Ido Laskov

Clinical outcome of neoadjuvant chemotherapy for advanced ovarian cancer

OBJECTIVE To evaluate clinical outcome in patients selected to receive neoadjuvant chemotherapy (NACT) compared to primary debulking surgery (PDS). METHODS Retrospective study including all consecutive patients diagnosed and treated for advanced (stages III-IV) ovarian cancers between the years 2003-2015. RESULTS 263 women were included in the study, of these, 127 patients were selected to receive NACT and 136 were treated with PDS followed by adjuvant chemotherapy. PDS was associated with longer OS in stage IIIc disease (median OS: 60.2 vs. 48.8months; p-value 0.039) compared with NACT. Patients achieved higher rates of complete cytoreduction in the NACT group compared to the PDS group (65.9% vs. 40.2%; p=0.001). Patients attaining complete cytoreduction after PDS had the best survival, (median OS 106months) followed by those with complete cytoreduction after NACT (median OS 71months), followed by those with residual disease after PDS (median OS 55months). Patients with residual disease following interval debulking after NACT had the worst outcome (median OS 36months). Platinum sensitivity following first line and second line chemotherapy was similar whether patients received neoadjuvant chemotherapy or not. CONCLUSION PDS was associated with improved outcome. NACT appears to improve survival outcome in patients that would have had residual disease after PDS, and attain complete cytoreduction at the time of interval cytoreduction. This treatment option can be used in selected patients that are not candidates for complete cytoreduction at PDS.

Metformin Increases E-cadherin in Tumors of Diabetic Patients With Endometrial Cancer and Suppresses Epithelial-Mesenchymal Transition in Endometrial Cancer Cell Lines.

Purpose Epithelial-mesenchymal transition (EMT) is a critical process for cancer metastasis and recurrence. Metformin, an effective oral antidiabetic drug, has been associated with decreased cancer risk and mortality. In this pilot study, we started to evaluate the effect of metformin on EMT in vivo and in vitro in endometrial cancer (EC). Methods Endometrial cancer cell lines and freshly isolated EC tumor specimens were used to assess EMT after metformin treatment. Cell lines were subjected to wound healing and AlamarBlue assays to determine cell migration and cell proliferation; messenger RNA levels were measured by real-time reverse transcriptase (RT) quantitative polymerase chain reaction (PCR), and protein levels were measured by Western blots to detect EMT marker expression. Results Protein expression and messenger RNA of E-cadherin was found to be increased (P = 0.02 and 0.04, respectively) in 30 EC tumor specimens of diabetic patients treated with metformin compared with 20 EC tumor specimens of diabetic patients treated with other antidiabetic agents. In vitro, metformin reduced cell migration at 5 mM for 48 hours, as determined by the wound healing assay in EC cell lines (Ishikawa, 45% reduction; HEC50, 40% reduction), whereas more than 90% of the cells remained viable on the AlamarBlue assay. Metformin reduced EMT in the cell lines and regulated the expression of the EMT-related epithelial markers, E-cadherin and Pan-keratin; the mesenchymal markers, N-cadherin, fibronectin, and vimentin; and the EMT drivers, Twist-1, snail-1, and ZEB-1. Conclusions Tumors of patients on metformin have increased E-cadherin expression, and metformin decreases EMT in EC cell lines in vitro, suggesting clinical biological relevance of metformin in women with EC.

Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors

BackgroundPhosphatase and Tensin homolog (PTEN) is a tumor suppressor gene. Loss of its function is the most frequent genetic alteration in endometrioid endometrial cancers (70–80%) and high grade tumors (90%). We assessed the sensitivity of endometrial cancer cell lines to PARP inhibitors (olaparib and BMN-673) and a PI3K inhibitor (BKM-120), alone or in combination, in the context of their PTEN mutation status. We also highlighted a direct pathway linking PTEN to DNA repair.MethodsUsing endometrial cancer cellular models with known PTEN status, we evaluated their homologous recombination (HR) functionality by RAD51 foci formation assay. The 50% Inhibitory concentration (IC50) of PI3K and PARP inhibitors in these cells was assessed, and western blotting was performed to determine the expression of proteins involved in the PI3K/mTOR pathway. Moreover, we explored the interaction between RAD51 and PI3K/mTOR by immunofluorescence. Next, the combination effect of PI3K and PARP inhibitors on cell proliferation was evaluated by a clonogenic assay.ResultsCells with mutated PTEN showed over-activation of the PI3K/mTOR pathway. These cells were more sensitive to PARP inhibition compared to PTEN wild-type cells. In addition, PI3K inhibitor treatment reduced RAD51 foci formation in PTEN mutated cells, and sensitized these cells to PARP inhibitor.ConclusionTargeting both PARP and PI3K might lead to improved personalized therapeutic approaches in endometrial cancer patients with PTEN mutations. Understanding the complex interaction of PTEN mutations with DNA repair in endometrial cancer will help to better select patients that are likely to respond to some of the new and costly targeted therapies.

Impact of lower uterine segment involvement in type II endometrial cancer and the unique mutational profile of serous tumors

Objective Evaluation of the impact of lower uterine segment involvement (LUSI) in type II endometrial cancer, and mutational profile of uterine papillary serous carcinomas (UPSC). Methods Retrospective cohort study comparing patients with type II endometrial cancer with LUSI to patients without LUSI. Genes commonly implicated in carcinogenesis were analyzed in a subgroup of 42 patients with UPSC using next generation sequencing. Results 83 patients with type II endometrial cancer were included in the study, of these, LUSI was diagnosed in 31.3%. During a median follow-up of 45.5 months, patients with LUSI developed more local and distant recurrences (local: 19.2% vs. 3.5%, P = .03; distant: 50% vs. 17.5%, P = .004) and progression events (73.1% vs. 26.3%, P < .001), with shorter mean progression-free survival (16 months compared to 26.5 months, P < .01). In a multivariate analysis, LUSI was the only significant pathological factor, associated with a 2.9-fold increase in the risk of progression (P = .007), and a 2.6-fold increase in the risk of death (P = .02). In the subgroup of patients with UPSC, mutations were identified in 54 genes, including TP53 (80%), PPP2R1A (40%), and PTEN (22.5%). Frequent mutations in the PTEN-PI3K-AKT signaling pathway were found in patients with tumor in the upper uterine segment only (P = .04), with PTEN being mutated in 29% of the samples (P = .07). Conclusion Type II endometrial cancers presenting in the LUS have a significantly worse prognosis and this might be associated with a unique mutational profile.

Dose dense carboplatin paclitaxel improves progression free survival in patients with endometrial cancer

OBJECTIVE Pilot study to assess the value of weekly paclitaxel plus carboplatin every 3weeks (dose dense regimen, DD) compared to the standard 3-weekly protocol in the adjuvant setting for endometrial cancer. METHODS Retrospective cohort study comparing consecutive patients with high and intermediate-high risk endometrial cancer, undergoing DD protocol (from 2011 to 2015) to a non-overlapping historical cohort with similar characteristics who received treatment every three weeks (2008-2011). RESULTS 122 patients with endometrial cancer were included in the study, of these, 61 patients received the dose dense protocol and 61 were treated with the standard 3-weekly protocol. After a median follow-up of 61.6months in the 3-weekly cohort, compared with 41.6months in the DD cohort, 40 progressions were recorded. 29 progressions were observed in women treated in the standard protocol, with a three years progression free survival (PFS) of 57.4%, compared to 11 progressions observed in patients in the DD schedule, with a three years PFS of 79.5% (P=0.03). Patients who were treated with the DD protocol were less likely to have progression events compared to the standard cohort with a hazard ratio of 0.4 on multivariate analysis (CI 95%, 0.2-0.8, P=0.01), had significantly less distant metastases (P=0.01), and had improved overall survival when diagnosed with advanced stage disease (P=0.02). Complaints of musculoskeletal pain were more frequent in the standard cohort (n=17, 27.9%) compared to the dose dense cohort (n=4, 6.6%), P=0.005. CONCLUSION Preliminary data suggests that dose dense chemotherapy might be a reasonable and superior option for adjuvant treatment of endometrial cancer, compared to standard chemotherapy.

Risk of Thromboembolic Disease With Cost Estimates in Patients Undergoing Robotic Assisted Surgery for Endometrial Cancer and Review of the Literature

OBJECTIVE This study sought to evaluate the incidence, risk factors, and estimated cost associated with venous thromboembolism (VTE) following robotic surgery for endometrial cancer. METHODS The study included all consecutive patients with newly diagnosed endometrial cancer who underwent robotic surgery, excluding patients with a previous history of VTE (3%), those taking long-term warfarin (3%), and patients with conversions to laparotomy (3%). The incidence of postoperative symptomatic VTE within 90 days was analyzed. Direct and indirect medical costs were estimated using a linked billing database for standardized, inflation-adjusted costs. RESULTS A total of 558 cases were identified. Median BMI was 29 kg/m2 (range, 17-85 kg/m2), median operative time was 227 minutes (range, 75-419 minutes), and median blood loss was 30 mL (range, 3-400 mL). All patients received thromboprophylaxis with intraoperative subcutaneous heparin and sequential pneumatic compression devices. Extended postoperative prophylaxis for 28 days was administered to 88 (17.2%) patients with high-risk factors. A total of eight patients (1.6%) developed symptomatic VTE, and all eight were in the group that did not receive extended prophylaxis. The number needed to treat to prevent one VTE was 52.8, with an absolute risk reduction 1.89% (95% CI 0.59% to 3.19%). The average cost for treatment of a VTE was

Distinct homologous recombination gene expression profiles after neoadjuvant chemotherapy associated with clinical outcome in patients with ovarian cancer

7653 (range,

Role of Laparoscopic and Robotic Surgery in Endometrial Cancer: The Inevitable Evolution

4396-

Progestogens in Endometrial Cancer

12 211), equivalent to the cost of treating 21 patients with extended prophylaxis (

Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer

356 per patient). CONCLUSION The incidence of VTE in patients with endometrial cancer who underwent robotic-assisted surgery was low (1.6%), and none of the VTEs occurred in the cohort of high-risk patients who received extended thromboprophylaxis.