Genetic heterogeneity of rectal cancer: identification of sub populations of tumor cells resistant to neoadjuvant CRT

• Grant number: 11/51130-6
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: November 01, 2011
• End date: October 31, 2015
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Rodrigo Oliva Perez
• Grantee: Rodrigo Oliva Perez
• Host Institution: Laboratório de Biologia Molecular. Instituto Ludwig de Pesquisa sobre o Câncer (ILPC). São Paulo , SP, Brazil
• Associated research grant(s): 18/15582-9 - Complete tumor regression in rectal cancer patients after neoadjuvant chemoradiation: molecular prediction of tumor response based on intratumoral heterogeneity and assessment of response by circulating tumoral DNA, AP.JP2
• Associated scholarship(s): 11/20149-3 - Genetic Heterogeneity of Rectal Cancer - Identification of Subpopulations of Tumor Cells Resistant to Neoadjuvant CRT, BP.JP

Abstract

One of the benefits of neoadjuvant CRT for the management of rectal cancer is tumor downstaging that can ultimately lead to complete tumor regression (known as complete pathological response - pCR). This tumor regression effect seems to be time-dependent as several retrospective data suggests that increased intervals between CRT completions are associated with increased pCR rates. In our previous study using PET/CT imaging to assess tumor response to CRT, 50% of rectal cancers showed a continuous decrease of its metabolic activity estimated by standard uptake value measurements between 6 and 12 weeks from CRT completion. The remaining 50% of the cases showed an increase metabolic activity within that period. This suggested that intervals longer than 6 weeks would probably not benefit nearly 50% of patients with rectal cancer in terms of further tumor regression. In fact, these patients could be potentially at risk for tumor progression and dissemination during that period. In addition, the observation of this metabolic activity increase could be determined by the presence of specific subpopulations of cells resistant to CRT. These resistant clones could significantly small in size and number at baseline due to significant tumor heterogeneity. However, after tumor cell death secondary to treatment of sensitive subpopulations, resistant clones could represent a more significant proportion of the residual tumor. At 6 weeks from CRT completion this resistant clone(s) could be responsible for the increase in metabolic activity detected by PET/CT. In this setting, the aim of the present study is to identify specific subpopulations of tumor cells determined by specific genetic mutations that are significantly smaller in the primary tumor than in residual tumors after CRT that exhibit an increase in its metabolic activity detected by PET/CT. Sequencing techniques will be used for quantitative and qualitative comparisons of specific genetic mutations of primary and residual rectal cancers in order to determine the presence of clonal expansion of resistant tumor cell subpopulations. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

HABR-GAMA, ANGELITA; PEREZ, RODRIGO O.; JULIAO, GUILHERME P. SAO; PROSCURSHIM, IGOR; FERNANDEZ, LAURA M.; FIGUEIREDO, MARLENY N.; GAMA-RODRIGUES, JOAQUIM; BUCHPIGUEL, CARLOS A.. Consolidation chemotherapy during neoadjuvant chemoradiation (CRT) for distal rectal cancer leads to sustained decrease in tumor metabolism when compared to standard CRT regimen. RADIATION ONCOLOGY, v. 11, FEB 24 2016. (11/51130-6)

BETTONI, FABIANA; MASOTTI, CIBELE; CORREA, BRUNA R.; DONNARD, ELISA; DOS SANTOS, FILIPE F.; SAO JULIAO, GUILHERME P.; VAILATI, BRUNA B.; HABR-GAMA, ANGELITA; GALANTE, PEDRO A. F.; PEREZ, RODRIGO O.; et al. The Effects of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer-The Impact in Intratumoral Heterogeneity. FRONTIERS IN ONCOLOGY, v. 9, SEP 27 2019. (13/07159-5, 11/51130-6, 10/12658-2)

BETTONI, FABIANA; MASOTTI, CIBELE; HABR-GAMA, ANGELITA; CORREA, BRUNA R.; GAMA-RODRIGUES, JOAQUIM; VIANNA, MARIA R.; VAILATI, BRUNA B.; SAO JULIAO, GUILHERME P.; FERNANDEZ, LAURA M.; GALANTE, PEDRO A.; et al. Intratumoral Genetic Heterogeneity in Rectal Cancer Are Single Biopsies representative of the entirety of the tumor?. ANNALS OF SURGERY, v. 265, n. 1, p. E4-E6, JAN 2017. (11/51130-6)