A metabolomic recurrence score for risk-stratification of elderly patients (pts) with early colorectal cancer (eCRC)

abstracts

Annals of Oncology

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A metabolomic recurrence score for risk-stratification of elderly patients (pts) with early colorectal cancer (eCRC)

Background: Adjuvant treatment decisions for pts with eCRC are currently based on suboptimal risk stratification factors, especially for elderly pts. Metabolomics measures multiple cancer-related metabolites with potential to identify new biomarkers in this setting. We have shown that serum metabolomics can discriminate pts with eCRC from pts with metastatic CRC (mCRC). We hypothesized that a metabolomic score derived from pts with mCRC may identify pts with eCRC with an increased risk of relapse. This hypothesis was tested in a cohort of elderly pts with eCRC. Methods: Serum samples from 103 pts aged 70 were collected from four clinical trials with 5 years follow up. These samples were derived from 55 pts with eCRC, and 48 with mCRC. Samples were retrospectively analyzed via proton nuclear magnetic resonance (1H NMR), to assess their metabolomic fingerprints. A Random Forest (RF) classification model was built using a training set of 30 eCRC pts free from relapse at 5 years and all mCRC pts (N ¼ 48). This model was then applied to a validation set constituted by the remaining eCRC pts (10 relapse-free and 15 relapsed). A risk-of-recurrence score was built on the basis of the likelihood of the sample being misclassified as metastatic. Results: In the eCRC group, 44% (n ¼ 24) received adjuvant chemotherapy, and 27% (n ¼ 15) experienced relapse. In the training set, the RF model discriminated eCRC from mCRC with an accuracy of 74.4%. The RF risk of recurrence score correlated with relapse, with an AUC of 0.754 in ROC analysis. In the training set, by maximizing specificity and sensitivity, a threshold for the RF score was set at 0.55. In the validation set, using this threshold, an AUC of 0.727 in ROC analysis, and a prediction accuracy of 76% (73.3% sensitivity, 80% specificity) were obtained in predicting relapse. Conclusions: Serum metabolomics performed on post-operative samples of elderly pts with eCRC identifies pts with higher risk of relapse with good accuracy. This may represent a tool to refine risk stratification in this population, to maximize the benefit from adjuvant chemotherapy. Based on these results, a prospective trial is ongoing (LIquid BIopsy and METabolomics in CRC - LIBIMET). Legal entity responsible for the study: The authors. Funding: Fondazione Sandro Pitigliani per la Lotto Contro i Tumori - ONLUS. Disclosure: S. Di Donato: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Servier; Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer. E. Mori: Travel / Accommodation / Expenses: Bayer. L. Malorni: Honoraria (self): AstraZeneca; Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Travel / Accommodation / Expenses: Roche. D. Becheri: Travel / Accommodation / Expenses: Daiichi-Sankyo; Travel / Accommodation / Expenses: Bristol-Myers Squibb. A. Di Leo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi-Sankyo; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genomic Health; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy, Travel / Accommodation / Expenses: Puma Biotechnology; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche. L. Biganzoli: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astrazeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Genomic Health; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.

Volume 30 | Supplement 5 | October 2019

RAS mutant allele fraction in plasma predicts benefit to antiangiogenic based first-line treatment in metastatic colorectal cancer

na4, G. Carat u3, J. Matito3, G. G. Martini1, E. Elez2, F.M. Mancuso3, M.A. Gomez Espa~ Argiles Martinez2, N. Mulet Margalef5, M.J. Ortiz Morales4, F.J. Ros Montana2, A. Garcia1, R. Comas1, C. Santos Vivas6, R. Perez-Lopez1, P.G. Nuciforo7, O. Casanovas8, R. Dienstmann9, J. Tabernero10, E. Aranda Aguilar11, A. Vivancos3 1 Oncology Department, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, 2 Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain, 3Cancer Genomics, Vall d’Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain, 4 Medical Oncology, University Hospital Reina Sofia, IMIBIC, Cordoba, Spain, 5Medical Oncology, Institut Catal a d’Oncologia Hospital Duran i Reynals, Barcelona, Spain, 6 Oncology Department, Catalan Institute of Oncology. Hospital Druan y Reynals, 7 Barcelona, Spain, Molecular Oncology Department, Vall d’Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain, 8Oncology Department, Institut Catal a d’Oncologia Hospital Duran i Reynals, Barcelona, Spain, 9Oncology Data Science (Odyssey) Group, Vall d’Hebron University Hospital, Barcelona, Spain, 10 Oncology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, 11Department of Medical Oncology, University Hospital Reina Sofia, Cordoba, Spain Background: So far, no biomarkers of response to anti-angiogenic drugs are available in colorectal cancer (CRC) treatment. Liquid biopsy technique identifies actionable targets in CRC patients (pts), tracking dynamic mutational changes. We and others described RAS mutant allele fraction in plasma (plMAF) as an independent prognostic marker in metastatic CRC (mCRC). Here, we explored the predictive value of plMAF in RAS mutant pts treated in first line with chemotherapy þ/- bevacizumab (bev). Methods: A multicentric prospective/retrospective analysis was conducted. We collected data from 226 mCRC pts and selected the subset not eligible for metastasis resection that had basal plMAF sample evaluable for RAS mutant MAF quantification using digital PCR (BEAMing). Pts were stratified as high ( 5.8%) or low (< 5.8%) plMAF based on previously defined cut-off (Sanz-Garcia E, ESMO GI, 2017). We investigated associations between different clinicopathological variables (gender, n and site of metastases, CEA levels, primary site location) and progression-free survival (PFS) stratified by plMAF RAS levels using Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: From October 2017 to May 2019, BEAMing analysis from 62 basal plasma samples was performed. 42 pts (67.7%) were classified as high and 20 pts (32,3%) as low plMAF. Among high RAS plMAF, 24 pts received FOLFOXþbev (57%) and 20 pts FOLFOX alone (43%). In this high plMAF subgroup, a statistically significant longer PFS favouring FOLFOXþbev was observed when compared to FOLFOX alone (10.7 versus 6.9 months, respectively; HR: 0.30; p ¼ 0.002). In the low RAS plMAF subgroup, no differences in terms of PFS were observed in either arm (8.9 versus 8.7 months, respectively; HR: 0.70; p ¼ 0.6). Multivariate PFS model showed no association between RAS plMAF and clinicopathological variables, except for high RAS plMAF and treatment benefit with FOLFOXþbev. Conclusions: Our results indicate that tumor-borne RAS plMAFs may constitute a potential predictive biomarker of efficacy for anti-angiogenic agents in mCRC. Confirmatory studies in randomized cohorts will be performed. Legal entity responsible for the study: VHIO (Vall d’Hebron Institute of Oncology). Funding: AECC (Asociaci on Espa~ nola Contra el Cancer). Disclosure: G. Martini: Research grant / Funding (self), Research Project supported by ESMO with the aid of a grant from Amgen: ESMO-AMGEN. E. Elez: Honoraria (self): Merck Serono; Honoraria (self): Sanofi; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Servier; Honoraria (self): Amgen; Honoraria (self): Array. G. Argiles Martinez: Honoraria (self), Honoraria (institution), Research grant / Funding (self), Travel / Accommodation / Expenses: Hoffmann-LaRoche, BristolMyers Squibb, Bayer, Servier, Amgen, Merck Serono, Menarini; Honoraria (self): Menarini; Honoraria (institution): Boston Pharmaceuticals; Honoraria (institution): Genentech; Honoraria (institution): Boehringer Ingelheim. M.J. Ortiz Morales: Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert Testimony: Sanofi. P.G. Nuciforo: Honoraria (self): BAYER; Honoraria (self): MSD; Honoraria (self): Novartis. R. Dienstmann: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Symphogen, Ipsen, Amgen, Sanofi, MSD, Servier; Research grant / Funding (self): MERCK. J. Tabernero: Advisory / Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Part. E. Aranda Aguilar: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merck; Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi. A. Vivancos: Advisory / Consultancy: sysmex; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck; Advisory / Consultancy: Bristol-Meyers Squidd; Advisory / Consultancy: Guardant Health. All other authors have declared no conflicts of interest.

doi:10.1093/annonc/mdz246 | v217

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S. Di Donato1, A. Vignoli2, E. Mori1, L. Tenori2, L. Malorni1, S. Cantafio3, G. Mottino4, D. Becheri4, A. Mccartney5, C. Biagioni1, F. Del Monte1, A. Di Leo6, C. Luchinat2, L. Biganzoli1 1 Sandro Pitigliani Medical Oncology Department, Nuovo Ospedale di Prato S. Stefano, Prato, Italy, 2Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Italy, 3U.O. Chirurgia Generale e Oncologica, Nuovo Ospedale di Prato S. Stefano, Prato, Italy, 4S.O.C. Geriatria, Nuovo Ospedale di Prato S. Stefano, Prato, Italy, 5 Sandro Pitigliani Medical Oncology Department, Nuovo Ospedale di Prato S. Stefano, Prato, Italy, 6Medical Oncology, Nuovo Ospedale di Prato, Prato, Italy

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