Tang Amy H, Hoefer Richard A, Guye Mary L, Bear Harry D
Department of Microbiology and Molecular Cell Biology, Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
School of Systems Biology, George Mason University, Manassas, VA 20110, USA.
Cancer Drug Resist. 2022 Jun 22;5(3):691-702. doi: 10.20517/cdr.2022.31. eCollection 2022.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It disproportionately affects BRCA mutation carriers and young women, especially African American (AA) women. Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies. With the approval of immune checkpoint blockade (ICB) for TNBC, the addition of pembrolizumab to systemic chemotherapy has become standard of care (SOC) in neoadjuvant systemic therapy (NST) for high-risk early-stage TNBC. Pembrolizumab plus chemotherapy significantly increased the pathologic complete response (pCR) and improved event-free survival in TNBC. However, clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes. Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse. Therefore, novel treatment strategies and innovative new research initiatives are needed. We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC. Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated (ON), indicating an ineffective response to treatment. These chemoresistant tumor clones persist in expressing SIAH (SIAH) and are linked to early tumor relapse and poorer prognosis. Conversely, the loss of SIAH expression (SIAH) in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation (OFF), indicating effective therapy and chemo-sensitive tumor cells. SIAH signal is linked to tumor remission and better prognosis post-NACT/NST. Therefore, SIAH is well-positioned to become a novel tumor-specific, therapy-responsive, and prognostic biomarker. Potentially, this new biomarker (SIAH) could be used to quantify therapy response, predict chemo-resistance, and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型。它对携带BRCA突变的人群和年轻女性影响尤为严重，特别是非裔美国（AA）女性。化疗耐药的TNBC是一种异质性且分子不稳定的疾病，这对我们应用个性化治疗的能力构成了挑战。随着免疫检查点阻断（ICB）获批用于TNBC治疗，在高危早期TNBC的新辅助全身治疗（NST）中，将帕博利珠单抗添加到全身化疗中已成为标准治疗（SOC）方案。帕博利珠单抗联合化疗显著提高了TNBC的病理完全缓解率（pCR），并改善了无事件生存期。然而，临床仍存在不确定性，因为接受类似治疗、对新辅助治疗具有相似肿瘤反应的TNBC部分缓解者，其临床结局往往存在差异。目前的方法在准确预测哪些高危患者会出现化疗耐药和肿瘤复发方面存在不足。因此，需要新的治疗策略和创新性的研究举措。我们提出，EGFR-K-RAS-SIAH通路激活是化疗耐药TNBC的主要肿瘤驱动因素。新辅助化疗（NACT）/新辅助全身治疗（NST）后残余肿瘤中SIAH的持续高表达反映出EGFR/K-RAS通路仍处于激活状态（开启），表明对治疗反应不佳。这些化疗耐药肿瘤克隆持续表达SIAH（SIAH），并与早期肿瘤复发和较差的预后相关。相反，NACT/NST后残余肿瘤中SIAH表达缺失（SIAH）反映出EGFR/K-RAS通路失活（关闭），表明治疗有效且肿瘤细胞对化疗敏感。SIAH信号与NACT/NST后的肿瘤缓解和较好预后相关。因此，SIAH很有潜力成为一种新型的肿瘤特异性、治疗反应性和预后生物标志物。这种新生物标志物（SIAH）有可能用于量化治疗反应、预测化疗耐药性，并识别TNBC中肿瘤复发风险最高和生存较差的患者。
