ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease.

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.

ESMO Expert Consensus Statements on the management of breast cancer during pregnancy (PrBC).

The management of breast cancer during pregnancy (PrBC) is a relatively rare indication and an area where no or little evidence is available since randomized controlled trials cannot be conducted. In general, advances related to breast cancer (BC) treatment outside pregnancy cannot always be translated to PrBC, because both the interests of the mother and of the unborn should be considered. Evidence remains limited and/or conflicting in some specific areas where the optimal approach remains controversial. In 2022, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process on this topic to gain insights from a multidisciplinary group of experts and develop statements on controversial topics that cannot be adequately addressed in the current evidence-based ESMO Clinical Practice Guideline. The aim of this consensus-building process was to discuss controversial issues relating to the management of patients with PrBC. The virtual meeting included a multidisciplinary panel of 24 leading experts from 13 countries and was chaired by S. Loibl and F. Amant. All experts were allocated to one of four different working groups. Each working group covered a specific subject area with two chairs appointed: Planning, preparation and execution of the consensus process was conducted according to the ESMO standard operating procedures.

Semi-physiological Enriched Population Pharmacokinetic Modelling to Predict the Effects of Pregnancy on the Pharmacokinetics of Cytotoxic Drugs.

BACKGROUND AND OBJECTIVE: As a result of changes in physiology during pregnancy, the pharmacokinetics (PK) of drugs can be altered. It is unclear whether under- or overexposure occurs in pregnant cancer patients and thus also whether adjustments in dosing regimens are required. Given the severity of the malignant disease and the potentially high impact on both the mother and child, there is a high unmet medical need for adequate and tolerable treatment of this patient population. We aimed to develop and evaluate a semi-physiological enriched model that incorporates physiological changes during pregnancy into available population PK models developed from non-pregnant patient data. METHODS: Gestational changes in plasma protein levels, renal function, hepatic function, plasma volume, extracellular water and total body water were implemented in existing empirical PK models for docetaxel, paclitaxel, epirubicin and doxorubicin. These models were used to predict PK profiles for pregnant patients, which were compared with observed data obtained from pregnant patients. RESULTS: The observed PK profiles were well described by the model. For docetaxel, paclitaxel and doxorubicin, an overprediction of the lower concentrations was observed, most likely as a result of a lack of data on the gestational changes in metabolizing enzymes. For paclitaxel, epirubicin and doxorubicin, the semi-physiological enriched model performed better in predicting PK in pregnant patients compared with a model that was not adjusted for pregnancy-induced changes. CONCLUSION: By incorporating gestational changes into existing population pharmacokinetic models, it is possible to adequately predict plasma concentrations of drugs in pregnant patients which may inform dose adjustments in this population.

The amount of preoperative endometrial tissue surface in relation to final endometrial cancer classification.

OBJECTIVE: To evaluate whether the amount of preoperative endometrial tissue surface is related to the degree of concordance with final low- and high-grade endometrial cancer (EC). In addition, to determine whether discordance is influenced by sampling method and impacts outcome. METHODS: A retrospective cohort study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC). Surface of preoperative endometrial tissue samples was digitally calculated using ImageJ. Tumor samples were classified into low-grade (grade 1-2 endometrioid EC (EEC)) and high-grade (grade 3 EEC + non-endometroid EC). RESULTS: The study cohort included 573 tumor samples. Overall concordance between pre- and postoperative diagnosis was 60.0%, and 88.8% when classified into low- and high-grade EC. Upgrading (preoperative low-grade, postoperative high-grade EC) was found in 7.8% and downgrading (preoperative high-grade, postoperative low-grade EC) in 26.7%. The median endometrial tissue surface was significantly lower in concordant diagnoses when compared to discordant diagnoses, respectively 18.7 mm2 and 23.5 mm2 (P = 0.022). Sampling method did not influence the concordance in tumor classification. Patients with preoperative high-grade and postoperative low-grade showed significant lower DSS compared to patients with concordant low-grade EC (P = 0.039). CONCLUSION: The amount of preoperative endometrial tissue surface was inversely related to the degree of concordance with final tumor low- and high-grade. Obtaining higher amount of preoperative endometrial tissue surface does not increase the concordance between pre- and postoperative low- and high-grade diagnosis in EC. Awareness of clinically relevant down- and upgrading is crucial to reduce subsequent over- or undertreatment with impact on outcome.

Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?

INTRODUCTION: The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals. METHOD: Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard. RESULTS: We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74-0.86), followed by RMI (0.71, 95%CI 0.64-0.78) and CA125 (0.69, 95%CI 0.62-0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same. CONCLUSION: HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital.

Installing oncofertility programs for breast cancer in limited versus optimum resource settings: Empirical data from 39 surveyed centers in Repro-Can-OPEN Study Part I & II.

PURPOSE: As a further step to elucidate the actual diverse spectrum of oncofertility practices for breast cancer around the globe, we present and discuss the comparisons of oncofertility practices for breast cancer in limited versus optimum resource settings based on data collected in the Repro-Can-OPEN Study Part I & II. METHODS: We surveyed 39 oncofertility centers including 14 in limited resource settings from Africa, Asia & Latin America (Repro-Can-OPEN Study Part I), and 25 in optimum resource settings from the United States, Europe, Australia and Japan (Repro-Can-OPEN Study Part II). Survey questions covered the availability of fertility preservation and restoration options offered to young female patients with breast cancer as well as the degree of utilization. RESULTS: In the Repro-Can-OPEN Study Part I & II, responses for breast cancer and calculated oncofertility scores showed the following characteristics: (1) higher oncofertility scores in optimum resource settings than in limited resource settings especially for established options, (2) frequent utilization of egg freezing, embryo freezing, ovarian tissue freezing, GnRH analogs, and fractionation of chemo- and radiotherapy, (3) promising utilization of oocyte in vitro maturation (IVM), (4) rare utilization of neoadjuvant cytoprotective pharmacotherapy, artificial ovary, and stem cells reproductive technology as they are still in preclinical or early clinical research settings, (5) recognition that technical and ethical concerns should be considered when offering advanced and innovative oncofertility options. CONCLUSIONS: We presented a plausible oncofertility best practice model to guide oncofertility teams in optimizing care for breast cancer patients in various resource settings.

Immunohistochemical biomarkers are prognostic relevant in addition to the ESMO-ESGO-ESTRO risk classification in endometrial cancer.

OBJECTIVE: Pre-operative immunohistochemical (IHC) biomarkers are not incorporated in endometrial cancer (EC) risk classification. We aim to investigate the added prognostic relevance of IHC biomarkers to the ESMO-ESGO-ESTRO risk classification and lymph node (LN) status in EC. METHODS: Retrospective multicenter study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), analyzing pre-operative IHC expression of p53, L1 cell-adhesion molecule (L1CAM), estrogen receptor (ER) and progesterone receptor (PR), and relate to ESMO-ESGO-ESTRO risk groups, LN status and outcome. RESULTS: A total of 763 EC patients were included with a median follow-up of 5.5-years. Abnormal IHC expression was present for p53 in 112 (14.7%), L1CAM in 79 (10.4%), ER- in 76 (10.0%), and PR- in 138 (18.1%) patients. Abnormal expression of p53/L1CAM/ER/PR was significantly related with higher risk classification groups, and combined associated with the worst outcome within the 'high and advanced/metastatic' risk group. In multivariate analysis p53-abn, ER/PR- and ESMO-ESGO-ESTRO 'high and advanced/metastatic' were independently associated with reduced disease-specific survival (DSS). Patients with abnormal IHC expression and lymph node metastasis (LNM) had the worst outcome. Patients with LNM and normal IHC expression had comparable outcome with patients without LNM and abnormal IHC expression. CONCLUSION: The use of pre-operative IHC biomarkers has important prognostic relevance in addition to the ESMO-ESGO-ESTRO risk classification and in addition to LN status. For daily clinical practice, p53/L1CAM/ER/PR expression could serve as indicator for surgical staging and refine selective adjuvant treatment by incorporation into the ESMO-ESGO-ESTRO risk classification.

Phase 2 study of anastrozole in patients with estrogen receptor/progesterone receptor positive recurrent low-grade endometrial stromal sarcomas: The PARAGON trial (ANZGOG 0903).

BACKGROUND: Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers. METHOD: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER ± PR + ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. RESULTS: 15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48-89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2-29.8%), partial response in three (20%, 95% CI 7.1-45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2-NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5-63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects. CONCLUSION: The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers.

Visceral obesity and muscle mass determined by CT scan and surgical outcome in patients with advanced ovarian cancer. A retrospective cohort study.

OBJECTIVE: Visceral obesity (VO) is a risk factor for developing postoperative complications in patients undergoing abdominal oncological surgery. However, in ovarian cancer patients this influence of body composition on postoperative morbidity is not well established. The aim of this study is to assess the association between body composition and complications in patients with advanced ovarian cancer undergoing cytoreductive surgery. METHODS: Patients with FIGO stage 3 or 4 ovarian cancer between 2006 and 2017 were included. Visceral fat area, total skeletal mass and total fat area were measured on a single slice on the level of L3-L4 of the preoperative CT-scan. VO was defined as visceral fat ≥100cm2. The perioperative data were extracted retrospectively. A multivariate logistic regression analysis was performed to test the predictive value of multiple variables such as body composition, albumin levels and preoperative morbidity. RESULTS: 298 consecutive patients out of nine referring hospitals were included. VO patients were more likely to be hypertensive (38% vs 17% p < 0.001), and to have an ASA 3 score (21% vs 10% P = 0.012). Complications occurred more often in VO patients (43% vs 21% P < 0.001). Thrombotic events were found in 4.9% of VO patients versus 0.6% of the non-visceral obese patients (p = 0.019). VO(OR: 4.37, p < 0.001), hypertension (OR:1.9, p = 0.046) and duration of surgery (OR: 1.004, p = 0.017) were predictors of post-surgical complications. Muscle mass is not a predictor of complications. CONCLUSION: Visceral obesity is associated with a higher occurrence of complications in patients with advanced ovarian cancer undergoing cytoreductive surgery.

The impact of cancer and chemotherapy during pregnancy on child neurodevelopment: A multimodal neuroimaging analysis.

BACKGROUND: This study applies multimodal MRI to investigate neurodevelopment in nine-year-old children born to cancer-complicated pregnancies. METHODS: In this cohort study, children born after cancer-complicated pregnancies were recruited alongside 1:1 matched controls regarding age, sex and gestational age at birth (GA). Multimodal MRI was used to investigate whole-brain and subcortical volume, cortical structure (using surface-based morphometry), white matter microstructure (using fixel-based analysis) and functional connectivity (using resting-state blood-oxygen-level-dependant signal correlations). Graph theory probed whole-brain structural and functional organization. For each imaging outcome we conducted two group comparisons: 1) children born after cancer-complicated pregnancies versus matched controls, and 2) the subgroup of children with prenatal chemotherapy exposure versus matched controls. In both models, we used the covariate of GA and the group-by-GA interaction, using false-discovery-rate (FDR) or family-wise-error (FWE) correction for multiple comparisons. Exploratory post-hoc analyses investigated the relation between brain structure/function, neuropsychological outcome and maternal oncological/obstetrical history. FINDINGS: Forty-two children born after cancer-complicated pregnancies were included in this study, with 30 prenatally exposed to chemotherapy. Brain organization and functional connectivity were not significantly different between groups. Both cancer and chemotherapy in pregnancy, as compared to matched controls, were associated with a lower travel depth, indicating less pronounced gyrification, in the left superior temporal gyrus (pFDR ≤ 006), with post-hoc analysis indicating platinum derivatives during pregnancy as a potential risk factor (p = .028). Both cancer and chemotherapy in pregnancy were related to a lower fibre cross-section (FCS) and lower fibre density and cross-section (FDC) in the posterior corpus callosum and its tapetal fibres, compared to controls. Higher FDC in the chemotherapy subgroup and higher FCS in the whole study group were observed in the anterior thalamic radiations. None of the psycho-behavioural parameters correlated significantly with any of the brain differences in the study group or chemotherapy subgroup. INTERPRETATION: Prenatal exposure to maternal cancer and its treatment might affect local grey and white matter structure, but not functional connectivity or global organization. While platinum-based therapy was identified as a potential risk factor, this was not the case for chemotherapy in general. FUNDING: This project has received funding from the European Union's Horizon 2020 research and innovation program (European Research council, grant no 647,047), the Foundation against cancer (Stichting tegen kanker, grant no. 2014-152) and the Research Foundation Flanders (FWO, grants no. 11B9919N, 12ZV420N).

The effect of the peritoneal tumor microenvironment on invasion of peritoneal metastases of high-grade serous ovarian cancer and the impact of NEOADJUVANT chemotherapy.

Peritoneal metastases of high-grade serous ovarian cancer (HGSOC) are small-sized deposits with superficial growth toward the peritoneal cavity. It is unknown whether integrity of the peritoneal elastic lamina (PEL) correlates with the peritoneal tumor microenvironment (pTME) and whether neoadjuvant chemotherapy (NACT) affects the pTME. We explored integrity of PEL, composition of pTME, effects of NACT, and the prognostic implications in patients with extensive peritoneal metastases of HGSOC. Peritoneal samples (n = 69) were collected during cytoreductive surgery between 2003 and 2016. Clinical data were collected from medical charts. Integrity of PEL was evaluated with elastic stains. T cell (CD3, CD8) and M2-macrophage markers (CD163) were scored using algorithms created in definiens tissue studio. Patients with a disrupted PEL (n = 39; 57%), more often had residual disease after surgery (p = 0.050), compared to intact PEL. An intact PEL was associated with increased intraepithelial (ie) CD8+ cells (p = 0.032), but was not correlated with improved survival. After NACT, increased ieCD3+ cells were shown, compared to no-NACT (p = 0.044). Abundance of total CD3+ and CD8+ cells were associated with PFS (multivariate HR 0.40; 95%CI 0.23-0.69 and HR 0.49; 95%CI 0.29-0.83) and OS (HR 0.33; 95%CI 0.18-0.62 and HR 0.36; 95%CI 0.20-0.64). M2-macrophage infiltration was not correlated with survival. NACT increases abundance of ieCD3+ cells in peritoneal metastases of HGSOC. Increase of CD3+ and CD8+ cells is associated with improved PFS and OS. This suggests that CD3+ and CD8+ cells may function as prognostic biomarkers. Their role as predictive biomarker for chemotherapy or immunotherapy response in HGSOC warrants further research.

Gynecologic cancers in pregnancy: guidelines based on a third international consensus meeting.

We aimed to provide comprehensive protocols and promote effective management of pregnant women with gynecological cancers. New insights and more experience have been gained since the previous guidelines were published in 2014. Members of the International Network on Cancer, Infertility and Pregnancy (INCIP), in collaboration with other international experts, reviewed existing literature on their respective areas of expertise. Summaries were subsequently merged into a manuscript that served as a basis for discussion during the consensus meeting. Treatment of gynecological cancers during pregnancy is attainable if management is achieved by collaboration of a multidisciplinary team of health care providers. This allows further optimization of maternal treatment, while considering fetal development and providing psychological support and long-term follow-up of the infants. Nonionizing imaging procedures are preferred diagnostic procedures, but limited ionizing imaging methods can be allowed if indispensable for treatment plans. In contrast to other cancers, standard surgery for gynecological cancers often needs to be adapted according to cancer type and gestational age. Most standard regimens of chemotherapy can be administered after 14 weeks gestational age but are not recommended beyond 35 weeks. C-section is recommended for most cervical and vulvar cancers, whereas vaginal delivery is allowed in most ovarian cancers. Breast-feeding should be avoided with ongoing chemotherapeutic, endocrine or targeted treatment. More studies that focus on the long-term toxic effects of gynecologic cancer treatments are needed to provide a full understanding of their fetal impact. In particular, data on targeted therapies that are becoming standard of care in certain gynecological malignancies is still limited. Furthermore, more studies aimed at the definition of the exact prognosis of patients after antenatal cancer treatment are warranted. Participation in existing registries (www.cancerinpregnancy.org) and the creation of national tumor boards with multidisciplinary teams of care providers (supplementary Box S1, available at Annals of Oncology online) is encouraged.

Neoadjuvant chemotherapy followed by surgery for advanced-stage endometrial cancer.

Background: Data showing the value of neoadjuvant chemotherapy (nact) followed by interval debulking surgery (ids) in the management of advanced-stage serous endometrial carcinoma (eca) are limited; the aim of the present study was to expand the knowledge about that treatment strategy in patients with advanced eca, including endometrioid eca. Methods: Data were collected retrospectively from all patients with advanced-stage eca treated with nact between 2005 and 2014 at 3 oncology referral centres. Primary outcomes were the radiologic response to nact and achievement of optimal or complete ids. Secondary outcomes were recurrence rate and progression-free and overall survival. Results: Of 102 eca cases included, a complete radiologic response was achieved in only 4 cases, with a partial response being achieved in 72% (64% of endometrioid cases, 80% of serous cases). Complete ids was achieved in 62% of the endometrioid cases and in 56% of the serous eca cases, with optimal ids achieved in 31% and 28% of those cases respectively. Survival rates were calculated for all patients with complete and optimal ids; recurrence was observed in 56% and 67% of the cases respectively, and progression-free survival was 18 months and 13 months respectively. Median survival duration was 24 months for endometrioid eca and 28 months for serous eca. Conclusions: For patients with advanced eca who are not suitable for primary debulking, nact followed by ids can be considered regardless of histologic subtype. The treatment options for this group of patients are limited and have to be explored.

The effect of adjuvant chemotherapy on survival in patients with FIGO stage I high-grade serous ovarian cancer.

OBJECTIVE: The benefit of adjuvant chemotherapy for FIGO stage I, high-grade serous ovarian cancer (HGSOC) after optimal staging is a matter of debate. We investigated the effect of adjuvant chemotherapy on recurrence-free survival (RFS) and overall survival (OS) in a population-based cohort study. METHODS: All patients diagnosed in the Netherlands between 2002 and 2014 with FIGO stage I HGSOC who underwent surgical staging were included. Data on clinical characteristics, histopathology, completeness of staging and survival were collected from the Netherlands Cancer Registry and Dutch Pathology Registry. Recurrence data was collected from hospital files. We used Kaplan-Meier methods to estimate RFS and OS and Cox-proportional hazard analyses to control for differences in baseline characteristics between patients who did or did not receive chemotherapy. RESULTS: We identified 223 patients who underwent optimal staging procedures including lymph node sampling. Events of disease recurrence occurred in 21 of the 101 patients (21%) who received adjuvant chemotherapy and in 46 of the 122 patients (38%) who did not (multivariable hazard ratio (HR), 0.37; 95%CI 0.22-0.64; p < 0.01). Five-year RFS was 81% after staging plus chemotherapy and 59% after staging only. At a median follow-up of 105 months, 21 patients (21%) in the chemotherapy group and 38 patients (31%) in the no-chemotherapy group had died (multivariable HR 0.50; 95%CI 0.28-0.89; p = 0.02). Ten-year OS was 78% with chemotherapy and 62% without chemotherapy. CONCLUSIONS: Adjuvant chemotherapy improves long-term RFS and OS in patients with FIGO stage I HGSOC after optimal staging.

Tamoxifen and pregnancy: an absolute contraindication?

PURPOSE: Breast cancer is the most common malignancy among young women of reproductive age. Adjuvant treatment with tamoxifen reduces the risk of recurrence in hormone-sensitive breast cancer. However, the use of tamoxifen is considered contraindicated during pregnancy, because of a limited number of case reports demonstrating potential adverse effects on the fetus. The objective of this report is to give a more broad overview of the available data on the effect of tamoxifen exposure during pregnancy. METHODS: A literature review was performed using PubMed and the databases of the Netherlands Pharmacovigilance Centre Lareb and of the International Network on Cancer, Infertility, and Pregnancy. RESULTS: A total of 238 cases of tamoxifen use during pregnancy were found. Of the 167 pregnancies with known outcome, 21 were complicated by an abnormal fetal development. The malformations described were non-specific and the majority of cases concerned healthy infants despite exposure to tamoxifen. CONCLUSION: There seems to be an increased risk of fetal abnormalities when taking tamoxifen during pregnancy (12.6% in contrast to 3.9% in the general population), but the evidence is limited and no causal relationship could be established. The possible disadvantage of postponing or discontinuing tamoxifen for the maternal prognosis is unclear. Patients should be counseled about the use of tamoxifen during pregnancy instead of presenting it as being absolutely contraindicated.

Rare ovarian tumours: Epidemiology, treatment challenges in and outside a network setting.

PURPOSE OF THE REVIEW: More than 50% of all gynaecological cancers can be classified as rare tumours (defined as an annual incidence of <6 per 100,000) and such tumours represent an important challenge for clinicians. RECENT FINDINGS: Rare cancers account for more than one fifth of all new cancer diagnoses, more than any of the single common cancers alone. Reviewing the RARECAREnet database, some of the tumours occur infrequently, whilst others because of their natural history have a high prevalence, and therefore appear to be more common, although their incidence is also rare. Harmonization of medical practice, guidelines and novel trials are needed to identify rare tumours and facilitate the development of new treatments. Ovarian tumours are the focus of this review, but we comment on other rare gynaecological tumours, as the diagnosis and treatment challenges faced are similar. FUTURE: This requires European collaboration, international partnerships, harmonization of treatment and collaboration to overcome the regulatory barriers to conduct international trials. Whilst randomized trials can be done in many tumour types, there are some for which conducting even single arm studies may be challenging. For these tumours alternative study designs, robust collection of data through national registries and audits could lead to improvements in the treatment of rare tumours. In addition, concentring the care of patients with rare tumours into a limited number of centres will help to build expertise, facilitate trials and improve outcomes.

Genomewide copy number alteration screening of circulating plasma DNA: potential for the detection of incipient tumors.

Background: Early cancer diagnosis might improve survival rates. As circulating tumor DNA (ctDNA) carries cancer-specific modifications, it has great potential as a noninvasive biomarker for detection of incipient tumors. Patients and methods: We collected cell-free DNA (cfDNA) samples of 1002 elderly without a prior malignancy, carried out whole-genome massive parallel sequencing and scrutinized the mapped sequences for the presence of (sub)chromosomal copy number alterations (CNAs) predictive for a malignancy. When imbalances were detected, 6-monthly clinical follow-up was carried out. Results: In 3% of participants chromosomal imbalances were detected. Follow-up analyses, including whole-body MRI screening, confirmed the presence of five hematologic malignancies: one Hodgkin lymphoma (HL), stage II; three non-HL (type chronic lymphocytic leukemia, Rai I-Binet A; type SLL, stage III; type mucosa-associated lymphoid tissue, stage I) and one myelodysplastic syndrome with excess blasts, stage II. The CNAs detected in cfDNA were tumor-specific. Furthermore, one case was identified with monoclonal B-cell lymphocytosis, a potential precursor of B-cell malignancy. In 24 additional individuals, CNAs were identified but no cancer diagnosis was made. For 9 of them, the aberrant cfDNA profile originated from peripheral blood cells. For 15 others the origin of aberrations in cfDNA remains undetermined. Conclusion(s): Genomewide profiling of cfDNA in apparently healthy individuals enables the detection of incipient hematologic malignancies as well as clonal mosaicism with unknown clinical significance. CNA screening of cellular DNA of peripheral blood in elderly has established that clonal mosaicism for these chromosomal anomalies predicts a 5- to 10-fold enhanced risk of a subsequent cancer. We demonstrate that cfDNA screening detects CNAs, which are not only derived from peripheral blood, but even more from other tissues. Since the clinical relevance of clonal mosaics in other tissues remains unknown, long-term follow-up is warranted. Taken together, this study demonstrates that genomewide cfDNA analysis has potential as an unbiased screening approach for hematological malignancies and premalignant conditions.

Management and outcome of colorectal cancer during pregnancy: report of 41 cases.

BACKGROUND: Colorectal cancer in pregnancy is rare, with an incidence of 0.8 per 100,000 pregnancies. Advanced disease (stage III or IV) is diagnosed more frequently in pregnant patients. We aimed to review all cases of colorectal cancer in pregnancy from the International Network on Cancer, Infertility and Pregnancy database in order to learn more about this rare disease and improve its management. METHODS: Data on the demographic features, symptoms, histopathology, diagnostic and therapeutic interventions and outcomes (obstetric, neonatal and maternal) were analysed. RESULTS: Twenty-seven colon and 14 rectal cancer cases were identified. Advanced disease was present in 30 patients (73.2%). During pregnancy, 21 patients (51.2%) received surgery and 12 patients (29.3%) received chemotherapy. Thirty-three patients (80.5%) delivered live babies: 21 by caesarean section and 12 vaginally. Prematurity rate was high (78.8%). Eight babies were small for gestational age (27.6%). Three patients (10.7%) developed recurrence of disease. Overall 2-year survival was 64.4%. CONCLUSION: Despite a more frequent presentation with advanced disease, colorectal cancer has a similar prognosis in pregnancy when compared with the general population. Diagnostic interventions and treatment should not be delayed due to the pregnancy but a balance between maternal and foetal wellbeing must always be kept in mind.