p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Chemotherapy in older adult gynecologic oncology patients: Can a phenotypic frailty score predict tolerance?

Objective: Evaluate the ability of an office-administered phenotypic frailty assessment to predict chemotherapy tolerance in older adult gynecologic oncology patients, and describe practice patterns for chemotherapy administration in this population. Methods: Prospective, single-institution cohort study of gynecologic oncology patients 65 or older initiating chemotherapy. Phenotypic frailty testing at an office visit encompassed components of two validated frailty assessments: Fried Score (physical testing and patient response) and FRAIL Scale (patient response only). Patients were followed through three cycles of neoadjuvant chemotherapy or six cycles of adjuvant chemotherapy. Standard statistics examined the relationship of frailty to chemotherapy regimen, ability to complete chemotherapy, and complications. Results: Eighty patients were included, 65% with ovarian and 34% with endometrial cancer. On average 57% of patients were fit, 32% intermediately frail, and 11% frail. 68% received adjuvant chemotherapy versus 32% neoadjuvant. The majority (81%) received IV chemotherapy on a 21-day cycle and 81% initially received a regimen consistent with standard-of-care chemotherapy (SOCC). Age was not associated with receiving SOCC, or tolerance or completion of chemotherapy. Frailty was associated with non-initiation of SOCC in all patients and inability to complete SOCC in adjuvant patients. Complications and regimen alterations were common but were not associated with frailty. Conclusions: There is a need to develop tools to help physicians predict chemotherapy tolerance among older adult gynecologic oncology patients in order to prevent both under- and over-treatment while minimizing morbidity. However, in this study phenotypic frailty assessment had limited predictive utility. Among adjuvant chemotherapy patients, frailty was associated with inability to complete SOCC and thus may be helpful in selecting patients appropriate for less aggressive chemotherapy regimens

Surgical Outcomes of Patients Undergoing Extrafascial Hysterectomy After Neoadjuvant Radiotherapy With or Without Chemotherapy for Locally Advanced Endometrial Cancer Clinically Extending to the Cervix or Parametria

Recent data have shown high rates of clinical and pathologic responses to neoadjuvant radiation therapy for locally advanced endometrial cancer. There are limited data on the surgical outcomes of these patients in the era of modern radiation and surgical techniques. We sought to characterize surgical outcomes after extrafascial hysterectomy in this population. Patients with endometrial cancer of all histologies clinically involving the cervix or parametria treated with neoadjuvant brachytherapy followed by extrafascial hysterectomy from 1999 to 2014 were identified. Patient charts were reviewed for data regarding treatment characteristics and postoperative outcomes. Pearson χ and logistic regression analyses were used to assess correlations between surgical complications and treatment-related variables. Twenty-nine patients met inclusion criteria. Mean operating time for the cohort was 115 minutes. Mean estimated blood loss was 100 mL. No visceral injuries occurred. Mean length of hospital stay was 1 and 4 days for the minimally invasive and laparotomy groups, respectively. Rates of postoperative ileus, blood transfusion, wound infection, and readmission were 3%, 3%, 6%, and 3%, respectively. No case of prolonged urodynamic dysfunction was noted. The rate of vaginal complications was significantly higher in the group of patients who underwent minimally invasive surgery as compared with laparotomy (33% vs 5%, P < 0.041). These data support adjuvant extrafascial hysterectomy after neoadjuvant radiotherapy for endometrial cancer with cervical or parametrial involvement as a safe and viable procedure, with low rates of postoperative complications. Extra care should be taken when closing the vaginal cuff to reduce the risk of vaginal cuff complications