Limitations in the Application of Clinicopathologic Factors Alone in Predicting Radiation Benefit for Women With Low-Risk DCIS After Breast Conserving Surgery: The Impact of a 7-Gene Biosignature Based on 10-Year Ipsilateral Breast Recurrence (IBR) Rates
International Journal of Radiation Oncology, Biology, Physics
Purpose/Objective(s): Most women diagnosed with ductal carcinoma in situ (DCIS) receive radiotherapy (RT) after breast conserving surgery (BCS); however, clinical trials show that over 70% of women with BCS alone will not have a recurrence and therefore not benefit from RT. Traditionally, clinicopathologic (CP) factors have been used to select for whom to de-escalate treatment, but prospective trials have failed to identify a low risk CP group that did not benefit from RT with respect to local control. This study assessed the re-classification of patients with low-risk CP into Risk groups defined by the 7-gene biosignature and compared to 10-yr IBR rates. Materials/Methods: Women (n = 926) from four international DCIS cohorts treated with BCS had formalin-fixed paraffin embedded tissue samples analyzed at a CLIA lab (Laguna Hills, CA). CP low-risk patients were identified using a) RTOG-9804-like criteria [Nuclear Grade 1 or 2 & Size ≤2.5 cm & non-Palpable & Screen Detected & margin negative (no-ink on tumor)] and b) MSKCC-like criteria [low-risk score<220, determined using nomogram weighted factors (excluding: number of re-excisions and RT treatment), and using no-ink-on-tumor instead of close margin]. The 7- gene DCIS biosignature combined biomarkers with CP factors (age, size, palpability, and margin status) using an algorithm reporting a Decision Score (DS) and Residual Risk subtype (RRt). Women with low-risk CP were classified into biosignature Low Risk (DS≤2.8, no RRt) or High Risk (DS>2.8 +/- RRt) groups. 10yr in-breast event (IBR) rates with and without RT were assessed by Kaplan-Meier rates and Cox proportional hazard analyses. Results: Overall, 37% of all women were classified into the biosignature Low Risk group, while 51% and 34% were classified into CP low-risk groups (RTOG-9804-like, MSKCC-like, respectively). The biosignature Low Risk group (n = 338) had a 10-yr IBR risk of 5.6% after BCS and no significant RT benefit (absolute RT benefit = 0.8%, p = 0.70), 99% negative predictive value (NPV) for RT benefit. CP low-risk groups had 10-yr IBR rates of 12% and 8% after BCS without RT with absolute 6% (p = 0.04) and 4% (p = 0.1) IBR rate reductions with RT. The biosignature reclassified 51% and 63% of CP low-risk patients into the biosignature High Risk group. Importantly, these patients had higher IBR rates without RT (20% and 12%) and significant 13% (p = 0.005) and 8% (p = 0.01) absolute IBR rate reductions from RT. CP low-risk patients with concordant biosignature Low Risk demonstrated no significant RT benefit. Conclusion: The 7-gene predictive biosignature more reliably identified patients with low 10-yr IBR rates and no significant RT benefit than the traditional CP low-risk criteria (RTOG-9804-like, MSKCC-like). Importantly, those CP low-risk patients who were re-classified as biosignature High Risk had increased 10-year IBR rates and significant RT benefit.
Vicini FA, Shah CS, Margenthaler J, Dabbs D, Warnberg F, Weinmann S, et al. Limitations in the application of clinicopathologic factors alone in predicting radiation benefit for women with low-risk DCIS after breast conserving surgery: the impact of 7-gene biosignature based on 10-year ipsilateral breast recurrence (IBR) rates. Int J Radiat Oncol Biol Phys. 2023 Oct;117(2 Suppl.):S5. doi:10.1016/j.ijrobp.2023.06.211