Heregulin (HRG) assessment for clinical trial eligibility testing in a molecular registry (PRAEGNANT) in Germany.

BACKGROUND: Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry. METHODS: Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor-positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria. RESULTS: Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive. CONCLUSION: Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials. TRIAL REGISTRATION: Clinicaltrials, NCT02338167 , Registered 14 January 2015 - retrospectively registered.

Risk assessment of venous thromboembolism and thromboprophylaxis in pregnant women hospitalized with cancer: Preliminary results from a risk score.

OBJECTIVES: Hospitalized patients with cancer are at high risk of developing venous thromboembolism, and the risk increases with pregnancy. The aim of this study was to apply a thromboprophylaxis protocol with a venous thromboembolism risk score for hospitalized pregnant women with cancer and to evaluate the effects on maternal morbidity and mortality. METHODS: A longitudinal and prospective study was conducted from December 2014 to July 2016. The venous thromboembolism risk score was modified from the guidelines of the Royal College of Obstetricians and Gynaecologists. Patients were classified as low (score <3) or high risk (score ≥3). The high-risk group received thromboprophylaxis with low-molecular-weight heparin, unless the patient had a contraindication for anticoagulation. One patient could have undergone more than one evaluation. RESULTS: Fifty-two ratings were descriptively analyzed: 34 (65.4%) were classified as high risk, and 28/34 (82.3%) received low-molecular-weight heparin, 1 received unfractionated heparin, and 5 did not receive intervention. Most patients (23/52; 44.2%) had breast cancer. The main risk factors for venous thromboembolism in the high-risk group were chemotherapy (within 6 months; 22/34; 64.7%). No patient exhibited venous thromboembolism, adverse effects of anticoagulation or death up to three months after hospitalization. CONCLUSIONS: Most pregnant women with cancer had a high risk for venous thromboembolism at the time of hospitalization. Breast cancer was the most prevalent cancer, and recent chemotherapy was the main risk factor for anticoagulation. The application of a thromboprophylaxis protocol and determination of a venous thromboembolism risk score for these patients was useful for the prevention of maternal morbidity and mortality due to venous thromboembolism.

Genetic and microscopic assessment of the human chemotherapy-exposed placenta reveals possible pathways contributive to fetal growth restriction.

INTRODUCTION: Fetal growth restriction (FGR) carries an increased risk of perinatal mortality and morbidity. A major cause of FGR is placental insufficiency. After in utero chemotherapy-exposure, an increased incidence of FGR has been reported. In a prospective cohort study we aimed to explore which pathways may contribute to chemotherapy-associated FGR. METHODS: Placental biopsies were collected from 25 cancer patients treated with chemotherapy during pregnancy, and from 66 control patients. Differentially expressed pathways between chemotherapy-exposed patients and controls were examined by whole transcriptome shotgun sequencing (WTSS) and Ingenuity Pathway Analysis (IPA). Immunohistochemical studies for 8-OHdG and eNOS (oxidative DNA damage), proliferation (PCNA) and apoptosis (Cleaved Caspase 3) were performed. The expression level of eNOS, PCNA and IGFBP6 was verified by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). RESULTS: Most differential expressed genes between chemotherapy-exposed patients and controls were related to growth, developmental processes, and radical scavenging networks. The duration of chemotherapy exposure had an additional impact on the expression of genes related to the superoxide radicals degeneration network. Immunohistochemical analyses showed a significantly increased expression of 8-OHdG (P = 0.003) and a decreased expression of eNOS (P=0.015) in the syncytiotrophoblast of the placenta of cancer patients. A decreased expression of PCNA was detected by immunohistochemistry as RT-qPCR (NS). CONCLUSION: Chemotherapy exposure during pregnancy results in an increase of oxidative DNA damage and might impact the placental cellular growth and development, resulting in an increased incidence of FGR in this specific population. Further large prospective cohort studies and longitudinal statistical analyses are needed.

Risk assessment of venous thromboembolism and thromboprophylaxis in pregnant women hospitalized with cancer: Preliminary results from a risk score

OBJECTIVES: Hospitalized patients with cancer are at high risk of developing venous thromboembolism, and the risk increases with pregnancy. The aim of this study was to apply a thromboprophylaxis protocol with a venous thromboembolism risk score for hospitalized pregnant women with cancer and to evaluate the effects on maternal morbidity and mortality. METHODS: A longitudinal and prospective study was conducted from December 2014 to July 2016. The venous thromboembolism risk score was modified from the guidelines of the Royal College of Obstetricians and Gynaecologists. Patients were classified as low (score <3) or high risk (score ≥3). The high-risk group received thromboprophylaxis with low-molecular-weight heparin, unless the patient had a contraindication for anticoagulation. One patient could have undergone more than one evaluation. RESULTS: Fifty-two ratings were descriptively analyzed: 34 (65.4%) were classified as high risk, and 28/34 (82.3%) received low-molecular-weight heparin, 1 received unfractionated heparin, and 5 did not receive intervention. Most patients (23/52; 44.2%) had breast cancer. The main risk factors for venous thromboembolism in the high-risk group were chemotherapy (within 6 months; 22/34; 64.7%). No patient exhibited venous thromboembolism, adverse effects of anticoagulation or death up to three months after hospitalization. CONCLUSIONS: Most pregnant women with cancer had a high risk for venous thromboembolism at the time of hospitalization. Breast cancer was the most prevalent cancer, and recent chemotherapy was the main risk factor for anticoagulation. The application of a thromboprophylaxis protocol and determination of a venous thromboembolism risk score for these patients was useful for the prevention of maternal morbidity and mortality due to venous thromboembolism.

A benefit-risk assessment of imatinib in chronic myeloid leukaemia and gastrointestinal stromal tumours.

Targeting constitutively activated tyrosine kinases, such as BCR-ABL, in chronic myeloid leukaemia (CML) and c-KIT in gastrointestinal stromal tumours (GIST) has substantially changed the clinical management of both diseases. The introduction of imatinib, a tyrosine kinase inhibitor mainly targeting BCR-ABL, c-KIT and PDGFR, has profoundly improved the prognosis of both entities, while being surprisingly well tolerated. This article summarizes recent data on clinical efficacy as well as safety aspects of imatinib for treatment of CML and GIST, including a final benefit-risk assessment. Imatinib induces high rates of cytogenetic and molecular responses in all phases of CML and also has substantial activity in GIST patients. In both diseases, only a few adverse effects, such as musculoskeletal and joint pain, muscle cramps, oedema and gastrointestinal symptoms, occur. Most of these are grade I or II toxicities and generally occur during the early phase of treatment (i.e. within the first 2 years). Thus, in view of the low rates of severe toxicities and the extraordinary efficacy of the drug in both diseases, imatinib represents an oral drug with a high benefit-risk ratio for the treatment of CML and GIST.

Reproductive health assessment for women with cancer: a pilot study.

OBJECTIVE: The purpose of this study was to pilot a survey instrument and to develop descriptive data about the reproductive goals of reproductive-aged women (15-44 years) with cancer. STUDY DESIGN: This was a cross-sectional pilot survey study of 20 women who were diagnosed with various types of cancers at the oncology clinic of Stroger Hospital of Cook County, Chicago, from January-July 2006. RESULTS: Of the 20 patients whose cases were surveyed, the mean age was 36.6 years, and 90% of the women had breast cancer. Ten percent of patients would continue pregnancy, if they became pregnant while receiving treatment. Contraception was used by 55% of patients (n = 11), of whom 55% of the women (n = 6) were using abstinence. CONCLUSION: The result of this pilot study demonstrates the need for reproductive health counseling in women with cancer; the range of discussion must include fertility interest, contraception, and fertility preservation.

Assessment of fetal risk associated with exposure to cancer chemotherapy during pregnancy: a multicenter study.

The objective of the present study was to evaluate and quantify fetal risks involved in the administration of cancer chemotherapy during gestation, as well as to assess the long-term effects on the exposed children. In this retrospective, cohort study, we reviewed the records of women aged 15 to 45 years with a diagnosis of malignancy or benign tumors with malignant behavior at three reference services in the State of Rio Grande do Sul, Brazil, from 1990 to 1997. All patients with a diagnosis of pregnancy at any time during the course of the disease were selected, regardless of whether or not they received specific medication. Fetal outcomes of 14 pregnancies with chemotherapy exposure were compared to that of 15 control pregnancies in which these drugs were not used. Long-term follow-up of the exposed children was carried out. Fisher's exact test was used to compare the groups. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. We found an increased rate of prematurity (6/8 vs 2/10; RR: 3.75; CI: 1.02-13.8; P = 0.03) in the exposed group. There was a trend to an increased fetal death rate (4/12 vs 0/10; P = 0.07) in the group exposed to chemotherapy. No malformations were detected in any child, which can be related to our small sample size as well as to the fact that most exposures occurred after the first trimester of pregnancy. Other larger, controlled studies are needed to establish the actual risk related to cancer chemotherapy during pregnancy.

Weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease.

Patients with nonmetastatic gestational trophoblastic disease were entered into this Gynecologic Oncology Group study to determine the efficacy, toxicity, and cost-effectiveness of weekly intramuscular (IM) methotrexate. Treatment was initiated with 30 mg/m2 of weekly IM methotrexate. If no major toxicity was encountered, the weekly dose was escalated 5 mg/m2 at three-week intervals until a maximum dose of 50 mg/m2 each week was achieved. Complete response was defined as three normal beta-hCG values measured on consecutive weeks. Fifty-one of 63 evaluable patients (81%) had a complete response to weekly IM methotrexate. Duration of therapy ranged from three to 19 weeks, with a median of seven. No major toxicity occurred. Thirteen patients experienced leukopenia at a median of 3300/microL, with a range of 2300-3900. Three patients had platelet nadirs of 66,000, 127,000, and 135,000/microL. Eleven patients with weekly IM methotrexate failure had a complete response after one to eight courses of dactinomycin administered 0.5 mg/m2 intravenously daily for five days; one refused therapy after three courses. Weekly IM methotrexate for nonmetastatic gestational trophoblastic disease is efficacious, minimally toxic, and cost-effective.

Metastatic pheochromocytoma in pregnancy and fetal biophysical assessment after maternal administration of alpha-adrenergic, beta-adrenergic, and dopamine antagonists.

Metastatic pheochromocytoma, a rare complication of pregnancy, was managed from 30 weeks' gestation until delivery three weeks later with a combination of alpha-adrenergic blockade (Minipres) beta-adrenergic blockade (Timolol), and dopamine synthesis inhibition (Demser). The biophysical parameters of fetal heart rate (FHR) baseline, variability, and reactivity, as well as fetal breathing movements, body movements, tone, and amniotic fluid volume were followed sequentially during this period. A 1450-g growth-retarded infant, who subsequently did well, was delivered by cesarean section; the mother received combined surgical and medical therapy for her metastatic disease in the postpartum period. The initial fetal biophysical alteration observed was a reduction in mean FHR baseline rate; further biophysical test abnormalities appeared only after overt fetal compromise was evident. Sequential multiple parameter biophysical testing in such circumstances appears to be a valid and valuable approach to antepartum management.

Pulse actinomycin D scheduling in nonmetastatic gestational trophoblastic neoplasia: cost-effective chemotherapy.

The currently accepted method of treatment of patients with nonmetastatic gestational trophoblastic neoplasia (NMGTN) is single-agent chemotherapy. While methotrexate and actinomycin D have shown superiority over other cytotoxic agents, doses of drug and length of treatment are subject to controversy. Recently, the demonstration of the long half-life of actinomycin D in both animal models and humans has necessitated a reevaluation of the method of administration of this drug for NMGTN. Following the demonstration of minimal severe toxicity of pulse actinomyin-D scheduling by E. S. Petrilli and C. P. Morrow (Actinomycin D toxicity in the treatment of trophoblastic disease, Gynecol. Oncol. 9, 18-22 (1980), 12 consecutive patients with nonmetastatic gestational trophoblastic neoplasia were treated. The remission rates, toxicity, and cost effectiveness of pulse actinomycin-D scheduling in these 12 patients are reported.