| Abstract |
Colorectal cancer (CLC) is the third most common cancer type and a common
cause of mortality, from solid tumors. Depending on the stage of the disease on
diagnosis, both treatment and prognosis may differ among patients. Stage III CRC
patients with have up to 60% 5-year survival, and adjuvant chemotherapy aims to
extend both disease-free and overall survival. Definitely, any additional information on
the process of tumorigenesis or the mechanisms of disease development and
progression (functional and/or structural DNA changes) can reveal new therapeutic
targets and guide patient management. Until recently, the oxaliplatin-fluoropyrimidine
combination, as fluorouracil-leucovorin-oxaliplatin (FOLFOX) or capecitabineoxaliplatin
(CAPOX) for 6 months was the “gold standard” regime for such patients.
Based on the increasing incidence of CRC, treatment toxicity, costs and limited
resources of health systems, the international IDEA study was designed to evaluate the
non-inferiority hypothesis of 3-month versus 6-month adjuvant chemotherapy, with
FOLFOX or CAPOX.
The aim of the present study was to investigate the molecular profile in the
tissue and the circulating tumor DNA (ctDNA) in the blood of stage III CRC patients,
who were also enrolled in the international IDEA study. At the same time, correlation
of the two markers (molecular profiling and ctDNA) with clinico-pathological and
epidemiological characteristics, as well as with the patients’ outcome, was carried out.
In the present study, surgical samples of primary tumor and healthy tissue, as a
control sample, were collected as formalin-fixed paraffin embedded tissues, from 237
patients with stage III CRC. Moreover, peripheral blood samples (15ml in EDTA) were
collected at various time points during treatment. Whole exome sequencing in patients’
tissues and plasma was performed with Illumina technology. Of all patients included in
the study, 164 (69.2%) had availability of healthy tissue, 151 (63.7%) were males, 158
(66.7%) had a tumor location in the left colon and 132 (55.7%) received CAPOX as
adjuvant chemotherapy. Of all patients, 116 (48.9%) and 121 (51.1%) received 3- and
6-month adjuvant chemotherapy, respectively. A total of 59 mutated genes belonging
in 10 different signaling pathways were identified in all patients, based on WES and
the KEGG CRC panel. From the analyses, one patient was excluded as no mutated gene
was detected. Patients had an average of 8 mutated genes (range, 2-21 genes). Several
concurrent mutations were detected in all patients APC/BIRC5; p=0.001; APC/CASP9 p=0.001; APC/DCC, p=0.004; APC/KRAS, p<0.001; APC/MSH3, p=0.003;
APC/PIK3R1, p=0.019; APC/PIK3R2, p=0.017; APC/TGFB1, p=0.009; APC/TP53,
p<0.001; BIRC5/TP53, p<0.001; PIK3R2/TP53, p<0.001; TGFB1/TP53, p<0.001),
although no correlation with clinicopathological/epidemiological characteristics and
patient prognosis was observed. APC2 mutations in patients are associated with shorter
overall survival (OS) (p=0.002). In addition to the frequent mutations detected in the
patient group, mutations in the genes AKT1, ARAF, BAD, MAPK10, RAC3, RHOA,
TGFB2 and TGFB3 were found to be associated with worse prognosis (p=0.039;
p=0.001; p=0.001; p= 0.036; p<0.001; p=0.001; p=0.009; p=0.040 and p=0.003,
respectively). Whereas mutations in ARAF (p=0.027)/ MAPK10 (p<0.001) and RAC3
(p=0.029)/ RHOA (p=0.006) genes emerged as independent prognostic factors for
reduced DFS and OS, respectively. Conversely, patients with MSH6 gene mutations
had a statistically longer OS (p=0.041). Regarding reduced DFS, patients with rectal
cancers had statistically reduced DFS compared to those with colon/sigmoid cancer
(p=0.025). Finally, colon/sigmoid tumor location is presented as an independent
prognostic factor for both reduced DFS (p=0.019) and OS (p=0.043), while for the first
time the role of ARAF and MAPK10 mutations as independent prognostic factors is
highlighted for reduced DFS (p=0.027 and p<0.001, respectively). Regarding ctDNA
analysis, patients with detectable ctDNA at baseline, presented a significantly shorter
DFS (p<0.001). Finally, patients with residual disease who received a 3-month of
adjuvant chemotherapy presented a non-statistically significant trend towards a higher
recurrence risk.
In conclusion, molecular characterization of tumor cells might contribute to a
better understanding of the biological disease course. The results of the present study
indicate the promising role of mutations as prognostic biomarkers. Since personalized
medicine is now the main mode of treatment, the exact mutational status in CRC
patients may lead to better treatment options. Clearly, further studies, with a larger
cohort of patients and international collaborations, is required to confirm the correlation
of the molecular profiling in such patients, with clinicopathological and
epidemiological characteristics, as well as with their clinical outcome. This is expected
to guide clinical decision-making, personalized and improved care, reducing treatment
toxicity, patient and health systems costs.
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