CN111684078A - 通过评价肿瘤遗传异质性来预测对治疗的应答的方法 - Google Patents
通过评价肿瘤遗传异质性来预测对治疗的应答的方法 Download PDFInfo
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Abstract
本发明是预测结肠直肠癌患者对治疗的响应的方法，该方法包括经由分析来自患者的样品的循环肿瘤DNA来测量肿瘤遗传异质性。
Description
发明领域
本发明涉及肿瘤学领域。更具体而言，本发明涉及癌症患者的基于核酸的测试领域。
发明背景
许多结肠直肠癌（CRC）患者在从较早期疾病进展后被诊断为转移性疾病。在那时，预后很差，并且有效治疗的最佳选择是至关重要的。目前，mCRC患者接受靶向抗EGFR治疗加上化学疗法（基于RAS野生型状态），或者所有来者对于抗血管生成加上化学疗法都是合格的。传统上，手术样本可以就突变的存在进行测试。现代诊断方法依赖于循环肿瘤DNA（ctDNA）中发现的突变，以预测肿瘤抗性和复发性。例如，抗性突变的突变体等位基因频率（AF）的增加指示了发展对特定靶向疗法的抗性。然而，需要从治疗前到治疗后的肿瘤进化的更一般评价，以便选择适当的治疗。
发明概述
在一些实施方案中，本发明是用于将癌症患者鉴定为可能积极响应治疗方案的方法，所述方法包括以下步骤：提供从患者获得的样品，其包括至少一种实体瘤样品和至少一种血浆样品；在样品中确定表1中列出的每种生物标记物的至少一部分的序列；确定生物标记物序列中的遗传异质性的量，所述异质性的量选自血浆回收率（PRR）、突变体等位基因肿瘤异质性（MATH）和多变体基因计数（MVGC）；如果遗传异质性的量低，则将患者鉴定为可能积极响应治疗方案；或如果遗传异质性的量高，则将患者鉴定为不太可能积极响应治疗方案。癌症可以是I、II、III或IV期的非小细胞肺癌（NSCLC）或结肠直肠癌（CRC）。对治疗的积极响应可以是增加的无进展存活（PFS）或增加的总体存活（OS）。治疗方案可以是同时或序贯的用FOLFOXIRI-贝伐珠单抗治疗和FOLFOX-贝伐珠单抗治疗。
在一些实施方案中，遗传异质性的量是组织-血浆一致性，其作为血浆回收率（PRR）、组织回收率（TRR）和Jaccard指数（JI）中的一种或多种进行测量。对于PRR，高异质性是PRR=0，低异质性是PRR=1，而中间异质性是0<PRR<1。PRR可以确定为共享血浆和匹配的组织变体与总血浆变体的比率。
在一些实施方案中，遗传异质性的量是突变体等位基因肿瘤异质性（MATH）。高异质性可能是高于中值、在顶部三分位数或顶部四分位数的MATH。MATH可以根据式1确定，或是例如根据式2确定的染色体加权的MATH（cwMATH）。
在一些实施方案中，遗传异质性的量是多变体基因计数（MVGC），并且高异质性是MVCG>0，而低异质性是MVGC=0。MVGC可以确定为具有多重突变的许多基因。
在一些实施方案中，在化学疗法过程前和在化学疗法后的多于一个时间点期间收集血浆样品，并且在时间点之间比较遗传异质性的量，并且如果比较检测到时间点之间的增加，则遗传异质性高。
在一些实施方案中，遗传异质性的量是例如在APC、TP53或FBXW7中基因截短的存在。基因截短的存在只能在治疗后血浆中进行测量。
在一些实施方案中，本发明是治疗II、III或IV期的非小细胞肺癌（NSCLC）或结肠直肠癌（CRC）患者的方法，其包括以下步骤：提供从患者获得的样品，其包括至少一种实体瘤样品和至少一种血浆样品；在样品中确定表1中列出的每种生物标记物的至少一部分的序列；确定生物标记物序列中的遗传异质性的量，所述异质性的量选自血浆回收率（PRR）、突变体等位基因肿瘤异质性（MATH）和多变体基因计数（MVGC）；如果遗传异质性的量低，则将患者鉴定为可能积极响应侵略性较小的治疗方案，并且施用侵略性较小的治疗方案；或如果遗传异质性的量高，则将患者鉴定为不太可能积极响应侵略性较小的治疗方案，并且施用侵略性较大的治疗方案。与侵略性较小的治疗方案相比，侵略性较大的治疗方案可以是更高剂量的治疗、一种或多种治疗剂的添加、以及延长的治疗持续时间。
在一些实施方案中，本发明是计算机系统，其设计为实施用于确定患者中的癌症遗传异质性的量的算法，其中所述算法分析关于从患者的样品获得的一种或多种生物标记物的测序数据，并且含有选自以下的一个或多个步骤：突变检测、突变频率得分、错误校正、样品是否为突变阳性的最终确定，以及确定选自以下的值的步骤：血浆回收率（PRR）、突变体等位基因肿瘤异质性（MATH）和多变体基因计数（MVGC），以确定癌症的遗传异质性。
在一些实施方案中，本发明是计算机系统，其设计为实施用于通过确定癌症的遗传异质性的量来选择用于癌症患者的治疗的算法，其中所述算法分析关于从患者的样品获得的一种或多种生物标记物的测序数据，并且含有选自以下的一个或多个步骤：突变检测、突变频率得分、错误校正、样品是否为突变阳性的最终确定，以及确定选自以下的值的步骤：血浆回收率（PRR）、突变体等位基因肿瘤异质性（MATH）和多变体基因计数（MVGC），以确定癌症的遗传异质性，并且如果遗传异质性高，则选择侵略性较大的治疗，且如果遗传异质性低，则选择侵略性较小的治疗。
在一些实施方案中，本发明是治疗II、III或IV期的非小细胞肺癌（NSCLC）或结肠直肠癌（CRC）患者的方法，其包括以下步骤：提供从患者获得的样品，其包括至少一种实体瘤样品和至少一种血浆样品；在样品中确定表1中列出的每种生物标记物的至少一部分的序列；确定血浆回收率（PRR），并且如果PRR高（例如=>0.8），则施用伊立替康，且如果PRR低（例如<0.8），则不施用伊立替康。
在一些实施方案中，本发明是治疗II、III或IV期的非小细胞肺癌（NSCLC）或结肠直肠癌（CRC）患者的方法，其包括以下步骤：提供从患者获得的样品，其包括至少一种实体瘤样品和至少一种血浆样品；在样品中确定表1中列出的每种生物标记物的至少一部分的序列；确定患者的样品中的遗传异质性的量；如果遗传异质性高，则施用转移靶向治疗。
附图简述
图1示出了治疗应答预测研究（STEAM试验）的设计。
图2是按血浆回收率（PRR）分组的患者的总体存活（OS）的Kaplan Meier图。
图3是按血浆回收率（PRR）分组的患者的无进展存活（PFS）的Kaplan Meier图。
图4是按治疗前测量的突变体等位基因肿瘤异质性（MATH）分组的患者的总体存活（OS）的Kaplan Meier图。
图5是按治疗后测量的突变体等位基因肿瘤异质性（MATH）分组的患者的总体存活（OS）的Kaplan Meier图。
图6是按治疗后检测到的基因截短突变的存在分组的患者的无进展存活（PFS）的Kaplan Meier图。
图7是按治疗后检测到的APC基因中的截短突变的存在分组的患者的无进展存活（PFS）的Kaplan Meier图。
图8是按治疗后测量的多变体基因计数（MVGC）分组的患者的总体存活（OS）的Kaplan Meier图。
图9是按治疗前和治疗后测量之间的基因计数（MVGC）中的增加分组的患者的总体存活（OS）的Kaplan Meier图。
图10是按具有0.8截止的血浆回收率（PRR）分组的患者的无进展存活（PFS）和总体存活（OS）的Kaplan Meier图。
图11是按具有0.8截止的PRR以及治疗方案分组的患者的无进展存活（PFS）和总体存活（OS）的Kaplan Meier图。
发明详述
定义
下述定义并非限制性的，而仅有助于理解本公开内容。
术语“PFS”在本文中用于描述患者的无进展存活时间。
术语“OS” 在本文中用于描述患者的总体存活时间。
术语“循环肿瘤DNA（ctDNA）” 在本文中用于描述在人血浆或血清中发现的源于肿瘤的一部分无细胞DNA（cfDNA）。循环肿瘤DNA通过肿瘤特有的突变与非肿瘤DNA区分开。
术语“生物标记物”在本文中用于描述含有与生物学或临床现象有关的信息的核苷酸序列。例如，该信息可以是核苷酸序列的突变状态。生物标记物可以是基因（包括编码序列、调节序列、内含子或剪接位点）或基因间区域。临床现象可能是患者的样品中恶性细胞，例如肿瘤细胞的存在。
本发明描述了选择用于非小细胞肺癌（NSCLC）患者、或结肠直肠癌（CRC）患者（包括转移性结肠直肠癌（mCRC）患者）的治疗方案的方法。
在一些实施方案中，本发明通过下一代测序（NGS），使用生物标记物实验对象组，以鉴定癌症相关基因中的体细胞突变和突变负担。在一些实施方案中，本发明利用了来自患者的血液或血液来源的样品。样品可以包括血液的任何级分，例如血清或血浆，其含有无细胞DNA，包括循环肿瘤DNA（cfDNA或ctDNA）。在一些实施方案中，在治疗期间的不同时间，例如在手术之前和之后，或者在化学治疗方案之前、之后和期间，连续获取样品。在一些实施方案中，肿瘤样品例如实体瘤样品用于与血液样品的比较。可以通过保存其中的DNA的合适手段，包括福尔马林固定石蜡包埋（FFPE）、新鲜的冷冻组织或在防腐介质中收集的血液组织，来收集固体组织或血液样品。
在一些实施方案中，本发明利用生物标记物实验对象组，包括基因实验对象组或突变实验对象组或体细胞变体实验对象组。如果突变发生在基因的编码区中，则突变可以包括对应于无义、错义和移码突变的单核苷酸变异（SNV）、缺失和插入（插入缺失（in-del））。其它类型的突变包括基因融合和易位。此类实验对象组的选择、大小和内容物已在例如美国专利申请序列号14/209,807、14/774,518以及名称为“Identification and Useof Circulating Tumor Markers”的国际申请号PCT/US2015/049838中进行描述。在一些实施方案中，本发明包括确定实验对象组中的生物标记物（例如表1中列出的基因）的序列。在一些实施方案中，确定基因的整个序列。在其它实施方案中，确定基因的整个编码序列。在其它实施方案中，仅确定已知在癌症中经历诱变的基因的一部分的序列。在另外其它实施方案中，生物标记物与编码序列不相关，但与调节序列或已知在人肿瘤中突变的未知功能的序列相关。
在本发明的上下文中，可以经由本领域已知的任何合适方法来确定生物标记物的序列。合适的方法将具有足够的准确度，例如灵敏度和特异性，以检测具有低错误率的稀有序列。在一些实施方案中，测序方法包括错误校正步骤，例如分子条形码的使用、错误定型（error stereotyping）和错误压制的其它化学或计算方法，如例如参见专利申请“Identification and Use of Circulating Tumor Markers”， 同上中所述。测序方法可以包括大规模平行测序方法，包括基于阵列的测序（Illumina，San Diego，Cal.）、基于乳液的测序（ThermoFisher，Waltham，Mass.）、基于光学测量的测序（Pacific BioSciences，Menlo Park，Cal.）、或基于纳米孔的测序（Roche Sequencing Solutions，Santa Clara，Cal.）。
在一些实施方案中，本发明利用生物标记物实验对象组，例如AVENIO® ctDNAAnalysis Kit（Roche Sequencing Solutions，Inc.，Pleasanton，Cal.），其能够分析患者的组织和血液，以鉴定且定量样品中的肿瘤特异性突变。AVENIO® ctDNA Analysis Kit中的生物标记物实验对象组（扩展实验对象组）的组成显示于表1中。AVENIO® ctDNAAnalysis Kit中的生物标记物实验对象组（监视实验对象组）的组成显示于表2中。
表1. 扩展生物标记物实验对象组的组成
| <i>APC</i> | <i>KRAS</i> | <i>ABL1</i> | <i>FGFR3</i> | <i>JAK3</i> | <i>RAF1</i> |
| <i>BRCA1</i> | <i>MET</i> | <i>AKT1</i> | <i>FLT1</i> | <i>KDR</i> | <i>RNF43</i> |
| <i>BRCA2</i> | <i>TP53</i> | <i>AKT2</i> | <i>FLT3</i> | <i>MAP2K1</i> | <i>TERT启动子</i> |
| <i>EGFR</i> | <i>KIT</i> | <i>ARAF</i> | <i>FLT4</i> | <i>MAP2K2</i> | <i>TSC1</i> |
| <i>ERBB2</i> | <i>NRAS</i> | <i>CDK6</i> | <i>GATA3</i> | <i>MTOR</i> | <i>TSC2</i> |
| <i>ALK</i> | <i>PDGFRA</i> | <i>CSF1R</i> | <i>GNA11</i> | <i>NFE2L2</i> | <i>PTEN</i> |
| <i>BRAF</i> | <i>RET</i> | <i>CTNNB1</i> | <i>GNAQ</i> | <i>NTRK1</i> | <i>RB1</i> |
| <i>DPYD</i> | <i>ROS1</i> | <i>DDR2</i> | <i>GNAS</i> | <i>PDGFRB</i> | <i>SMAD4</i> |
| <i>AR</i> | <i>MSH2</i> | <i>EZH2</i> | <i>IDH1</i> | <i>PIK3CA</i> | <i>SMO</i> |
| <i>CCND1</i> | <i>MSH6</i> | <i>FGFR1</i> | <i>IDH2</i> | <i>PIK3R1</i> | <i>STK11</i> |
| <i>CCND2</i> | <i>NF2</i> | <i>FGFR2</i> | <i>JAK2</i> | <i>PTCH1</i> | <i>VHL</i> |
| <i>CCND3</i> | <i>PDCD1LG2</i> | <i>CDK4</i> | <i>ESR1</i> | <i>KEAP1</i> | <i>UGT1A1</i> |
| <i>CD274</i> | <i>PMS2</i> | <i>CDKN2A</i> | <i>FBXW7</i> | <i>MLH1</i> | <i></i> |
表2. 监视生物标记物实验对象组的组成
| <i>ABCC5</i> | <i>CSMD1</i> | <i>FAT1</i> | <i>HTR1E</i> | <i>MAP7D3</i> | <i>PIK3CA</i> | <i>SV2A</i> |
| <i>ABCG2</i> | <i>CSMD3</i> | <i>FBN2</i> | <i>HTR2C</i> | <i>MKRN3</i> | <i>PIK3CG</i> | <i>T</i> |
| <i>ACTN2</i> | <i>CTNNB1</i> | <i>FBXL7</i> | <i>IFI16</i> | <i>MMP16</i> | <i>PKHD1L1</i> | <i>THSD7A</i> |
| <i>ADAMTS12</i> | <i>CTNND2</i> | <i>FBXW7</i> | <i>IL7R</i> | <i>MTX1</i> | <i>POLE</i> | <i>TIAM1</i> |
| <i>ADAMTS16</i> | <i>CYBB</i> | <i>FCRL5</i> | <i>INSL3</i> | <i>MYH7</i> | <i>POM121L12</i> | <i>TMEM200A</i> |
| <i>ARFGEF1</i> | <i>DCAF12L1</i> | <i>FOXG1</i> | <i>ITGA10</i> | <i>MYT1L</i> | <i>PREX1</i> | <i>TNFRSF21</i> |
| <i>ASTN1</i> | <i>DCAF12L2</i> | <i>FRYL</i> | <i>ITSN1</i> | <i>NAV3</i> | <i>PTPLA</i> | <i>TNN</i> |
| <i>ASTN2</i> | <i>DCAF4L2</i> | <i>GBA3</i> | <i>KCNA5</i> | <i>NEUROD4</i> | <i>RALYL</i> | <i>TNR</i> |
| <i>AVPR1A</i> | <i>DCLK1</i> | <i>GBP7</i> | <i>KCNB2</i> | <i>NFE2L2</i> | <i>RFX5</i> | <i>TRHDE</i> |
| <i>BCHE</i> | <i>DCSTAMP</i> | <i>GJA8</i> | <i>KCNC2</i> | <i>NLGN4X</i> | <i>RIN3</i> | <i>TRIM58</i> |
| <i>BPIFB4</i> | <i>DDI1</i> | <i>GPR139</i> | <i>KCNJ3</i> | <i>NLRP3</i> | <i>RNASE3</i> | <i>TRPS1</i> |
| <i>C6</i> | <i>DLGAP2</i> | <i>GRIA2</i> | <i>KCTD8</i> | <i>NMUR1</i> | <i>ROBO2</i> | <i>UGT3A2</i> |
| <i>C6orf118</i> | <i>DMD</i> | <i>GRIK3</i> | <i>KEAP1</i> | <i>NOL4</i> | <i>SEMA5B</i> | <i>USH2A</i> |
| <i>CA10</i> | <i>DNTTIP1</i> | <i>GRIN2B</i> | <i>KIAA1211</i> | <i>NPAP1</i> | <i>SLC18A3</i> | <i>USP29</i> |
| <i>CACNA1E</i> | <i>DOCK3</i> | <i>GRIN3B</i> | <i>KIF17</i> | <i>NR0B1</i> | <i>SLC39A12</i> | <i>VPS13B</i> |
| <i>CDH12</i> | <i>DSC3</i> | <i>GRM1</i> | <i>KIF19</i> | <i>NRXN1</i> | <i>SLC6A5</i> | <i>WBSCR17</i> |
| <i>CDH18</i> | <i>DSCAM</i> | <i>GRM5</i> | <i>KLHL31</i> | <i>NXPH4</i> | <i>SLC8A1</i> | <i>WIPF1</i> |
| <i>CDH8</i> | <i>EGFLAM</i> | <i>GRM8</i> | <i>KPRP</i> | <i>NYAP2</i> | <i>SLITRK1</i> | <i>WSCD2</i> |
| <i>CDH9</i> | <i>EPHA5</i> | <i>GSX1</i> | <i>LPPR4</i> | <i>OPRD1</i> | <i>SLITRK4</i> | <i>ZC3H12A</i> |
| <i>CDKN2A</i> | <i>EPHA6</i> | <i>HCN1</i> | <i>LRFN5</i> | <i>P2RY10</i> | <i>SLITRK5</i> | <i>ZFPM2</i> |
| <i>CHRM2</i> | <i>EYS</i> | <i>HCRTR2</i> | <i>LRP1B</i> | <i>PAX6</i> | <i>SLPI</i> | <i>ZIC1</i> |
| <i>CNTN5</i> | <i>FAM135B</i> | <i>HEBP1</i> | <i>LRRC7</i> | <i>PCDH15</i> | <i>SMAD4</i> | <i>ZIC4</i> |
| <i>CNTNAP2</i> | <i>FAM151A</i> | <i>HECW1</i> | <i>LRRTM1</i> | <i>PDYN</i> | <i>SOX9</i> | <i>ZNF521</i> |
| <i>CPXCR1</i> | <i>FAM5B</i> | <i>HS3ST4</i> | <i>LRRTM4</i> | <i>PDZRN3</i> | <i>SPTA1</i> | <i>ZSCAN1</i> |
| <i>CPZ</i> | <i>FAM5C</i> | <i>HS3ST5</i> | <i>LTBP4</i> | <i>PGK2</i> | <i>ST6GALNAC3</i> | <i>KIT</i> |
| <i>CRMP1</i> | <i>FAM71B</i> | <i>HTR1A</i> | <i>MAP2</i> | <i>PHACTR1</i> | <i>STK11</i> | <i>NRAS</i> |
| <i>APC</i> | <i>KRAS</i> | <i>ALK</i> | <i>PDGFRA</i> | <i>MET</i> | <i>BRAF</i> | <i>RET</i> |
| <i>BRCA1</i> | <i>BRCA2</i> | <i>TP53</i> | <i>DPYD</i> | <i>EGFR</i> | <i>ERBB2</i> | <i>UGT1A1</i> |
在一些实施方案中，使用表1中列出的77种基因的实验对象组。在一些实施方案中，使用表2中列出的197种基因的实验对象组。在一些实施方案中，在化学治疗之前、期间和之后的血浆样品中均确定突变状态，并且确定变化。在一些实施方案中，突变状态在化学治疗前的肿瘤样品中进行确定，并且与血浆样品的突变状态进行比较。
发明人已设计了使用基于血浆的肿瘤异质性的量来开出治疗方案的处方的方法。在一些实施方案中，治疗选自FOLFOXIRI或FOLFOX与贝伐珠单抗（BEV）的组合。在一些实施方案中，本发明是基于肿瘤遗传异质性，将治疗从侵略性较小的治疗改变为侵略性较大的治疗的方法。与侵略性较小的治疗方案相比，侵略性较大的治疗方案可以包括更高剂量的治疗、一种或多种治疗剂的添加、以及延长的治疗持续时间中的一种或多种。
本发明包括通过分析循环肿瘤DNA（ctDNA）中的体细胞突变的完整概况，来测量患者的样品中的遗传异质性的步骤。本发明人用称为ctDNA的突变(ctDNA-calledmutations)获得了出乎意料的良好预测结果。不预期受特定理论的束缚，本发明人假设出乎意料的良好预测结果是由于以下事实：ctDNA可能包含来自原发性肿瘤的多重区域和来自多重转移性肿瘤（包括仍无法检测的转移性肿瘤）的核酸。相比之下，现有方法利用代表单个肿瘤的单个区域的肿瘤活组织检查。在一些实施方案中，该方法包括比较来自相同患者的肿瘤和ctDNA中的遗传异质性的步骤。在一些实施方案中，该方法包括比较在治疗期间从相同患者和多个点收集的ctDNA样品中的遗传异质性的步骤。
在一些实施方案中，测量遗传异质性包括测量血浆-组织不一致性，其可以作为血浆回收率（PRR）、组织回收率（TRR）和Jaccard指数（JI）中的一种或多种进行测量。
在一些实施方案中，血浆-组织不一致性的量是血浆回收率（PRR）。PRR是共享血浆和匹配的组织变体与总血浆变体的比率。完全的血浆-组织不一致性和一致性分别定义为PRR=0和PRR=1。PRR为0意指在组织中未观察到血浆中观察到的变体，并且是异质性和快速癌症进化的强指标，即转移性克隆与原发性肿瘤并未共享任何变体。图2和3中显示了使用PRR的实例。
在另一个实施方案中，本发明是治疗方法。本发明人已评价了接受伊立替康的患者中的肿瘤遗传异质性（如PRR）。基于该评价，本发明包括用伊立替康治疗癌症患者的方法。该方法包括确定PRR的步骤。如果PRR高，则向患者施用伊立替康。
在另一个实施方案中，本发明是治疗处于转移性肿瘤的风险中的患者的方法，所述转移性肿瘤例如远侧的非肝转移性肿瘤。基于遗传异质性的评价，本发明包括癌症患者的靶向转移的治疗的方法。该方法包括确定遗传异质性的步骤，并且如果遗传异质性高，则施用靶向转移的治疗。在一些实施方案中，靶向转移的治疗是脑转移的照射。在一些实施方案中，靶向转移的治疗是施用生物膦酸盐，以减少由骨转移引起的骨折。参见Riihimaki等人，（2016）Patterns of metastasis in colon and rectal cancer，Scientific Reports第6卷，论文编号: 29765 doi:10.1038/srep29765。
在一些实施方案中，血浆-组织不一致性的量是组织回收率（TRR），共享血浆和匹配的组织变体与总组织变体的比率。在一些实施方案中，血浆-组织不一致性的量是Jaccard指数（Jaccard Index，JI），共享血浆和匹配的组织变体与血浆或组织中检测到的总变体的比率。
在一些实施方案中，测量遗传异质性包括测量基于血浆的等位基因级分分散度，其可以作为突变体-等位基因肿瘤异质性（MATH），包括染色体加权的MATH（cwMATH）以及从治疗前到治疗后的MATH或cwMATH中的变化进行测量。
在一些实施方案中，基于血浆的等位基因级分分散度的量是突变体-等位基因肿瘤异质性（MATH）。MATH是此处应用于血浆的变体等位基因频率分散度的量。MATH基本上是分布宽度与分布中心的比率，类似于变异系数，并且首先在Mroz，E. A. & Rocco，J. W.MATH，a novel measure of intratumor genetic heterogeneity，is high in poor- outcome classes of head and neck squamous cell carcinoma. Oral Oncology（2013）中定义。MATH根据式1进行计算。
式1：
MATH = 100 x MAD/中值（X）
MAD（中值绝对偏差）=中值（|Xi-中值（X）|）。
Xi是第i个变体的变体等位基因频率（VAF）
中值（X）是样品中的体细胞变体的所有VAF的中值。
MATH先前已使用关于具有匹配正常值的组织样品的完整外显子组测序数据应用于实体瘤。本发明人设计了使用没有匹配正常值的血浆样品的MATH的方法。本发明人发现，具有高血浆分散度（在顶部四分位数中的MATH）的患者具有较差的总体存活。使用MATH的实例显示于图4和5中。
在一些实施方案中，该方法包括调用体细胞相对于种系单核苷酸变体或多态性（SNV或SNP）的步骤。该方法进一步包括以下步骤：排除纯合的SNV（SNP），并且利用杂合的SNP（hetSNP）分布来计算本底异质性，以计算称为cwMATH的修饰得分。cwMATH校正了仅由拷贝数变化而非亚克隆性驱动的等位基因频率分散度。
在一些实施方案中，遗传异质性的量是根据式2确定的cwMATH。式2：
cwMATH = 100 x {中值（CWscale |Xi-中值（X）|）}/中值。
在一个实例中，CWscale和cwMATH使用下述步骤进行计算：
i. 按染色体的权重计算hetSNP与0.5的平均偏差（CWscale）。选择平均值代替中值，以捕获可以影响sSNV（体细胞SNV）AF的潜在局部CNV。平均偏差定义为平均值（abs（x-0.5）/0.5），其中x是hetSNP等位基因频率。x范围为0至1。CWscale是1 - 平均值（abs（x-0.5）/0.5），使得在具有与预期0.5较高的hetSNP偏差的染色体上的sSNV将在MATH计算中向回缩放至更接近于中值。
ii. 计算sSNV的中值AF。将此设为中值（sSNV.AF）。
iii. 使用CW缩放每个sSNV与中值的绝对偏差。换言之，ScaledMedianAbsDev =abs（sSNV.AF-中值（sSNV.AF））乘以（该chr的CWscale）。
iv. 获取sSNV绝对偏差的中值，除以中值sSNV AF，再乘以148.26（如MATH中）。在数学上，这是中值AbsDevMed = 1.4826 *中值（ScaledMedianAbsDev）和cwMATH = 100 *中值AbsDevMed/中值（sSNV.AF）。
在一些实施方案中，在MATH或cwMATH之前，将基于血浆的等位基因级分分散度的量修改为利用对数比例的等位基因级分或其它转化的等位基因级分。
在一些实施方案中，基于血浆的等位基因级分分散度的量是MATH或cwMATH从治疗前到治疗后的变化。
在一些实施方案中，测量遗传异质性包括测量作为多变体基因计数（MVGC）（血浆中具有多重突变的基因计数）测量的基因内变体异质性。由于异质性（亚克隆在相同基因中具有不同突变）或纯合的体细胞激活/失活，这个得分可以> 0（即，至少一种基因具有多于一个体细胞突变），指示癌症适应。MVGC是强大的总体测量，因为它不需要鉴定单一的抗性途径/基因/变体，而是捕获了癌症在遗传上适应治疗的潜力。使用MVGC的实例显示于图8上。
在一些实施方案中，测量遗传异质性包括测量MVGC从治疗前到治疗后的变化。使用MVGC中的变化的实例显示于图9上。
在一些实施方案中，测量遗传异质性包括测量基因中的截短突变。在一些实施方案中，基因包括TP53、FBXW7和APC中的一种或多种。在一些实施方案中，仅在没有实体瘤组织样品的血浆中测量基因截短。在一些实施方案中，仅在治疗后（诱导后）血浆中测量基因截短。使用截短突变的实例显示于图6和图7上。
在STEAM临床试验中，用AVENIO ctDNA Kit对CRC患者执行的ctDNA分析，揭示了测量基于血浆的肿瘤内异质性的潜在预后价值。本发明人发现诱导前，更大的组织-血浆不一致性和高血浆分散度与更短的存活相关联。诱导后，高血浆分散度和基因内异质性也与更短的存活相关联。诱导后血浆中的截短APC突变也与更短的存活相关联，并且可以是转移的生物标记物。相应地，在一些实施方案中，本发明是治疗患有癌症的患者的方法，其包括在通过测量PRR、MATH或MVGC中的一种或多种，评价肿瘤遗传异质性中的变化的步骤后，施用另外量的治疗剂（维持当前治疗）、或施用不同治疗剂的步骤。本发明的方法可以补充评价治疗功效的当前方法，包括血液癌胚抗原（CEA）水平中的变化、以及放射学评价的原发性肿瘤和转移灶的大小的变化。
实施例
实施例1. 使用转移性结肠直肠癌（mCRC）患者的无细胞肿瘤DNA和实体瘤DNA来检
测突变。
在该实施例中，使用了来自STEAM临床试验的样品。STEAM（NCT01765582）评估了同时（c）和序贯（s）的FOLFOXIRI-贝伐珠单抗（BEV）相对于FOLFOX-BEV用于mCRC的第一线治疗的功效和安全性。基于下一代测序的AVENIO® ctDNA Expanded and Surveillance Kits（Roche Sequencing Solutions，Pleasanton，Cal.）用于鉴定体细胞突变和突变负担。通过在组织以及诱导前和诱导后的血浆样品（分别为n = 182、150和118）中的下一代测序（NGS），使用Expanded Kit来分析77种癌症相关基因。Surveillance Kits用于概况分析在诱导前和诱导后的血浆样品中的197种癌症相关基因中的体细胞突变。
实施例2. 使用突变状态来确定肿瘤异质性。
如实施例1中所述，通过两种试剂盒检测的变体被聚集以计算肿瘤异质性。异质性作为组织-血浆不一致性，基于血浆的肿瘤内突变体等位基因级分分散度，基因间变体异质性和多重APC截短突变的存在进行测量。
基于血浆的肿瘤内异质性通过测量血浆-组织不一致性来计算，所述血浆-组织不一致性作为血浆回收率（PRR）（共享血浆和匹配的组织变体与总血浆变体的比率）进行测量。完全的血浆-组织不一致性和一致性分别定义为PRR=0和PRR=1。PRR为0意指在组织中未观察到血浆中观察到的变体，并且是异质性和快速癌症进化的强指标，即转移性克隆与原发性肿瘤并未共享任何变体。患者按PRR分组以评价存活（参见图2和3上的结果）。
基于血浆的等位基因级分分散度作为治疗前和治疗后的突变体-等位基因肿瘤异质性（MATH）进行测量。患者按MATH分组以评价存活（参见图4和5上的结果）。
基因内变体异质性作为多变体基因计数（MVGC）和MVGC从治疗前到治疗后的变化进行测量。（参见图8和9上的结果）。
特异性分子标记物中的变化作为任何基因或特异性地APC基因中的截短突变，以及截短突变数目从治疗前到治疗后的变化进行测量。（参见图6和7上的结果）。
具有完全的组织-血浆一致性（提示克隆性和有限的癌症进化）的受试者具有更长的PFS（18.3相对于9.5 mo，HR 0.43，对数轶p = 0.037）。完全的组织-血浆不一致性与非肝脏受限疾病具有一定关联（p = 0.0895），所述非肝脏受限疾病已知与预后较差有关（Riihimaki等人，Metastatic spread in patients with gastric cancer. Oncotarget.2016 Aug 9；7（32）:52307-52316）。具有高诱导前或诱导后血浆MATH的受试者具有较短的PFS（分别为8.1相对于11.7 mo，HR 1.8，对数轶p = 0.026；7.4相对于12.2 mo，HR 2.9，对数轶p = 0.00012）。对于OS可见类似趋势。具有诱导后的基因内血浆异质性的受试者也具有较短的OS，并且具有从诱导前到诱导后血浆MVGC中的增加的受试者具有较短的OS（14.8相对于26.4 mo，HR 4.6，对数轶p = 0.00029）。截短的APC突变与较短的PFS相关联（7.6相对于12.2 mo，HR 2.3，对数轶p = 0.0017），并且与高诱导后MATH显著相关（对数轶p =0.006），与遗传上多样的转移的积累一致。APC突变计数和转移潜力在原发性肿瘤中的作用已得到研究（Schell，M. J.等人A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC. Nat Commun. 2016 Jun15；7:11743），并且在这种背景下特别感兴趣的是，治疗后血浆样品中的新APC截短突变的积累似乎与转移扩散的进展速率相关联。
实施例3. 使用肿瘤异质性来确定治疗方案。
如实施例2中所述测量血浆回收率（PRR）。异质性定义为PRR<0.8（低）和PRR>＝0.8（高）（参见图10上的结果）。患者按PRR分组，且进一步按治疗方案分组：使用或不使用伊立替康，以评价作为PFS和OS的存活（图11）。基于结果（图11），伊立替康被指示用于高异质性（PRR高），而不被指示用于低异质性（PRR低）。
Claims (15)
1.一种用于将癌症患者鉴定为可能积极响应治疗方案的方法，所述方法包括以下步骤：
（a）提供从所述患者获得的样品，其包括至少一种实体瘤样品和至少一种血浆样品；
（b）在所述样品中确定表1中列出的每种生物标记物的至少一部分的序列；
（c）确定所述生物标记物序列中的遗传异质性的量，所述异质性的量选自血浆回收率（PRR）、突变体等位基因肿瘤异质性（MATH）和多变体基因计数（MVGC）；
（d）如果遗传异质性的量低，则将所述患者鉴定为可能积极响应治疗方案；或
（e）如果遗传异质性的量高，则将所述患者鉴定为不太可能积极响应治疗方案。
2.权利要求1的方法，其中所述癌症选自I、II、III和IV期的非小细胞肺癌（NSCLC）和结肠直肠癌（CRC）。
3.权利要求1的方法，其中对治疗的积极响应选自增加的无进展存活（PFS）和增加的总体存活（OS）。
4.权利要求1的方法，其中所述治疗方案选自用FOLFOXIRI-贝伐珠单抗的治疗和FOLFOX-贝伐珠单抗治疗。
5.权利要求1的方法，其中所述遗传异质性的量是组织-血浆一致性，其作为血浆回收率（PRR）、组织回收率（TRR）和Jaccard指数（JI）中的一种或多种进行测量。
6.权利要求1的方法，其中所述遗传异质性的量是突变体等位基因肿瘤异质性（MATH）。
7.权利要求9的方法，其中MATH是染色体加权的MATH（cwMATH）。
8.权利要求1的方法，其中所述遗传异质性的量是多变体基因计数（MVGC），并且高异质性是MVCG>0，而低异质性是MVGC=0。
9.权利要求1的方法，其中在化学疗法过程前和在化学疗法后的多于一个时间点期间收集血浆样品，并且在时间点之间比较遗传异质性的量。
10.权利要求1的方法，其中所述遗传异质性的量是基因截短的存在。
11.一种治疗II、III或IV期的非小细胞肺癌（NSCLC）或结肠直肠癌（CRC）患者的方法，其包括以下步骤：
（a）提供从所述患者获得的样品，其包括至少一种实体瘤样品和至少一种血浆样品；
（b）在所述样品中确定表1中列出的每种生物标记物的至少一部分的序列；
（c）确定所述生物标记物序列中的遗传异质性的量，所述异质性的量选自血浆回收率（PRR）、突变体等位基因肿瘤异质性（MATH）和多变体基因计数（MVGC）；
（d）如果遗传异质性的量低，则将所述患者鉴定为可能积极响应侵略性较小的治疗方案，并且施用所述侵略性较小的治疗方案；或
（e）如果遗传异质性的量高，则将所述患者鉴定为不太可能积极响应侵略性较小的治疗方案，并且施用所述侵略性较大的治疗方案。
12.一种计算机系统，其设计为实施用于确定患者中的癌症遗传异质性的量的算法，其中所述算法分析关于从所述患者的样品获得的一种或多种生物标记物的测序数据，并且含有选自以下的一个或多个步骤：突变检测、突变频率得分、错误校正、样品是否为突变阳性的最终确定，以及确定选自以下的值的步骤：血浆回收率（PRR）、突变体等位基因肿瘤异质性（MATH）和多变体基因计数（MVGC），以确定癌症的遗传异质性。
13.一种计算机系统，其设计为实施用于通过确定癌症的遗传异质性的量而选择用于癌症患者的治疗的算法，其中所述算法分析关于从所述患者的样品获得的一种或多种生物标记物的测序数据，并且含有选自以下的一个或多个步骤：突变检测、突变频率得分、错误校正、样品是否为突变阳性的最终确定，以及确定选自以下的值的步骤：血浆回收率（PRR）、突变体等位基因肿瘤异质性（MATH）和多变体基因计数（MVGC），以确定癌症的遗传异质性，并且如果遗传异质性高，则选择侵略性较大的治疗，且如果遗传异质性低，则选择侵略性较小的治疗。
14.一种治疗II、III或IV期的非小细胞肺癌（NSCLC）或结肠直肠癌（CRC）患者的方法，其包括以下步骤：
（a）提供从所述患者获得的样品，其包括至少一种实体瘤样品和至少一种血浆样品；
（b）在所述样品中确定表1中列出的每种生物标记物的至少一部分的序列；
（c）确定所述生物标记物序列中作为血浆回收率（PRR）的遗传异质性的量；
（d）如果PRR高，则施用伊立替康；或
（e）如果PRR低，则不施用伊立替康。
15.一种治疗II、III或IV期的非小细胞肺癌（NSCLC）或结肠直肠癌（CRC）患者的方法，其包括以下步骤：
（a）提供从所述患者获得的样品，其包括至少一种实体瘤样品和至少一种血浆样品；
（b）在所述样品中确定表1中列出的每种生物标记物的至少一部分的序列；
（c）确定所述患者的样品中的遗传异质性的量；
（d）如果遗传异质性高，则施用转移靶向治疗。
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| CN111100909A (zh) * | 2020-01-10 | 2020-05-05 | 信华生物药业(广州)有限公司 | 一种肿瘤内遗传异质性的计算方法 |
| CN114717319A (zh) * | 2022-04-19 | 2022-07-08 | 南京世和基因生物技术股份有限公司 | 用于胆管癌预后评估的基因标志物 |
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