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Mutational and clinical predictors of pathologic complete response in the treatment of locally advanced rectal cancer.

ABSTRACT: Preoperative chemoradiation (CRT) for locally advanced rectal adenocarcinoma achieves pathologic complete response (pCR) in 8-20% of patients. Mutations in critical cancer genes may contribute to lack of pCR. We retrospectively evaluated our institutional experience to determine potential mutational and clinical predictors of pCR in patients treated with CRT.Patients with locally advanced rectal adenocarcinoma treated with preoperative CRT (n?=?79) were identified. A clinical cancer genotyping assay evaluated 140 hotspot mutation sites across 15 cancer genes in 47 patients with sufficient tissue. Mutational profiles were compared in pre- and post-CRT specimens and with pCR rate. Clinical variables were evaluated using logistic regression.Genotyping identified mutations in KRAS (43%), APC (17%), BRAF (4%), NRAS (4%), PIK3CA (4%), and TP53 (11%). In the entire cohort, 21.5% had a pCR. No patients with BRAF, NRAS, APC, or TP53 achieved a pCR. pCR rate was 23.5% (4/17) in wild-type tumors versus 3.3% (1/30) in those with a mutation. There was no difference in the mutation rates in pre- versus post-CRT specimens. On univariate analysis, clinical predictors of pCR included post-RT carcinoembriogenic antigen level of ?2.5 and smaller tumor size. No patients with a pCR developed recurrence.Patients without mutations in commonly mutated cancer genes may be associated with a higher likelihood of having a pCR after preoperative CRT. This should be confirmed in a prospective study.

SUBMITTER: Russo AL

PROVIDER: S-EPMC4361942 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Mutational and clinical predictors of pathologic complete response in the treatment of locally advanced rectal cancer.

Russo Andrea L AL Ryan David P DP Borger Darrell R DR Wo Jennifer Y JY Szymonifka Jackie J Liang Wen-Yih WY Kwak Eunice L EL Blaszkowsky Lawrence S LS Clark Jeffrey W JW Allen Jill N JN Zhu Andrew X AX Berger David L DL Cusack James C JC Mamon Harvey J HJ Haigis Kevin M KM Hong Theodore S TS

Journal of gastrointestinal cancer 20140301 1

<h4>Purpose</h4>Preoperative chemoradiation (CRT) for locally advanced rectal adenocarcinoma achieves pathologic complete response (pCR) in 8-20% of patients. Mutations in critical cancer genes may contribute to lack of pCR. We retrospectively evaluated our institutional experience to determine potential mutational and clinical predictors of pCR in patients treated with CRT.<h4>Methods</h4>Patients with locally advanced rectal adenocarcinoma treated with preoperative CRT (n = 79) were identified ...[more]

PMID: 24006244

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Project description:Background: MicroRNAs (miRNAs) are small, non-coding, RNA molecules which regulate numerous cellular processes. Specific miRNA may be abnormally down-regulated or up-regulated in colorectal cancer and have been found associated with prognosis or response to treatments. However, no study has ever addressed their predictive role in rectal cancer. Therefore, we used microarray technology and RT-PCR to profile miRNA expression patterns in patients (pts) with rectal cancer, with the aim to identify a specific M-bM-^@M-^\signatureM-bM-^@M-^] associated with pathological complete response after neoadjuvant chemo-radiotherapy. Methods: 38 pts with locally advanced rectal cancer (cT3-4/N+) were treated with capecitabine-oxaliplatin and pelvic conformal radiotherapy (45 cGy) followed by surgery (after 6-8 weeks). Pathologic response was scored according to the tumor regression grade (TRG) scale. MiRNA expression profile was analysed by microarray on fresh frozen biopsies obtained before treatment start and confirmed by RT-PCR. The correlation between miRNA expression profile and the TRG coded as TRG1 (pathologic Complete Response-pCR) versus TRG >1 (no pCR) was assessed by statistical analysis methods specifically designed for this study. Findings: 14 miRNAs were selected by arrays analysis as differentially expressed in TRG1 pts and 13 were confirmed by RT-PCR. In particular, 11 miRNAs (miR-1183, miR-483-5p, miR-622, miR-125a-3p, miR-1224-5p, miR-188-5p, miR-1471, miR-671-5p, miR-1909*, miR-630 and miR-765) were significantly up-regulated in TRG1 pts, while 2 miRNAs were under -expressed (miR-1274b and miR-720). miR-622 and miR-630 showed 100% sensitivity and specificity in selecting TRG1 cases and were significantly correlated with EGFR (M-OM-^G2=11M-bM-^@M-"793; p= 0M-bM-^@M-"001) and TS expression (M-OM-^G2=10M-bM-^@M-"589; p= 0M-bM-^@M-"001). Interpretation: A set of 13 miRNAs is strongly associated with pathologic complete response and may represent a specific marker of response to chemo-radiotherapy in locally advanced rectal cancer. Experiments were performed on purified RNA from preoperatory biopsies of 38 patients with histological diagnosis of rectal adenocarcinoma invading through the intestinal wall and/or with pelvic lymph node involvement as evaluated by endorectal ultrasonography (uT3-T4 and/or uN+). Patients were treated with neoadjuvant chemo-radiotherapy (capecitabine + oxaliplatin in combination with 45 Gy of pelvic conformal radiotherapy). Patients have been divided in the following two groups: group A those who had obtained a pathologic complete response M-bM-^@M-^S TRG 1, including the patient without detectable disease who refused surgery, group B any pathologic response other than complete.

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Mutational and clinical predictors of pathologic complete response in the treatment of locally advanced rectal cancer.

Publications

Mutational and clinical predictors of pathologic complete response in the treatment of locally advanced rectal cancer.

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