In the Journals

Classifier predicts radiotherapy benefit, locoregional recurrence risk in early-stage breast cancer

A newly developed clinico-genomic classifier identified which women with early-stage breast cancer would benefit substantially from adjuvant radiotherapy as well as those with an elevated risk for locoregional recurrence, according to study results published in Journal of Clinical Oncology.

“Adjuvant whole-breast radiotherapy after breast-conserving surgery is standard of care for women with early-stage invasive breast cancer for local management of their disease,” Martin Sjöström, MD, PhD, postdoctoral fellow in the department of oncology and pathology at Lund University in Sweden, and colleagues wrote. “Meta-analyses from the Early Breast Cancer Trialists’ Collaborative Group have shown that at 10 years after surgery, 10% of patients with node-negative disease will still experience a local recurrence after breast-conserving surgery, even with the receipt of radiotherapy.”

Sjöström and colleagues developed the Adjuvant Radiotherapy Intensification Classifier, or ARTIC, to predict radiotherapy benefit and guide intensification strategies for this patient population. They used three publicly available cohorts to develop ARTIC, which is composed of 27 genes and patient age.

Researchers validated ARTIC for locoregional recurrence among 748 women with early-stage breast cancer from the SweBCG91-RT trial, in which women were randomly assigned to standard adjuvant whole-breast radiotherapy or no radiotherapy. They compared previously published genomic signatures to determine the classifier’s accuracy for predicting radiotherapy benefit in the trial.

ARTIC appeared highly prognostic for locoregional recurrence among women treated with radiotherapy (HR = 3.4; 95% CI, 2-5.9) and predictive of radiotherapy benefit (P interaction = .005).

Patients with low ARTIC scores benefited greatly from radiotherapy (HR = 0.33; 95% CI, 0.21-0.52; 10-year cumulative incidence of locoregional recurrence, 6% vs. 21%). However, patients with high ARTIC scores did not benefit significantly from radiotherapy (HR = 0.73; 95% CI, 0.44-1.2; 10-year cumulative incidence of locoregional recurrence, 25% vs. 32%).

Among the 84 patients treated with whole-breast radiotherapy who had high ARTIC scores, 20 (23.8%) experienced local recurrence and nine (10.7%) experience regional recurrence. Among the 272 patients who received whole-breast radiotherapy and had low ARTIC scores, 25 (9.2%) experienced local recurrence and only one (0.4%) experienced regional recurrence (P < .001 for all).

Radiotherapy’s effects on local and regional recurrences appeared more notable among patients with low ARTIC scores (local recurrence, 9.2% vs. 22.8%; P < .001; regional recurrence, 0.4% vs. 4.8%; P = .001) compared with those with high ARTIC scores (local recurrence, 23.8% vs. 34%; P = .05; regional recurrence, 10.7% vs. 5.8%).

Researchers noted that among eight previously published genomic signatures that claim to predict locoregional recurrence in early-stage breast cancer, none was predictive of benefit from radiotherapy in the trial.

This study provides further evidence that tumor biology is predictive of locoregional recurrence, Mylin A. Torres, MD, oncologist at Winship Cancer Institute at Emory University, wrote in an accompanying editorial.

“However, there are emerging data showing that growth factors and stimulatory wound fluid released following lumpectomy perpetuate proliferation, migration and invasion,” Torres wrote. "These factors may galvanize residual malignant cells or otherwise dormant cells to de-differentiate and develop into locoregional recurrence. If these proteins indeed perpetuate locoregional recurrence, future studies on the interplay between the ability of the host to produce growth factors and ARTIC, indicative of tumor biology, may help refine the ARTIC classifier even in an era when locoregional recurrence is relatively rare.” – by John DeRosier

Disclosures: PFS Genomics funded this study. Sjöström reports funding to his institution from PFS Genomics. Please see the study for all other authors’ relevant financial disclosures. Torres reports honoraria from Blue Earth Diagnostics and the CDC; research funding from Emory University, NCI, Pfizer Oncology, Wilbur and Hilda Glenn Family Foundation and Winship Cancer Institute; and travel expenses from International Breast Cancer Conference, MedStar Georgetown University Hospital, Pfizer Oncology and Prime Oncology.

A newly developed clinico-genomic classifier identified which women with early-stage breast cancer would benefit substantially from adjuvant radiotherapy as well as those with an elevated risk for locoregional recurrence, according to study results published in Journal of Clinical Oncology.

“Adjuvant whole-breast radiotherapy after breast-conserving surgery is standard of care for women with early-stage invasive breast cancer for local management of their disease,” Martin Sjöström, MD, PhD, postdoctoral fellow in the department of oncology and pathology at Lund University in Sweden, and colleagues wrote. “Meta-analyses from the Early Breast Cancer Trialists’ Collaborative Group have shown that at 10 years after surgery, 10% of patients with node-negative disease will still experience a local recurrence after breast-conserving surgery, even with the receipt of radiotherapy.”

Sjöström and colleagues developed the Adjuvant Radiotherapy Intensification Classifier, or ARTIC, to predict radiotherapy benefit and guide intensification strategies for this patient population. They used three publicly available cohorts to develop ARTIC, which is composed of 27 genes and patient age.

Researchers validated ARTIC for locoregional recurrence among 748 women with early-stage breast cancer from the SweBCG91-RT trial, in which women were randomly assigned to standard adjuvant whole-breast radiotherapy or no radiotherapy. They compared previously published genomic signatures to determine the classifier’s accuracy for predicting radiotherapy benefit in the trial.

ARTIC appeared highly prognostic for locoregional recurrence among women treated with radiotherapy (HR = 3.4; 95% CI, 2-5.9) and predictive of radiotherapy benefit (P interaction = .005).

Patients with low ARTIC scores benefited greatly from radiotherapy (HR = 0.33; 95% CI, 0.21-0.52; 10-year cumulative incidence of locoregional recurrence, 6% vs. 21%). However, patients with high ARTIC scores did not benefit significantly from radiotherapy (HR = 0.73; 95% CI, 0.44-1.2; 10-year cumulative incidence of locoregional recurrence, 25% vs. 32%).

Among the 84 patients treated with whole-breast radiotherapy who had high ARTIC scores, 20 (23.8%) experienced local recurrence and nine (10.7%) experience regional recurrence. Among the 272 patients who received whole-breast radiotherapy and had low ARTIC scores, 25 (9.2%) experienced local recurrence and only one (0.4%) experienced regional recurrence (P < .001 for all).

Radiotherapy’s effects on local and regional recurrences appeared more notable among patients with low ARTIC scores (local recurrence, 9.2% vs. 22.8%; P < .001; regional recurrence, 0.4% vs. 4.8%; P = .001) compared with those with high ARTIC scores (local recurrence, 23.8% vs. 34%; P = .05; regional recurrence, 10.7% vs. 5.8%).

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Researchers noted that among eight previously published genomic signatures that claim to predict locoregional recurrence in early-stage breast cancer, none was predictive of benefit from radiotherapy in the trial.

This study provides further evidence that tumor biology is predictive of locoregional recurrence, Mylin A. Torres, MD, oncologist at Winship Cancer Institute at Emory University, wrote in an accompanying editorial.

“However, there are emerging data showing that growth factors and stimulatory wound fluid released following lumpectomy perpetuate proliferation, migration and invasion,” Torres wrote. "These factors may galvanize residual malignant cells or otherwise dormant cells to de-differentiate and develop into locoregional recurrence. If these proteins indeed perpetuate locoregional recurrence, future studies on the interplay between the ability of the host to produce growth factors and ARTIC, indicative of tumor biology, may help refine the ARTIC classifier even in an era when locoregional recurrence is relatively rare.” – by John DeRosier

Disclosures: PFS Genomics funded this study. Sjöström reports funding to his institution from PFS Genomics. Please see the study for all other authors’ relevant financial disclosures. Torres reports honoraria from Blue Earth Diagnostics and the CDC; research funding from Emory University, NCI, Pfizer Oncology, Wilbur and Hilda Glenn Family Foundation and Winship Cancer Institute; and travel expenses from International Breast Cancer Conference, MedStar Georgetown University Hospital, Pfizer Oncology and Prime Oncology.