Department of Oncology, the Second Affiliated Hospital of Nanchang University, Nanchang, China.
JiangXi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China.
Mol Med. 2020 Sep 17;26(1):88. doi: 10.1186/s10020-020-00197-9.
Patients newly diagnosed with lung adenocarcinoma with bone metastases (LABM) have poor survival rates after treatment with conventional therapies. To improve outcomes, we retrospectively investigated whether the application of a more comprehensive genetic test of tumor biopsies samples from LABM patients could provide the basis for treatment with more effective tyrosine kinase inhibitors (TKIs) regimens.
Fine needle biopsies were taken from the primary tumor (PT) and a secondary bone metastasis (BM) of 17 LABM patients before treatment. Simple genetic profiles for selecting therapies were initially obtained using an ARMS-PCR test for EGFR and ALK fusion mutations. More detailed genetic profiles of somatic exon SNVs and CNVs in 457 cancer-related genes were retrospectively derived using capture single molecule amplification and resequencing technology (capSMART).
ARMS-PCR identified 14 EGFR positive, 3 EGFR negative and 1 ALK fusion positive patient. A therapy regimen incorporating TKIs Gefitinib and Crizotinib was offered to the EGFR and ALK fusion positive patients, respectively. With the exception of two patients, molecular profiling of matching PT and BM biopsies identified a highly shared somatic variant fingerprint, although the BMs exhibited additional genomic instability. In six of 13 EGFR positive patients and in all three EGFR negative patients, examination of the genetic profiles identified additional clinically significant mutations that are known or experimental drug targets for treatment of lung cancer.
Our findings firstly suggest that treatment regimens based on comprehensive genetic assessment of newly diagnosed LABM patients should target both the PT and secondary BMs, including rogue clones with potential to form new BMs. Second, the additional information gained should allow clinicians to design and implement more personalized treatment regimens and potentially improve outcomes for LABM patients.
接受常规治疗后，新诊断为肺腺癌伴骨转移（LABM）的患者生存率较差。为了改善预后，我们回顾性研究了对 LABM 患者肿瘤活检样本进行更全面的基因检测是否能为更有效的酪氨酸激酶抑制剂（TKI）治疗方案提供依据。
在治疗前，对 17 例 LABM 患者的原发肿瘤（PT）和继发性骨转移灶（BM）进行了细针活检。最初使用 ARMS-PCR 检测 EGFR 和 ALK 融合突变来获得用于选择治疗方案的简单基因谱。然后使用捕获单分子扩增和重测序技术（capSMART）回顾性地获得 457 个与癌症相关基因的体细胞外显子 SNVs 和 CNVs 的更详细的基因谱。
ARMS-PCR 鉴定出 14 例 EGFR 阳性、3 例 EGFR 阴性和 1 例 ALK 融合阳性患者。分别为 EGFR 和 ALK 融合阳性患者提供了包含 TKI 吉非替尼和克唑替尼的治疗方案。除了两名患者外，匹配的 PT 和 BM 活检的分子谱分析确定了高度共享的体细胞变异指纹，尽管 BM 表现出额外的基因组不稳定性。在 13 例 EGFR 阳性患者中的 6 例和所有 3 例 EGFR 阴性患者中，对基因谱的检查确定了其他具有临床意义的突变，这些突变是治疗肺癌的已知或实验性药物靶点。
我们的研究结果首先表明，基于对新诊断的 LABM 患者全面遗传评估的治疗方案应针对 PT 和继发性 BM，包括可能形成新 BM 的流氓克隆。其次，获得的额外信息应使临床医生能够设计和实施更个性化的治疗方案，并有可能改善 LABM 患者的预后。
