title: Comprehensive evaluation of the effectiveness of gene expression signatures to predict complete response to neoadjuvant chemoradiotherapy and guide surgical intervention in rectal cancer.
abstract: Neoadjuvant chemoradiotherapy (nCRT) may lead to complete tumor regression in rectal cancer patients. Prediction of complete response to nCRT may allow a personalized management of rectal cancer and spare patients from unnecessary radical total mesorectal excision with or without sphincter preservation. To identify a gene expression signature capable of predicting complete pathological response (pCR) to nCRT, we performed a gene expression analysis in 25 pretreatment biopsies from patients who underwent 5FU-based nCRT using RNA-Seq. A supervised learning algorithm was used to identify expression signatures capable of predicting pCR, and the predictive value of these signatures was validated using independent samples. We also evaluated the utility of previously published signatures in predicting complete response in our cohort. We identified 27 differentially expressed genes between patients with pCR and patients with incomplete responses to nCRT. Predictive gene signatures using subsets of these 27 differentially expressed genes peaked at 81.8% accuracy. However, signatures with the highest sensitivity showed poor specificity, and vice-versa, when applied in an independent set of patients. Testing previously published signatures on our cohort also showed poor predictive value. Our results indicate that currently available predictive signatures are highly dependent on the sample set from which they are derived, and their accuracy is not superior to current imaging and clinical parameters used to assess response to nCRT and guide surgical intervention.
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil.
authors.forename: Camila
authors.initials: C
authors.lastname: Lopes-Ramos
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil; Ludwig Institute for Cancer Research São Paulo Branch, São Paulo, Brazil.
authors.forename: Fernanda C
authors.initials: FC
authors.lastname: Koyama
authors.affiliation: Angelita & Joaquim Gama Institute, São Paulo, Brazil; University of São Paulo, School of Medicine, São Paulo, Brazil.
authors.forename: Angelita
authors.initials: A
authors.lastname: Habr-Gama
authors.affiliation: Ludwig Institute for Cancer Research São Paulo Branch, São Paulo, Brazil.
authors.forename: Anna Christina M
authors.initials: AC
authors.lastname: Salim
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Bettoni
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil.
authors.forename: Paula F
authors.initials: PF
authors.lastname: Asprino
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil; University of São Paulo, Department of Biochemistry, São Paulo, Brazil.
authors.forename: Gustavo S
authors.initials: GS
authors.lastname: França
authors.affiliation: Angelita & Joaquim Gama Institute, São Paulo, Brazil; University of São Paulo, School of Medicine, São Paulo, Brazil.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Gama-Rodrigues
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil.
authors.forename: Raphael B
authors.initials: RB
authors.lastname: Parmigiani
authors.affiliation: Ludwig Institute for Cancer Research São Paulo Branch, São Paulo, Brazil; Angelita & Joaquim Gama Institute, São Paulo, Brazil; University of São Paulo, School of Medicine - Colorectal Surgery Division, São Paulo, Brazil.
authors.forename: Rodrigo O
authors.initials: RO
authors.lastname: Perez
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil.
authors.forename: Pedro A F
authors.initials: PA
authors.lastname: Galante
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil; Ludwig Institute for Cancer Research São Paulo Branch, São Paulo, Brazil. Electronic address: aacamargo@mochsl.org.bra.
authors.forename: Anamaria A
authors.initials: AA
authors.lastname: Camargo
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000628:therapy*; D059248:Chemoradiotherapy; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D020411:Oligonucleotide Array Sequence Analysis; D012004:Rectal Neoplasms / Q000235:genetics* / Q000628:therapy*; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D005472:Fluorouracil
keywords: RNA-Seq; Rectal cancer; complete response; gene signature; neoadjuvant chemoradiotherapy