最新研究发现：基因网络或通路表达水平变化，与单一基因突变相比，可更精准地预测早期乳腺癌术前新辅助靶向疗法的有效性和耐药性。
2016年9月29日，欧洲肿瘤内科学会官方期刊、牛津大学出版社旗下《肿瘤学年鉴》在线发表美国耶鲁大学、西班牙瓦尔德西布伦肿瘤学研究所、英国前沿科学、德国慕尼黑大学、比利时布鲁塞尔自由大学、西班牙乳腺癌协作组、澳大利亚彼得·麦卡勒姆癌症中心、巴西莫伊尼奥斯德万托医院、加拿大不列颠哥伦比亚癌症中心、英国国家卫生研究院临床研究中心、日本京都大学医院、德国基尔大学医院、美国诺华、美国纽约纪念斯隆-凯特林癌症中心的研究报告，通过对人类基因组中2万个蛋白质编码基因进行筛查，最终发现耐药背后复杂的新机制，同时还确定了有助于预测靶向疗法对恶性乳腺癌患者是否有效的特殊突变模式。
该研究利用国际多中心大规模非盲随机Ⅲ期新辅助研究（NeoALTTO）的203份HER2阳性乳腺癌活检标本，通过全外显子组测序，评估哪些基因突变有助于预测患者对HER2靶向疗法的有效性和耐药性。NeoALTTO研究的早期乳腺癌患者在外科手术前随机接受紫杉醇化疗和靶向疗法（曲妥珠单抗、拉帕替尼、曲妥珠单抗＋拉帕替尼）治疗。
HER2阳性乳腺癌是一种恶性乳腺癌，约占所有乳腺癌病例的20%。曲妥珠单抗是针对HER2阳性乳腺癌的主要靶向药物之一，但是不同的乳腺癌患者可能通过不同的基因产生不同的突变对曲妥珠单抗耐药，这些基因可能参与人体正常生长过程，而这些生物过程都通过PIK3CA基因进行。
已知PIK3CA基因突变是人体对曲妥珠单抗敏感性较低的标志物（比值比=0.42, P=0.0185），该研究又将这种相关性扩大到更广泛的基因网络，并确定了一系列不同的基因，这些基因的突变与人体对靶向药物敏感性有直接相关性，而且其中所有基因都参与RhoA活性调节通路。
该研究发现：
714个通路其中33个突变与疗效有显著相关性，但是在不同的个体受到影响的基因不同。
PIK3CA存在于其中23个通路，包括459个基因（曲妥珠单抗耐药网络）。
“曲妥珠单抗耐药网络”突变病例与未突变病例相比，对曲妥珠单抗的病理学完全缓解（pCR）率低（2/50比9/16，4%比56%，比值比=0.035，P＜0.001）。
“RhoA活性调节通路”突变与pCR率较高有相关性：拉帕替尼（比值比=14.8，校正P=0.001）、拉帕替尼＋曲妥珠单抗（比值比=3.0，校正P=0.09）、所有治疗组（比值比=3.77，校正P=0.02）。
在“曲妥珠单抗耐药网络”突变但RhoA通路完整的124例患者中，单用曲妥珠单抗的41例pCR率为2%（1/41，比值比=0.026，P=0.001），曲妥珠单抗＋拉帕替尼的38例pCR率提高至45%（17/38，比值比=1.68，P=0.3）。
在基因均无突变的46例患者中，单用拉帕替尼的15例pCR率为6%（1/15），单用曲妥珠单抗的15例pCR率为52%（8/15）。
因此，基因网络或通路突变与单一基因突变相比，可以更有效地预测靶向疗法效果。RhoA通路突变与拉帕替尼的pCR有显著相关性，PIK3CA相关基因网络突变与曲妥珠单抗的耐药有显著相关性。这两个通路联合突变的患者对单用曲妥珠单抗的有效率很低，可以通过加用拉帕替尼或换用拉帕替尼提高有效率。
Ann Oncol. 2016 Sep 29. [Epub ahead of print]
Pathway level alterations rather than mutations in single genes predict response to HER2 targeted therapies in the neo-ALTTO trial.
Shi W, Jiang T, Nuciforo P, Hatzis C, Holmes E, Harbeck N, Sotiriou C, Pena L, Loi S, Rosa DD, Chia S, Wardley A, Ueno T, Rossari J, Eidtmann H, Armour A, Piccart-Gebhart M, Rimm DL, Baselga J, Pusztai L.
Yale University, Yale Cancer Center, New Haven CT; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Frontier Science, Inverness, Scotland; University of Munich, Germany; Université Libre de Bruxelles, Brussels, Belgium; Spanish Breast Cancer Cooperative Group SOLTI, Barcelona, Spain; Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; Hospital Moinhos de Vento, Porto Alegre, RS, Brazil; BC Cancer Agency, Vancouver, Canada; The Christie/NIHR Clinical Research Facility, Manchester, UK; Kyoto University Hospital, Kyoto 606 8507, Japan; University Hospital Kiel, Kiel, Germany; Novartis, New York, New York; Memorial Sloan-Kettering Cancer Center, New York, New York.
BACKGROUND: We performed whole exome sequencing of pre-treatment biopsies and examined if genome-wide metrics of overall mutational load, clonal heterogeneity or alterations at variant, gene, and pathway levels are associated with treatment response and survival.
METHODS: 203 biopsies from the NeoALTTO trial were analyzed. Mutations were called with MuTect, and Strelka, using pooled normal DNA. Associations between DNA alterations and outcome were evaluated by logistic and Cox-proportional hazards regression.
RESULTS: There were no recurrent single gene mutations significantly associated with pCR, except PIK3CA (OR=0.42, p=0.0185). Mutations in 33 out of 714 pathways were significantly associated with response but different genes were affected in different individuals. PIK3CA was present in 23 of these pathways defining a "trastuzumab resistance-network" of 459 genes. Cases with mutations in this network had low pCR rates to trastuzumab (2/50, 4%) compared to cases with no mutations (9/16, 56%), OR=0.035; p < 0.001. Mutations in the "Regulation of RhoA activity" pathway were associated with higher pCR rate to lapatinib (OR=14.8, adjusted P=0.001), lapatinib + trastuzumab (OR=3.0, adjusted P=0.09), and all arms combined (OR=3.77, adjusted P=0.02). Patients (n=124) with mutations in the trastuzumab resistance-network but intact RhoA pathway had 2% (1/41) pCR rate with trastuzumab alone (OR=0.026, p=0.001) but adding lapatinib increased pCR rate to 45% (17/38, OR=1.68, p=0.3). Patients (n=46) who had no mutations in either gene set had 6% pCR rate (1/15) with lapatinib, but had the highest pCR rate, 52% (8/15) with trastuzumab alone.
CONCLUSIONS: Mutations in the RhoA pathway are associated with pCR to lapatinib and mutations in a PIK3CA related network are associated with resistance to trastuzumab. The combined mutation status of these two pathways could define patients with very low response rate to trastuzumab alone that can be augmented by adding lapatinib or substituting trastuzumab with lapatinib.
KEYWORDS: Breast Cancer NeoALTTO trial; PIK3CA related network; Regulation of RhoA activity; Whole Exome Sequencing
PMID: 27687302
PII: mdw434
DOI: 10.1093/annonc/mdw434
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