TUMOR PROFILING

A Virtual Molecular Tumor Board to Improve Efficiency and Scalability of Delivering Precision Oncology to Physicians and Their Patients

Using virtual, cloud-based, interconnected computing techniques applied to 51,000 variables based on tumors from more than 1,700 people, researchers reduced the time needed to assess a cancer patient's tumor profile and suitability for clinical trials from 14 to 4 days (JAMIA Open 2019; doi: 10.1093/jamiaopen/ooz045). This method also increased twofold, over a 4-year period, the number of cases that could be assessed compared to conventional methods. A conventional tumor board approach is burdensome and typically does not allow tumor board review for all cases. In their study, the researchers modeled virtual molecular tumor boards (VMTB) to assess the genetic makeup, previous treatment history, and other factors for 1,725 cancer patients. They also compared VMTB outcomes with reviews by five gastrointestinal oncologists who performed tumor board duties in a conventional manner. The time spent assessing appropriate trials was noted and the results were compared to the virtual method. Over a 4-year period, the investigators found that virtual boards could make assessments based on patient tumors for over 2,000 clinical trials, more than 1,000 cancer drugs, and nearly 200 genetic biomarkers associated with targets known to be amenable to treatment. From 2014 to 2017, the number of cases assessed virtually increased from 46 to 622 compared to conventional board assessments going from 3 cases to 14. Additionally, the virtual board process integrated comprehensive information about the distance between a patient and a potential treatment center, providing practical resources for a patient looking for a clinical trial. Notably, fewer than 5 percent of pancreatic cancer patients currently enroll in clinical trials, but 22 percent of such patients whose cases were reviewed by a virtual board enrolled in a clinical trial.

NEUROBLASTOMA

Maintaining Outstanding Outcomes Using Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children's Oncology Group Study ANBL0531

A recent Children's Oncology Group study identified a treatment algorithm that can help reduce therapy for some neuroblastoma patients with intermediate-risk disease, while maintaining good clinical outcomes. The study's findings are particularly significant because they suggest that many infants and young children with this disease may be spared unpleasant or lingering side effects of prolonged therapy (J Clin Oncol 2019; doi: 10.1200/JCO.19.00919). Neuroblastoma is the most common extracranial malignant solid tumor of childhood. It primarily affects infants and children up to age 5, but can occur in older children and young adults. The disease is classified as high-risk or non-high-risk based on the patient's age at diagnosis, the extent of the disease, and particular genetic features of the tumor cells. Treatment of high-risk neuroblastoma involves very intensive therapy, but for patients with non-high-risk neuroblastoma, recent clinical trials have shown that therapy can often be reduced due to the generally excellent prognoses for these patients. The prospective phase III study (NCT00499616) enrolled 404 children in three groups across North America with intermediate-risk neuroblastoma. The researchers developed and then tested an algorithm based on tumor biology and anticipated response to treatment, and designed to reduce therapy for patients without compromising overall survival rates. They focused on patients whose disease was determined to have favorable clinical and biologic features. The study results showed a 3-year overall survival (OS) rate of 94.9 percent among all patients. Among patients under age 1, those with favorable-biology stage IV disease had a significantly superior event-free survival compared to infants with unfavorable stage IV disease (87% vs. 67%), but OS was not significantly different between these two groups (95% vs. 86.7%). Patients with localized disease had an OS rate of 100 percent. The researchers noted that continued research is needed to identify more effective treatment strategies for infants who have stage IV neuroblastoma with unfavorable biology.

LUNG CANCER

Electronic-Cigarette Smoke Induces Lung Adenocarcinoma and Bladder Urothelial Hyperplasia in Mice

Exposure to electronic-cigarette (e-cig) smoke caused mice to develop lung cancer, a new study finds (Proc Natl Acad Sci U S A 2019; doi: 10.1073/pnas.1911321116). The study found that nine of 40 mice (22.5%) exposed to e-cig smoke with nicotine for 54 weeks developed lung adenocarcinomas. None of the 20 mice from the study exposed to the same e-cig smoke without nicotine developed cancer. Twenty-three of 40 mice (57.5%) exposed to e-cig smoke developed bladder hyperplasia, genetic changes that make cells more likely to multiply, and a step toward abnormal tissue growth seen in cancer. Only one of the 17 mice exposed to the zero-nicotine e-cig smoke developed hyperplasia. Some of the study's limitation included that it was conducted in a relatively small number of mice susceptible to developing cancer over their lifetime (1-year study period designed to offset age-related cancer). The study mice also did not inhale smoke like a human would, but, instead, were surrounded by it (whole-body exposure). The study found that mammalian cells contain their own nitrosonium ions, which directly react with nicotine to form nitrosamines, including nicotine-derived nitrosamine ketone (NNK). Many studies have also shown that human and mouse cells also have ample supplies of cytochrome p450, which further converts N-nitrosonoricotine and NNK into compounds (e.g., formaldehyde and CH3N=NOH) that can react with DNA to form damaging adducts (e.g., gamma-OH-PdG and O6-methyl-dG). The results confirm that nicotine from e-cig smoke can cause cancer in the lungs and precancerous growth in the bladders of mice. Furthermore, the results argue that nicotine, once inside cells, is converted into nitrosamines that do not leave cells and, therefore, could never be captured by tests that measure nitrosamine levels outside of cells (e.g., blood tests).

COLON CANCER

Mutated CEACAMs Disrupt Transforming Growth Factor Beta Signaling and Alter the Intestinal Microbiome to Promote Colorectal Carcinogenesis

A mutant protein found in humans with colon cancer blocks a pathway that regulates proliferation and expansion of cells, increasing amounts of bacterial species associated with the development of colon cancer, according to recent research findings (Gastroenterology 2019; doi: 10.1053/j.gastro.2019.09.023). A research team looked at the interactions among proteins of the carcinoembryonic antigen-related cell adhesion molecular (CAECAM) family, which interact with microbes, leading to changes in the growth factor beta (TGF-[beta]) signaling pathway. The team collected data on DNA sequences, mRNA expression levels, and patient survival times from 456 colorectal adenocarcinoma cases and a separate set of 594 samples of colorectal adenocarcinomas in The Cancer Genome Atlas. The team then used the GW Genomics Core to perform shotgun metagenomic sequencing analysis of feces from mice with defects in TGF-[beta] signaling to identify changes in the microbiome before colon tumors developed. The team found that the expression of CEACAMs and genes that regulate stem cell features of cells are increased in colon cancer and inversely correlated with expression of TGF-[beta] pathway genes. They also found colon cancer to express mutant forms of CEACAM5 that inhibit TGF-[beta] signaling and increase proliferation and colony formation. This could lead to less-invasive screening techniques for colon cancer, particularly for younger patients.