[Prioritising breast cancer care during the corona crisis]. / Prioritering van borstkankerzorg tijdens coronacrisis.

Over the past few months, regular care has been postponed where possible in order to increase the healthcare capacity for COVID-19 patients. The pressure imposed on the healthcare system by the new coronavirus has led to the need for the prioritising of breast cancer care. Several professional scientific and medical organisations have published proposals to prioritise oncological care. Due to the poor prognosis, care for patients with progressive disease during neoadjuvant systemic therapy and a triple negative, may not be postponed. In certain groups of patients, including those with ductal carcinoma in situ or an endocrine sensitive tumour, treatment may be postponed or modified, although with certain reservations.At the initiative of the NationaalBorstkankerOverleg Nederland, prospective data are currently being collected in order to gain more insight into the impact of COVID-19 on breast cancer care.

Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies: a phase I exposure escalation study.

BACKGROUND: (Pre)clinical evidence is accumulating that intermittent exposure to increased doses of protein kinase inhibitors may improve their treatment benefit. In this phase I trial, the safety of high-dose, pulsatile sorafenib was studied. PATIENTS AND METHODS: High-dose sorafenib was administered once weekly in exposure escalation cohorts according to a 3 + 3 design. Drug monitoring was performed in weeks 1-3 and doses were adjusted to achieve a predefined target plasma area under the curve (AUC)(0-12 h). The effect of low gastric pH on improving sorafenib exposure was investigated by intake of the acidic beverage cola. RESULTS: Seventeen patients with advanced malignancies without standard treatment options were included. Once weekly, high-dose sorafenib exposure was escalated up to a target AUC(0-12 h) of 125-150 mg/L/h, achieving a twofold higher Cmax compared to standard continuous dosing. Dose-limiting toxicity was observed in three patients: grade 3 duodenal perforation (2800 mg sorafenib), grade 5 multiorgan failure (2800 mg sorafenib) and grade 5 biliary tract perforation (3600 mg sorafenib). The mean difference between observed and target AUC(0-12 h) was 45% (SD ± 56%) in week 1 using a fixed starting dose of sorafenib compared to 2% (SD ± 32%) in week 3 as a result of drug monitoring (P = 0.06). Dissolving sorafenib in cola, instead of water, did not improve sorafenib exposure. Clinical benefit with stable disease as the best response was observed in two patients. CONCLUSION: Treatment with high-dose, once weekly sorafenib administration resulted in dose-limiting toxicity precluding dose escalation above the exposure cohort of 125-150 mg/L/h. Drug monitoring was a successful strategy to pursue a target exposure.

[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

Radiomics analysis of pre-treatment [18F]FDG PET/CT for patients with metastatic colorectal cancer undergoing palliative systemic treatment.

BACKGROUND: The aim of this study was to assess radiomics features on pre-treatment [18F]FDG positron emission tomography (PET) as potential biomarkers for response and survival in patients with metastatic colorectal cancer (mCRC). METHODS: Patients with mCRC underwent [18F]FDG PET/computed tomography (CT) prior to first- or third-line palliative systemic treatment. Tumour lesions were semiautomatically delineated and standard uptake value (SUV), metabolically active tumour volume (MATV), total lesion glycolysis (TLG), entropy, area under the curve of the cumulative SUV-volume histogram (AUC-CSH), compactness and sphericity were obtained. RESULTS: Lesions of 47 patients receiving third-line systemic treatment had higher SUVmax, SUVpeak, SUVmean, MATV and TLG, and lower AUC-CSH, compactness and sphericity compared to 52 patients receiving first-line systemic treatment. Therefore, first- and third-line groups were evaluated separately. In the first-line group, anatomical changes on CT correlated negatively with TLG (ρ = 0.31) and MATV (ρ = 0.36), and positively with compactness (ρ = -0.27) and sphericity (ρ = -0.27). Patients without benefit had higher mean entropy (p = 0.021). Progression-free survival (PFS) and overall survival (OS) were worse with a decreased mean AUC [hazard ratio (HR) 0.86, HR 0.77] and increase in mean MATV (HR 1.15, HR 1.22), sum MATV (HR 1.14, HR 1.19), mean TLG (HR 1.16, HR 1.22) and sum TLG (HT1.12, HR1.18). In the third-line group, AUC-CSH correlated negatively with anatomical change (ρ = 0.21). PFS and OS were worse with an increased mean MATV (HR 1.27, HR 1.68), sum MATV (HR 1.35, HR 2.04), mean TLG (HR 1.29, HR 1.52) and sum TLG (HT 1.27, HR 1.80). SUVmax and SUVpeak negatively correlated with OS (HR 1.19, HR 1.21). Cluster analysis of the 10 radiomics features demonstrated no complementary value in identifying aggressively growing lesions or patients with impaired survival. CONCLUSION: We demonstrated an association between improved clinical outcome and pre-treatment low tumour volume and heterogeneity as well as high sphericity on [18F]FDG PET. Future PET imaging research should include radiomics features that incorporate tumour volume and heterogeneity when correlating PET data with clinical outcome.

Optimal use of anti-EGFR monoclonal antibodies for patients with advanced colorectal cancer: a meta-analysis.

This meta-analysis was performed to determine the optimal use of anti-EGFR mAb in the treatment of metastasized colorectal cancer (mCRC). Seventeen randomized clinical trials were included, all evaluating the added value of anti-EGFR mAb to standard treatment line in patients with KRAS wild-type mCRC. Hazard and odds ratios were pooled using a random effect model, weighted according to cohort size. Pooled data of six first- and two second-line studies demonstrated a significantly improved ORR (OR 1.62, CI 1.27-2.04; OR 4.78, CI 3.39-6.75, respectively) and PFS (HR 0.79, CI 0.67-0.94; HR 0.80, CI 0.71-0.91, respectively) with the addition of anti-EGFR mAb to chemotherapy, while OS remained similar. Two third-line anti-EGFR mAb monotherapy studies revealed an improved PFS and OS (HR 0.44, CI 0.35-0.52; HR 0.55, CI 0.41-0.74). Addition of anti-EGFR versus anti-VEGF mAb to first-line chemotherapy was evaluated in three studies; ORR and PFS were comparable, while OS was improved (HR 0.8, CI 0.65-0.97). The influence of the chemotherapy backbone on anti-EGFR mAb efficacy, evaluated with meta-regression, indicated a higher ORR with irinotecan-based versus oxaliplatin-based regimens, but comparable PFS and OS. Reported toxicity (≥3 grade) increased ~20% in all treatment lines with the addition of anti-EGFR mAb. Anti-EGFR treatment significantly improves response and survival outcome of patients with (K)RAS wild-type mCRC, regardless of treatment line or chemotherapeutic backbone. Saving anti-EGFR mAb as third-line monotherapy is a valid and effective option to prevent high treatment burden caused by combination therapy. Combination treatment with anti-EGFR mAb to achieve radical resection of metastases needs further investigation.

Synchronous vs. Metachronous Metastases in Adrenocortical Carcinoma: an Analysis of the Dutch Adrenal Network.

Adrenal Cortical Carcinoma (ACC) is a rare malignancy with an incidence of 1.0 per million per year in the Netherlands. Median survival varies according to the European Network for the Study of Adrenal Tumours (ENS@T) tumour stage. It is unknown whether time until development of metastases is of influence on prognosis. To asses this, data were retrospectively obtained from centres of the Dutch Adrenal Network. Patients who presented with ACC between January 1, 2004 and October 31, 2013 were included. Date of detection of metastases, number of metastases and affected organs were registered. One hundred sixty patients were included in the analysis. Synchronous metastases were defined as diagnosis of metastasis ≤6 months after the initial diagnosis of ACC. Overall survival rate was calculated from the date of diagnosis of metastasis until death from any cause. At first presentation, 50 patients (31 %) had ACC with metastases (ENS@T stage IV). Another 67 (42 %) developed metastases during follow-up. Amongst the 117 patients with metastases, 84 (72 %) patients had synchronous metastases and 33 (28 %) developed metachronous metastases. Diagnosis of synchronous metastases (p = 0.046), more than one affected organ (p < 0.001) and four or more metastases (p < 0.001) were found to be associated with reduced overall survival. Limitations included retrospective design and limited details regarding pathological data. We conclude that synchronous metastases of ACC are associated with a poorer prognosis compared to metachronous metastases of ACC. The clinical characteristics associated with prognosis in this study support the view to refine the prognostic classification for patients with stage IV ACC.

Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial.

BACKGROUND: Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1. PATIENTS AND METHODS: HER2-positive mBC patients with IHC3+ or FISH ≥ 2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with (89)Zr-trastuzumab. [(18)F]2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2-PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant (89)Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load 'positive'); patterns C and D were considered negative (>50% or all of the tumor load 'negative'). Early FDG-PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2-PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF). RESULTS: In the 56 patients analyzed, 29% had negative HER2-PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2-PET/CT were 88%/72% and 83%/96% for early FDG-PET/CT. Combining HER2-PET/CT and FDG-PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months [n = 12, 95% confidence interval (CI) 1.4-7.6] from those with a TTF of 15 months (n = 25, 95% CI 9.7-not calculable). CONCLUSIONS: Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1. CLINICALTRIALSGOV IDENTIFIER: NCT01565200.

Epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2) are prognostic biomarkers for patients with resected colorectal cancer liver metastases.

BACKGROUND: Resection of colorectal cancer liver metastasis (CRCLM) with curative intent has long-term benefit in ~40% of cases. Prognostic biomarkers are needed to improve clinical management and reduce futile surgeries. Expression of epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2; also known as cyclooxygenase-2) has been associated with carcinogenesis and survival. We investigated the prognostic value of EGFR and PTGS2 expression in patients with resected CRCLM. METHODS: Formalin-fixed paraffin-embedded CRCLM tissue and corresponding primary tumour specimens from a multi-institutional cohort of patients who underwent liver resection between 1990 and 2010 were incorporated into tissue microarrays (TMAs). TMAs were stained for EGFR and PTGS2 by immunohistochemistry. The hazard rate ratio (HRR) for the association between expression in CRCLM and overall survival was calculated using a 500-fold cross-validation procedure. RESULTS: EGFR and PTGS2 expression could be evaluated in 323 and 351 patients, respectively. EGFR expression in CRCLM was associated with poor prognosis (HRR 1.54; P<0.01) with a cross-validated HRR of 1.47 (P=0.03). PTGS2 expression was also associated with poor prognosis (HRR 1.60; P<0.01) with a cross-validated HRR of 1.63 (P<0.01). Expression of EGFR and PTGS2 remained prognostic after multivariate analysis with standard clinicopathological variables (cross-validated HRR 1.51; P=0.02 and cross-validated HRR 1.59; P=0.01, respectively). Stratification for the commonly applied systemic therapy regimens demonstrated prognostic value for EGFR and PTGS2 only in the subgroup of patients who were not treated with systemic therapy (HRR 1.78; P<0.01 and HRR 1.64; P=0.04, respectively), with worst prognosis when both EGFR and PTGS2 were highly expressed (HRR 3.08; P<0.01). Expression of PTGS2 in CRCLM was correlated to expression in patient-matched primary tumours (P=0.02, 69.2% concordance). CONCLUSIONS: EGFR and PTGS2 expressions are prognostic molecular biomarkers with added value to standard clinicopathological variables for patients with resectable CRCLM.

[Cardiotoxicity of trastuzumab of significance in the adjuvant treatment of breast cancer]. / Cardiotoxiciteit van trastuzumab van betekenis bij de adjuvante behandeling van borstkanker.

Three women aged 53, 52 and 36 years, respectively, underwent surgery for breast cancer, i.e. right-sided grade II invasive ductal carcinoma, left-sided grade III invasive ductal carcinoma, and left-sided multifocal grade III invasive ductal carcinoma, respectively. All 3 received adjuvant anthracycline-containing chemotherapy followed by trastuzumab. They developed significant cardiac dysfunction, as determined by a decrease in left ventricular ejection fraction (LVEF), which necessitated trastuzumab discontinuation. Trastuzumab therapy was resumed in the third patient after LVEF recovery but was stopped definitively when the LVEF decreased again. Trastuzumab has been shown to improve both disease-free and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, symptomatic cardiac failure due to cardiomyopathy has been observed in 0.6-4.1% of patients treated with trastuzumab after adjuvant anthracycline-based chemotherapy, whereas in 5-19% of the patients the decline in cardiac function led to permanent discontinuation of trastuzumab therapy. Cardiac function should be monitored regularly during trastuzumab therapy. An LVEF less than 50% or an absolute reduction of more than 10% warrant treatment discontinuation and close follow-up. Cardiac dysfunction is usually reversible; however, the long-term consequences of LVEF reduction following trastuzumab therapy are still unknown and warrant close attention, given the relatively young age and long life expectancy of these patients.

Pheochromocytoma mimicking an acute myocardial infarction.

We report a 42-year-old female who presented with retrosternal pain, dyspnoea and nausea. Electrocardiography suggested a recent anterior myocardial infarction. However, emergency coronary angiography showed normal blood flow through all the coronary arteries. Paroxysmal hypertension raised the suspicion of a pheochromocytoma. Indeed, abdominal ultrasonography and computed tomography revealed a mass in the left adrenal gland. Elevated levels of plasma and urine catecholamines supported the diagnosis of pheochromocytoma. Left adrenalectomy was performed without complications and pathological examination revealed a 5.5 cm pheochromocytoma. After surgery, all antihypertensive medication was discontinued and the blood pressure returned to normal within several days. Currently, the patient is asymptomatic, has normal catecholamine levels and the electrocardiographic signs of ischaemia have resolved entirely. This case illustrates that a rare clinical entity such as pheochromocytoma should be considered in the differential diagnosis of acute coronary syndrome. (Neth Heart J 2007;15:248-51.).