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Test Could Identify Which Prostate Cancers Require Treatment

The level of expression of three genes associated with aging can be used to predict whether seemingly low-risk prostate cancer will remain slow-growing, according to researchers at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center. Use of this three-gene biomarker, in conjunction with existing cancer-staging tests, could help physicians better determine which men with early prostate cancer can be safely followed with “active surveillance” and spared the risks of prostate removal or other invasive treatment. The findings were published recently in the online edition of Science Translational Medicine.

Independent Study: Health Diagnostic Laboratory, Inc. Services Lead to Cost Savings of 23% and Significantly Improved Health Outcomes After Two Years

Advanced cardiometabolic testing paired with follow-up health management from Health Diagnostic Laboratory, Inc. has resulted in a 23 percent decrease in a patient’s overall healthcare costs and an improved lipid profile in just two years, according to a new independent study published recently in Population Health Management.

Biomarker May Predict Prostate Cancers Requiring Treatment

Not all early-stage prostate cancer diagnoses are alike. While some patients have aggressive tumors, others have slow-growing, low Gleason score tumors that may not require treatment, but instead can be monitored with regular clinical evaluations. But distinguishing between prostate cancers that require treatment and those that do not is still a major challenge.

Researchers at Columbia University in New York City have now identified a 3-gene signature that could indicate whether a particular early-stage prostate cancer is indolent. The test relies on a tissue sample, and along with a prostate-specific antigen (PSA) test and a histology assessment, could help clinicians make an accurate diagnosis. The early results, including a blinded retrospective analysis of 43 patients, show that the signature can accurately predict which patients with low-risk disease would develop metastatic prostate cancer and which patients would not progress. The study is published in Science Translational Medicine.

“These types of markers will, for the first time, give us the opportunity to measure biological features of cancer in the same patient, with multiple biopsies spread out over many years,” said Eric Klein, MD, chairman, Glickman Urological and Kidney Institute at the Cleveland Clinic in Ohio.
Cory Abate-Shen, PhD, professor of urological oncology at Columbia University; Andrea Califano, PhD, professor of systems biology at Columbia University; and colleagues used a computational approach that identified three genes—FGFR1, PMP22, and CDKN1A—all associated with aging, that could accurately predict outcomes of low-risk, low Gleason score prostate tumors. Protein and mRNA levels of all three genes were high in those patients who had non-aggressive, indolent disease and low in those who had aggressive tumors.

Clinicians still rely on the Gleason score, a histology and pathology evaluation that does not incorporate any molecular assessment. Those patients with a Gleason score of 8 or higher are candidates for immediate treatment, but whether men with a score of 6 or 7 require treatment is difficult to assess—no test exists to identify the small percentage of patients who have early-stage prostate cancer that is more likely to metastasize.

The 3-gene signature was validated using an independent prostate cancer cohort. According to the study authors, the signature was prognostic and improved prognosis compared with the use of PSA and clinical assessment.

“We would predict that the test would be beneficial for patients with low Gleason score prostate tumors,” said Abate-Shen. “These patients are now typically monitored on active surveillance protocols, and the patients get a biopsy periodically. The test would be conducted on the biopsy.”

Rather than focusing on the entire genome, the researchers focused on 377 genes involved in aging, predicting that genes involved in aging and senescence are critical for tumor suppression. Cellular senescence is known to play a role in tumor suppression and is associated with benign prostate tumors both in the clinic and in mouse models, according to the researchers. Using a computational analysis called gene set enrichment analysis (GSEA), they narrowed the long gene list to 19 genes, and then to a set of 3 genes that could identify indolent tumors.

“To focus on senescence genes is intellectually interesting,” said Klein. “There is already a body of work supporting the role of these genes in prostate cancer, but to my knowledge no one has looked at them in early-stage disease before.”

Forty-three patients, who had been under active surveillance for 10 years at Columbia University Medical School, were used for the blinded retrospective analysis to assess the predictive value of the gene signature. Each patient had been diagnosed with low-risk prostate cancer, with a Gleason score of 6 or less. The test was correctly able to identify all 14 patients who eventually developed advanced prostate cancer.

CDKN1A has been shown to be linked to senescence and to regulate the cell cycle. Previous studies have shown that downregulation of the gene is linked to cancer progression. The correlation of FGFR1 (fibroblast growth factor receptor 1) with indolent tumors was surprising, as fibroblast growth factors have been shown to play a role in prostate cancer development. But, as the authors highlight in their discussion, FGFR1 signaling in prostate cancer is likely complex. The third gene in the signature, PMP22, encodes a glycoprotein expressed in neurons and has not been previously associated with prostate cancer.

This 3-gene signature is different from previously identified biomarkers, which have largely focused on advanced tumors. The potential biomarker test could complement other approaches in development, such as urine or blood tests, according to the authors.

A trial to validate the genetic signature is underway at Columbia University, and a national trial is being planned.

“It is really important to find novel ways to help to define early-stage tumors that may or may not progress to aggressive disease,” said Abate-Shen. “This will ultimately really help to minimize overtreatment, while capitalizing on the benefits of cancer screening.”

Other genomic approaches to distinguish indolent and aggressive disease are also underway. The first-generation expression-based tests, including Oncotype DX prostate and Prolaris, can facilitate clinical decisions based on the molecular characteristics of a prostate tumor. Both the available tests and the new ones “promise to reduce overtreatment and help men make the right decisions based on biology rather than uncertainty,” said Klein. 

Study: A Molecular Signature Predictive of Indolent Prostate Cancer [Science Translational Medicine]

Source: CancerNetwork

Mayo Clinic Researchers Identify Biomarker for Smoker’s Lung Cancer

Mayo Clinic researchers have shown that a specific protein pair may be a successful prognostic biomarker for identifying smoking-related lung cancers. The protein — ASCL1 — is associated with increased expression of the RET oncogene, a particular cancer-causing gene called RET. The findings appear in the online issue of the journal Oncogene.

“This is exciting because we’ve found what we believe to be a ‘drugable target’ here,” says George Vasmatzis, Ph.D., a Mayo Clinic molecular medicine researcher and senior author on the study. “It’s a clear biomarker for aggressive adenocarcinomas. These are the fast-growing cancer cells found in smokers’ lungs.”

ASCL1 is known to control neuroendocrine cell development and was previously linked to regulation of thyroid and small cell lung cancer development, but not smoking-related lung cancer. The research also showed that patients with ASCL1 tumors with high levels of the RET oncogene protein did not survive as long as ASCL1 patients with low levels of RET.

When researchers blocked the ASCL1 protein in lung cancer cell lines expressing both genes, the level of RET decreased and tumor growth slowed. This leads researchers to believe this mechanism will be a promising target for potential drugs and a strong candidate for clinical trials.

The co-authors of the study include Farhad Kosari, Ph.D.; Cristiane Ida, M.D.; Marie Christine Aubry, M.D.; Lin Yang, Ph.D.; Irina Kovtun, Ph.D.; Janet Schaefer Klein; Yan Li, M.D.; Sibel Erdogan; Sandra Tomaszek, M.D.; Stephen Murphy, Ph.D.; Lynn Bolette; Christopher Kolbert; Ping Yang, M.D., Ph.D.; and Dennis Wigle, M.D., Ph.D., all of Mayo Clinic.

The research was supported by a Waterman Biomarker Discovery grant and by the Mayo Clinic Center for Individualized Medicine.

Study: ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation [Oncogene]

Source: Mayo Clinic

Researchers to Identify Genetic Biomarkers for Aggressive Breast Cancer

The Avon Foundation for Women recently awarded a $300,000 grant to Dolores Di Vizio, MD, PhD, associate professor in the Department of Surgery and the Department of Pathology and Laboratory Medicine and a member of the Cancer Biology and Urologic Oncology Research Programs at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute to advance scientific research in aggressive breast cancer.

Di Vizio will collaborate with the Cedars-Sinai Women’s Cancer Program to investigate biomarkers in patient blood samples that may identify individuals with aggressive breast cancer. Biomarkers are genes or other molecules that can indicate a person’s predisposition to specific medical conditions.

Research findings have the potential to create a novel standard of care and a new source of biomarkers. The possible new source of biomarkers, known as large oncosomes, are tumor-derived vesicles that transmit signaling complexes between cell compartments, providing valuable insight into the progression of disease. Findings may also help researchers and clinicians predict the aggressiveness of breast cancer earlier in the diagnostic process.

“This kind of research is the essential foundation to get us to our real goal, which is to improve diagnostic and prognostic capabilities and find effective treatments for breast cancer,” said Di Vizio. “With this study, we hope to identify previously unrecognized large oncosomes as potential biomarkers in advanced tumors that can be visualized, quantified and isolated using methods easily translatable to the clinic.”

Funding from the Avon Foundation for Women, a nonprofit organization and longtime supporter of Cedars-Sinai, will provide an opportunity for researchers to further spearhead new technologies, therapies and surgical interventions that may provide better patient outcomes, beginning at diagnosis.

Working with Di Vizio to provide these advancements is collaborator Beth Y. Karlan, MD, director of the Women’s Cancer Program, director of the Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology, the Cedars-Sinai Board of Governors Chair in Gynecologic Oncology and the director of the Cedars-Sinai Gilda Radner Hereditary Cancer Program.

“I’m excited to be a collaborator on this research study, as it holds promise to provide tangible improvements in earlier diagnostics and detection in aggressive breast cancer and is perfectly aligned with the program goals of the Cedars-Sinai Women’s Cancer Program,” said Karlan. “This Avon Foundation for Women grant will further our program’s commitment to studying cancer biology, developing new approaches to early detection and preventing and improving cancer survival for all patients.”

This is the first study on large oncosomes analyses in patients with breast cancer. Pilot funding for this grant is supported by the Martz Breast Cancer Discovery Fund.

Source: EurekAlert!