Highlights • Mutations in the ligand binding domain of ESR1 lead to ER constitutive activity. • ESR1 mutations are associated with acquired endocrine resistance. • Cell-free DNA is a good substrate ...for ESR1 mutation detection. • ESR1 mutation analyses have great potential for clinical decision-making.
Abstract Background Androgen receptor splice variant 7 ( AR-V7 ) in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) was recently demonstrated ...to be associated with resistance to abiraterone and enzalutamide. Cabazitaxel might, however, remain effective in AR-V7 -positive patients. Objective To investigate the association between AR-V7 expression in CTCs and resistance to cabazitaxel. Design, setting, and participants We selected patients with mCRPC from the multicenter, randomized, phase 2, randomized, open-label, multicenter study in mCRPC on the pharmacodynamic effects of budesonide on cabazitaxel (Jevtana) (CABARESC). Before the start of the first and third cabazitaxel cycle, CTCs were enumerated using the CellSearch System. In patients with ≥10 CTCs in 7.5 ml blood at baseline, the expression of AR-V7 was assessed by quantitative polymerase chain reaction. Outcome measures and statistical analysis The primary end point was the association between the AR-V7 status and the CTC response rate (decrease to fewer than five CTCs in 7.5 ml blood during treatment). Secondary end points were the prostate-specific antigen (PSA) response rate (RR) and overall survival (OS). Analyses were performed using chi-square and log-rank tests. Results and limitations AR-V7 was detected in 16 of 29 patients (55%) with ≥10 CTCs and was more frequently found in abiraterone pretreated patients (5 of 5 100% treated vs 7 of 20 35% untreated; p = 0.009). We found no differences in CTC and PSA RRs. The presence of AR-V7 in CTCs was not associated with progression-free survival (hazard ratio HR: 0.8; 95% confidence interval CI, 0.4–1.8) or overall survival (HR 1.6; 95% CI, 0.6–4.4). Conclusions The response to cabazitaxel seems to be independent of the AR-V7 status of CTCs from mCRPC patients. Consequently, cabazitaxel might be a valid treatment option for patients with AR-V7 -positive CTCs. Patient summary Tools are needed to select specific treatments for specific patients at specific times. The presence of the gene AR-V7 in CTCs has been associated with resistance to anti-androgen receptor treatments. We investigated whether this holds true for cabazitaxel, but we found cabazitaxel to be effective independent of the presence of AR-V7.
PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived ...growth factor receptor, was explored in patients with advanced STS. PATIENTS AND METHODS Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR(12 weeks)). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; alpha = beta = .1) for each stratum. Results One hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR(12 weeks), five 26% of19). PFR(12 weeks) was 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%). CONCLUSION Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.
Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid-suppressive (GAS) agents such as proton pump inhibitors could affect ...exposure of pazopanib, and thereby its therapeutic effects.
The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for ≥80% of treatment duration, and subsequently using various thresholds. The impact of concomitant GAS therapy was assessed on progression-free survival (PFS) and overall survival (OS) using multivariate Cox models, exploring and comparing also the potential effect on placebo-treated patients.
Of 333 eligible patients, 59 (17.7%) received concomitant GAS therapy for >80% of pazopanib treatment duration. Median PFS was shorter in GAS therapy users versus nonusers: 2.8 vs. 4.6 months, respectively HR, 1.49; 95% confidence interval (CI), 1.11-1.99;
= 0.01. Concomitant administration of GAS therapy was also associated with a shorter median OS: 8.0 vs. 12.6 months (HR, 1.81; 95% CI, 1.31-2.49;
< 0.01). The longer the overlapping use of GAS agents and pazopanib, the worse the outcome with pazopanib. These effects were not observed in placebo-treated patients (HR, 0.82; 95% CI, 0.51-1.34;
= 0.43 for PFS and HR, 0.84; 95% CI, 0.48-1.48;
= 0.54 for OS).
Coadministration of long-term GAS therapy with pazopanib was associated with significantly shortened PFS and OS. Withdrawal of GAS agents must be considered whenever possible. Therapeutic drug monitoring of pazopanib plasma concentrations may be helpful for patients on pazopanib and GAS therapy.
Pazopanib (GW786034, Votrient®) is a vascular endothelial growth factor receptor-focused multi-tyrosine kinase inhibitor involved in inhibiting the angiogenesis pathway. The agent was recently ...registered for use in soft tissue sarcomas, a group of diseases with a major unmet medical need.
The relevance of angiogenesis in soft tissue sarcomas is discussed. These data were the basis to decide on the development of pazopanib in these diseases. The clinical pharmacology of pazopanib, as far as practically relevant, is summarized. After the first observations of possible activity in soft tissue sarcomas in the Phase I study, a Phase II and subsequent randomized placebo-controlled Phase III study were performed and are being put into perspective in this review.
Pazopanib is an active drug for the treatment of chemotherapy-failing nonadipocytic soft tissue sarcomas. It almost triples progression-free survival significantly from 1.6 to 4.6 months in this heavily pretreated population. The safety profile is manageable, exemplified by the high dose intensity that can be achieved over time. Pazopanib can be considered as part of the standard of care for patients with soft tissue sarcomas.
Identification of specific subtypes of circulating tumor cells in peripheral blood of cancer patients can provide information about the biology of metastasis and improve patient management. However, ...to be effective, the method used to identify circulating tumor cells must detect all tumor cell types. We investigated whether the five subtypes of human breast cancer cells that have been defined by global gene expression profiling—normal-like, basal, HER2-positive, and luminal A and B—were identified by CellSearch, a US Food and Drug Administration–approved test that uses antibodies against the cell surface–expressed epithelial cell adhesion molecule (EpCAM) to isolate circulating tumor cells. We used global gene expression profiling to determine the subtypes of a well-defined panel of 34 human breast cancer cell lines (15 luminal, nine normal-like, five basal-like, and five Her2-positive). We mixed 50-150 cells from 10 of these cell lines with 7.5 mL of blood from a single healthy human donor, and the mixtures were subjected to the CellSearch test to isolate the breast cancer cells. We found that the CellSearch isolation method, which uses EpCAM on the surface of circulating tumor cells for cell isolation, did not recognize, in particular, normal-like breast cancer cells, which in general have aggressive features. New tests that include antibodies that specifically recognize normal-like breast tumor cells but not cells of hematopoietic origin are needed.
Treatment planning of gastrointestinal stromal tumors (GISTs) includes distinguishing GISTs from other intra-abdominal tumors and GISTs’ molecular analysis. The aim of this study was to evaluate ...radiomics for distinguishing GISTs from other intra-abdominal tumors, and in GISTs, predict the
c-KIT
,
PDGFRA
,
BRAF
mutational status, and mitotic index (MI). Patients diagnosed at the Erasmus MC between 2004 and 2017, with GIST or non-GIST intra-abdominal tumors and a contrast-enhanced venous-phase CT, were retrospectively included. Tumors were segmented, from which 564 image features were extracted. Prediction models were constructed using a combination of machine learning approaches. The evaluation was performed in a 100 × random-split cross-validation. Model performance was compared to that of three radiologists. One hundred twenty-five GISTs and 122 non-GISTs were included. The GIST vs. non-GIST radiomics model had a mean area under the curve (AUC) of 0.77. Three radiologists had an AUC of 0.69, 0.76, and 0.84, respectively. The radiomics model had an AUC of 0.52 for
c-KIT
, 0.56 for
c-KIT
exon 11, and 0.52 for the MI. The numbers of
PDGFRA
,
BRAF
, and other
c-KIT
mutations were too low for analysis. Our radiomics model was able to distinguish GISTs from non-GISTs with a performance similar to three radiologists, but less observer dependent. Therefore, it may aid in the early diagnosis of GIST, facilitating rapid referral to specialized treatment centers. As the model was not able to predict any genetic or molecular features, it cannot aid in treatment planning yet.
Nivolumab treatment is subject to large interpatient variability in both efficacy and toxicity, which may partly be explained by differences in nivolumab exposure. Exposure–response relationships in ...regular healthcare have not been extensively investigated for nivolumab. Therefore, we aimed to identify possible exposure–response relationships in nivolumab-treated patients with non–small-cell lung cancer (NSCLC).
Patients with NSCLC who started second-line nivolumab therapy (3 mg/kg Q2W) between May 5th 2016 and August 1st 2017, and from whom serial blood samples, toxicity data and outcome data were prospectively collected, were included. Follow-up was carried out until November 1st 2017. Patients were classified according to the best overall response (BOR) based on the Response Evaluation Criteria in Solid Tumours, v1.1, and toxicities according to the Common Terminology Criteria for Adverse Events. Nivolumab trough concentrations were measured after 2, 4 and 10 weeks of treatment, excluding dose delays, and calculated geometric means were tested versus BOR or toxicity using analysis of variance and an independent samples t-test, respectively. Overall survival (OS) and progression-free survival were compared between high and low trough concentration groups.
Seventy-six patients were evaluable for analyses. Responders (n = 15) had higher mean trough concentrations than patients with progression (n = 33): 47% higher after 2 weeks (p = 0.001), 53% higher after 4 weeks (p = 0.008) and 73% higher after 10 weeks (p = 0.002). Higher trough concentrations were associated with longer OS (p = 0.001).
This study shows that patients with NSCLC with a response to nivolumab had a higher nivolumab exposure than patients with progression, indicating a potential exposure–response relationship. Further clinical research should focus on clarifying these exposure–response relationships.
•Responders to nivolumab treatment had higher nivolumab exposure than progressors.•No difference in exposure was seen in patients with and without toxicity.•Factors influencing exposure should be clarified in future research.
Rapid increase in cost continues to have negative impact on patients’ accessibility to life-changing anticancer medications. Moreover, the rising cost does not equate to similar increase in ...medication effectiveness. We recognise our responsibility as a university hospital to tackle this imbalance and strive to provide high quality, sustainable, affordable and accessible care. An active approach in cost containment of expensive and innovative cancer drugs was adopted in our organisation to safeguard accessibility and improve quality of life for patients. In this article, we described four inverventions: 1) identify right patient and minimise overtreatment, 2) in-house medicine production for selected indications, 3) minimise medicine spillages and 4) effective procurement strategies. We call on other hospitals to take action and, favourably, to collaborate on a European level. Together, we will safeguard the current and future care of our patients.
methylation was proposed as mechanism for endocrine resistance in metastatic breast cancer patients. To evaluate its potential as a minimally invasive biomarker, we investigated the feasibility of ...measuring
methylation in cell-free DNA (cfDNA) and its association with endocrine resistance. First, we provided evidence that demethylation in vitro restores ER expression. Subsequently, we found that
methylation in cfDNA was not enriched in endocrine-resistant versus endocrine-sensitive patients. Interestingly, we found a correlation between
methylation and age. Publicly available data confirm an age-related increase in
methylation in leukocytes, confounding the determination of the
methylation status of tumors using cfDNA.
PDF
