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BACKGROUND

Due to the undesirable cumulative toxicity of multiple drugs, de-escalated neoadjuvant chemotherapy strategies are needed for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Pyrotinib, a small-molecule irreversible pan-HER receptor tyrosine kinase inhibitor, shows promising efficacy in the neoadjuvant setting. We aimed to determine the efficacy, safety and predictive biomarkers of the de-escalated neoadjuvant nab-paclitaxel combined with pyrotinib and trastuzumab in intrinsic HER2-enriched breast cancer.

METHODS

In this multicenter phase 2 study (NCT05659056), patients who were histologically diagnosed with HER2-positive breast cancer (clinical stage ⅡA-ⅢC) were deemed suitable to participate in this study. Participants received pyrotinib (400 mg once), trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance dose), and nab-paclitaxel (260 mg/m) on day 1 of each 3-week cycle for six cycles. The primary endpoint was the rate of total pathological complete response (tpCR) among BluePrint HER2-enriched breast cancers, which was defined as complete disappearance of invasive tumor in breast specimen and all sampled axillary lymph nodes (ypT0/is, ypN0). This study has been completed.

FINDINGS

Between 3 December 2022 and 6 June 2024, 74 participants were finally enrolled in the study. Of all enrolled participants, 66 had baseline BluePrint and MammaPrint results. Among the 43 participants with BluePrint HER2-enriched breast cancer, 23 achieved tpCR (53%, 95% CI 38%-69%), and 28 achieved breast pathological complete response (bpCR) (65%, 95% CI 49%-79%). Among the 23 participants with non-HER2-enriched subtypes, 7 achieved tpCR (30%, 95% CI 13%-53%), while 10 achieved bpCR (43%, 95% CI 23%-66%). Of 66 participants with MammaPrint risk score index, the tpCR rate in MammaPrint ultra-high group (24/39) was significantly higher than that in high group (6/27, = 0.0024). With the median follow-up of 19.9 months (IQR, 15.5-25.4), no cases of recurrence, metastasis, or mortality events were observed. Grade 3-4 treatment-related adverse events occurred in 17 (23%) participants. The most common grade 3-4 adverse event was diarrhea (10/74). No treatment-related deaths occurred. Of all enrolled participants, no treatment discontinuations occurred due to disease progression during the neoadjuvant therapy period.

INTERPRETATION

De-escalated neoadjuvant cytotoxic chemotherapy regimen is promising for BluePrint HER2-enriched breast cancer. Our results provide critical references for the efficacy and biomarkers of de-escalated neoadjuvant therapy in HER2-positive breast cancer.

FUNDING

National Natural Science Foundation of China and Natural Science Foundation of Jiangsu Province.

背景

由于多种药物存在不良累积毒性，人表皮生长因子受体2（HER2）阳性乳腺癌需要采用降阶梯新辅助化疗策略。吡咯替尼是一种小分子不可逆泛HER受体酪氨酸激酶抑制剂，在新辅助治疗中显示出有前景的疗效。我们旨在确定降阶梯新辅助白蛋白结合型紫杉醇联合吡咯替尼和曲妥珠单抗治疗原发性HER2富集型乳腺癌的疗效、安全性及预测生物标志物。

方法

在这项多中心2期研究（NCT05659056）中，经组织学诊断为HER2阳性乳腺癌（临床分期ⅡA-ⅢC）的患者被认为适合参与本研究。参与者在每3周周期的第1天接受吡咯替尼（400 mg，每日1次）、曲妥珠单抗（8 mg/kg负荷剂量，随后6 mg/kg维持剂量）和白蛋白结合型紫杉醇（260 mg/m²），共6个周期。主要终点是Blueprint HER2富集型乳腺癌中的总病理完全缓解（tpCR）率，其定义为乳腺标本和所有取样腋窝淋巴结中浸润性肿瘤完全消失（ypT0/is，ypN0）。本研究已完成。

结果

在2022年12月3日至2024年6月6日期间，最终有74名参与者入组本研究。在所有入组参与者中，66人有基线Blueprint和MammaPrint结果。在43例Blueprint HER2富集型乳腺癌参与者中，23例达到tpCR（53%，95%CI 38%-69%），28例达到乳腺病理完全缓解（bpCR）（65%，95%CI 49%-79%）。在23例非HER2富集型亚型参与者中，7例达到tpCR（30%，95%CI 13%-53%），10例达到bpCR（43%，95%CI 23%-66%）。在66例有MammaPrint风险评分指数的参与者中，MammaPrint超高风险组（24/39）的tpCR率显著高于高风险组（6/27，P = 0.0024）。中位随访19.9个月（IQR，15.5-25.4），未观察到复发、转移或死亡事件。17例（23%）参与者发生3-4级治疗相关不良事件。最常见的3-4级不良事件是腹泻（10/74）。未发生治疗相关死亡。在所有入组参与者中，新辅助治疗期间无因疾病进展而停药的情况。