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2015年12月14日 讯 /生物谷BIOON/ –近日，在举办的2015年圣安东尼奥乳癌研讨会(San Antonio Breast Cancer Symposium)上，来自耶鲁大学的研究人员表示，他们通过对人类基因组中2万个蛋白编码基因进行筛查，最终发现了耐药性背后的新型复杂性机制，同时还鉴别出了特殊的突变模式，来帮助预测疗法是否对恶性乳腺癌患者有效。
Her2阳性的乳腺癌是一种恶性乳腺癌，在所有乳腺癌病例中占到了20%，利用国际上多个中心进行的开放性随机III期临床试验（NeoALTTO）中的组织，研究人员对203份Her2阳性的乳腺癌样本进行测序来评估哪些基因突变可以帮助预测患者对Her2靶向疗法的反应或耐药性。
这项研究中研究者表示，患早期乳腺癌的患者在外科手术前利用紫杉酚化疗法结合两种乳腺癌药物（曲妥珠单抗或拉帕替尼）进行治疗，亦或者是仅利用药物进行治疗。Lajos Pusztai博士表示，关键的一点就是不同的癌症都会通过不同基因产生的不同突变来获得对曲妥珠单抗的耐药性，而目前唯一的希望就是这些基因可以参与日常的机体生化过程，而这所有的生化过程都是通过PIK3CA基因来进行的。
PIK3CA基因的突变被认为是机体对药物曲妥珠单抗较低敏感性的标志物，但最新的研究又将这种关联扩大到了更为广泛的基因网络，研究者们也鉴别出了一系列不同的基因，这些基因的突变和机体对拉帕替尼的较强敏感性直接相关，而所有基因都参与了机体名为RhoA激活的生化过程调节，该过程可以控制细胞的运动。
最后研究者总结道，调节性通路在水平上的改变或许会为科学家们提供更多的信息来作为预测性的标志物，而这远比单一的基因突变要有效地多。（基因宝jiyinbao.com）
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Pusztai L, Shi W, Jiang T, Nuciforo P, Holmes E, Harbeck N, Sotiriou C, Rimm D, Hatzis C, de la Peña L, Armour A, Piccart-Gebhart M, Baselga J. Yale University, New Haven, CT; Vall d’Hebron Institute of Oncology, Barcelona, Spain; Frontier Science (Scotland) Ltd; University of Munich; Jules Bordet Institute; Memorial Sloan Kettering Cancer Center; SOLTI Clinical Trial Group; Novartis
Background: We examined if alterations in nucleic acid variants, genes, pathways, and overall mutational load and clonal entropy are associated with pathologic complete response (pCR) and survival after neoadjuvant anti-HER2 therapies in the NeoALTTO trial.
Methods: Whole exome sequencing was performed of 203 baseline biopsies with outcome information. The mean nucleotide coverage was 150x with >90% of target bases showing > 30x coverage in > 99% of samples. Somatic mutations were called by MuTect and indels by Strelka, using pooled reference normal DNA. Significantly mutated genes (FDR<10%) were identified by MutSigCV. Mutations in 714 canonical biological pathways were assessed and mutational load and genome clonal entropy (MATH) were calculated. Association with pCR and survival were evaluated by logistic regression adjusted for ER status and Cox-proportional hazards regression.
Results: Only 12 genes had mutation rates significantly above background and among these only PI3KCA was associated with lower pCR rate (OR=0.42, p=0.019). Genes with somatic mutations in more than 10 patients were also assessed, but none were associated with pCR or survival. Clonal entropy or adjusted mutation load also did not correlate with response. Mutations in 33 pathways showed significant association with response in the entire cohort. In the trastuzumab arm, 23 of the 33 pathways showed an association with response but none was independent of PIK3CA mutation. We constructed “PIK3CA-gene network” that included all unique genes (n=439) from theese 23 pathways. Of the 66 patients in the trastuzumab arm, 50 carried at least one mutation in one of the 439 genes and among these only 2 achieved pCR (4%) compared to 9 of 16 pCR (56%) among the wild type (OR=0.035; p < 0.001). The same genes/mutations had little impact on pCR in the lapatinib arm (pCR 20%). In the lapatinib arm, mutations in 3 pathways conferred higher probability of pCR. The “Regulation of RhoA activity” pathway, had the most significant association with pCR in the entire cohort (OR=3.77, p=0.0009) and in the lapatininb (pCR 67% vs 17%, OR=14.8, p=0.008) and lapatinib + trastuzumab (OR=3.0, p=0.06) arms, but not in the trastuzumab arm (OR=1.4, p=0.7). Event free and overall survival were also significantly higher in patients who had mutations in this pathway. Twenty seven of the 48 genes in this pathway had mutations affecting 33 patients but different genes were affected in different individuals.
Conclusions: There are no high frequency recurrent single mutations associated with response to HER2-targeted therapies, other than PIK3CA. We identified several biological pathways, including RhoA activity, and a network of PIK3CA associated genes that are significantly associated with response when affected by mutations, however, different genes are mutated in different individuals.