Sep 30

SS 46 - Right-Sizing Radiation in Early Breast Cancer: Omission, Shortening, and Targeted Approaches

352 - HER2-Low as an Independent Prognostic Entity in Node-Negative Early Breast Cancer: Implications for Classification and Adjuvant Treatment/Radiation De-Escalation

09:45am - 09:55am ET

Room 258

Presenter(s)

George Naoum, MD, MS - Memorial Sloan Kettering Cancer Center, New York, NY

G. E. Naoum¹, N. Toumbacaris², Z. Zhang², L. Z. Braunstein³, A. J. Xu¹, D. A. Roth O’Brien¹, Z. Abou Yehia¹, Q. LaPlant¹, J. Cuaron¹, B. A. Mueller¹, D. Guttman¹, B. McCormick¹, S. N. Powell¹, and A. J. Khan¹; ¹Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, ²Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, ³Memorial Sloan Kettering Cancer Center, New York, NY

Purpose/Objective(s):

Despite adoption of HER2-low as a therapeutic category in metastatic breast cancer, its prognostic relevance in early-stage node-negative disease remains unclear. As node negative (N0) disease increasingly undergoes treatment de-escalation, we evaluated whether HER2-low status functions as a risk-modifying prognostic entity.

Materials/Methods: We reviewed 9,069 breast cancer patients treated at our institution between 2009–2021. Patients with cN0 undergoing upfront surgery and confirmed to be pathological N0 were included. Neoadjuvant chemotherapy patients were excluded. Tumors were classified as HER2-low (HER2-L) (immunohistochemistry “IHC” 1+ or 2+ with negative FISH) or HER2-zero (HER2-0/IHC-0) and then stratified according to estrogen/progesterone status into hormonal positive or negative (HORM+ or HORM-). HER2-enriched tumors (FISH+ or IHC 3+) were grouped separately. Primary endpoints were locoregional recurrence (LRR) and any invasive disease recurrence (IDR) defined as any local or distant recurrence. Fine Gray multivariable models (adjusted for lumpectomy or mastectomy and all pathology factors) were applied with death as a competing risk.

Results: A total of 5,199 patients were included, with a median follow-up of 7.8 years. Of these, 54% were HORM+/HER2-L, 6% HORM-/HER2-L, 23% HORM+/HER2-0, 5% HORM-/HER2-0, and 13% HER2-enriched. On multivariable analysis, HER2-L tumors were associated with lower LRR and lower IDR regardless of hormonal positivity. For LRR, HORM+/HER2-L tumors demonstrated a significantly lower risk compared with HORM+/HER2-0 (multivariable HR 0.67, p<0.01), with a similar trend in HORM-/HER2-L disease (multivariable HR 0.63, p=0.085). For IDR, HORM+/HER2-L tumors again showed improved outcomes (multivariable HR 0.72, p<0.01), with a similar effect in HORM-/HER2-L tumors (multivariable HR 0.66, p=0.05). Subgroup analysis within the HER2-L cohort showed that FISH copy number was not associated with either LRR or IDR. Among patients aged >65 years who underwent lumpectomy for HORM+, T1–2 tumors and were eligible for radiotherapy omission, receipt of adjuvant radiotherapy was associated with lower 10-year LRR and IDR. When divided by HER2 status and radiotherapy receipt, 10-year LRR was 17% versus 4.5% in HER2-L tumors and 18% versus 6.1% in HER2-0 tumors (no RT vs RT, P<0.01, respectively). Similarly, radiotherapy improved 10-year IDR in both HER2-0 (25% vs 9%) and HER2-L disease (18% vs 7%) (no RT vs RT, respectively, P<0.01), with larger absolute risk reduction observed in HER2-0 tumors.

Conclusion: For node negative patients, HER2 low status was independently associated with lower recurrence risks regardless of hormonal positivity. This novel finding supports consideration of HER2 low expression in risk stratification. In older hormone positive patients, RT decisions should not rely solely on hormonal status and account for HER2-L. Moreover, hormone negative, HER2-L tumors can be considered for de-escalation.