Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer.

BACKGROUND: Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy. METHODS: We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival. RESULTS: A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P = 0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects. CONCLUSIONS: In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.).

A phase II, multicenter, open-label study of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancer: ALEPRO trial.

BACKGROUND: Low-grade serous and endometrioid ovarian cancers and adult-type granulosa cell tumors are rare ovarian malignancies that show high estrogen receptor positivity. Recurrences of these subtypes of ovarian cancer are often treated with conventional chemotherapy, although response rates are disappointing. PRIMARY OBJECTIVE: To determine the overall response rate of the combination therapy of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancers. STUDY HYPOTHESIS: The combination therapy of abemaciclib and letrozole will provide a clinically meaningful therapeutic benefit, with an overall response rate of >25%. TRIAL DESIGN: This is a phase II, international, multicenter, open-label, single-arm study to evaluate the efficacy and safety of abemaciclib and letrozole in patients with advanced, recurrent, and/or metastatic estrogen receptor-positive, rare ovarian cancer. The study will follow a tandem two-stage design. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients must have histologically confirmed low-grade serous/endometrioid ovarian cancer or adult-type granulosa cell tumor with estrogen receptor positivity on immunohistochemistry. Patients need to have recurrent and measurable disease according to Radiologic Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A maximum of two prior lines of endocrine therapy are allowed, and patients cannot have previously received a cyclin-dependent kinase inhibitor. Patients with platinum-refractory disease are not allowed in any stage of the study. PRIMARY ENDPOINT: Investigator-assessed confirmed overall response rate, defined as the proportion of patients with a complete or partial response according to RECIST v1.1. SAMPLE SIZE: 40 to 100 patients will be included, depending on the results of the interim analysis. Patients will be included in Belgium, France and the Netherlands. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed by the end of 2025 and reporting of the final study results will be done by the end of 2027. TRIAL REGISTRATION NUMBER: NCT05872204.

Predicting resectable disease in relapsed epithelial ovarian cancer by using whole-body diffusion-weighted MRI.

OBJECTIVE: To determine the diagnostic value of whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) to predict resectable disease at the time of secondary cytoreductive surgery for relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months. METHODS: A retrospective cohort study between January 2012 and December 2021 in a tertiary referral hospital. Inclusion criteria were: (a) first recurrence of epithelial ovarian cancer; (b) platinum-free interval of ≥6 months; (c) intent to perform secondary cytoreductive surgery with complete macroscopic resection; and (d) WB-DWI/MRI was performed.Diagnostic tests of WB-DWI/MRI for predicting complete resection during secondary cytoreductive surgery are calculated as well as the progression-free and overall survival of the patients with a WB-DWI/MRI scan that showed resectable disease or not. RESULTS: In total, 238 patients could be identified, of whom 123 (51.7%) underwent secondary cytoreductive surgery. WB-DWI/MRI predicted resectable disease with a sensitivity of 93.6% (95% confidence interval [CI] 87.3% to 96.9%), specificity of 93.0% (95% CI 87.3% to 96.3%), and an accuracy of 93.3% (95% CI 89.3% to 96.1%). The positive predictive value was 91.9% (95% CI 85.3% to 95.7%).Prediction of resectable disease by WB-DWI/MRI correlated with improved progression-free survival (median 19 months vs 9 months; hazard ratio [HR] for progression 0.36; 95% CI 0.26 to 0.50) and overall survival (median 75 months vs 28 months; HR for death 0.33; 95% CI 0.23 to 0.47). CONCLUSION: WB-DWI/MRI accurately predicts resectable disease in patients with a platinum-free interval of ≥6 months at the time of secondary cytoreductive surgery and could be of complementary value to the currently used models.

Real-life data on treatment and outcomes in advanced ovarian cancer: An observational, multinational cohort study (RESPONSE trial).

BACKGROUND: This study aimed to describe the treatment strategies and outcomes for women with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer (OC). METHODS: This observational study collected real-world medical record data from eight Western countries on the diagnostic workup, clinical outcomes, and treatment of adult women with newly diagnosed advanced (Stage III-IV) high-grade serous or endometrioid OC. Patients were selected backward in time from April 1, 2018 (the index date), with a target of 120 patients set per country, followed for ≥20 months. RESULTS: Of the 1119 women included, 66.9% had Stage III disease, 11.7% had a deleterious BRCA mutation, and 26.6% received bevacizumab; 40.8% and 39.3% underwent primary debulking surgery (PDS) and interval debulking surgery (IDS), respectively. Of the patients who underwent PDS, 55.5% had no visible residual disease (VRD); 63.9% of the IDS patients had no VRD. According to physician-assessed responses (at the first assessment after diagnosis and treatment), 53.2% of the total population had a complete response and 25.7% had a partial response to first-line chemotherapy after surgery. After ≥20 months of follow-up, 32.9% of the patients were disease-free, 46.4% had progressive disease, and 20.6% had died. Bevacizumab use had a significant positive effect on overall survival (hazard ratio [HR], 0.62; 95% CI, 0.42-0.91; p = .01). A deleterious BRCA status had a significant positive effect on progression-free survival (HR, 0.60; 95% CI, 0.41-0.84; p < .01). CONCLUSIONS: Women with advanced high-grade serous or endometrioid OC have a poor prognosis. Bevacizumab use and a deleterious BRCA status were found to improve survival in this real-world population. LAY SUMMARY: Patients with advanced (Stage III or IV) ovarian cancer (OC) have a poor prognosis. The standard treatment options of surgery and chemotherapy extend life beyond diagnosis for 5 years or more in only approximately 45% of patients. This study was aimed at describing the standard of care in eight Western countries and estimating how many patients who are diagnosed with high-grade serous or endometrioid OC could potentially be eligible for first-line poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) maintenance therapy. The results highlight the poor prognosis for these patients and suggest that a significant proportion (79%) would potentially be eligible for first-line PARPi maintenance treatment.

Randomized CLIO/BGOG-ov10 trial of olaparib monotherapy versus physician's choice chemotherapy in relapsed ovarian cancer.

OBJECTIVE: Comparison of olaparib (OLA) monotherapy versus chemotherapy in patients with platinum-sensitive (PSOC) or platinum-resistant ovarian cancer (PROC). METHODS: Patients with measurable disease and ≥ 1 prior line of chemotherapy (CT) were randomized 2:1 to OLA (300 mg tablets, BID) or physician's choice CT.: for PSOC: Carboplatin-Pegylated-Liposomal-Doxorubicin (PLD) or Carboplatin-Gemcitabine; for PROC: PLD, Topotecan, Paclitaxel or Gemcitabine. RESULTS: 160 patients (60 with PSOC and 100 with PROC) were randomized 2:1 to OLA (n = 107) or CT (n = 53). Baseline characteristics were similar between both arms. Overall objective response rate (ORR) for OLA and CT were similar (24.3% (26/107) and 28.3% (15/53), respectively). Clinical benefit rate (≥ 12 weeks) was similar with 54.2% (58/107) and 56.6% (30/53), respectively. In PSOC, ORR was 35.0% (14/40) and 65.0% (13/20) for OLA and CT (p = 0.053); in PROC, ORR was 17.9% (12/67) and 6.1% (2/33) for OLA and CT (p = 0.134). ORR in heavily pretreated PROC (>4 prior lines) was 22.9% (8/35) with OLA versus 0% (0/14) for CT. ORR of 35.7% (5/14) and 13.2% (7/53) was observed in BRCA-mutated and -wildtype PROC cases, respectively. Median PFS in PROC was not significantly different with 2.9 months (95% CI 2.8-5.1 in the OLA group versus 3.8 months (95% CI 3.0-6.4) in the CT group (hazard ratio [HR] 1.11 [95% CI 0.72-1.78]; log-rank p = 0.600). CONCLUSION: OLA monotherapy showed overall an equal response rate in relapsed ovarian cancer compared with CT. In PROC, ORR and TFST tended to be higher with OLA than with CT. In heavily pretreated patients (four lines or more) with PROC disease, OLA treatment seemed to be more effective than CT.

Prospective non-interventional BELOVA/BGOG-ov16 study on safety of frontline bevacizumab in elderly patients with FIGO stage IV ovarian cancer: a study of the Belgian and Luxembourg Gynaecological Oncology Group.

OBJECTIVE: Because elderly patients with ovarian cancer are underrepresented in randomized studies, this study aimed to expand our knowledge on the safety and effectiveness of frontline treatment with bevacizumab in combination with standard carboplatin and paclitaxel chemotherapy in patients aged 70 years and older with a diagnosis of Federation of Gynecology and Obstetrics (FIGO) stage IV ovarian cancer in routine clinical practice in Belgium. METHODS: Patients aged 70 years and older with FIGO stage IV ovarian cancer were included in a multicenter, non-interventional prospective studyto evaluate the safety and effectiveness of treatment with bevacizumab in combination with frontline carboplatin and paclitaxel chemotherapy. Comprehensive geriatric assessments were performed at baseline and during treatment. RESULTS: The most frequently reported adverse events for bevacizumab were hypertension (55%), epistaxis (32%) and proteinuria (21%). The Kaplan-Meier estimate of progression-free survival was 14.5 months. The results of the comprehensive geriatric assessments during treatment indicated a slight improvement in the geriatric eight health status screening tool score for general health status and the mini-nutritional assessment score for nutritional status. The median change from baseline score was close to zero for the instruments measuring independency, activity of daily living and instrumental activities of daily living, and for the mobility-tiredness test measuring self-perceived fatigue. CONCLUSIONS: No new safety signals were registered in this study in patients aged 70 years and older treated with bevacizumab and frontline carboplatin and paclitaxel for FIGO stage IV ovarian cancer. Elderly patients should not be excluded from treatment for advanced ovarian cancer based on age alone. EU PAS REGISTER: ENCEPP/SDPP/13849. CLINICALTRIALSGOV IDENTIFIER: NCT02393898.

TRP channel expression correlates with the epithelial-mesenchymal transition and high-risk endometrial carcinoma.

Transient receptor potential (TRP) channels excel in cellular sensing as they allow rapid ion influx across the plasma membrane in response to a variety of extracellular cues. Recently, a distinct TRP mRNA expression signature was observed in stromal cells (ESC) and epithelial cells (EEC) of the endometrium, a tissue in which cell phenotypic plasticity is essential for normal functioning. However, it is unknown whether TRP channel mRNA expression is subject to the phenotypic switching that occurs during epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), and whether TRP channel mRNA expression is associated with aggressive phenotypes in endometrial cancer (EC). Here, we induced EMT and MET in vitro using in primary EEC and ESC, respectively, and analyzed expression and functionality of TRP channels using RT-qPCR and intracellular Ca2+ imaging. The outcome of these experiments showed a strong association between TRPV2 and TRPC1 mRNA expression and the mesenchymal phenotype, whereas TRPM4 mRNA expression correlated with the epithelial phenotype. In line herewith, increased TRPV2 and TRPC1 mRNA expression levels were observed in both primary and metastatic EC biopsies and in primary EC cells with a high EMT status, indicating an association with an aggressive tumor phenotype. Remarkably, TRPV2 mRNA expression in primary EC biopsies was associated with tumor invasiveness and cancer stage. In contrast, increased TRPM4 mRNA expression was observed in EC biopsies with a low EMT status and less aggressive tumor phenotypes. Taken together, this dataset proved for the first time that TRP channel mRNA expression is strongly linked to cellular phenotypes of the endometrium, and that phenotypic transitions caused by either experimental manipulation or malignancy could alter this expression in a predictable manner. These results implicate that TRP channels are viable biomarkers to identify high-risk EC, and potential targets for EC treatment.

Immunotherapy in rare ovarian cancer.

PURPOSE OF REVIEW: Ovarian cancer (OC) is a heterogeneous disease and a mounting body of evidence shows that a 'one-size-fits-all' approach is obsolete. Differences in epidemiology, tumor biology, genetic profiles and treatment responses of these different types necessitate a tumor and patient-specific approach. Ninety percentage consists of epithelial OC with 70% being high-grade serous OC. The other rarer subtypes are low-grade serous (5%), clear cell (12%), endometrioid (11%) and mucinous carcinoma (3%). The remaining 10% are nonepithelial rare OCs: germ cell (3%) and sex-cord stromal tumors (7%). RECENT FINDINGS: Over the past few decades, the 5-year survival rates have only improved modestly, therefore novel therapies are urgently needed. Recently, immunotherapy has been introduced into clinical practice in a number of solid tumors. Although preclinical data confirm the presence of an immunogenic microenvironment in a number of ovarian tumor types, no single-agent immune checkpoint inhibitor has been approved hitherto. Identifying suitable treatment combinations, adequate patient selection and thus correct implementation of immunotherapy remain major challenges. SUMMARY: In this review, we focus on the rationale of incorporating immune therapy in rare OC, we summarize the recent developments with preclinical data and results of clinical trials, with particular focus on rare ovarian histological subtypes.

Concordance between results of inexpensive statistical models and multigene signatures in patients with ER+/HER2- early breast cancer.

Multigene signatures (MGS) are used to guide adjuvant chemotherapy (aCT) decisions in patients diagnosed with estrogen receptor (ER)-positive HER2-negative early breast cancer. We used results from three MGS (Oncotype DX® (ODX), MammaPrint® (MP) or Prosigna®) and assessed the concordance between high or low risk of recurrence and the predicted risk of recurrence based on statistical models. In addition, we looked at the impact of MGS results on final aCT administration during the multidisciplinary meeting (MDM). We retrospectively included 129 patients with ER-positive HER2-negative early breast cancer for which MGS testing was performed after MDM at University Hospitals Leuven between May 2013 and April 2019 in case there was doubt about aCT recommendation. Tumor tissue was analyzed either by ODX (N = 44), MP (N = 28), or Prosigna® (N = 57). Eight statistical models were computed: Magee equations (ME), Memorial Sloan Kettering simplified risk score (MSK-SRS), Breast Cancer Recurrence Score Estimator (BCRSE), OncotypeDXCalculator (ODXC), new Adjuvant! Online (nAOL), Mymammaprint.com (MyMP), PREDICT, and SiNK. Concordance, negative percent agreement, and positive percent agreement were calculated. Of 129 cases, 53% were MGS low and 47% MGS high risk. Concordances of 100.0% were observed between risk results obtained by ODX and ME. For MP, BCRSE demonstrated the best concordance, and for Prosigna® the average of ME. Concordances of <50.0% were observed between risk results obtained by ODX and nAOL, ODX and MyMP, ODX and SiNK, MP and MSK-SRS, MP and nAOL, MP and MyMP, MP and SiNK, and Prosigna® and ODXC. Integration of MGS results during MDM resulted in change of aCT recommendation in 47% of patients and a 15% relative and 9% absolute reduction. In conclusion, statistical models, especially ME and BCRSE, can be useful in selecting ER-positive HER2-negative early breast cancer patients who may need MGS testing resulting in enhanced cost-effectiveness and reduced delay in therapeutic decision-making.

Radical hysterectomy without adjuvant radiotherapy in patients with cervix carcinoma FIGO 2009 IB1, with or without positive Sedlis criteria.

INTRODUCTION: Lymphovascular space invasion (LVSI), deep (>1/3) stromal invasion (DSI) and large tumor size (>4 cm) have been identified as predictors for intermediate risk for recurrence according to Sedlis (at least two of the prior risk factors) in FIGO stage I cervical cancer. Adjuvant radiotherapy (RT) has been advocated in these patients(1,2), but remains controversial. METHOD: All consecutive patients (1997-2017) with cervical cancer FIGO (2009) stage IB1 (≤4 cm) were included. Primary aim was to analyze the recurrence rate. Secondary aim was to identify the risk factors for disease recurrence and survival. RESULTS: One-hundred-and-eighty-two patients were included in this retrospective study. Median follow-up was 13 years (range 8-17). Postoperatively, 21 patients received adjuvant therapy due to presence of positive lymph nodes, positive section margins or if a simple hysterectomy was performed (RT: n = 7, concomitant chemo radiotherapy (CCRT): n = 14). None of the patients with a combination of intermediate risk factors according to Sedlis (excluding patients >4 cm) underwent adjuvant RT/CCRT. Disease recurrence was observed in 19 patients (10%). Eleven patients died of disease. LVSI influenced progression-free survival (PFS) (HR 3.950, p = 0.0163) and disease-specific survival (DSS) (HR 4.637, p = 0.0497) significantly. However, the combination of LVSI, tumor size and DSI according to Sedlis did not influence overall survival (OS), DSS or PFS. CONCLUSION: Recurrence rate was low (10%), despite the fact that patients with intermediate risk factors according to Sedlis did not receive postoperative RT/CCRT. LVSI was the sole risk factor influencing PFS and DSS. Combinations of risk factors according to Sedlis did not predict worse outcome.

Comprehensive immunomolecular profiling of endometrial carcinoma: A tertiary retrospective study.

OBJECTIVE: Combined immunohistochemical and molecular classification using the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) independently predicts prognosis in endometrial carcinoma (EC). As next-generation sequencing (NGS) is entering clinical practice, we evaluated whether more comprehensive immunomolecular profiling (CIMP), including NGS and extended immunohistochemical analysis, could further refine the current ProMisE classification. METHODS: A series of 120 consecutive ECs, classified according to ProMisE, was stained immunohistochemically for CD3, CD8, PD-L1, beta-catenin and L1CAM. An in-house 96 gene NGS panel was performed on a subset of 44 ECs, representing the 4 ProMisE subgroups (DNA polymerase epsilon catalytic subunit exonuclease domain mutated (POLEmut), mismatch repair deficient (MMRd), p53 abnormal (p53 abn) and no specific molecular profile (NSMP) ECs). Cases harboring non-hotspot POLE variants were analyzed with Illumina TruSight Oncology 500 NGS panel (TSO500) as a surrogate for whole-exome sequencing. RESULTS: Eight cases harbored POLE variants, half of which were hotspots. Using TSO500, non-hotspot POLE variants were classified as pathogenic (3) or variant of unknown significance (1). POLEmut and MMRd ECs typically showed higher numbers of CD3+/CD8+ tumor-infiltrating lymphocytes and higher PD-L1 expression in tumor-infiltrating immune cells. p53 abn ECs showed significantly higher L1CAM immunoreactivity and frequently harbored gene amplifications including HER2 (25%), but typically lacked ARID1A or PTEN variants. Beta-catenin-positivity and FGFR2 variants were predominantly found in NSMP ECs. CONCLUSIONS: Our data show that CIMP adds significant value to EC characterization and may help to determine pathogenicity of non-hotspot POLE variants, encountered more frequently than expected in our series. In addition, CIMP may reveal ECs benefitting from immune checkpoint inhibition and allows upfront identification of targetable alterations, such as HER2 amplification in p53 abn ECs.

Experience with PlasmaJet™ in debulking surgery in 87 patients with advanced-stage ovarian cancer.

OBJECTIVE: The aim was to evaluate the effectiveness and safety of PlasmaJet™ in cytoreductive surgery in patients with advanced-stage ovarian cancer. METHODS: All patients between September 2013 and January 2018 undergoing surgical cytoreduction for advanced-stage ovarian cancer with the help of PlasmaJet™ were identified and analyzed retrospectively. RESULTS: Eighty-seven patients diagnosed with advanced-stage ovarian cancer underwent surgery with PlasmaJet™. Primary debulking surgery was performed in 15 cases. Fifty-seven patients underwent interval debulking after neoadjuvant chemotherapy. Secondary and tertiary debulking was done in, respectively, 11 and three patients, and one patient underwent quaternary debulking using PlasmaJet™. In all 87 patients but one, complete resection of all macroscopic disease was obtained. PlasmaJet™ was used to remove carcinomatosis on the peritoneum, bowel serosa, intestinal mesentery, and lesions in the upper abdomen (diaphragm and liver surface). No damage to the bladder or ureter was noted in relation to the use of PlasmaJet™. Three patients developed a bowel leakage postoperatively. In one of these patients, PlasmaJet™ was used to treat tumoral implants in the affected region. CONCLUSIONS: Our series suggests that the use of PlasmaJet™ is efficient and safe in obtaining complete resection of all macroscopic tumoral lesions in advanced-stage ovarian cancer.

Combination of weekly paclitaxel-carboplatin plus standard bevacizumab as neoadjuvant treatment in stage IB-IIB cervical cancer.

OBJECTIVE: In this study we investigated response rates of bevacizumab in addition to weekly paclitaxel and carboplatin in neoadjuvant setting in cervical cancer stage IB-IIB. METHODS: In this retrospective study we included patients with FIGO 2018 stage IB-IIB cervical cancer. Treatment consisted of 9 weeks' neoadjuvant paclitaxel and carboplatin (paclitaxel 60 mg/m2, carboplatin AUC 2.7; both weekly) and bevacizumab (15 mg/kg every 3 weeks). The radiologic response rate was analyzed using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. The definition of optimal pathological response was complete disappearance of tumor (complete response, pCR) or residual disease with less than 3 mm stromal invasion (pPR1). Suboptimal pathologic response (pPR2) was defined as persistent residual disease with more than 3 mm stromal invasion. RESULTS: A total of 30 patients were included. Six patients had FIGO 2018 stage IB1-IB2 (20%), one had stage IB3 (3%), five had stage IIA (17%), and 18 had stage IIB (60%). After completing the neoadjuvant chemotherapy, all patients showed a RECIST response (seven (23%) complete response; 23 (77%) partial response). Six patients (20%) were judged to be still inoperable. After radical hysterectomy, optimal pathological response was observed in 11 patients (38%) (pCR in nine patients (29%) and pPR1 in two patients (8%)). Six patients (20%) received postoperative adjuvant chemoradiotherapy. Hematological toxicity was similar to neoadjuvant weekly paclitaxel and carboplatin, as we reported earlier. Grade IV proteinuria or hypertension was not observed and no administration of bevacizumab was delayed or dose-reduced. CONCLUSION: Bevacizumab in addition to weekly paclitaxel and carboplatin showed a 100% radiological RECIST response and an optimal pathological response of 38%. Although bevacizumab has an established role in the treatment of recurrent cervical cancer in combination with paclitaxel and carboplatin, we did not observe a tendency toward superior effect on the pathological response rate of bevacizumab in the neoadjuvant chemotherapy setting.

Impact of clinical factors and surgical outcome on long-term survival in high-grade serous ovarian cancer: a multicenter analysis.

INTRODUCTION: Long-term survivors of ovarian cancer are a unique group of patients in whom prognostic factors for long-term survival have been poorly described. Such factors may provide information for a more personalized therapeutic approach. The objective of this study is to determine further characteristics of long-term survivors with high-grade serous ovarian cancer. METHODS: Long-term survivors were defined as patients living longer than 8 years after first diagnosis and were recruited within seven high volume centers across Europe from November 1988 to November 2008. The control group included patients with high-grade serous ovarian cancer with less than 5 years' survival identified from the systematic 'Tumorbank ovarian cancer' database. A subanalysis of Charité patients only was performed separately for in-depth analysis of tumor dissemination. Propensity score matching with nearest-neighbor caliper width was used to match long-term survivors and the control group regarding age, FIGO stage, and residual tumor. RESULTS: A total of 276 patients with high-grade serous ovarian cancer were included, divided into 131 long-term survivors and 145 control group patients. After propensity score matching and multivariable adjustment, platinum sensitivity (p=0.002) was an independent favorable prognostic factor whereas recurrence (p<0.001) and ascites (p=0.021) were independent detrimental predictors for long-term survival. Significantly more long-term survivors tested positive for mutation in the BRCA1 gene than the BRCA2 gene (p=0.016). Intraoperatively, these patients had less tumor involvement of the upper abdomen at initial surgery (p=0.024). Complexity of surgery and surgical techniques were similar in both cohorts. CONCLUSION: Platinum sensitivity constitutes a favorable factor for long-term survival whereas tumor involvement of the upper abdomen, ascites, and recurrence have a negative impact. Based on clinical estimation, long-term survival is associated with combinations of clinical, surgical, and molecular factors.

Para-aortic lymph node surgical staging in locally-advanced cervical cancer: comparison between robotic versus conventional laparoscopy.

OBJECTIVE: With the expansion of the use of minimally invasive surgical techniques within the field of gynecological oncology, a robot assisted procedure seems to be an attractive technique for para-aortic lymph node sampling. The aim of this study was to compare robotic versus conventional laparoscopic para-aortic lymphadenectomy in patients with locally advanced cervical cancer. METHODS: In this monocentric retrospective study, we included patients with locally-advanced cervical cancer (International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2-IVA or IB1 with suspicious pelvic lymph nodes), who underwent a para-aortic lymphadenectomy up to the inferior mesenteric artery between December 1994 and December 2016 (robotic technique starting from December 2012). RESULTS: A total of 217 patients were included in the study (robotic, n=55 vs laparoscopic, n=162). When comparing conventional laparoscopic versus robotic para-aortic lymphadenectomy, the median age was 48 versus 49 years and the median body mass index was 24.4 vs 24.7 kg/m2, respectively. In the robotic or laparoscopic group, 85% and 83% were squamous carcinomas, respectively. Patients who underwent a robotic procedure had a higher American Society of Anesthesiologists (ASA) score (ASA2: 62% vs 56%, ASA3: 20% vs 2%, p<0.001), more prior major abdominal surgery (18% vs 6%, p=0.016), less estimated blood loss (median, 25 mL vs 62.5 mL, p<0.001), more para-aortic lymph nodes removed (11 vs 6, p<0.001), shorter postoperative stay (1.8 vs 2.3 days, p=0.002), and a higher, but non-significant, rate of metastatic para-aortic lymph nodes (13% vs 5%, p=0.065) compared with the laparoscopic procedure, respectively. There was no difference in complication rates between the two approaches. The most frequent complications were grade I and grade II according to the Clavien Dindo classification. No difference was observed in progression-free survival between robotic and laparoscopic para-aortic lymphadenectomy after 2 years (both groups 66%) (p=0.472). Also, 2 year overall survival was similar between the groups (77% vs 81% for robotic vs conventional laparoscopy group, respectively) (p=0.749). CONCLUSION: Robotic para-aortic lymphadenectomy in patients with locally-advanced cervical cancer resulted in better perioperative outcomes and similar survival outcomes when compared with a conventional laparoscopic approach.

Atezolizumab in combination with bevacizumab and chemotherapy versus bevacizumab and chemotherapy in recurrent ovarian cancer - a randomized phase III trial (AGO-OVAR 2.29/ENGOT-ov34).

BACKGROUND: Improvement in clinical outcomes of patients with platinum-resistant disease is an unmet medical need and trials in this population are urgently needed. Checkpoint-inhibitors have already shown activity in multiple other tumor entities and ovarian cancer, especially in the combination with anti-angiogenic treatment. PRIMARY OBJECTIVE: To test if the activity of non-platinum-based chemotherapy and bevacizumab could be improved by the addition of atezolizumab. STUDY HYPOTHESIS: The addition of atezolizumab to standard non-platinum combination of chemotherapy and bevacizumab improves median overall survival from 15 to 20 months. TRIAL DESIGN: Patients are randomized to chemotherapy (paclitaxel weekly or pegylated liposomal doxorubicin) + bevacizumab + placebo vs chemotherapy + bevacizumab + atezolizumab. Stratification factors are: number of prior lines, planned type of chemotherapy, prior use of bevacizumab, and tumor programmed death-ligand 1 (PD-L1) status. MAJOR INCLUSION/EXCLUSION CRITERIA: Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer with up to three prior therapies and a treatment-free interval after platinum of less than 6 months. Patients with three prior lines of chemotherapy are eligible irrespective of the platinum free-interval. A de novo tumor tissue sample biopsy for determination of PD-L1 status prior to randomization for stratification is mandatory. Major exclusion criteria consider bevacizumab-specific and immunotherapy-specific criteria. PRIMARY ENDPOINT: Overall survival and progression-free survival are co-primary endpoints. SAMPLE SIZE: It is planned to randomize 664 patients. TRIAL REGISTRATION: NCT03353831.

The association between weight at birth and breast cancer risk revisited using Mendelian randomisation.

Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10-8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73-1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study.

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study.

BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Morphology and tumour-infiltrating lymphocytes in high-stage, high-grade serous ovarian carcinoma correlated with long-term survival.

AIMS: Advanced-stage ovarian high-grade serous carcinoma (HGSC) is a poor-prognosis cancer; however, a small and poorly characterised subset of patients shows long-term survival. We aimed to establish a cohort of HGSC long-term survivors for histopathological and molecular analysis. METHODS AND RESULTS: Paraffin blocks from 151 patients with primary FIGO III/IV HGSC and progression-free survival (PFS) >5 years were collected within the Tumorbank Ovarian Cancer (TOC) Network; 77 HGSC with a PFS <3 years were used as a control group. A standardised analysis of histological type and morphological features was performed. Ki67 index, tumour-infiltrating lymphocytes (TILs) and major histocompatibility complex expression (MHC1/2) were determined by immunohistochemistry. A total of 117 of 151 tumours (77.5%) in the long-term survivor group fulfilled the World Health Organisation (WHO) criteria of HGSC after review, and of these, 83 patients (70.9%) fulfilled all clinical criteria for inclusion into our cohort. Tumours of long-term survivors had significantly higher CD3+ and CD8+ TILs and were more frequently positive for MHC2 than controls (P = 0.004, P = 0.025, P = 0.048). However, there were also long-term survivors (up to 20%) with low TILs or low MHC expression. TILs and MHC had no impact on survival in long-term survivors. Morphological and Ki67 analysis revealed no differences between long-term survivors and controls. CONCLUSIONS: HGSC from long-term survivors have higher-level T cell infiltration and antigen-presentation capacity; however, this is not a prerequisite for an excellent prognosis. Histopathological criteria are not capable to identify these patients. Further extensive clinical and molecular characterisation of this enigmatic subgroup is ongoing to understand the reasons of long-term survival in HGSC.

Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma: Results of the INNOVATE pilot study.

BACKGROUND: Tumor Treating Fields (TTFields) are an anti-mitotic therapy comprising continuous delivery of low-intensity alternating electric fields at intermediate frequencies to the tumor region by a home-use medical device. METHODS: The INNOVATE (EF-22) Study was a phase 2, single arm clinical trial, which tested the safety and efficacy of TTFields (200 kHz) in combination with weekly paclitaxel (weekly for 8 weeks and then on days 1, 8, 15 of each subsequent 28 day-cycle; starting dose 80 mg/m2) in 31 patients with recurrent, platinum-resistant ovarian carcinoma. The primary endpoint was safety and secondary endpoints included OS, PFS and RR. RESULTS: Median age was 60 (range: 45-77), 24 patients (77%) had serous histology, 16 patients (52%) ECOG score 0 and 15 (48%) ECOG 1, the median number of prior chemotherapy lines was 4 (range: 1-11). All patients received prior platinum-based chemotherapy and 30 (97%) received prior taxanes. No serious adverse events related to TTFields were reported. There was no increase in grade 3-4 adverse events compared to the frequency of such events reported in the literature with single agent weekly paclitaxel. Twenty-six patients (84%) had the expected TTFields-related dermatitis but only one patient permanently discontinued TTFields due to dermatitis. The median PFS was 8.9 months, 7 patients (25%) had partial response and the clinical benefit rate was 71%. The median overall survival was not reached: the one-year survival rate was 61%. CONCLUSION: TTFields combined with weekly paclitaxel were safe in platinum-resistant recurrent ovarian cancer and warrants evaluation in a randomized phase 3 trial.