JP7136697B2 - デンスブレストを有する女性における乳癌の検出のためのバイオマーカー - Google Patents
デンスブレストを有する女性における乳癌の検出のためのバイオマーカー Download PDFInfo
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Description
本出願は米国特許法§119(e)の下において、その全体が参照により本明細書に組み入れられる、2015年9月25日に出願された米国特許出願第62/233,010号の恩典を主張する。
本発明は、概して、癌の検出のための方法、より具体的には、デンスブレストを有する女性における乳癌の予測および診断のための方法に関連する。
疾患を早期に検出できる、ならびに/または、疾患の進行および再発をモニタリングできるバイオマーカーの研究においては懸命な努力がなされている。分子標的治療の出現によって、癌の生物学的サブタイプに関連するバイオマーカーが、治療的介入に対する反応を予測するために有用となる可能性がある。
[本発明1001]
以下の段階を含む、デンスブレスト組織を有する対象における乳癌を診断または予後予測するための方法であって、前記対象の乳房組織はデンスブレスト組織であると特徴付けられている、前記方法:
(a)対象由来のサンプル中における少なくとも1つのタンパク質バイオマーカーおよび少なくとも1つの自己抗体のレベルを測定する段階であって、該少なくとも1つのタンパク質バイオマーカーがVEGF、FasL、TNF-A、IL-8、IL-12、HGF、およびCEAより選択される、段階;ならびに
(b)腫瘍の存在を判定するために、前記対象の乳房組織の画像解析を行う段階。
[本発明1002]
前記サンプルが、腹水、血清、血漿、糞便、リンパ液、脳脊髄液、乳頭吸引液、または尿などの体液である、本発明1001の方法。
[本発明1003]
前記少なくとも1つのタンパク質バイオマーカーが、ERBB2、HGF、IFNG、IL6、OPN、VEGFC、VEGFD、ATF3、ATP6AP1、BDNF、CTBP1、DBT、EIF3E、FRS3、HOXD1、p53、PDCD6IP、RAC3、SELL、SF3A1、SOX2、TFCP2、TRIMP2、UBAP1、ZMYM6、IGF2PB2、MUC1、BAT4、BMX、C15orf48、CSNK1E、GPR157、MYOZ2、RAB5A、SERPINH1、SLC33A1、およびZNF510のうちの1つまたは複数をさらに含む、本発明1001の方法。
[本発明1004]
前記自己抗体が、RAC3、IGF2BP2、MUC1、ErbB2、ATP6AP1、PDCD6IP、DBT、CSNK1E、FRS3、HOXD1、SF3A1、CTBP1、C15orf48、MYOZ2、EIF3E、BAT4、ATF3、BMX、RAB5A、UBAP1、SOX2、GPR157、BDNF、ZMYM6、SLC33A1、TRIM32、ALG10、TFCP2、SERPINH1、SELL、ZNF510、またはp53に特異的に結合する、本発明1001の方法。
[本発明1005]
前記自己抗体がp53に特異的に結合し、かつ前記バイオマーカーが、VEGF、FasL、TNF-A、IL-8、IL-12、HGF、およびCEAのうちの少なくとも1つであるか、またはそれらの任意の組み合わせである、本発明1001の方法。
[本発明1006]
生検組織の組織学的解析をさらに含む、本発明1001の方法。
[本発明1007]
画像解析をさらに含む、本発明1001の方法。
[本発明1008]
前記少なくとも1つのタンパク質バイオマーカーのレベルが、タンパク質アレイ解析によって決定される、本発明1001の方法。
[本発明1009]
前記対象が哺乳動物である、本発明1001の方法。
[本発明1010]
哺乳動物がヒトである、本発明1001の方法。
[本発明1011]
治療薬または治療レジメンを前記対象に施す段階をさらに含む、本発明1001の方法。
[本発明1012]
治療レジメンを患者に処方する段階をさらに含む、本発明1001の方法。
[本発明1013]
(b)が、前記少なくとも1つのタンパク質バイオマーカーまたは前記少なくとも1つの自己抗体の発現産物を測定することを含む、本発明1001の方法。
[本発明1014]
前記発現産物が、タンパク質、マイクロRNA、またはmRNAである、本発明1013の方法。
[本発明1015]
腫瘍が良性である、本発明1001の方法。
[本発明1016]
腫瘍が癌性である、本発明1001の方法。
[本発明1017]
デンスブレスト組織を有すると前記対象を特徴付ける段階をさらに含む、本発明1001の方法。
[本発明1018]
以下の段階を含む、デンスブレスト組織を有する対象における乳癌を検出するための方法であって、前記対象の乳房組織はデンスブレスト組織であると特徴付けられている、前記方法:
(a)対象由来のサンプル中における少なくとも1つのタンパク質バイオマーカーおよび少なくとも1つの自己抗体のレベルを測定する段階であって、該少なくとも1つのタンパク質バイオマーカーがVEGF、FasL、TNF-A、IL-8、IL-12、HGF、およびCEAより選択される、段階;ならびに
(b)腫瘍の存在を判定するために、前記対象の乳房組織の画像解析を行う段階。
[本発明1019]
前記サンプルが、腹水、血清、血漿、糞便、リンパ液、脳脊髄液、乳頭吸引液、または尿などの体液である、本発明1018の方法。
[本発明1020]
前記少なくとも1つのタンパク質バイオマーカーが、ERBB2、HGF、IFNG、IL6、OPN、VEGFC、VEGFD、ATF3、ATP6AP1、BDNF、CTBP1、DBT、EIF3E、FRS3、HOXD1、p53、PDCD6IP、RAC3、SELL、SF3A1、SOX2、TFCP2、TRIMP2、UBAP1、ZMYM6、IGF2PB2、MUC1、BAT4、BMX、C15orf48、CSNK1E、GPR157、MYOZ2、RAB5A、SERPINH1、SLC33A1、およびZNF510のうちの1つまたは複数をさらに含む、本発明1018の方法。
[本発明1021]
前記自己抗体が、RAC3、IGF2BP2、MUC1、ErbB2、ATP6AP1、PDCD6IP、DBT、CSNK1E、FRS3、HOXD1、SF3A1、CTBP1、C15orf48、MYOZ2、EIF3E、BAT4、ATF3、BMX、RAB5A、UBAP1、SOX2、GPR157、BDNF、ZMYM6、SLC33A1、TRIM32、ALG10、TFCP2、SERPINH1、SELL、ZNF510、またはp53に特異的に結合する、本発明1018の方法。
[本発明1022]
前記自己抗体がp53に特異的に結合し、かつ前記バイオマーカーが、VEGF、FasL、TNF-A、IL-8、IL-12、HGF、およびCEAのうちの少なくとも1つであるか、またはそれらの任意の組み合わせである、本発明1018の方法。
[本発明1023]
生検組織の組織学的解析をさらに含む、本発明1018の方法。
[本発明1024]
画像解析をさらに含む、本発明1018の方法。
[本発明1025]
前記少なくとも1つのタンパク質バイオマーカーのレベルが、タンパク質アレイ解析によって決定される、本発明1018の方法。
[本発明1026]
前記対象が哺乳動物である、本発明1018の方法。
[本発明1027]
哺乳動物がヒトである、本発明1018の方法。
[本発明1028]
治療薬を前記対象に投与する段階をさらに含む、本発明1018の方法。
[本発明1029]
治療レジメンを患者に処方する段階をさらに含む、本発明1018の方法。
[本発明1030]
(b)が、前記少なくとも1つのタンパク質バイオマーカーまたは前記少なくとも1つの自己抗体の発現産物を測定することを含む、本発明1018の方法。
[本発明1031]
前記発現産物が、タンパク質、マイクロRNA、またはmRNAである、本発明1030の方法。
[本発明1032]
腫瘍が良性である、本発明1018の方法。
[本発明1033]
腫瘍が癌性である、本発明1018の方法。
[本発明1034]
デンスブレスト組織を有すると前記対象を特徴付ける段階をさらに含む、本発明1018の方法。
[本発明1035]
以下の段階を含む、乳癌を処置する治療レジメンに対する対象の感受性を判定するための、または、デンスブレスト組織を有する対象における乳癌の進行をモニタリングするための方法であって、前記対象の乳房組織はデンスブレスト組織であると特徴付けられている、前記方法:
(a)対象由来のサンプル中における少なくとも1つのタンパク質バイオマーカーおよび少なくとも1つの自己抗体のレベルを測定する段階であって、該少なくとも1つのタンパク質バイオマーカーがVEGF、FasL、TNF-A、IL-8、IL-12、HGF、およびCEAより選択される、段階;
(b)腫瘍の存在を判定するために、前記対象の乳房組織の画像解析を行う段階;ならびに
(c)治療レジメンまたは癌の進行を評価する段階。
[本発明1036]
前記治療レジメンが、化学療法剤の投与を含む、本発明1036の方法。
本発明は、乳癌に関連するバイオマーカーに関する。それは、特定のバイオマーカーを測定することによって癌、特に乳癌を予測、評価、診断、およびモニタリングする方法を提供する。血清タンパク質バイオマーカーを含むバイオマーカーとTAAbのセットによって、対象における乳癌の検出可能な分子シグニチャーが提供される。さらに、本出願はAAbとSPBを組み合わせることによって、いずれかのバイオマーカー単独の場合と比べて、良性のものと乳癌とを区別するより高い感度および特異度が提供されるという概念の証拠を明らかにするものである。
デンスブレストを有する女性における乳癌の検出
年齢に関連する多様性:848例の前向き収集された患者サンプルの後向き解析により、デンスブレストを有する女性における乳癌の検出についての組み合わせタンパク質バイオマーカーアッセイ(Combinatorial Protein Biomarker Assay)の有用性を判定する。
乳癌の正確な診断はしばしば、女性における良性乳房組織および高い乳腺密度の存在によって混乱させられる。しかし、乳癌に関連する生化学的(タンパク質)マーカーを検出する新しい技術の開発によって、検出の正確さが改善される可能性がある。解剖学的異常を特定する画像法とプロテオミクスのアプローチとを組み合わせることによって、強力な検出パラダイムの提供が約束される。さらに、プロテオミクスに基づくアプローチによって、逐年検診において乳癌を見落としてしまう主な原因であるデンスブレストを有する女性における乳癌を検出する強力なツールが提供される。乳癌の存在についてのタンパク質シグニチャーは理解しづらいままではあるが、ここで本発明者らは、血清タンパク質バイオマーカー(SPB)、腫瘍関連自己抗体(TAAb)を患者の臨床データと組み合わせる、組み合わせプロテオミクスバイオマーカーアッセイ(CPBA、Videssa(商標)Breast)の最適化について説明する。良性乳房疾患を浸潤性乳癌(IBC)/非浸潤性乳管癌(DCIS)と識別するためのVidessa(商標)Breastの臨床的妥当性を評価するために、2つの前向き無作為化多施設共同臨床試験が実施された。
乳癌の検出における最も大きな課題の1つは、乳房組織の密度である。通常の乳腺密度を有する女性と比較して、乳腺密度の高い女性は乳癌と診断される可能性が4~5倍高いが、それは現行の放射線学的スクリーニング法の公知の限界によるところが大きい。その結果、画像法の感度および特異度が低いことによって、患者や医療制度にとって不必要な負担となる偽陽性の結果の増加が導かれる。従って、IBC/DCISのような、臨床的に重要な疾患を確実に検出する、乳腺密度や病変サイズに非依存的な技術が非常に必要とされている。
848例の患者の解析によって、25~75歳の女性において高い感度およびNPVで良性乳房疾患を浸潤性乳癌(IBC)/DCISと区別する、(SPBとTAAbおよび患者データとを組み合わせた)組み合わせタンパク質バイオマーカーアッセイの能力が示される。
Claims (16)
- 以下の段階を含む、デンスブレスト組織を有する対象における乳癌の診断または予後予測を補助するための方法であって、前記対象の乳房組織はデンスブレスト組織であると特徴付けられている、前記方法:
(a)対象由来の血清または組織サンプルにおいて、FasL、TNF-A、またはFasLおよびTNF-Aを含むタンパク質バイオマーカーのセットにおけるタンパク質バイオマーカーのレベルと、自己抗体のレベルとを測定する段階であって、該自己抗体が、RAC3、IGF2BP2、MUC1、ERBB2、ATP6AP1、PDCD6IP、DBT、CSNK1E、FRS3、HOXD1、SF3A1、CTBP1、C15orf48、MYOZ2、EIF3E、BAT4、ATF3、BMX、RAB5A、UBAP1、SOX2、GPR157、BDNF、ZMYM6、SLC33A1、TRIM32、ALG10、TFCP2、SERPINH1、SELL、ZNF510、またはp53に特異的に結合する、段階;ならびに
(b)腫瘍の存在の判定を補助するために、前記対象の乳房組織の画像解析を行う段階。 - 複数のタンパク質バイオマーカーのレベルが測定される、請求項1に記載の方法。
- 複数の自己抗体のレベルが測定される、請求項1に記載の方法。
- 前記タンパク質バイオマーカーのセットが、ERBB2、HGF、IFNG、IL6、IL-8、IL-12、OPN、VEGF、VEGFC、VEGFD、ATF3、ATP6AP1、BDNF、CTBP1、DBT、EIF3E、FRS3、HOXD1、p53、PDCD6IP、RAC3、SELL、SF3A1、SOX2、TFCP2、TRIMP2、UBAP1、ZMYM6、IGF2PB2、MUC1、BAT4、BMX、C15orf48、CSNK1E、GPR157、MYOZ2、RAB5A、SERPINH1、SLC33A1、CEA、およびZNF510のうちの1つまたは複数をさらに含む、請求項2に記載の方法。
- 生検組織の組織学的解析をさらに含む、請求項1~4のいずれか一項に記載の方法。
- RAC3、IGF2BP2、MUC1、ERBB2、ATP6AP1、PDCD6IP、DBT、CSNK1E、FRS3、HOXD1、SF3A1、CTBP1、C15orf48、MYOZ2、EIF3E、BAT4、ATF3、BMX、RAB5A、UBAP1、SOX2、GPR157、BDNF、ZMYM6、SLC33A1、TRIM32、ALG10、TFCP2、SERPINH1、SELL、ZNF510、またはp53に特異的に結合する自己抗体のレベルが、測定される、請求項1~4のいずれか一項に記載の方法。
- 生検組織の組織学的解析をさらに含む、請求項6に記載の方法。
- p53に特異的に結合する自己抗体のレベルが測定され、かつタンパク質バイオマーカーのセットが、VEGF、IL-8、IL-12、HGF、およびCEAのうちの少なくとも1つを含む、請求項1~4のいずれか一項に記載の方法。
- 生検組織の組織学的解析をさらに含む、請求項8に記載の方法。
- 前記タンパク質バイオマーカーのセットにおけるタンパク質バイオマーカーのレベルが、タンパク質アレイ解析によって決定される、請求項1~4のいずれか一項に記載の方法。
- 前記対象が哺乳動物である、請求項1~4のいずれか一項に記載の方法。
- 哺乳動物がヒトである、請求項11に記載の方法。
- 前記タンパク質バイオマーカーのセットにおけるタンパク質バイオマーカーのレベルまたは前記自己抗体のレベルが、サンプル中のタンパク質またはmRNAの量を決定することによって測定される、請求項1~4のいずれか一項に記載の方法。
- 腫瘍が良性である、請求項1~4のいずれか一項に記載の方法。
- 腫瘍が癌性である、請求項1~4のいずれか一項に記載の方法。
- 前記サンプルが血清である、請求項1~4のいずれか一項に記載の方法。
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CN109752547A (zh) * | 2018-12-17 | 2019-05-14 | 杭州京北生物科技有限公司 | 一种乳腺癌自身免疫抗体检测试剂盒及其制备方法与应用 |
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