Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial.

BACKGROUND: DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline. PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR. RESULTS: As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1. CONCLUSIONS: Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.

The impact of age on vitamin D receptor expression, vitamin D metabolism and cytokine production in ex vivo Rhodococcus equi infection of equine alveolar macrophages.

Rhodococcus equi (R. equi), a pneumonia-causing intracellular bacterium, results in significant morbidity and mortality in young foals, while healthy adult horses rarely develop disease. Survival and replication within alveolar macrophages (AMφ) are the hallmarks of R. equi's pathogenicity. The vitamin D receptor (VDR) and its ligand, the active vitamin D metabolite 1,25(OH)2D, are important in immune responses to intracellular bacteria. The vitamin D/VDR pathway regulates the downstream production of cytokines in infected human AMφ. The immunomodulatory role of the vitamin D/VDR pathway in equine leukocytes is unknown. The objective of the current study was to determine the impact of R. equi infection and age on synthesis of 1,25(OH)2D, VDR expression, and cytokine production in an ex vivo model of R. equi infection in equine AMφ. AMφ were collected from ten healthy foals at 2-, 4- and 8-weeks old and from nine healthy adult horses once via bronchoalveolar lavage. AMφ were mock infected (CONTROL) or infected with a virulent laboratory strain of R. equi for 7 days (INFECTED). VDR expression was determined via RT-qPCR from cell lysates. 1,25(OH)2D and cytokines were measured in cell supernatant by immunoassays. VDR expression was impacted by age (P = 0.001) with higher expression in AMφ from 8-week-old foals than from 2-week-old foals and adults. There was no significant effect of infection in foal AMφ, but in adults, relative VDR expression was significantly lower in INFECTED AMφ compared to CONTROL AMφ (P = 0.002). There was no effect of age or infection on 1,25(OH)2D concentration (P > 0.37). Mean TNFα production was significantly higher from INFECTED compared to CONTROL AMφ from 4- and 8-week-old foals and adults (P < 0.005). Mean IFNγ production was significantly higher from AMφ from foals at 8-weeks-old compared to 2-weeks-old (P = 0.013) and higher from INFECTED AMφ than from CONTROL AMφ in foals at 4-weeks-old and in adults (P < 0.027). The proportion of samples producing IL-1ß and IL-10 was also significantly higher from INFECTED compared to CONTROL AMφ isolated from 4-week-old foals (P < 0.008). Similarly, in adult samples, IL-17 was produced from a greater proportion of INFECTED compared to CONTROL samples (P = 0.031). These data document age-associated changes in VDR expression and cytokine production in equine AMφ in response to R. equi infection. This preliminary investigation supports the need for further research to fully elucidate if the vitamin D pathway has an immunomodulatory role in the horse.

Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase II trial (DESTINY-Breast01).

BACKGROUND: Primary analysis of the multicenter, open-label, single-arm, phase II DESTINY-Breast01 trial (median follow-up 11.1 months) demonstrated durable antitumor activity with trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab emtansine (T-DM1). We report updated cumulative survival outcomes with a median follow-up of 26.5 months (data cut-off 26 March 2021). PATIENTS AND METHODS: Patients with HER2-positive mBC resistant or refractory to T-DM1 received T-DXd 5.4 mg/kg intravenously every 3 weeks until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR). Secondary endpoints included overall survival (OS), duration of response (DoR), progression-free survival (PFS), and safety. RESULTS: The ORR by ICR was 62.0% [95% confidence interval (CI) 54.5% to 69.0%] in patients who received T-DXd 5.4 mg/kg every 3 weeks (n = 184). Median OS was 29.1 months (95% CI 24.6-36.1 months). Median PFS and DoR were 19.4 months (95% CI 14.1-25.0 months) and 18.2 months (95% CI 15.0 months-not evaluable), respectively. Drug-related treatment-emergent adverse events (TEAEs) were observed in 183 patients (99.5%), and 99 patients (53.8%) had one or more grade ≥3 TEAEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 15.8% of patients (n = 29), of which 2.7% (n = 5) were grade 5. CONCLUSIONS: These updated results provide further evidence of sustained antitumor activity of T-DXd with a consistent safety profile in heavily pretreated patients with HER2-positive mBC.

Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study.

BACKGROUND: In the DESTINY-Breast03 clinical trial, trastuzumab deruxtecan (T-DXd) showed superior progression-free survival and overall survival versus trastuzumab emtansine (T-DM1) and manageable safety in patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer. Here, patient-reported outcomes (PROs) are reported along with hospitalization data. PATIENTS AND METHODS: Patients in DESTINY-Breast03 were assessed for prespecified PRO measures, including European Organization for Research and Treatment of Cancer quality of life (EORTC-QoL) questionnaires [the oncology-specific EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and breast cancer-specific EORTC QLQ-BR45] and the generic EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) visual analogue scale. Analyses included change from baseline, time to definitive deterioration (TDD), and hospitalization-related endpoints. RESULTS: EORTC QLQ-C30 baseline global health status (GHS) scores for T-DXd (n = 253) and T-DM1 (n = 260) were similar, with no clinically meaningful change (<10-point change from baseline) while on either treatment (median treatment duration: T-DXd, 14.3 months; T-DM1, 6.9 months). TDD analyses of QLQ-C30 GHS (primary PRO variable) and all other prespecified PROs (QLQ-C30 subscales, the QLQ-BR45 arm symptoms scale, and the EQ-5D-5L visual analogue scale) suggested T-DXd was numerically favored over T-DM1 based on TDD hazard ratios. Of all randomized patients, 18 (6.9%) receiving T-DXd versus 19 (7.2%) receiving T-DM1 were hospitalized, and the median time to first hospitalization was 219.5 versus 60.0 days, respectively. CONCLUSIONS: In DESTINY-Breast03, EORTC GHS/QoL was maintained on both therapies throughout treatment, indicating that despite the longer treatment duration with T-DXd versus T-DM1, health-related QoL did not worsen on T-DXd. Furthermore, TDD hazard ratios numerically favored T-DXd over T-DM1 in all prespecified variables of interest including pain, suggesting T-DXd may delay time until health-related QoL deterioration compared with T-DM1. Median time to first hospitalization was three times longer with T-DXd versus T-DM1. Together with reported improved efficacy and manageable toxicity, these results support the overall benefit of T-DXd for patients with HER2+ metastatic breast cancer.

Age-related changes in vitamin D metabolism and vitamin D receptor expression in equine alveolar macrophages: A preliminary study.

The vitamin D receptor (VDR)-vitamin D axis modulates pulmonary immunity in people but its role in equine immunity is unknown. Bacterial pneumonia causes high morbidity/mortality in foals and alveolar macrophages (AMφ) are important for pulmonary defenses. Age-related variations in vitamin D-mediated function of AMφ might contribute to the foal's susceptibility to pneumonia. Our aim was to assess the impact of age on equine vitamin D metabolism and VDR expression in AMφ. AMφ and plasma was collected from healthy foals (2, 4 and 8 weeks old) and adult horses (once). AMφ VDR expression was determined via RT-qPCR and plasma vitamin D metabolites quantified via immunoassays. Data were analyzed with linear mixed models. Inactive-vitamin D metabolite concentrations were lowest in foals at 2 weeks and lower at 2 and 4 weeks compared to adults (P < 0.001). Active-vitamin D metabolite concentrations were higher in foals than adults (P < 0.05). VDR expression was detected in AMφ in all animals and was highest in 2-week-old foals. Vitamin D metabolism and AMφ VDR expression are impacted by age in horses. This may have immunological consequences in foals given the key role that the VDR-vitamin D axis has in pulmonary immunity in other species.

Transitioning into the workforce during the COVID-19 pandemic: Understanding the experiences of student diagnostic radiographers.

INTRODUCTION: The COVID-19 pandemic, with associated pressures on healthcare services and workforce, had implications for final year Diagnostic Radiography students completing their training and transitioning into employment. The aim of this study was to explore their experience as novice practitioners starting work and integrating into the workforce during a time of national crisis. METHODS: Five early career Diagnostic Radiographers, eligible to join the temporary HCPC register, were recruited. One to one interviews were completed online exploring their thoughts, feelings and experiences. Participants had the option of using photographs to aid communication. RESULTS: Interviews were transcribed, emerging themes identified and coded. Four main themes emerged specifically related to the COVID-19 pandemic, (i) perceived challenges associated with joining the workforce, (ii) managing expectations and unexpected outcomes during transition, (iii) adapting to changes in systems and structures, (iv) sense of uncertainty relating to professional identity. The impacts were experienced beyond the work environment into social and personal lives. Participants demonstrated resilience as they adapted to their shifting lives and drew on the support of clinical colleagues and University academics for help. They did report feelings of concern and anxiety. The participants all expressed a sense of feeling valued and supported in their new roles. CONCLUSION: The Pandemic was unprecedented and created uncertainty in terms of workforce requirements. This study highlights the personal impact and professional responses of novice practitioners, who felt a sense of duty and care to help support the NHS and others. IMPLICATIONS FOR PRACTICE: This will help in the understanding of the transition of student into employment and what wider support needs to be in place prior, during and after this phase.

An evaluation of the current mentorship/preceptorship practices for newly qualified radiographers in Northern Ireland.

INTRODUCTION: Mentorship/Preceptorship (M/P) has been utilised within the nursing profession since the early 1980's. Successful, structured M/P programmes can be hugely beneficial to Northern Ireland (NI) Trusts who recruit regularly and often rely on the fluidity of staff movement regionally. In the absence of standardised tools to accurately and universally measure the competency of newly qualified Radiographers (NQR) as they evolve, establishing the benchmark for effective practice within Radiology departments in NI is difficult and highly subjective at best. This study aimed to evaluate the current M/P strategies within NI as perceived by NQR and Radiology Managers (RM). METHODS: A mix of both qualitative and quantitative data was obtained using questionnaires through a scoping exercise. Opinions were sought from a target audience of NQR, who began full-time employment following graduation in 2018, and RM involved in the delivery of current M/P programmes within the NI Trusts. RESULTS: Responses were gained from all five NI trusts to achieve a representative regional sample, with final opinions of RM (n = 8, 54%) and NQR (n = 30, 67%) received. With the exception of one response, all NQRs confirmed receiving some form of M/P support within their inaugural post. CONCLUSION: Significant variations were apparent in both the structure and delivery of Trust M/P induction programmes, calling into question the comparable competency of NQRs regionally. IMPLICATIONS FOR PRACTICE: The disparity in approach towards M/P programmes across NI, and subsequent lack of comparability of NQR competence, endorses the development of a more robust and universal method for the regional assessment of NQRs, such as that of the 'Flying Start NHS®' programme utilised by National Health Service (NHS) Scotland, in combination with knowledge and skills framework (KSF) practices in supervision.

Service user involvement in radiotherapy and oncology education; the patient perspective.

INTRODUCTION: The Health & Care Professions Council (HCPC) recently mandated the integration of the service-user voice into all aspects of allied healthcare education in the UK. However, the potential benefits and harms of this integration to service users are largely unknown. This study aimed to determine service user perspectives on relaying their personal experience of the cancer treatment pathway to students in an undergraduate Radiotherapy and Oncology programme. METHODS: A qualitative study was conducted where seven patients led educational sessions with students and were interviewed (1:1) 1 week later using an iterative semi-structured format. RESULTS: Unanimously, the primary motivation for participation was the opportunity for patients to tell their unique story to positively influence the future behaviour and understanding of student healthcare professionals. Patients experiencing significant cancer-related psychological trauma reported reacting more emotionally to the experience but also reported particularly positive benefits from their participation, including therapeutic healing. CONCLUSION: Findings highlight the array of benefits to service users associated with teaching in allied healthcare education. Post traumatic growth (PTG) may also potentially occur through this type of intervention in certain participants and this warrants further investigation in future studies.