The nationwide cancer genome screening project in Japan, SCRUM-Japan GI-SCREEN: Efficient identification of cancer genome alterations in advanced colorectal cancer

Yuki, Satoshi; Kato, Takeshi; Taniguchi, H.; Hamaguchi, Tetsuya; Akagi, Kiwamu; Denda, T.; Mizukami, Takuro; Oki, Eiji; Yamada, Takaaki; Shiozawa, Manabu; Kudo, Takashi; Tamura, Takao; Esaki, Taito; Naruge, D.; Kajiwara, T.; Nomura, Shosaku; Fujii, Satoshi; Shitara, K.; Ohtsu, A.; Yoshino, T.

doi:10.1093/annonc/mdx393.092

Cited by 4 publications

(2 citation statements)

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“…In addition, several studies reported that BRAF-mutated CRC patients were more frequently observed in Caucasian than Asian or African American individuals [33][34][35][36]. Indeed, the prevalence of BRAF-mutated CRC was relatively low (6.4%) in the Japanese Nationwide Cancer Genome Screening Project (SCRUM-Japan), compared to those of large-scale studies mainly conducted in Western countries (8-12%) [3,37]. It is known that there are distinctive features in the metastatic site between BRAF V600E -mutated CRC and others.…”

Section: Distinctive Characteristics Of Braf-mutated Crc: Molecular Amentioning

confidence: 99%

BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

Nakayama

Hirota

Shinozaki

2020

Cancers

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The Raf murine sarcoma viral oncogene homolog B (BRAF) mutation is detected in 8–12% of metastatic colorectal cancers (mCRCs) and is strongly correlated with poor prognosis. The recent success of the BEACON CRC study and the development of targeted therapy have led to the determination of BRAF-mutated mCRCs as an independent category. For nearly two decades, a growing body of evidence has established the significance of the BRAF mutation in the development of CRC. Herein, we overview both basic and clinical data relevant to BRAF-mutated CRC, mainly focusing on the development of treatment strategies. This review is organized into eight sections, including clinicopathological features, molecular features, prognosis, the predictive value of anti-epidermal growth factor receptor (EGFR) therapy, resistant mechanisms for BRAF-targeting treatment, the heterogeneity of the BRAF mutation, future perspectives, and conclusions. A characterization of the canonical mitogen-activated protein kinase (MAPK) pathway is essential for controlling this malignancy, and the optimal combination of multiple interventions for treatments remains a point of debate.

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Section: Distinctive Characteristics Of Braf-mutated Crc: Molecular Amentioning

confidence: 99%

BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

Nakayama

Hirota

Shinozaki

2020

Cancers

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“…In a preclinical study with cell lines positive for HER2 amplification, this agent manifested a pronounced antitumor effect on neighboring HER2‐negative cells, a so‐called “bystander killing effect”. However, the frequency of HER2 amplification in metastatic CRC was found to be only 2.8% in a Japanese cohort and 5.2% in an Italian cohort wild type for KRAS , suggesting that few CRC patients would benefit from treatment strategies that target HER2 amplification. On the other hand, the frequency of HER2 protein overexpression in CRC is much higher (up to 47.4%) than that of HER2 amplification .…”

Section: Introductionmentioning

confidence: 99%

[fam‐] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification

Takegawa

Tsurutani

Kawakami

et al. 2019

Intl Journal of Cancer

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Therapies targeted to human epidermal growth factor receptor 2 (HER2) have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for the treatment of tumors that express HER2 protein in the absence of HER2 amplification. [fam‐] trastuzumab deruxtecan (DS‐8201a) is a novel antibody–drug conjugate composed of the anti‐HER2 antibody and the topoisomerase I inhibitor, an exatecan derivative. It has shown efficacy against tumors that express HER2 and is currently under evaluation in clinical trials. We here show that the antitumor activity of [fam‐] trastuzumab deruxtecan is dependent on the expression level of HER2 protein in colorectal cancer (CRC) cell lines negative for HER2 amplification. We established isogenic CRC cell lines that express various levels of HER2 protein in the absence of HER2 amplification, and we found that cells that express HER2 at a high level were sensitive to [fam‐] trastuzumab deruxtecan but not to conventional HER2‐targeted therapies. Furthermore, [fam‐] trastuzumab deruxtecan manifested a bystander killing effect both in vitro and in vivo, with cells essentially negative for HER2 expression also being killed in the presence of HER2‐expressing cells, an effect that has the potential to overcome heterogeneity of HER2 expression in CRC tumors. Our results thus suggest that [fam‐] trastuzumab deruxtecan warrants further study as a potential treatment for CRC tumors that express HER2 protein in the absence of HER2 amplification.

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Temporal dynamics from phosphoproteomics using endoscopic biopsy specimens provides new therapeutic targets in stage IV gastric cancer

Hirano

Abe

Nojima

et al. 2022

Sci Rep

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Phosphoproteomic analysis expands our understanding of cancer biology. However, the feasibility of phosphoproteomic analysis using endoscopically collected tumor samples, especially with regards to dynamic changes upon drug treatment, remains unknown in stage IV gastric cancer. Here, we conducted a phosphoproteomic analysis using paired endoscopic biopsy specimens of pre- and post-treatment tumors (Ts) and non-tumor adjacent tissues (NATs) obtained from 4 HER2-positive gastric cancer patients who received trastuzumab-based treatment and from pre-treatment Ts and NATs of 4 HER2-negative gastric cancer patients. Our analysis identified 14,622 class 1 phosphosites with 12,749 quantified phosphosites and revealed molecular changes by HER2 positivity and treatment. An inhibitory signature of the ErbB signaling was observed in the post-treatment HER2-positive T group compared with the pre-treatment HER2-positive T group. Phosphoproteomic profiles obtained by a case-by-case review using paired pre- and post-treatment HER2-positive T could be utilized to discover predictive or resistant biomarkers. Furthermore, these data nominated therapeutic kinase targets which were exclusively activated in the patient unresponded to the treatment. The present study suggests that a phosphoproteomic analysis of endoscopic biopsy specimens provides information on dynamic molecular changes which can individually characterize biologic features upon drug treatment and identify therapeutic targets in stage IV gastric cancer.

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The nationwide cancer genome screening project in Japan, SCRUM-Japan GI-SCREEN: Efficient identification of cancer genome alterations in advanced colorectal cancer

Cited by 4 publications

References 0 publications

BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

[fam‐] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification

Temporal dynamics from phosphoproteomics using endoscopic biopsy specimens provides new therapeutic targets in stage IV gastric cancer

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