A Prospective Randomised Trial to Determine the Effect of a Reduced Versus Standard Dose of Enzalutamide on Side Effects in Frail Patients with Prostate Cancer.

BACKGROUND AND OBJECTIVE: Enzalutamide is a potent androgen receptor signalling inhibitor, effectively used for the treatment of different stages of prostate cancer. Side effects occur frequently at the registered dose, whilst a lower dose might be equally effective. Therefore, the aim of this study is to determine the effect of a reduced dose of enzalutamide on side effects in frail patients with prostate cancer. METHODS: This multicentre randomised trial compared the standard enzalutamide dose of 160 mg once daily (OD) with a reduced dose of 120 mg OD in frail patients with prostate cancer. Fatigue, cognitive side effects, and depressive symptoms were measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire, Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, and Geriatric Depression Scale-15 (GDS-15). Linear mixed-effect models were used to study differences in side effects over time between both groups. KEY FINDINGS AND LIMITATIONS: In total, 52 patients were included in the analysis (25 reduced dose and 27 standard dose). Patients treated with the reduced dose had significantly lower fatigue after 24 wk than those with the standard dose (difference FACIT-Fatigue 6.2; 95% confidence interval 1.4-11.0; p = 0.01). Patients treated with the reduced dose showed stable fatigue, cognitive side effects, and depressive symptoms over time, whilst patients with the standard dose showed significantly worse side effects after 24 wk than at baseline. CONCLUSIONS AND CLINICAL IMPLICATIONS: A reduced dose of enzalutamide results in less fatigue, cognitive side effects, and depressive symptoms in frail patients with prostate cancer than the standard dose, without any indication of interference with efficacy endpoints. PATIENT SUMMARY: In this report, we looked at the side effects of enzalutamide at two dose levels. We found that, in frail patients, three tablets a day result in less fatigue than four tablets a day. Patients treated with four tablets a day showed an increase in fatigue, cognitive side effects, and depression. We conclude that a lower dose of three tablets can be used to alleviate side effects without indications for less efficacy.

Time trends in real-world treatment patterns and survival in patients diagnosed with de novo HER2+ metastatic breast cancer: an analysis of the SONABRE registry.

PURPOSE: The aim was to determine whether the real-world first-line progression-free survival (PFS) of patients diagnosed with de novo human epidermal growth factor receptor 2 positive (HER2+) advanced breast cancer (ABC) has improved since the introduction of pertuzumab in 2013. In addition to PFS, we aimed to determine differences in overall survival (OS) and the use of systemic and locoregional therapies. METHODS: Included were patients systemically treated for de novo HER2+ ABC in ten hospitals in 2008-2017 from the SONABRE Registry (NCT-03577197). First-line PFS and OS in 2013-2017 versus 2008-2012 was determined using Kaplan-Meier analyses and multivariable Cox proportional hazards modelling. First-given systemic therapy and the use of locoregional therapy within the first year following diagnosis were determined per period of diagnosis. RESULTS: Median and five-year PFS were 26.6 months and 24% in 2013-2017 (n = 85) versus 14.5 months and 10% in 2008-2012 (n = 81) (adjusted HR = 0.65, 95%CI:0.45-0.94). Median and five-year OS were 61.2 months and 51% in 2013-2017 versus 26.1 months and 28% in 2008-2012 (adjusted HR = 0.55, 95%CI:0.37-0.81). Of patients diagnosed in 2013-2017 versus 2008-2012, 84% versus 60% received HER2-targeted therapy and 59% versus 0% pertuzumab-based therapy as first-given therapy. Respectively, 27% and 23% of patients underwent locoregional breast surgery, and 6% and 7% surgery of a metastatic site during the first year following diagnosis. CONCLUSION: The prognosis of patients with de novo HER2 + ABC has improved considerably. Since 2013 one in four patients were alive and free from progression on first-given therapy for at least five years.

Molecular imaging predicts lack of T-DM1 response in advanced HER2-positive breast cancer (final results of ZEPHIR trial).

Efficacy of the human epidermal growth factor receptor (HER)2-targeting trastuzumab emtansine (T-DM1) in breast cancer (BC) relies on HER2 status determined by immunohistochemistry or fluorescence in-situ hybridization. Heterogeneity in HER2 expression, however, generates interest in "whole-body" assessment of HER2 status using molecular imaging. We evaluated the role of HER2-targeted molecular imaging in detecting HER2-positive BC lesions and patients unlikely to respond to T-DM1. Patients underwent zirconium-89 (89Zr) trastuzumab (HER2) PET/CT and [18F]-2-fluoro-2-deoxy-D-glucose (FDG) PET/CT before T-DM1 initiation. Based on 89Zr-trastuzumab uptake, lesions were visually classified as HER2-positive (visible/high uptake) or HER2-negative (background/close to background activity). According to proportion of FDG-avid tumor load showing 89Zr-trastuzumab uptake (entire/dominant part or minor/no part), patients were classified as HER2-positive and HER2-negative, respectively. Out of 265 measurable lesions, 93 (35%) were HER2-negative, distributed among 42 of the 90 included patients. Of these, 18 (19%) lesions belonging to 11 patients responded anatomically (>30% decrease in axial diameter from baseline) after three T-DM1 cycles, resulting in an 81% negative predictive value (NPV) of the HER2 PET/CT. In combination with early metabolic response assessment on FDG PET/CT performed before the second T-DM1 cycle, NPVs of 91% and 100% were reached in predicting lesion-based and patient-based (RECIST1.1) response, respectively. Therefore, HER2 PET/CT, alone or in combination with early FDG PET/CT, can successfully identify BC lesions and patients with a low probability of clinical benefit from T-DM1.

Continuity of care for patients with de novo metastatic cancer during the COVID-19 pandemic: A population-based observational study.

During the COVID-19 pandemic recommendations were made to adapt cancer care. This population-based study aimed to investigate possible differences between the treatment of patients with metastatic cancer before and during the pandemic by comparing the initial treatments in five COVID-19 periods (weeks 1-12 2020: pre-COVID-19, weeks 12-20 2020: 1st peak, weeks 21-41 2020: recovery, weeks 42-53 2020: 2nd peak, weeks 1-20 2021: prolonged 2nd peak) with reference data from 2017 to 2019. The proportion of patients receiving different treatment modalities (chemotherapy, hormonal therapy, immunotherapy or targeted therapy, radiotherapy primary tumor, resection primary tumor, resection metastases) within 6 weeks of diagnosis and the time between diagnosis and first treatment were compared by period. In total, 74,208 patients were included. Overall, patients were more likely to receive treatments in the COVID-19 periods than in previous years. This mainly holds for hormone therapy, immunotherapy or targeted therapy and resection of metastases. Lower odds were observed for resection of the primary tumor during the recovery period (OR 0.87; 95% CI 0.77-0.99) and for radiotherapy on the primary tumor during the prolonged 2nd peak (OR 0.84; 95% CI 0.72-0.98). The time from diagnosis to the start of first treatment was shorter, mainly during the 1st peak (average 5 days, p < .001). These findings show that during the first 1.5 years of the COVID-19 pandemic, there were only minor changes in the initial treatment of metastatic cancer. Remarkably, time from diagnosis to first treatment was shorter. Overall, the results suggest continuity of care for patients with metastatic cancer during the pandemic.

The prognostic impact of BMI in patients with HR+/HER2- advanced breast cancer: a study of the SONABRE registry.

PURPOSE: This study determines the prognostic impact of body mass index (BMI) in patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced (i.e., metastatic) breast cancer (ABC). METHODS: All patients with HR+/HER2- ABC who received endocrine therapy +-a cyclin-dependent kinase 4/6 inhibitor as first-given systemic therapy in 2007-2020 in the Netherlands were identified from the Southeast Netherlands Advanced Breast Cancer (SONABRE) registry (NCT03577197). Patients were categorised as underweight (BMI: < 18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), or obese (≥ 30.0 kg/m2). Overall survival (OS) and progression-free survival (PFS) were compared between BMI classes using multivariable Cox regression analyses. RESULTS: This study included 1456 patients, of whom 35 (2%) were underweight, 580 (40%) normal weight, 479 (33%) overweight, and 362 (25%) obese. No differences in OS were observed between normal weight patients and respectively overweight (HR 0.99; 95% CI 0.85-1.16; p = 0.93) and obese patients (HR 1.04; 95% CI 0.88-1.24; p = 0.62). However, the OS of underweight patients (HR 1.45; 95% CI 0.97-2.15; p = 0.07) tended to be worse than the OS of normal weight patients. When compared with normal weight patients, the PFS was similar in underweight (HR 1.05; 95% CI 0.73-1.51; p = 0.81), overweight (HR 0.90; 95% CI 0.79-1.03; p = 0.14), and obese patients (HR 0.88; 95% CI 0.76-1.02; p = 0.10). CONCLUSION: In this study among 1456 patients with HR+/HER2- ABC, overweight and obesity were prevalent, whereas underweight was uncommon. When compared with normal weight, overweight and obesity were not associated with either OS or PFS. However, underweight seemed to be an adverse prognostic factor for OS.

Trastuzumab Resistance in Patients With HER2-Positive Advanced Breast Cancer: Results From the SONABRE Registry.

BACKGROUND: This study aims to explore whether first-line pertuzumab use modifies the effect of prior use of (neo-) adjuvant trastuzumab on the PFS of first-line HER2-targeted therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). METHODS: Patients diagnosed with HER2-positive ABC in 2008 to 2018 in 9 Dutch hospitals were derived from the SONABRE Registry (NCT03577197). Patients diagnosed with de novo metastatic breast cancer were excluded. Patients receiving first-line trastuzumab-based therapy for ABC were selected and divided into trastuzumab naïve (n = 113) and trastuzumab pretreated (n = 112). Progression-free survival (PFS) was compared using multivariable Cox proportional hazard models. The interaction effect of first-line pertuzumab was tested using the likelihood-ratio test. RESULTS: The median follow-up time was 47 months (95% confidence interval [CI]: 42-52). When comparing trastuzumab pretreated with trastuzumab naïve patients, the hazard ratio for first-line progression was 2.07 (CI:1.47-2.92). For trastuzumab pretreated patients who received first-line trastuzumab without pertuzumab, the hazard ratio for progression was 2.60 (95% CI:1.72-3.93), whereas for those who received first-line trastuzumab with pertuzumab the hazard ratio was 1.43 (95% CI: 0.81-2.52) (P interaction = .10). CONCLUSIONS: Prior use of trastuzumab as (neo-)adjuvant treatment had a negative impact on PFS of first-line HER2-targeted therapy outcomes. Adding pertuzumab to first-line trastuzumab-based therapy decreased the negative impact of prior (neo-)adjuvant trastuzumab use on first-line PFS. Further studies are needed to assess the effect of prior (neo-)adjuvant pertuzumab use on the outcomes of first-line pertuzumab-based therapy.

Real-world time trends in overall survival, treatments and patient characteristics in HR+/HER2- metastatic breast cancer: an observational study of the SONABRE Registry.

Background: This study aims to evaluate whether changes in therapeutic strategies have improved survival of patients diagnosed with hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer (ABC) in real-world. Methods: All 1950 patients systemically treated for HR+/HER2- ABC and diagnosed between 2008 and 2019 in eight hospitals were retrieved from the SONABRE Registry (NCT-03577197). Patients were categorized per three-year cohorts based on year of ABC diagnosis. Tests for trend were used to examine differences in baseline characteristics, Kaplan-Meier methods and Cox proportional hazards for survival analyses, and competing-risk methods for 3-year use of systemic therapy. Findings: Over time, patients were older (≥70 years, 37%, n = 169/456 in 2008-2010, 47%, n = 233/493 in 2017-2019, p = 0.004) and more often had multiple metastatic sites at ABC diagnosis (48%, n = 220/456 in 2008-2010, 56%, n = 275/493 in 2017-2019, p = 0.002). Among patients with metachronous metastases the prior exposure to (neo-) adjuvant therapies increased over time (chemotherapy, 38%, n = 138/362 in 2008-2010, 48%, n = 181/376 in 2017-2019, p = <0.001; endocrine therapy, 64%, n = 231/362 in 2008-2010, 72%, n = 271/376 in 2017-2019, p = <0.001). Overall survival significantly improved from median 31.1 months (95% CI:28.2-34.3) for patients diagnosed in 2008-2010 to 38.4 months (95% CI:34.0-41.1) in 2017-2019 (adjusted hazard ratio = 0.76, 95% CI:0.64-0.90; p = 0.001). Three-year use of CDK4/6 inhibitors increased from 0% for patients diagnosed in 2008-2010 to 54% for diagnosis in 2017-2019. Conversely, three-year use of chemotherapy was 50% versus 36%, respectively. Interpretation: Over time, patients diagnosed with HR+/HER2- ABC presented with less favourable patient characteristics. Nevertheless, we observed that overall survival of ABC increased between 2008 and 2019, with increased use of endocrine/targeted therapies. Funding: The SONABRE Registry is supported by the Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer; and Eli Lilly & Co. Funding sources had no role in the writing of the manuscript.

De-ESCAlating RadioTherapy in breast cancer patients with pathologic complete response to neoadjuvant systemic therapy: DESCARTES study.

PURPOSE: Neoadjuvant systemic therapy (NST) is increasingly used in breast cancer patients and depending on subtype, 10-89% of patients will attain pathologic complete response (pCR). In patients with pCR, risk of local recurrence (LR) after breast conserving therapy is low. Although adjuvant radiotherapy after breast conserving surgery (BCS) reduces LR further in these patients, it may not contribute to overall survival. However, radiotherapy may cause early and late toxicity. The aim of this study is to show that omission of adjuvant radiotherapy in patients with a pCR after NST will result in acceptable low LR rates and good quality of life. METHODS: The DESCARTES study is a prospective, multicenter, single arm study. Radiotherapy will be omitted in cT1-2N0 patients (all subtypes) who achieve a pCR of the breast and lymph nodes after NST followed by BCS plus sentinel node procedure. A pCR is defined as ypT0N0 (i.e. no residual tumor cells detected). Primary endpoint is the 5-year LR rate, which is expected to be 4% and deemed acceptable if less than 6%. In total, 595 patients are needed to achieve a power of 80% (one-side alpha of 0.05). Secondary outcomes include quality of life, Cancer Worry Scale, disease specific and overall survival. Projected accrual is five years. CONCLUSION: This study bridges the knowledge gap regarding LR rates when adjuvant radiotherapy is omitted in cT1-2N0 patients achieving pCR after NST. If the results are positive, radiotherapy may be safely omitted in selected breast cancer patients with a pCR after NST. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov on June 13th 2022 (NCT05416164). Protocol version 5.1 (15-03-2022).

Outcomes for the first four lines of therapy in patients with HER2-positive advanced breast cancer: results from the SONABRE registry.

PURPOSE: We assessed the systemic treatment choices and outcomes in patients diagnosed with human epidermal growth factor receptor-2-positive (HER2 +) advanced breast cancer (ABC), for the first four lines of systemic therapy and by hormone receptor (HR) status. METHODS: We identified 330 patients diagnosed with HER2 + ABC in 2013-2018 in the Southeast of The Netherlands, of whom 64% with HR + /HER2 + and 36% with HR-/HER2 + disease. Overall survival (OS) from start of therapy was calculated using the Kaplan-Meier method. RESULTS: In real world, 95% of patients with HR + /HER2 + and 74% of patients with HR-/HER2 + disease received systemic therapy. In HR + /HER2 + disease, use of endocrine, chemo- and HER2-targeted therapy was , respectively, 64%, 46% and 60% in first line, and 39%, 64% and 75% in fourth line. In HR-/HER2 + disease, 91-96% of patients received chemotherapy and 77-91% HER2-targeted therapy, irrespective of line of therapy. In patients with HR + /HER2 + disease, median OS was 34.9 months (95%CI:25.8-44.0) for the first line and 12.8 months (95%CI:10.7-14.9) for the fourth line. In HR-/HER2 + disease, median OS was 39.9 months (95%CI:23.9-55.8) for the first line and 15.2 months (95%CI:10.9-19.5) for the fourth line. For patients treated with first-line pertuzumab, trastuzumab plus chemotherapy, median OS was not reached at 56.0 months in HR + /HER2 + disease and 48.4 months (95%CI:32.6-64.3) in HR-/HER2 + disease. CONCLUSION: Survival times for later lines of therapy are surprisingly long and justify the use of multiple lines of systemic therapy in well-selected patients with HER2 + ABC. Our real-world evidence adds valuable observations to the accumulating evidence that within HER2 + ABC, the HR status defines two distinct disease subtypes.

Quality of integrated female oncofertility care is suboptimal: A patient-reported measurement.

BACKGROUND: Clinical practice guidelines recommend to inform female cancer patients about their infertility risks due to cancer treatment. Unfortunately, it seems that guideline adherence is suboptimal. In order to improve quality of integrated female oncofertility care, a systematic assessment of current practice is necessary. METHODS: A multicenter cross-sectional survey study in which a set of systematically developed quality indicators was processed, was conducted among female cancer patients (diagnosed in 2016/2017). These indicators represented all domains in oncofertility care; risk communication, referral, counseling, and decision-making. Indicator scores were calculated, and determinants were assessed by multilevel multivariate analyses. RESULTS: One hundred twenty-one out of 344 female cancer patients participated. Eight out of 11 indicators scored below 90% adherence. Of all patients, 72.7% was informed about their infertility, 51.2% was offered a referral, with 18.8% all aspects were discussed in counseling, and 35.5% received written and/or digital information. Patient's age, strength of wish to conceive, time before cancer treatment, and type of healthcare provider significantly influenced the scores of three indicators. CONCLUSIONS: Current quality of female oncofertility care is far from optimal. Therefore, improvement is needed. To achieve this, improvement strategies that are tailored to the identified determinants and to guideline-specific barriers should be developed.

The initial hormone receptor/HER2 subtype is the main determinator of subtype discordance in advanced breast cancer: a study of the SONABRE registry.

PURPOSE: The hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) are the main parameters in guiding systemic treatment choices in breast cancer, but can change during the disease course. This study aims to evaluate the biopsy rate and receptor subtype discordance rate in patients diagnosed with advanced breast cancer (ABC). METHODS: Patients diagnosed with ABC in seven hospitals in 2007-2018 were selected from the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry. Multivariable logistic regression analyses were performed to identify factors influencing biopsy and discordance rates. RESULTS: Overall, 60% of 2854 patients had a biopsy of a metastatic site at diagnosis. One of the factors associated with a reduced biopsy rate was the HR + /HER2 + primary tumor subtype (versus HR + /HER2- subtype: OR = 0.68; 95% CI: 0.51-0.90). Among the 748 patients with a biopsy of the primary tumor and a metastatic site, the overall receptor discordance rate was 18%. This was the highest for the HR + /HER2 + primary tumor subtype, with 55%. In 624 patients with metachronous metastases, the HR + /HER2 + subtype remained the only predictor significantly related to a higher discordance rate, irrespective of prior (neo-)adjuvant therapies (OR = 7.49; 95% CI: 3.69-15.20). CONCLUSION: The HR + /HER2 + subtype has the highest discordance rate, but the lowest biopsy rate of all four receptor subtypes. Prior systemic therapy was not independently related to subtype discordance. This study highlights the importance of obtaining a biopsy of metastatic disease, especially in the HR + /HER2 + subtype to determine the most optimal treatment strategy.

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium.

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Survival before and after the introduction of pertuzumab and T-DM1 in HER2-positive advanced breast cancer, a study of the SONABRE Registry.

PURPOSE: Immediate and proper implementation of a new and more potent therapy is important to ensure that the patient achieves the best possible outcome. This study aimed to examine whether the real-world overall survival (OS) has improved in patients with human epidermal growth factor receptor 2-positive (HER2 +) advanced breast cancer (ABC) since the market release of pertuzumab and T-DM1. Furthermore, we aimed to assess the implementation and survival rates per hormone receptor (HR) subtype. PATIENTS AND METHODS: We included 493 systemically treated patients consecutively diagnosed with HER2 + ABC in 2008-2017 from the SOutheast Netherlands Advanced BREast cancer (SONABRE) Registry. Median OS was obtained using the Kaplan-Meier method and differences between periods (2008-2012 versus 2013-2017) were tested using multivariable Cox proportional hazards regression modeling. The 3-year implementation rates were estimated for any HER2-targeted therapy, pertuzumab, and T-DM1 by using the competing risk method and calculated from the date of diagnosis of ABC to start of HER2-targeted therapy of interest. RESULTS: The median OS in 2008-2012 versus 2013-2017 was 28.3 versus 39.7 months in all patients (adjusted hazard ratio (adjHR) 0.85, 95%CI 0.66-1.08), 29.9 versus 36.3 months in patients with HR + /HER2 + disease (adjHR 0.97, 95%CI 0.72-1.32), and 22.7 versus 40.9 months in patients with HR-/HER2 + disease (adjHR 0.59, 95%CI 0.38-0.92). Any HER2-targeted therapy was used in 79% of patients in 2008-2012 and in 84% in 2013-2017. The use of pertuzumab and T-DM1 in 2013-2017 was 48% and 29%, respectively. For patients diagnosed with HR + /HER2 + and HR-/HER2 + disease, implementation rates in 2013-2017 were , respectively, 77% and 99% for any HER2-targeted therapy, 38% and 69% for pertuzumab, and 24% and 40% for T-DM1. CONCLUSION: The survival of patients with HER2 + ABC improved since the introduction of pertuzumab and T-DM1. There is room for improvement in implementation of these HER2-targeted therapies, especially in patients with HR + /HER2 + disease.

Oxaliplatin infusion-related venous pain: prevention by simultaneous intravenous fluids.

OBJECTIVE: Oxaliplatin is a cytotoxic agent frequently used in the treatment of gastrointestinal cancer patients. A known side effect of oxaliplatin administration via a peripheral vein is infusion-related pain. In this retrospective cohort study we compared the incidence of infusion-related pain in patients treated with oxaliplatin with or without simultaneous fluid infusion (FI) (800 mL glucose 5% in 2 hours). METHODS: We retrospectively defined two cohorts: Patients treated with oxaliplatin and simultaneous intravenous FI and the same number of patients treated without FI.The incidence of infusion-related venous pain was the primary outcome measure. Secondary outcomes included: Incidence of hypersensitivity reactions, infusion time, dose density, number of patients switched to a central venous catheter and incidence of peripheral neuropathy. RESULTS: 100 patients were included, 50 patients in both groups. Baseline characteristics were comparable, except for age (median 66.8 vs 62.4 years in groups with and without FI; p=0.017), and body mass index (28.0 vs 25.7 kg/m2, respectively; p=0.012). Patients treated with simultaneous FI experienced significantly less vascular pain compared with those without FI (10% vs 78%, respectively; p<0.0001; OR 0.031 (95% CI: 0.01 to 0.098)). No difference was observed in dose density, treatment delay or the need of central venous catheter. Logistic regression analysis showed no confounders affecting the primary outcome. No adverse events of FI were observed. CONCLUSION: Concurrent infusion of 800 mL glucose 5% with peripheral venous administration of oxaliplatin significantly reduces the incidence of infusion-related pain in gastrointestinal cancer patients and is highly feasible and affordable in everyday clinical practice.

Dutch Oncology COVID-19 consortium: Outcome of COVID-19 in patients with cancer in a nationwide cohort study.

AIM OF THE STUDY: Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19. METHODS: This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible. RESULTS: Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years). CONCLUSION: The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered.

HER2, chromosome 17 polysomy and DNA ploidy status in breast cancer; a translational study.

Breast cancer treatment depends on human epidermal growth factor receptor-2 (HER2) status, which is often determined using dual probe fluorescence in situ hybridisation (FISH). Hereby, also loss and gain of the centromere of chromosome 17 (CEP17) can be observed (HER2 is located on chromosome 17). CEP17 gain can lead to difficulty in interpretation of HER2 status, since this might represent true polysomy. With this study we investigated whether isolated polysomy is present and how this effects HER2 status in six breast cancer cell lines and 97 breast cancer cases, using HER2 FISH and immunohistochemistry, DNA ploidy assessment and multiplex ligation dependent probe amplification. We observed no isolated polysomy of chromosome 17 in any cell line. However, FISH analysis did show CEP17 gain in five of six cell lines, which reflected gains of the whole chromosome in metaphase spreads and aneuploidy with gain of multiple chromosomes in all these cases. In patients' samples, gain of CEP17 indeed correlated with aneuploidy of the tumour (91.1%; p < 0.001). Our results indicate that CEP17 gain is not due to isolated polysomy, but rather due to widespread aneuploidy with gain of multiple chromosomes. As aneuploidy is associated with poor clinical outcome, irrespective of tumour grade, this could improve future therapeutic decision making.

Prospective Study of Drug-induced Interstitial Lung Disease in Advanced Breast Cancer Patients Receiving Everolimus Plus Exemestane.

BACKGROUND: Everolimus-related interstitial lung disease (ILD) (also: pneumonitis) poses a difficulty for physicians, as it is hard to discriminate ILD from other causes of respiratory symptoms and to decide on safe treatment continuation. OBJECTIVE: We investigated the capability of pulmonary function tests (PFT), plasma biomarkers, everolimus pharmacokinetics, and FDG-PET to discriminate between everolimus-related ILD and other causes of respiratory problems and to predict the severity of ILD. PATIENTS AND METHODS: Women starting treatment with everolimus plus exemestane for advanced breast cancer were included. At baseline and during the first 3 months, respiratory symptoms, PFT with diffusion capacity of the lungs for carbon monoxide corrected for hemoglobin (DLCOc) and forced vital capacity, serum plasma biomarkers (including SP-D and YKL-40), everolimus trough concentration, and 18F-FDG-PET were prospectively recorded. RESULTS: Twenty-seven (out of 29 included) patients were evaluable for analysis. Fifteen patients (56%) developed everolimus-related respiratory signs or symptoms and four patients (15%) needed everolimus discontinuation and received corticosteroids. Change in DLCOc differentiated ILD from alternative diagnoses with 0.91 sensitivity and 0.78 specificity. Decrease in DLCOc (non-significant) was greatest in patients who needed everolimus discontinuation. Serum SP-D and YKL-40 could differentiate ILD from alternative diagnoses with 0.83 and 0.83 sensitivity, and 0.85 and 0.62 specificity, respectively. 18F-FDG-PET abnormalities did not precede clinical symptoms. No relationship between ILD and everolimus trough concentration was found. CONCLUSIONS: This study shows that everolimus-related ILD occurs frequently. Prospective monitoring of DLCOc in combination with measurement of serum SP-D and YKL-40 appear useful to discriminate ILD from other causes of respiratory symptoms. Clinicaltrials.gov identifier: NCT01978171.

Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane.

BACKGROUND: Treating breast cancer patients with everolimus and exemestane can be challenging due to toxicity and suboptimal treatment responses. OBJECTIVE: We investigated whether everolimus exposure and early metabolic response are predictors for toxicity and effectiveness in these patients. PATIENTS AND METHODS: We performed pharmacokinetic assessments 14 and 35 days after starting treatment. [18F]fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) was performed at baseline, and 14 and 35 days after the start of the therapy. We recorded toxicity, defined as dose interventions within 3 months, and progression-free survival (PFS). RESULTS: Among 44 evaluable patients, the geometric mean (GM) Ctrough was higher in patients with toxicity compared to patients without (17.4 versus 12.3 µg/L (p = 0.02)). The optimal cut-off value to predict toxicity was Ctrough > 19.2 µg/L. GM Ctrough of patients with and without progressive disease (PD) within 3 months was not significantly different (12.0 versus 15.2 µg/L (p = 0.118)). In 28 evaluable patients, PD within 3 months could best be predicted using the percentage decrease in peak standardized uptake value normalized by lean body mass of the lesion with highest FDG uptake (SULpeak high) at day 14. Patients with <11% versus >11% decrease in SULpeak high at day 14 had a median PFS of 90 days versus 411 days, respectively (p = 0.0013) and more frequently had PD within 3 months: 70 vs 11%, respectively. CONCLUSIONS: Our results show that everolimus toxicity is related to everolimus Ctrough. No relation was observed between everolimus exposure and treatment effectiveness. An early FDG-PET can identify patients at high risk of nonresponse. These results warrant further validation. Clinicaltrials.gov identifier: NCT01948960.

Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer.

Diversity in colorectal cancer biology is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of metastatic CRC patients. Candidate genes were selected from 389 genes involved in DNA Damage Repair by correlation analyses between gene methylation status and drug response in 32 cell lines. A large series of samples (n=818) from two phase III clinical trials was used to evaluate these candidate genes by correlating methylation status to progression-free survival after treatment with first-line single-agent fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy (Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the discovery (n=185) and initial validation set (n=166), patients with methylated Decoy Receptor 1 (DCR1) did not benefit from CAPIRI over Capecitabine treatment (discovery set: HR=1.2 (95%CI 0.7-1.9, p=0.6), validation set: HR=0.9 (95%CI 0.6-1.4, p=0.5)), whereas patients with unmethylated DCR1 did (discovery set: HR=0.4 (95%CI 0.3-0.6, p=0.00001), validation set: HR=0.5 (95%CI 0.3-0.7, p=0.0008)). These results could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated DCR1 for FOLFIRI over 5FU treatment (methylated DCR1: HR=0.7 (95%CI 0.5-0.9, p=0.01), unmethylated DCR1: HR=0.8 (95%CI 0.6-1.2, p=0.4)). In conclusion, DCR1 promoter hypermethylation status is a potential predictive biomarker for response to treatment with irinotecan, when combined with capecitabine. This finding could not be replicated in an external validation set, in which irinotecan was combined with 5FU. These results underline the challenge and importance of extensive clinical evaluation of candidate biomarkers in multiple trials.

Neutrophil Recovery in Breast Cancer Patients Receiving Docetaxel-Containing Chemotherapy with and without Granulocyte Colony-Stimulating Factor Prophylaxis.

OBJECTIVE: The primary outcome of the current study is, whether there is a protective effect of prior chemotherapy or of prior granulocyte colony-stimulating factor (G-CSF) on the next cycle blood cell counts. METHODS: Hematologic toxicity was evaluated, based on a randomized phase III study in breast cancer patients (n = 167) with >20% risk of febrile neutropenia. The primary endpoint was the nadir blood cell counts for patients treated with G-CSF given during all 6 chemotherapy cycles or limited to the first 2 chemotherapy cycles only. RESULTS: For the present analyses, 47 patients were eligible. In the G-CSF 1-6 arm, the median white blood cell count (WBC) and absolute neutrophil count (ANC) nadir slowly decreased from 10.8 × 109/L in cycle 1 to 7.5 × 109/L in cycle 6 and from 7.1 × 109/L to 5.5 × 109/L, respectively. The median WBC nadir in the G-CSF 1-2 arm decreased from 1.2 × 109/L in cycle 3 to 0.9 × 109/L in cycle 6 and the ANC nadir showed a grade 4 neutropenia of 0.1 × 109/L in cycles 3-6. All patients had ANC recovery to normal levels (≥1.5 × 109/L) without delay on day 1 of the next cycle. CONCLUSION: We conclude that there is no protective effect of prior G-CSF or prior chemotherapy use on nadir blood cell counts in subsequent cycles.