Friedlaender Alex, Tsantoulis Petros, Chevallier Mathieu, De Vito Claudio, Addeo Alfredo
Oncology Department, University Hospital Geneva, Geneva, Switzerland.
Pathology Department, University Hospital Geneva, Geneva, Switzerland.
Front Oncol. 2021 Mar 30;11:644472. doi: 10.3389/fonc.2021.644472. eCollection 2021.
EGFR mutations represent the most common currently targetable oncogenic driver in non-small cell lung cancer. There has been tremendous progress in targeting this alteration over the course of the last decade, and third generation tyrosine kinase inhibitors offer previously unseen survival rates among these patients. Nonetheless, a better understanding is still needed, as roughly a third of patients do not respond to targeted therapy and there is an important heterogeneity among responders. Allelic frequency, or the variant EGFR allele frequency, corresponds to the fraction of sequencing reads harboring the mutation. The allelic fraction is influenced by the proportion of tumor cells in the sample, the presence of copy number alterations but also, most importantly, by the proportion of cells within the tumor that carry the mutation. Mutations that occur early in tumor evolution, often called clonal or truncal, have a higher allelic frequency than late, subclonal mutations, and are more often drivers of cancer evolution and attractive therapeutic targets. Most, but not all, EGFR mutations are clonal. Although an exact estimate of clonal proportion is hard to derive computationally, the allelic frequency is readily available to clinicians and could be a useful surrogate. We hypothesized that tumors with low allelic frequency of the EGFR mutation will respond less favorably to targeted treatment.
表皮生长因子受体（EGFR）突变是目前在非小细胞肺癌中最常见的可靶向致癌驱动因素。在过去十年中，针对这一改变已经取得了巨大进展，第三代酪氨酸激酶抑制剂为这些患者带来了前所未有的生存率。尽管如此，仍需要更好地理解，因为大约三分之一的患者对靶向治疗无反应，而且反应者之间存在重要的异质性。等位基因频率，即变异的EGFR等位基因频率，对应于携带该突变的测序读数的比例。等位基因比例受样本中肿瘤细胞比例、拷贝数改变的影响，但最重要的是受肿瘤内携带该突变的细胞比例的影响。在肿瘤进化早期发生的突变，通常称为克隆性或主干性突变，其等位基因频率高于晚期的亚克隆性突变，并且更常是癌症进化的驱动因素和有吸引力的治疗靶点。大多数（但不是全部）EGFR突变是克隆性的。虽然很难通过计算得出克隆比例的确切估计值，但等位基因频率对临床医生来说很容易获得，并且可能是一个有用的替代指标。我们假设EGFR突变等位基因频率低的肿瘤对靶向治疗的反应较差。
