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Pharmacogenetics Biomarkers and Their Specific Role in Neoadjuvant Chemoradiotherapy Treatments: An Exploratory Study on Rectal Cancer Patients.

ABSTRACT: Pathological complete response (pCR) to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) is still ascribed to a minority of patients. A pathway based-approach could highlight the predictive role of germline single nucleotide polymorphisms (SNPs). The primary aim of this study was to define new predictive biomarkers considering treatment specificities. Secondary aim was to determine new potential predictive biomarkers independent from radiotherapy (RT) dosage and cotreatment with oxaliplatin.Thirty germ-line SNPs in twenty-one genes were selected according to a pathway-based approach. Genetic analyses were performed on 280 LARC patients who underwent fluoropyrimidine-based CRT. The potential predictive role of these SNPs in determining pathological tumor response was tested in Group 1 (94 patients undergoing also oxaliplatin), Group 2 (73 patients treated with high RT dosage), Group 3 (113 patients treated with standard RT dosage), and in the pooled population (280 patients).Nine new predictive biomarkers were identified in the three groups. The most promising one was rs3136228-MSH6 (p = 0.004) arising from Group 3. In the pooled population, rs1801133-MTHFR showed only a trend (p = 0.073).This exploratory study highlighted new potential predictive biomarkers of neoadjuvant CRT and underlined the importance to strictly define treatment peculiarities in pharmacogenetic analyses.

SUBMITTER: Dreussi E

PROVIDER: S-EPMC5037760 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Pharmacogenetics Biomarkers and Their Specific Role in Neoadjuvant Chemoradiotherapy Treatments: An Exploratory Study on Rectal Cancer Patients.

Dreussi Eva E Cecchin Erika E Polesel Jerry J Canzonieri Vincenzo V Agostini Marco M Boso Caterina C Belluco Claudio C Buonadonna Angela A Lonardi Sara S Bergamo Francesca F Gagno Sara S De Mattia Elena E Pucciarelli Salvatore S De Paoli Antonino A Toffoli Giuseppe G

International journal of molecular sciences 20160905 9

<h4>Background</h4>Pathological complete response (pCR) to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) is still ascribed to a minority of patients. A pathway based-approach could highlight the predictive role of germline single nucleotide polymorphisms (SNPs). The primary aim of this study was to define new predictive biomarkers considering treatment specificities. Secondary aim was to determine new potential predictive biomarkers independent from radiotherapy (R ...[more]

PMID: 27608007

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Project description:BackgroundTo evaluate the value of pretreatment inflammatory-nutritional biomarkers in predicting responses to neoadjuvant chemoradiotherapy (nCRT) and survival in patients with locally advanced rectal cancer (LARC).MethodsPatients with LARC who underwent nCRT and subsequent surgery between October 2012 and December 2019 were considered for inclusion. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and prognostic nutritional index (PNI) were calculated from according to routine laboratory data within 1 week prior to nCRT. The correlations between baseline inflammatory-nutritional biomarkers and responses were analyzed using Chi-square test or Fisher's exact test, and multivariate logistic regression analysis was performed to identify the independent predictors of pathological responses to nCRT. Univariate and multivariate Cox proportional hazard models were used to assess the correlations of predictors with disease-free survival (DFS) and overall survival (OS).ResultsA total of 273 patients with LARC were enrolled in this study. Higher LMR and PNI were observed in the good-response group, meanwhile higher NLR and PLR were observed in the poor-response group. Multivariate logistic regression analysis results revealed that PLR and PNI independently predicted responses to nCRT. Multivariable Cox regression analysis determined that PNI was an independent predictor of DFS and OS in patients with LARC. The value of pretreatment PNI in predicting responses and survival was continuously superior to those of NLR, PLR, and LMR. The optimal cutoff value of the PNI was approximate 45. Subgroup analyses indicated that the pathological responses and survival in the high PNI group (≥ 45) were significantly better than those in the low PNI group (< 45), especially in patients with clinical stage III rectal cancer.ConclusionThe pretreatment PNI can serve as a promising predictor of response to nCRT and survival in patients with LACR, which is superior to NLR, PLR, and LMR, and the patients with clinical stage III rectal cancer who have a higher PNI are more likely to benefit from nCRT.

Project description:Background: Neoadjuvant chemoradiotherapy (NCRT) is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Methods: Forty-eight candidates for NCRT were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade (TRG).Results: Both Smoothing and Hidden Markov Model (HMM) approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 7q21, 7q36, 13q12, 13q32-34, 16p13, 17p12 chromosomal regions. Conclusion: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information about response to NCRT and help to optimize therapy in rectal cancer patients. 48 samples included in the study were analyzed on whole genome BAC arrays with the aim to characterize genomic alterations and correlate them with the tumor response to therapy. The case series was composed by 15%,81% and 4% of uT2, uT3 and uT4 tumors, respectively. At the diagnosis 56% of patients had uN0 tumors and 44% uN+. 30%,13%, 23% and 34% of patients reached/mantained respectively ypT0, ypT1, ypT2 and ypT3. With regard to response to NCRT, according to TRG criteria proposed by Dworak, two group were defined: non responders (TRG0-2= 56%) and responders (TRG3-4=44%). Clinical and pathological parameters: uT: pre-therapy stage determined by ultrasounds techniques uN: pre-therapy lymph node status determined by ultrasounds techniques ypT: pathologic stage after a neoadjuvant treatment ypN: pathologic lymph node status after a neoadjuvant treatment

Project description:BACKGROUND:In recent decades, neoadjuvant therapy (NT) has been the standardized treatment for locally advanced rectal cancer (LARC). Approximately 8%-35% of patients with LARC who received NT were reported to have achieved a complete pathological response (pCR). If the pathological response (PR) can be accurately predicted, these patients may not need surgery. In addition, no response after NT implies that the tumor is destructive, resistant to both chemotherapy and radiotherapy, and prone to having a high metastatic potential. Therefore, developing accurate models to predict PR has great clinical significance and can help achieve individualized treatment in LARC patients. AIM:To establish nomograms for predicting PR to different NT regimens based on pretreatment parameters for patients with LARC. METHODS:Rectal cancer patients were identified from the database of The Sixth Affiliated Hospital, Sun Yat-sen University from January 2012 to December 2016. Logistic regression and nomograms were developed to predict the probability of pCR and good downstaging to ypT0-2N0M0 (ypTNM 0-I), respectively, based on pretreatment parameters for all LARC patients. Nomograms were also developed for three NT regimens (capecitabine/deGramont-RT, mFOLFOX6, and mFOLFOX6-RT) to predict pCR probability. RESULTS:Four hundred and three patients were included in this study; 72 (17.9%) had pCR at the final pathology report, and 177 (43.9%) achieved good downstaging to ypT0-2N0M0 (ypTNM 0-I). The nomogram for predicting pCR probability showed that NT regimens, tumor differentiation, mesorectal fascia (MRF) status, and tumor length significantly influenced pCR probability. When predicting the probability of good downstaging, tumor differentiation, MRF status, and clinical T stage were the significant factors. Nomograms were developed based on NT regimens. For the capecitabine/de Gramont-RT group, the multivariate analysis showed that the neutrophil-lymphocyte ratio (NLR) was the only significant factor, thus we could not develop a nomogram for this regimen. For the mFOLFOX6-RT group, the analysis showed that the significant factors were tumor length and MRF status; and for the mFOLFOX6 group, the significant factors were tumor length and tumor differentiation. CONCLUSION:We established accurate nomograms for predicting the PR to preoperative NT regimens based on pretreatment parameters for LARC patients.

Dataset Information

Pharmacogenetics Biomarkers and Their Specific Role in Neoadjuvant Chemoradiotherapy Treatments: An Exploratory Study on Rectal Cancer Patients.

Publications

Pharmacogenetics Biomarkers and Their Specific Role in Neoadjuvant Chemoradiotherapy Treatments: An Exploratory Study on Rectal Cancer Patients.

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