DNA methylation markers prognostic for metastatic breast cancer

 

A novel panel of DNA methylation markers may aid in predicting survival outcomes in metastatic breast cancer (MBC), according to new findings.

Using a new quantitative assay known as cMethDNA, researchers found that a high cumulative methylation index (CMI) level, as measured with a six-gene panel after beginning a new treatment, was consistently associated with both progression-free survival and overall survival, as well as progressive disease.

Even though these results are encouraging, however, its clinical application is still unknown, they noted.

Bruce Jancin/Frontline Medical News

“Although monitoring for the change in the CMI for treatment response has prognostic usefulness, its clinical usefulness in influencing changes in therapy must now be evaluated formally in randomized clinical trials,” wrote Kala Visvanathan, MD, of Johns Hopkins University, Baltimore, and her colleagues. “Furthermore, whether there is meaningful risk reclassification of patients with the addition of the CMI is worth careful assessment in future larger validation studies.”

Epigenetic alterations are common in human malignancies, and DNA methylation is a form of epigenetic alteration that is heritable during DNA replication. The authors developed a highly sensitive, high-throughput quantitative multiplex methylation-specific polymerase chain reaction assay known as cMethDNA that was able to detect circulating cell-free methylated DNA.

In this study, 10 genes were tested from 141 women with MBC who were beginning a new systemic therapy and who received treatment at participating academic medical centers.

Among patients with a high CMI, the median progression-free survival and overall survival were significantly shorter (PFS, 2.1 months; OS, 12.3 months), compared with those with a low CMI (PFS, 5.8 months; OS, 21.7 months), Dr. Visvanathan and her associates reported (J Clin Oncol. 2016 Nov. 21 doi: 10.1200/JCO.2015.66.2080).

Upon multivariable analysis, a high CMI versus low CMI at 4 weeks was independently associated with poorer PFS (hazard ratio, 1.79; 95% CI, 1.23-2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21-2.54; P = .003). Rising CMI levels from baseline to week 4 also were associated with worse PFS (P less than .001) as well as a 4.6-fold increase in the risk of progressive disease at first restaging (OR, 4.58; 95% CI, 1.82-11.60; P = .001) when compared with either a drop in CMI or no change at all.

The CMI level at week 4 was observed to be a strong predictor of PFS and improved the prediction of the base model, even in the presence of circulating tumor cells (P = .004).

Dr. Visvanathan and her colleagues concluded that these 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 study was supported by the Avon Foundation for Women, the Breast Cancer Research Foundation, Janssen Diagnostics, the Rubenstein Family Fund, the Susan G. Komen Foundation, and National Institutes of Health Grants. Dr. Visvanathan has declared holding patents, royalties, and other intellectual property, and several coauthors also have declared relationships with industry.
 

 

A novel panel of DNA methylation markers may aid in predicting survival outcomes in metastatic breast cancer (MBC), according to new findings.

Using a new quantitative assay known as cMethDNA, researchers found that a high cumulative methylation index (CMI) level, as measured with a six-gene panel after beginning a new treatment, was consistently associated with both progression-free survival and overall survival, as well as progressive disease.

Even though these results are encouraging, however, its clinical application is still unknown, they noted.

Bruce Jancin/Frontline Medical News

“Although monitoring for the change in the CMI for treatment response has prognostic usefulness, its clinical usefulness in influencing changes in therapy must now be evaluated formally in randomized clinical trials,” wrote Kala Visvanathan, MD, of Johns Hopkins University, Baltimore, and her colleagues. “Furthermore, whether there is meaningful risk reclassification of patients with the addition of the CMI is worth careful assessment in future larger validation studies.”

Epigenetic alterations are common in human malignancies, and DNA methylation is a form of epigenetic alteration that is heritable during DNA replication. The authors developed a highly sensitive, high-throughput quantitative multiplex methylation-specific polymerase chain reaction assay known as cMethDNA that was able to detect circulating cell-free methylated DNA.

In this study, 10 genes were tested from 141 women with MBC who were beginning a new systemic therapy and who received treatment at participating academic medical centers.

Among patients with a high CMI, the median progression-free survival and overall survival were significantly shorter (PFS, 2.1 months; OS, 12.3 months), compared with those with a low CMI (PFS, 5.8 months; OS, 21.7 months), Dr. Visvanathan and her associates reported (J Clin Oncol. 2016 Nov. 21 doi: 10.1200/JCO.2015.66.2080).

Upon multivariable analysis, a high CMI versus low CMI at 4 weeks was independently associated with poorer PFS (hazard ratio, 1.79; 95% CI, 1.23-2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21-2.54; P = .003). Rising CMI levels from baseline to week 4 also were associated with worse PFS (P less than .001) as well as a 4.6-fold increase in the risk of progressive disease at first restaging (OR, 4.58; 95% CI, 1.82-11.60; P = .001) when compared with either a drop in CMI or no change at all.

The CMI level at week 4 was observed to be a strong predictor of PFS and improved the prediction of the base model, even in the presence of circulating tumor cells (P = .004).

Dr. Visvanathan and her colleagues concluded that these 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 study was supported by the Avon Foundation for Women, the Breast Cancer Research Foundation, Janssen Diagnostics, the Rubenstein Family Fund, the Susan G. Komen Foundation, and National Institutes of Health Grants. Dr. Visvanathan has declared holding patents, royalties, and other intellectual property, and several coauthors also have declared relationships with industry.
 

 

A novel panel of DNA methylation markers may aid in predicting survival outcomes in metastatic breast cancer (MBC), according to new findings.

Using a new quantitative assay known as cMethDNA, researchers found that a high cumulative methylation index (CMI) level, as measured with a six-gene panel after beginning a new treatment, was consistently associated with both progression-free survival and overall survival, as well as progressive disease.

Even though these results are encouraging, however, its clinical application is still unknown, they noted.

Bruce Jancin/Frontline Medical News

“Although monitoring for the change in the CMI for treatment response has prognostic usefulness, its clinical usefulness in influencing changes in therapy must now be evaluated formally in randomized clinical trials,” wrote Kala Visvanathan, MD, of Johns Hopkins University, Baltimore, and her colleagues. “Furthermore, whether there is meaningful risk reclassification of patients with the addition of the CMI is worth careful assessment in future larger validation studies.”

Epigenetic alterations are common in human malignancies, and DNA methylation is a form of epigenetic alteration that is heritable during DNA replication. The authors developed a highly sensitive, high-throughput quantitative multiplex methylation-specific polymerase chain reaction assay known as cMethDNA that was able to detect circulating cell-free methylated DNA.

In this study, 10 genes were tested from 141 women with MBC who were beginning a new systemic therapy and who received treatment at participating academic medical centers.

Among patients with a high CMI, the median progression-free survival and overall survival were significantly shorter (PFS, 2.1 months; OS, 12.3 months), compared with those with a low CMI (PFS, 5.8 months; OS, 21.7 months), Dr. Visvanathan and her associates reported (J Clin Oncol. 2016 Nov. 21 doi: 10.1200/JCO.2015.66.2080).

Upon multivariable analysis, a high CMI versus low CMI at 4 weeks was independently associated with poorer PFS (hazard ratio, 1.79; 95% CI, 1.23-2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21-2.54; P = .003). Rising CMI levels from baseline to week 4 also were associated with worse PFS (P less than .001) as well as a 4.6-fold increase in the risk of progressive disease at first restaging (OR, 4.58; 95% CI, 1.82-11.60; P = .001) when compared with either a drop in CMI or no change at all.

The CMI level at week 4 was observed to be a strong predictor of PFS and improved the prediction of the base model, even in the presence of circulating tumor cells (P = .004).

Dr. Visvanathan and her colleagues concluded that these 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 study was supported by the Avon Foundation for Women, the Breast Cancer Research Foundation, Janssen Diagnostics, the Rubenstein Family Fund, the Susan G. Komen Foundation, and National Institutes of Health Grants. Dr. Visvanathan has declared holding patents, royalties, and other intellectual property, and several coauthors also have declared relationships with industry.