University Hospital Geelong, Geelong, Victoria, Australia.
School of Medicine, Deakin University, Geelong, Victoria, Australia.
PLoS One. 2019 Feb 14;14(2):e0210891. doi: 10.1371/journal.pone.0210891. eCollection 2019.
This study evaluated the feasibility of achieving high response rates in stage II or III breast cancer by tailoring neoadjuvant therapy using clinical and histopathological features and the Oncotype DX Breast Recurrence Score. Genomic determinants of response and resistance were also explored.
Fifty-one patients were enrolled. The primary cohort comprised 40 patients: 15 human epidermal growth factor receptor type 2 (HER2)-amplified; 15 triple-negative (TNBC); and ten hormone receptor (HR)-positive, HER2-non-amplified tumours; with recurrence scores ≥25. Patients were treated with epirubicin and cyclophosphamide, followed by nab-paclitaxel, with the addition of trastuzumab if HER2-amplified. The primary endpoint was pathological complete response (pCR) in the breast. Pre- and post-treatment tumour samples underwent variant burden, gene and gene pathway, mutational signature profile and clonal evolution analyses.
The pCR rates were: overall 55% (n = 22), HER2-amplified 80% (n = 12), triple-negative 46% (n = 7) and HR-positive, HER2-non-amplified 30% (n = 3). Grade 3 or 4 adverse events included febrile neutropenia (8%), neutropenia (18%), sensory neuropathy (5%), deranged transaminases (5%), fatigue (2%), diarrhoea (2%), and pneumothorax (2%). Molecular analyses demonstrated strong similarities between residual disease and matched primary tumour. ATM signalling pathway alterations and the presence of a COSMIC Signature 3 implied the majority of tumours contained some form of homologous repair deficiency. ATM pathway alterations were identified in the subset of TNBC patients who did not achieve pCR; Signature 3 was present in both pCR and non-pCR subgroups. Clonal evolution analyses demonstrated both persistence and emergence of chemoresistant clones.
This treatment regime resulted in a high rate of pCR, demonstrating that tailored neoadjuvant therapy using a genomic recurrence score is feasible and warrants further investigation. Molecular analysis revealed few commonalities between patients. For TNBC future clinical gains will require precision medicine, potentially using DNA sequencing to identify specific targets for individuals with resistant disease.
Clinicaltrials.gov NCT01830244.
本研究旨在通过临床和组织病理学特征以及 Oncotype DX 乳腺癌复发评分来调整新辅助治疗，评估在 II 期或 III 期乳腺癌中实现高缓解率的可行性。还探讨了反应和耐药的基因组决定因素。
共纳入 51 例患者。主要队列包括 40 例患者：15 例人表皮生长因子受体 2（HER2）扩增；15 例三阴性（TNBC）；10 例激素受体（HR）阳性、HER2 非扩增肿瘤；复发评分≥25。患者接受表柔比星和环磷酰胺治疗，随后接受nab-紫杉醇治疗，如果 HER2 扩增，则加用曲妥珠单抗。主要终点是乳房病理完全缓解（pCR）。治疗前后的肿瘤样本进行了变异负担、基因和基因通路、突变特征谱和克隆进化分析。
pCR 率为：总体 55%（n=22），HER2 扩增 80%（n=12），三阴性 46%（n=7），HR 阳性、HER2 非扩增 30%（n=3）。3 或 4 级不良事件包括发热性中性粒细胞减少症（8%）、中性粒细胞减少症（18%）、感觉神经病变（5%）、转氨酶异常（5%）、疲劳（2%）、腹泻（2%）和气胸（2%）。分子分析表明残留疾病与匹配的原发性肿瘤之间具有很强的相似性。ATM 信号通路改变和存在 COSMIC Signature 3 表明大多数肿瘤都存在同源修复缺陷的某种形式。在未达到 pCR 的 TNBC 患者亚组中发现了 ATM 通路改变；Signature 3 存在于 pCR 和非 pCR 亚组中。克隆进化分析表明，化疗耐药克隆既有持续性又有新出现性。
这种治疗方案导致 pCR 率很高，表明使用基因组复发评分的靶向新辅助治疗是可行的，值得进一步研究。分子分析显示患者之间很少有共同之处。对于 TNBC，未来的临床获益将需要精准医学，可能需要使用 DNA 测序来确定耐药患者的特定靶点。
Clinicaltrials.gov NCT01830244。
