The impact of endoxifen-guided tamoxifen dose reductions on endocrine side-effects in patients with primary breast cancer.

BACKGROUND: Tamoxifen is important in the adjuvant treatment of hormone-sensitive breast cancer and substantially reduces recurrence; however, almost 50% of patients are non-compliant mainly due to side-effects. The aim of this study was to investigate whether endoxifen-guided tamoxifen dose reduction could lead to fewer side-effects. MATERIALS AND METHODS: Effects of tamoxifen dose reduction were investigated in patients with bothersome side-effects and endoxifen levels ≥32 nM and compared to patients with side-effects who remained on tamoxifen 20 mg. Endocrine symptoms and health-related quality of life (HR-QOL) were assessed after 3 months with the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire. RESULTS: Tamoxifen dose was reduced in 20 patients, 17 of whom were assessable for side-effect analyses. A clinically relevant improvement of >6 points was observed in endocrine symptoms and HR-QOL in 41% and 65% of the patients, respectively. In total, there was a significant and clinically relevant improvement in endocrine symptoms [5.7, 95% confidence interval (CI) -0.5-11.5] and HR-QOL (8.2, 95% CI 0.9-15.4) after dose reduction. This was not seen in patients whose doses were not reduced (n = 60). In 21% of patients, endoxifen dropped slightly below the 16-nM threshold (12.8, 15.5, 15.8, 15.9 nM). CONCLUSIONS: Endoxifen-guided dose reduction of tamoxifen significantly improved tamoxifen-related side-effects and HR-QOL. Nearly 80% of patients remained above the most conservative endoxifen threshold.

Cardiotoxicity during long-term trastuzumab use in patients with HER2-positive metastatic breast cancer: who needs cardiac monitoring?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted. METHODS: We included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40-50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab. RESULTS: In total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8-31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity. CONCLUSIONS: Serial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.

Radiological complete remission in HER2-positive metastatic breast cancer patients: what to do with trastuzumab?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab may experience durable tumor response for many years. It is unknown if patients with durable radiological complete remission (rCR) can discontinue trastuzumab. We analyzed clinical characteristics associated with rCR and overall survival (OS) in a historic cohort of patients with HER2-positive MBC and studied the effect of stopping trastuzumab in case of rCR. METHODS: We included patients with HER2-positive MBC treated with first or second-line trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Data were collected from medical records. We used multivariable regression models to identify independent prognostic factors for rCR and OS. Time-to-progression after achieving rCR for patients who continued and stopped trastuzumab, and breast cancer-specific survival were also evaluated. RESULTS: We identified 717 patients with a median age of 53 years at MBC diagnosis. The median follow-up was 109 months (IQR 72-148). The strongest factor associated with OS was achievement of rCR, adjusted hazard ratio 0.27 (95% CI 0.18-0.40). RCR was observed in 72 patients (10%). The ten-year OS estimate for patients who achieved rCR was 52 versus 7% for patients who did not achieve rCR. Thirty patients with rCR discontinued trastuzumab, of whom 20 (67%) are alive in ongoing remission after 78 months of median follow-up since rCR. Of forty patients (58%) who continued trastuzumab since rCR, 13 (33%) are in ongoing remission after 68 months of median follow-up. Median time-to-progression in the latter group was 14 months. CONCLUSIONS: Achieving rCR is the strongest predictor for improved survival in patients with HER2-positive MBC. Trastuzumab may be discontinued in selected patients with ongoing rCR. Further research is required to identify patients who have achieved rCR and in whom trastuzumab may safely be discontinued.

ANCA-Positive Patients: The Influence of PR3 and MPO Antibodies on Survival Rate and The Association with Clinical and Laboratory Characteristics.

OBJECTIVES: To compare the survival rate, and the clinical and laboratory characteristics in patients, characterized by the presence of certain anti-neutrophil cytoplasmic auto-antibodies (ANCAs). METHODS: In a retrospective observational study, we analyzed the data of all patients with a positive ANCA test between 1995 and 2005 at our hospital. Based on serology patients were divided in three subgroups (ANCA-Proteinase 3 (PR3), ANCA-Myeloperoxidase (MPO) and atypical ANCA), irrespective of the diagnosis. Patient survival was compared by Kaplan Meier survival analysis. Differences in clinical and laboratory characteristics between the groups of specific ANCAs were determined. RESULTS: Fifty-four ANCA-positive patients were analyzed. Eighteen of these patients were ANCA-PR3-positive, 17 were ANCA-MPO-positive and 19 had a atypical ANCA. A random control group was created of matched ANCA negative patients. Average follow-up time was 52 months. The calculated five year survival rate in respectively the ANCA-PR3- positive group, the ANCA-MPO-positive group, the atypical ANCA group and the ANCA-negative group was 45%, 81%, 90% and 100%. (P = 0.012, Wilcoxon test). A higher mean leukocyte count, a higher mean erythrocyte sedimentation rate and more fever was observed in the ANCA-PR3-positive group compared to the ANCA-MPO-positive group. CONCLUSIONS: A remarkable lower survival rate was observed in ANCA-PR3-positive patients compared to ANCA-MPO-positive patients. We also demonstrated that patients characterized by the presence of a defined ANCA differ in clinical and laboratory characteristics.

Ethnic differences in prenatal growth and the association with maternal and fetal characteristics.

OBJECTIVES: The objectives of this study were to determine ethnic differences in prenatal growth and to examine their association with differences in maternal and fetal characteristics such as maternal height, weight, age, parity and fetal gender. METHODS: A total of 1494 women from Rotterdam, The Netherlands, with a low-risk pregnancy who participated in a population-based cohort study, the Generation R Study, were offered three ultrasound examinations during pregnancy. Multilevel modeling was applied to determine ethnic differences in (estimated) fetal weight (including birth weight) and in the separate biometric variables that were used to calculate the estimated fetal weight (abdominal circumference, head circumference and femur length). Additionally the association of ethnic differences with maternal and fetal characteristics (i.e. maternal weight, height, age, parity and fetal gender) was studied. RESULTS: Turkish, Cape Verdian, Surinamese-Creole and Surinamese-Hindustani women had on average smaller fetuses than the native Dutch women. The differences became more pronounced towards term. In the Turkish group the differences were no longer statistically significant when adjusted for maternal weight, height, age, parity and fetal gender. In the Cape Verdian, Surinamese-Creole and Surinamese-Hindustani groups the differences decreased after adjustment (31%, 16% and 39%, respectively). CONCLUSIONS: This study shows that there are ethnic differences in fetal growth, which to a large extent may be attributed to differences in maternal weight, height, age and parity. For some ethnic groups, however, additional factors are involved, as differences remain significant after correction for fetal and maternal characteristics.