Molecular classification improves preoperative risk assessment of endometrial cancer.

OBJECTIVE: We aimed to evaluate the performance of endometrial cancer (EC) molecular classification in predicting extrauterine disease after primary surgery alone and in combination with other clinical data available in preoperative setting. METHODS: Retrospective single-center observational study including patients with endometrial adenocarcinoma treated with primary surgery between December 1994 and May 2022. Molecular profiling was performed using immunohistochemistry of p53, MLH1, PMS2, MSH2 and MSH6; and KASP genotyping of the 6 most common mutations of POLE gene. Clinical, pathological and imaging information was reviewed. Logistic regression, regression trees and random forest classification techniques (CART) were performed. RESULTS: We enrolled 658 patients, 47 with POLEmut (7.1%), 234 with MMRd (35.6%), 95 with p53abn (14.4%) and 282 with NSMP (42.8%) tumors. Advanced stage after primary surgery (III-IV FIGO 2009) was diagnosed in 11.7% of patients, p53abn tumors showed increased extrauterine spread (34.1%) and nodal involvement (30.1%) (p < .001). In multivariate analysis, only p53abn subgroup (aOR = 16.0, CI95% = 1.5-165.1) and radiological suspicion of extrauterine disease (aOR = 24.2, CI95% = 12.2-48.2) independently predicted the finding of extrauterine disease after primary surgery. In patients with preoperative uterine-confined disease, deep myometrial and cervical involvement in radiological assessment and p53abn molecular subtype were the best variables to identify patients at-risk of occult extrauterine disease after the staging surgery. CONCLUSION: EC molecular classification is more accurate than histotype or grade in preoperative biopsy to predict advanced disease, and together with imaging tests are the most reliable preoperative information. This work provides an initial framework for using molecular information preoperatively to tailor surgical treatment.

Molecular profile is a strong predictor of the pattern of recurrence in patients with endometrial cancer.

OBJECTIVES: To investigate the pattern of first recurrence of disease in patients with endometrial cancer according to molecular classification, and to assess the independent role of molecular profiling in each type of failure. METHODS: Retrospective single-center study including patients diagnosed with endometrial cancer stage I-IVB (International Federation of Gynecology and Obstetrics 2009) between December 1994 and May 2022, who underwent primary surgical treatment and had a complete molecular profile. First recurrence was classified as isolated or multiple, and as vaginal, pelvic, peritoneal, nodal, and distant according to its location. The log-rank test and univariate and multivariate adjusted Cox regression models were used for comparison between groups. RESULTS: A total of 658 patients were included. Recurrence was observed in 122 patients (18.5%) with a recurrence rate of 12.4% among mismatch-repair deficient tumors, 14.5% among non-specific molecular profile, 2.1% among POLE-mutated, and 53.7% among p53-abnormal tumors. Recurrences were found to be isolated in 80 (65.6%) and multiple in 42 (34.4%) patients, with no differences in molecular subtype (p=0.92). Patients with p53-abnormal tumors had a recurrence mainly as distant (28.4%) and peritoneal (21.1%) disease, while patients with non-specific molecular profile tumors presented predominantly with distant failures (10.3%), and mismatch-repair deficient tumors with locoregional recurrences (9.4%).On multivariate analysis, p53-abnormal molecular profile was the only independent risk factor for peritoneal failure (OR=8.54, 95% CI 2.0 to 36.3). Vaginal recurrence was independently associated with p53-abnormal molecular profile (OR=6.51, 95% CI 1.1 to 37.4) and lymphovascular space invasion. p53-abnormal and non-specific molecular profiles were independent predictors for distant recurrence (OR=3.13, 95% CI 1.1 to 8.7 and OR=2.35, 95% CI 1.1 to 5.0, respectively), along with lymphovascular space invasion and high-grade tumors. Molecular profile was not independently associated with pelvic and nodal recurrences. CONCLUSIONS: Endometrial cancer featured different patterns of recurrence depending on the molecular profile. p53-abnormal molecular profiling was the only independent risk factor for peritoneal relapse, while non-specific molecular profile showed a strong association with distant failures.

Outcomes of minimal residual disease at upfront debulking surgery compared with complete cytoreduction after neoadjuvant chemotherapy.

OBJECTIVE: The aim of this study was to compare surgical complexity, post-operative complications, and survival outcomes between patients with minimal residual disease (completeness of cytoreduction (CC) score) CC-1 at the time of primary debulking surgery and those with complete cytoreduction (CC-0) at the time of interval debulking surgery. METHODS: A retrospective multicenter study was conducted of patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIIC-IV) who underwent cytoreductive surgery achieving either minimal or no residual disease between January 2008 and December 2015. Patients underwent either primary or interval debulking surgery after receiving ≥3 cycles of neoadjuvant chemotherapy. The sub-group of patients with primary debulking surgery/CC-1 was compared with those with interval debulking surgery/CC-0. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS: A total of 549 patients were included, with upfront surgery performed in 175 patients (31.9%) and 374 patients (68.1%) undergoing interval debulking surgery. After primary debulking surgery, 157/175 (89.7%) had complete cytoreduction and 18/175 (10.3%) had minimal residual disease (primary debulking surgery/CC-1 group), while after interval debulking surgery, 324/374 (86.6%) had complete cytoreduction (interval debulking surgery/CC-0 group) and 50/374 (13.4%) had minimal residual disease. The rate of patients with peritoneal cancer index >10 was 14/17 (82.4%) for the primary debulking surgery/CC-1 group and 129/322 (40.1%) for the interval debulking surgery/CC-0 (p<0.001). The rate of patients with an Aletti score of ≥8 was 11/18 (61.1%) and 132/324 (40.7%), respectively (p=0.09) and the rate of major post-operative complications was 5/18 (27.8%) and 64/324 (19.8%), respectively (p=0.38). Overall median disease-free and overall survival were 19.4 months (95% CI 18.0 to 20.6) and 56.7 months (95%CI 50.2 to 65.8), respectively. Median disease-free survival for the primary debulking surgery/CC-1 group was 16.7 months (95% CI 13.6 to 20.0) versus 18.2 months (95% CI 16.4 to 20.0) for the interval debulking surgery/CC-0 group (p=0.56). Median overall survival for the primary debulking surgery/CC-1 group was 44.7 months (95% CI 34.3 to not reached) and 49.4 months (95% CI 46.2 to 57.3) for the interval debulking surgery/CC-0 group (p=0.97). CONCLUSIONS: Patients with primary debulking surgery with minimal residual disease and those with interval debulking surgery with no residual disease had similar survival outcomes. Interval surgery should be considered when achieving absence of residual disease is challenging at upfront surgery, given the lower tumor burden found during surgery.

Procalcitonin and C-reactive protein as early markers of anastomotic leakage in intestinal resections for advanced ovarian cancer (EDMOCS).

INTRODUCTION: Serum levels of procalcitonin and C-reactive protein (CRP) have been used to predict anastomotic leakage after colorectal surgery, but information is scarce in advanced ovarian cancer (AOC) surgery with bowel resection. This study aimed to assess the predictive value of procalcitonin and CRP in detecting anastomotic leakage after AOC surgery with bowel resection. The study also aimed to determine the optimal postoperative reference values and the best day for evaluating these markers. MATERIAL AND METHODS: This prospective, observational and multicentric trial included 92 patients with AOC undergoing debulking surgery with bowel resection between 2017 and 2020 in 10 reference hospitals in Spain. Procalcitonin and CRP levels were measured at baseline and on postoperative days 1-6. Receiver operating characteristic analysis was performed to evaluate the predictive value of procalcitonin and CRP at each postoperative day. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: Anastomotic leakage was detected in six patients (6.5%). Procalcitonin and CRP values were consistently higher in patients with anastomotic leakage at all postoperative days. The maximum area under the curve (AUC) for procalcitonin was observed at postoperative day 1 (AUC = 0.823) with a cutoff value of 3.8 ng/mL (83.3% sensitivity, 81.3% specificity). For CRP, the maximum AUC was found at postoperative day 3 (AUC = 0.833) with a cutoff level of 30.5 mg/dL (100% sensitivity, 80.4% specificity). CONCLUSIONS: Procalcitonin and C-reactive protein are potential biomarkers for early detection of anastomotic leakage after ovarian cancer surgery with bowel resection. Further prospective studies with a larger sample size are needed to confirm these findings.

Molecular profile in endometrial carcinoma: can we predict the lymph node status? A systematic review and meta-analysis.

PURPOSE: Molecular classification of endometrial cancer (EC) has become a promising information to tailor preoperatively the surgical treatment. We aimed to evaluate the rate of lymph node metastases (LNM) in patients with EC according to molecular profile. METHODS: A systematic review and meta-analysis were performed according to PRISMA guidelines by searching in two major electronic databases (PubMed and Scopus), including original articles reporting lymph node metastases according to the molecular classification of EC as categorized in the ESGO-ESMO-ESP guidelines. RESULTS: Fifteen studies enrolling 3056 patients were included. Pooled prevalence LNM when considering only patients undergoing lymph node assessment was 4% for POLE-mutated (95%CI: 0-12%), 22% for no specific molecular profile (95% CI: 9-39%), 23% for Mismatch repair-deficiency (95%CI: 10-40%) and 31% for p53-abnormal (95%CI: 24-39%). CONCLUSIONS: The presence of LNM seems to be influenced by molecular classification. P53-abnormal group presents the highest rate of nodal involvement, and POLE-mutated the lowest.

Patterns of First Recurrence and Oncological Outcomes in Locally Advanced Cervical Cancer Patients: Does Surgical Staging Play a Role?

BACKGROUND: We aimed to determine whether surgical aortic staging by minimally invasive paraaortic lymphadenectomy (PALND) affects the pattern of first recurrence and survival in treated locally advanced cervical cancer (LACC) patients when compared to patients staged by imaging (noPALND). METHODS: This study was a multicenter observational retrospective cohort study of patients with LACC treated at tertiary care hospitals throughout Spain. The inclusion criteria were histological diagnosis of squamous carcinoma, adenosquamous carcinoma, and/or adenocarcinoma; FIGO stages IB2, IIA2-IVA (FIGO 2009); and planned treatment with primary chemoradiotherapy between 2000 and 2016. Propensity score matching (PSM) was performed before the analysis. RESULTS: After PSM and sample replacement, 1092 patients were included for analysis (noPALND n = 546, PALND n = 546). Twenty-one percent of patients recurred during follow-up, with the PALND group having almost double the recurrences of the noPALND group (noPALND: 15.0%, PALND: 28.0%, p < 0.001). Nodal (regional) recurrences were more frequently observed in PALND patients (noPALND:2.4%, PALND: 11.2%, p < 0.001). Among those who recurred regionally, 57.1% recurred at the pelvic nodes, 37.1% recurred at the aortic nodes, and 5.7% recurred simultaneously at both the pelvic and aortic nodes. Patients who underwent a staging PALND were more frequently diagnosed with a distant recurrence (noPALND: 7.0%, PALND: 15.6%, p < 0.001). PALND patients presented poorer overall, cancer-specific, and disease-free survival when compared to patients in the noPALND group. CONCLUSION: After treatment, surgically staged patients with LACC recurred more frequently and showed worse survival rates.

Cervical Cancer Evades the Host Immune System Through the Inhibition of Type I Interferon and CXCL9 by LIF.

BACKGROUND: Cervical cancer (CC) is a viral-associated tumor caused by the infection with the human papilloma virus. CC is then an immunogenic cancer that expresses viral antigens. Despite being immunogenic, CC does not fully respond to immune checkpoint inhibitors (ICI). LIF is a crucial cytokine in embryo implantation, involved in maternal tolerance that acts as an immunomodulatory factor in cancer. LIF is expressed in CC and high levels of LIF is associated with poor prognosis in CC. METHODS: We evaluated the impact of LIF on the immune response to ICI using primary plasmocytoid dendritic cells (pDCs) and macrophage cultures, syngeneic animals and patient-derived models that recapitulate the human tumor microenvironment. RESULTS: We found that the viral proteins E6 and E7 induce the expression of LIF via the NFκB pathway. The secreted LIF can then repress type I interferon expressed in pDCs, and CXCL9 expressed in tumor associated macrophages. Blockade of LIF promotes the induction of type I interferon and CXCL9 inducing the tumor infiltration of CD8 T cell. This results in the sensitization of the tumor to ICI. Importantly, we observed that patients with CC expressing high levels of LIF tent to be resistant to ICI. CONCLUSION: Our data show that the HPV virus induces the expression of LIF to provide a selective advantage to the tumor cell by generating local immunosuppression via the repression of type I interferon and CXCL9. Combinatory treatment with blocking antibodies against LIF and ICI could be effective against CC expressing high levels of LIF.

Oncological outcomes of intraperitoneal chemotherapy in advanced ovarian cancer: BRCA mutation role.

INTRODUCTION: The knowledge of BRCA status offers a chance to evaluate the role of the intraperitoneal route in patients selected by biomolecular profiles after primary cytoreduction surgery in advanced ovarian cancer. MATERIALS AND METHODS: We performed a retrospective, multicenter study to assess oncological outcomes depending on adjuvant treatment (intraperitoneal [IP] vs intravenous [IV]) and BRCA status (BRCA1/2 mutated vs. BRCA wild type [WT]). The primary endpoint was to determine progression-free survival. The secondary objectives were overall survival and toxicity. RESULTS: A total of 288 women from eight centers were included: 177 in the IP arm and 111 in the IV arm, grouped into four arms according to BRCA1/2 status. Significantly better PFS was observed in BRCA1/2-mutated patients with IP chemotherapy (HR: 0.35; 95% CI, 0.16-0.75, p = 0.007), which was not present in BRCA1/2-mutated patients with IV chemotherapy (HR: 0.65; 95% CI, 0.37-1.12, p = 0.14). Significantly better OS was also observed in IP chemotherapy (HR: 0.17; 95% CI, 0.06-043, p < 0.0001), but was not present in IV chemotherapy in relation with BRCA mutation (HR: 0.52; 95% CI, 0.22-1.27, p = 0.15). For BRCA WT patients, worse survival was observed regardless of the adjuvant route used. The IP route was more toxic compared to the IV route, but toxicity was equivalent at the long-term follow-up. CONCLUSION: This retrospective study suggests that BRCA status can help to offer an individualized, systematic treatment after optimal primary surgery for advanced ovarian cancer, but is limited by the small sample size. Prospective trials are essential to confirm these results.

Corrigendum: FXYD5/Dysadherin, a biomarker of endometrial cancer myometrial invasion and aggressiveness: its relationship with TGF-ß1 and NF-κB pathways.

[This corrects the article DOI: 10.3389/fonc.2019.01306.].