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

Per Karlsson; Anthony Fyles; Laura Chang; Bradley Arrick; Frederick L. Baehner; Per Malmstrom; Martin Ferno; 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

Per Karlsson^*, Anthony Fyles, Laura Chang, Bradley Arrick, Frederick L. Baehner, Per Malmstrom, Martin Ferno, 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. FengCorey W. Speers, Lori J. Pierce, John P. Bennett, Karen J. Taylor

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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<0.001). 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 = 0.832). The test for interaction between RT and POLAR was statistically significant (p = 0.022).

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.

Original language	English
Article number	djae262
Journal	Journal of the National Cancer Institute (JNCI)
Early online date	18 Oct 2024
DOIs	https://doi.org/10.1093/jnci/djae262
Publication status	E-pub ahead of print - 18 Oct 2024

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Karlsson, P., Fyles, A., Chang, L., Arrick, B., L. Baehner, F., Malmstrom, P., Ferno, M., Holmberg, E., Sjöström, M., Liu, F.-F., Cameron, D. A., Williams, L. J., Bartlett, J. MS., Dunlop, J., Caldwell, J., Loane, J. F., Mallon, E., Piper, T., Kunkler, I., ... Taylor, K. J. (2024). Validation of a breast cancer assay for radiotherapy omission: an individual participant data meta-analysis. Journal of the National Cancer Institute (JNCI), Article djae262. Advance online publication. https://doi.org/10.1093/jnci/djae262

@article{6e79db57821f4a40936eab655305b748,

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

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{\textquoteright} 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<0.001). 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 = 0.832). The test for interaction between RT and POLAR was statistically significant (p = 0.022).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.",

author = "Per Karlsson and Anthony Fyles and Laura Chang and Bradley Arrick and {L. Baehner}, Frederick and Per Malmstrom and Martin Ferno and Erik Holmberg and Martin Sj{\"o}str{\"o}m and Fei-Fei Liu and Cameron, {David A} and Williams, {Linda J} and Bartlett, {John MS} and Joanna Dunlop and Jacqueline Caldwell and Loane, {Joseph F.} and Elizabeth Mallon and Tammy Piper and Ian Kunkler and {Y. Feng}, Felix and Speers, {Corey W.} and Pierce, {Lori J.} and Bennett, {John P.} and Taylor, {Karen J.}",

year = "2024",

month = oct,

day = "18",

doi = "10.1093/jnci/djae262",

language = "English",

journal = "Journal of the National Cancer Institute (JNCI)",

issn = "0027-8874",

publisher = "Oxford University Press",

}

Karlsson, P, Fyles, A, Chang, L, Arrick, B, L. Baehner, F, Malmstrom, P, Ferno, M, Holmberg, E, Sjöström, M, Liu, F-F, Cameron, DA , Williams, LJ , Bartlett, JMS, Dunlop, J, Caldwell, J, Loane, JF, Mallon, E, Piper, T, Kunkler, I, Y. Feng, F, Speers, CW, Pierce, LJ, Bennett, JP & Taylor, KJ 2024, 'Validation of a breast cancer assay for radiotherapy omission: an individual participant data meta-analysis', Journal of the National Cancer Institute (JNCI). https://doi.org/10.1093/jnci/djae262

TY - JOUR

T1 - Validation of a breast cancer assay for radiotherapy omission: an individual participant data meta-analysis

AU - Karlsson, Per

AU - Fyles, Anthony

AU - Chang, Laura

AU - Arrick, Bradley

AU - L. Baehner, Frederick

AU - Malmstrom, Per

AU - Ferno, Martin

AU - Holmberg, Erik

AU - Sjöström, Martin

AU - Liu, Fei-Fei

AU - Cameron, David A

AU - Williams, Linda J

AU - Bartlett, John MS

AU - Dunlop, Joanna

AU - Caldwell, Jacqueline

AU - Loane, Joseph F.

AU - Mallon, Elizabeth

AU - Piper, Tammy

AU - Kunkler, Ian

AU - Y. Feng, Felix

AU - Speers, Corey W.

AU - Pierce, Lori J.

AU - Bennett, John P.

AU - Taylor, Karen J.

PY - 2024/10/18

Y1 - 2024/10/18

N2 - 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<0.001). 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 = 0.832). The test for interaction between RT and POLAR was statistically significant (p = 0.022).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.

AB - 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<0.001). 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 = 0.832). The test for interaction between RT and POLAR was statistically significant (p = 0.022).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.

U2 - 10.1093/jnci/djae262

DO - 10.1093/jnci/djae262

M3 - Article

SN - 0027-8874

JO - Journal of the National Cancer Institute (JNCI)

JF - Journal of the National Cancer Institute (JNCI)

M1 - djae262

ER -

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

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