Validation of a breast cancer assay for radiotherapy omission: an individual participant data meta-analysis

Per Karlsson; Anthony Fyles; S Laura Chang; Bradley Arrick; Frederick L Baehner; Per Malmström; Mårtin Fernö; Erik Holmberg; Martin Sjöström; Fei-Fei Liu; David A Cameron; Linda J Williams; John Ms Bartlett; Joanna Dunlop; Jacqueline Caldwell; Joseph F Loane; Elizabeth Mallon; Tammy Piper; Ian Kunkler; Felix Y Feng; Corey W Speers; Lori J Pierce; John P Bennett; Karen J Taylor

doi:10.1093/jnci/djae262

Validation of a breast cancer assay for radiotherapy omission: an individual participant data meta-analysis

J Natl Cancer Inst. 2024 Oct 18:djae262. doi: 10.1093/jnci/djae262. Online ahead of print.

Authors

Per Karlsson^{1

2}, Anthony Fyles³, S Laura Chang⁴, Bradley Arrick⁴, Frederick L Baehner⁴, Per Malmström^{5

6}, Mårtin Fernö⁵, Erik Holmberg¹, Martin Sjöström^{5

7}, Fei-Fei Liu³, David A Cameron^{8

9}, Linda J Williams⁹, John Ms Bartlett⁸, Joanna Dunlop¹⁰, Jacqueline Caldwell¹⁰, Joseph F Loane¹¹, Elizabeth Mallon¹¹, Tammy Piper⁸, Ian Kunkler⁸, Felix Y Feng⁷, Corey W Speers¹², Lori J Pierce¹³, John P Bennett⁴, Karen J Taylor⁸

Affiliations

¹ Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
² Sahlgrenska Comprehensive Cancer Center, Sahlgrenska University Hospital, Gothenburg, Sweden.
³ Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
⁴ Exact Sciences Corporation, Madison, WI, USA.
⁵ Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.
⁶ Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
⁷ Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
⁸ Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁹ Usher Institute, University of Edinburgh, Edinburgh, UK.
¹⁰ Public Health Scotland, Edinburgh, UK.
¹¹ Queen Elizabeth University Hospital, Glasgow, Scotland.
¹² Department of Radiation Oncology, Case Comprehensive Cancer Center, OH, USA.
¹³ Department of Radiation Oncology, Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.

PMID: 39423142
DOI: 10.1093/jnci/djae262

Abstract

Background: There are currently no molecular tests to identify individual breast cancers where radiotherapy (RT) offers no benefit. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify low risk cancers where RT will not further reduce recurrence rates.

Methods: An individual participant data meta-analysis was performed in 623 cases of node-negative ER+/HER2-negative early breast cancer enrolled in three RT randomized trials for whom primary tumor material was available for analysis. A Cox proportional hazards model on time to locoregional recurrence (LRR) was used to test the interaction between POLAR score and RT.

Results: 429 (69%) patients' tumors had a high POLAR score and 194 (31%) had a low score. Patients with high POLAR score had, in the absence of RT, a 10-year cumulative incidence of LRR: 20% (15%-26%) vs 5% (2%-11%) for those with a low score. Patients with a high POLAR score had a large benefit from RT (hazard ratio [HR] for RT vs no RT: 0.37 [0.23-0.60], p < .001). In contrast, there was no evidence of benefit from RT for patients with a low POLAR score (HR: 0.92 [0.42-2.02], p = .832). The test for interaction between RT and POLAR was statistically significant (p = .022).

Conclusions: POLAR is not only prognostic for locoregional recurrence but also predictive of benefit from radiotherapy in selected patients. Patients ≥ 50 years with ER+/HER2-negative disease and a low POLAR score could consider omitting adjuvant RT. Further validation in contemporary clinical cohorts is required.