Health-related quality of life in patients with newly diagnosed advanced ovarian cancer treated with niraparib vs placebo: Results from the phase 3 randomized PRIMA/ENGOT-OV26/GOG-3012 trial.

OBJECTIVE: To assess patient-reported health-related quality of life (HRQoL) in patients with ovarian cancer (OC) who received niraparib as first-line maintenance therapy. METHODS: PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) enrolled patients with newly diagnosed advanced OC who responded to first-line platinum-based chemotherapy. Patients were randomized (2:1) to niraparib or placebo once daily in 28-day cycles until disease progression, intolerable toxicity, or death. HRQoL was assessed as a prespecified secondary end point using patient-reported responses to the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30), the EORTC QLQ Ovarian Cancer Module (EORTC QLQ-OV28), the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), and EQ-5D-5L questionnaires. Assessments were collected at baseline and every 8 weeks (±7 days) for 56 weeks, beginning on cycle 1/day 1, then every 12 weeks (±7 days) thereafter while the patient received study treatment. RESULTS: Among trial participants (niraparib, n = 487; placebo, n = 246), PRO adherence exceeded 80% for all instruments across all cycles. Patients reported no decline over time in HRQoL measured via EORTC QLQ-C30 Global Health Status/QoL and FOSI overall scores. Scores for abdominal/gastrointestinal symptoms (EORTC QLQ-OV28) and nausea and vomiting, appetite loss, and constipation (EORTC QLQ-C30) were higher (worse symptoms) in niraparib-treated patients than placebo-treated patients; except for constipation, these differences resolved over time. Patients did not self-report any worsening from baseline of fatigue, headache, insomnia, or abdominal pain on questionnaires. CONCLUSIONS: Despite some early, largely transient increases in gastrointestinal symptoms, patients with OC treated with niraparib first-line maintenance therapy reported no worsening in overall HRQoL.

A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer.

OBJECTIVE: This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. METHODS: Patients with histologic diagnosis of endometrial cancer (1-2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2-4, 9-11, 16-18, and 23-25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1-3, 8-10, 15-17, and 22-24. RESULTS: Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58-1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43-1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. CONCLUSIONS: Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02725268.

European multidisciplinary tumor boards support cross-border networking and increase treatment options for patients with rare gynecological tumors.

OBJECTIVE: To evaluate outcomes of European cross-border multidisciplinary tumor boards in terms of participation, adherence to treatment recommendations, and access to novel treatment strategies. METHODS: The European reference network for rare gynecological tumors (EURACAN G2 domain) aims to improve the diagnosis, management, and treatment of patients with these cancers. Cross-border multidisciplinary tumor boards were initiated to facilitate intercollegiate clinical discussions across Europe and increase patients' access to specialist treatment recommendations and clinical trials. All G2 healthcare providers were invited to participate in monthly multidisciplinary meetings. Patient data were collected using a standardized form and case summaries were distributed before each meeting. After each tumor board, a meeting summary with treatment recommendations was sent to all participants and the project manager at the coordinating center. The multidisciplinary tumor board format and outcomes were regularly discussed at G2 domain meetings. Anonymized clinical data and treatment recommendations were registered in a prospective database. For this report, clinical data were collected between November 2017 and December 2020 and follow-up data retrieved until May 2021. RESULTS: During the 3-year period, 31 multidisciplinary tumor boards were held with participants from 10 countries and 20 centers. 91 individual patients were discussed between one and six times for a total of 109 case discussions. Follow-up data were retrieved from 64 patients and 80 case discussions. Adherence to treatment recommendations was 99%. Multidisciplinary tumor board recommendations resulted in 11 patients getting access to off-label treatment and one patient being enrolled in a clinical trial in another European country. 14/91 patients were recommended for surveillance only when additional treatment had been considered locally. CONCLUSION: Cross-border multidisciplinary tumor boards enable networking and clinical collaboration between healthcare professionals in different countries. Surveillance strategies, off-label drug use, and increased participation in clinical trials are possible benefits to patients with rare gynecological tumors.

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.

Impact of disease progression on health-related quality of life of advanced ovarian cancer patients - Pooled analysis from the PRIMA trial.

OBJECTIVE: Progression-free survival (PFS) is an important early efficacy endpoint in ovarian cancer (OC) and its relevance to patients should be assessed. PRIMA, a phase III trial, assessed niraparib in patients with OC; this post hoc analysis examined the relationship between disease progression in OC and health-related quality of life (HRQoL). METHODS: The PRIMA trial randomized patients with advanced OC responsive to first-line platinum-based chemotherapy to once daily maintenance oral niraparib or placebo. This post hoc analysis evaluated the impact of disease progression on HRQoL by comparing HRQoL at the last visit pre-progression to end of treatment (EoT), and after 4, 8, 12, and 24 weeks. Assessments included the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), the European Quality of Life Five Dimension Five Level questionnaire (EQ-5D-5L) and EQ Visual Analogue Scale (EQ-VAS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC-QLQ-C30), and the EORTC Quality of Life Questionnaire Ovarian Cancer module (EORTC-QLQ-OV28). RESULTS: This post hoc analysis included 733 patients. Mean FOSI, EQ-5D-5L, and EQ-VAS scores deteriorated from last visit pre-progression to EoT and remained low up to 24-week follow-up. Least squares mean changes from last visit pre-progression to EoT were -2.1 (95% confidence interval -2.4, -1.7) for FOSI, -4.6 (-5.6, -3.5) for the EQ-5D-5L index, and -7.9 (-9.6, -6.3) for EQ-VAS. CONCLUSIONS: Disease progression negatively impacted HRQoL in patients with OC. PFS is clinically relevant, and prolonging PFS may preserve HRQoL.

Importance of pathological review of gestational trophoblastic diseases: results of the Belgian Gestational Trophoblastic Diseases Registry.

OBJECTIVE: To evaluate the added value of a centralized pathology review of the diagnoses of gestational trophoblastic diseases by expert pathologists and its potential impact on clinical management in a prospective multicenter study based on the Belgian Gestational Trophoblastic Diseases Registry. METHODS: From July 2012 to December 2020, the two referral centers of the registry were solicited to advise on 1119 cases. Referral pathologists systematically reviewed all of the initial histological diagnoses. Cases initially assessed by expert pathologists were excluded. A total of 867 files were eligible for the study. Concordance between diagnoses of gestational trophoblastic diseases made by general 'non-expert' and expert pathologists was analyzed together with the potential impact of the alterations on clinical management. Expert pathologists were working in an academic setting with high exposure to placental pathology and national recognition. RESULTS: The rate of discordance between expert and non-expert pathologists for the initial diagnoses was 35%. Almost 95% of complete moles were confirmed by the expert pathologists, but only 61% for partial moles. Compared with previous studies, ancillary techniques (p57 immunohistochemistry, karyotype) were used twice as often by both groups of pathologists in this survey. The diagnosis of gestational trophoblastic neoplasia was altered in 42% of cases. When the initial diagnosis was altered, the clinical relevance of this correction was estimated as down staging, up staging, or not relevant in 65%, 33% and 2% of cases respectively. CONCLUSION: Systematic centralized pathological review of gestational trophoblastic diseases modified the diagnosis in a third of cases. The results also show that a change in diagnosis would impact clinical management in 98% of patients.

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.

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.

Subspecialty training in Europe: a report by the European Network of Young Gynaecological Oncologists.

BACKGROUND: ESGO (European Society of Gynaecological Oncology) and partners are continually improving the developmental opportunities for gynaecological oncology fellows. The objectives of this survey were to evaluate the progress in the infrastructure of the training systems in Europe over the past decade. We also evaluated training and assessment techniques, the perceived relevance of ENYGO (European Network of Young Gynaecological Oncologists) initiatives, and unmet needs of trainees. METHODOLOGY: National representatives of ENYGO from 39 countries were contacted with an electronic survey. A graduation in well/moderately/loosely-structured training systems was performed. Descriptive statistical analysis and frequency tables, as well as two-sided Fisher's exact test, were used. RESULTS: National representatives from 33 countries answered our survey questionnaire, yielding a response rate of 85%. A national fellowship is offered in 22 countries (66.7%). A logbook to document progress during training is mandatory in 24 (72.7%) countries. A logbook of experience is only utilized in a minority of nations (18%) for assessment purposes. In 42.4% of countries, objective assessments are recognized. Trainees in most countries (22 (66.7%)) requested additional training in advanced laparoscopic surgery. 13 (39.4%) countries have a loosely-structured training system, 11 (33.3%) a moderately-structured training system, and 9 (27.3%) a well-structured training system. CONCLUSION: Since the last publication in 2011, ENYGO was able to implement new activities, workshops, and online education to support training of gynaecological oncology fellows, which were all rated by the respondents as highly useful. This survey also reveals the limitations in establishing more accredited centers, centralized cancer care, and the lack of laparoscopic training.

Behavior of metastatic breast cancer according to subtype.

PURPOSE: To explore the impact of breast cancer subtype on metastatic behavior and long-term outcome defined as breast cancer specific survival (BCSS). METHODS: Retrospective single centre cross-sectional study of 5972 patients with newly diagnosed, unilateral first diagnosis of breast cancer, diagnosed 2000-2010. Patients had either early breast cancer (EBC) treated primarily by surgery (SURG n = 5072), neoadjuvant systemic therapy (NEO n = 592), or upfront metastatic disease (META n = 308). Surrogate breast cancer subtypes were defined according to classical pathological criteria. Analysis was performed using Kaplan-Meier method and logistic/Cox regression. RESULTS: After median follow-up time of 103.6 months (IQR 73.4-139.2 months), 817 patients with EBC at diagnosis (14.4%) developed distant metastases of which 621 (12.2%) SURG and 196 (33.1%) NEO. Metastasis rate after EBC was: LuminalA 8.1%, LuminalB1(HER2-) 20.4%, LuminalB2(HER2+) without (neo)adjuvant trastuzumab 21.7%, LuminalB2(HER2+) with trastuzumab 9.0%, HER2Positive(ER-) without trastuzumab 30.0%, HER2Positive(ER-) with trastuzumab 19.9% and TripleNegative 25.3%. There were major differences in site of first metastases according to subtype. For single site first metastases, median BCSS assessed from time of metastases was worst for brain localization (13.9 months) and best for bone (48.4 months). Multiple sites of first metastases had worse BCSS from date of metastases than single site first metastases (median BCSS for 1 site 40.0, 2 sites 27.1, ≥ 3 sites 20.5 months). Median BCSS from date of metastases is longer in upfront metastases compared to secondary metastases after EBC (43.4 vs. 27.9 months). CONCLUSIONS: Tumor subtype influences the metastatic behavior and survival after development of distant metastases.

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.

Characteristics of patients with cervical cancer during pregnancy: a multicenter matched cohort study. An initiative from the International Network on Cancer, Infertility and Pregnancy.

BACKGROUND: Treatment of cervical cancer during pregnancy is often complex and challenging. This study aimed to analyze current patterns of practice in the management of pregnant patients diagnosed with cervical cancer. METHODS: This was a matched cohort study comprising patients managed for cervical cancer during pregnancy from six European centers. Patient information was retrieved from the dataset of the International Network for Cancer, Infertility and Pregnancy from 1990 to 2012. Each center matched its patients with two non-pregnant controls for age (±5 years) and International Federation of Gynecology and Obstetrics (FIGO) 2009 stage. Information on age, histological type, grade, lymphovascular space invasion, stage, tumor size, method of diagnosis, site of recurrence, delivery, date of recurrence, and date of death was recorded. Progression-free survival was compared using multivariable Cox proportional hazards regression. RESULTS: A total of 132 pregnant patients and 256 controls were analyzed. The pregnant patients (median age 34 years, range 21-43) were diagnosed at a median gestational age of 18.4 weeks of pregnancy (range 7-39). Stage distribution during pregnancy was 14.4% for stage IA, 47.0% for IB1, 18.9% for IB2, and 19.7% for II-IV. For treatment during pregnancy, 17.4% of the patients underwent surgery, 16.7% received neoadjuvant chemotherapy, 26.5% delayed their treatment, 12.9% had a premature delivery, and 26.5% had their pregnancy terminated. Median follow-up was 84 months (67 months for pregnant and 95 months for non-pregnant patients). The unadjusted hazard ratio of pregnancy for progression-free survival was 1.18 (95% confidence interval 0.74 to 1.88). CONCLUSION: Surgery and chemotherapy is increasingly used in the management of pregnant patients with cervical cancer and prognosis is similar to that of non-pregnant patients.

Oncological management and obstetric and neonatal outcomes for women diagnosed with cancer during pregnancy: a 20-year international cohort study of 1170 patients.

BACKGROUND: Awareness is growing that cancer can be treated during pregnancy, but the effect of this change on maternal and neonatal outcomes is unknown. The International Network on Cancer, Infertility and Pregnancy (INCIP) registers the incidence and maternal, obstetric, oncological, and neonatal outcomes of cancer occurring during pregnancy. We aimed to describe the oncological management and obstetric and neonatal outcomes of patients registered in INCIP and treated in the past 20 years, and assess associations between cancer type or treatment modality and obstetric and neonatal outcomes. METHODS: This descriptive cohort study included pregnant patients with cancer registered from all 37 centres (from 16 countries) participating in the INCIP registry. Oncological, obstetric, and neonatal outcome data of consecutive patients diagnosed with primary invasive cancer during pregnancy between Jan 1, 1996, and Nov 1, 2016, were retrospectively and prospectively collected. We analysed changes over time in categorical patient characteristics, outcomes, and treatment methods with log-binomial regression. We used multiple logistic regression to analyse preterm, prelabour rupture of membranes (PPROM) or preterm contractions, small for gestational age, and admission to the neonatal intensive care unit (NICU). The INCIP registry study is registered with ClinicalTrials.gov, number NCT00330447, and is ongoing. FINDINGS: 1170 patients were included in the analysis and 779 (67%) received treatment during pregnancy. Breast cancer was the most common malignant disease (462 [39%]). Every 5 years, the likelihood of receiving treatment during pregnancy increased (relative risk [RR] 1·10, 95% CI 1·05-1·15), mainly related to an increase of chemotherapeutic treatment (1·31, 1·20-1·43). Overall, 955 (88%) of 1089 singleton pregnancies ended in a livebirth, of which 430 (48%) of 887 pregnancies ended preterm. Each 5 years, we observed more livebirths (RR 1·04, 95% CI 1·01-1·06) and fewer iatrogenic preterm deliveries (0·91, 0·84-0·98). Our data suggest a relationship between platinum-based chemotherapy and small for gestational age (odds ratio [OR] 3·12, 95% CI 1·45-6·70), and between taxane chemotherapy and NICU admission (OR 2·37, 95% CI 1·31-4·28). NICU admission seemed to depend on cancer type, with gastrointestinal cancers having highest risk (OR 7·13, 95% CI 2·86-17·7) and thyroid cancers having lowest risk (0·14, 0·02-0·90) when compared with breast cancer. Unexpectedly, the data suggested that abdominal or cervical surgery was associated with a reduced likelihood of NICU admission (OR 0·30, 95% CI 0·17-0·55). Other associations between treatment or cancer type and outcomes were less clear. INTERPRETATION: Over the years, the proportion of patients with cancer during pregnancy who received antenatal treatment increased, especially treatment with chemotherapy. Our data indicate that babies exposed to antenatal chemotherapy might be more likely to develop complications, specifically small for gestational age and NICU admission, than babies not exposed. We therefore recommend involving hospitals with obstetric high-care units in the management of these patients. FUNDING: Research Foundation-Flanders, European Research Council, Charles University, Ministry of Health of the Czech Republic.

Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy.

BACKGROUND: Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking. METHODS: In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months. RESULTS: A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings. CONCLUSIONS: Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; ClinicalTrials.gov number, NCT00330447.).

Influence of CA125, platelet count and neutrophil to lymphocyte ratio on the immune system of ovarian cancer patients.

OBJECTIVE: The effect of CA125, neutrophil to lymphocyte ratio (NLR) and thrombocytosis on survival has been studied in ovarian cancer. This study explores the link between these variables and serum markers of ovarian cancer patients, such as signaling proteins and cytokines. METHODS: Serum samples of 39 patients with high-grade serous ovarian cancer (HGSOC) were collected at diagnosis and were retrospectively analysed for clinical characteristics, clinical parameters (NLR, CA125, platelet count) and immune profile [IL-4 (interleukin), IL-10, IL-13, IL-17, transforming growth factor-ß, Arginase-1, Interferon gamma), vascular endothelial growth factor (VEGF), galectin-1 and chemokine (C-C) motif ligand 2. RESULTS: CA125 correlates negatively with VEGF (p = 0.02) and if CA125 rises above 500 kU/L, IL-10 is significantly increased (p = 0.01). NLR > 6 (p < 0.01) was significantly correlated with decreased overall survival. Thrombocytosis was significantly correlated with IL-10 (p < 0.01) and a platelet count > 400 × 109/l led to an improvement in progression free survival (p < 0.01). CONCLUSIONS: A correlation, at the time of diagnosis, of HGSOC between CA125, NLR and thrombocytes and an immunosuppressive cytokine-profile in serum is shown, and correlates with survival.

The genetic landscape of 87 ovarian germ cell tumors.

BACKGROUND: Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized. METHODS: We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape. RESULTS: The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas. CONCLUSION: We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT.