Germline BRCA1/2-associated epithelial ovarian cancer has been associated with better progression-free survival and overall survival than sporadic epithelial ovarian cancer, but conclusive data are ...lacking. We matched 389 BRCA1-associated and 123 BRCA2-associated epithelial ovarian cancer patients 1:1 to sporadic epithelial ovarian cancer patients on year of birth, year of diagnosis, and FIGO stage ( = IIB). Germline DNA test was performed before or after epithelial ovarian cancer diagnosis. All patients received chemotherapy. We used Cox proportional hazards models to estimate the associations between mutation status (BRCA1 or BRCA2 versus sporadic) and progression-free survival and overall survival. To investigate whether DNA testing after epithelial ovarian cancer diagnosis resulted in survival bias, we performed additional analyses limited to BRCA1/2-associated epithelial ovarian cancer patients with a DNA test result before cancer diagnosis (n = 73 BRCA1; n = 9 BRCA2) and their matched sporadic controls. The median follow-up was 4.4 years (range 0.1-30.1). During the first three years after epithelial ovarian cancer diagnosis, progression-free survival was better for BRCA1 (HR 0.88, 95% CI 0.74-1.04) and BRCA2 (HR 0.58, 95% CI 0.41-0.81) patients than for sporadic patients. Overall survival was better during the first six years after epithelial ovarian cancer for BRCA1 (HR 0.7, 95% CI 0.58-0.84) and BRCA2 (HR 0.41, 95% CI 0.29-0.59) patients. After surviving these years, survival benefits disappeared or were in favor of the sporadic patients. For epithelial ovarian cancer patients who received chemotherapy, we confirmed survival benefit for BRCA1 and BRCA2 germline pathogenic variant carriers. This may indicate higher sensitivity to chemotherapy, both in first line treatment and in the recurrent setting. The observed benefit appears to be limited to a relatively short period after epithelial ovarian cancer diagnosis.
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.
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.
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.
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.
Research Foundation—Flanders, European Research Council, Charles University, Ministry of Health of the Czech Republic.
(1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients' monitoring. However, the best ways to analyze its decline and prognostic role are ...poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% 0.70; 0.80 at 24 and 36 months and 0.74 0.69; 0.80 and 0.75 0.69; 0.80 at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 0.68; 0.78 at 24 months and 0.71 0.65; 0.76 at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy.
To determine the clinical benefit of monotherapy with PI3K/AKT/mTOR inhibitors in patients diagnosed with advanced or recurrent ovarian cancer and to investigate the predictive value of current ...PI3K/AKT/mTOR biomarkers on therapy response.
A systematic search was conducted in PubMed, Embase and the Cochrane Library for articles reporting on treatment with PI3K/AKT/mTOR inhibitors in ovarian cancer. The primary endpoint was defined as the clinical benefit rate (CBR), including the proportion of patients with complete (CR) and partial response (PR) and stable disease (SD). Secondary endpoints included the overall response rate (ORR, including CR and PR) and drug-related grade 3 and 4 adverse events.
We included 233 patients from 19 studies and observed a pooled CBR of 32% (95% CI 20–44%) and ORR of 3% (95% CI 0–6%) in advanced or recurrent ovarian cancer patients treated with PI3K/AKT/mTOR inhibitors. Subgroup analysis tended to favor the studies who selected patients based on current PI3K/AKT/mTOR biomarker criteria (e.g. genomic alterations or loss of PTEN protein expression), but the difference in CBR was not statistically significant from studies with unselected populations (respectively, CBR of 42% (95% CI 23–62%) and 27% (95% CI 14–42%), P = 0.217). To better reflect true patient benefit, we excluded SD <6 months as a beneficial outcome which resulted in a pooled CBR of 7% (95% CI 2–13%). The overall proportion of patients with drug-related grade 3 and 4 adverse events was 36%.
The efficacy of monotherapy with PI3K/AKT/mTOR inhibitors in advanced recurrent ovarian cancer patients is limited to a small subgroup and selection of patients with the use of current biomarkers did not improved the CBR significantly. Given the toxicity profile, we suggest that current treatment with PI3K/AKT/mTOR inhibitors should not be initiated unless in clinical trials. Furthermore, improved biomarkers to measure functional PI3K/AKT/mTOR pathway activity are needed to optimize patient selection.
•Monotherapy with PI3K/AKT/mTOR inhibitors resulted in a pooled CBR of 32% and ORR of 3% in ovarian cancer patients.•Exclusion of stable disease for a period below 6 months as a beneficial outcome measure reduced the pooled CBR to 7%.•Drug-related grade 3 and 4 toxicities occurred in 36% (range 0–80%) of the patients.•Current PI3K/AKT/mTOR biomarkers insufficiently predict therapy response indicating the need for improved biomarker assays.•Combined treatments regimes targeting two signaling pathways may provide favorable outcomes over single agent therapy.
To investigate the prevalence of and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic
-pathogenic variant (PV) ...carriers.
We included
-PV carriers who underwent RRSO between 1995 and 2018 from the Hereditary Breast and Ovarian cancer in the Netherlands study. All pathology reports were screened, and histopathology reviews were performed for RRSO specimens with epithelial abnormalities or where HGSC developed after normal RRSO. We then compared clinical characteristics, including parity and oral contraceptive pill (OCP) use, for women with and without HGSC at RRSO.
Of the 2,557 included women, 1,624 had
, 930 had
, and three had both
-PV. The median age at RRSO was 43.0 years (range: 25.3-73.8) for
-PV and 46.8 years (27.6-77.9) for
-PV carriers. Histopathologic review confirmed 28 of 29 HGSCs and two further HGSCs from among 20 apparently normal RRSO specimens. Thus, 24 (1.5%)
-PV and 6 (0.6%)
-PV carriers had HGSC at RRSO, with the fallopian tube identified as the primary site in 73%. The prevalence of HGSC in women who underwent RRSO at the recommended age was 0.4%. Among
PV carriers, older age at RRSO increased the risk of HGSC and long-term OCP use was protective.
We detected HGSC in 1.5% (
-PV) and 0.6% (
-PV) of RRSO specimens from asymptomatic
-PV carriers. Consistent with the fallopian tube hypothesis, we found most lesions in the fallopian tube. Our results highlight the importance of timely RRSO with total removal and assessment of the fallopian tubes and show the protective effects of long-term OCP.
A diagnosis of breast cancer during pregnancy (PrBC) does not impact prognosis if standard treatment is offered. However, caution is warranted as gestational changes in pharmacokinetics may lead to ...reduced chemotherapy concentration.
Survival of PrBC patients treated with chemotherapy during pregnancy was compared to non-pregnant breast cancer patients treated with chemotherapy, diagnosed after 2000, excluding patients older than 45 years or with a postpartum diagnosis. The data was registered in two multicenter registries (the International Network of Cancer, Infertility and Pregnancy and the German Breast Group). Cox proportional hazards regression was used to compare disease-free (DFS) and overall survival (OS) between both groups, adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status and histology, weighted by propensity scoring to account for the differences in baseline characteristics between pregnant patients and controls.
In total, 662 pregnant and 2081 non-pregnant patients were selected. Pregnant patients were more likely to have stage II breast cancer (60.1% vs 56.1%, p = 0.035), grade 3 tumors (74.0% vs 62.2%, p < 0.001), hormone receptor-negative tumors (48.4% vs 34.0%, p < 0.001) or triple-negative breast cancer (38.9% vs 26.9%, p < 0.001). Median follow-up was 66 months. In multivariable analysis, DFS and OS were comparable for pregnant and non-pregnant patients (DFS: HR 1.02, 95% CI 0.82–1.27, p = 0.83; OS: HR 1.08, 95% CI 0.81–1.45, p = 0.59).
Outcome of women with breast cancer treated with chemotherapy during pregnancy is comparable to young non-pregnant women. These results support chemotherapy for PrBC when indicated.
•Pregnant breast cancer patients (PrBC) have similar survival as non-pregnant controls.•Pregnancy does not impact the effectiveness of chemotherapy for breast cancer.•This cohort study supports initiation of chemotherapy for PrBC when indicated.
Ranitidine, a histamine 2 blocker, is the standard of care to prevent hypersensitivity reactions (HSRs) caused by paclitaxel infusion. However, the added value of ranitidine in this premedication ...regimen is controversial. Therefore, we compared the incidence of HSRs during paclitaxel treatment between a standard regimen including ranitidine and a regimen without ranitidine.
This prospective, pre-post interventional, non-inferiority study compared the standard premedication regimen (N = 183) with dexamethasone, clemastine and ranitidine with a premedication regimen without ranitidine (N = 183). The primary outcome was the incidence of HSR grade ≥3. Non-inferiority was determined by checking whether the upper bound of the two-sided 90% confidence interval (CI) for the difference in HSR rates excluded the +6% non-inferiority margin.
In both the pre-intervention (with ranitidine) and post-intervention (without ranitidine) group 183 patients were included. The incidence of HSR grade ≥3 was 4.4% (N = 8) in the pre-intervention group and 1.6% (N = 3) in the post-intervention group: difference -2.7% (90% CI: -6.2 to 0.1).
As the upper boundary of the 90% CI does not exceed the predefined non-inferiority margin of +6%, it can be concluded that a premedication regimen without ranitidine is non-inferior to a premedication regimen with ranitidine.
www.trialregister.nl ; NL8173.
Phenotypic plasticity, defined as the ability of individual cells with stable genotypes to exert different phenotypes upon exposure to specific environmental cues, represent the quintessential ...hallmark of the cancer cell en route from the primary lesion to distant organ sites where metastatic colonization will occur. Phenotypic plasticity is driven by a broad spectrum of epigenetic mechanisms that allow for the reversibility of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions (EMT/MET). By taking advantage of the co-existence of epithelial and quasi-mesenchymal cells within immortalized cancer cell lines, we have analyzed the role of EMT-related gene isoforms in the regulation of epithelial mesenchymal plasticity (EMP) in high grade serous ovarian cancer. When compared with colon cancer, a distinct spectrum of downstream targets characterizes quasi-mesenchymal ovarian cancer cells, likely to reflect the different modalities of metastasis formation between these two types of malignancy, i.e. hematogenous in colon and transcoelomic in ovarian cancer. Moreover, upstream RNA-binding proteins differentially expressed between epithelial and quasi-mesenchymal subpopulations of ovarian cancer cells were identified that underlie differential regulation of EMT-related isoforms. In particular, the up- and down-regulation of RBM24 and ESRP1, respectively, represent a main regulator of EMT in ovarian cancer cells. To validate the functional and clinical relevance of our approach, we selected and functionally analyzed the Tropomyosin 1 gene (TPM1), encoding for a protein that specifies the functional characteristics of individual actin filaments in contractile cells, among the ovarian-specific downstream AS targets. The low-molecular weight Tpm1.8/9 isoforms are specifically expressed in patient-derived ascites and promote invasion through activation of EMT and Wnt signaling, together with a broad spectrum of inflammation-related pathways. Moreover, Tpm1.8/9 expression confers resistance to taxane- and platinum-based chemotherapy. Small molecule inhibitors that target the Tpm1 isoforms support targeting Tpm1.8/9 as therapeutic targets for the development of future tailor-made clinical interventions.
Patients with unresectable disease during cytoreductive surgery (CRS) for advanced-stage ovarian cancer are underreported. Knowledge of treatment and survival after surgery is limited. The aim of ...this study is to address the knowledge gap about postoperative treatment and survival of patients whose surgery was abandoned due to unresectability after abdominal exploration.
Women with FIGO stage IIIB-IV epithelial ovarian cancer whose disease was considered to be unresectable during surgery were included in this prospective study, a post hoc analysis of the PlaComOv study. The unresectable disease was defined as the inability to achieve at least suboptimal CRS without attempted CRS after careful inspection of the entire abdomen. Preoperative clinical data, perioperative findings, postoperative treatment and survival data were analyzed.
From 2018 to 2020, 27 patients were included in this analysis. Treatment ranged from the cessation of treatment to one or several lines of chemotherapy with or without maintenance therapy. The median overall survival was 16 (IQR 5-21) months (95%CI 14-18). At 24 months of follow-up, four patients (15%) were alive.
This study indicated a two-year survival of 15%. Optimal treatment strategies in terms of survival benefits are still ill-defined. Further study of this specific group of patients is warranted. We advocate an (inter)national registry of patients with unresectable cancer and comprehensive follow-up.
Most physicians encounter pregnant women with cancer incidentally, leading to a lack of expertise or confidence to inform and treat these patients based on the most recent guidelines and expert ...opinions. In the Netherlands, a national multidisciplinary tumour board for cancer, infertility and pregnancy (CIP-MDT) was founded in December 2012, including 35 specialists from a variety of disciplines. This study evaluates the frequency of consultation of the CIP-MDT, the types of questions asked and the satisfaction of consulting physicians with its existence.
Of all requests to the CIP-MDT between December 2012 and June 2021, tumour type, stage, gestational age at diagnosis and recommendations were collected and analysed. For evaluating the methods of the CIP-MDT, a survey with questions regarding experiences with the CIP-MDT and its impact on treatment decisions was sent out to physicians that consulted the CIP-MDT.
Recommendations (n = 213) concerned preferred and safest options for imaging, treatment options during pregnancy, possible effects on the child and fertility preserving options. Most frequently discussed malignancies were breast cancer (n = 66), cervical cancer (n = 34), haematological malignancies (n = 32) and melanoma (n = 21). The questionnaire was completed by 54% of the physicians (n = 50). Satisfaction with the recommendations of the CIP-MDT was high, and 94% of the physicians informed their patients about consulting the CIP-MDT and felt supported by the received recommendations.
The national Dutch CIP-MDT contributes to a high level of satisfaction among physicians requesting advice. Further research should be executed to confirm that a CIP-MDT improves the outcomes for pregnant women and their children.
•Describes a multidisciplinary tumour board for cancer, infertility and pregnancy (CIP-MDT).•CIP-MDT contributes to high-level satisfaction in physicians requesting expert advice.•This article shows the important steps necessary to establish a CIP-MDT.
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