Study of Ras Mutations’ Prognostic Value in Metastatic Colorectal Cancer: STORIA Analysis

Ottaiano, Alessandro; Normanno, Nicola; Facchini, Sergio; Cassata, Antonino; Nappi, Anna; Romano, Carmela; Silvestro, Lucrezia; Stefano, Alfonso De; Rachiglio, Anna Maria; Roma, Cristin; Maiello, Monica R.; Scala, Stefania; Delrio, Paolo; Tatangelo, Fabiana; Mauro, Annabella Di; Botti, Gerardo; Avallone, Antonio; Nasti, Guglielmo

doi:10.3390/cancers12071919

Cited by 35 publications

(30 citation statements)

References 34 publications

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“…Moreover, studies have shown KRAS mutation to occur in approximately 50% of patients with mCRC only. 22 Thus, studies that evaluate the clinical utility of ctDNA as a prognostic biomarker in patients with mCRC for MRD detection and predicting disease progression have been limited.…”

Section: Introductionmentioning

confidence: 99%

Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases

Loupakis

Sharma

Derouazi

et al. 2021

JCO Precision Oncology

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PURPOSE More than 50% of patients with stage IV colorectal cancer (metastatic colorectal cancer [mCRC]) relapse postresection. The efficacy of postoperative systemic treatment is limited in this setting. Thus, these patients would greatly benefit from the use of a reliable prognostic biomarker, such as circulating tumor DNA (ctDNA) to identify minimal or molecular residual disease (MRD). PATIENTS AND METHODS We analyzed a cohort of 112 patients with mCRC who had undergone metastatic resection with curative intent as part of the PREDATOR clinical trial. The study evaluated the prognostic value of ctDNA, correlating MRD status postsurgery with clinical outcomes by using a personalized and tumor-informed ctDNA assay (bespoke multiple PCR, next-generation sequencing assay). Postresection, systemic therapy was given to 39.2% of the patients at the discretion of the treating physician. RESULTS Postsurgical, MRD positivity was observed in 54.4% (61 of 112) of patients, of which 96.7% (59 of 61) progressed at the time of data cutoff (hazard ratio [HR]: 5.8; 95% CI, 3.5 to 9.7; P < .001). MRD-positive status was also associated with an inferior overall survival: HR: 16.0; 95% CI, 3.9 to 68.0; P < .001. At the time of analyses, 96% (49 of 51) of patients were alive in the MRD-negative arm compared with 52.4% (32 of 61) in the MRD-positive arm. Patients who did not receive systemic therapy and were MRD-negative in the combined ctDNA analysis at two time points had an overall survival of 100%. In the multivariate analysis, ctDNA-based MRD status was the most significant prognostic factor associated with disease-free survival (HR: 5.78; 95% CI, 3.34 to 10.0; P < .001). CONCLUSION This study confirms that in mCRC undergoing resection of metastases, postoperative MRD analysis is a strong prognostic biomarker. It holds promises for being implemented in clinical decision making, informing clinical trial design, and further translational research.

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Section: Introductionmentioning

confidence: 99%

Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases

Loupakis

Sharma

Derouazi

et al. 2021

JCO Precision Oncology

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“…Interestingly, wt KRAS patients received more CT lines (43.3% vs 20.6% in mut KRAS patients) and had a longer cumulative median time-on-therapy (20.5 vs 16.9 months in mut KRAS patients). This was indirectly related to the detrimental prognostic effect on survival of mut KRAS ( 11 ).…”

Section: Resultsmentioning

confidence: 99%

“…The study was exploratory considering the scarcity of data about the prognostic power of different mutational evolutions of KRAS oncogene in primary vs metastatic lesions and, thus, it does not have a pre-specified study design. All patients registered in an observational database (STORIA database) ( 11 ) between 2015 and 2018 and who accepted to perform liquid biopsy before starting first-line chemotherapy were enrolled. We chose do not prolong the enrolment period to avoid any prognostic interferences related to therapeutic and methodologic changes occurring in clinical practice.…”

Section: Methodsmentioning

confidence: 99%

KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer

et al. 2021

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BackgroundWe previously reported that loss of KRAS mutations (“regressive” mutational trajectories) from primary tumors to metastases associated with the oligo-metastatic status in colorectal cancer (CRC). The present study was undertaken in order to analyze the mutational trajectories of KRAS in a well-characterized cohort of CRC patients who developed poly- or oligo-metastatic disease.Material and MethodsPatients were treated and followed-up according to European Society of Medical Oncology guidelines. Primary CRC FFPE tissue and metastatic circulating-free DNA were extracted using the QIAamp DNA specific kits (Qiagen, Hilden, Germany). Samples were sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Plasma collection for liquid biopsy was done from 1 to 14 days before starting first-line chemotherapy. Analysis of the prognostic power of KRAS evolutionary trajectories was done with uni- and multivariate analyses.ResultsOne-hundred-fourteen patients were enrolled. Sixty-three patients presented with mutated KRAS (mutKRAS) and 51 with wild-type KRAS (wtKRAS). KRAS mutational concordance was high (70.1%).Two divergent subsets were identified: mutKRAS in primary tumors and wtKRAS in metastatic ones (regressive: mutKRAS → wtKRAS in 8.8% of patients), and vice versa (progressive: wtKRAS → mutKRAS in 21.1% of patients). An association between KRAS regressive trajectory and the oligo-metastatic status (P <0.0001) was found. At multivariate analysis, regressive and progressive mutational trajectories emerged as independent prognostic factors for survival, with Hazard Ratios of 0.22 (CI 95%: 0.08–0.61; median survival: not reached) and 2.70 (CI 95%: 1.11–6.56, median survival: 12.1 months), respectively.ConclusionsOur data provide evidence that the evolutionary trajectories of KRAS can have a strong clinical prognostic role and that they can be involved in discriminating between poly-metastatic aggressive vs oligo-metastatic indolent CRC.

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“…Among these Ras oncogenic versions, the K-Ras protein in which the glycine at codon 12 is mutated into a valine or a serine remains in the GTP-bound constitutive active form. K-Ras is associated with the worst prognosis in many cancer types [4,[35][36][37][38].…”

Section: The Expression Of the Oncogene Ras V12 Alone Is Not Sufficient To Create Neoplastic Invasive Tumorsmentioning

confidence: 99%

RasV12; scrib−/− Tumors: A Cooperative Oncogenesis Model Fueled by Tumor/Host Interactions

Dillard

Reis

Rusten

2021

IJMS

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The phenomenon of how oncogenes and tumor-suppressor mutations can synergize to promote tumor fitness and cancer progression can be studied in relatively simple animal model systems such as Drosophila melanogaster. Almost two decades after the landmark discovery of cooperative oncogenesis between oncogenic RasV12 and the loss of the tumor suppressor scribble in flies, this and other tumor models have provided new concepts and findings in cancer biology that has remarkable parallels and relevance to human cancer. Here we review findings using the RasV12; scrib−/− tumor model and how it has contributed to our understanding of how these initial simple genetic insults cooperate within the tumor cell to set in motion the malignant transformation program leading to tumor growth through cell growth, cell survival and proliferation, dismantling of cell–cell interactions, degradation of basement membrane and spreading to other organs. Recent findings have demonstrated that cooperativity goes beyond cell intrinsic mechanisms as the tumor interacts with the immediate cells of the microenvironment, the immune system and systemic organs to eventually facilitate malignant progression.

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Study of Ras Mutations’ Prognostic Value in Metastatic Colorectal Cancer: STORIA Analysis

Cited by 35 publications

References 34 publications

Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases

Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases

KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer

RasV12; scrib−/− Tumors: A Cooperative Oncogenesis Model Fueled by Tumor/Host Interactions

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