Abstract P1-05-26: MammaPrint Genomic Signature, Molecular Subtype Characteristics and Outcomes of HER2-Low Early Breast Cancer (EORTC10041 / BIG 03-04 MINDACT Trial)

Abstract Background: HER2-low breast cancers (BC) are heterogeneous with different degrees of HER2 expression and hormone receptor (HR) status. Recent developments in anti-HER2 antibody–drug conjugates (ADCs) open new therapeutic options for HER-low BC. We aim to further characterize HER2-low BC using genomic assay and molecular subtype and its association with clinical outcome. Methods: In this exploratory analysis of the MINDACT trial (EORTC 10041/BIG 3-04) we selected HER2-low tumors (i.e. HER2 1+ or 2+ non-amplified) tested by immunohistochemistry (IHC)/-ISH and with available HR status (Estrogen and Progesterone receptor) both accessed by central pathology review. HER2 expression was evaluated with the HercepTest kit (Dako polyclonal). Molecular subtype by BluePrint classified patients in Luminal A (blueprint luminal AND MammaPrint (MP) low risk), Luminal B (blueprint luminal AND MP high risk), HER2-enriched and Basal. Genomic risk was defined using 70-gene signature using MP. Association of molecular subtype and genomic risk with distant metastasis free survival (DMFS) was evaluated. DMFS were adjusted for chemotherapy and endocrine therapy administration. Results: From a total of 5929 enrolled patients in MINDACT with central pathology review, 2320 (39.1%) patients were classified as HER2 low, 1505 (64.9%) were HER2 1+ and 815 (35.1%) had HER2 2+/-ISH negative tumors. Median age at diagnosis was 55 years, 1675 (72.2%) of tumors had ≤ 2cm, 1400 (60.4%) were grade 2, 1830 (78.9%) had lymph-node negative disease and 2186 (94.2%) were HR (ER and/or PgR) positive. HER2-low tumors molecular subtype distribution was: 1574 (67.8%) Luminal A, 554 (23.9%) Luminal B, 25 (1.1%) HER2 enriched and Basal 167 (7.2%). Genomic risk classified HER2-low as MP low risk 1589 (68.4%) vs. 731 (31.5%) high risk (p<.0001). Molecular BC subtype distribution according to HER2-low score 1+ vs. 2+ were: Luminal A 1116 (74.2%) vs 458 (56.2%), Luminal B 272 (18.1%) vs 282 (34.6%), HER2 enriched 14 (0.9%) vs 11 (1.3%) and Basal 103 (6.8%) vs. 64 (7.9%), respectively (p<.0001). Genomic risk distribution according to HER2-low score 1+ vs. 2+ were: low risk 1125 (74.8%) vs 464 (56.9%) and high risk 380 (25.2%) vs. 351 (43.1%), respectively (p<.0001). Median follow-up was 108.5 months (95% CI, 107.8 - 109.3). The HER2-low 5-year DMFS according to genomic risk was 96.5% (95% CI, 95.6-97.4) in MP low vs. 92.5% (95% CI, 90.5-94.4) in MP high risk (HR 1.9 [95% CI, 1.4-2.5], p<.0001). The HER2-low 5-year DMFS according to molecular subtype was 96.5% (95% CI, 95.5-97.4) for Luminal A, 92.8% (95% CI, 90.7-95.1) for Luminal B, 88% (95% CI, 76.1-100) for HER2 enriched and 92.6% (95% CI, 88.7-96.7) for Basal (p<0.0001). In the multivariable analysis, age > 50 years (HR 1.34, [95% CI, 1.0-1.8], p=0.0490), lymph node positive (HR 1.75, [95% CI, 1.2-2.4], p=0.0003) and genomic high risk (HR 2.02, [95% CI, 1.5-2.7], p<0.0001) were independently associated with worse DMFS. Conclusions: In the MINDACT trial exploratory analysis most HER2-low tumors were HR positive, Luminal A BC molecular subtype and Low MP genomic risk. However, HER2-low BC is not a uniform biological entity with an enrichment of Luminal B and High MP genomic risk in the HER2 2+ score subset. In addition, this analysis demonstrated that clinical outcome of HER2-low early BC is associated with MP genomic risk. The MINDACT trial exploratory analysis, using a central pathology review and long-term follow-up, shows that HER2-low BC has heterogeneous molecular profile, genomic risk and clinical outcomes and thus these results may influence future clinical trials with new agents for the treatment of HER2-low early BC. Citation Format: Gustavo Werutsky, Marcia Graudenz, Rafaela Gomes, Giuseppe Viale, Emiel J T Rutgers, Martine Piccart, Coralie Poncet, Laura J. van ’t Veer, Fatima Cardoso. MammaPrint Genomic Signature, Molecular Subtype Characteristics and Outcomes of HER2-Low Early Breast Cancer (EORTC10041 / BIG 03-04 MINDACT Trial) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-05-26.