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Figure 1. SIAH is the most conserved downstream signaling gatekeeper in the EGFR/K-RAS/SIAH pathway, whose persistent activation is driving TNBC malignancy, tumor relapse, and metastasis. (A) SIAH is the most evolutionarily conserved and the most downstream signaling module identified in the EGFR/K-RAS signaling pathway thus far. (B) Loss of SIAH expression (SIAH^Low/OFF) after effective NACT is correlated with EGFR/K-RAS pathway inactivation and tumor regression/remission, whereas persistent SIAH expression (SIAH^High/ON) after ineffective NACT is correlated with EGFR/K-RAS pathway activation and tumor progression/early relapse. Persistent high SIAH expression (SIAH^High/ON) in high-risk residual tumors post NACT is correlated with EGFR/K-RAS pathway activation, chemo-resistance, and early tumor relapse. (C-D) TNBC tumors were stained with H&E, SIAH, Ki67, phospho-ERK, and EGFR. SIAH outperforms Ki67. SIAH is prognostic and Ki67 is not prognostic in NACT-treated high-risk and locally advanced breast cancer. We found that SIAH^Low/OFF post-NACT correlates with tumor remission and prolonged survival (Alive at 5 years) (C). We found that persistent SIAH^High/ON expression in residual tumors post-NACT is associated with tumor relapse and poor survival (Dead before3-5 years) (D). (E) SIAH1 and (F) SIAH2 are extraordinarily conserved across metazoan species. Conclusion: We found that SIAH^ON/OFF expression is a binary code that reflects tumor-driving EGFR/K-RAS/SIAH pathway activation^ON/inactivation^OFF in TNBC primary and residual tumors As such, SIAH is strategically well positioned to become a new TNBC target, and a new tumor-specific, therapy-responsive, and prognostic biomarker to risk-stratify pIR patients, detect the emergence of treatment-refractory tumors, quantify NACT/NST efficacy, augment RCB classifications, forecast early relapse, and predict patient survival in real time in the clinic. SIAH: Human homologs of Drosophila Seven In Absentia (SINA); NACT: neoadjuvant chemotherapy; RCB: residual cancer burden; TNBC: triple-negative breast cancer.