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


METHODS
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).


RESULTS
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).


CONCLUSIONS
This exploratory study highlighted new potential predictive biomarkers of neoadjuvant CRT and underlined the importance to strictly define treatment peculiarities in pharmacogenetic analyses.
Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy. edreussi@cro.it.
Eva
E
Dreussi
Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy. ececchin@cro.it.
Erika
E
Cecchin
Unit of Cancer Epidemiology, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy. polesel@cro.it.
Jerry
J
Polesel
Pathology, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy. vcanzonieri@cro.it.
Vincenzo
V
Canzonieri
First Surgical Clinic Section, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padova 35128, Italy. m.agostini@unipd.it.|Nano-Inspired Biomedicine Laboratory, Institute of Pediatric Research-Città della Speranza, Corso Stati Uniti 4, Padova 35127, Italy. m.agostini@unipd.it.|Department of Nanomedicine, The Methodist Hospital Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA. m.agostini@unipd.it.
Marco
M
Agostini
Radiation Oncology, Istituto Oncologico Veneto-IRCCS, Padova 35128, Italy. caterina.boso@ioveneto.it.
Caterina
C
Boso
Surgical Oncology, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy. cbelluco@cro.it.
Claudio
C
Belluco
Medical Oncology B, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33801, Italy. abuonadonna@cro.it.
Angela
A
Buonadonna
Medical Oncology 1, Istituto Oncologico Veneto-IRCCS, Padova 35128, Italy. sara.lonardi@ioveneto.it.
Sara
S
Lonardi
Medical Oncology 1, Istituto Oncologico Veneto-IRCCS, Padova 35128, Italy. francesca.bergamo@ioveneto.it.
Francesca
F
Bergamo
Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy. sgagno@cro.it.
Sara
S
Gagno
Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy. edemattia@cro.it.
Elena
E
De Mattia
First Surgical Clinic Section, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padova 35128, Italy. puc@unipd.it.
Salvatore
S
Pucciarelli
Radiation Oncology, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy. adepaoli@cro.it.
Antonino
A
De Paoli
Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico, National Cancer Institute, Aviano 33081, Italy. gtoffoli@cro.it.
Giuseppe
G
Toffoli
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D059248:Chemoradiotherapy; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
chemoradiotherapy; locally advanced rectal cancer; pharmacogenetics