三阴性原发性炎性乳腺癌女性新型靶向药物＋新辅助化疗安全、有效
编者按：炎性乳腺癌的临床表现酷似急性乳腺炎，预后差、进展快、转移率高、生存率低，新辅助化疗的病理完全缓解率仅15.2%，常规化疗＋靶向治疗可能改善炎性乳腺癌患者的病理完全缓解率。表皮生长因子受体（EGFR、HER1）过表达约占所有乳腺癌的18%，其中炎性乳腺癌高达50%，EGFR过表达为炎性乳腺癌患者总生存率低的独立预测因素。潘尼妥木单抗（帕尼单抗、帕木单抗）属于抗EGFR抗体，已于2006年被美国批准治疗EGFR过表达的转移性结直肠癌。潘尼妥木单抗＋新辅助化疗对于人表皮生长因子受体2（HER2）阴性原发性炎性乳腺癌患者是否安全有效尚不明确。
2018年6月7日，《美国医学会杂志》肿瘤学分册在线发表德克萨斯大学MD安德森癌症中心的单组非盲二期研究报告，评估了潘尼妥木单抗＋新辅助化疗对HER2阴性原发性炎性乳腺癌患者的安全性和有效性，结果发现可使HER2阴性激素受体阳性、三阴性炎性乳腺癌患者的病理完全缓解率分别达到14%、42%，治疗相关血液和皮肤毒性反应明显但是短暂，并且无治疗相关死亡。因此，潘尼妥木单抗＋新辅助化疗治疗HER2阴性原发性炎性乳腺癌效果显著，尤其对于三阴性炎性乳腺癌患者。
该单中心单组非盲二期研究（NCT01036087）于2010年11月～2015年7月入组年龄≥18岁HER2阴性原发性未转移炎性乳腺癌女性患者40例（年龄23～68岁，中位57岁，绝经后29例，占72%）接受潘尼妥木单抗2.5mg/kg每周1次×5次＋新辅助化疗（白蛋白结合型纳米紫杉醇100mg/m²＋卡铂每周1次×4次→氟尿嘧啶500mg/m²＋表柔比星100mg/m²＋环磷酰胺500mg/m²每3周1次×4次）。中位随访时间为19.3个月。潘尼妥木单抗首次用药前后，采集肿瘤组织进行免疫组织化学染色和核糖核酸（RNA）测序分析，以确定预测病理完全缓解的生物标志。主要研究终点为病理完全缓解率，次要研究终点为安全性，探索目标为确定预测病理完全缓解的生物标志。
结果发现，其中三阴性炎性乳腺癌19例、激素受体阳性HER2阴性（单阴性）炎性乳腺癌21例，病理完全缓解患者与病理完全缓解率分别为：
所有40例：11例（28%，95%置信区间：15%～44%）
三阴19例： 8例（42%，95%置信区间：20%～66%）
单阴21例： 3例（14%，95%置信区间： 3%～36%）
3例患者由于毒性反应（2例）或远处转移（1例）未完成治疗。潘尼妥木单抗＋白蛋白结合型纳米紫杉醇＋卡铂治疗期间，10例患者由于治疗所致毒性反应而住院，其中5例为中性粒细胞减少所致事件。无治疗所致死亡。最常见的非血液学不良事件为皮疹。
病理完全缓解的若干可能预测因素包括磷酸化EGFR过表达（P=0.05）和COX-2过表达（P=0.05），与EGFR过表达、上皮钙黏素（上皮钙黏着蛋白）、波形蛋白、淋巴结无关。
因此，该研究表明，潘尼妥木单抗＋化疗对于三阴性炎性乳腺癌患者的病理完全缓解率较高。目前正在进行一项随机二期研究（NCT02876107）以确定潘尼妥木单抗对于三阴性乳腺癌患者的作用，并进一步验证预测疗效的生物标志。
相关阅读
JAMA Oncol. 2018 Jun 7. [Epub ahead of print]
Safety and Efficacy of Panitumumab Plus Neoadjuvant Chemotherapy in Patients With Primary HER2-Negative Inflammatory Breast Cancer.
Naoko Matsuda; Xiaoping Wang; Bora Lim; Savitri Krishnamurthy; Ricardo H. Alvarez; Jie S. Willey; Charla A. Parker; Juhee Song; Yu Shen; Jianhua Hu; Wenhui Wu; Nan Li; Gildy V. Babiera; James L. Murray; Banu K. Arun; Abenaa M. Brewster; James M. Reuben; Michael C. Stauder; Chad M. Barnett; Wendy A. Woodward; H. T. Carisa Le-Petross; Anthony Lucci; Sarah M. DeSnyder; Debu Tripathy; Vicente Valero; Naoto T. Ueno.
The University of Texas MD Anderson Cancer Center, Houston.
This single-arm, open-label trial evaluates the safety and efficacy of the anti-epidermal growth factor receptor antibody panitumumab plus neoadjuvant chemotherapy (nab-paclitaxel and carboplatin followed by fluorouracil, epirubicin, and cyclophosphamide) in patients with primary HER2-negative inflammatory breast cancer.
QUESTION: Is the combination of the anti-epidermal growth factor receptor antibody panitumumab and neoadjuvant chemotherapy safe and effective in patients with primary human epidermal growth factor receptor 2 (HER2)-negative inflammatory breast cancer (IBC)?
FINDINGS: In this single-arm, open-label trial, the combination of panitumumab and neoadjuvant chemotherapy produced pathologic complete response rates of 14% in patients with HER2-negative, hormone receptor-positive disease and 42% in patients with triple-negative IBC. Treatment-related hematological and dermatological toxic effects were substantial but transient, and there were no treatment-related deaths.
MEANING: The combination of panitumumab and neoadjuvant chemotherapy for primary HER2-negative IBC had significant efficacy, particularly in patients with triple-negative IBC.
IMPORTANCE: Combining conventional chemotherapy with targeted therapy has been proposed to improve the pathologic complete response (pCR) rate in patients with inflammatory breast cancer (IBC). Epidermal growth factor receptor (EGFR) expression is an independent predictor of low overall survival in patients with IBC.
OBJECTIVE: To evaluate the safety and efficacy of the anti-EGFR antibody panitumumab plus neoadjuvant chemotherapy in patients with primary human epidermal growth factor receptor 2 (HER2)-negative IBC.
DESIGN, SETTING, AND PARTICIPANTS: Women with primary HER2-negative IBC were enrolled from 2010 to 2015 and received panitumumab plus neoadjuvant chemotherapy. Median follow-up time was 19.3 months. Tumor tissues collected before and after the first dose of panitumumab were subjected to immunohistochemical staining and RNA sequencing analysis to identify biomarkers predictive of pCR.
INTERVENTION: Patients received 1 dose of panitumumab (2.5 mg/kg) followed by 4 cycles of panitumumab (2.5 mg/kg), nab-paclitaxel (100 mg/m2), and carboplatin weekly and then 4 cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks.
MAIN OUTCOMES AND MEASURES: The primary end point was pCR rate; the secondary end point was safety. The exploratory objective was to identify biomarkers predictive of pCR.
RESULTS: Forty-seven patients were accrued; 7 were ineligible. The 40 enrolled women had a median age of 57 (range, 23-68) years; 29 (72%) were postmenopausal. Three patients did not complete therapy because of toxic effects (n=2) or distant metastasis (n=1). Nineteen patients had triple-negative and 21 had hormone receptor-positive IBC. The pCR and pCR rates were overall, 11 of 40 (28%; 95% CI, 15%-44%); triple-negative IBC, 8 of 19 (42%; 95% CI, 20%-66%); and hormone receptor-positive/HER2-negative IBC, 3 of 21 (14%; 95% CI, 3%-36%). During treatment with panitumumab, nab-paclitaxel, and carboplatin, 10 patients were hospitalized for treatment-related toxic effects, including 5 with neutropenia-related events. There were no treatment-related deaths. The most frequent nonhematologic adverse event was skin rash. Several potential predictors of pCR were identified, including pEGFR expression and COX-2 expression.
CONCLUSIONS AND RELEVANCE: This combination of panitumumab and chemotherapy showed the highest pCR rate ever reported in triple-negative IBC. A randomized phase 2 study is ongoing to determine the role of panitumumab in patients with triple-negative IBC and to further validate predictive biomarkers.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01036087
DOI: 10.1001/jamaoncol.2018.1436
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