The complexity of neoplasia and its treatment are a challenge to the formulation of general criteria that are applicable across solid cancers. Determining the number of prior lines of therapy (LoT) ...is critically important for optimising future treatment, conducting medication audits, and assessing eligibility for clinical trial enrolment. Currently, however, no accepted set of criteria or definitions exists to enumerate LoT. In this article, we seek to open a dialogue to address this challenge by proposing a systematic and comprehensive framework to determine LoT uniformly across solid malignancies. First, key terms, including LoT and 'clinical progression of disease' are defined. Next, we clarify which therapies should be assigned a LoT, and why. Finally, we propose reporting LoT in a novel and standardised format as LoT N (CLoT + PLoT), where CLoT is the number of systemic anti-cancer therapies (SACT) administered with curative intent and/or in the early setting, PLoT is the number of SACT given with palliative intent and/or in the advanced setting, and N is the sum of CLoT and PLoT. As a next step, the cancer research community should develop and adopt standardised guidelines for enumerating LoT in a uniform manner.
Patients with coronavirus disease 2019 (COVID-19) who have underlying malignancy have a higher mortality rate compared with those without cancer, although the magnitude of such excess risk is not ...clearly defined. We performed a systematic review and pooled analysis to provide precise estimates of the mortality rate among patients with both cancer and COVID-19.
A systematic literature search involving peer-reviewed publications, preprints and conference proceedings up to July 16, 2020, was performed. The primary end-point was the case fatality rate (CFR), defined as the rate of death among patients with cancer and COVID-19. The CFR was assessed with a random effects model, which was used to derive a pooled CFR and its 95% confidence interval (CI).
Fifty-two studies, involving a total of 18,650 patients with both COVID-19 and cancer, were selected for the pooled analysis. A total of 4243 deaths were recorded in this population. The probability of death was 25.6% (95% CI: 22.0%–29.5%; I2 = 48.9%) in this patient population.
Patients with cancer who develop COVID-19 have high probability of mortality. Appropriate and aggressive preventive measures must be taken to reduce the risk of COVID-19 in patients with cancer and to optimally manage those who do contract the infection.
•Patients with both cancer and coronavirus disease 2019 (COVID-19) have a higher mortality than reported in the overall COVID-19-positive population.•We aim to provide precise mortality estimates among patients with cancer and COVID-19.•Pooled case mortality rate was 25.6% (95% CI: 22.0%–29.5%; I2 = 48.9%).•Aggressive measures must be taken to reduce risk of infection in patients with cancer.
Summary Alterations of signal transduction pathways leading to uncontrolled cellular proliferation, survival, invasion, and metastases are hallmarks of the carcinogenic process. The ...phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and the Raf/mitogen-activated and extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways are critical for normal human physiology, and also commonly dysregulated in several human cancers, including breast cancer (BC). In vitro and in vivo data suggest that the PI3K/AKT/mTOR and Raf/MEK/ERK cascades are interconnected with multiple points of convergence, cross-talk, and feedback loops. Raf/MEK/ERK and PI3K/AKT/mTOR pathway mutations may co-exist. Inhibition of one pathway can still result in the maintenance of signaling via the other (reciprocal) pathway. The existence of such “escape” mechanisms implies that dual targeting of these pathways may lead to superior efficacy and better clinical outcome in selected patients. Several clinical trials targeting one or both pathways are already underway in BC patients. The toxicity profile of this novel approach of dual pathway inhibition needs to be closely monitored, given the important physiological role of PI3K/AKT/mTOR and Raf/MEK/ERK signaling. In this article, we present a review of the current relevant pre-clinical and clinical data and discuss the rationale for dual inhibition of these pathways in the treatment of BC patients.
Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is ...associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.
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•33,879 patients with malignancies and SARS-CoV-2 infection were included in this meta-analysis.•The overall case-fatality rate (CFR) was 25.4% (95% CI 22.9%–28.2%).•The CFR among ...patients with lung cancer and SARS-CoV2 infection was 32.4% (95% CI 26.5%–39.6%).•The CFR among patients with breast cancer and SARS-CoV2 infection was 14.2% (95% CI 9.3%–21.8%).
A systematic review and meta-analysis was performed to estimate mortality in adult patients with solid or hematological malignancies and SARS-CoV-2 infection.
A systematic search of PubMed, up to 31 January 2021, identified publications reporting the case-fatality rate (CFR) among adult patients with solid or hematological malignancies and SARS-CoV-2 infection. The CFR, defined as the rate of death in this population, was assessed with a random effect model; 95% confidence intervals (CI) were calculated.
Among 135 selected studies (N = 33,879 patients), the CFR was 25.4% (95% CI 22.9%–28.2%). At a sensitivity analysis including studies with at least 100 patients, the CFR was 21.9% (95% CI 19.1%–25.1%). Among COVID-19 patients with lung (N = 1,135) and breast (N = 1,296) cancers, CFR were 32.4% (95% CI 26.5%–39.6%) and 14.2% (95% CI 9.3%–21.8%), respectively.
Patients with solid or hematological malignancies and SARS-CoV-2 infection have a high probability of mortality, with comparatively higher and lower CFRs in patients with lung and breast cancers, respectively.
Three cardinal manifestations of neoplasia, namely inflammation, immune dysfunction, and coagulopathy are also seen in patients with severe SARS-CoV-2 infection, providing a biological rationale for ...testing selected anticancer drugs for their ability to control the symptoms and/or modify the course of COVID-19.
The landscape in immuno-oncology (I-O) has undergone profound changes since its early beginnings up through the rapid advances happening today. The current drug development pipeline consists of ...thousands of potential I-O therapies and therapy combinations, many of which are being evaluated in clinical trials. The efficient and successful development of these assets requires the investment in and utilization of appropriate tools and technologies that can facilitate the rapid transitions from preclinical evaluation through clinical development. These tools include (i) appropriate preclinical models, (ii) biomarkers of pharmacodynamic, predictive and monitoring utility, and (iii) evolving clinical trial designs that allow rapid and efficient evaluation during the development process. This article provides an overview of how novel discoveries and insights into each of these three areas have the potential to further address the clinical management needs for patients with cancer.
As the first responders, neutrophils lead the innate immune response to infectious pathogens and inflammation inducing agents. The well-established pathogen neutralizing strategies employed by ...neutrophils are phagocytosis, the action of microbicide granules, the production of ROS, and the secretion of neutrophil extracellular traps (NETs). Only recently, the ability of neutrophils to sense and respond to pathogen-associated molecular patterns is being appreciated. This review brings together the current information about the intracellular recognition of DNA by neutrophils and proposes models of signal amplification in immune response. Finally, the clinical relevance of DNA sensing by neutrophils in infectious and non-infectious diseases including malignancy are also discussed.
Advanced breast cancer (aBC) remains incurable and the quest for more effective systemic anticancer agents continues. Promising results have led to the FDA approval of three antibody-drug conjugates ...(ADCs) and two immune checkpoint inhibitors (ICIs) to date for patients with aBC.
With the anticipated emergence of newer ADCs and ICIs for patients with several subtypes of breast cancer, and given their potential synergy, their use in combination is of clinical interest. In this article, we review the use of ADCs and ICIs in patients with breast cancer, assess the scientific rationale for their combination, and provide an overview of ongoing trials and some early efficacy and safety results of such dual therapy.
Improvement in the medicinal chemistry of next-generation ADCs, their rational combination with ICIs and other agents, and the development of multiparametric immune biomarkers could help to significantly improve the outlook for patients with refractory aBC.
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