Martinelli Erika, Troiani Teresa, Sforza Vincenzo, Martini Giulia, Cardone Claudia, Vitiello Pietro Paolo, Ciardiello Davide, Rachiglio Anna Maria, Normanno Nicola, Sartore-Bianchi Andrea, Marsoni Silvia, Bardelli Alberto, Siena Salvatore, Ciardiello Fortunato
Dipartimento di Internistica Clinica e Sperimentale 'F Magrassi', Università degli Studi della Campania L Vanvitelli, Napoli, Italy.
Cell Biology and Biotherapy Unit, National Cancer Institute 'Fondazione Giovanni Pascale', Napoli, Italy.
ESMO Open. 2018 Jan 10;3(1):e000299. doi: 10.1136/esmoopen-2017-000299. eCollection 2018.
Constitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of primary and secondary cancer resistance to cetuximab or panitumumab in preclinical and clinical models of metastatic colorectal cancer (mCRC). Both HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) cohort A and My Pathway clinical trials provided clinical evidence that anti-HER2 therapies could be active in these patients.
HER2 gene amplification and HER2 protein overexpression analysis were performed in tumour tissue by fluorescence in situ hybridisation and immunohistochemistry. HER2 positivity was defined according to HERACLES CRC-specific HER2 scoring criteria. DNA analysis for multiple assessment of gene mutations or amplifications was carried out with the next-generation sequencing (NGS) Ion AmpliSeq Colon and Lung Cancer Panel and by using a more extensive targeted high-multiplex PCR-based NGS panel (OncoMine Comprehensive Assay).
We report the clinical case of a patient with HER2 gene amplified and RAS/BRAF wild-type mCRC who experienced a long lasting and relevant clinical efficacy from sequential anti-HER2 therapies (trastuzumab plus lapatinib, pertuzumab plus trastuzumab, trastuzumab emtansine, trastuzumab plus capecitabine) achieving a cumulative clinical benefit of 29 months, after failure of the first three lines of standard treatments, which included all the potentially active drugs in mCRC, and which accounted for only 14 months of disease control. HER gene amplification was confirmed by NGS on two different metastatic lesions during the evolution of the disease.
The clinical case highlights the role of HER2 gene amplification as a key genetic driver of cancer development and progression in mCRC and suggests that sequential HER2 blockade could be a potential therapeutic strategy.
在转移性结直肠癌（mCRC）的临床前和临床模型中，HER2基因扩增或HER2突变导致的HER2依赖性细胞内信号的组成性激活已被证明是癌症对西妥昔单抗或帕尼单抗产生原发性和继发性耐药的一种机制。结直肠癌HER2扩增增强分层（HERACLES）队列A和My Pathway临床试验均提供了临床证据，表明抗HER2疗法对这些患者可能有效。
通过荧光原位杂交和免疫组织化学对肿瘤组织进行HER2基因扩增和HER2蛋白过表达分析。HER2阳性根据HERACLES结直肠癌特异性HER2评分标准定义。使用下一代测序（NGS）Ion AmpliSeq结肠和肺癌检测板以及更广泛的基于靶向高多重PCR的NGS检测板（OncoMine综合检测）对基因突变或扩增进行多次评估的DNA分析。
我们报告了1例HER2基因扩增且RAS/BRAF野生型mCRC患者的临床病例，该患者在前三线标准治疗失败后（前三线标准治疗包括mCRC中所有可能有效的药物，仅实现了14个月的疾病控制），接受序贯抗HER2治疗（曲妥珠单抗加拉帕替尼、帕妥珠单抗加曲妥珠单抗、曲妥珠单抗-恩杂鲁胺、曲妥珠单抗加卡培他滨）获得了持久且显著的临床疗效，累积临床获益达29个月。在疾病进展过程中，通过NGS在两个不同的转移病灶上证实了HER基因扩增。
该临床病例突出了HER2基因扩增作为mCRC癌症发生和进展的关键遗传驱动因素的作用，并表明序贯HER2阻断可能是一种潜在的治疗策略。
