JP2019162138A - 少なくとも7個の遺伝子のサインを用いて、固形癌を患う患者の生存期間および処置に対する応答性を予測するための方法 - Google Patents
少なくとも7個の遺伝子のサインを用いて、固形癌を患う患者の生存期間および処置に対する応答性を予測するための方法 Download PDFInfo
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Abstract
Description
本発明は、固形癌を患う患者の生存期間および応答性を予測するための方法およびキットに関する。
癌は依然として先進国において深刻な公衆衛生上の問題である。従って、癌処置は、最も効果的であるために、悪性腫瘍の早期検出および処置または除去だけではなく、悪性腫瘍の重篤度の信頼性のある評価および癌再発の可能性の予測を必要とする。癌のステージはどれだけ遠くに癌が広がっているかを示す。処置は癌のステージに従って決定されることが多いので、ステージ分類は重要である。現在まで、癌は、一般的に、UICC−TNMシステムに従って分類されている。TNM(「腫瘍−所属リンパ節−転移」)分類システムは、腫瘍のサイズ、所属リンパ節における腫瘍の有無、および遠隔転移の有無を使用して、腫瘍にステージを割り当てる。TNMシステムは、原発部位に小さな腫瘍を有する患者は、より大きなサイズの腫瘍を有する患者よりも良好な予後を有するという観察から開発された。一般的に、原発部位に限局された腫瘍を有する患者は、所属リンパ節にも併発している患者よりも良好な予後を有し、また所属リンパ節併発患者は、他の臓器まで疾病が遠隔に広がった患者よりも良好な予後を有する。従って、癌は一般的に4つのステージに分けることができる。ステージIは、リンパ節に癌を全く有さない非常に限局された癌である。ステージIIの癌は、原発臓器により深く広がっている(典型的にはT3、T4腫瘍)。ステージIIIの癌は、リンパ節にまで広がっている。ステージIVの癌は、生体の別の部分にまで広がっている。割り当てられたステージは、適切な療法の選択のためのおよび予後診断目的のための基礎として使用される。例えば、ステージIVの癌を有する患者には常に化学療法が推奨される。逆に、UICC−TNMステージIIまたはIIIの癌を有する患者に化学療法を処方するための関連するガイドラインは全くない。従って、多数の利用可能な新規な療法のための重要な工程が適切な癌療法のための効率的な患者の選択であるため一層、処置の決定を導く信頼性ある診断ツールが必要とされる。
上記のTNM分類は、有用であるが不完全であり、癌の転帰の信頼性ある予後診断を可能としない。近年、Galon et al.は、腫瘍内の適応的免疫応答に関連した遺伝子発現の分析は、患者における癌の転帰を予測するのに適切であり得ることを示唆した(国際公開公報第2007/045996号)。従って、彼らは、癌の進行について患者の予後診断のために有用であり得る、遺伝子およびその組合せのリストを提供する。しかしながら、前記文書に示された方法は、癌患者の生存期間の予測のためにおよび患者の処置に対する応答を予測するためにTNM分類が提供するよりも、より良好な成績を与える特定の遺伝子の組合せを指摘できていない。
本発明は、固形癌を患う患者の生存期間および応答性を予測するための方法およびキットに関する。
国際特許出願の国際公開公報第2007045996号は、遺伝子間の組合せを考慮せずに選択された、腫瘍の微小環境を説明する一般的に選択された最も重要な遺伝子(〜300個)に関する。サインの数を限定するために、患者コホートに対する100回の交差検定後でも高度にログランクで有意であった、僅か7〜21個の遺伝子が使用された。前記遺伝子は、CCR2、CD3D、CD3E、CD3G、CD8A、CXCL10、CXCL11、GZMA、GZMB、GZMK、GZMM、IL15、IRF1、PRF1、STAT1、CD69、ICOS、CXCR3、STAT4、CCL2およびTBX2からなる群より選択される。例えば、国際特許出願の国際公開公報第2007045996号に記載された300中約21個の遺伝子の非重複サインの見込まれる数は、1.0×1037個を超える。本発明者らは、同定された21個の遺伝子のサインは、UICC−TNM分類が与えるよりも大きな感度および選択性を与えることを実証する。本発明者らは、種々の癌の上のサインを検証する。さらに、本発明者らは、同じサインが、処置に対する患者の応答を予測するのに適切であることを実証した。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 決定された少なくとも1つの発現レベル値がその予め決定された値よりも高い場合には中度の予後を与える工程、
を含む、固形癌を患う患者の生存期間を予測するための方法に関する。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 決定された少なくとも1つの発現レベル値がその予め決定された値よりも高い場合には中度の予後を与える工程、
を含む、固形癌を患う患者の生存期間を予測するための方法に関する。
− CCR2(ELCCR2)の発現レベルを決定し、前記レベルをCCR2(ELRCCR2)について予め決定された参照レベルと比較する工程、
− CD3D(ELCD3D)の発現レベルを決定し、前記レベルをCD3D(ELRCD3D)について予め決定された参照レベルと比較する工程、
− CD3E(ELCD3E)の発現レベルを決定し、前記レベルをCD3E(ELRCD3E)について予め決定された参照レベルと比較する工程、
− CD3G(ELCD3G)の発現レベルを決定し、前記レベルをCD3G(ELRCD3G)について予め決定された参照レベルと比較する工程、
− CD8A(ELCD8A)の発現レベルを決定し、前記レベルをCD8A(ELRCD8A)について予め決定された参照レベルと比較する工程、
− CXCL10(ELCXCL10)の発現レベルを決定し、前記レベルをCXCL10(ELRCXL10)について予め決定された参照レベルと比較する工程、
− CXCL11(ELCXCL11)の発現レベルを決定し、前記レベルをCXCL11(ELRCXCL11)について予め決定された参照レベルと比較する工程、
− GZMA(ELGZMA)の発現レベルを決定し、前記レベルをGZMA(ELRGZMA)について予め決定された参照レベルと比較する工程、
− GZMB(ELGZMB)の発現レベルを決定し、前記レベルをGZMB(ELRGZMB)について予め決定された参照レベルと比較する工程、
− GZMK(ELGZMK)の発現レベルを決定し、前記レベルをGZMK(ELRGZMK)について予め決定された参照レベルと比較する工程、
− GZMM(ELGZMM)の発現レベルを決定し、前記レベルをGZMM(ELRGZMM)について予め決定された参照レベルと比較する工程、
− IL15(ELIL15)の発現レベルを決定し、前記レベルをIL15(ELRIL15)について予め決定された参照レベルと比較する工程、
− IRF1(ELIRF1)の発現レベルを決定し、前記レベルをIRF1(ELRIRF1)について予め決定された参照レベルと比較する工程、
− PRF1(ELPRF1)の発現レベルを決定し、前記レベルをPRF1(ELRPRF1)について予め決定された参照レベルと比較する工程、
− STAT1(ELSTAT1)の発現レベルを決定し、前記レベルをSTAT1(ELRSTAT1)について予め決定された参照レベルと比較する工程、
− CD69(ELCD69)の発現レベルを決定し、前記レベルをCD69(ELRCD69)について予め決定された参照レベルと比較する工程、
− ICOS(ELICOS)の発現レベルを決定し、前記レベルをICOS(ELRICOS)について予め決定された参照レベルと比較する工程、
− CXCR3(ELCXCR3)の発現レベルを決定し、前記レベルをCXCR3(ELRCXCR3)について予め決定された参照レベルと比較する工程、
− STAT4(ELSTAT4)の発現レベルを決定し、前記レベルをSTAT4(ELRSTAT4)について予め決定された参照レベルと比較する工程、
− CCL2(ELCCL2)の発現レベルを決定し、前記レベルをCCL2(ELRCCL2)について予め決定された参照レベルと比較する工程、
− TBX21(ELTBX21)の発現レベルを決定し、前記レベルをTBX21(ELRTBX21)について予め決定された参照レベルと比較する工程。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 決定された少なくとも1つの発現レベル値がその予め決定された値よりも高い場合には中度の予後を与える工程、
を含む、乳癌を患う患者の生存期間を予測するための方法に関する。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 決定された少なくとも1つの発現レベル値がその予め決定された値よりも高い場合には中度の予後を与える工程、
を含む、乳癌を患う患者の生存期間を予測するための方法に関する。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 少なくとも1つの発現の場合には中度の予後を与える工程、
を含む、子宮頸癌を患う患者の生存期間を予測するための方法に関する。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 少なくとも1つの発現の場合には中度の予後を与える工程、
を含む、肝細胞癌を患う患者の生存期間を予測するための方法に関する。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 少なくとも1つの発現の場合には中度の予後を与える工程、
を含む、肺癌を患う患者の生存期間を予測するための方法に関する。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 少なくとも1つの発現の場合には中度の予後を与える工程、
を含む、黒色腫を患う患者の生存期間を予測するための方法に関する。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 少なくとも1つの発現の場合には中度の予後を与える工程、
を含む、卵巣癌を患う患者の生存期間を予測するための方法に関する。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 少なくとも1つの発現の場合には中度の予後を与える工程、
を含む、卵巣癌を患う患者の生存期間を予測するための方法に関する。
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、
− 工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または
− 決定された少なくとも1つの発現レベル値がその予め決定された値よりも高い場合には中度の予後を与える工程、
を含む、膵臓癌を患う患者の生存期間を予測するための方法に関する。
ベルとして適切である、サイズに基づいて異なる波長(565nm、655nm、705nm、または800nmの発光波長)で発光する量子ドットは、Life Technologies (Carlshad, Calif.)から入手可能である。
a)癌を患う患者の腫瘍組織サンプルの収集物を準備する工程;
b)工程a)で準備された収集物に含まれる各腫瘍組織サンプルについての遺伝子発現レベルを決定する工程;
c)前記発現レベルに従って腫瘍組織サンプルを順位付けする工程;
d)その発現レベルに従って順位付けされたそれぞれ増加しているメンバー番号、減少しているメンバー番号の部分集合の対に、前記腫瘍組織サンプルを分類する工程;
e)工程a)で準備した各腫瘍組織サンプルについて、対応する癌患者についての実際の臨床転帰に関する情報(すなわち、無病生存期間(DFS)または全生存期間(OS)またはその両方)を準備する工程;
f)腫瘍組織サンプルの各部分集合対について、生存曲線のカプランマイヤー率を得る工程;
g)腫瘍組織サンプルの各部分集合対について、両方の部分集合間の統計学的有意性(p値)を計算する工程;
h)発現レベルの参照値として、p値が最も小さい発現レベル値を選択する工程。
材料および方法
患者およびデータベース:
1996年から2004年までの間にLaennec-HEGP病院でその腫瘍の初回切除を受けた結腸直腸癌(CRC)患者の記録が、論評され、以前に記載されていた(Galon et al. 2006)。十分なRNAの品質および量を有する、1996年から2004年までのLaennec-HEGP病院から入手可能な凍結腫瘍サンプルが選択された(検証コホート1、n=108)。分析したRNAサンプルは108人の異なる患者からのものであった。これらの患者は、遺伝子発現実験のために使用された(Taqmanコホート)。コホートの観察時間は診断から最後の接触(死亡または最後のフォローアップ)までの時間であった。データは、再発または死亡しなかった患者については最後のフォローアップ時に検討されていた。進行/死亡または最後のフォローアップまでの最低:最高値は、それぞれ、(0:136)か月であった。フォローアップデータが入手できなかった3人の患者は、生存分析から除外された。再発までの期間または無病期間は、再発患者については手術日から確定腫瘍再発日までの区間として、無病患者については手術日から最後のフォローアップ日までの時間として定義された。
組織サンプルは、手術後15分以内に急速凍結され、液体窒素中に保存されていた。十分なRNAの品質および量を有する、Laennec-HEGP病院から入手可能な無作為に選択された患者の凍結腫瘍サンプル(コホート1、n=108)を、遺伝子発現分析のために選択した。分析したRNAサンプルは108人の異なる患者からのものであった。全RNAを、RNeasy分離キット(Qiagen, Valencia, CA)による均質化によって分離した。RNAの完全性および量を、バイオアナライザー2100(Agilent Technologies, Palo Alto, CA)で評価した。RT−PCR実験を、製造業者の説明書(Applied-Biosystems, Foster City, CA)に従って実施した。定量的リアルタイムTaqMan−PCRを、低密度アレイおよび7900ロボット化リアルタイムPCR装置(Applied-Biosystems)を使用して実施した。18SリボソームRNAプライマーおよびプローブが、内部対照として使用された。遺伝子発現分析は、18SリボソームRNAに規準化されたCt値(閾値サイクル)を使用して実施された(ΔCt)。データは、SDSソフトウェアv2.2(Applied-Biosystems)およびTME統計モジュールを使用して分析された。
本発明者らは、腫瘍サンプルにおける遺伝子CCR2、CD3D、CD3E、CD3G、CD8A、CXCL10、CXCL11、GZMA、GZMB、GZMK、GZMM、IL15、IRF1、PRF1、STAT1、CD69、ICOS、CXCR3、STAT4、CCL2およびTBX2の発現レベル(EL)を決定した。予め決定された参照値(ELR)は、国際公開公報第2007045996号およびJerome Galon, et al. (Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome Science 313, 1960 (2006); DOI: 10.1126/science.1129139)に従って以前に決定された。その後、本発明者らは、以下のようにスコアを構築した:0個の遺伝子が、その予め決定された参照値よりも高いその発現レベルを有する場合にはI0(すなわち、全ての遺伝子が、その予め決定された参照値よりも低いその発現レベルを有する)、n子の遺伝子がそのそれぞれの予め決定された参照値よりも高いその発現レベルを有する場合にはIn(I1−I21)。結果の解釈を明瞭にするために、本発明者らは患者を2つの群に分ける:I0−I10のスコアを有する患者については「低いレベル」、I11−I21のスコアを有する患者については「高いレベル」。その後、2つの患者群についてのKM曲線を描いた。結果を図1〜6に示す。本発明者らは、患者(非転移性患者または転移性患者)のステージがどのようなものであろうとも、スコアが高くなればなるほど、患者の生存期間が長くなると判定した(図1、3および4)。興味深いことに、非転移性結腸直腸癌について、本発明者らは、高いスコアを有する患者は、有利なことに、低いスコアを有する患者と比較して化学療法剤による処置の恩恵を受けると判定した(図2)。逆に、転移性結腸直腸癌については、本発明者らは、低いスコアを有する患者は、有利なことに、低いスコアを有する患者と比較して化学療法剤による処置の恩恵を受けると判定した(図4)。より興味深いことには、初期の進行非転移性結腸直腸癌(ステージII)について、本発明者らは、高いスコアを有する患者は、有利なことに、低いスコアを有する患者と比較して化学療法剤による処置の恩恵を受けると判定した(図6)。従って、化学療法剤に適格である患者を選択するためのガイドラインが現在全く存在しない前記カテゴリーの患者について、同定されたサインは、患者が有利には化学療法剤による処置を受けるかどうかを決定するのに非常に役立つであろう。
実施例1で同定された21個の遺伝子のサインは、乳癌、子宮頸癌、肝細胞癌、肺癌、黒色腫、卵巣癌または膵臓癌を患う患者の生存期間を予測するために検証された(例えば、図7、12、14および16を参照されたい)。少なくとも7個の遺伝子の最小のサインも決定された(図8、9、10、11、13、15、17、18および19を参照されたい)。
図20は、ステージIB−IIIVの肺癌患者(NSCLC)を示し、「Hi」な適応的免疫遺伝子サインを有する患者は、延長された生存期間を有し、化学療法による処置を必要としない(化学療法による処置により恩恵を全く受けない)。化学療法による処置の有意で有益な効果は、「Lo」な適応的免疫遺伝子サインを有する患者で観察され得る。
本出願全体を通して、種々の参考文献が、本発明が属する技術分野の最新技術を記載している。これらの参考文献の開示は、本開示への参照によって本明細書に組み入れられる。
Claims (1)
- i)患者から得られた腫瘍サンプルにおいて、CCR2、CD3D、CD3E、CD3G、CD8A、CXCL10、CXCL11、GZMA、GZMB、GZMK、GZMM、IL15、IRF1、PRF1、STAT1、CD69、ICOS、CXCR3、STAT4、CCL2およびTBX21からなる群より選択された少なくとも7個の遺伝子の遺伝子発現レベルを決定する工程、ii)工程i)で決定されたあらゆる発現レベルを、その予め決定された参照値と比較する工程、およびiii)工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも高い場合には良好な予後を与える工程、または、工程i)で決定された全ての発現レベルが、その予め決定された参照値よりも低い場合には悪い予後を与える工程、または決定された少なくとも1つの発現レベル値がその予め決定された値よりも高い場合には中度の予後を与える工程を含む、固形癌を患う患者の生存期間を予測するための方法。
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DK2872646T3 (en) | 2017-12-04 |
US20220259665A1 (en) | 2022-08-18 |
EP2872646B1 (en) | 2017-08-30 |
WO2014009535A3 (en) | 2014-04-17 |
JP2015528698A (ja) | 2015-10-01 |
EP2872646A2 (en) | 2015-05-20 |
US20150203919A1 (en) | 2015-07-23 |
ES2648176T3 (es) | 2017-12-28 |
JP6936277B2 (ja) | 2021-09-15 |
NO2872646T3 (ja) | 2018-01-27 |
PL2872646T3 (pl) | 2018-03-30 |
JP6923291B2 (ja) | 2021-08-18 |
US11242564B2 (en) | 2022-02-08 |
JP2021166539A (ja) | 2021-10-21 |
JP7378443B2 (ja) | 2023-11-13 |
WO2014009535A2 (en) | 2014-01-16 |
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