Molecular Diagnosis of Response to Neoadjuvant Chemoradiation Therapy in Patients with Locally Advanced Rectal Cancer

Abstract

Background Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) is an important prognostic factor in locally advanced rectal cancer. However, it is uncertain whether histopathological techniques accurately detect pCR. We tested a novel molecular approach for detecting pCR and compared it to current histopathological approaches. Study design Pre-treatment tumor biopsies and surgical specimens were collected from 96 patients with locally advanced rectal cancer treated with neoadjuvant CRT and surgery. Tumor response was categorized by tumor regression grade (TRG). Tumor DNA from pre-CRT tumor biopsies was screened for K-ras and p53 mutations. DNA from paired surgical specimens was then screened for the same mutations using highly sensitive polymerase chain reaction (PCR)-based techniques. Results Sixty-eight out of 96 (71%) pre-treatment biopsies harbored K-ras and/or p53 mutation; 36 (38%) had K-ras mutations, 52 (54%) had p53 mutations and 20 (21%) carried both mutations. Of 70 patients with TRG 1–3, 66 (94%) had a concordant K-ras and p53 mutation profile in pre- and post-treatment tissues. Of 26 patients with TRG 0 (pCR), 12 had K-ras or p53 mutations in pre-treatment biopsies. Of these, 2 (17%) patients had the same K-ras (n=1) or p53 (n=1) mutation detected in post-treatment tissue. Conclusions Sensitive molecular techniques detect K-ras and p53 mutations in post-CRT surgical specimens in some patients with a pCR. This suggests histopathological techniques may not be completely accurate, and that some patients diagnosed with a pCR to CRT may indeed have occult cancers cells in their surgical specimens with K-ras and p53 mutations serving as reliable surrogates for residual disease.

Identification of a Biomarker Profile Associated With Resistance to Neoadjuvant Chemoradiation Therapy in Rectal Cancer

“…This tissue is usually outside the radiation field and it is unlikely that it received the full dose of radiation, but it was exposed to chemotherapy. While we have recently shown that mutations in KRAS and p53 remain largely unchanged in rectal cancer after CRT, 56 the possibility of mutations arising due to treatment can not be totally excluded.…”

Nonoperative management of rectal cancer after chemoradiation opposed to resection after complete clinical response. A comparative study

“…Even pCR patients may harbor residual cancer cells, as cancer-related DNA mutations in K-ras and p53 genes were detected by polymerase chain reaction (PCR) DNA amplification. 35 Early detection of local recurrences through strict follow-up is today the main tool to grant local control.…”

Chromosomal copy number alterations are associated with tumor response to chemoradiation in locally advanced rectal cancer

“…However, the control tissue was obtained from the proximal resection margin, which is usually outside the radiation field and there is no data indicating that CNAs arise following chemotherapy treatment of normal tissue. Furthermore, we have recently shown that mutations in KRAS and TP53 , two genes which play a role in the pathogenesis of rectal cancer, remain largely unchanged after CRT in these patients (Chen et al, 2011). …”