Identification of Transcriptional Subgroups in EGFR-Mutated and EGFR/KRAS-Wild Type Lung Adenocarcinoma Reveals Gene Signatures Associated with Patient Outcome

We sought to determine whether transcriptional subgroups of clinical relevance exist within EGFR-mutated, KRAS-mutated, or EGFR and KRAS-wild type (EGFRwt/KRASwt) adenocarcinomas. We identified transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt adenocarcinomas with significant differences in clinicopathological characteristics and patient outcome, not limited to a mutation specific setting.

Clinical, Pathological and Biological Features Associated with BRAF Mutations in Non-Small Cell Lung Cancer

BRAF mutations are found in a subset of non-small cell lung cancers (NSCLCs). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. We identified five BRAF mutations not previously reported in NSCLC; two of the five were associated with increased BRAF kinase activity. BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC.

Targeted Genetic Dependency Screen Facilitates Identification of Actionable Mutations in FGFR4, MAP3K9, and PAK5 in Lung Cancer

Here we demonstrate that a targeted genetic dependency screen is an efficient approach to identify somatic cancer alterations that are functionally important. By using this approach, we have identified three kinases with gain-of-function mutations in lung cancer, namely FGFR4, MAP3K9, and PAK5. Mutations in these kinases are activating toward the ERK pathway, and targeted depletion of the mutated kinases inhibits proliferation, suppresses constitutive activation of downstream signaling pathways, and results in specific killing of the lung cancer cells.

Clinical, Pathological and Biological Features Associated with BRAF Mutations in Non-Small Cell Lung Cancer

We report for the first time to our knowledge that V600E and non-V600E BRAF mutations affect different patients with non-small cell lung cancer. V600E mutations are significantly associated with female sex and represent a negative prognostic factor. In addition, we identified a number of other clinicopathologic parameters potentially useful for the selection of patients carrying BRAF mutations.

Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations

The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation–positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). 

In this phase III study, it was found that afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Next-Generation Sequencing Reveals High Concordance of Recurrent Somatic Alterations Between Primary Tumor and Metastases From Patients With Non-Small-Cell Lung Cancer

We undertook this study to compare genomic alterations identified in archived primary tumors from patients with NSCLC with those identified in metachronous or synchronous metastases.

TP53 mutations were the most frequently observed recurrent alterations (12 patients). Tumors harbored two or more (maximum four) recurrent alterations in 10 patients. Comparative analysis of recurrent alterations between primary tumor and matched metastasis revealed a concordance rate of 94% compared with 63% for likely passenger alterations

Genome Sequencing of Mucosal Melanomas Reveals That They are Driven by Distinct Mechanisms from Cutaneous Melanoma

Mucosal melanoma displays distinct clinical and epidemiological features compared to cutaneous melanoma. Here we used whole genome and whole exome sequencing to characterize the somatic alterations and mutation spectra in the genomes of ten mucosal melanomas. We observed somatic mutation rates that are considerably lower than occur in sun-exposed cutaneous melanoma, but comparable to the rates seen in cancers not associated with exposure to known mutagens. In particular…”

Punctuated Evolution of Prostate Cancer Genomes

“The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term “chromoplexy,” frequently accounts for…”

Lung Cancer That Harbors a HER2 Mutation: Epidemiologic Characteristics and Therapeutic Perspectives

HER2 mutations are identified in approximately 2%of non–small-cell lung cancers (NSCLC). There are few data available that describe the clinical course of patients with HER2-mutated NSCLC.

This study, the largest to date dedicated to HER2-mutated NSCLC, reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.