Mutational and Clinical Predictors of Pathologic Complete Response in the Treatment of Locally Advanced Rectal Cancer

Abstract

Purpose Preoperative chemoradiation (CRT) for locally advanced rectal adenocarcinoma achieves pathologic complete response (pCR) in 8–20 % of patients. Mutations in critical cancer genes may contribute to lack of pCR. We retrospectively evaluated our institutional experience to determine potential mutational and clinical predictors of pCR in patients treated with CRT. Methods Patients with locally advanced rectal adenocarcinoma treated with preoperative CRT (n = 79) were identified. A clinical cancer genotyping assay evaluated 140 hotspot mutation sites across 15 cancer genes in 47 patients with sufficient tissue. Mutational profiles were compared in pre- and post-CRT specimens and with pCR rate. Clinical variables were evaluated using logistic regression. Results Genotyping identified mutations in KRAS (43 %), APC (17 %), BRAF (4 %), NRAS (4 %), PIK3CA (4 %), and TP53 (11 %). In the entire cohort, 21.5 % had a pCR. No patients with BRAF, NRAS, APC, or TP53 achieved a pCR. pCR rate was 23.5 % (4/17) in wild-type tumors versus 3.3 % (1/30) in those with a mutation. There was no difference in the mutation rates in pre- versus post-CRT specimens. On univariate analysis, clinical predictors of pCR included post-RT carcinoembriogenic antigen level of ≤2.5 and smaller tumor size. No patients with a pCR developed recurrence. Conclusion Patients without mutations in commonly mutated cancer genes may be associated with a higher likelihood of having a pCR after preoperative CRT. This should be confirmed in a prospective study.

Cyclin-dependent kinase 1 targeting improves sensitivity to radiation in BRAF V600E colorectal carcinoma cells

“…23 However, the impact of BRAF mutational status on response to preoperative chemoradiation is still controversial, with some studies showing low pathological complete response rates in RAS-or BRAFmutated tumors 6,7 and others no impact 8,9 and this is likely due to the small number of BRAF-mutated rectal carcinomas in these clinical series. In such a context, the question whether BRAF oncogenic mutations enhance the apoptotic threshold of rectal cancer cells and impact on response to radiation is extremely relevant, since it is established that human BRAF V600E CRCs are resistant to apoptosis and poorly responsive to standard chemotherapeutics and molecular targeted agents.…”

“…5 By contrast, conflicting results have been proposed on the role of BRAF mutations in driving the sensitivity of rectal carcinoma cells to radiation, with some studies showing poor responses and others no influence. [6][7][8][9] Thus, this study was designed to evaluate in vitro the radiosensitivity of CRC cells with different RAS/BRAF mutational profiles and exploit cyclin-dependent kinase 1 (CDK1) targeting as a strategy to improve efficacy of radiation therapy in BRAF V600E tumor cells.…”

Predictive immunohistochemical features for tumour response to chemoradiotherapy in rectal cancer

“…This variation could be ascribed to the use of different methodologies. Some studies also examined genetic/epigenetic changes or protein expression levels, although research is still at an early stage. Nevertheless, large‐scale validation studies of predictive markers are necessary before incorporating such methodologies into future clinical practice.…”

National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer

“…Although RT activates RAS‐MAPK signaling in KRAS‐mutant cells, inhibition of MAPK signaling by mitogen‐activated protein extracellular signal‐regulated kinase (MEK) inhibition can attenuate survival after RT . Emerging clinical evidence also supports the finding of relative RT resistance in tumors that harbor KRAS mutations . Trametinib, a potent and selective MEK1/MEK2 inhibitor that is FDA approved for metastatic or unresectable, BRAF V600E/V600K‐mutant melanoma, has been shown to have antiproliferative activity in human KRAS‐mutant or BRAF‐mutant CRC cell lines with reductions in extracellular signal‐regulated kinase (ERK) activation .…”

“…[25][26][27] Emerging clinical evidence also supports the finding of relative RT resistance in tumors that harbor KRAS mutations. 19,[28][29][30][31] Trametinib, a potent and selective MEK1/MEK2 inhibitor that is FDA approved for metastatic or unresectable, BRAF V600E/V600K-mutant melanoma, has been shown to have antiproliferative activity in human KRAS-mutant or BRAF-mutant CRC cell lines with reductions in extracellular signalregulated kinase (ERK) activation. 32 Multiple groups have shown that MEK1/MEK2 inhibitors in RASmutant carcinoma preclinical models result in effective radiosensitization (with or without the additive effects of 5-FU), resulting in tumor cell death and tumor growth delay through increased apoptosis, DNA damage-induced cell death, reduced DNA repair, and a reduction in hypoxic response.…”