Case for Liquid Biopsies Builds in Advanced Lung Cancer

Excerpt:

“For patients with advanced lung cancer, a non-invasive liquid biopsy may be a more effective and suitable alternative to the gold standard tissue biopsy to detect clinically relevant mutations and help guide their course of treatment, suggests a new study published this week in the journal Clinical Cancer Research from researchers at the Abramson Cancer Center at the University of Pennsylvania(ACC).

“In patients with advanced non-small cell lung cancer (NSCLC) treated at Penn’s ACC, mutations detected from liquid biopsies (cell-free circulating tumor DNA (ctDNA) captured from blood) closely paralleled the mutations from tissue biopsies identified in next generation sequencing tests: EGRF, TP53, and ALK, to name a few. What’s more, in several cases, liquid biopsies captured clinically relevant mutations not found in tissue biopsies as patients’ disease progressed.”

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Combination of Ibrutinib, Rituximab Induced Responses in High-Risk CLL

Editor’s note: This article discusses the results of a clinical trial—a research study with volunteer patients. The goal of the trial is to test a new treatment for high-risk chronic lymphocytic leukemia (CLL). The treatment combines two drugs, ibrutinib and rituximab. Patients participating in the trial have had promising responses to the treatment. Further studies will continue to evaluate the new treatment.

“Patients with high-risk chronic lymphocytic leukemia demonstrated encouraging rates of objective response and durable remission after treatment with ibrutinib plus rituximab, according to results of a single-center phase 2 study.

“Jan A. Burger, MD, PhD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues assessed the activity and safety of ibrutinib (Imbruvica; Pharmacyclics, Janssen), a Bruton’s tyrosine kinase inhibitor, in combination with the chimeric monoclonal antibody rituximab (Rituxan; Genentech, Biogen Idec) in 40 adults with high-risk CLL.

“All patients either experienced short PFS — defined as less than 36 months — after first-line chemoimmunotherapy, or they demonstrated high-risk cytogenetic abnormalities, such as deletion 17p, deletion 11q or TP53 mutation…

“ ‘From this study, can we state that the time for ibrutinib monotherapy is over, and that combination with anti-CD20 antibodies the preferential treatment partner, as is the case for idelalisib (Zydelig, Gilead)?’ Ghia wrote. ‘Despite [these] promising results, we will probably need to wait. Short follow-up of only 18 months makes it difficult to ascertain whether an actual benefit in PFS or OS exists when compared with the monotherapy regimen. The clinical advantage of adding a second drug (rituximab) needs to be consistently proven because of the relevant economic consequences: The additional cost of combinations might jeopardize the overall sustainability of future treatments.’ ”


Antioxidants May Actually Speed Lung Cancer Growth in Some Cases

Antioxidants are chemicals that neutralize particles called free radicals that can damage DNA. Preventing such damage may help lower cancer risk for some people. However, tumors themselves can contain high levels of free radicals; by eliminating these free radicals, antioxidants may help cancer cells grow. In a laboratory, lung cancer cells treated with the antioxidants vitamin E and acetylcysteine (ACC) multiplied faster than untreated cells. Vitamin E and ACC also increased tumor growth and decreased survival time in mice with lung cancer. The so-called ‘tumor suppressor’ protein p53 can sense certain free radicals to detect cells with DNA damage and stop their growth. Antioxidants may interfere with this cancer-suppressing mechanism by reducing free radical levels. Taking antioxidants may therefore not be recommended for lung cancer patients and smokers.


New Targeted Drugs May Offer Treatment for KRAS-Mutant Lung Cancer

Abnormalities in the KRAS gene are the most common mutations in lung cancer, especially in lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC). However, no effective targeted therapy directed at KRAS has been found. Instead, researchers have begun to focus on blocking molecules “downstream” in the chain of chemical reactions through which KRAS affects the cell. Two such molecules are TBK1 and MEK. A recent study found that the drug CYT387 blocks TBK1. CYT387 reduced tumor growth in mice with KRAS-mutant lung adenocarcinoma. Also in mice, CYT387 and the MEK inhibitor AZD6244, given together, shrank aggressive lung tumors with mutations in both the KRAS and the TP53 gene. Researchers now hope to investigate the two drugs in people.


E-Cigarette Vapor Promotes Cancer-Like Transformations of Airway Cells with Predisposing Mutations

E-cigarettes (electronic cigarettes that use a battery-powered system to deliver nicotine without producing smoke) are advertised as a safer alternative to tobacco cigarettes. However, very few studies have investigated how e-cigarettes affect lung function and lung cancer risk. Researchers examined human airway cells with mutations in the TP53 and KRAS genes, which are often mutated in the airways of current or former smokers at high risk of lung cancer. When the cells were exposed to e-cigarette vapor, they developed cancer-cell-like behaviors and gene expression changes very similar to what was seen when these cells were exposed to tobacco smoke. E-cigarettes may increase the risk of developing lung cancer in high-risk people, including current and former tobacco smokers.


Epigenetic Inactivation of MicroRNA-34b/c Predicts Poor Disease-Free Survival in Early Stage Lung Adenocarcinoma

The microRNA-34b/c (miR-34b/c) has been considered a tumor suppressor in different tumor types and it is a known transcriptional target of the tumor suppressor gene TP53. The main objectives of this study were to investigate the clinical implications of miR-34b/c methylation in early stage lung adenocarcinoma (AC) patients and to determine the functional role of miR-34b/c re-expression in lung AC cell lines.

Epigenetic inactivation of miR-34b/c by DNA methylation has independent prognostic value in early stage lung AC patients with surgically resected tumors. Re-expression of miR-34b/c leads to a less aggressive phenotype in lung AC cell lines.


Pan-Cancer Patterns of Somatic Copy Number Alteration

“Determining how somatic copy number alterations (SCNAs) promote cancer is an important goal. We characterized SCNA patterns in 4,934 cancers from The Cancer Genome Atlas Pan-Cancer data set. Whole-genome doubling, observed in 37% of cancers, was associated with higher rates of every other type of SCNA, TP53 mutations, CCNE1 amplifications and alterations of the PPP2R complex. SCNAs that were internal to chromosomes tended to be shorter than telomere-bounded SCNAs, suggesting different mechanisms underlying their generation. Significantly recurrent focal SCNAs were observed in 140 regions, including 102 without known oncogene or tumor suppressor gene targets and 50 with significantly mutated genes. Amplified regions without known oncogenes were enriched for genes involved in epigenetic regulation. When levels of genomic disruption were accounted for, 7% of region pairs were anticorrelated, and these regions tended to encompass genes whose proteins physically interact, suggesting related functions. These results provide insights into mechanisms of generation and functional consequences of cancer-related SCNAs. Rameen Beroukhim and colleagues analyzed somatic structural alterations in 12 tumor types. Whole-genome doubling was found in over a third of all cancers, associated with TP53 mutation.”


Pan-Cancer Patterns of Somatic Copy Number Alteration

“Determining how somatic copy number alterations (SCNAs) promote cancer is an important goal. We characterized SCNA patterns in 4,934 cancers from The Cancer Genome Atlas Pan-Cancer data set. Whole-genome doubling, observed in 37% of cancers, was associated with higher rates of every other type of SCNA, TP53 mutations, CCNE1 amplifications and alterations of the PPP2R complex. SCNAs that were internal to chromosomes tended to be shorter than telomere-bounded SCNAs, suggesting different mechanisms underlying their generation. Significantly recurrent focal SCNAs were observed in 140 regions, including 102 without known oncogene or tumor suppressor gene targets and 50 with significantly mutated genes. Amplified regions without known oncogenes were enriched for genes involved in epigenetic regulation. When levels of genomic disruption were accounted for, 7% of region pairs were anticorrelated, and these regions tended to encompass genes whose proteins physically interact, suggesting related functions. These results provide insights into mechanisms of generation and functional consequences of cancer-related SCNAs. Rameen Beroukhim and colleagues analyzed somatic structural alterations in 12 tumor types. Whole-genome doubling was found in over a third of all cancers, associated with TP53 mutation.”


Pan-Cancer Patterns of Somatic Copy Number Alteration

“Determining how somatic copy number alterations (SCNAs) promote cancer is an important goal. We characterized SCNA patterns in 4,934 cancers from The Cancer Genome Atlas Pan-Cancer data set. Whole-genome doubling, observed in 37% of cancers, was associated with higher rates of every other type of SCNA, TP53 mutations, CCNE1 amplifications and alterations of the PPP2R complex. SCNAs that were internal to chromosomes tended to be shorter than telomere-bounded SCNAs, suggesting different mechanisms underlying their generation. Significantly recurrent focal SCNAs were observed in 140 regions, including 102 without known oncogene or tumor suppressor gene targets and 50 with significantly mutated genes. Amplified regions without known oncogenes were enriched for genes involved in epigenetic regulation. When levels of genomic disruption were accounted for, 7% of region pairs were anticorrelated, and these regions tended to encompass genes whose proteins physically interact, suggesting related functions. These results provide insights into mechanisms of generation and functional consequences of cancer-related SCNAs. Rameen Beroukhim and colleagues analyzed somatic structural alterations in 12 tumor types. Whole-genome doubling was found in over a third of all cancers, associated with TP53 mutation.”