Despite major advances in therapy, cancer continues to be a leading cause of mortality. In addition, toxicities of traditional therapies pose a significant challenge to tolerability and adherence. ...TTFields, a noninvasive anticancer treatment modality, utilizes alternating electric fields at specific frequencies and intensities to selectively disrupt mitosis in cancerous cells. TTFields target proteins crucial to the cell cycle, leading to mitotic arrest and apoptosis. TTFields also facilitate an antitumor immune response. Clinical trials of TTFields have proven safe and efficacious in patients with glioblastoma multiforme (GBM), and are FDA approved for use in newly diagnosed and recurrent GBM. Trials in other localized solid tumors are ongoing.
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Background
A prior meta‐analysis found no association between BRCA1 mutation and prostate cancer (PCa). Subsequent
BRCA2 mutation studies have shown an association with PCa risk and mortality. We ...conducted a meta‐analysis of overall
BRCA mutation carriers and in subgroups to (1) estimate PCa risk in
BRCA mutation carriers, (2) evaluate the frequency of
BRCA mutation carriers in patients with PCa, and (3) compare cancer‐specific survival (CSS) and overall survival (OS) among
BRCA mutation carriers and noncarriers.
Methods
We searched the PubMed/MEDLINE, Embase, and Cochrane databases. Unadjusted odds ratio (OR), percentage (%), and hazard ratio (HR) were used to calculate pooled estimates for PCa risk, frequency, and survival, respectively. Subgroup analyses by mutation type (
BRCA1 or
BRCA2) were conducted for the three objectives. Further subgroup analyses by study design (age‐sex‐adjusted or crude), ascertainment method (ascertained or inferred genotyping), population (Ashkenazi Jewish or general population), and survival outcomes (CSS or OS) were conducted. The associations were evaluated using random‐effects models, in two‐sided statistical tests.
Results
A total of 8 cohort, 7 case‐control, 4 case‐series, 28 frequency, and 11 survival studies were included. Being a BRCA mutation carrier (
BRCA1 and/or
BRCA2) was associated with a significant increase in PCa risk (OR = 1.90, 95% CI = 1.58‐2.29), with
BRCA2 mutation being associated with a greater risk of PCa (OR = 2.64, 95% CI = 2.03‐3.47) than
BRCA1 (OR = 1.35, 95% CI = 1.03‐1.76). The frequency of
BRCA1 and
BRCA2 carriers in patients with PCa was 0.9% and 2.2%, respectively. OS (HR = 2.21, 95% CI = 1.64‐2.30) and CSS (HR = 2.63, 95% CI = 2.00‐3.45) were significantly worse among
BRCA2 carriers compared to noncarriers, whereas OS (HR = 0.47, 95% CI = 0.11‐1.99) and CSS (HR = 1.07, 95% CI = 0.38‐2.96) were statistically not significant when comparing
BRCA1 carriers and noncarriers.
Conclusions
There is a 1.90‐fold greater risk of PCa in overall BRCA mutation carriers. This elevated PCa risk is attributable mainly to a 2.64‐fold greater risk of PCa in
BRCA2 carriers compared to a moderate 1.35‐fold greater risk in
BRCA1 carriers. The frequency of
BRCA2 mutations was higher than
BRCA1 mutations among patients with PCa.
BRCA2 but not
BRCA1 mutations were associated with higher PCa mortality. The
BRCA mutation may be a clinical factor to stratify high‐risk patients and guide clinical strategies for more effective treatments for patients with PCa.
Cardiotoxic effects of chemotherapy and targeted drugs are ubiquitous and challenging in the field of oncology therapeutics. The broad spectrum of toxicities ranging from ischemic, hypertensive, ...cardiomyopathic, and arrhythmic complications can present as a significant challenge for clinicians treating cancer patients. If early diagnosis and intervention of cardiotoxic complications is missed, this can lead to delay or abrogation of planned treatment, which can potentially culminate to significant morbidity due to not only the cardiotoxic complications but also the progression of cancer. Hence, full knowledge of cardiovascular complications of chemotherapeutic agents, essential diagnostics tests to order, and appropriate management is paramount to oncologist, oncology pharmacists, and scientific clinical investigators. The aforementioned is particularly true in the current oncology era of plenteous early clinical trials studying several pathway/molecular-targeting agents with an increased cardiotoxic potential and the rapid expedited approval of those drugs by the FDA. Herein, we present a review discussing cardiotoxic effects of drugs and guidelines for management of the toxicities to assist the medical field in general managing patients with cancer.
Fibroblast growth factor receptors (FGFR 1-4) are a highly conserved family of receptor tyrosine kinases, involved in several physiological processes. Genetic aberrations of FGFRs and their ligands, ...fibroblast growth factors (FGFs) are involved in several pathological processes including cancer. The FGF-FGFR axis has emerged as a treatment target in oncology. Because these aberrations drive cancer progression, the development of FGFR targeted therapies have been accelerated.
In this comprehensive review, we evaluate molecular pathology and targeted therapies to FGFRs. We reviewed the evidence for safety and efficacy from preclinical and clinical studies (phase I-III) of FGFR targeted therapies. We also discuss potential challenges in bringing these targeted therapies from bench to bedside and the potential opportunities.
Despite the challenges of the clinical development of FGFR targeted therapies, two FGFR small-molecule inhibitors, namely Erdafitinib and Pemigatinib, are FDA approved for urothelial cancer and cholangiocarcinoma, respectively. Understanding and detection of FGFR genomic aberrations, protein overexpression and the development of isoform-specific inhibitors are factors in the clinical success of these therapies. An enhanced understanding of patient selection based on a gene signatures or biomarkers is key to success of FGFR targeted therapies.
Non-Hodgkin lymphoma (NHL) is the most common adult hematologic malignancy. Conventional methods of treatment are chemotherapy and radiation, which were associated with toxicities and lack of ...specificity. Potential cell surface targets for treatment of B-cell NHL (B-NHL) include CD19, CD20, and CD22 which are highly expressed on malignant B-cells. The development of monoclonal antibody (mAb) therapy directed against CD20 had the most clinical impact in the treatment of B-NHL. Early clinical trials with rituximab (RTX), the first chimeric mAb against CD20, showed efficacy and minimal toxicities. RTX was later approved as first line in combination with CHOP chemotherapy for Diffuse Large B-NHL (DLBCL). The emergence of resistance to RTX prompted the development of the next-generation of mAbs targeting CD20 (e.g. obinituzumab, ofatumumab), and includes ublituximab (Ub), with higher complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) against malignant B-cells. Areas covered: Herein, we discuss clinical trials of Ub, highlighting efficacy, tolerability and an expert opinion on drug development in B-NHL. A pubmed search was conducted to evaluate all Ub clinical trials. Expert opinion: Ub demonstrated efficacy in patients with high-risk CLL and B-NHL in both first line, subsequent lines, and in rituximab refractory patients.
The treatment landscape of biliary cancers is rapidly changing. Inhibitors against the actionable targets FGFR and IDH1 are now being included in the treatment guidelines of multiple countries for ...patients with advanced cholangiocarcinoma. However, there remains an unmet need in identifying the mechanisms of resistance and treatment strategies involving possible tumor sequencing.
In this review article, we address clinical trials evaluating FGFR, IDH, BRAF and HER2 inhibitors in advanced cholangiocarcinoma. We also review the mechanisms of resistance described thus far and approaches to overcome them. Articles selected for this review were based on reported studies indexed in PubMed (2010-2022).
Precision medicine in biliary cancers has already been incorporated into the treatment landscape of the disease in many countries. Fusions of FGFR2 and mutations in IDH1 are the first drivers with targetable treatments approved in these cancers. HER2 and BRAF would be the next drivers with possible tumor-agnostic or cholangiocarcinoma-specific approvals. The advent of ctDNA could improve the accessibility of sequencing and recruitment in these clinical trials. However, limitations of detecting fusions should be considered and addressed in these platforms.
Abstract
Background
Suspicious F-18 fluciclovine PET/CT findings for osseous metastases from prostate cancer (PC) were targeted for core needle biopsy. We correlated the maximum standardized uptake ...value (SUVmax) of biopsied lesions, with biopsy results, other diagnostic outcomes, and blood and tissue molecular analysis (TMA).
Material and Methods
Patients with castrate resistant prostate cancer (CRPC) were recruited from a university oncology clinic. SUVmax, histology, blood, and TMA were correlated.
Results
Fifteen patients were enrolled and 12 underwent bone biopsies. Fifty percent of bone biopsies demonstrated malignancy. Higher SUVmax was associated with positive biopsies for adenocarcinoma (P = .003), and lesions with SUVmax ≥ 5.1 were all positive for malignancy. Significant correlation between blood and somatic TMA (P = .002) was also found.
Conclusion
Higher uptake of F-18 fluciclovine was associated with higher predictive value for osseous metastasis on biopsy. There was a significant correlation between blood and TMA.
This study provides a valuable model for amino acid PET, as well as important molecular data on tumors. ctDNA correlates with tissue next-generation sequencing in prostate cancer.
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•Indirect comparisons yielded no differences in OS and PFS between PD-1/PD-L1 inhibitors in NSCLC.•Indirect comparisons showed higher ORR for pembrolizumab and nivolumab relative to ...atezolizumab.•Pembrolizumab ranked 1 st in OS/ORR and OS subgroups: adenoCa, EGFR mutant, ECOG 1, male, age <65y.•Nivolumab ranked 1 st in PFS and OS groups: squamous cell disease, EGFR-wild type, ECOG 0.
Two PD-1 (pembrolizumab, nivolumab) and one PD-L1(atezolizumab) inhibitors are approved for previously treated advanced non-small cell lung cancer but have not been compared in head-to-head trials.
A network meta-analysis was conducted to compare efficacy/safety of PD-1/PD-L1 inhibitors.
In five-trials (including long-term updates) with docetaxel as common comparator there were no differences in OS and PFS between PD-1/PD-L1 inhibitors. Pembrolizumab (odds ratio(OR) = 2.22, 95%CrI = 1.28–3.70) and nivolumab (OR = 1.92, 95%CrI = 1.15–3.23) had higher ORRs than atezolizumab and at PD-L1 expression ≥50% and ≥1%. Probabilistically, pembrolizumab ranked first in OS and ORR, and in OS sub-analyses for adenocarcinoma, EGFR-mutant, ECOG-score-1, male, and age <65 years. Nivolumab ranked first in PFS, and in OS sub-analyses for squamous-cell disease, EGFR-wild-type, and ECOG-score-0. Pembrolizumab and nivolumab ranked the best option for most of adverse events.
While pembrolizumab and nivolumab prevailed in rank in OS and ORR benefit, patient characteristics, safety and tolerance should be considered in treatment decision-making.
The Leukemia Inhibitory Factor (LIF) is a member of the interleukin-6 (IL-6) cytokine family. Known to induce differentiation of myeloid leukemia cells, evidence has accumulated supporting its role ...in cancer evolution through regulating cell differentiation, renewal, and survival. LIF has recently emerged as a biomarker and therapeutic target for pancreatic ductal adenocarcinoma (PDAC). The first in-human clinical trial has shown promising safety profile and has suggested a potential role for LIF inhibitor in combination regimen.
Herein, we summarize, discuss, and give an expert opinion on the role of LIF in PDAC promotion, and its potential role as a biomarker and target of anti-cancer therapy. We conducted an exhaustive PubMed search for English-language articles published from 1 January 1970, to 1 August 2022.
PDAC carries a devastating prognosis for patients, highlighting the need for advancing drug development. The results of the phase 1 trial with MSC-1 demonstrated tolerability and safety but modest efficacy. Future research should focus on investigating LIF targets in combination with current standard-of-care chemotherapy, and immunotherapy can be a promising approach. Further, larger multicenter clinical trials are needed to define the use of LIF as a new biomarker in PDAC patients.
A phase 2 trial comparing talimogene laherparepvec plus ipilimumab vs ipilimumab monotherapy in patients with advanced unresectable melanoma found no differential benefit in progression-free survival ...(PFS) but noted objective response rates (ORRs) of 38.8% (38 of 98 patients) vs 18.0% (18 of 100 patients), respectively.
To perform an economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy.
For PFS, cost-effectiveness and cost-utility analyses using a 2-state Markov model (PFS vs progression or death) was performed. For ORRs, cost-effectiveness analysis of the incremental cost of 1 additional patient achieving objective response was performed. In this setting based on a US payer perspective (2017 US dollars), participants were patients with advanced unresectable melanoma.
The PFS life-years and PFS quality-adjusted life-years were determined, and the associated incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs) were estimated. Also estimated was the ICER per 1 additional patient (out of 100 treated patients) achieving objective response. Base-case analyses were validated by sensitivity analyses.
In PFS analyses, the cost of talimogene laherparepvec plus ipilimumab ($494 983) exceeded the cost of ipilimumab monotherapy ($132 950) by $362 033. The ICER was $2 129 606 per PFS life-years, and the ICUR was $2 262 706 per PFS quality-adjusted life-year gained. Probabilistic sensitivity analyses yielded an ICER of $1 481 208 per PFS life-year gained and an ICUR of $1 683 191 per PFS quality-adjusted life-year gained. In 1-way sensitivity analyses, the PFS hazard ratio and the utility of response were the most influential parameters. Talimogene laherparepvec plus ipilimumab has a 50% likelihood of being cost-effective at a willingness-to-pay threshold of $1 683 191 per PFS quality-adjusted life-year gained. In ORR analyses, talimogene laherparepvec plus ipilimumab ($474 904) vs ipilimumab alone ($132 810), a $342 094 difference, yielded an ICER of $1 629 019 per additional patient achieving objective response. In subgroup analyses by disease stage and BRAFV600E mutation status, ICERs ranged from $1 069 044 to $17 104 700 per 1 additional patient achieving objective response.
The cost to gain 1 additional progression-free quality-adjusted life-year, 1 additional progression-free life-year, or to have 1 additional patient attain objective response is about $1.6 million. This amount may be beyond what payers typically are willing to pay. Combination therapy of talimogene laherparepvec plus ipilimumab does not offer an economically beneficial treatment option relative to ipilimumab monotherapy at the population level. This should not preclude treatment for individual patients for whom this regimen may be indicated.
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