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.

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.

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.

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.

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.

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.

Feasibility of whole-body diffusion-weighted MRI for detection of primary tumour, nodal and distant metastases in women with cancer during pregnancy: a pilot study.

OBJECTIVES: To evaluate the feasibility of whole-body diffusion-weighted MRI (WB-DWI/MRI) for detecting primary tumour, nodal and distant metastases in pregnant women with cancer. METHODS: Twenty pregnant patients underwent WB-DWI/MRI in additional to conventional imaging. Reproducibility of WB-DWI/MRI between two readers was evaluated using Cohen's κ statistics and accuracy was compared to conventional imaging for assessing primary tumour site, nodal and visceral metastases. RESULTS: Both WB-DWI/MRI readers showed good-very good agreement for lesion detection (primary lesions: κ=1; lymph nodes: κ=0.89; distant metastases: κ=0.61). Eight (40 %) patients were upstaged after WB-DWI/MRI. For nodal metastases, WB-DWI/MRI showed 100 % (95 % CI: 83.2-100) sensitivity for both readers with specificity of 99.4 % (96.9-100) and 100 % (80.5-100) for readers 1 and 2, respectively. For distant metastases, WB-DWI/MRI showed 66.7 % (9.4-99.2) and 100 % (29.2-100) sensitivity and specificity of 94.1 % (71.3-99.9) and 100 % (80.5-100) for readers 1 and 2, respectively. Conventional imaging showed sensitivity of 50 % (27.2-72.8) and 33.3 % (0.8-90.6); specificity of 100 % (98-100) and 100 % (80.5-100), for nodal and distant metastases respectively. CONCLUSIONS: WB-DWI/MRI is feasible for single-step non-invasive staging of cancer during pregnancy with additional value for conventional imaging procedures. KEY POINTS: • In our study, WB-DWI/MRI was more accurate than conventional imaging during pregnancy. • WB-DWI/MRI improves diagnostic assessment of patients with cancer during pregnancy. • Accurate imaging and oncologic staging improves treatment and outcome.

Positive DESKTOP and Tian Scores Systems Are Adequate to Predict Optimal (R0) Secondary Debulking Surgery in Ovarian Cancer, But a Negative Score Does Not Preclude Secondary Surgery.

OBJECTIVE: The aim of this study was to assess the safety and feasibility of macroscopically complete (R0) secondary debulking surgery (SDS) in a single-center cohort of patients with recurrent ovarian cancer. The performances of existing prediction models (DESKTOP score, Tian model) for R0 SDS were evaluated in this cohort. METHODS: Patient, disease, and treatment characteristics of 102 patients undergoing SDS for recurrent ovarian cancer at the University Hospitals Leuven between 1997 and 2014 were collected. RESULTS: R0 SDS was achieved in 73% of patients and associated with improved progression-free survival (P = 0.0002) and overall survival (P = 0.0003) compared with non-R0 resection. Variables associated with R0 SDS were site of relapse (P = 0.046) and absence of ascites (P = 0.045). The DESKTOP score and Tian model showed positive predictive values for R0 SDS of 80% and 73%, respectively. However, a false-negative rate for R0 resection of 61% and 70% was observed in our study. Progression-free survival and overall survival did not significantly differ between DESKTOP score-positive and -negative patients with R0 SDS. CONCLUSIONS: We confirmed a high positive predictive value in the selection of candidates for R0 SDS with the DESKTOP score and the Tian model. However, because 61% and 70% of the patients with a negative score were debulked to R0, we suggest that other selection criteria based on anatomic and metabolic imaging such as whole-body diffusion-weighted magnetic resonance imaging should be evaluated when selecting patients for SDS.

Psychological distress and cognitive coping in pregnant women diagnosed with cancer and their partners.

OBJECTIVE: A cancer diagnosis during pregnancy may be considered as an emotional challenge for pregnant women and their partners. We aimed to identify women and partners at risk for high levels of distress based on their coping profile. METHODS: Sixty-one pregnant women diagnosed with cancer and their partners filled out the Cognitive Emotion Regulation Questionnaire (CERQ) and the newly constructed Cancer and Pregnancy Questionnaire (CPQ). K-means cluster analysis was performed on the CERQ scales. Scores on the CPQ were compared between the women and their partners and between the CERQ-clusters. RESULTS: Comparison of women and partners on the CPQ did not reveal significant differences on distress about the child's health, the cancer disease, and the pregnancy or on information satisfaction (P = .16, P = .44, P = .50, and P = .47, respectively). However, women were more inclined to maintain the pregnancy than their partners (P = .011). Three clusters were retrieved based on the CERQ scales, characterized by positive coping, internalizing coping, and blaming. Women and partners using internalizing strategies had significantly higher scores on concerns about the child's health (P = .039), the disease and treatment (P < .001), and the pregnancy and delivery (P = .009) compared with positive and blaming strategies. No cluster differences were found for information satisfaction (P = .71) and tendency to maintain the pregnancy (P = .35). CONCLUSION: Women and partners using internalizing coping strategies deal with the highest levels of distress and may benefit from additional psychosocial support.

Management of gynecological cancers during pregnancy.

The diagnosis of a gynecological malignancy during pregnancy is rare but not uncommon. Cancer treatment during pregnancy is possible, but both maternal and fetal interests need to be respected. Different treatment plans may be justifiable and multidisciplinary treatment is advised. Clinical trials are virtually impossible, and current evidence is mainly based on small case series and expert opinion. Individualization of treatment is necessary and based on tumor type, stage, and gestational age at time of diagnosis. Termination of pregnancy is not necessary in most cases. Surgery and chemotherapy (second trimester and onwards) are possible types of treatment during pregnancy. Radiotherapy of the pelvic area is not compatible with an ongoing pregnancy. This article discusses the current recommendations for the management of gynecological malignancies (cervical, ovarian, and vulvar cancers) during pregnancy.

Gynecologic cancers in pregnancy: guidelines of a second international consensus meeting.

OBJECTIVES: This study aimed to provide timely and effective guidance for pregnant women and health care providers to optimize maternal treatment and fetal protection and to promote effective management of the mother, fetus, and neonate when administering potentially teratogenic medications. New insights and more experience were gained since the first consensus meeting 5 years ago. METHODS: Members of the European Society of Gynecological Oncology task force "Cancer in Pregnancy" in concert with other international experts reviewed the existing literature on their respective areas of expertise. The summaries were subsequently merged into a complete article that served as a basis for discussion during the consensus meeting. All participants approved the final article. RESULTS: In the experts' view, cancer can be successfully treated during pregnancy in collaboration with a multidisciplinary team, optimizing maternal treatment while considering fetal safety. To maximize the maternal outcome, cancer treatment should follow a standard treatment protocol as for nonpregnant patients. Iatrogenic prematurity should be avoided. Individualization of treatment and effective psychologic support is imperative to provide throughout the pregnancy period. Diagnostic procedures, including staging examinations and imaging, such as magnetic resonance imaging and sonography, are preferable. Pelvic surgery, either open or laparoscopic, as part of a treatment protocol, may reveal beneficial outcomes and is preferably performed by experts. Most standard regimens of chemotherapy can be administered from 14 weeks gestational age onward. Apart from cervical and vulvar cancer, as well as important vulvar scarring, the mode of delivery is determined by the obstetrician. Term delivery is aimed for. Breast-feeding should be considered based on individual drug safety and neonatologist-breast-feeding expert's consult. CONCLUSIONS: Despite limited evidence-based information, cancer treatment during pregnancy can succeed. State-of-the-art treatment should be provided for this vulnerable population to preserve maternal and fetal prognosis. SUPPLEMENTARY INFORMATION: Supplementary data on teratogenic effects, ionizing examinations, sentinel lymph node biopsy, tumor markers during pregnancy, as well as additional references and tables are available at the extended online version of this consensus article, go to http://links.lww.com/IGC/A197.

Breast cancer incidence, stage distribution, and treatment shifts during the 2020 COVID-19 pandemic: a nationwide population-level study.

BACKGROUND: The first COVID-19 wave in 2020 necessitated temporary suspension of non-essential medical services including organized cancer screening programs in Belgium. This study assessed the impact of the pandemic on breast cancer (BC) incidence, stage at diagnosis, and management in Belgium in 2020. METHODS: All Belgian residents diagnosed with in situ or invasive BC in 2015-2020 in the nationwide, population-based cancer registry database were included. Incidence trends for 2015-2019 were extrapolated to predict incidence and stage distribution for 2020 and compared with the observed values. National healthcare reimbursement data were used to examine treatment strategies. Exact tumor diameter and nodal involvement, extracted from pathology reports, were analyzed for 2019 and 2020. RESULTS: 74,975 tumors were selected for analysis of incidence and clinical stage. Invasive BC incidence declined by -5.0% in 2020, with a drop during the first COVID-19 wave (Mar-Jun; -23%) followed by a rebound (Jul-Dec; +7%). Predicted and observed incidence (in situ + invasive) was not different in patients < 50 years. In the 50-69 and 70 + age groups, significant declines of -4.1% and - 8.4% respectively were found. Excess declines were seen in clinical stage 0 and I in Mar-Jun, without excess increases in clinical stage II-IV tumors in Jul-Dec. There was no increase in average tumor diameter or nodal involvement in 2020. Patients diagnosed in Mar-Jun received significantly more neoadjuvant therapy, particularly neoadjuvant hormonal therapy for patients with clinical stage I-II BC. CONCLUSIONS: BC incidence decline in 2020 in Belgium was largely restricted to very early-stage BC and patients aged 50 and over. Delayed diagnosis did not result in an overall progression to higher stage at diagnosis in 2020. Observed treatment adaptations in Belgium were successful in prioritizing patients for surgery while preventing tumor progression in those with surgical delay. Continuation of monitoring BC incidence and stage in the future is crucial.

Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study.

BACKGROUND: Chemotherapy for the treatment of maternal cancers during pregnancy has become more acceptable in the past decade; however, the effect of prenatal exposure to chemotherapy on cardiac and neurodevelopmental outcomes of the offspring is still uncertain. We aimed to record the general health, cardiac function, and neurodevelopmental outcomes of children who were prenatally exposed to chemotherapy. METHODS: We did an interim analysis of a multicentre observational cohort study assessing children who were prenatally exposed to maternal cancer staging and treatment, including chemotherapy. We assessed children at birth, at age 18 months, and at age 5-6, 8-9, 11-12, 14-15, or 18 years. We did clinical neurological examinations, tests of the general level of cognitive functioning (Bayley or intelligence quotient [IQ] test), electrocardiography and echocardiography, and administered a questionnaire on general health and development. From age 5 years, we also did audiometry, the Auditory Verbal Learning Test, and subtasks of the Children's Memory Scale, and the Test of Everyday Attention for Children, and we also completed the Child Behavior Checklist. This study is registered with ClinicalTrials.gov, number NCT00330447. FINDINGS: 236 cycles of chemotherapy were administered in 68 pregnancies. We assessed 70 children, born at a median gestational age of 35·7 weeks (range 28·3-41·0; IQR 3·3; 47 women at <37 weeks), with a median follow-up period of 22·3 months (range 16·8-211·6; IQR 54·9). Although neurocognitive outcomes were within normal ranges, cognitive development scores were lower for children who were born preterm than for those born at full term. When controlling for age, sex, and country, the score for IQ increased by an average 11·6 points (95% CI 6·0-17·1) for each additional month of gestation (p<0·0001). Our measurements of the children's behaviour, general health, hearing, and growth corresponded with those of the general population. Cardiac dimensions and functions were within normal ranges. We identified a severe neurodevelopmental delay in both members of one twin pregnancy. INTERPRETATION: Fetal exposure to chemotherapy was not associated with increased CNS, cardiac or auditory morbidity, or with impairments to general health and growth compared with the general population. However, subtle changes in cardiac and neurocognitive measurements emphasise the need for longer follow-up. Prematurity was common and was associated with impaired cognitive development. Therefore, iatrogenic preterm delivery should be avoided when possible. FUNDING: Research Foundation-Flanders; Research Fund-K U Leuven; Agency for Innovation by Science and Technology; Stichting tegen Kanker; Clinical Research Fund-University Hospitals Leuven; and Belgian Cancer Plan, Ministery of Health.

Treatment of breast cancer during pregnancy: an observational study.

BACKGROUND: Little is known about the treatment of breast cancer during pregnancy. We aimed to determine whether treatment for breast cancer during pregnancy is safe for both mother and child. METHODS: We recruited patients from seven European countries with a primary diagnosis of breast cancer during pregnancy; data were collected retrospectively if the patient was diagnosed before April, 2003 (when the registry began), or prospectively thereafter, irrespective of the outcome of pregnancy and the type and timing of treatment. The primary endpoint was fetal health for up to 4 weeks after delivery. The registry is ongoing. The study is registered with ClinicalTrials.gov, number NCT00196833. FINDINGS: From April, 2003, to December, 2011, 447 patients were registered, 413 of whom had early breast cancer. Median age was 33 years (range 22-51). At the time of diagnosis, median gestational age was 24 weeks (range 5-40). 197 (48%) of 413 women received chemotherapy during pregnancy with a median of four cycles (range one to eight). 178 received an anthracycline, 15 received cyclophosphamide, methotrexate, and fluorouracil, and 14 received a taxane. Birthweight was affected by chemotherapy exposure after adjustment for gestational age (p=0·018), but not by number of chemotherapy cycles (p=0·71). No statistical difference between the two groups was observed for premature deliveries before the 37th week of gestation. 40 (10%) of 386 infants had side-effects, malformations, or new-born complications; these events were more common in infants born before the 37th week of gestation than they were in infants born in the 37th week or later (31 [16%] of 191 infants vs nine [5%] of 195 infants; p=0·0002). In infants for whom maternal treatment was known, adverse events were more common in those who received chemotherapy in utero compared with those who were not exposed (31 [15%] of 203 vs seven [4%] of 170 infants; p=0·00045). Two infants died; both were exposed to chemotherapy and delivered prematurely, but both deaths were thought not to be related to treatment. Median disease-free survival for women with early breast cancer was 70·6 months (95% CI 62·1-105·5) in women starting chemotherapy during pregnancy and 94·4 months (lower 95% CI 64·4; upper 95% CI not yet reached) in women starting chemotherapy after delivery (unadjusted hazard ratio 1·13 [95% CI 0·76-1·69]; p=0·539). INTERPRETATION: Although our data show that infants exposed to chemotherapy in utero had a lower birthweight at gestational age than did those who were unexposed, and had more complications, these differences were not clinically significant and, since none of the infants was exposed to chemotherapy in the first trimester, were most likely related to premature delivery. Delay of cancer treatment did not significantly affect disease-free survival for mothers with early breast cancer. Because preterm birth was strongly associated with adverse events, a full-term delivery seems to be of paramount importance. FUNDING: BANSS Foundation, Biedenkopf, Germany and the Belgian Cancer Plan, Ministry of Health, Belgium.

Bowel obstruction in advanced tubo-ovarian cancer: a retrospective cohort study.

Ten to fifty percent of women with advanced or recurrent ovarian cancer develop malignant bowel obstruction (MBO). We described the management and examined the complications and survival of MBO in primary epithelial tubo-ovarian cancer patients. Materials and methods: The authors conducted a retrospective monocentric cohort study of tubo-ovarian cancer patients diagnosed with MBO between January 1st, 2011 until August 31st, 2017 at the University Hospitals Leuven, Belgium. Results: Seventy-three patients with a total of 165 MBO episodes (median 1/patient; range 1-14) were included. The median time interval between cancer diagnosis and first MBO episode was 373 days (range 0-1937). The median time interval between MBO episodes was 44 days (range 6-2004). Complications were bowel perforation (n=5; 7%) and bowel ischemia (n=1; 1%). Conservative treatment was applied in 150 (91%) episodes, including gastrostomy in 4 (2%) episodes and octreotide in 79 (48%) episodes. Surgery was necessary in 15 (9%) episodes. Total parenteral nutrition was administered in 16 (22%) patients. During the study period 62 (85%) patients died (median 167 days since first MBO; range 6-2256). A significant difference in survival was found regarding the tumor marker CA 125 at cancer diagnosis, the use of palliative chemotherapy after the first episode of MBO and palliative surgical treatment for MBO in a group of well selected patients. Conclusion: Tubo-ovarian cancer patients with MBO have a poor prognosis: 85% of the study population died within a relatively short time interval since the first MBO. In our study population, the majority of patients with MBO were treated conservatively. Both palliative chemotherapy and palliative surgical management are considerable treatment options depending on the individual patient profile.

Poor Outcome in Postpartum Breast Cancer Patients Is Associated with Distinct Molecular and Immunologic Features.

PURPOSE: Patients with postpartum breast cancer diagnosed after cessation of breastfeeding (postweaning, PP-BCPW) have a particularly poor prognosis compared with patients diagnosed during lactation (PP-BCDL), or to pregnant (Pr-BC) and nulliparous (NP-BC) patients, regardless of standard prognostic characteristics. Animal studies point to a role of the involution process in stimulation of tumor growth in the mammary gland. However, in women, the molecular mechanisms that underlie this poor prognosis of patients with PP-BCPW remain vastly underexplored, due to of lack of adequate patient numbers and outcome data. EXPERIMENTAL DESIGN: We explored whether distinct prognostic features, common to all breast cancer molecular subtypes, exist in postpartum tumor tissue. Using detailed breastfeeding data, we delineated the postweaning period in PP-BC as a surrogate for mammary gland involution and performed whole transcriptome sequencing, immunohistochemical, and (multiplex) immunofluorescent analyses on tumor tissue of patients with PP-BCPW, PP-BCDL, Pr-BC, and NP-BC. RESULTS: We found that patients with PP-BCPW having a low expression level of an immunoglobulin gene signature, but high infiltration of plasma B cells, have an increased risk for metastasis and death. Although PP-BCPW tumor tissue was also characterized by an increase in CD8+ cytotoxic T cells and reduced distance among these cell types, these parameters were not associated with differential clinical outcomes among groups. CONCLUSIONS: These data point to the importance of plasma B cells in the postweaning mammary tumor microenvironment regarding the poor prognosis of PP-BCPW patients. Future prospective and in-depth research needs to further explore the role of B-cell immunobiology in this specific group of young patients with breast cancer.

Association of body mass index with clinicopathological features and survival in patients with primary invasive lobular breast cancer.

PURPOSE: Invasive lobular carcinoma (ILC) represents up to 15% of all breast carcinomas. While the proportion of women with overweight and obesity increases globally, the impact of body mass index (BMI) at primary diagnosis on clinicopathological features of ILC and the prognosis of the patients has not been investigated yet. PATIENTS AND METHODS: We performed a multicentric retrospective study including patients diagnosed with non-metastatic pure ILC. The association of BMI at diagnosis with clinicopathological variables was assessed using linear or multinomial logistic regression. Univariable and multivariable survival analyses were performed to evaluate the association of BMI with disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS). RESULTS: The data of 2856 patients with ILC and available BMI at diagnosis were collected, of which 2570/2856 (90.0%) had oestrogen receptor (ER)-positive and human epidermal growth factor receptor (HER2) not amplified/overexpressed (ER+/HER2-) ILC. Of these 2570 patients, 80 were underweight (3.1%), 1410 were lean (54.9%), 712 were overweight (27.7%), and 368 were obese (14.3%). Older age at diagnosis, a higher tumour grade, a larger tumour size, a nodal involvement, and multifocality were associated with a higher BMI. In univariable models, higher BMI was associated with worse outcomes for all end-points (DFS: hazard ratio (HR) 1.21, 95CI 1.12-1.31, p value<0.01; DRFS: HR 1.25, 95CI 1.12-1.40, p value<0.01; OS: HR 1.25, 95CI 1.13-1.37, p value<0.01). This association was not statistically significant in multivariable analyses (DFS: HR 1.09, 95CI 0.99-1.20, p value 0.08; DRFS: HR 1.03, 95CI 0.89-1.20, p value 0.67; OS: HR 1.11, 95CI 0.99-1.24, p value 0.08), whereas grade, tumour size, and nodal involvement were still prognostic for all end-points. CONCLUSION: Worse prognostic factors such as higher grade, larger tumour size, and nodal involvement are associated with higher BMI in ER+/HER2- ILC, while there was no statistical evidence for an independent prognostic role for BMI. Therefore, we hypothesise that the effect of BMI on survival could be mediated through its association with these clinicopathological variables.

Physiologic variations of serum tumor markers in gynecological malignancies during pregnancy: a systematic review.

BACKGROUND: Recent insights provide support for the treatment of cancer during pregnancy, a coincidence that poses both mother and fetus at risk. Our aim was to critically review studies on the physiologic variations during pregnancy, the most common tumor markers used in diagnosis and follow-up of gynecological cancers. METHODS: We conducted a systematic review of six tumor markers during normal pregnancy: carbohydrate antigen (CA) 15-3 (breast cancer); squamous cell carcinoma antigen (cervical cancer); and CA 125, anti-Müllerian hormone, inhibin B and lactate dehydrogenase (ovarian cancer). RESULTS: For CA 15-3, 3.3% to 20.0% of all measurements were above the cut-off (maximum 56 U/mL in the third trimester). Squamous cell carcinoma antigen values were above cut-off in 3.1% and 10.5% of the measurements (maximum 4.3 µg/L in the third trimester). Up to 35% of CA 125 levels were above cut-off: levels were highest in the first trimester, with a maximum value up to 550 U/mL. Inhibin B, anti-Müllerian hormone and lactate dehydrogenase levels were not elevated in maternal serum during normal pregnancy. CONCLUSION: During normal pregnancy, tumor markers including CA 15.3, squamous cell carcinoma antigen and CA 125 can be elevated; inhibin B, anti-Müllerian hormone and lactate dehydrogenase levels remain below normal cut-off values. Knowledge of physiological variations during pregnancy can be clinically important when managing gynecological cancers in pregnant patients.

Chemotherapy during pregnancy.

PURPOSE OF REVIEW: Cancer during pregnancy is uncommon, although not rare. As women in developed societies defer childbearing and the incidence of most malignancies rises with increasing age, the situation in which cancer complicates pregnancy is expected to become more common. Cancer staging and treatment can be performed during pregnancy and should be defined in a multidisciplinary setting. Here, we describe the potential to use chemotherapy during pregnancy. RECENT FINDINGS: New insights add to the practice of administering chemotherapy from 14 weeks gestational age onwards. The placental barrier function protects the fetus. The physiologic gestational changes reduce the maternal serum levels of chemotherapy, although the pharmacodynamic impact remains unknown. Comedication to chemotherapy can be administered on strict indications. Chemotherapy after 35 weeks is not recommended as an interval of at least 3 weeks is preferred between chemotherapy administration and delivery. Recent data show that the long-term outcome of children antenatally exposed to chemotherapy is comparable to children of the same age. Nevertheless, a higher rate of neurodevelopmental problems was encountered after preterm birth, also in this selected patient population. SUMMARY: Administration of chemotherapy during pregnancy may decrease the need for early delivery, and thus prematurity.