Clinical Cancer Research

Five-MicroRNA Signature: Predicting Outcomes in HPV-Negative Head and Neck Cancer

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The prognosis for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma is generally poorer than for those with HPV-positive disease. Dr. Julia Hess, of the German Research Center for Environmental Health GmbH in Neuherberg, and colleagues sought to find prognostic markers to help predict the risk of recurrence in this patient population and thus create personalized treatments with radiation, targeted drugs, and immune checkpoint inhibitors. They may have succeeded: By retrospectively performing microRNA (miRNA) expression profiling, they discovered a “five-miRNA signature [that] is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative head and neck squamous cell carcinoma,” the authors reported. Of note, added Dr. Hess in Clinical Cancer Research, “its prognostic significance is independent from known clinical parameters.”

The five-miRNA signature, when combined with established risk factors, allowed four prognostically distinct groups to be defined. Recursive-partitioning analysis classified 162 patients into being at low (n = 17), low-intermediate (n = 80), high-intermediate (n = 48), or high risk (n = 17) for recurrence (P < .001).

“[The five-miRNA signature] represents the basis for a more focused search for molecular therapeutic targets,” which would potentially improve “therapy success for appropriate patients,” the researchers stated. Currently, even when given state-of-the-art, standard-of-care therapy, patients with HPV-negative head and neck squamous cell carcinoma cancer have an overall survival rate of only about 50%.

Hopes Raised for Early Pancreatic Cancer Detection.

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Scientists at the Johns Hopkins University School of Medicine say a simple blood test based on detection of tiny epigenetic alterations may reveal the earliest signs of pancreatic cancer. The findings of their research, if confirmed, they add, could be an important step in reducing mortality from the cancer, which has an overall five-year survival rate of less than 5% and has seen few improvements in survival over the last three decades.

“While far from perfect, we think we have found an early detection marker for pancreatic cancer that may allow us to locate and attack the disease at a much earlier stage than we usually do,” explains Nita Ahuja, M.D., an associate professor of surgery, oncology and urology at the Johns Hopkins and leader of the study (“Novel Methylation Biomarker Panel for the Early Detection of Pancreatic Cancer”) described online this month in the journal Clinical Cancer Research.

For their study, Dr. Ahuja and her colleagues focused on two genes.

“We used a nanoparticle-enabled MOB (Methylation On Beads) technology to detect early-stage pancreatic cancers by analyzing DNA methylation in patient serum,” wrote the investigators in their journal article. “We identified two novel genes, BNC1 (92%) and ADAMTS1 (68%), that showed a high frequency of methylation in pancreas cancers (n=143), up to 100% in PanIN-3 and 97% in Stage I invasive cancers.”

Together, BNC1 and ADAMTS1 were detectable in 81% of blood samples from 42 people with early-stage pancreatic cancer, but not in patients without the disease or in patients with a history of pancreatitis, a risk factor for pancreatic cancer.

Dr. Ahuja’s team found that, in pancreatic cancer cells, it appears that chemical alterations to BNC1 and ADAMTS1, i.e., epigenetic modifications that alter the way the genes function without changing the underlying DNA sequence, silence the genes and prevent them from making their protein product, the role of which is not well understood. These alterations are caused by the addition of a methyl group to the DNA.

Using MOB, the researchers were able to single out in the blood even the smallest strands of DNA of those two genes with their added methyl groups. The technique uses nanoparticle magnets to latch on to the few molecules being shed by the tumors, which are enough to signal the presence of pancreatic cancer in the body, the researchers found.

Dr. Ahuja says the practical value of any blood test for cancer markers depends critically on its sensitivity (meaning the proportion of tumors it detects) and its specificity (meaning how many of the positive results are false alarms). The specificity of this new pair of markers is 85%, meaning 15% would be false alarms. She hopes further research will help refine the test, possibly by adding another gene or two, in order to go over 90% in both sensitivity and specificity.

Researchers identify three subtypes of high-grade serous ovarian cancer.

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Findings may indicate how patients will respond to treatment

New research led by Dana-Farber Cancer Institute scientists may soon enable doctors to determine which patients with high-grade serous ovarian cancer (HGSOC) – the most common cancer of the ovary – are most likely to benefit from a certain class of drugs.

Using technology able to pick out abnormalities in single units of the genetic code, the researchers sorted tumor samples from HGSOC patients into three subtypes based on the extent of a particular kind of genetic damage within the cells. Patients in the subtype with the highest levels of damage – representing one-third to one-half of all HGSOC patients – were the slowest to develop resistance to platinum chemotherapy treatment such as carboplatin. Overall, these patients lived longer without having their disease worsen than more did patients in the two other groups.

“Our findings suggest that, for the first time, we can determine which patients have the best chance of responding to specific categories of drugs for high-grade serous ovarian cancer,” says Dana-Farber’s Ursula Matulonis, MD, one of the senior authors of the study, which has been published online by the journal Clinical Cancer Research. “For this disease, one of the most difficult to treat of all gynecologic cancers, the study is an important step forward.”

J. Dirk Iglehart, MD, of Dana-Farber and Brigham and Women’s Hospital, is the paper’s other senior author, and Zhigang Wang, MD, PhD, of Dana-Farber, is the first author.

HGSOC cells have a high degree of “genomic instability,” their nuclei littered with large numbers of extra or missing chromosomes or chromosome fragments. One of the consequences of this havoc is a process known as loss of heterozygosity (LOH). LOH occurs in cells that lack the usual complement of two normal copies of each gene, having instead a normal and mutant copy of certain genes. When the normal gene in these mismatched pairs becomes inactive or mutated, the cell has no normal copy of the gene left – and is said to have lost heterozygosity.

In the study, investigators used single nucleotide polymorphism (SNP) arrays – technology that reads the elements of the genetic code one by one – to probe HGSOC tissue samples for instances of LOH. The samples tested fell neatly into three groups based on the patterns of LOH within them.

One of these groups was distinguished by a high level of LOH and a deleted segment of chromosome 13. When researchers reviewed the medical records of patients in this group, they found the patients were slow to develop resistance to chemotherapy drugs.

“Patients with the greatest burden of LOH had the longest progression-free survival – the period of time after treatment when their disease is not advancing,” says Wang. “This is the group which stands to derive the most from treatment with certain classes of drugs.”

LOH hampers cancer cells’ ability to survive, rendering the cells particularly dependent on proteins that repair damaged chromosomes. Drugs that target those repair proteins, including a class of agents known as PARP inhibitors, may be especially effective against HGSOC cells with high levels of LOH, the study authors assert.

The authors also found that LOH patterns in HGSOC were similar to those in triple-negative breast cancer, a form of breast cancer also characterized by a high level of chromosomal instability. The discovery suggests that agents effective in treating HGSOC might be effective against this type of breast cancer as well, the authors claim.

Source: http://www.dana-farber.org