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2022年5月

2022年05月のまとめ。

臓器横断的なKRAS G12Cの頻度に関する網羅的な解析

Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers | JCO Precision Oncology
PURPOSE Promising single-agent activity from sotorasib and adagrasib in KRASG12C-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking. MATERIALS AND METHODS Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRASG12C comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers. RESULTS Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRASG12C and 12,126 (88.1%) harboring other KRAS variants (KRASnon-G12C). Compared with KRASnon-G12C across all tumor subtypes, KRASG12C was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR-P] = .0006), current or prior smokers (85% v 56%, FDR-P < .0001), and patients age > 60 years (73% v 63%, FDR-P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRASG12C was most prevalent in patients with non–small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRASnon-G12C-mutated, KRASG12C-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR-P < .0001). KRASG12C-mutated tumors exhibited a distinct comutation profile from KRASnon-G12C-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR-P < .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR-P < .01). CONCLUSION This study presents the first large-scale, pan-cancer genomic characterization of KRASG12C. The KRASG12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRASG12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.
https://ascopubs.org/doi/full/10.1200/PO.21.00245

大腸癌のctDNAの転移部位別解析

Effects of Metastatic Sites on Circulating Tumor DNA in Patients With Metastatic Colorectal Cancer | JCO Precision Oncology
PURPOSE Low concordance between plasma-based and tissue-based tests for determining the RAS mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology. MATERIALS AND METHODS We investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315). RESULTS Of 1,187 patients with mCRC enrolled in GOZILA, 138 were eligible (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only metastases). The concordance of RAS/BRAF status between Guaradant360 and tissue in vitro diagnostic tests was 95.9% in patients with liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only metastases. ctDNA fraction, as measured by the median maximum variant allelic fraction (max VAF), and median number of detected variants were 23.1% and five in liver-only, 6.0% and five in lymph node-only, 0.4% and three in peritoneum-only, and 0.4% and three in lung-only metastases, respectively (all P < .001, Kruskal-Wallis test). Few patients with liver-only (2.0%) and lymph node-only metastasis (13.3%) had a max VAF < 0.2%, which is required to ensure a detection limit of 95%, but max VAF was more frequently < 0.2% in patients with lung-only (27.7%) or peritoneum-only metastasis (29.6%). CONCLUSION Patients with lung-only and peritoneum-only metastatic disease have significantly lower levels of ctDNA, suggesting decreased clinical sensitivity for subclonal variants. This observation suggests that such patients may benefit from concurrent tissue and plasma testing to provide optimal genotyping for subsequent therapy selection.
https://ascopubs.org/doi/abs/10.1200/PO.21.00535

BRAF変異大腸癌はCA19-9/CEA比が高い

BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer - PubMed
To date, this is the first report utilizing the ratio of tumor markers CA19-9/CEA as a predictive rather than just prognostic tool to identify BRAF-V600E MSS and MSI-High CRC patients.
https://pubmed.ncbi.nlm.nih.gov/32399264/

Let me shamelessly self promote the
“KASI”formula🔢 that I’ve found helpful in identifying the subsets of #colorectalcancer #CRCSM early:

🧬BRAFV600E MSS 🆚 MSI-High 🆚 Others. Simple, rapid, & cheap👇🏾

✅ CA19-9➗CEA ratio

💡Small but novel finding. https://t.co/4fccZ3RAfN pic.twitter.com/wghlVNXF98

— Pashtoon Kasi MD, MS (@pashtoonkasi) May 21, 2022

リンチ症候群患者の正常大腸上皮に遺伝子変異が蓄積しているか

Mutational landscape of normal epithelial cells in Lynch Syndrome patients - Nature Communications
It is unclear whether somatic mutation rates are elevated in Lynch Syndrome (LS), which is the most common cause of hereditary colorectal cancer. Here, the authors use whole-genome sequencing and organoid cultures to show that normal tissues in LS patients are genomically stable, while ancestor cells of neoplastic tissues undergo multiple cycles of clonal evolution.
https://www.nature.com/articles/s41467-022-29920-2

第3世代EGFR・ALK阻害剤に関する薬剤耐性獲得に関するレビュー

Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management - Nature Reviews Clinical Oncology
Patients with non-small-cell lung cancers (NSCLCs) harbouring oncogenic EGFR or ALK alterations can benefit from therapies targeting these alterations, although acquired resistance to these agents is common. Third-generation inhibitors have extended the response durations of many patients with NSCLCs harbouring these alterations, albeit with differing patterns of resistance to those associated with earlier-generation agents. Here, the authors describe the mechanisms of acquired resistance to third-generation EGFR and ALK inhibitors and provide insights into future research directions in this area.
https://www.nature.com/articles/s41571-022-00639-9

まだ全部読めていません。あとで読む。

新規承認薬は真に患者に有用性をもたらしているか

An appraisal of FDA approvals for adult solid tumours in 2017–2021: has the eagle landed? - Nature Reviews Clinical Oncology
In this Perspective, Nathan Cherny appraises the FDA approvals of therapeutic agents granted for use in adult patients with solid tumours during the 5 years 2017–2021 against the aspirations of the Cancer Moonshot, in terms of sheer number of approvals, the strength of the supporting evidence and the magnitude of clinical benefit. He also outlines areas where improvements are needed to more confidently ensure that the clinical benefits of approved treatments justify the associated risks.
https://www.nature.com/articles/s41571-022-00636-y

2017~2021年にFDAが承認した固形腫瘍に用いる抗がん剤161製品のうち、明確なOS延長が認められてるのは27%しかなかった。同時にESMO-MCBSで評価したら、明らかな臨床的ベネフィットがあるものは3割くらい、とFDAを煽ってる。 https://t.co/aLNcHcVGlL

— уон (@Yoh_tw) May 9, 2022

オキサリプラチン末梢神経障害に対する予防的手指冷却(結果に難あり)

Multicenter randomized controlled trial to evaluate the efficacy and tolerability of frozen gloves for the prevention of chemotherapy-induced peripheral neuropathy - PubMed
NL39650.015.12.
https://pubmed.ncbi.nlm.nih.gov/31912787/

セツキシマブの隔週投与法に関するメタ解析

Efficacy and Safety of Cetuximab Dosing (biweekly vs weekly) in Patients with KRAS Wild-type Metastatic Colorectal Cancer: A Meta-analysis - PubMed
This meta-analysis demonstrated no significant differences in efficacy and safety between Q2W versus Q1W cetuximab administration in mCRC patients.
https://pubmed.ncbi.nlm.nih.gov/35522557/

2021年4月にFDAがmCRCに対するCETのq2w,500mg/m2を承認した根拠は開発初期のP1試験、PPKに加えてRWDや過去の研究を再解析したもので、q2wとq1wを直接比較したP3はない。CRYSTALと5つのP2でメタ解析したらq2wがq1wとで有効性、安全性に明らかな差は示されなかったというもの。 https://t.co/HLnxVJH7R8

— уон (@Yoh_tw) May 10, 2022

臨床試験へのアクセスを改善するために(コメント)

Increase Access to Clinical Trials
Urge Congress to Support the DIVERSE Trials Act
https://asco.quorum.us/campaign/39559/

アクセプトされた論文はSNSで宣伝すると閲覧者が増える

Impact of Tweeting Summaries by the Japanese Circulation Society Official Account on Article Viewership ― Pilot Trial ―
Access full-text academic articles: J-STAGE is an online platform for Japanese academic journals.
https://www.jstage.jst.go.jp/article/circj/86/4/86_CJ-21-0944/_article

我々のパイロット研究によれば、Twitter投稿により、論文閲覧数は情報する可能性があり、その効果は特に投稿当日に顕著です

By 水野篤 @atmizu

https://t.co/Z4BHhhHGvF

#circ_j pic.twitter.com/FtKziUTfye

— 日本循環器学会 情報広報部会 (@JCIRC_IPR) May 9, 2022

インターネットに溢れるがんにまつわるウソ情報から真実を見出だす

Online Medical Misinformation in Cancer: Distinguishing Fact From Fiction | JCO Oncology Practice
It is without question that the Internet has democratized access to medical information, with estimates that 70% of the American population use it as a resource, particularly for cancer-related information. Such unfettered access to information has led to an increase in health misinformation. Fortunately, the data indicate that health care professionals remain among the most trusted information resources. Therefore, understanding how the Internet has changed engagement with health information and facilitated the spread of misinformation is an important task and challenge for cancer clinicians. In this review, we perform a meta-synthesis of qualitative data and point toward empirical evidence that characterizes misinformation in medicine, specifically in oncology. We present this as a call to action for all clinicians to become more active in ongoing efforts to combat misinformation in oncology.
https://ascopubs.org/doi/abs/10.1200/OP.21.00764

20220331 JCOPO
インターネットに溢れるがんにまつわるウソ情報から真実を見出だすためのレビュー
個人的には真実で殴るタイプの人間ではないんだけど、ウソで儲けるのはよくないよね(全く説明になっていない) https://t.co/OYp5ZaNdYC

— じなん (@MTCOSB) April 1, 2022

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*1 Nat Genet 2021 https://www.nature.com/articles/s41588-021-00930-y
*2 https://www.biorxiv.org/content/10.1101/2021.04.14.437578v1

更新日:2022-05-28 閲覧数:615 views.