抗がん剤治療中にliquid biopsyを行うと・・・・・

liquid biopsyというのは造語である。あたかも採血で腫瘍マーカーを測るように、血清からDNAシークエンスにより腫瘍遺伝子変異を検索する技術のことをいう。

５症例に19回 liquid biopsyを試み、以下の薬剤で新たな変異遺伝子出現を見つけたとのレポートである。
以下の変異例は、これは症例報告であるから、絶対的なものではないが、抗がん剤治療に対し抵抗性のクローンが出現し始めるのを検出するのにいい指標にはなるかもしれない。Vogelsteinによる liquid biopsy研究では、画像イメージで再発が検出される前少なくとも６ヶ月には liquid biopsyは変化を示しているとのことであった。

1. an activating mutation in PIK3CA：paclitaxel⁸ 
2. a truncating mutation in RB1：cisplatin⁹ 
3. a truncating mutation in MED1 (mediator complex subunit 1)： tamoxifen and trastuzumab^{10, 11}and following subsequent treatment with lapatinib^{12, 13}　
4. a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient
5. a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) ： gefitinib¹⁴

こんなグラフがいくつも紹介される。この例は乳癌でエピルビシンからパクリタキセルに変えた前後のliquid biopsyプロフィル


Nature(2013) 
Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA

Muhammed Murtaza, Sarah-Jane Dawson & others, & Nitzan Rosenfeld 

Received 05 October 2012 
Accepted 11 March 2013 
Published online 07 April 2013 

Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection^{1, 2}. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity^{3, 4}. Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy^{5, 6, 7}. Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1–2 years. For each case, exome sequencing was performed on 2–5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel⁸; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin⁹; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab^{10, 11}, and following subsequent treatment with lapatinib^{12, 13}, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib¹⁴. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.