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

背景：浸润性小叶癌(ILC)约占所有乳腺癌的10%-15%， 其特征是激素受体阳性(HR+)，缺乏HER2扩增，Ki-67评分低，以及 细胞黏附受体，如E-钙粘附素。虽然这些肿瘤最初往往是无痛的，但晚期复发和 远处转移是常见的。有效的系统性治疗，可以改善手术和长期治疗 这些患者的结果是需要的。ILC对这两种疾病的病理完全应答率(PCR)很低 新辅助化疗(3%)和新辅助内分泌治疗(ET，0%)。HER2基因突变丰富 在约5%-10%的未选择的ILC中，一些报告显示，多形性ILC的患病率高达27% 和较高级别的ILC。ILC中的HER2突变与抗雌激素耐药有关，更糟糕的是 预后。 Neratinib是FDA批准的一种治疗HER2扩增(HER2+)早期乳腺癌的辅助疗法，已经 联合ET治疗转移性HER2突变HR+乳腺癌安全有效。我们的假设 奈拉替尼和ET的联合应用将改善HER2突变HR+ILC的临床和分子活性， 代表了一种新颖而合理的新辅助治疗选择。 试验设计：我们建议对30名I-期患者进行非盲法、多机构的II期临床试验。 HER2突变的III型ILC。患者最初将随机接受4周的奈拉替尼+ET或ET 单独进行；将在导入阶段结束时进行活组织检查。所有患者将获得20美元的组合 手术前给予ET和奈拉替尼数周。 关键终点：这项研究的主要目标是确定术前内分泌预后 这些患者手术标本上的指数(PEPI)评分。次要临床目标将是评估 PCR率、残留癌负荷(RCB)指数、保乳术率。此外，我们 提出相关研究，以促进对neratinib如何与抗雌激素协同作用的理解 在治疗前和治疗中评估肿瘤细胞周期停滞和凋亡标记物的治疗(4 周)，对ET±neratinib臂进行活组织检查。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。我们将开发患者衍生的有机化合物，并进行单次- 细胞RNA和ATAC测序和DNA测序以阐明转录和表观遗传程序 通过持续的HER2导向治疗和躯体改变使乳腺癌存活 抵抗。 我们推测，neratinib和ET的结合将改善HER2的临床和分子活性。 突变的HR+ILC，解决了这一具有挑战性的治疗乳腺癌亚型的未得到满足的需求。

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.