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Simple Summary: Breast cancer patients often receive anti-hormonal treatment if their tumor is positive for the Estrogen Receptor (ER), but tumors may become resistant to this therapy and still metastasize. We studied 101 of such metastatic lesions and investigated these lesions for mutated genes and mutation patterns, in combination with the level of expression of relevant genes. Our aim was to better understand the mechanisms that are involved in the resistance to anti-hormonal treatment. The analyses showed two distinct groups of patients, each with specific mutations. One group clearly showed an ongoing, active ER and its associated signal route; these patients probably still would benefit from ER-targeting agents. We advocate for combining mutation and expression analyses on metastatic lesions, to maximize the group of patients that still may benefit from existing or new anti-hormonal treatments targeting ER or its signaling network. Mutations in the estrogen receptor gene (ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of ESR1 target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of ESR1 and its target genes. Samples in this cluster were significantly enriched for mutations in ESR1 and amplifications in FGFR1 and TSPYL. Patients in the other cluster showed relatively lower expression levels of ESR1 and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including NF1, and ESR1 transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of ESR1 and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with HER2-positive metastatic breast cancer develop brain metastases in up to 30% of cases. The aim of this systematic review and meta-analysis was to determine the effect of different systemic therapies in patients with HER2-positive metastatic breast cancer and brain metastases, acknowledging the heterogeneity and sometimes low quality of 51 included studies. Tucatinib (combined with trastuzumab and capecitabine) and trastuzumab-deruxtecan appear to constitute the most effective systemic therapy, while pyrotinib might be an option in Asian patients. Preferably, future research will comprise of randomized controlled trials, including patients with active and/or inactive brain metastases. Aim: Patients with HER2-positive (HER2+) metastatic breast cancer (mBC) develop brain metastases (BM) in up to 30% of cases. Treatment of patients with BM can consist of local treatment (surgery and/or radiotherapy) and/or systemic treatment. We undertook a systematic review and meta-analysis to determine the effect of different systemic therapies in patients with HER2+ mBC and BM. Methods: A systematic search was performed in the databases PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and the Wiley/Cochrane Library. Eligible articles included prospective or retrospective studies reporting on the effect of systemic therapy on objective response rate (ORR) and/or median progression free survival (mPFS) in patients with HER2+ mBC and BM. The timeframe within the databases was from inception to 19 January 2022. Fixed-effects meta-analyses were used. Quality appraisal was performed using the ROBINS-I tool. Results: Fifty-one studies were included, involving 3118 patients. Most studies, which contained the largest patient numbers, but also often carried a moderate-serious risk of bias, investigated lapatinib and capecitabine (LC), trastuzumab-emtansine (T-DM1) or pyrotinib. The best quality data and/or highest ORR were described with tucatinib (combined with trastuzumab and capecitabine, TTC) and trastuzumab-deruxtecan (T-DXd). TTC demonstrated an ORR of 47.3% in patients with asymptomatic and/or active BM. T-DXd achieved a pooled ORR of 64% (95% CI 43–85%, I2 0%) in a heavily pretreated population with asymptomatic BM (3 studies, n = 96). Conclusions: Though our meta-analysis should be interpreted with caution due to the heterogeneity of included studies and a related serious risk of bias, this review provides a comprehensive overview of all currently available systemic treatment options. T-Dxd and TTC that appear to constitute the most effective systemic therapy in patients with HER2+ mBC and BM, while pyrotinib might be an option in Asian patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Identifying predictors of treatment toxicity and overall survival (OS) is important for selecting patients who will benefit from chemotherapy. In younger patients with cancer, muscle mass and radiodensity are associated with treatment toxicity and OS. In this study, we investigated whether muscle mass, radiodensity, and strength were associated with treatment toxicity and OS in patients with advanced cancer aged 60 years or older. Materials and Methods: Before starting palliative chemotherapy, muscle mass and radiodensity were assessed using computed tomography scans and muscle strength was assessed using a hydraulic hand grip dynamometer. Treatment toxicity was defined as any toxicity resulting in dose reduction and/or discontinuation of treatment. Multiple logistic and Cox regression analyses were performed to study potential associations of muscle mass, radiodensity, and strength with treatment toxicity and OS, respectively. Results: The participants were 103 patients, with a mean age of 70 years, with advanced colorectal, prostate, or breast cancer. Muscle parameters were not significantly associated with treatment toxicity. Higher muscle strength was associated with longer OS (hazard ratio 1.03; 95% confidence interval 1.00–1.05). Muscle mass and radiodensity were not significantly associated with OS. Conclusion: Higher muscle strength at the start of palliative chemotherapy is associated with significantly better OS in older patients with advanced cancer. None of the investigated muscle parameters were related to treatment toxicity. Future studies are needed to evaluate whether muscle strength can be used for treatment decisions in older patients with advanced cancer. Implications for Practice: This study in older patients with advanced cancer showed that adequate muscle strength is associated with longer overall survival. The results of this study imply that muscle strength might be helpful in estimating survival and therefore in identifying older patients who will benefit from anticancer treatment. [ABSTRACT FROM AUTHOR]

Background/Introduction: Psychological distress occurs frequently in patients with cancer. Psychological distress includes mild and severe forms of both anxious and depressive mood states. Literature indicates that effective management of psychological distress seems to require targeted selection of patients (T), followed by enhanced care (E), and the application of evidence based interventions. Besides, it is hypothesized that delivering care according to the stepped care (S) approach results in an affordable program. The aim of the current study is to evaluate the (cost)-effectiveness of the TES program compared to usual care in reducing psychological distress in patients with metastatic colorectal cancer (mCRC). Methods: This study is designed as a cluster randomized trial with 2 treatment arms: TES program for screening and treatment of psychological distress versus usual care. Sixteen hospitals participate in this study, recruiting patients with mCRC. Outcomes are evaluated at the beginning of chemotherapy and after 3, 10, 24, and 48 weeks. Primary outcome is the difference in treatment effect over time in psychological distress, assessed with the Hospital Anxiety and Depression Scale. Secondary outcomes include quality of life, patient evaluation of care, recognition and management of psychological distress, and societal costs. Discussion: We created optimal conditions for an effective screening and treatment program for psychological distress in patients with mCRC. This involves targeted selection of patients, followed by enhanced and stepped care. Our approach will be thoroughly evaluated in this study. We expect that our results will contribute to the continuing debate on the (cost-) effectiveness of screening for and treatment of psychological distress in patients with cancer. Trial Registration: This trial is registered in the Netherlands Trial Register NTR4034 [ABSTRACT FROM AUTHOR]

We determined whether progression-free survival (PFS) in metastatic breast cancer (MBC) patients receiving everolimus plus exemestane (EVE/EXE) varies depending on circulating tumour DNA (ctDNA) characteristics. Baseline plasma cell-free DNA (cfDNA) from 164 postmenopausal women with ER-positive, HER2-negative MBC refractory to a nonsteroidal aromatase inhibitor and treated with standard EVE/EXE (Everolimus Biomarker Study, Eudract 2013-004120-11) was characterised for 10 relevant breast cancer genes by next-generation sequencing with molecular barcoding. ctDNA molecule numbers, number of mutations and specific variants were related with PFS and overall survival (OS). Missense hotspot mutations in cfDNA were detected in 125 patients. The median of 54 ctDNA molecules per mL plasma distinguished patients with high and low/no ctDNA load. Patients with low/no ctDNA load (N = 102) showed longer median PFS of 5.7 months (P = 0.006) and OS of 124.8 months (P = 0.008) than patients with high ctDNA load (N = 62; 4.4 months and 107.7 months, respectively) in multivariate analyses. Patients with < 3 specific mutations (N = 135) had longer median PFS of 5.4 months compared to those with ≥ 3 mutations (3.4 months; P < 0.001). In conclusion, MBC patients with low/no ctDNA load or < 3 hotspot mutations experience longer PFS while treated with EVE/EXE., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Purpose: The somatostatin analogue [DOTA0, Tyr3]octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) beta-emitters, such as 177Lu or 90Y, for tumor therapy. In this study, DOTATOC labeled with the high-LET alpha-emitter, 213Bi, was evaluated., Experimental Design: The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of 213Bi-DOTATOC (specific activity 7.4 MBq/microg) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1 and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq 213Bi-DOTATOC was determined in a rat pancreatic carcinoma model., Results: Radiolabeling of the 213Bi-DOTATOC was achieved with radiochemical purity >95% and an incorporation yield > or = 99.9%. Biodistribution data showed specific binding to somatostatin receptor-expressing tissues. Administration of free 213Bi, compared with 213Bi-DOTATOC, resulted in higher radioactivity accumulation at 3 hours postinjection in the kidneys [34.47 +/- 1.40% injected dose/g (ID/g) tissue versus 11.15 +/- 0.46%, P < 0.0001] and bone marrow (0.31 +/- 0.01% ID/g versus 0.06 +/- 0.02%, P < 0.0324). A significant decrease in tumor growth rate was observed in rats treated with >11 MBq of 213Bi-DOTATOC 10 days postinjection compared with controls (P < 0.025). Treatment with >20 MBq of 213Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving <11 MBq (P < 0.02)., Conclusions: 213Bi-DOTATOC showed dose-related antitumor effects with minimal treatment-related organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. 213Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.