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Articles on Gastrointestinal Cancer

A selection of peer-reviewed articles on Gastrointestinal Cancer. All content available on the Advances in Gastrointestinal Cancer Resource Center, including original and review articles, interviews, guidelines and congress highlights, is independently selected by the members of the Editorial Board.


  • Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers

    Soo Young Cho , Jun Won Park , Yang Liu , Young Soo Park , Ju Hee Kim , Hanna Yang , Hyejin Um , Woo Ri Ko , Byung Il Lee , Sun Young Kwon , Seung Wan Ryu , Chae Hwa Kwon , Do Youn Park , Jae-Hyuk Lee , Sang Il Lee , Kyu Sang Song , Hoon Hur , Sang-Uk Han , Heekyung Chang , Su-Jin Kim , Byung-Sik Kim , Jeong-Hwan Yook , Moon-Won Yoo , Beom-Su Kim , In-Seob Lee , Myeong-Cherl Kook , Nina Thiessen , An He , Chip Stewart , Andrew Dunford , Jaegil Kim , Juliann Shih , Gordon Saksena , Andrew D. Cherniack , Steven Schumacher , Amaro-Taylor Weiner , Mara Rosenberg , Gad Getz , Eun Gyeong Yang , Min-Hee Ryu , Adam J. Bass , Hark Kyun Kim

    Gastroenterology, August 2017, Volume 153, Issue 2, Pages 536-549.e26

    Editorial comment by Dr Elizabeth Smyth:
    Non-familial early onset gastric cancer is often associated with diffuse histology, female gender and poor prognosis. In this Gastroenterology manuscript, Cho and co-authors explore the molecular profile of non-familial young onset diffuse gastric cancer and compare it to later onset diffuse gastric cancer in a large Korean dataset. They find that somatic mutations in CDH1 or TGFBR1 are more common in early onset diffuse gastric cancer whereas somatic mutations in RHOA are more common in patients with later onset diffuse gastric cancer. Both CDH1 alterations and RHOA were associated with increased nuclear β-catenin immunostaining, suggesting WNT pathway activation. Somatic mutations in CDH1 were associated with worse survival; this may account for the poor prognosis of patients with early onset diffuse gastric cancer.

    This work is the largest and most comprehensive analysis of early onset and diffuse gastric cancer to date, and suggests a rationale for the aggressive clinical behaviour of early onset diffuse gastric cancer. Although direct targeting of dysregulated CDH1 or RHOA signalling is not yet possible, CDH1 or RHOA dysregulated tumours may have other active pathways e.g. WNT which are suitable for therapeutic intervention. As the detailed genomic and transcriptomic characterisation of gastric cancer continues to demonstrate prognostically important molecularly defined subgroups of patients, clinical trial design incorporating biomarker selection or enrichment for these populations will be essential in order to develop more effective treatments.

  • Overall survival analysis of the FOXFIRE prospective randomized studies of first-line selective internal radiotherapy (SIRT) in patients with liver metastases from colorectal cancer

    Ricky A. Sharma, Harpreet Singh Wasan, Guy A. Van Hazel, Volker Heinemann, Navesh K. Sharma, Julien Taieb, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3507)

    Editorial comment from Prof Ducreux:
    This large trial has included more than 1100 patients to evaluate the impact on survival of a combination of systemic treatment using oxaliplatin based regimen with a local treatment of the liver metastases using yttrium-resin microspheres. This is the largest trial evaluating this kind of strategy. As previously reported, even if a local active treatment is able to control the liver disease (better response rate, better liver progression-free survival), this advantage did not convert in a prolonged overall survival. This result remains difficult to understand because it has always been considered that in patients with limited liver disease, a prolonged local control could prevent the death of the patients. It has to be imagined that extra-hepatic disease is responsible of death in these patients. It may also be considered that the administration of yttrium-resin microspheres could decrease the tolerance of further systemic patients. This is disappointing regarding the cost of this kind of procedure and all the attempts that have been made to control liver diseases in the subgroup of patients with liver limited disease (Intra-arterial hepatic chemotherapy, irinotecan loaded DC-Beads, and now yttrium-resin microspheres. Furthermore, similar negative results have been observed in trials comparing these yttrium-resin microspheres versus sorafenib in hepatocellular carcinoma. It seems to suggest that the control of the liver disease is clearly not the main problem of these patients.

  • A randomized, double-blind, placebo-controlled, multi-centered phase 3 trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer (FRESCO)

    Jin Li, Shukui Qin, Yuxian Bai, Yanhong Deng, Lei Yang, Rui-hua Xu, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3508)

    Editorial comment from Prof Ducreux:
    The data presented here are very interesting mimicking with a new compound the data already obtained with two drugs: regorafenib and trifluridine/tipiracil.  Fruquintinib is an oral kinase inhibitor selectively targeting vascular endothelial growth factor receptors, thus this drug should be considered as quite similar to regorafenib even if it does not work on the same targets…  The hazard ratio observed in this study was even better than the one observed in the CORRECT study evaluating the role of regorafenib in refractory metastatic colorectal cancer (0.77, median survival: 6.4 versus 5.0 months)). However, it was less favorable that the hazard ratio observed in the Concur trial evaluating regorafenib versus placebo in Asian population (0.55, median survival: 8.8 versus 6.3 months), with a better effect in patients who did not receive targeted therapies before administration of regorafenib. Trifluridine/tipiracil is a completely different agent, combining a cytototoxic drug and a molecule inhibiting the degradation of this drug. In a very similar population of refractory metastatic patients, this compound showed an efficacy in terms of overall survival with a hazard ratio of 0.68, (median overall survival: 7.1 versus 5.3 months in the placebo group). The toxicity profile of this agent is neutropenia, contrasting with the toxicity of the tyrosine kinase inhibitors. Thus we will have in the future more and more compounds to treat the patients with late stage refractory metastatic colorectal cancer. However nobody knows if patients who have received and failed to regorafenib could be treated with fruquintinib. As it has been reported in the Concur trial it is clearly possible that resistance to any drug targeting angiogenesis have been developed during the first treatment with an agent of this therapeutic class. The competition could thus be imagined more between fruquintinib and regorafenib than with trifluridine/tipiracil… Finally, the availability of a Chinese drug on the occidental market is clearly not guaranteed. 

  • Final DFS results of the SCOT study: An international phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer

    Timothy Iveson, Rachel Kerr, Mark P. Saunders, Niels Henrik Hollander, Josep Tabernero, Andrew Mark Haydon, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3502)

    Editorial comment from Prof Ducreux:
    The aim of the IDEA initiative was to try to reduce the time of adjuvant chemotherapy after resection of a localized colon cancer. A consortium was created when it was considered that 6 countries were trying to launch or had already launched a trial raising this issue. These trials have some slight differences but their design was very common allowing putting together 12,834 patients to evaluate the ideal length of adjuvant chemotherapy of colon cancer.Despite this large number of patients, the results of the global analysis were not as clear as it was anticipated: the non-inferiority boundary was not reached for the global population of patients, however it was reached for Xelox (and not for Folfox), as it was reached too for T1-3 N1 tumors. These results could allow drawing the conclusion that Xelox 3 month is the best adjuvant treatment for these patients and that only pT4 and/or N2 patients should receive 6 months of treatment.  No difference between 6 and 3 months of treatment was reported in the Scottish trial including 6088 patients. On the other hand, the Italian trial did not confirm the non-inferiority of 3 months of Xelox or Folfox versus 6 months of treatment. Curiously this trial that included 3759 (two thirds of stage III, one third of stage II disease), showed rather worse results with 3 months of treatment in stage II patients. This result contradicts the idea that 3 months of treatment is sufficient for the less severe tumors…. Finally, the French trial including 2022 patients showed that 6 months of Folfox (only 10% of patients treated with Xelox) were superior to 3 months of treatment…..  At the end, it is not completely easy to give a conclusive advice that could be used in clinical practice. It has also to be kept in mind that the comparison between Xelox and Folfox was not the endpoint of these trials, even if it can be considered that in monotherapy capecitabine seemed to give better results that 5FU… At this stage, my recommendations would be to follow the results of the global analysis: 3 months of treatment for stage III “light” pT1-3N1, 6 months for pT4 or N2… And maybe it would be good to recommend a larger use of  Xelox regimen.… We are waiting for new presentations of more complete data during ESMO Madrid 2017….

  • FOLFOX4/XELOX in stage II–III colon cancer: Efficacy results of the Italian three or six colon adjuvant (TOSCA) trial

    Alberto F. Sobrero, Sara Lonardi, Gerardo Rosati, Maria Di Bartolomeo, Monica Ronzoni, Nicoletta Pella, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3501)
  • Three versus six months adjuvant oxaliplatin-based chemotherapy for patients with stage III colon cancer: The French participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project

    Thierry Andre, Franck Bonnetain, Laurent Mineur, Jaafar Bennouna, Jérôme Desrame, Roger Faroux, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3500)
  • Circulating tumor DNA (ctDNA) utilizing a high-sensitivity panel to detect minimal residual disease post liver hepatectomy and predict disease recurrence

    Michael J. Overman, Jean-Nicolas Vauthey, Thomas A. Aloia, Claudius Conrad, Yun Shin Chun, Allan Andresson Lima Pereira, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3522)

    Editorial comment from Dr Cremolini
    The potential interest of the quantitative and qualitative evaluation of cfDNA in liquid biopsy is a field of interest in many solid malignancies. With regard to colorectal cancer, the potential application of liquid biopsy has been mainly focused on the early identification of mechanisms of acquired resistance to anti-EGFRs, but in spite of interesting and promising proof-of-concept findings, their way toward clinical practice has been halted by the lack of high levels of evidence. These works, commented in the poster discussion session, highlight another potential application of cfDNA in colorectal cancer, focusing on its prognostic impact in locally advanced rectal cancer and in patients undergoing radical resection of their liver metastases. The detection of cfDNA after neoadjuvant chemoradiotherapy or after rectal surgery predicts relapse with high specificity, independently of the exposure to adjuvant chemotherapy and the histopathological complete response. Similarly, the detection of cfDNA after liver metastases’ surgical resection predicts both relapse free and overall survival. These findings continue and corroborate previous results achieved by Tie et al. (Sci Transl Med 2016), evidencing the ability of cfDNA in unveiling the minimal residual disease following resection of stage II colorectal cancer. A currently ongoing clinical trial in stage II resected patients (where tools able to estimate the risk of relapse are extremely needed) incorporates results of cfDNA as decision drivers to administer or not adjuvant chemotherapy.

  • The potential of circulating tumor DNA (ctDNA) to guide adjuvant chemotherapy decision making in locally advanced rectal cancer (LARC)

    Jeanne Tie, Joshua Cohen, Yuxuan Wang, Lu Li, Isaac Kinde, Hany Elsaleh, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3521)

    Editorial comment from Dr Cremolini
    The potential interest of the quantitative and qualitative evaluation of cfDNA in liquid biopsy is a field of interest in many solid malignancies. With regard to colorectal cancer, the potential application of liquid biopsy has been mainly focused on the early identification of mechanisms of acquired resistance to anti-EGFRs, but in spite of interesting and promising proof-of-concept findings, their way toward clinical practice has been halted by the lack of high levels of evidence. These works, commented in the poster discussion session, highlight another potential application of cfDNA in colorectal cancer, focusing on its prognostic impact in locally advanced rectal cancer and in patients undergoing radical resection of their liver metastases. The detection of cfDNA after neoadjuvant chemoradiotherapy or after rectal surgery predicts relapse with high specificity, independently of the exposure to adjuvant chemotherapy and the histopathological complete response. Similarly, the detection of cfDNA after liver metastases’ surgical resection predicts both relapse free and overall survival. These findings continue and corroborate previous results achieved by Tie et al. (Sci Transl Med 2016), evidencing the ability of cfDNA in unveiling the minimal residual disease following resection of stage II colorectal cancer. A currently ongoing clinical trial in stage II resected patients (where tools able to estimate the risk of relapse are extremely needed) incorporates results of cfDNA as decision drivers to administer or not adjuvant chemotherapy.

  • Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance)

    Heinz-Josef Lenz, Fang-Shu Ou, Alan P. Venook, Howard S. Hochster, Donna Niedzwiecki, Richard M. Goldberg, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3511)

    Editorial comment from Dr Cremolini
    The Consensus Molecular Subgroups (CMS) classification of colorectal cancer is based on the identification of different gene signatures characterizing different tumours. Authors of two recent and extremely relevant trials (FIRE-3 and CALGB80405) in the landscape of metastatic colorectal cancer investigated the prognostic and predictive impact of this classification in stage IV patients treated with a chemotherapy doublet plus bevacizumab or cetuximab. CMS1 subtype (immune, enriched in MSI-high and BRAF V600E mutants) is associated with the worse prognosis in both trials, thus confirming results in terms of survival after relapse already reported by Guinney et al. in the original series of mainly stage II and III patients. Less clear and consistent data emerge in terms of predictivity: while in FIRE-3 no differential effect of bevacizumab versus anti-EGFR is evident among CMS subtypes, in CALGB80405 CMS1 tumours seems to derive more benefit from bevacizumab than cetuximab, and CMS2 and 4 cancers seem more sensitive to EGFR than angiogenesis inhibition.

    As a major limitation, these analyses are conducted in the RAS (FIRE-3) or KRAS (CALGB80405) wild-type populations, thus not considering the potential impact of other biomarkers routinely used in the daily practice, such as BRAF V600E mutation or microsatellite instability. In spite of the obvious biologic and scientific interest of these findings, they will become relevant for clinical practice only when their added value (as compared with information provided by other easy-to-obtain markers) will be demonstrated.

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