Dalal Sharvari, Petersen Jeffrey, Jhala Darshana
and are Staff Pathologists and is Chief, Pathology and Laboratory Medicine, all at Corporal Michael J. Crescenz Veteran Affairs Medical Center in Philadelphia, Pennsylvania. Sharvari Dalal is Adjunct Assistant Professor of Clinical Pathology and Laboratory Medicine, Jeffrey Petersen is Assistant Professor of Clinical Pathology and Laboratory Medicine, and Darshana Jhala is Professor of Clinical Pathology and Laboratory Medicine, all at the University of Pennsylvania Perelman School of Medicine.
Fed Pract. 2021 Jan;38(1):8-14. doi: 10.12788/fp.0065.
Liquid biopsy in solid tumors is a major milestone in the field of precision oncology by analyzing circulating tumor cells in peripheral blood and genomic alterations. DNA damage repair gene (DDR) mutations have been reported in 25 to 40% of prostatic cancers and > 50% of non-small cell lung cancers (NSCLC). Tp53 mutation has been found to be associated with a poor prognosis and increased germline mutations. We herein present a quality assurance study for the utility of liquid biopsies with frequency of DDR, Tp53, and androgen receptor (AR) mutations and the clinical impact in advanced lung and prostate cancers in the veteran patient population; these quality assurance observations are the study endpoints.
We reviewed documentation from advanced cancer biomarker tests on liquid biopsies performed at the Corporal Michael J. Crescenz Veteran Affairs Medical Center in Philadelphia, Pennsylvania, from May 2019 to April 15, 2020.
Mutations were detected in 29 of 31 (93.5%) liquid biopsies, hence, 29 liquid biopsies had sufficient ctDNA for analysis. Notable mutations were found in 23 cases (79.3%), irrespective of the cancer type showed. Of 21 prostate cancers biopsies 4 (19.0%) biomarker test directed the targeted therapy to driver mutations of the gene. Gene mutations from the DDR gene family were detected in 8 of 23 (34.7%) advanced prostate and lung cancer liquid biopsies, and in 6 of 21 (28.5%) prostate cancer cases indicating poor outcome and possible resistance to the current therapy. Irrespective of the cancer type, 15 of 23 (65.2%) patients harbored Tp53 mutations, which is much more frequent than is documented in the literature. Of 31 patients, 15 (48.4%) were Vietnam era veterans with the potential of Agent Orange exposure and, 20 of 31 (64.5%) had a smoking history. Seven (46.6%) of the Vietnam era veterans with potential exposure to Agent Orange were positive for Tp53 mutations irrespective of the cancer type.
The minimally invasive liquid biopsy shows a great promise as a diagnostic and prognostic tool in the personalized clinical management of advanced prostate and NSCLC in veteran patient population with unique demographic characteristics. Difference in frequency of the genetic mutations (DDR, TP53, AR) in this cohort provides valuable information for disease progression, lack of response, mechanism of resistance to the implemented therapy and clinical decision making. Precision oncology can be further tailored for this cohort by focusing on DNA repair genes and Tp53 mutations in future for personalized targeted therapy.
实体瘤的液体活检是精准肿瘤学领域的一个重要里程碑，通过分析外周血中的循环肿瘤细胞和基因组改变来实现。据报道，25%至40%的前列腺癌和超过50%的非小细胞肺癌（NSCLC）存在DNA损伤修复基因（DDR）突变。已发现Tp53突变与预后不良和生殖系突变增加有关。我们在此展示了一项质量保证研究，涉及液体活检在老年患者群体中DDR、Tp53和雄激素受体（AR）突变频率的实用性以及对晚期肺癌和前列腺癌的临床影响；这些质量保证观察结果为研究终点。
我们回顾了2019年5月至2020年4月15日在宾夕法尼亚州费城的下士迈克尔·J·克雷森茨退伍军人事务医疗中心进行的晚期癌症生物标志物液体活检检测的文档。
31例液体活检中有29例（93.5%）检测到突变，因此，29例液体活检有足够的循环肿瘤DNA（ctDNA）用于分析。在23例（79.3%）病例中发现了显著突变，与所显示的癌症类型无关。在21例前列腺癌活检中，4例（19.0%）生物标志物检测将靶向治疗指向该基因的驱动突变。在23例晚期前列腺癌和肺癌液体活检中的8例（34.7%）以及21例前列腺癌病例中的6例（28.5%）检测到DDR基因家族的基因突变，表明预后不良且可能对当前治疗有抗性。与癌症类型无关，23例患者中有15例（65.2%）携带Tp53突变，这比文献记载的更为常见。31例患者中，15例（48.4%）是越战时期的退伍军人，有可能接触过橙剂，31例中有20例（64.5%）有吸烟史。7例（46.6%）有可能接触过橙剂的越战时期退伍军人无论癌症类型如何，Tp53突变均为阳性。
微创液体活检作为一种诊断和预后工具，在具有独特人口统计学特征的老年患者群体的晚期前列腺癌和非小细胞肺癌个性化临床管理中显示出巨大潜力。该队列中基因突变（DDR、TP53、AR）频率的差异为疾病进展、无反应、对实施治疗的抗性机制和临床决策提供了有价值的信息。未来通过关注DNA修复基因和Tp53突变，可为该队列进一步量身定制精准肿瘤学以实现个性化靶向治疗。
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