Kidney cancer represents about 5% of all new cancer diagnoses. The most common form of kidney cancer arises from renal epithelium, named renal cell carcinoma (RCC). This entity comprises different histological and molecular subtypes. Unraveling the molecular biology and cytogenetic of RCC has enabled the development of several targeted agents that have improved treatment outcomes of these patients. This article reviews all the agents currently approved for the treatment of RCC, and discuss upcoming molecules. Mechanism of action, preclinical and clinical development and ongoing trials, are presented for each agent, providing a broad vision of the current state of targeted therapy in RCC and possible future developments.
KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS-mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients' clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclindependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step in KRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens. @ERSpublications MEK inhibition and immunotherapy are very promising therapeutic advances in KRAS-mutated nonsmall cell lung cancer http://ow.ly/U2ohp KRAS mutations in lung cancer: epidemiology and clinical outcomesSince the beginning of the 21st century, the paradigm of precision medicine has shaken up the landscape of lung cancer classification and treatment. The discovery of cancer-related driver molecular abnormalities led to the development of efficient targeted therapies. RAS proteins are GTP kinases, discovered in the 1960s, whose GTP-RAS active isoform stimulates several pathways involved in cellular growth. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations are found in ∼25-35% of newly diagnosed nonsmall cell lung cancer (NSCLC), with a higher proportion in the adenocarcinoma subtype [1,2]. Figure 1 summarises the main amino acid substitutions and genomic features that are associated with KRAS mutations in NSCLC [3,4]. Other molecular abnormalities related to RAS pathway activation are diagnosed in 25% of NSCLC cases, such as epidermal growth factor receptor (EGFR) (10-23%), BRAF mutations (2%), MET amplifications (2%), human epidermal growth factor (HER)2 (1%) and NRAS (0.2%) mutations. Loss of the negative regulator neurofibromin is found in ∼11% of other cases.
Introduction The dissemination of SARS-Cov2 may have delayed the diagnosis of new cancers. This study aimed at assessing the number of new cancers during and after the lockdown. Methods We collected prospectively the clinical data of the 11.4 million of patients referred to the Assistance Publique Hôpitaux de Paris Teaching Hospital. We identified new cancer cases between January 1 st 2018 and September 31 st 2020, and compared indicators for 2018 and 2019 to 2020 with a focus on the French lockdown (March 17 th to May 11 th , 2020), across cancer types and patient age classes. Results Between January and September, 21,681, 20,778 and 16,764 new cancer cases were identified in 2018, 2019 and 2020, respectively. The monthly median number of new cases reached 2,520 (interquartile range, IQR, 2,328; 2,586), 2,322 (IQR 2,307; 2,399) and 1,949 (IQR 1,586; 2,045) in 2018, 2019 and 2020, respectively. From March 1 st to May 31 st , new cancer decreased by 33% in 2020 compared to the 2018-19 average; then by 19% from June 1 st to September 31 st . This evolution was consistent across all tumor types: -33% and -19% for colon, -30% and -8% for lung, -29% and -13% for breast, -30% and -18% for prostate cancers, respectively. For patients aged < 70 years, the decrease of colorectal and breast new cancers in April between 2018-2019 average and 2020 reached 46% and 44%, respectively. Conclusion The SARS-Cov2 pandemic led to a substantial decrease of new cancer cases. Delays in cancer diagnoses may affect clinical outcomes in the coming years.
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