Mixed Responses to Systemic Therapy Revealed Potential Genetic Heterogeneity and Poor Survival in Patients with Non‐Small Cell Lung Cancer

• Published in: The oncologist (Dayton, Ohio) Vol. 22; no. 1; pp. 61 - 69
• Main Authors: Dong, Zhong‐Yi, Zhai, Hao‐Ran, Hou, Qing‐Yi, Su, Jian, Liu, Si‐Yang, Yan, Hong‐Hong, Li, Yang‐Si, Chen, Zhi‐Yong, Zhong, Wen‐Zhao, Wu, Yi‐Long
• Format: Journal Article
• Language: English
• Published: United States Wiley-Blackwell 01.01.2017
• Subjects: Aged; Carcinoma, Non-Small-Cell Lung - diagnostic imaging; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Disease-Free Survival; EGFR; Erlotinib Hydrochloride - administration & dosage; Erlotinib Hydrochloride - adverse effects; Female; Genetic Heterogeneity; Global Health and Cancer; Humans; Male; Middle Aged; Mixed response; Mutation; Neoplasm Staging; Non‐small cell lung cancer; Positron Emission Tomography Computed Tomography; Prognosis; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Quinazolines - administration & dosage; Quinazolines - adverse effects; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Survival; Non‐small cell lung cancer; Genetic heterogeneity; Survival; EGFR; Mixed response
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2016-0150

Background A subset of patients with non‐small cell lung cancer (NSCLC) fosters mixed responses (MRs) to epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) or chemotherapy. However, little is known about the clinical and molecular features or the prognostic significance and potential mechanisms. Methods The records of 246 consecutive patients with NSCLC receiving single‐line chemotherapy or TKI treatment and who were assessed by baseline and interim positron emission tomography/computed tomography scans were collected retrospectively. The clinicopathological correlations of the MR were analyzed, and a multivariate analysis was performed to explore the prognostic significance of MR. Results The overall incidence of MR to systemic therapy was 21.5% (53/246) and predominated in patients with stage IIIB–IV, EGFR mutations and those who received TKI therapy (p < .05). Subgroup analyses based on MR classification (efficacious versus inefficacious) showed significant differences in subsequent treatment between the two groups (p < .001) and preferable progression‐free survival (PFS) and overall survival (OS) in the efficacious MR group. Multivariate analyses demonstrated that the presence of MR was an independent unfavorable prognostic factor for PFS (hazard ratio [HR], 1.474; 95% confidence interval [CI], 1.018–2.134; p = .040) and OS (HR, 1.849; 95% CI, 1.190–2.871; p = .006) in patients with NSCLC. Induced by former systemic therapy, there were more T790M (18%), concomitant EGFR mutations (15%), and changes to EGFR wild type (19%) in the MR group among patients with EGFR mutations, which indicated higher incidence of genetic heterogeneity. Conclusion MR was not a rare event in patients with NSCLC and tended to occur in those with advanced lung adenocarcinoma treated with a TKI. MR may result from genetic heterogeneity and is an unfavorable prognostic factor for survival. Further studies are imperative to explore subsequent treatment strategies. Implications for Practice Tumor heterogeneity tends to produce mixed responses (MR) to systemic therapy, including TKI and chemotherapy; however, the clinical significance and potential mechanisms are not fully understood, and the subsequent treatment after MR is also a clinical concern. The present study systemically assessed patients by PET/CT and differentiated MR and therapies. The study identified a relatively high incidence of MR in patients with advanced NSCLC, particularly those treated with targeted therapies. An MR may be an unfavorable prognostic factor and originate from genetic heterogeneity. Further studies are imperative to explore subsequent treatment strategies. 摘要 背景. 部分非小细胞肺癌（NSCLC）患者对表皮生长因子受体（EGFR）‐酪氨酸激酶抑制剂（TKI）或化疗的反应不一（MR）。但目前对于MR的临床和分子特征、预后意义及潜在机制知之甚少。 方法. 回顾性采集了246例连续NSCLC患者的记录, 这些患者均接受单线化疗或TKI治疗, 且在基线时和治疗期间进行了正电子发射计算机断层成像/计算机断层扫描评估。分析了MR的临床病理学相关性, 并通过一项多变量分析探索MR的预后意义。 结果. 全身治疗后MR的总体发生率为21.5%（53/246）, 主要见于IIIB‐IV期、携带EGFR突变和接受TKI治疗的患者（p<0.05）。基于MR分类（有效 vs.无效）进行亚组分析, 结果显示两组间的后续治疗存在显著差异（p<0.001）, 有效MR组的无进展生存期（PFS）和总生存期（OS）优于无效MR组。多变量分析显示, MR是NSCLC患者PFS[风险比（HR）：1.474；95%置信区间(CI)：1.018‐2.134；p=0.040]和OS（HR：1.849；95%CI：1.190‐2.871；p=0.006）不佳的独立预后因素。经过全身治疗后, 携带EGFR突变的MR患者中出现T790M突变（18%）、合并EGFR突变（15%）和转变为EGFR野生型（19%）的人数较多, 说明遗传异质性的发生率较高。 结论. MR在NSCLC患者中并不罕见, 更常发生于接受TKI治疗的晚期肺腺癌患者中。MR可能是由遗传异质性所致, 是生存期不佳的预后因素。需要开展进一步研究来探索后续治疗策略。 对临床实践的提示：肿瘤异质性常导致患者对包括TKI和化疗在内的全身治疗反应不一（MR）, 但目前尚未完全阐明其临床意义和潜在机制, 且MR之后的后续治疗也是临床上关注的问题之一。本研究通过PET/CT对患者进行系统评估, 并根据MR和治疗进行分组分析。研究发现, 晚期NSCLC患者的MR发生率相对较高, 接受靶向治疗的患者尤其如此。MR是由遗传异质性所致, 可能是一种不利预后因素。需要开展进一步研究来探索后续治疗策略。 The occurrence and prognostic significance of mixed responses to systemic therapies among patients with non‐small cell lung cancer were evaluated by positron emission tomography/computed tomography scans (PET/CT) to provide comprehensive measurements of each lesion. Clinical biomarkers were explored to identify potential molecular mechanisms resulting in mixed response. The results of this study may help us to understand the clinical and molecular features of mixed response and provide a foundation to explore subsequent therapeutic strategies.