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Purpose: Adjuvant therapy with tamoxifen significantly reduces breast cancer recurrence and mortality in estrogen receptor positive disease. CYP2D6 is the main enzyme involved in the activation of the prodrug tamoxifen into the anti-estrogen endoxifen. Endoxifen is thought to be a main determinant for clinical efficacy in breast cancer patients using tamoxifen. As the large interindividual variation in endoxifen levels is only partly explained by CYP2D6 genotype, we explored the use of the C-dextromethorphan breath test (DM-BT) for phenotyping CYP2D6 and to predict serum steady-state endoxifen levels as a marker for clinical outcome in breast cancer patients using tamoxifen. Methods: In 65 patients with early breast cancer using tamoxifen, CYP2D6 phenotype was assessed by DM-BT. CYP2D6 genotype using Amplichip and serum steady-state levels of endoxifen were determined. Genotype was translated into the gene activity score and into ultrarapid, extensive, heterozygous extensive, intermediate or poor metabolizer CYP2D6 predicted phenotype. Results: CYP2D6 phenotype determined by the DM-BT explained variation in serum steady-state endoxifen levels for 47.5 % ( R = 0.475, p < 0.001). Positive and negative predictive values for a recently suggested threshold serum level of endoxifen (5.97 ng/mL) for breast cancer recurrence rate were 100 and 90 %, respectively, for both CYP2D6 phenotype by DM-BT (delta-over-baseline at t = 50 min (DOB) values of 0.7-0.9) and genotype (CYP2D6 gene activity score of 1.0). Conclusion: DM-BT might be, along with CYP2D6 genotyping, of value in selection of individualized endocrine therapy in patients with early breast cancer, especially when concomitant use of CYP2D6 inhibiting medication alters the phenotype. [ABSTRACT FROM AUTHOR]

Background: In vitro haemolysis is a major operational challenge for medical laboratories. A new experimental design was used to investigate under what conditions algorithms could be designed to report either quantitative or qualitative aspartate aminotransferase and lactate dehydrogenase results outside the manufacturer's haemolysis specifications. Quantitative corrections were required to meet prespecified quality specifications., Methods: Twenty-five patient samples were used to design reporting algorithms and another 41 patient samples were used to validate the algorithms. Aspartate aminotransferase, lactate dehydrogenase and haemolysis index were determined using a Cobas 6000 analyser (Roche diagnostics, Mannheim, Germany). Correction factors were determined, and the accuracy of the correction was investigated. Reporting algorithms were designed based on (i) the manufacturer's cut-off for the haemolysis index, (ii) corrections within the total allowable error specification and (iii) qualitative reporting based on obtained results. The impact of the reporting algorithms was retrospectively determined by recalculating six months of aspartate aminotransferase and lactate dehydrogenase results., Results: No correction for aspartate aminotransferase/lactate dehydrogenase was possible for results below the upper reference interval limit, while results equal to or greater than the upper reference interval limit could, up to mild haemolysis, be corrected within the total error criterion. All samples generated from the validated patient cohort fulfilled the set criteria. The algorithms allowed reporting 88.5% and 85.9% of otherwise unreported aspartate aminotransferase and lactate dehydrogenase results, respectively., Conclusions: An approach is presented that allows to generate and validate reporting algorithms for aspartate aminotransferase and lactate dehydrogenase compatible with prespecified quality specifications. The designed algorithms resulted in a significant reduction of otherwise unreported aspartate aminotransferase and lactate dehydrogenase results.

Introduction: The anti-tumor activity of WEE1 inhibitors (WEE1i) in gynecological malignancies has recently been demonstrated in clinical trials and its rationale is based on biological/molecular features of gynecological cancers. With this systematic review, we aim to outline the clinical development and current evidence regarding the efficacy and safety of these targeted agents in in this patient group., Methods: Systematic literature review of trials including patients with gynecological cancers treated with a WEE1i. The primary objective was to summarize the efficacy of WEE1i in gynecological malignancies regarding objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and progression-free survival (PFS). Secondary objectives included toxicity profile, Maximum Tolerated Dose (MTD), pharmacokinetics, drug-drug interactions and exploratory objectives such as biomarkers for response., Results: 26 records were included for data extraction. Almost all trials used the first-in-class WEE1i adavosertib; one conference abstract reported about Zn-c3. The majority of the trials included diverse solid tumors (n = 16). Six records reported efficacy results of WEE1i in gynecological malignancies (n = 6). Objective response rates of adavosertib monotherapy or in combination with chemotherapy ranged between 23% and 43% in these trials. Median PFS ranged from 3.0 to 9.9 months. The most common adverse events were bone marrow suppression, gastrointestinal toxicities and fatigue. Mainly alterations in cell cycle regulator genes TP53 and CCNE1 were potential predictors of response., Conclusion: This report summarizes encouraging clinical development of WEE1i in gynecological cancers and considers its application in future studies. Biomarker-driven patient selection might be essential to increase the response rates., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be seen as a potential conflict of interest to the presented work. Each author provided a detailed conflict of interest statement according to the Journals policy. N Steeghs received research grants (All outside the submitted work, all payment to the Netherlands Cancer Institute) from: Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda. N. Steeghs received consulting fees (All outside the submitted work, all payment to the Netherlands Cancer Institute) from Boehringer Ingelheim, Cogent Biosciences, Ellipses Pharma, Luszana., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: BI 1810631 is a human HER2-selective tyrosine kinase inhibitor that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertion mutations, whilst sparing EGFR signaling. This phase Ia/Ib, open-label, non-randomized study will determine the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of BI 1810631 in patients with HER2 aberration-positive solid tumors (NCT04886804)., Patients and Methods: In phase Ia, patients with histologically/cytologically confirmed HER2 aberration-positive advanced/metastatic solid tumors will receive BI 1810631 orally twice daily (BID) or once daily (QD) at escalating doses. Starting dose level is 15 mg BID; QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee. Dose escalation will continue until MTD/recommended phase II dose and preferred phase Ib schedule for each schedule is determined. In phase Ib, patients with HER2 tyrosine kinase domain (TKD) mutation-positive non-small cell lung cancer (NSCLC) who have previously received ≥1 line of systemic therapy will be enrolled initially, with possible inclusion of additional NSCLC cohorts in the future, including untreated patients. The primary endpoints will be MTD based on number of dose-limiting toxicities (DLTs)/number of patients with DLTs (phase Ia) and objective response (phase Ib). Secondary endpoints include PK parameters (phase Ia/Ib); duration of response, disease control, duration of disease control, and progression-free survival (phase Ib)., Conclusions: BI 1810631 could be an effective and tolerable EGFR-sparing oral treatment for patients with HER2 mutation-positive NSCLC, including exon 20 insertion mutations., Gov Identifier: NCT04886804., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

There is a growing need for systems that efficiently support the work of medical teams at the precision-oncology point of care. Here, we present the implementation of the Molecular Tumor Board Portal (MTBP), an academic clinical decision support system developed under the umbrella of Cancer Core Europe that creates a unified legal, scientific and technological platform to share and harness next-generation sequencing data. Automating the interpretation and reporting of sequencing results decrease the need for time-consuming manual procedures that are prone to errors. The adoption of an expert-agreed process to systematically link tumor molecular profiles with clinical actions promotes consistent decision-making and structured data capture across the connected centers. The use of information-rich patient reports with interactive content facilitates collaborative discussion of complex cases during virtual molecular tumor board meetings. Overall, streamlined digital systems like the MTBP are crucial to better address the challenges brought by precision oncology and accelerate the use of emerging biomarkers., (© 2022. The Author(s).)

Background: An increasing number of maternity care providers encounter pregnant women who request less care than recommended. A designated outpatient clinic for women who request less care than recommended was set up in Nijmegen, the Netherlands. The clinic's aim is to ensure that women make well-informed choices and arrive at a care plan that is acceptable to all parties. The aim of this study is to make the clinic's approach explicit by examining care providers' experiences who work with or within the clinic., Methods: qualitative analysis of in-depth interviews with Dutch midwives ( n = 6) and obstetricians ( n = 4) on their experiences with the outpatient clinic "Maternity Care Outside the Guidelines" in Nijmegen, the Netherlands., Results: Four main themes were identified: (1) "Trusting mothers, childbirth and colleagues"; (2) "A supportive communication style"; (3) "Continuity of carer"; (4) "Willingness to reconsider responsibility and risk". One overarching theme emerged from the data, which was "Guaranteeing women's autonomy". Mutual trust is a prerequisite for a constructive dialogue about birth plans and can be built and maintained more easily when there is continuity of carer during pregnancy and birth. Discussing birth plans at the clinic was believed to be successful because the care providers listen to women, take them seriously, show empathy and respect their right to refuse care. A change in vision on responsibility and risk is needed to overcome barriers such as providers' fear of adverse outcomes. Taking a more flexible approach towards care outside the guidelines demands courage but is necessary to guarantee women's autonomy., Key Conclusions and Implications for Practice: In order to fulfil women's needs and to prevent negative choices, care providers should care for women with trust, respect for autonomy, and provide freedom of choice and continuity. Care providers should reflect on and discuss why they are reluctant to support women's wishes that go against their personal values. The structured approach used at this clinic could be helpful to maternity care providers in other contexts, to make them feel less vulnerable when working outside the guidelines.

Lessons Learned: Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d. Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined., Background: Antitumor effects of MEK inhibitors are limited in KRAS-mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3-kinase-AKT pathway. Therefore, this phase I trial was initiated with the pan-HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild-type tumors., Methods: Afatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy., Results: Twenty-six patients were enrolled with colorectal cancer (n = 19), non-small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose-limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response., Conclusion: Afatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Purpose: Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity in patients treated with a standard dose of a fluoropyrimidine such as 5-fluorouracil or capecitabine (CAP). Administration of oral uracil and subsequent measurement of uracil and dihydrouracil (DHU) plasma concentrations has been used to identify patients with DPD deficiency. Liver metastasis might influence systemic DPD activity. The aim of the study was to investigate the effect of metastatic disease on the pharmacokinetics of uracil and DHU after oral administration of uracil., Methods: 500 mg/m(2) uracil was administered orally to 12 subjects with stages II-III colorectal cancer (CRC) who were treated in the adjuvant setting and to 12 subjects with stage IV metastasized CRC, all treated with CAP containing therapy. All subjects had a normal DPD activity defined as >6 nmol/mg/h determined in peripheral blood mononuclear cells., Results: The mean uracil clearance [CL 51.7 (SD 6.4) vs. 46.7 (SD 13.0) l/h], area under the curve [AUC0-220min 20.6 (SD 6.4) vs. 21.0 (SD 5.7) h mg/l], elimination half-life [t 1/2 21 (SD 7) vs. 21 (SD 8) min], maximum concentration time [T max 27 (SD 9) vs. 25 (SD 9) min], volume of distribution [V 26.58 (SD 10.11) vs. 21.10 (SD 8.48) l] and the elimination constant [k el 2.01 (SD 0.56) vs. 2.41 (SD 0.72) h(-1)] did not differ significantly (p > 0.05) non-metastatic CRD versus metastatic CRC., Conclusions: Metastasis does not alter uracil pharmacokinetics and is similar in CRC patients with and without metastasis. Therefore, the uracil test dose could be used as a DPD phenotype test in both adjuvantly treated and metastatic CRC patients using similar cutoff criteria to identify patients with DPD deficiency.

In a previous study, we found that the CYP2D6 phenotype determined by (13)C-dextromethorphan breath test (DM-BT) might be used to predict tamoxifen treatment outcome in breast cancer patients in the adjuvant setting. However, large variation in the delta-over-baseline (DOB) values was observed in the extensive metabolizer predicted phenotype group based on single point measures. In the present work we aimed to analyze the variability of phenotype results and determine reproducibility to further characterize the clinical utility of DM-BT by introducing multiple breath sampling instead of single breath sampling and by administration of a fixed dose of (13)C-DM.

The majority of knee arthroplasties (KAs) are performed in patients with osteoarthritis (OA). Although bone mass may be increased in these patients, subjects with knee OA may have an increased risk of hip fracture, possibly due to an increased severity of falls. However, in patients with KAs, risk of hip fracture has not been studied extensively. We evaluated the association between KAs and hip fracture risk in a population-based case-control study using the Dutch PHARMO Record Linkage System (1991-2002, n = 33,104). Cases were patients with a first admission for hip fracture; controls were matched by age, gender, and geographic location. Neither group had a previous history of fracture. Time since first KA was calculated. Analyses were adjusted for disease and drug history. A 54% increased hip fracture risk was found in patients who underwent KA (adjusted [adj.] OR = 1.54, 95% CI 1.19-2.00). We found a strong effect modification by age in these patients: the youngest patients (aged 18-70 years) were at more increased risk for hip fracture (adj. OR = 2.76, 95% CI 1.16-6.59), while we could not detect a statistical increase in patients aged >80 years. Furthermore, the association tended to be greater during the first few years after surgery, although it did not reach statistical significance. We found that KAs are associated with a 54% increased risk of hip fracture, in particular among adult patients aged <71 years old. Fracture risk assessment could be considered in patients who are about to undergo a KA.

Background/aim: Statin intolerance is increasingly recognized as a therapy limiting factor in the primary and secondary prevention of cardiovascular disease. Since vulnerability to dose related adverse events differ between subjects treated with statins we hypothesized low-dose simvastatin would be tolerated and effective in statin-intolerant patients., Method: A single center open label prospective observational study was performed assessing tolerability and efficacy of low-dose simvastatin treatment in 35 statin-intolerant patients. Statin intolerance was defined as not being able to tolerate a registered dose statin due to myalgia-myopathy, myositis, or elevation of serum liver enzyme levels. These statin-intolerant patients were treated with simvastatin with an initial dose of 2.5mg every other day. The dose was titrated upwards if possible. Tolerability was defined as remaining on treatment. Efficacy was defined as change of LDL-cholesterol compared to baseline., Results: The reached simvastatin dose ranged from 0.825 to 8.75mg/day with a mean dose of 4mg/day. Fifty-seven percent of the patients tolerated low-dose therapy and remained on treatment. Of these patients, 30% noted recurrent myalgia. Low-dose simvastatin significantly decreased mean(SD) LDL-cholesterol levels with 25.9(12.1)% (p<0.001). Eleven percent of the patients reached LDL-cholesterol target levels (<2.6mmol/l) in an intention to treat analysis and in 20% of patients that tolerated low-dose simvastatin., Conclusion: Low-dose simvastatin therapy is tolerated in a considerable proportion of statin-intolerant patients with significant lipid lowering efficacy. Low-dose statin therapy can be considered in multidrug regimens in statin-intolerant patients.