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Monday, January 23, 2017

​​Scientists may be able to quickly predict how ovarian cancer patients are likely to respond to chemotherapy treatment using a simple blood test, according to a recent study published in PLOS Medicine (doi: 10.1371/journal.pmed.1002198).

In a study of 40 patients with high-grade serous ovarian cancer, the researchers monitored tumor DNA that could be detected in a blood sample taken before each chemotherapy treatment. By measuring the levels of the mutated cancer gene TP53, they found those who responded well to treatment had a rapid fall in the levels of this circulating DNA.

The researchers tested levels of this circulating tumour DNA in patients before and after treatment. They found that it took longer for the disease to progress in patients whose tumor DNA count in the blood fell by more than a half after one cycle of chemotherapy, compared with patients whose DNA count did not drop. They also showed that the level of tumor DNA in the blood reflects the amount of cancer seen on scans carried out before chemotherapy.

This test may be particularly useful for patients with high-grade serous ovarian cancer because the mutated cancer gene TP53 is found in more than 99 percent of patients with this form of the disease. This type represents two thirds of all ovarian cancers.

"There's a need for a test to find out quickly whether ovarian cancer patients are benefiting from chemotherapy," said James Brenton, MD, one of the lead authors of the study at the University of Cambridge. "These are early results, but if bigger trials are successful, this test looking at the tumor DNA circulating in the blood could be a cheap, quick, and easy way to get this information."

"Although we're making great progress, we still have more to do for people with ovarian cancer, as only one in three patients survive for 10 years or longer," added Peter Johnson, MD, Cancer Research UK's Chief Clinician. "Having a test to tell us early on whether chemotherapy is working would be a big help, and in the future might be a useful way to suggest other types of treatment that could work better. This could be a good way to test new types of drugs that target cancer cells specifically and spare patients the side effects from treatments if they are not working."

Monday, January 23, 2017

​​A new study has identified an effective combination therapy for treating ovarian cancer cells.

The findings may result in a new treatment option for different types of ovarian cancer, including those that develop resistance to chemotherapy and other treatments (Anticancer Research 2016;36(11):5731-42).

Ovarian cancer accounts for about 3 percent of cancers among women; however; it causes more deaths than any other cancer of the female reproductive system. Researchers at Boston University School of Medicine under the direction of Sibaji Sarkar, PhD, Instructor of Medicine, combined protease calpain inhibitor calpeptin with epigenetic (histone deacetylase) inhibitors sodium butyrate and SAHA. When used in suboptimal doses in combination, they produced enhanced ovarian cancer cell growth inhibition and induced ovarian cancer cell death.

According to the researchers, one of the interesting observations of this study was the finding that calpeptin also works as an epigenetic drug as it is capable of removing the methyl tags from genes.

"Calpeptin possibly has a dual role. It can kill cancer cells and, in addition, it may act as an epigenetic drug as well. We believe that epigenetic drugs alone are not the best choice for cancer therapy," Sarkar explained. "We need other target specific and other types of inhibitors, but the addition of epigenetic drugs can increase the efficacy of the therapy, inhibiting formation of new cancer progenitor/stem cells by re-expressing tumor suppressor genes and blocking the expression of growth promoting genes even after remission after standard therapy."

In a previous study, this same research group had proposed that epigenetics play a significant role in the formation of cancer progenitor cells, cancer progression, metastasis, and cancer drug resistance. They described an epigenetic switch concept, which is turned on during carcinogenesis. Results from other studies have shown that epigenetic drugs sensitize platinum drug resistance ovarian cancer cells and kill breast cancer stem cells, supporting this hypothesis.

In a comparative analysis, the authors previously described the similarities in the genetic and epigenetic events of breast and ovarian cancer suggesting a common epigenetic origin. They have shown before that combination of histone deacetylase inhibitors with calpain inhibitor produced enhanced growth inhibition and cell death in different types of breast cancer cells including triple negative breast cancer cells as they observed in different types of ovarian cancer cells in this study.

Thursday, January 12, 2017

Breast cancer screening in Denmark was associated with a substantial increase in the incidence of nonadvanced tumors and DCIS but not with a reduction in the incidence of advanced tumors. The rate of overdiagnosis was also substantial, according to findings of a cohort study recently published in Annals of Internal Medicine (doi: 10.7326/M16-0270).

Effective breast cancer screening should detect early-stage cancer and prevent advanced disease. Overdiagnosis occurs when mammography detects small tumors that may never affect the patient's health during a lifetime. The problem with overdiagnosis is that it exposes patients to the potential harms of treatment, such as surgery, chemotherapy, and radiation, without a clinical benefit. Whether screening reduces the incidence of advanced tumors has important treatment implications.

"Effective breast cancer screening should reduce the incidence of advanced tumors," study authors wrote. "Screening mammography detects many small tumors that would not have become clinically evident in the remaining lifetime without screening (overdiagnosis). Whether screening reduces the incidence of advanced tumors has important therapeutic implications. Overdiagnosed lesions may be unnecessarily treated with surgery, chemotherapy, and radiation, which subjects women to the harms of therapy without benefit."

Using data from two comprehensive Danish cancer registries, researchers sought to examine the association of screening with a reduction in the incidence of advanced cancer and estimate the level of overdiagnosis in the country's breast screening program, which offered biennial mammography for women aged 50 - 69 years beginning in different regions at different times.

Women in Denmark who lived in areas covered by Danish breast cancer screening programs from 1991 to 2010 were compared with those who lived in areas of Denmark that did not offer mammography screening.

The authors measured the incidence of advanced (>20mm) and nonadvanced (<20 mm) breast cancer tumors in screened and unscreened women. To examine trends in overdiagnosis, the authors compared the incidence of advanced tumors in women aged 50 to 84 in screening and nonscreening areas and compared the incidence for nonadvanced tumors among women aged 35 to 49, 50 to 69, and 70 to 84 years in both screening and nonscreening areas.

They concluded that screening was not associated with lower incidence of advanced tumors and approximately 1 in 3 invasive tumors and cases of DCIS diagnosed in screened women represent overdiagnosis.

In an accompanying editorial, Otis Brawley, MD, MACP, Chief Medical Officer of the American Cancer Society said that it's time to accept that overdiagnosis is real and that the benefits of breast screening have been overstated (doi: 10.7326/M16-2850). He writes that "considering all small breast cancer lesions to be deadly aggressive cancer is the "pathology equivalent of racial profiling."

This does not mean that screening should be abandoned, but we should try to recognize its limitations, use it in the most effective way possible, and try to improve it.

"We must carefully examine screening, realize its limitations, maximize its effectiveness, and try to improve it," Brawley wrote. "In addition, we must examine all elements of breast cancer control (to include prevention) and evaluate how they are best used."

Brawley suggests that more emphasis should be focused on preventing breast cancer through diet, weight control, and exercise.

Thursday, January 5, 2017

The American Association for Cancer Research (AACR) announced the first public release of cancer genomic data aggregated through its initiative known as AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE). The data set includes nearly 19,000 de-identified genomic records collected from patients who were treated at eight international institutions, making it among the largest fully public cancer genomic data sets released to date.

The release includes data for 59 major cancer types, including data on nearly 3,000 patients with lung cancer, more than 2,000 patients with breast cancer, and more than 2,000 patients with colorectal cancer. The genomic data and a limited amount of linked clinical data for each patient can be accessed via the AACR website.

"We are excited to make publicly available this very large set of clinical-grade, next-generation sequencing data obtained during routine patient care," said Charles L. Sawyers, MD, FAACR, AACR Project GENIE Steering Committee Chairperson, Chairperson of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York, and a Howard Hughes Medical Institute investigator. "These data were generated as part of routine patient care and without AACR Project GENIE they would likely never have been shared with the global cancer research community. We are committed to sharing not only the real-world data within the AACR Project GENIE registry but also our best practices, from tips about assembling an international consortium to the best variant analysis pipeline, because only by working together will information flow freely and patients benefit rapidly."

The newly released data are fully de-identified in compliance with the Health Insurance Portability and Accountability Act (HIPAA). They are derived from patients whose tumors were genetically sequenced as part of their care at one of the eight international institutions that participated in the first phase of AACR Project GENIE. Therefore, the genomic data are clinical grade, which means they are the highest quality possible.

By releasing the data to the global cancer research community, the consortium aims to catalyze new clinical research that will accelerate the pace of progress against cancer. There are many ways in which the data can be exploited to benefit patients in the future, including through the following: the validation of gene signatures of drug response or prognosis; the ability to identify new patient populations for drugs previously approved by the FDA; the expansion of patient populations that will benefit from existing drugs; and the identification of new drug targets and biomarkers.

"I am extremely proud that the American Association for Cancer Research, as the Coordinating Center for AACR Project GENIE, is delivering on its promise to make these important data publicly available just over a year after unveiling the initiative," said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. "I would like to thank like to thank Dr. Sawyers for his vision in conceptualizing this exciting project and also the eight international institutions that have contributed these valuable data to AACR Project GENIE. By actively collaborating to create this extensive, freely available data set, they are leading a revolution in cancer genomics research that holds the promise for significantly enhancing the future utility of precision medicine in the treatment of cancer and for the benefit of patients around the world."

The eight institutions participating in AACR Project GENIE phase 1 are:

  • Dana-Farber Cancer Institute, Boston, Mass.;
  • Gustave Roussy Cancer Campus, Paris-Villejuif, France;
  • The Netherlands Cancer Institute, Amsterdam, on behalf of the Center for Personalized Cancer Treatment, Utrecht, The Netherlands;
  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Md.;
  • Memorial Sloan Kettering Cancer Center, New York, N.Y.;
  • Princess Margaret Cancer Centre, Toronto, Ontario, Canada;
  • University of Texas MD Anderson Cancer Center, Houston, Texas; and,
  • Vanderbilt-Ingram Cancer Center, Nashville, Tenn.​

To expand the AACR Project GENIE registry, the consortium is now accepting applications for new participating centers, which is a year sooner than originally anticipated. Any nonprofit institution that meets certain criteria should submit an application to become a project participant.

Tuesday, January 3, 2017

​​An enzyme that plays an active role in inflammation could be a natural way to suppress tumors and ulcers in the colon that are found in colitis associated cancer (CAC), a type of colorectal cancer that is driven by chronic inflammation, according to a new study.

Researchers at Georgia State University and Stony Brook University have identified the tumor suppressor role of matrix-metalloproteinase (MMP9), which belongs to a family of enzymes called proteinases and serves as an essential regulator of extracellular matrix components via a novel mechanistic pathway. The findings are reported in the journal Oncotarget (doi: 10.18632/oncotarget.13406).

"In the setting of chronic inflammation, MMP9 expression functions as a silver lining by suppressing the advancement of the tumor microenvironment in CAC," said Pallavi Garg, PhD, Assistant Professor in the Institute for Biomedical Sciences at Georgia State.

Inflammation can be a beneficial response to tissue damage or pathogens, but if unregulated it can become chronic inflammation and induce malignant cells in tissue that lead to cancer. Patients with chronically active ulcerative colitis have a significantly higher risk (up to 50% depending on the group of subjects) of developing CAC. The risk of CAC increases with the duration of the disease and the severity of inflammation.

The protein expression and activity of MMP9 is undetectable in most healthy adult tissues, including the colon and intestine, but it is highly expressed in a variety of inflammatory states. Previous studies have shown that MMP9 derived from epithelial cells plays a protective role in the development of CAC. Almost 80 percent of cancers have epithelial cell origin. This study aimed to determine whether epithelial-derived MMP9 has a defensive role of tumor suppressor in CAC and the underlying molecular mechanism.

Researchers used transgenic mice that expressed MMP9 in the colonic epithelium for in vivo experiments. In vitro experiments used human colon carcinoma cells with and without MMP9 and mouse embryonic fibroblasts, which are connective tissue cells that make the extracellular matrix and collagen and play an important role in tissue repair.

The researchers found mice that expressed MMP9 in the epithelium exhibited fewer tumors and increased apoptosis, or programmed cell death that gets rid of cells that are no longer needed or are a threat to the organism. Human colon carcinoma cells that overexpressed MMP9 showed decreased cell proliferation, less DNA damage and cell cycle arrest in the S-phase to prevent cell proliferation.

In addition, they found that epithelial-derived MMP9 suppresses tumors in CAC by activating the MMP9-Notch1-ARF-p53 axis pathway, which increases apoptosis, initiates cell cycle arrest and keeps a check on DNA damage.