Neoadjuvant Neratinib in Stage I-III HER2-mutated Lobular Breast Cancer

新辅助来那替尼治疗 I-III 期 HER2 突变小叶乳腺癌

• 批准号: 10660734
• 负责人: Carlos L Arteaga
• 金额: $ 51.03万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-26 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660734
• 关键词: ATAC-seq; Address; Adjuvant Chemotherapy; Adjuvant Therapy; Agonist; Antiestrogen Therapy; Apoptosis; Aromatase Inhibitors; Biopsy; Breast biopsy; Breast conservation; Breast-Conserving Surgery; CASP3 gene; Cancer Burden; Caring; Cell Adhesion; Cell Cycle Arrest; Cells; Clinical; Clinical Trials; Correlative Study; DNA; DNA sequencing; Diffuse; Distant Metastasis; Drug Tolerance; Drug resistance; E-Cadherin; ERBB2 gene; Endocrine; Epigenetic Process; Estrogen Antagonists; Estrogens; Evolution; Exclusion; FDA approved; Gene Amplification; Genes; Genetic Transcription; Goals; Gonadotropin Hormone Releasing Hormone; Growth; Histology; Hormone Receptor; Hormones; Human; In Vitro; In complete remission; Indolent; Induction of Apoptosis; Institution; Lead; Light; Lobular; Lobular Carcinoma; Longitudinal Studies; Menopausal Status; Metastatic breast cancer; Molecular; Molecular Target; Mutate; Mutation; Neoadjuvant Therapy; Newly Diagnosed; Oncogenic; Operative Surgical Procedures; Organoids; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Phase; Phase II Clinical Trials; Prevalence; Prognosis; Proliferating; Proto-Oncogene Proteins c-akt; Randomized; Recurrence; Refractory; Repeat Surgery; Reporting; Residual Cancers; Residual Neoplasm; Resistance; Safety; Sampling; Signal Transduction; Therapeutic Effect; Time; Trastuzumab; Tumor Tissue; Tyrosine Kinase Inhibitor; adhesion receptor; adjuvant endocrine therapy; arm; breast cancer survival; cancer subtypes; chemotherapy; deprivation; drug response prediction; hormone receptor-positive; hormone therapy; improved; indexing; inhibitor; innovation; malignant breast neoplasm; molecular marker; mutant; neoplastic cell; novel; phase III trial; prevent; prognostic index; programs; receptor; single-cell RNA sequencing; standard care; surgery outcome; synergism; trial design; tumor; tumor diagnostic; tumor heterogeneity

BACKGROUND: Invasive lobular carcinoma (ILC) accounts for approximately 10-15% of all breast cancers and is characterized by hormone receptor positivity (HR+), lack of HER2 amplification, low Ki-67 score, and loss of cell adhesion receptors such as e-cadherin. While these tumors tend to be indolent initially, late recurrences and distant metastasis are common. Effective systemic treatments that can improve both surgical and long-term outcomes for these patients are needed. ILC has very low rates of pathologic complete response (pCR) to both neoadjuvant chemotherapy (3%) and neoadjuvant endocrine therapies (ET, 0%). HER2 mutations are enriched in about 5-10% of unselected ILC, with some reports showing the prevalence as high as 27% in pleomorphic and higher grade ILCs. HER2 mutations in ILC are associated with antiestrogen resistance and a worse prognosis. Neratinib, an FDA-approved adjuvant treatment for HER2-amplified (HER2+) early-stage breast cancer, has shown safety and efficacy in combination with ET in metastatic HER2-mutant HR+ breast cancer. Our hypothesis is that the combination of neratinib and ET will improve clinical and molecular activity in HER2-mutant HR+ ILC, representing a novel and rational neoadjuvant therapy option. TRIAL DESIGN: We propose an unblinded, multi-institutional Phase II clinical trial for 30 patients with Stage I- III ILCs with HER2 mutations. Patients will be initially randomized to either 4 weeks of neratinib + ET OR ET alone; a biopsy will be done at the end of the lead-in phase. All patients then will receive a combination of 20 weeks of ET and neratinib prior to proceeding to surgery. KEY ENDPOINTS: The primary objective of this study is to determine the pre-operative endocrine prognostic index (PEPI) score on the surgical sample in these patients. The secondary clinical objectives will be to evaluate the pCR rate, residual cancer burden (RCB) index, and rates of breast conserving surgery. In addition, we propose correlative studies that will promote understanding of how neratinib synergizes with antiestrogen therapies by evaluating tumor cell cycle arrest and apoptosis markers in the pre-treatment and on-treatment (4 week) biopsy in both the ET ± neratinib arms. Finally, we will study the longitudinal evolution of therapy tolerance and resistance in HER2-mutated breast cancer. We will develop patient-derived organoids and perform single- cell RNA and ATAC sequencing and DNA sequencing to elucidate transcriptional and epigenetic programs that permit breast cancer survival upon continuous HER2-directed therapy and somatic alterations that drive resistance. We hypothesize that the combination of neratinib and ET will improve clinical and molecular activity in HER2- mutant HR+ ILC, addressing an unmet need for this challenging to treat breast cancer subtype.

背景：浸润性小叶癌 (ILC) 约占所有乳腺癌的 10-15% 其特点是激素受体阳性 (HR+)、缺乏 HER2 扩增、Ki-67 评分低以及丧失 细胞粘附受体，例如 e-钙粘蛋白。虽然这些肿瘤最初往往是惰性的，但后期会复发和 远处转移很常见。有效的全身治疗可以改善手术和长期效果 需要这些患者的结果。 ILC 对这两种疾病的病理完全缓解 (pCR) 率非常低 新辅助化疗（3%）和新辅助内分泌治疗（ET，0%）。 HER2突变丰富 约 5-10% 的未选择 ILC，一些报告显示多形性 ILC 的患病率高达 27% 和更高等级的 ILC。 ILC 中的 HER2 突变与抗雌激素耐药性和更严重的情况相关 预后。 Neratinib 是 FDA 批准的一种用于 HER2 扩增 (HER2+) 早期乳腺癌的辅助治疗药物， 与 ET 联合治疗转移性 HER2 突变 HR+ 乳腺癌显示出安全性和有效性。我们的假设 neratinib 和 ET 的组合将改善 HER2 突变 HR+ ILC 的临床和分子活性， 代表了一种新颖且合理的新辅助治疗选择。 试验设计：我们建议对 30 名 I 期患者进行非盲式、多机构 II 期临床试验 III 具有 HER2 突变的 ILC。患者最初将被随机分配接受 4 周的来那替尼 + ET 或 ET 独自的;导入阶段结束时将进行活检。然后所有患者将接受 20 种药物的组合治疗 手术前接受 ET 和来那替尼治疗数周。 关键终点：本研究的主要目的是确定术前内分泌预后 这些患者手术样本的指数（PEPI）评分。次要临床目标是评估 pCR 率、残余癌症负荷 (RCB) 指数和保乳手术率。此外，我们 提出相关研究，以促进对来那替尼如何与抗雌激素协同作用的理解 通过在治疗前和治疗中评估肿瘤细胞周期停滞和细胞凋亡标志物来进行治疗（4 周）对 ET ± neratinib 组进行活检。最后，我们将研究治疗耐受性的纵向演变 以及 HER2 突变乳腺癌的耐药性。我们将开发源自患者的类器官并进行单 细胞 RNA 和 ATAC 测序以及 DNA 测序，以阐明转录和表观遗传程序 允许乳腺癌在持续的 HER2 导向治疗和驱动体细胞改变的情况下存活 反抗。 我们假设来那替尼和 ET 的组合将改善 HER2- 的临床和分子活性 突变型 HR+ ILC，解决了这种具有挑战性的乳腺癌亚型治疗未得到满足的需求。