MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study.

BACKGROUND: Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response. METHODS: TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing. FINDINGS: Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43-59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours. The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]). No treatment-related deaths were reported. INTERPRETATION: In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer. FUNDING: Roche Netherlands.

Clinical Guidance for Dosing and Monitoring Oral Antihormonal Drugs in Patients with Breast Cancer After Roux-en-Y Gastric Bypass.

ABSTRACT: Obesity is associated with an increased risk of cancers, such as breast cancer. Roux-en-Y gastric bypass (RYGB) is a common surgical intervention used to induce weight loss, reduce comorbidities, and improve overall survival. Due to alterations in the gastrointestinal tract, RYGB is associated with changes in oral drug disposition, which can affect treatment outcomes. Oral antihormonal agents were monitored in 9 patients who previously underwent RYGB. The results of therapeutic drug monitoring and estradiol concentrations were analyzed, and a review of the relevant literature was performed. As only 1 of the 6 patients prescribed tamoxifen achieved a therapeutic endoxifen concentration with the standard dose of 20 mg/d, a higher starting dose of 40 mg/d was recommended to increase the probability of attaining a therapeutic plasma concentration. All patients with decreased CYP2D6 metabolic activity could not achieve therapeutic plasma concentrations; therefore, CYP2D6 genotyping was recommended before the initiation of tamoxifen therapy to identify patients who should be switched to aromatase inhibitors. Anastrozole and letrozole exposure in patients who underwent RYGB patients appeared sufficient, with no dose adjustment required. However, until more data become available, monitoring aromatase inhibitor efficacy is recommended. Monitoring the drug concentrations is a viable option; however, only indicative data on therapeutic drug monitoring are available. Therefore, estradiol concentrations should be measured.

Ribociclib plus letrozole in male patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: subgroup analysis of the phase IIIb CompLEEment-1 trial.

PURPOSE: CompLEEment-1 (NCT02941926) is a single-arm, open-label, multicentre phase IIIb study investigating the safety and efficacy of ribociclib plus letrozole (RIB + LET) in a large, diverse cohort who have not received prior endocrine therapy (ET) for advanced disease. We present an exploratory analysis of male patients. METHODS: Eligible patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), who had no prior ET and ≤ 1 line of prior chemotherapy for advanced disease, received RIB + LET. Male patients also received goserelin or leuprolide. Primary endpoint was safety and tolerability; efficacy was a secondary endpoint. RESULTS: In total, 39/3246 patients were male. Baseline characteristics were similar to the overall population. Male patients experienced fewer treatment-related adverse events (AEs) and treatment-related serious AEs compared with the overall population; fewer male patients had treatment-related AEs leading to discontinuation, adjustment/interruption, or additional therapy. One male patient died as a result of a serious AE that was not considered to be treatment-related. The most common AE was neutropenia; the incidence of grade ≥ 3 neutropenia in males (41.0%) was lower than in the overall population (57.2%). Median follow-up was 25.4 months; median time to progression was not reached in males versus 27.1 months for the overall population. CONCLUSION: The clinical benefit and overall response rates in males were consistent with the overall population. This analysis demonstrates the safety and efficacy of ribociclib in a close-to-real-world setting, supporting the use of RIB + LET in male patients with HR+, HER2- ABC. TRIAL REGISTRATION NUMBER: NCT02941926 (Registered 2016).

Extravasation of an antibody-drug conjugate: A case report of epidermal necrosis after trastuzumab-emtansine extravasation.

WHAT IS KNOWN AND OBJECTIVE: Trastuzumab-emtansine is an antibody-drug conjugate developed to decrease off-target toxicity. According to the product label, reactions secondary to extravasation are mild or moderate. CASE SUMMARY: We report on a 51-year-old woman who developed epidermal necrosis after extravasation of trastuzumab-emtansine, which required surgical intervention. Six weeks later, the lesions were healed with residual hyperpigmentation. WHAT IS NEW AND CONCLUSION: We describe the course of a case of severe toxicity following trastuzumab-emtansine extravasation. We provide treatment recommendations and recommend amending the information on the product label on extravasation.

Real-world palbociclib effectiveness in patients with metastatic breast cancer: Focus on neutropenia-related treatment modification strategies and clinical outcomes.

INTRODUCTION: In addition to clinical trials, real-world data is needed to verify the effectiveness of the CDK 4/6 inhibitor palbociclib. The primary aim was to examine real-world variation in treatment modification strategies for neutropenia and its relation to progression-free survival (PFS). The secondary aim was to assess if there is a gap between real-world and clinical trial outcomes. MATERIALS AND METHODS: In this multicenter, retrospective observational cohort study 229 patients were analyzed who started palbociclib and fulvestrant as second- or later-line therapy for HR-positive, HER2-negative metastatic breast cancer in the Santeon hospital group in the Netherlands between September 2016 and December 2019. Data were manually retrieved from patients' electronic medical records. PFS was examined using the Kaplan-Meier method to compare neutropenia-related treatment modification strategies within the first three months after neutropenia grade 3 - 4 occurred, as well as patients' eligibility to have participated in the PALOMA-3 clinical trial or not. RESULTS: Even though treatment modification strategies differed from those in PALOMA-3 (dose interruptions: 26 vs 54%, cycle delays: 54 vs 36%, and dose reductions: 39 vs 34%), these did not influence PFS. Patients who were PALOMA-3 ineligible experienced a shorter median PFS than those who were eligible (10.2 vs. 14.1 months; HR 1.52; 95% CI 1.12 - 2.07). An overall longer median PFS was found compared to PALOMA-3 (11.6 vs. 9.5 months; HR 0.70; 95% CI 0.54 - 0.90). CONCLUSION: This study suggests no impact of neutropenia-related treatment modifications on PFS and confirms inferior outcomes outside clinical trial eligibility.

A prognostic model for short term adverse events in normotensive patients with pulmonary embolism.

Risk stratification of patients with PE has gained interest in terms of the identification of patients in whom treatment on an outpatient base can be considered. Previous studies are of limited value due to their focus on adverse clinical events within several months after diagnosis of PE. We developed a prognostic model, based on easily accessible, clinical, and laboratory parameters, to predict adverse events during the first 10 days after the diagnosis of acute PE. We have analyzed the data of 210 outpatients with confirmed PE. Collected data included medical history, pulse rate, blood pressure, NT-proBNP, and D-dimer concentrations. The primary outcome was the occurrence of adverse clinical events in a 10 day follow-up period. Our final prognostic model to predict short-term adverse events consists of NT-proBNP levels, D-dimer concentrations, pulse rate, and the occurrence of active malignancy; the total score ranges from 0 to 37 points. Patients with a low score (no active malignancy, pulse rate <90 bpm, NT-proBNP <500 pg/ml, and D-dimer <3,000 µg/l FEU) have a 10-day adverse event risk <1.5%. This risk increases to over 30% in patients with a maximum score, based on high pulse rate, D-dimer concentrations, and NT-proBNP levels. Our prognostic model, once prospectively validated in an independent sample of patients, can be used in the early risk stratification of PE to estimate the risk of adverse events and to differentiate between candidates for in- or out- hospital treatment.

Risk stratification of patients with pulmonary embolism based on pulse rate and D-dimer concentration.

To enable outpatient treatment of a selected group of patients with pulmonary embolism (PE), insight in the determinants of adverse clinical outcome is warranted. We have identified risk factors for serious adverse events (SAE) within the first 10 days of acute PE. We have retrospectively analysed data of 440 consecutive patients with acute PE. Collected data included age, gender, medical history, blood pressure, pulse rate and D-dimer concentration. The variables associated with SAE in the first 10 days in univariate analysis (p<0.15) have been included in a multivariate logistic regression model (backward conditional, p out >0.10). In 440 patients with acute PE, 20 SAEs occurred in a 10-day follow-up period. Pulse rate > or = 100 beats per minute (bpm) (OR, 6.85; 95%CI 1.43-32.81) and D-dimer concentration > or = 3,000 microg/ml (OR, 5.51; 95%CI 0.68-44.64) were significantly related to the SAEs. All SAEs were predicted by a pulse rate > or = 100 bpm and/or a D-dimer concentration > or = 3,000 microg/ml. Older age, gender, history of venous thromboembolism (VTE), heart failure, chronic obstructive pulmonary disease, cancer or a systolic blood pressure < 90 mm Hg had no significant influence on short term SAEs. Pulse rate and D-dimer concentration can be used to identify patients with acute PE, who are at risk for adverse clinical outcome during the first 10 days of hospitalisation. Outpatient treatment of PE-patients with a pulse rate > or = 100 bpm and/or a D-dimer concentration > or = 3,000 microg/ml has to be discouraged.

Real-World Effectiveness of Palbociclib Versus Clinical Trial Results in Patients With Advanced/Metastatic Breast Cancer That Progressed on Previous Endocrine Therapy.

OBJECTIVE: The aim of this study was to assess the real-world effectiveness and tolerability of palbociclib combined with endocrine therapy for the treatment of hormone receptor positive (HR-positive), human epidermal growth factor receptor 2 negative (HER2-negative), advanced/metastatic breast cancer that progressed on previous endocrine therapy, and to compare these results with the outcomes of the PALOMA-3 clinical trial. METHODS: This study was a retrospective observational cohort study including all patients who started with palbociclib in the St. Antonius Hospital between September 1, 2016 and April 1, 2018 for the treatment of HR-positive, HER2-negative advanced/metastatic breast cancer that progressed on previous endocrine therapy. Individual patient data were collected from electronic medical records. Primary study outcomes were progression-free survival (PFS) and the number of permanent treatment discontinuations before disease progression due to adverse events (AEs). Secondary outcomes were the frequency of all (serious) AEs and the frequency of and reasons for dose reductions, -interruptions and cycle delays. RESULTS: A total of 46 patients were studied with a median follow-up of 13.0 months. Overall, the median PFS in real-world clinical practice was 10.0 months (95% confidence interval (CI) 4.9-15.1), compared with 9.5 months in PALOMA-3 (95% CI 9.2-11.0). Two patients discontinued treatment because of AEs. Neutropenia was the most frequent grade 3-4 AE, but with no febrile neutropenia events. Most AEs were managed with palbociclib dose modifications. Regarding these modifications, more cycle delays, less dose reductions, and less dose interruptions occurred in clinical practice compared with PALOMA-3 (59 vs 36%, 22 vs 34%, and 9 vs 54%, respectively). Patients who did not meet the PALOMA-3 study eligibility criteria (n = 16) showed a lower median PFS of 5.5 months (95% CI 4.7-6.4). CONCLUSIONS: The effectiveness and tolerability of palbociclib in real-world clinical practice corresponded well with the results obtained in the PALOMA-3 clinical trial. Despite the differences in dose modifications, this study suggests that there is no efficacy-effectiveness gap in this patient population.

The role of fibrin monomers in optimizing the diagnostic work-up of deep vein thrombosis.

Despite the use of a clinical score and D-dimers to exclude deep vein thrombosis (DVT), the majority of patients still need repeated ultrasound (US). The aim of the study was to investigate whether fibrin monomers (FMs), as markers of thrombin generation, have additional value in the diagnosis of DVT. This is a posthoc analysis of 464 outpatients, participants in a management study using D-dimers (Tina-Quant and a clinical score in the exclusion of DVT. Two new FM assays (Auto LIA-FM and IATRO SF, Japan) were performed. Overall sensitivity, negative predictive value (NPV) and specificity of the D-dimer test were 98%, 98% and 42%. The optimal cut-off point for the Auto LIA-FM test was

Out of hospital anticoagulant therapy in patients with acute pulmonary embolism is frequently practised but not perfect.

INTRODUCTION: Traditionally, patients with pulmonary embolism (PE) are treated in-hospital until they reach an adequate international normalized ratio (INR). Analogous to patients with a deep venous thrombosis, therapy with low-molecular-weight heparin facilitates out of hospital treatment of PE. We retrospectively analysed the current practice of early anticoagulant therapy in 86 acute PE patients with emphasis on the occurrence and safety of outpatient treatment. METHODS: Data were collected from two large regional teaching hospitals and from a specialized anticoagulation clinical, where patients were followed in the period after hospital discharge. The course of hospitalization and LMWH transitioning therapy and the quality of treatment in the first three months after diagnosis were compared between patients discharged before and patients discharged after reaching adequate INR. RESULTS: Forty-four patients (51.2%) were discharged early, before reaching an adequate INR, and 42 patients (48.8%) were discharged after reaching adequate INR. Early discharged patients needed more time to reach adequate INR compared to other patients (13 versus 6 days). In 28 patients (32.6%), the LMWH transitioning therapy was stopped prematurely; 21 patients were from the early discharged group. During the first 3 months, the mean individual times below, in and above the INR range were equal between the two groups. CONCLUSION: Enhanced compliance to existing guidelines and tools, and further development of guidelines, with focus on intensification of monitoring of INR values in an outpatient setting and preventing premature discontinuation of transitioning therapy, are warranted for a safe and early discharge of stable patients with PE.