Efficacy and Safety of BRAF Inhibitors With or Without MEK Inhibitors in BRAF-Mutant Advanced Non–Small-Cell Lung Cancer: Findings From a Real-Life Cohort

BackgroundReal-life comparative data on BRAF inhibitors (BRAFi) and BRAFi + MEK inhibitors (MEKi) combination in BRAF-mutant (BRAFm) non–small-cell lung cancer (NSCLC) is lacking.Patients and MethodsConsecutive BRAFm advanced NSCLC patients (n = 58) treated in 9 Israeli centers in 2009-2018 were identified. These were divided according to mutation subtype and treatment into groups A1 (V600E, BRAFi; n = 5), A2 (V600E, BRAFi + MEKi; n = 15), A3 (V600E, no BRAFi; n = 7), B1 (non-V600E, BRAFi ± MEKi; n = 7), and B2 (non-V600E, no BRAFi; n = 23); one patient received both BRAFi and BRAFi + MEKi. Safety, objective response rate, progression-free survival with BRAFi ± MEKi, and overall survival were assessed.ResultsObjective response rate was 40%, 67%, and 33% in groups A1, A2, and B1, respectively (P = .5 for comparison between groups A1 and A2). In group B1, G469A and L597R mutations were associated with response to BRAFi + MEKi. Median progression-free survival was 1.2 months (95% confidence interval [CI], 0.5-5.3), 5.5 months (95% CI, 0.7-9.3), and 3.6 months (95% CI, 1.5-6.7) for groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .04). Median overall survival with BRAFi ± MEKi was 1.7 months (95% CI, 0.5-NR), 9.5 months (95% CI, 0.2-14.9), and 7.1 months (95% CI, 1.8-NR) in groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .6). Safety profiles differed slightly, and similar treatment discontinuation rates were observed with BRAFi and BRAFi + MEKi.ConclusionIn the real-life setting, activity and safety of BRAFi + MEKi in V600E BRAFm NSCLC are comparable to those observed in prospective clinical trials; the combination of BRAFi + MEKi is superior to monotherapy with a BRAFi. Further research should be done to explore the impact of BRAFi + MEKi treatment on the natural history of BRAFm NSCLC.     

The role of Notch in tumorigenesis: oncogene or tumour suppressor?

Notch signalling participates in the development of multicellular organisms by maintaining the self-renewal potential of some tissues and inducing the differentiation of others. Involvement of Notch in cancer was first highlighted in human T-cell leukaemia, fuelling the notion that aberrant Notch signalling promotes tumorigenesis. However, there is mounting evidence that Notch signalling is not exclusively oncogenic. It can instead function as a tumour suppressor.     

The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination?

Peptide vaccines incorporate one or more short or long amino acid sequences as tumor antigens, combined with a vaccine adjuvant. Thus, they fall broadly into the category of defined antigen vaccines, along with vaccines using protein, protein subunits, DNA, or RNA. They remain one of the most immunogenic approaches, based on measures of T-cell response in the blood or in draining lymph nodes. However, existing peptide vaccines have had limited success at inducing clinical tumor regressions, despite reliable induction of T-cell responses. Several new developments offer promise for improving peptide vaccines, including use of long peptides, optimization of adjuvants including toll-like receptor agonists, and combination with systemic therapies that may reduce tumor-associated immune dysfunction, such as blockade of PD-1/PD-L1 interactions. To apply these new approaches optimally, it will be critical to study their effects in the context of defined antigens, for which peptide vaccines are optimal.     

Melanoma, Parkinson's disease and levodopa: causal or spurious link? A review of the literature

Since the early 1970s, a number of case reports have suggested that levodopa therapy for Parkinson's disease increases the risk of cutaneous malignant melanoma. As yet, no formal epidemiological study has been conducted to verify this hypothesis. To elucidate the relationship between levodopa and the risk of cutaneous malignant melanoma, a systematic literature search using computerized bibliographic databases was done. This review presents the case history evidence for and against the hypothesis of a causal association, and explores possible epidemiological, genetic, social, biochemical and toxicological factors that may increase the risk of melanoma in Parkinson's disease patients. All the case reports in the literature were considered. We concluded that (1) there is no epidemiological or experimental evidence of a causal role of levodopa in increasing the risk of melanoma incidence or progression; (2) there is good evidence of an excess risk of melanoma in patients with Parkinson's disease; (3) there is good evidence of a protective effect of tobacco smoking on the risk for Parkinson's disease; (4) there is good evidence of positive correlation between social class and melanoma risk; (5) the relationship between the risk of Parkinson's disease and the risk of melanoma may be due to a common genetic profile or it can be attributed to a confounding role of social class, associated with both melanoma and Parkinson's disease possibly through an inverse relationship with tobacco smoking.     

Brain Metastases From Small Cell Lung Cancer: Chemotherapy, Radiotherapy, or Both?

Brain metastasis is one of the most troublesome forms of metastatic disease in small cell lung cancer and is seen in more than half of the patients during the course of their disease. Treatment is very often indicated to improve the usually dramatic symptoms. Whole brain radiotherapy is effective with regard to improvement of clinical symptoms in the majority of the patients. Evaluation with currently used standard response criteria if it is used as a single treatment modality has unfortunately not been carried out in the reported studies. Chemotherapy results in roentgenologically documented responses in most patients who present with brain metastases at the time of diagnosis of small cell lung cancer. Patients relapsing in the brain after or during chemotherapy have the same chance to respond to second line chemotherapy in the brain as patients who are treated for a relapse at other sites. It is unclear if the combination of chemotherapy and radiotherapy is better than the single treatment modalities. For daily practice, whole brain radiotherapy still is considered as standard therapy for brain metastases of small cell lung cancer. However, if chemotherapy is administered for tumor outside the brain, one might delay the start of radiotherapy until the effect of the chemotherapy on the brain is known.     

The Scots' Paradox: can sun exposure, or lack of it, explain major paradoxes in epidemiology?

Five epidemiological paradoxes that have puzzled epidemiologists for a decade or more can be explained by the UVB-vitamin D hypothesis. The Scots' Paradox is examined in detail as an example. Many subsidiary factors varying over time and place influence the amount of UVB which reaches the skin of individuals and so the amount of vitamin D synthesised, while other factors influence the amount ingested. These factors are plotted leading to a common pathway that ends in vitamin D insufficiency and consequent disease. Examples suggest that the factors interact to increase mortality in Scotland in a way consistent with causation according to the criteria of Bradford Hill. It is suggested that different degrees of vitamin D insufficiency in populations can explain important differences in the health of nations and resolve health paradoxes. The analysis also shows that vitamin D insufficiency is a consequence of industrialisation and, like other consequences of industrial growth, such as water and air pollution, needs to be corrected by public health measures. Direct intervention with use of supplements and fortification of foods with vitamin D can be expected to provide considerable health gains, but progress will be slow until there is greater recognition of the vitamin D health crisis by the public, professionals and politicians. Health professionals need to be trained and motivated to encourage use of supplements, particularly by pregnant and nursing mothers, and infants. The importance of open sunny spaces and clean air that allows full penetration of UVB needs to be recognised by city planners and politicians. New advice and new fashions are needed to encourage maximum exposure of skin to summer sun without burning. Use of sunlamps to boost vitamin D synthesis could be useful.     

The value of magnetic resonance imaging in esophageal carcinoma: Tool or toy?

Currently, the use of magnetic resonance imaging (MRI) in patients with esophageal carcinoma is limited. However, the quality of MRI for esophageal carcinoma continues to improve and the importance of MRI in patients with esophageal carcinoma has been gradually recognized. Compared with endoscopic ultrasound and computed tomography applied in T and N staging, MRI has now achieved excellent results after the imaging technique has been optimized. We review the literature on MRI and discuss the future of MRI in esophageal carcinoma. While the role of MRI in staging, tumor volume target delineation and evaluation for preoperative chemoradiotherapy, prognosis and recurrence is still evolving. The application of MRI in esophageal carcinoma has a bright future and potential to improve precision of T and N staging as well as treatment delivery.     

The continuum model of selection in human tumors: general paradigm or niche product?

Berger and colleagues recently proposed a continuum model of how somatic mutations cause tumors to grow, thus supplementing the established binary models, such as oncogene activation and "two hits" at tumor suppressor loci. In the basic continuum model, decreases or increases in gene function, short of full inactivation or activation, impact linearly on cancer development. An extension, called the fail-safe model, envisaged an optimum level of gene derangement for tumor growth, but proposed that the cell gained protection from tumorigenesis because additional mutations caused excessive derangement. Most of the evidence in support of the continuum model came from Pten mutant mice rather than humans. In this article, we assess the validity and applicability of the continuum and fail-safe models. We suggest that the latter is of limited use: In part, it restates the existing "just right" of optimum intermediate gene derangement in tumorigenesis, and in part it is inherently implausible that a cell should avoid becoming cancerous only when it is some way down the road to that state. In contrast, the basic continuum model is a very useful addition to the other genetic models of tumorigenesis, especially in certain scenarios. Fittingly for a quantitative model, we propose that the continuum model is most likely to apply where multiple, cancer-promoting mutations have relatively small, additive effects, either through the well-established case of additive germline predisposition alleles or in a largely hypothetical situation where cancers may have acquired several somatic "mini-driver" mutations, each with weaker effects than classical tumor suppressors or fully activated oncogenes.     

The decline in breast cancer incidence: Real or imaginary?

Breast cancer is a major global problem, with nearly 1 million cases occurring each year. Over the past several decades, the disease’s incidence has risen worldwide, increasing in developing and developed countries. This rise in breast cancer incidence has been attributed to changes in lifestyle and reproductive factors and to the dissemination of population-wide mammographic screening, which facilitates diagnosis. Recently, a decline in breast cancer incidence was reported in the United States and several other developed countries, and a substantial reduction in menopausal hormone therapy use was proposed as a possible cause. However, significant controversy remains as to the timing, causes, generalizability, and longevity of this reported decline in incidence.     

The role and its mechanism of intermittent fasting in tumors:friend or foe?

Intermittent fasting(IF)is becoming a prevailing topic worldwide,as it can cause changes in the body’s energy metabolism processes,improve health,and affect the progression of many diseases,particularly in the circumstance of oncology.Recent research has shown that IF can alter the energy metabolism of tumor cells,thereby inhibiting tumor growth and improving antitumor immune responses.Furthermore,IF can increase cancer sensitivity to chemotherapy and radiotherapy and reduce the side effects of these traditional anticancer treatments.IF is therefore emerging as a promising approach to clinical cancer treatment.However,the balance between long-term benefits of IF compared with the harm from insufficient caloric intake is not well understood.In this article,we review the role of IF in tumorigenesis and tumor therapy,and discuss some scientific problems that remain to be clarified,which might provide some assistance in the application of IF in clinical tumor therapy.     

The role of the unfolded protein response in tumour development: friend or foe?

Having accumulated mutations that overcome cell-cycle and apoptotic checkpoints, the main obstacle to survival faced by a cancer cell is the restricted supply of nutrients and oxygen. These conditions impinge on protein folding in the endoplasmic reticulum and activate a largely cytoprotective signalling pathway called the unfolded protein response. Prolonged activation of this response can, however, terminate in apoptosis. Recent delineation of the components of this response, coupled with several clinical studies, indicate that it is uniquely poised to have a role in regulating the balance between cancer cell death, dormancy and aggressive growth, as well as altering the sensitivity of solid tumours to chemotherapeutic agents.