Abstract
Simple SummaryThe overall genomic copy number changes profile of three subgroups of locally advanced rectal carcinoma patients with significantly different response to neoadjuvant treatment with radiochemotherapy (ranging from complete to poor- or no-response) was analyzed and compared with a set of normal samples from healthy individuals with negative colonoscopies from the Castilla y León (Spain) region. We identified and validated a novel genetic signature, which combined with clinicopathological features, predicts response to neoadjuvant treatment and clinical outcome.Administering preoperative radiochemotherapy (RCT) in stage II-III tumors to locally advanced rectal carcinoma patients has proved to be effective in a high percentage of cases. Despite this, 20–30% of patients show no response or even disease progression. At present, preoperative response is assessed by a combination of imaging and tumor regression on histopathology, but recent studies suggest that various genetic abnormalities may be associated with the sensitivity or resistance of rectal cancer tumor cells to neoadjuvant therapy. In the present study we investigated the relationship between genetic lesions detected by high-density single-nucleotide polymorphisms (SNP) arrays 6.0 and response to neoadjuvant RCT, evaluated according to Dworak criteria in 39 rectal cancer tumors before treatment. The highest frequency of copy-number (CN) losses detected corresponded to chromosomes 18q (n = 27; 69%), 1p (n = 22; 56%), 15q (n = 19; 49%), 8p (n = 18; 48%), 4q (n = 17; 46%), and 22q (n = 17; 46%); in turn, CN gains more frequently involved chromosomes 20p (n = 22; 56%), 8p (n = 20; 51%), and 15q (n = 16; 41%). There was a significant association between alterations in the 1p, 3q, 7q, 12p, 17q, 20p, and 22q chromosomal regions and the degree of response to therapy prior to surgery. However, 4q, 15q11.1, and 15q14 chromosomal region alterations were identified as important by five prediction algorithms, i.e., those with the greatest influence on predicting the tumor response to treatment with preoperative RCT. Multivariate analysis of prognostic factors showed that gains on 15q11.1 and carcinoembryonic antigen (CEA) levels serum at diagnosis were the only independent variables predicting disease-free survival (DFS). Lymph node involvement also showed a prognostic impact on overall survival (OS) in the multivariate analysis. A deep-learning-based algorithm showed a 100% success rate in predicting both DFS and OS at 60 months after diagnosis of the disease. In summary, our results indicate the existence of an association between tumor genetic abnormalities at diagnosis, response to neoadjuvant therapy, and survival of patients with locally advanced rectal cancer. In addition to the clinical and biological characteristics of locally advanced rectal cancer patients, these could be used in the future as therapeutic and prognostic biomarkers, to identify patients sensitive or resistant to preoperative treatment, helping guide therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of the newly identified biomarkers.
Highlights
Surgery is currently the key stage in the treatment of locally advanced rectal cancer (LARC), there is growing evidence from randomized clinical trials that administering preoperative radiotherapy combined with chemotherapy in stage II-III tumors produces a significant reduction in tumor size, tumor stage, and local recurrence rates [1], increasing the rate of sphincter-conserving surgery, survival and, improving the quality of life of patients with LARC
Thirty-four patients (87%) showed some sign of tumor regression, and 5 (13%) showed no regression according to Dvorak grade. 67% and 31% of the patients were diagnosed as stages T3 and T4 pre-treatment, respectively; only 43% were T3 and none were T4 after surgery (p < 0.001)
We construct a comprehensive map of the genetic alterations present in LARC through the use of high-resolution single-nucleotide polymorphisms (SNP) arrays, with a median distance between interrogated singlenucleotide polymorphisms (SNPs) of 680 bases; our primary goal was to gain insight into the most frequent genetic alterations that could be associated with response or resistance to neoadjuvant therapy, as well as with survival of the disease
Summary
Surgery is currently the key stage in the treatment of locally advanced rectal cancer (LARC), there is growing evidence from randomized clinical trials that administering preoperative radiotherapy combined with chemotherapy in stage II-III tumors produces a significant reduction in tumor size, tumor stage, and local recurrence rates [1], increasing the rate of sphincter-conserving surgery, survival and, improving the quality of life of patients with LARC. It is estimated that between 20 and 30% of patients do not respond to treatment [2] and tumor progression is found in a minority of cases [3] It is not known which types of tumor are more radiosensitive and what factors determine a better response to preoperative RCT. Rectal magnetic resonance imaging (MRI) plays a key role in the pre- and post-treatment evaluation of rectal cancer, assisting the multidisciplinary team in tailoring the most appropriate treatment option [4]. In this sense, several MRI biomarkers have been proposed for identification of complete responders. Murahashi et al [6] and others [7] showed that preoperative ctDNA levels are significantly consistent with the degree of response to neoadjuvant treatment, showing that ctDNA can accurately reflect the real-time tumor burden
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