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%， 特征为激素受体阳性（HR+），缺乏HER 2扩增，Ki-67评分低， 细胞粘附受体如E-钙粘蛋白。虽然这些肿瘤最初往往是无痛的，但晚期复发， 远处转移是常见的。有效的全身治疗，可以改善手术和长期 这些患者的治疗结果是必要的。ILC对这两种药物的病理完全缓解（pCR）率非常低。 新辅助化疗（3%）和新辅助内分泌治疗（ET，0%）。HER 2突变富集 在大约5-10%的多形性ILC中，一些报告显示在多形性ILC中的患病率高达27%。 以及更高等级的ILC。ILC中的HER 2突变与抗雌激素抵抗相关， 预后 来那替尼是FDA批准的用于HER 2扩增（HER 2+）早期乳腺癌的辅助治疗， 在转移性HER 2突变型HR+乳腺癌中显示出与ET组合的安全性和有效性。我们的假设 来那替尼和ET联合治疗将改善HER 2突变型HR+ ILC的临床和分子活性， 代表一种新的和合理的新辅助治疗选择。 试验设计：我们提出了一个非盲的，多机构的II期临床试验的30例患者的I- III具有HER 2突变的ILC。患者最初将随机分配至4周来那替尼+ ET或ET组 单独;将在导入期结束时进行活检。所有患者将接受20种 手术前接受ET和来那替尼治疗6周。 关键终点：本研究的主要目的是确定术前内分泌预测 指数（PEPI）评分对这些患者的手术样本。次要临床目的是评价 pCR率、残留癌负荷（RCB）指数和保乳手术率。另外我们 提出相关研究，以促进对来那替尼如何与抗雌激素药物协同作用的理解 通过评估治疗前和治疗中的肿瘤细胞周期阻滞和凋亡标志物来评估治疗（4 两个ET ±来那替尼组的活检结果。最后，我们将研究治疗耐受性的纵向演变 以及HER 2突变乳腺癌的耐药性。我们将开发患者源性类器官，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HER 2导向治疗和体细胞改变后存活， 阻力 我们假设来那替尼和ET联合治疗将改善HER 2 - 1的临床和分子活性。 突变HR+ ILC，解决了这种具有挑战性的治疗乳腺癌亚型的未满足的需求。

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.