TKI用于HER2阳性转移性乳腺癌能否实现个体化治疗？
2017年8月7日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表旧金山加利福尼亚大学综合癌症中心的述评：酪氨酸激酶抑制剂用于HER2阳性转移性乳腺癌能否实现个体化治疗？本文对中国医学科学院肿瘤医院最新发表的吡咯替尼研究等重大进展进行了全面回顾和展望。本文作者之一、该校综合癌症中心教授 Hope S. Rugo 原拟于2017年10月20日来华出席第十二届上海国际乳腺癌论坛发表《HER2家族引领治愈之路》专题报告，但是根据最新消息可能因故无法成行，特此编译本文以飨读者。
Hope S. Rugo
旧金山加利福尼亚大学：常被误译为加州大学旧金山分校，是位于美国加利福尼亚州旧金山的研究型公立大学，十所加利福尼亚大学之一，以医科和生物技术而闻名，其医学院在全美国排名五名以内，由于其主要为医学院，大部分学生都是已有学士学位的研究生或医学生，以研究生为主，故并未被美国新闻与世界报导列入大学排名。
加利福尼亚大学：是位于美国加利福尼亚州不同城市的十所独立大学，如同中国的交通大学，并非一所大学，并无所谓的主校，分校只是中文翻译的误区，并应区别于加利福尼亚州的教学型公立大学系统：加利福尼亚州立大学（该校在旧金山也有校区）。
人表皮生长因子受体2（HER2）属于受体酪氨酸激酶HER家族，该家族还包括EGFR、HER3、HER4。HER家族跨膜受体的一般结构包括细胞外配体结合区、跨膜结构区、细胞内酪氨酸激酶区。HER2阳性乳腺癌高度依赖于HER2致癌基因蛋白质及其复杂下游信号通路的持续过表达。抗体类药物曲妥珠单抗、帕妥珠西单抗、曲妥珠单抗-安坦辛（T-DM1）主要针对HER2的细胞外结合区，并已转变了HER2阳性乳腺癌的预后【1】。利用小分子酪氨酸激酶抑制剂（TKI）针对HER2的细胞内酪氨酸激酶区也是一种非常合理的治疗方法，对于治疗其他致癌基因驱动恶性肿瘤非常成功。然而，用于HER2阳性乳腺癌治疗的TKI远远低于预期，其在HER2阳性乳腺癌治疗体系中的地位仍在不断进展。
拉帕替尼是EGFR和HER2的高度特异性可逆TKI，是目前唯一被批准用于治疗HER2阳性晚期乳腺癌的TKI。拉帕替尼于2007年被批准联合卡培他滨用于晚期HER2阳性乳腺癌患者，此类乳腺癌既往通常使用曲妥珠单抗和化疗进行治疗。该批准根据Ⅲ期随机研究的结果，该研究显示与单用卡培他滨相比，无进展生存延长4个月（EGF100151. N Engl J Med. 2006; 355: 2733 - 2743. NCT 00078572），而总生存未延长【2】。后续研究未能显示联合紫杉类或用于早期乳腺癌的相应获益，包括腹泻和皮疹在内的毒性反应使药物用量受到限制【3】。2013年，抗体药物缀合物T-DM1获得批准，根据Ⅲ期研究EMILIA（曲妥珠单抗-安坦辛对比卡培他滨＋拉帕替尼用于HER2阳性局部晚期或转移性乳腺癌患者的研究）的数据，显示T-DM1与拉帕替尼＋卡培他滨相比，无进展生存和总生存较好，且毒性反应较少，取代了一线以后的TKI联合治疗方案【4】。目前，HER2阳性转移性乳腺癌的一线疗法包括曲妥珠单抗和帕妥珠单抗，二线疗法包括T-DM1。迄今，曲妥珠单抗、帕妥珠单抗、T-DM1治疗HER2阳性转移性乳腺癌无效后尚无标准方案，尽管拉帕替尼联合方案仍为一种选择。
与受体不可逆结合的较新TKI，提供了改善曲妥珠单抗耐药乳腺癌疗效的可能性。奈拉替尼（来那替尼）是一种高效TKI，单药即已显示出对曲妥珠单抗无效型转移性乳腺癌的有效性，但是研究受限于腹泻率高，需要一线预防腹泻疗法【5】。一项正在进行的Ⅲ期注册研究随机分配转移性乳腺癌患者接受卡培他滨＋奈拉替尼或卡培他滨＋拉帕替尼结合预防腹泻疗法（NCT01808573：奈拉替尼＋卡培他滨对比拉帕替尼＋卡培他滨用于既往曾经接受≥2个HER2靶向药物的HER2阳性转移性乳腺癌患者[NALA]），还有一项研究正在对不同预防腹泻药物进行评价（NCT02400476：奈拉替尼＋洛哌丁胺治疗早期HER2阳性乳腺癌患者时的腹泻发生率和严重性）。最新数据显示，延长术后辅助治疗的无病生存改善（ExteNET. Lancet Oncol. 2016; 17: 367 - 377. NCT 00878709），故美国食品药品管理局于2017年7月批准1年曲妥珠单抗后再予1年每天1次奈拉替尼。阿法替尼已被批准用于非小细胞肺癌，但是用于乳腺癌的结果获得令人失望【6】。
相关阅读
妥卡替尼（ONT-380）是一种新的口服选择性TKI，对HER2的选择性高于EGFR。在最新发表的难治型晚期乳腺癌患者Ⅰ期研究中，所有患者接受过曲妥珠单抗，82%接受过拉帕替尼，妥卡替尼的缓解率为14%，临床获益率为27%【7】。有趣的是，该药物与其他TKI相比，所致腹泻率较低，Ⅰ期研究限制剂量的毒性反应为转氨酶升高。联合方案研究正在进行中，包括联合T-DM1的Ⅰ期研究、卡培他滨和曲妥珠单抗联合妥卡替尼或安慰剂的随机Ⅱ期注册研究。
由于TKI的独特属性，令人对两种特殊病情产生兴趣。第一是对于肿瘤HER2阴性而体细胞HER2突变阳性患者的活性【8】，第二是对于小分子穿过血脑屏障治疗乳腺癌脑转移亚组患者的能力【9】。TKI用于这两种病情的研究正在积极开展，奈拉替尼和妥卡替尼都有令人鼓舞的数据。
在与本述评对应的论文中，中国医学科学院肿瘤医院马飞等学者【10】发表了一个新的、口服、不可逆、泛ErbB受体TKI吡咯替尼用于对其他TKI无效的HER2阳性转移性乳腺癌患者的Ⅰ期研究结果。共有38例患者入组并按若干剂量水平进行治疗，总缓解率为50%。以最大耐受剂量治疗的8例患者中，有7例客观缓解。正如预料，既往是否接受曲妥珠单抗，对缓解有显著影响；全部患者中有65.8%接受过曲妥珠单抗，38例转移患者中有11例（28.9%）接受过曲妥珠单抗。24例患者既往接受过曲妥珠单抗，缓解率为33.3%。虽然没有报道，但是可能几乎没有患者既往曾经接受过帕妥珠单抗或T-DM1治疗。虽然限制剂量的毒性反应为腹泻，但是以最大耐受剂量治疗的8例患者毒性反应似乎相当轻微，没有必要减少剂量，并且几乎没有其他HER家族TKI通常所见皮疹、肝功能障碍或其他胃肠毒性反应报告。
相关阅读
寻找吡咯替尼预测生物标志的初步分析发现，在18例可获得血液用于检测的患者中，有8例循环肿瘤DNA（ctDNA）存在PI3K或p53突变，该8例患者无一对吡咯替尼出现缓解，而在10例无基因突变患者中，6例出现客观缓解以及无进展生存显著延长。在19例存档标本中，是否存在突变与缓解情况无关。对于12例有匹配标本（ctDNA和存档组织）的患者，其中5例突变状态不一致。
ctDNA与临床结局的相关性，可能是该研究最有吸引力的数据，需要在更大队列中进一步探索。虽然根据与存档组织进行比较，可能解释突变所致疾病进展的不一致，但是使用血液作为疗效和耐药标志的可能性更有吸引力，并为了解肿瘤生物学机制提供可再生和实时的资源。ctDNA（液体活检）与组织活检相比，不仅创伤性较小，而且可以更好地代表所有疾病部位的分子异质性，并且可以在每次后续进展发生时方便地重复检测，以检测指示耐药或新靶点的新突变。其他研究已经得出令人鼓舞的结果，确定ESR1和PI3K突变，以及ctDNA的HER2阳性突变，与肿瘤组织不一致【11】。在BELLE-2（氟维司群＋BKM120或安慰剂用于芳香酶抑制剂难治型激素受体阳性HER2阴性局部晚期绝经后或转移性乳腺癌患者的Ⅲ期研究）和BELLE-3（氟维司群＋BKM120用于mTOR抑制剂难治型激素受体阳性HER2阴性局部晚期或转移性乳腺癌患者的Ⅲ期研究）随机研究中，ctDNA的PIK3CA突变患者可获益于PI3K抑制剂＋标准激素疗法【12,13】，无PI3K突变患者获益有限。同样，在Ma等【14】的研究中，HER2阳性突变等位基因变异率变化，与用奈拉替尼治疗患者的临床结局相关。因此，ctDNA有可能使我们更全面、更深入地了解肿瘤的生物学特征，改变我们实时确定药物靶点并个体化患者治疗的能力，使我们更接近HER2阳性乳腺癌的精确医学。
相关阅读
我们应该如何将这些数据应用于现有HER2阳性乳腺癌治疗方案以及正在评估中的多个其他TKI？吡咯替尼的早期研究结果，已经显示出对HER2阳性转移性乳腺癌治疗的临床有效性，并且是又一种曲妥珠单抗无效后有潜在活性的HER家族TKI。然而，值得注意的是，吡咯替尼Ⅰ期研究的中国患者人群，与欧美类似患者相比，接受过的治疗较少，欧美类似患者通常在使用TKI之前根据现有指南已经接受了帕妥珠单抗和T-DM1治疗。不过，多项研究由于毒性反应限制了TKI的使用，而吡咯替尼的腹泻率较低、总体安全性良好，故值得期待。显然，这些初步的毒性反应和有效性数据，需要通过目前正在进行中的、有更多难治型患者的更大规模研究得到证实。虽然不少在研发中的HER家族TKI比吡咯替尼更先进，但是TKI的阿喀琉斯之踵（致命弱点）大部分与其脱靶效应和治疗窗狭窄有关。因此，在众多HER家族TKI中，哪个将在HER2治疗殿堂获得一席之地，将取决于个体毒性反应特征以及有效性，并且根据我们所知，始终存在改进余地。
参考文献
Loibl S, Gianni L. HER2-positive breast cancer. Lancet. 2017;389:2415-2429.
Cameron D, Casey M, Oliva C, et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: Final survival analysis of a phase III randomized trial. Oncologist. 2010;15:924-934.
Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol. 2016;34:1034-1042.
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.
Prové A, Dirix L. Neratinib for the treatment of breast cancer. Expert Opin Pharmacother. 2016;17:2243-2248.
Harbeck N, Huang CS, Hurvitz S, et al. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): An open-label, randomised, phase 3 trial. Lancet Oncol. 2016;17:357-366.
Moulder SL, Borges VF, Baetz T, et al. Phase I study of ONT-380, a HER2 inhibitor, in patients with HER2(+)-advanced solid tumors, with an expansion cohort in HER2(+) metastatic breast cancer (MBC). Clin Cancer Res. 2017;23:3529-3536.
Ben-Baruch NE, Bose R, Kavuri SM, et al. HER2-mutated breast cancer responds to treatment with single-agent neratinib, a second-generation HER2/EGFR tyrosine kinase inhibitor. J Natl Compr Canc Netw. 2015;13:1061-1064.
Freedman RA, Gelman RS, Wefel JS, et al. Translational Breast Cancer Research Consortium (TBCRC) 022: A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2016;34:945-952.
Ma F, Li Q, Chen S, et al. Phase I study and biomarker analysis of pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2017 May 12. [Epub ahead of print] DOI: 10.1200/JCO.2016.69.6179
De Mattos-Arruda L, Caldas C. Cell-free circulating tumour DNA as a liquid biopsy in breast cancer. Mol Oncol. 2016;10:464-474.
Baselga J, Im SA, Iwata H, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:904-916.
Di Leo A, Seok Lee K, Ciruelos E, et al. BELLE-3: A phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2-, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment. Cancer Res. 2017;77(4 Suppl):S4-07.
Ma CX, Bose R, Gao F, et al. Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 non-amplified metastatic breast cancer. Clin Cancer Res. 2017 Jul 5. [Epub ahead of print] DOI: 10.1158/1078-0432.CCR-17-0900
Hope S. Rugo
J Clin Oncol. 2017 Aug 7. [Epub ahead of print]
Tyrosine Kinase Inhibitors for Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: Is Personalizing Therapy Within Reach?
Chien AJ, Rugo HS.
University of California San Francisco Comprehensive Cancer Center, San Francisco, CA.
Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of receptor tyrosine kinases that also includes EGFR, HER3, and HER4. The general structure of the HER family of transmembrane receptors includes an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. HER2-positive breast cancers are highly dependent on the continued overexpression of the HER2 oncoprotein and its complex downstream signaling pathways. The antibody-based drugs trastuzumab, pertuzumab, and trastuzumab-emtansine (T-DM1) target the extracellular binding domain of HER2 and have collectively transformed the prognosis of HER2-positive breast cancer[1]. Targeting the intracellular tyrosine kinase domain of HER2 with small-molecule tyrosine kinase inhibitors (TKIs) is a highly rational therapeutic approach that has been extremely successful in the treatment of other oncogene-driven malignancies. However, TKIs for the treatment of HER2-positive breast cancer have thus far fallen short of expectations, and their place in the treatment landscape for HER2-positive breast cancer is evolving.
Lapatinib, a highly specific reversible EGFR/HER2 TKI, is currently the only TKI approved for the treatment of HER2-positive advanced breast cancer. Lapatinib was approved in 2007 in combination with capecitabine for patients with advanced HER2-positive breast cancer who were previously treated with trastuzumab and chemotherapy. This approval was based on results from a randomized phase III trial demonstrating a 4-month improvement in progression-free survival (PFS) compared with capecitabine alone, without improvement in overall survival[2]. Subsequent studies failed to show a corresponding benefit with taxanes or in early-stage breast cancer, and toxicity that includes diarrhea as well as rash have limited drug exposure[3]. The approval of the antibody drug conjugate T-DM1 in 2013 on the basis of data from the phase III EMILIA (A Study of Trastuzumab Emtansine Versus Capecitabine + Lapatinib in Participants With HER2-Positive Locally Advanced or Metastatic Breast Cancer) trial, which demonstrated superior PFS and overall survival and less toxicity with T-DM1 compared with lapatinib-capecitabine, displaced the TKI combination to even later line therapy[4]. The current approach to treating HER2-positive metastatic breast cancer (MBC) includes trastuzumab and pertuzumab in the first-line setting and T-DM1 in the second-line setting. At this time, there is no standard approach to the treatment of HER2-positive MBC after trastuzumab, pertuzumab, and T-DM1, although lapatinib combinations remain an option.
Newer TKIs with irreversible receptor binding offer the potential for improved efficacy in trastuzumab-resistant disease. Neratinib, a highly potent TKI, has demonstrated efficacy as a single agent in metastatic disease that progresses on trastuzumab, but studies have been limited by high rates of diarrhea requiring first-line antidiarrheal prophylaxis[5]. A phase III registration study that randomly assigned patients with MBC to capecitabine and neratinib or capecitabine and lapatinib with prophylactic antidiarrheal therapy is ongoing (ClinicalTrials.gov identifier: NCT01808573: A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metastatic Setting [NALA]), along with a study evaluating different prophylactic regimens to prevent diarrhea (ClinicalTrials.gov identifier: NCT02400476: A Study Looking [at] the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide). Recent data demonstrating improved disease-free survival in the extended adjuvant setting led to approval of neratinib in July 2017 by the US Food and Drug Administration, given daily for 1 year after 1 year of trastuzumab. Afatinib has been approved in non-small-cell lung cancer but has had disappointing results in breast cancer[6].
Tucatinib (ONT-380) is a new oral selective HER TKI with greater selectivity for HER2 than EGFR. In a recently published phase I trial that included patients heavily pretreated for advanced disease in which all patients received prior trastuzumab and 82% received prior lapatinib, the response rate was 14% with a clinical benefit rate of 27%[7]. Interestingly, this agent causes lower rates of diarrhea than that reported with other TKIs, and the dose-limiting toxicity in the phase I trial was transaminitis. Combination studies are ongoing, including a phase I study with T-DM1 and a randomized phase II registration study of capecitabine and trastuzumab combined with tucatinib or placebo.
The unique attributes of the TKIs have generated two special areas of interest. One is activity in patients whose tumors do not overexpress HER2 but do have somatic HER2-activating mutations[8], and the second is the ability of small molecules to cross the blood-brain barrier to treat the frequent CNS metastases observed in this breast cancer subset[9]. TKIs are actively being studied in both of these disease settings, with encouraging data shown for both neratinib and tucatinib.
In the article that accompanies this editorial, Ma and colleagues [10] present results of a phase I trial of pyrotinib, a new oral irreversible pan-ErbB receptor TKI, in patients with HER2-positive MBC naive to other HER2 TKIs. A total of 38 patients were enrolled and treated at several dose levels, with an overall response rate of 50%. Seven of eight patients treated at the maximum tolerated dose had objective responses. As expected, there was significant variation in response on the basis of exposure to prior trastuzumab; 65.8% of patients had received prior trastuzumab in any setting, and 11 of 38 patients had received trastuzumab in the metastatic setting. Of 24 patients previously exposed to trastuzumab, the response rate was 33.3%. Although not reported, it is likely that few if any patients were previously treated with pertuzumab or T-DM1. Although the dose-limiting toxicity was diarrhea, toxicity for the eight patients treated at the maximum tolerated dose seemed to be quite modest, with no required dose reductions and few reports of rash, liver dysfunction, or other GI toxicities commonly seen with other HER-family TKIs.
An exploratory analysis looking for predictive biomarkers for pyrotinib found PI3K or p53 mutations in circulating tumor DNA (ctDNA) from eight of 18 patients with blood available for testing. None of the eight patients responded to pyrotinib with a best response of progressive disease or stable disease, whereas six of 10 patients with wild-type for either gene demonstrated objective response as well as markedly longer PFS. In 19 archival samples, the presence or absence of mutations did not correlate with response. For the 12 patients with matched samples (ctDNA and archival tissue), five were discordant for mutation status.
The association of ctDNA with clinical outcome is perhaps the most intriguing data in this study and requires further exploration in a larger cohort. Discordance may be explained on the basis of mutations acquired with disease progression compared with archival tissue, but the potential to use blood as a marker of both response and resistance is highly appealing and provides a renewable and real-time resource for understanding tumor biology. ctDNA (liquid biopsy) is not only less invasive but may better represent the molecular heterogeneity of all disease sites, and it can be repeated easily at the time of each sequential progression episode to detect new mutations that indicate either resistance or new targets. Encouraging results have been presented in other trials with the identification of ESR1 and PI3K mutations, as well as HER2-activating mutations in ctDNA, as has discordance with tumor tissue[11]. In the BELLE-2 (Phase III Study of BKM120/Placebo With Fulvestrant in Postmenopausal Patients With Hormone Receptor Positive HER2-Negative Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitor) and BELLE-3 (A Phase III Study of BKM120 With Fulvestrant in Patients With HR+, HER2-, AI Treated, Locally Advanced or Metastatic Breast Cancer Who Progressed on or After mTORi) randomized trials, patients with PIK3CA mutations in ctDNA benefitted from adding a PI3K inhibitor to standard hormone therapy[12,13]; limited benefit was seen in those with wild-type PI3K. Similarly, in a study by Ma et al[14], changes in variant allele frequency of activating HER2 mutations were correlated with clinical outcome in patients treated with neratinib. Thus, ctDNA has the potential to transform our ability to identify druggable targets in real-time and individualize treatment of patients on the basis of a more comprehensive and relevant understanding of their tumor biology, bringing us closer to precision medicine for HER2-positive disease.
How do we put these data into context among the current treatment options for HER2-positive disease, as well as the multiple other TKIs under evaluation? Pyrotinib has demonstrated early clinical efficacy in the treatment of HER2-positive MBC and is yet another HER-family TKI with potential activity after progression on trastuzumab. However, it is important to note that the patient population in this phase I study was less heavily pretreated than similar patients treated in the United States and Europe, where pertuzumab and T-DM1 are generally administered before a TKI following established guidelines. Nevertheless, the lower rate of diarrhea and overall favorable adverse-effect profile with pyrotinib is promising, given that toxicity has limited the use of TKIs in multiple studies. Clearly, these preliminary toxicity and efficacy data will need to be confirmed in larger trials with more heavily pretreated patients, which are already in development. Although there are a number of HER-family TKIs further along in development than pyrotinib, the Achilles heel of TKIs has been largely related to their off-target effects and narrow therapeutic window. Thus, which of the numerous HER-family TKIs will win a place in the HER2 treatment landscape will depend as much on the individual toxicity profile as the efficacy and, as we have learned, there is always room for improvement.
REFERENCE
Loibl S, Gianni L. HER2-positive breast cancer. Lancet. 2017;389:2415-2429.
Cameron D, Casey M, Oliva C, et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: Final survival analysis of a phase III randomized trial. Oncologist. 2010;15:924-934.
Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol. 2016;34:1034-1042.
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.
Prové A, Dirix L. Neratinib for the treatment of breast cancer. Expert Opin Pharmacother. 2016;17:2243-2248.
Harbeck N, Huang CS, Hurvitz S, et al. Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): An open-label, randomised, phase 3 trial. Lancet Oncol. 2016;17:357-366.
Moulder SL, Borges VF, Baetz T, et al. Phase I study of ONT-380, a HER2 inhibitor, in patients with HER2(+)-advanced solid tumors, with an expansion cohort in HER2(+) metastatic breast cancer (MBC). Clin Cancer Res. 2017;23:3529-3536.
Ben-Baruch NE, Bose R, Kavuri SM, et al. HER2-mutated breast cancer responds to treatment with single-agent neratinib, a second-generation HER2/EGFR tyrosine kinase inhibitor. J Natl Compr Canc Netw. 2015;13:1061-1064.
Freedman RA, Gelman RS, Wefel JS, et al. Translational Breast Cancer Research Consortium (TBCRC) 022: A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases. J Clin Oncol. 2016;34:945-952.
Ma F, LI Q, Chen S, et al. Phase I study and biomarker analysis of pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2017 May 12. [Epub ahead of print] DOI: 10.1200/JCO.2016.69.6179
De Mattos-Arruda L, Caldas C. Cell-free circulating tumour DNA as a liquid biopsy in breast cancer. Mol Oncol. 2016;10:464-474.
Baselga J, Im SA, Iwata H, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:904-916.
Di Leo A, Seok Lee K, Ciruelos E, et al. BELLE-3: A phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2-, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment. Cancer Res. 2017;77(4 Suppl):S4-07.
Ma CX, Bose R, Gao F, et al. Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 non-amplified metastatic breast cancer. Clin Cancer Res. 2017 Jul 5. [Epub ahead of print] DOI: 10.1158/1078-0432.CCR-17-0900
PMID: 28783451
DOI: 10.1200/JCO.2017.73.5670