Johnston Stephen, Trudeau Maureen, Kaufman Bella, Boussen Hamouda, Blackwell Kimberley, LoRusso Patricia, Lombardi Donald P, Ben Ahmed Slim, Citrin Dennis L, DeSilvio Michelle L, Harris Jennifer, Westlund Ron E, Salazar Vanessa, Zaks Tal Z, Spector Neil L
Department of Medicine-Breast Unit, Royal Marsden Hospital, London, United Kingdom.
J Clin Oncol. 2008 Mar 1;26(7):1066-72. doi: 10.1200/JCO.2007.13.9949. Epub 2008 Jan 22.
Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity.
Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected.
Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib.
Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.
炎性乳腺癌（IBC）是最具侵袭性的乳腺癌形式之一。拉帕替尼是一种口服的表皮生长因子受体（EGFR）和人EGFR 2（HER-2）可逆抑制剂，在I期试验的五例IBC患者中有四例显示出临床活性。我们开展了一项II期试验，以确认IBC对拉帕替尼的敏感性，确定反应是否依赖HER-2或EGFR，并阐明预测拉帕替尼敏感性的分子特征。
我们的开放标签多中心II期试验（EGF103009）评估了拉帕替尼单药治疗复发性或蒽环类难治性IBC患者的临床活性和安全性。患者被分配到队列A（HER-2过表达[HER-2+]）或队列B（HER-2-/EGFR+），并收集新鲜的预处理肿瘤活检样本。
45例患者（队列A中30例；队列B中15例）连续每日一次接受1500 mg拉帕替尼治疗。临床表现和生物标志物分析显示出与IBC一致的肿瘤分子特征。拉帕替尼总体耐受性良好，主要为1/2级皮肤和胃肠道毒性。队列A中有15例患者（50%）对拉帕替尼在皮肤和/或可测量疾病方面有临床反应（根据实体瘤疗效评价标准），而队列B中只有1例患者有反应。在队列A中，磷酸化（p）HER-3和p53表达缺失预测对拉帕替尼有反应（P <.05）。同时表达pHER-2和pHER-3的肿瘤更有可能对拉帕替尼有反应（10例中有9例对14例中有4例；P =.0045）。既往曲妥珠单抗治疗以及磷酸酶和张力蛋白同源物10（PTEN）缺失并不排除对拉帕替尼的反应。
拉帕替尼在HER-2+但非EGFR+/HER-2-的、接受过大量治疗的IBC患者中耐受性良好且具有临床活性。在本研究中，肿瘤中pHER-2和pHER-3的共表达似乎预测对拉帕替尼有良好反应。这些发现值得进一步研究拉帕替尼单药治疗或联合治疗HER-2+ IBC。
