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Purpose To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors.MethodsIn this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states.ResultsCompared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (Cmax) by 16% and systemic exposure (area under the plasma concentration–time curve [AUC]) by 6%; AUC0–t decreased by 7% and time to maximum plasma concentration was delayed by 1.97 h (P = 0.0009). The 90% confidence interval of the geometric least-squares mean treatment ratio for AUC and AUC0–t was contained within the no-effect limits (0.8–1.25), while that of Cmax crossed the lower bound of the no-effect limits. Adverse events (AEs) related to adavosertib treatment were reported by 20 (64.5%) of the 31 patients treated in this study. Grade ≥ 3 AEs were reported by four (12.9%) patients (one in the fed state, three in the fasted state); two of these AEs were considered treatment-related by the investigator. Three serious AEs were reported in three (9.7%) patients; these were not considered treatment-related. No patients discontinued because of treatment-related AEs, and no new safety signals were reported.ConclusionA high-fat meal did not have a clinically relevant effect on the systemic exposure of adavosertib, suggesting that adavosertib can be administered without regard to meals.

Objectives Triple-negative (ER-/PR-/HER2-) breast carcinomas (TNBC) are aggressive tumours with underexplored imaging features. This study investigates whether their vascular characteristics as assessed by dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast-enhanced (DSC) MRI are distinct from the prognostically more favourable ER+/PR+/HER2- cancers. Methods Patients with primary breast cancer underwent MRI before neoadjuvant chemotherapy and were identified as ER-/PR-/HER2- or ER+/PR+/HER2- from core biopsy specimens. MRI parameters reflecting tissue perfusion, permeability, and extracellular leakage space were measured. Values for inflow transfer constant (K trans ), outflow rate constant (k ep ), leakage space (v e ), area under the gadolinium curve (IAUGC 60 ), relative blood volume (rBV) and flow (rBF), and Mean Transit Time (MTT) were compared across receptor status and with known prognostic variables. Results Thirty seven patients were assessable in total (16 ER-/PR-/HER2-, 21 ER+/PR+/HER2-). Lower v e ( p  = 0.001), shorter MTT ( p  = 0.007) and higher k ep values ( p  = 0.044) were observed in TNBC. v e was lower across all T stages, node-negative ( p  = 0.004) and low-grade TNBC ( p  = 0.037). v e was the best predictor of triple negativity (ROC AUC 0.80). Conclusions TNBC possess characteristic features on imaging, with lower extracellular space (higher cell density) and higher contrast agent wash-out rate (higher vascular permeability) suggesting a distinctive phenotype detectable by MRI.

For this patient group, hormone replacement therapy (HRT) is contraindicated, especially on the back of the HABITS study which demonstrated a threefold increased risk of a new breast cancer event with HRT,2 although interestingly only 21% of patients were on concurrent tamoxifen therapy at the time within this study. [...]the previous, common use of ‘Megace’ stopped in clinical practice, leaving patients and their clinicians with the less efficacious options. [...]there is new hope on the horizon following the publication in Nature in July 2015 by Jason Carroll and his team in Cambridge who have been researching the role of the progesterone receptor and its effect on the oestrogen receptor.5 Their in-vitro and pre-clinical in-vivo work has demonstrated, the previously known anti-cancer effect of progesterone on oestrogen-induced breast cancer cell lines, and increased efficacy and tumour inhibition when tamoxifen and progesterone were administered together.

Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. UK National Institute for Health Research, Health Technology Assessment Programme.

PurposeAdavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine).MethodsPeriod 1: patients with locally advanced or metastatic solid tumors received ‘cocktail’: caffeine 200 mg, omeprazole 20 mg, and midazolam 2 mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225 mg twice daily on days 1–3 (five doses), with cocktail on day 3. After cocktail alone or in combination with adavosertib administration, 24-h pharmacokinetic sampling occurred for probe substrates and their respective metabolites paraxanthine, 5-hydroxyomeprazole (5-HO), and 1′-hydroxymidazolam (1′-HM). Safety was assessed throughout.ResultsOf 33 patients (median age 60.0 years, range 41–83) receiving cocktail, 30 received adavosertib. Adavosertib co-administration increased caffeine, omeprazole, and midazolam exposure by 49%, 80%, and 55% (AUC0–12), respectively; AUC0–t increased by 61%, 98%, and 55%. Maximum plasma drug concentration (Cmax) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1′-HM exposure by 43% and 54% (AUC0–12) and 49% and 58% (AUC0–t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased Cmax for paraxanthine and 5–HO by 19% and 7%; Cmax increased by 33% for 1′-HM. After receiving adavosertib, 19 (63%) patients had treatment-related adverse events (six [20%] grade ≥ 3).ConclusionAdavosertib (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19, and CYP3A.ClinicalTrials.govNCT03333824

PurposeAdavosertib is a small-molecule, ATP-competitive inhibitor of Wee1 kinase. Molecularly targeted oncology agents have the potential to increase the risk of cardiovascular events, including prolongation of QT interval and associated cardiac arrhythmias. This study investigated the effect of adavosertib on the QTc interval in patients with advanced solid tumors.MethodsEligible patients were ≥ 18 years of age with advanced solid tumors for which no standard therapy existed. Patients received adavosertib 225 mg twice daily on days 1–2 at 12-h intervals and once on day 3. Patients underwent digital 12-lead electrocardiogram and pharmacokinetic assessments pre-administration and time-matched assessments during the drug administration period. The relationship between maximum plasma drug concentration (Cmax) and baseline-adjusted corrected QT interval by Fridericia (QTcF) was estimated using a prespecified linear mixed-effects model.ResultsTwenty-one patients received adavosertib. Concentration–QT modeling of ΔQTcF and the upper limit of the 90% confidence interval corresponding to the geometric mean of Cmax observed on days 1 and 3 were below the threshold for regulatory concern (not > 10 ms). No significant relationship between ΔQTcF (vs baseline) and adavosertib concentration was identified (P = 0.27). Pharmacokinetics and the adverse event (AE) profile were consistent with previous studies at this dose. Eleven (52.4%) patients experienced 17 treatment-related AEs in total, including diarrhea and nausea (both reported in six [28.6%] patients), vomiting (reported in two [9.5%] patients), anemia, decreased appetite, and constipation (all reported in one [4.8%] patient).ConclusionAdavosertib does not have a clinically important effect on QTc prolongation.ClinicalTrials.govNCT03333824.

Quantitative DCE-MRI parameters including K trans (transfer constant min −1 ) can predict both response and outcome in breast cancer patients treated with neoadjuvant chemotherapy (NAC). Quantitative methods are time-consuming to calculate, requiring expensive software and interpretive expertise. For diagnostic purposes, signal intensity–time curves (SITCs) are used for tissue characterisation. In this study, we compare the ability of NAC-related changes in SITCs with K trans to predict response and outcomes. 73 women with primary breast cancer underwent DCE-MRI studies before and after two cycles of NAC. Patients received anthracycline and/or docetaxel-based chemotherapy. At completion of NAC, patients had local treatment with surgery & radiotherapy and further systemic treatments. SITCs for paired DCE-MRI studies were visually scored using a five-curve type classification schema encompassing wash-in and wash-out phases and correlated with K trans values and to the endpoints of pathological response, OS and DFS. 58 paired patients studies were evaluable. The median size by MRI measurement for 52 tumours was 38 mm (range 17–86 mm) at baseline and 26 mm (range 10–85 mm) after two cycles of NAC. Median baseline K trans (min −1 ) was 0.214 (range 0.085–0.469), and post-two cycles of NAC was 0.128 (range 0.013–0.603). SITC shapes were significantly related to K trans values both before ( χ 2  = 43.3, P  = 0.000) and after two cycles of NAC ( χ 2 = 60.5, P  = 0.000). Changes in curve shapes were significantly related to changes in K trans ( χ 2  = 53.5, P  = 0.000). Changes in curve shape were significantly correlated with clinical ( P  = 0.005) and pathological response ( P  = 0.005). Reductions in curve shape of ≥1 point were significant for overall improved survival using Kaplan–Meier analysis with a 5-year OS of 80.9 versus 68.6 % ( P  = 0.048). SITCs require no special software to generate and provide a useful method of assessing the effectiveness of NAC for primary breast cancer.

Breast magnetic resonance imaging (MRI) is now at a stage where the evidence is suggesting widespread potential in the management of patients with known or suspected breast cancers. MRI is used as a supplementary tool to complement conventional methods of breast evaluation because it has excellent problem-solving capabilities. Many indications for clinical breast MRI are recognized, including resolving findings on mammography, staging of breast cancer when multiple or bilateral disease is suspected, and detecting the occult primary breast cancer presenting with malignant axillary lymphadenopathy but no detectable lesion on conventional breast examination. There is also encouraging ongoing research evaluating its role for the assessment of patients at high risk of breast cancer, for primary staging of cancers in radiographically dense breasts and for the assessment of response to chemotherapy. This article will review both the technical aspects of performing and interpreting breast MRI, as well as the current and possible future roles of breast MRI, comparing its strengths and weaknesses with conventional imaging.

Neoadjuvant chemotherapy (NAC) is being increasingly used in the treatment of primary breast cancer (PBC). With the primary tumour in situ, the neoadjuvant treatment setting allows an in vivo assessment of tumour chemo-responsiveness and permits an evaluation of the possible underlying biological mechanisms of response. Angiogenesis is critical for the growth and metastases of breast cancer and with the development of novel agents targeting this process, an understanding of the vascular effects of conventional chemotherapy will enable the rational design of future drug combinations. Functional magnetic resonance imaging (MRI) provides a non-invasive method for assessing tumour microvasculature. Using this technique, pre-treatment tumour vascularity and changes following two cycles of anthracycline-based NAC were measured in a series of patients with PBC. This demonstrated a significant reduction in the permeability and perfusion-related MRI parameters in tumours responding to treatment. The degree of change in K* was able to predict for pathological non-response with a positive predictive value of 84%. Further, an evaluation of the pathophysiological correlates of functional MRI demonstrated an association between the permability/perfusion-related parameters and aggressive tumour features. An evaluation of the effect of anthracycline-based NAC on immunohistochemically-derived measures of tumour angiogenesis was performed on a series of patients treated for PBC. A quantitative and a qualitative measure of tumour angiogenesis was performed (microvessel density MVD and pericyte coverage index PCI respectively), together with an assessment of VEGF expression. This demonstrated no change in MVD following treatment but a significant increase in PCI reflecting a reduction in the proportion of immature proliferating blood vessels. This was accompanied by a reduction in VEGF expression, which may be mediating this effect. These observations may have clinical importance as they may help identify patients who could benefit from alternative therapies early in their treatment course and they may assist in the rational design of combination cytotoxic and antiangiogenic treatment regimens.