Colon cancer molecular subtype intratumoral heterogeneity and its prognostic impact: An extensive molecular analysis of the PETACC-8

Laurent‐Puig, Pierre; Marisa, Laëtitia; Ayadi, Mira; Blum, Yuna; Balogoun, Ralyath; Pilati, Camilla; Malicot, Karine Le; Lepage, Côme; Émile, Jean-François; Salazar, Ramón; Aust, Daniela E.; Duval, Alex; Sèlves, Janick; Guénot, Dominique; Milano, Gérard; Seitz, Jean‐François; Taı̈eb, Julien; Boige, Valérie; Reyniès, Aurélien de

doi:10.1093/annonc/mdy269.058

Cited by 14 publications

(13 citation statements)

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“…In a post-hoc analysis of the PETACC-8 trial, a deleterious effect of cetuximab was observed in the CMS1 subtype [71]. In addition, Laurent-Puig et al observed from the same trial that in fact, at least 50% of the tumors simultaneously exhibit characteristics of 2 CMS subtypes, strongly suggesting the existence of intra-tumor heterogeneity [72]. Moreover, the prognosis of the tumors was significantly different according to their heterogeneity [72].…”

Section: Biomarkers and Efficacy Of Adjuvant Chemotherapymentioning

confidence: 99%

Adjuvant Chemotherapy for Stage III Colon Cancer

Taı̈eb

Gallois

2020

Cancers

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In patients with stage III colon cancer (CC), adjuvant chemotherapy with the combination of oxapliplatin to a fluoropyrimidine (FOLFOX or CAPOX) is a standard of care. The duration of treatment can be reduced from 6 months to 3 months, depending on the regimen, for patients at low risk of recurrence, without loss of effectiveness and allowing a significant reduction in the risk of cumulative sensitive neuropathy. However, our capacity to identify patients that do really need this doublet adjuvant treatment remains limited. In fact, only 30% at the most will actually benefit from this adjuvant treatment, 50% of them being already cured by the surgery and 20% of them experiencing disease recurrence despite the adjuvant treatment. Thus, it is necessary to be able to better predict individually for each patient the risk of recurrence and the need for adjuvant chemotherapy together with the need of new treatment approaches for specific subgroups. Many biomarkers have been described with their own prognostic weight, without leading to any change in clinical practices for now. In this review, we will first discuss the recommendations for adjuvant chemotherapy, and then the different biomarkers described and the future perspectives for the management of stage III CC.

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Section: Biomarkers and Efficacy Of Adjuvant Chemotherapymentioning

confidence: 99%

Adjuvant Chemotherapy for Stage III Colon Cancer

Taı̈eb

Gallois

2020

Cancers

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“…A recent study showed that 57% of primary tumor samples of patients enrolled in the PETACC-8 adjuvant trial demonstrated intratumor heterogeneity in CMS classification, with the presence of two or three different sub-clonal CMS populations in the same sample. 53 , 54 This strong heterogeneity could be explained by gene expression variations between different regions of the tumor, associated with tumor microenvironment components. Changes in the tumor microenvironment are linked to prognosis but can also result in inaccurate CMS subtyping.…”

Section: Cms: a Multilevel Crc Classificationmentioning

confidence: 99%

Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer

Martini

Dienstmann²,

Ros

et al. 2020

Ther Adv Med Oncol

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Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAFV600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history.

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“…Similarly, in the PETACC-8 subtype analysis, the authors demonstrated significantly different prognostic value when the CMS4 subtype was further subdivided into CMS4-C4 (worse DFS and OS) and CMS4-not C4, based on Marisa classification [8]. More recently, the same authors demonstrated how 57% of 1779 profiled PETACC-8 samples showed intra-tumor heterogeneity assessed using an in-silico deconvolution algorithm and this heterogeneity was an independent predictor of relapse [28]. These examples highlight how CMS subtypes define the overall profiles of major CRC subgroups; however, even within each subtype, there may be biological variability and important sub-subtypes with distinctive clinical/biological parameter that requires careful consideration.…”

Section: Equivocal Factor 2: Additional Heterogeneity Leading To Sub-mentioning

confidence: 99%

Context matters—consensus molecular subtypes of colorectal cancer as biomarkers for clinical trials

Fontana

Eason²,

Cervantes

et al. 2019

Annals of Oncology

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The Colorectal Cancer Subtyping Consortium identified four gene expression consensus molecular subtypes, CMS1 (immune), CMS2 (canonical), CMS3 (metabolic), and CMS4 (mesenchymal), using multiple microarray or RNA-sequencing datasets of primary tumor samples mainly from early stage colon cancer patients. Consequently, rectal tumors and stage IV tumors (possibly reflective of more aggressive disease) were underrepresented, and no chemo- and/or radiotherapy pretreated samples or metastatic lesions were included. In view of their possible effect on gene expression and consequently subtype classification, sample source and treatments received by the patients before collection must be carefully considered when applying the classifier to new datasets. Recently, several correlative analyses of clinical trials demonstrated the applicability of this classification to the metastatic setting, confirmed the prognostic value of CMS subtypes after relapse and hinted at differential sensitivity to treatments. Here, we discuss why contexts and equivocal factors need to be taken into account when analyzing clinical trial data, including potential selection biases, type of platform, and type of algorithm used for subtype prediction. This perspective article facilitates both our clinical and research understanding of the application of this classifier to expedite subtype-based clinical trials.

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Colon cancer molecular subtype intratumoral heterogeneity and its prognostic impact: An extensive molecular analysis of the PETACC-8

Cited by 14 publications

References 0 publications

Adjuvant Chemotherapy for Stage III Colon Cancer

Adjuvant Chemotherapy for Stage III Colon Cancer

Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer

Context matters—consensus molecular subtypes of colorectal cancer as biomarkers for clinical trials

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