Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.
Oncology Unit 1, Veneto Institute of Oncology-IRCCS, Padova, Italy.
JCO Precis Oncol. 2022 Apr;6:e2200037. doi: 10.1200/PO.22.00037.
Several uncommon genomic alterations beyond and BRAFV600E mutations drive primary resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC). Our PRESSING panel (including exon 20// mutations, / amplifications, gene fusions, and microsatellite instability-high status) represented a paradigm of negative hyperselection with more precise tailoring of EGFR blockade. However, a modest proportion of hyperselected mCRC has intrinsic resistance potentially driven by even rarer genomic alterations.
A prospective data set at three Italian Academic Hospitals included 650 patients with mCRC with comprehensive genomic profiling by FoundationOne CDx and treated with anti-EGFRs. PRESSING2 panel alterations were selected on the basis of previous clinico-biologic studies and included , , , //, pathogenic mutations; / loss; , , , , , and amplification; and rearrangements. These were collectively associated with outcomes in patients with hyperselected disease, ie, / wild-type, PRESSING-negative, and microsatellite stable.
Among 162 hyperselected patients, 24 (15%) had PRESSING2 alterations, which were mutually exclusive except in two samples and were numerically higher in right-sided versus left-sided cancers (28% 13%; = .149). Independently of sidedness and other factors, patients with PRESSING2-positive status had significantly worse progression-free survival and overall survival compared with PRESSING2-negative ones (median progression-free survival 6.4 12.8 months, adjusted hazard ratio 4.19 [95% CI, 2.58 to 6.79]; median overall survival: 22.6 49.9 months, adjusted hazard ratio 2.98 [95% CI, 1.49 to 5.96]). The combined analysis of primary tumor sidedness and PRESSING2 status allowed us to better stratify outcomes.
Negative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with and wild-type, microsatellite stable mCRC.
除了 和 BRAFV600E 突变之外，几种罕见的基因组改变会导致转移性结直肠癌（mCRC）对表皮生长因子受体（EGFR）的原发性耐药。我们的 PRESSING 面板（包括 外显子 20// 突变、/扩增、基因融合和微卫星不稳定高状态）代表了一种负超选择的范例，通过更精确地调整 EGFR 阻断来实现。然而，一小部分经过超选择的 mCRC 可能具有内在的耐药性，这可能是由更罕见的基因组改变驱动的。
意大利三所学术医院的前瞻性数据集包括 650 名接受 FoundationOne CDx 全面基因组分析并接受抗 EGFR 治疗的 mCRC 患者。根据先前的临床生物学研究选择了 PRESSING2 面板改变，包括 、 、 、//、 致病性突变；/ 缺失； 、 、 、 、 、 和 扩增；以及 重排。这些改变与超选择疾病（即 / 野生型、PRESSING 阴性和微卫星稳定）患者的结局相关。
在 162 名超选择患者中，24 名（15%）存在 PRESSING2 改变，除了两个样本外，这些改变是相互排斥的，并且右半结肠癌的发生率高于左半结肠癌（28% 比 13%； =.149）。独立于侧别和其他因素，与 PRESSING2 阴性患者相比，PRESSING2 阳性患者的无进展生存期和总生存期显著更差（中位无进展生存期 6.4 比 12.8 个月，调整后的危险比 4.19[95%CI，2.58 至 6.79]；中位总生存期：22.6 比 49.9 个月，调整后的危险比 2.98[95%CI，1.49 至 5.96]）。对原发肿瘤侧别和 PRESSING2 状态的联合分析使我们能够更好地分层结局。
负超选择需要进一步研究，旨在最大限度地提高 EGFR 阻断策略在 / 野生型、微卫星稳定 mCRC 患者中的获益。
