/NT (19 vs 26) (P =0.08). There were no statistically significant differences in CTSA between BRCA1/2 and neg/NT patients: carboplatin (73.7% response vs 61.6% response, P = 0.43), cisplatin (64.3% vs 49.3% P = 0.39), carboplatin with paclitaxel (80% vs 80%, P = 1.00), carboplatin with docetaxel (83.3% vs 85.3%, P = 1.00), carboplatin with gemcitabine (77.3% vs 76.7%, P = 1.00), doxorubicin (20.0% vs 33.7%, P = 0.37), gemcitabine (35.0% vs 32.3%, P = 0.80), paclitaxel (57.9 vs 56.4%, P = 1.00), and docetaxel (37.5% vs 34.4%, P = 0.78). Conclusions: In this review of primary OVCA patients tested with CTSA, no significant difference in chemosensitivities based on BRCA mutation status was observed. Although BRCA mutation has been linked to increased platinum sensitivity, this was not demonstrated based on the drug assay. An in vivo mechanism not evaluated by in vitro assay may account for clinically observed increased platinum sensitivity. doi:10.1016/j.ygyno.2014.03.217
Figure: 198 — Poster Session A Inhibition of chaperone-mediated autophagy may be a novel approach to increase platinum susceptibility in ovarian cancer cell lines L.A. Spoozak1, C. Park1, M.R. Ewart1, G.L. Goldberg2, A.M. Cuervo1. 1 Albert Einstein College of Medicine, Bronx, NY, USA, 2Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
doi:10.1016/j.ygyno.2014.03.216
Objectives: Chaperone-mediated autophagy (CMA) assures lysosomal degradation of specific damaged cytosolic proteins. Our group has previously shown that CMA is upregulated in different types of cancer cells and is required for lung and melanoma tumor growth. We hypothesized that upregulation of CMA may underlie chemotherapy resistance in serous ovarian cancer by removing cellular damage generated by the treatment. Methods: CMA and macroautophagy (MA) activity were assessed in ovarian cancer cell lines with different sensitivities to cisplatin and in formalin-fixed tumor specimens using biochemical and image-based procedures. Markers of both pathways were measured by immunoblot,
81
196 — Poster Session A Gene expression profiles of high-grade serous ovarian cancers in patients with normal CA-125 levels at the time of recurrence V. Broach, F. Dao, D.A. Levine. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
197 — Poster Session A Association of in vitro chemotherapy drug resistance assays in ovarian cancer patients with BRCA1/2 mutations J. Lee, A.W. Menzin, V.S. John, J.L. Lovecchio, J.S. Whyte. Hofstra — North Shore Long Island Jewish School of Medicine, Manhasset, NY, USA.
Objectives: CA-125 is a useful tool for monitoring response to therapy and recurrence in patients with high-grade serous ovarian cancer (HGSOC). However, 15% to 20% of patients have normal levels of CA-125 at the time of recurrence, limiting the prognostic ability of CA-125 in this population. We aimed to determine differences in gene expression profiles of tumors from patients with and without elevated CA-125 levels at the time of recurrence. Methods: Patients with stage IIIC or IV HGSOC who underwent primary surgical cytoreduction and initial platinum-based chemotherapy were identified from The Cancer Genome Atlas (TCGA). All patients had platinum-sensitive, radiographic-confirmed recurrent disease. Patients were stratified into two groups: those with elevated CA-125 (N35 U/mL) and those with normal CA-125 (≤35 U/mL) at time of recurrence. Gene expression profiling was performed using 1 Agilent and 2 Affymetrix expression microarray platforms. Expression data were combined across microarrays using factor analysis for genes present on all array platforms. Gene expression levels for 11,864 genes were analyzed. Mean gene expression was compared using student t-test and significance was defined as P b 0.001. Results: Data were available for 21 patients with normal CA-125 (≤35 U/mL) and 32 patients with elevated CA-125 (N35 U/mL) at the time of recurrence. There were no statistical differences in mean age (56 years, STD 11 years) or median time to recurrence (13 months, range 6–50 months) between the two study groups. Of the 11,864 genes analyzed, 14 showed a statistically significant difference in expression between the two groups (figure); six genes had increased expression and eight genes had decreased expression in patients with normal CA-125 levels at recurrence. The gene functions were consistent with known CA-125/MUC16 biology, including regulation of transcription and DNA binding, which would affect growth, mobility, and invasion. Conclusions: Gene expression profiles vary between advancedstage, platinum-sensitive HGSOC patients who recur with and without elevated CA-125 levels. These findings may indicate inherent differences in tumor biology. Further evaluation of the functional significance of this variable gene expression may lead to better stratification and monitoring approaches based on primary tumor genomics.
Objectives: To evaluate performance of an in vitro chemotherapy drug response assay in BRCA1/2-deficient patients with primary ovarian cancer (OVCA). Methods: Retrospective review of newly diagnosed OVCA patients undergoing primary staging/debulking surgery with performance of commercially available in vitro chemosensitivity assays (CSTA). All patients were offered genetic counseling and testing. Progressionfree survival (PFS) and overall survival (OS) were analyzed. Comparative analysis was performed using Fisher's exact test. PFSs were analyzed using Kaplan–Meier curves. Results: A total of 140 patients met inclusion criteria and had adequate follow-up information. Deleterious mutations in BRCA1 and BRCA2 were found in 8.6% (12/140) and 6.4% (9/140) of patients, respectively, with 25.7% (25/140) patients negative for BRCA mutation. The remaining 59.3% (83/140) declined testing. All patients underwent primary chemotherapy with a platinum agent and a taxane. The mean age at diagnosis was 55 and 61 years in BRCA1/2 mutated and negative/not tested patients (neg/NT). The majority of patients were diagnosed with stage III/IV disease: 71.4% (15/21) BRCA and 80.7% (96/119) neg/NT patients. BRCA1/2 patients had a trend toward improved PFS when compared to PFS in neg/NT (19 vs 26) (P =0.08). There were no statistically significant differences in CTSA between BRCA1/2 and neg/NT patients: carboplatin (73.7% response vs 61.6% response, P = 0.43), cisplatin (64.3% vs 49.3% P = 0.39), carboplatin with paclitaxel (80% vs 80%, P = 1.00), carboplatin with docetaxel (83.3% vs 85.3%, P = 1.00), carboplatin with gemcitabine (77.3% vs 76.7%, P = 1.00), doxorubicin (20.0% vs 33.7%, P = 0.37), gemcitabine (35.0% vs 32.3%, P = 0.80), paclitaxel (57.9 vs 56.4%, P = 1.00), and docetaxel (37.5% vs 34.4%, P = 0.78). Conclusions: In this review of primary OVCA patients tested with CTSA, no significant difference in chemosensitivities based on BRCA mutation status was observed. Although BRCA mutation has been linked to increased platinum sensitivity, this was not demonstrated based on the drug assay. An in vivo mechanism not evaluated by in vitro assay may account for clinically observed increased platinum sensitivity. doi:10.1016/j.ygyno.2014.03.217
Figure: 198 — Poster Session A Inhibition of chaperone-mediated autophagy may be a novel approach to increase platinum susceptibility in ovarian cancer cell lines L.A. Spoozak1, C. Park1, M.R. Ewart1, G.L. Goldberg2, A.M. Cuervo1. 1 Albert Einstein College of Medicine, Bronx, NY, USA, 2Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
doi:10.1016/j.ygyno.2014.03.216
Objectives: Chaperone-mediated autophagy (CMA) assures lysosomal degradation of specific damaged cytosolic proteins. Our group has previously shown that CMA is upregulated in different types of cancer cells and is required for lung and melanoma tumor growth. We hypothesized that upregulation of CMA may underlie chemotherapy resistance in serous ovarian cancer by removing cellular damage generated by the treatment. Methods: CMA and macroautophagy (MA) activity were assessed in ovarian cancer cell lines with different sensitivities to cisplatin and in formalin-fixed tumor specimens using biochemical and image-based procedures. Markers of both pathways were measured by immunoblot,