The gist: New research shows that it may soon be possible to measure how aggressive a patient’s triple-negative breast cancer might be. Patients with aggressive cancer might benefit from different treatment approaches from those prescribed for patients with less aggressive cancer. The new technique looks at patterns of “DNA methylation” in a tumor. In DNA methylation, molecules called methyl groups become attached to DNA molecules in distinctive patterns. The new research shows that certain DNA methylation patterns can indicate whether a tumor is likely to be aggressive.
“Australian researchers have identified epigenetic ‘signatures’ that could help clinicians tell the difference between highly aggressive and more benign forms of triple-negative breast cancer.
“The new study, published in Nature Communications, compares the breast cancer DNA ‘methylome’ with that of healthy individuals. The methylome provides a new picture of the genome and shows how it is epigenetically ‘decorated’ with methyl groups, a process known as DNA ‘methylation’.
“The study reveals ‘distinct methylation patterns’ in the primary biopsy breast cancer cells indicating better or worse prognosis.
“Triple-negative breast cancers, which make up 15-20% of all breast cancers, lack any of the three receptors (oestrogen, progesterone or HER2) that would make them responsive to targeted drugs. Overall, patients have a higher risk of disease recurrence and shorter survival than those with other breast cancers.
“Triple-negative breast cancer patients tend to fall into two categories: those that succumb to their disease within 3-5 years, regardless of treatment; and those that remain disease free for longer than the average non-triple-negative breast cancer patient (at least 8 years post-diagnosis).”
The gist: Breast cancer can be broken down into different subtypes that behave differently and might be treated differently. New research has shown that characteristics of DNA known as epigenetic marks can be used to categorize different subtypes of breast cancer. Tumors with different epigenetic marks might need different treatment. In the future, doctors might use epigenetic marks to identify which patients need more aggressive treatments.
“Breast cancer is the most common in women. One in nine will suffer breast cancer over their lifetime. Progress in prevention and early detection, and the use of chemotherapy after surgery (adjuvant chemotherapy), have achieved significantly increase survival in this disease in the last ten years, but much remains to be done.
“The identification of patients with high-risk breast cancer is key to knowing whether a patient will require only the removal of the tumor by surgery or whether if she will need additional chemotherapy to make sure the removal of breast cancer cells. Currently, known genetic mutations and expression patterns are determined, but the puzzle of the genetics of the disease remains a large unfinished part.
“The director of the Program Epigenetics and Cancer Biology (PEBC) at Bellvitge Biomedical Research Instiute (IDIBELL), Professor of Genetics at the University of Barcelona and ICREA researcher, Manel Esteller, has established the epigenetic patterns of breast cancer and also its clinical consequences. The finding is published in the journal Molecular Oncology.
” ‘We’ve analyzed epigenetic alterations, namely the chemical signal called DNA methylation in 500 breast tumors and have compared the patterns obtained with the clinical behavior of these cancers,’ says Esteller.”
American Gastroenterological Association | Aug 28, 2014
This article describes the results of a clinical trial—a research study with volunteer patients. The trial tested adding a third drug to a standard two-drug chemotherapy treatment for colorectal cancer. The standard treatment consists of the drugs fluorouracil and leucovorin. It is given to patients after tumor-removal surgery to keep the cancer from coming back (recurrence). In the trial, a third drug called irinotecan was added. The researchers found that stage III patients whose tumors tested positive for a genetic change called CIMP benefitted from the irinotecan addition. Stage III CIMP-negative patients did not.
“When added to the standard chemotherapy treatment — fluorouracil and leucovorin — adjuvant irinotecan therapy improved overall survival rates for patients with the CpG island methylator phenotype (CIMP). CIMP is seen in about 10 to 20 percent of colorectal cancers. Patients with CIMP-negative tumors, however, exhibited significant harm from the addition of irinotecan — overall survival was 68 percent compared with 78 percent for those receiving the standard treatment alone.
“Our results serve as an example that the molecular characterization of individual tumors may help to determine the most appropriate treatment for patients with colon cancer,” said lead study author Stacey Shiovitz, MD, from the department of medicine, University of Washington, Seattle, WA, and the clinical research division of Fred Hutchinson Cancer Research Center, also in Seattle. “Based on our findings, identification of a tumor’s CIMP status should play a greater role in the clinical setting.”
Ruscio AD, Ebralidze AK, Benoukraf T, Amabile G, et al. Nature. Oct 9, 2013.
DNA methylation was first described almost a century ago; however, the rules governing its establishment and maintenance remain elusive. Here we present data demonstrating that active transcription regulates levels of genomic methylation. We identify a novel RNA arising from the CEBPA gene locus that is critical in regulating the local DNA methylation profile.
There is an absence of biomarkers to indicate which patients with stage I non–small cell lung cancer (NSCLC) would best benefit from adjuvant chemotherapy. In a study reported in the Journal of Clinical Oncology, Juan Sandoval, PhD, of the Bellvitge Biomedical Research Institute in Barcelona, and colleagues identified a DNA methylation signature that discriminated high- and low-risk patents.
Sandoval J, Mendez-Gonzalez J, Nadal E, Chen G, et al. Journal of Clinical Oncology. Sept 30, 2013.
A DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.
Haldrup C, Mundbjerg K, Vestergaard EM, Lamy P, et al. Journal of Clinical Oncology. Aug 5, 2013.
“Purpose: Diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, causing overtreatment of indolent PC and risk of delayed treatment of aggressive PC. Here, we identify six novel candidate DNA methylation markers for PC with promising diagnostic and prognostic potential…We identified six novel candidate DNA methylation markers for PC. C1orf114 hypermethylation and a three-gene methylation signature were independent predictors of time to biochemical recurrence after RP in two PC patient cohorts.”
Kron K, Trudel D, Pethe V, Briollais L, et al. Clinical Cancer Research. Apr 2, 2013.
“To assess differentially methylated “landscapes” according to prostate cancer Gleason score (GS) and ERG oncogene expression status, and to determine the extent of polycomb group (PcG) target gene involvement, we sought to assess the genome-wide DNA methylation profile of prostate cancer according to Gleason score and ERG expression.”
Nigro CL, Wang H, McHugh A, Lattanzio L, et al. J Invest Dermatol. Feb 14, 2013.
“Transcriptional silencing of tissue factor pathway inhibitor 2 (TFPI2) occurs in several human tumors including melanoma. We investigated methylated TFPI2 as a biomarker of metastatic melanoma using qRT-PCR to assess TFPI2 expression and pyrosequencing to analyze CpG island methylation in malignant melanoma cell lines, in benign nevi, in 112 primary and metastatic melanomas, and in serum from 6 healthy individuals and 35 patients: 20 patients with primary and 15 patients with metastatic melanoma…”