RNF43 突变预测 BRAFV600E 转移性结直肠癌对抗 BRAF/EGFR 联合疗法的反应,Nature Medicine

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RNF43 突变预测 BRAFV600E 转移性结直肠癌对抗 BRAF/EGFR 联合疗法的反应
Nature Medicine ( IF 58.7 ) Pub Date : 2022-09-12 , DOI: 10.1038/s41591-022-01976-z
Elena Elez _{1,

2} , Javier Ros _{1,

2,

3} , Jose Fernández ₂ , Guillermo Villacampa ₂ , Ana Belén Moreno-Cárdenas ₂ , Carlota Arenillas _{2,

4} , Kinga Bernatowicz ₂ , Raquel Comas ₂ , Shanshan Li ₅ , David Philip Kodack ₆ , Roberta Fasani ₂ , Ariadna Garcia ₂ , Javier Gonzalo-Ruiz ₂ , Alejandro Piris-Gimenez ₂ , Paolo Nuciforo ₂ , Grainne Kerr ₇ , Rossana Intini ₈ , Aldo Montagna ₈ , Marco Maria Germani ₉ , Giovanni Randon ₁₀ , Ana Vivancos ₂ , Ron Smits ₅ , Diana Graus _{7,

11} , Raquel Perez-Lopez _{2,

12} , Chiara Cremolini ₉ , Sara Lonardi ₈ , Filippo Pietrantonio ₁₀ , Rodrigo Dienstmann ₂ , Josep Tabernero _{1,

2,

4,

13} , Rodrigo A Toledo _{2,

4}

Affiliation

Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Institute of Health Carlos III (ISCIII), Madrid, Spain.
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.
Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Oncology Department, Novartis Institutes for Biomedical Research, Novartis, Basel, Switzerland.
Department of Oncology, Veneto Institute of Oncology IRCCS, Padova, Italy.
Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Department of Trans-lational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Ridgeline Discovery, Basel, Switzerland.
Radiology Department, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
UVic-UCC, IOB-Quirón, Barcelona, Spain.

抗 BRAF/EGFR 疗法最近被批准用于治疗转移性BRAF ^V600E结直肠癌 (mCRC ^BRAF-V600E )。然而，很大一部分患者没有反应，强调需要确定治疗反应的分子决定因素。在接受抗 BRAF/EGFR 治疗的mCRC ^BRAF-V600E患者的发现队列中使用全外显子组测序，我们发现RNF43中的失活突变（WNT 的负调节因子）预测微卫星患者的反应率和生存结果改善-稳定的 (MSS) 肿瘤。对独立验证队列的分析证实了RNF43突变与预测临床获益的相关性（72.7% 对 30.8%；P = 0.03），以及更长的无进展生存期（风险比 (HR)，0.30；95% 置信区间 (CI)，0.12–0.75；P = 0.01）和总生存期（HR，0.26；95% CI， 0.10–0.71；P = 0.008），在MSS- RNF43^突变与MSS- RNF43^野生型肿瘤患者中。微卫星不稳定肿瘤总是携带编码 p.G659fs 的野生型样RNF43基因型，并呈现中间反应谱。^{在 MSS-mCRC BRAF-V600E}患者的对照队列中，我们发现RNF43突变与患者结果没有关联未暴露于抗 BRAF 靶向治疗的肿瘤。总的来说，我们的研究结果表明 MAPK 和 WNT 通路之间的相互作用可能调节抗 BRAF/EGFR 疗法的抗肿瘤活性，并发现预测性生物标志物以优化这些患者的临床管理。

"点击查看英文标题和摘要"

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAF^V600E colorectal cancer (mCRC^BRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRC^BRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43^mutated versus MSS-RNF43^wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRC^BRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

更新日期：2022-09-13

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