DNA METHYLATION AS BREAST CANCER PROGNOSTIC-PREDICTIVE FACTOR

NEW YORK (Reuters Health) - Methylation of a 6-gene panel predicts outcomes in women with metastatic breast cancer, according to results from the TBCRC 005 Prospective Biomarker Study.

"Our study demonstrated a real promise of methylation levels in blood to be able to prognosticate and predict treatment response in women with breast cancer," Dr. Kala Visvanathan from Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, Maryland told Reuters Health by email.

Currently in metastatic breast cancer, several months are necessary to determine whether treatment has been effective. Earlier evaluation of therapeutic benefit could contribute to clinical decision-making, lower morbidity from ineffective therapy, and better outcomes, as well as reduced costs from additional imaging studies.

Dr. Visvanathan and colleagues developed a highly sensitive serum DNA methylation assay (cMethDNA) and prospectively tested its ability to predict disease progression and survival in 141 women with metastatic breast cancer.

The researchers included 6 genes in their cumulative methylation index (CMI) - AKR1B1, HOXB4, RASGRF2, RASSF1, HIST1H3C, and TM6SF1.

Based on cut points that maximized the log-rank statistic, patients with a high CMI at week 4 had a significantly worse progression-free survival (PFS) and overall survival (OS) than those with a low CMI, after adjusting for age, ethnicity, prior therapy, tumor phenotype, and disease burden.

The median PFS was 2.1 months among women in the high CMI group versus 5.8 months among women in the low CMI group, and the median OS was nearly 10 months shorter for women in the high CMI group (12.3 months) than for women in the low CMI group (21.7 months).

CMI also provided an indication of responsive disease at first restaging. The median CMI at week 4 was highest in women with progressive disease, lowest in women with responsive disease, and intermediate in women with stable disease at first restaging.

Moreover, increases in the CMI from baseline to week 4 were associated with worse PFS and an increased risk of progressive disease at first restaging, compared with a reduction or no change in the CMI, according to the November 21st Journal of Clinical Oncology online report.

Higher levels of circulating tumor cells (CTCs) at week 4 were also associated with worse PFS and OS but not with disease status at first restaging.

The addition of either the week 4 CMI or CTCs improved the ability of a model of established risk factors to predict PFS and OS, but the CMI at week 4 significantly improved the production of PFS (but not OS) even when the presence of CTCs was included in the model.

"Pending validation of CMI in studies examining specific treatments, CMI in blood could have clinical usefulness as an early predictor of progressive disease when compared to imaging studies for women with metastatic breast cancer," Dr. Visvanathan said. "CMI may also be clinically useful in the neoadjuvant and adjuvant setting. We are currently examining this."

"Our findings must be validated to determine the clinical usefulness of the cMethDNA assay for specific treatments and tumor phenotypes in patients with metastatic disease and early-stage breast cancer," the researchers note.

Dr. Rodney J. Scott from Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia, who recently reported DNA methylation profiles of triple negative breast cancer-specific genes, told Reuters Health by email, "There has been much written about circulating tumor DNA yet there has been little focus on cMethDNA. This report (and the others quoted by the authors) is important since methylated DNA is more stable than non-methylated DNA and as such may be a more robust analyte, thereby lending itself to widespread use."

"If CMI assessment is reproducible and can be routinely undertaken then it would certainly help in monitoring breast cancer patients who have metastatic disease and aid in defining the best possible treatment (as one would assume that by reducing the CMI in those women where it is high would result in improved outcomes - if we assume OS and PFS extension occurs) for them," Dr. Scott said.

"Serum DNA methylation is potentially a viable marker to measure disease progression," he concluded. "There remain, however, many questions about whether, in this setting, early detection equates to better outcomes. It will certainly offer the possibility of providing patients with effective treatment options that can be monitored to assess efficacy, thereby reducing the use of ineffective treatment and focusing on therapies that result in reducing the CMI."