Chen Dawei, Huang Xuesong, Cai Jie, Guo Sheng, Qian Wubin, Wery Jean-Pierre, Li Qi-Xiang
Crown Bioscience, Inc., Santa Clara, CA 95054, USA.
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
Oncotarget. 2015 Dec 1;6(38):40815-21. doi: 10.18632/oncotarget.5886.
Cetuximab is a standard of care for treating EGFR-expressing metastatic colorectal carcinoma (mCRC) exclusive of those with KRAS mutations at codons 12/13. However, retrospective analysis has recently suggested that KRAS-G13D patients can still benefit, while only a fraction of KRAS wild-type patients can benefit, from the treatment. We set out to test this contradicting issue experimentally in an independent cohort of patient derived xenograft (PDX) diseases. We conducted a mouse clinical trial (MCT) enrolling a random cohort of 27 transcriptome sequenced CRC-PDXs to evaluate cetuximab activity. The treatment responses were analyzed against the KRAS 12/13 mutation alleles, as well as several other well-known oncogenic alleles. If the response is defined by >80% tumor growth inhibition, 8/27 PDXs (30%) are responders versus 19/27 non-/partial responders (70%). We found that indeed there are no significantly fewer KRAS-12/13-allele responders (4/8 or 50%) than non-/partial responders (7/19, or 37%). In particular, there are actually no fewer G13D responders (4/8, or 50%) than in non-/partial responders (2/19 or 10.5%) statistically. Furthermore, majority of the non-/partial responders tend to have certain activating oncogenic alleles (one or more of the following common ones: K/N-RAS-G12V/D, -A146T, -Q61H/R, BRAF-V600E, AKT1-L52R and PIK3CA-E545G/K). Our data on an independent cohort support the recent clinical observation, but against the current practiced patient stratification in the cetuximab CRC treatment. Meanwhile, our data seem to suggest that a set of the six-oncogenic alleles may be of better predictive value than the current practiced stratification, justifying a new prospective clinical investigation on an independent cohort for confirmation.
西妥昔单抗是治疗表达表皮生长因子受体（EGFR）的转移性结直肠癌（mCRC）的标准疗法，但不包括那些在第12/13密码子处有KRAS突变的患者。然而，最近的回顾性分析表明，KRAS - G13D患者仍能从该治疗中获益，而只有一小部分KRAS野生型患者能从中受益。我们着手在一个独立的患者来源异种移植（PDX）疾病队列中通过实验来验证这一矛盾问题。我们进行了一项小鼠临床试验（MCT），纳入了27个经转录组测序的结直肠癌PDX的随机队列，以评估西妥昔单抗的活性。针对KRAS 12/13突变等位基因以及其他几个知名的致癌等位基因分析了治疗反应。如果将反应定义为肿瘤生长抑制>80%，则27个PDX中有8个（约30%）为反应者，19个（约70%）为非/部分反应者。我们发现，KRAS - 12/13等位基因反应者（4/8或50%）确实并不比非/部分反应者（7/19或37%）明显少。特别是，从统计学上看，G13D反应者（4/8或50%）实际上并不比非/部分反应者（2/19或10.5%）少。此外，大多数非/部分反应者往往有某些激活致癌等位基因（以下常见的一种或多种：K/N - RAS - G12V/D、- A146T、- Q61H/R、BRAF - V600E、AKT1 - L52R和PIK3CA - E545G/K）。我们在一个独立队列中的数据支持了最近的临床观察结果，但与西妥昔单抗治疗结直肠癌目前实行的患者分层方法相悖。同时，我们的数据似乎表明，一组六个致癌等位基因可能比目前实行的分层方法具有更好的预测价值，这为在一个独立队列中进行新的前瞻性临床研究以进行验证提供了依据。
