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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

基本信息

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
项目类别：
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

项目摘要

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%