Biomarkers for Cetuximab-Based Neoadjuvant Radiochemotherapy in Locally Advanced Rectal Cancer

Abstract

Purpose: Phase II trials in locally advanced rectal cancer have shown that cetuximab-based neoadjuvant radiochemotherapy is feasible but without an improvement in complete pathologic response rates. Our goal was to identify patients who would benefit from cetuximab-based neoadjuvant chemoradiation measuring gene expression levels of proteins involved in tumor growth [endothelial growth factor receptor (EGFR)], angiogenesis [VEGF, VEGF receptors 1 and 2 (VEGFR1, VEGFR2)], DNA repair [excision repair cross-complementing 1 (ERCC1)], and drug metabolism [thymidylate synthetase (TS)]. We also determined mutation status of KRAS and BRAF.Experimental Design: This study was carried out on 130 patients with locally advanced rectal cancer who were enrolled in 4 different phase II clinical trials, using cetuximab-based chemoradiation. Tumor tissues were obtained before neoadjuvant and at surgical therapy. After microdissection, intratumoral gene expression levels and KRAS/BRAF mutation status were analyzed.Results: A significant decrease of TS, VEGFR1, and VEGFR2 gene expression was seen following neoadjuvant therapy (P < 0.03). High pretreatment VEGF gene expression levels were associated with nonresponse (P ¼ 0.070). KRAS mutations were found in 42% and mutant KRAS (KRAS mt) was significantly associated with pathologic nonresponse (P ¼ 0.037). In patients with wild-type KRAS (KRAS wt), low EGFR was significantly associated with higher nonresponse and VEGF mRNA expressions were associated with complete pathologic response (P ¼ 0.012; P ¼ 0.06). KRAS transversion (KRAS tv) was associated with tumor regression: nonresponse was more common in patients with KRAS tv than with KRAS wt (P ¼ 0.007). BRAF V600E mutations were not detected in any of the patients.Conclusion: This study suggests that pretreatment intratumoral EGFR and VEGF mRNA expression levels as well as KRAS mutation status are predictive markers of pathologic response to neoadjuvant cetuximabbased chemoradiation in locally advanced rectal cancer. Clin Cancer Res; 17(10); 3469-77. Ó2011 AACR.

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

“…In particular, no patients with a BRAF , NRAS , APC , or TP53 mutation achieved a pCR, and only one patient with a combined KRAS/PIK3CA mutation had a pCR. Similarly, others have shown that mutations in KRAS predict for lack of pCR and p53 wild type to be predictive of pCR [9, 10]. …”

“…Several studies have identified clinical and biologic predictors of pCR, including a longer interval from completion of CRT to surgery, pre- and post-CRT carcinoembriogenic antigen (CEA) levels, KRAS status, and expression of EGFR or VEGF [7–10]. We sought to assess both clinical and biologic predictors of pCR, focusing specifically on targetable genetic mutations in order to identify patients who may benefit from more intensive or alternative treatment.…”

The relevance of BRAF and extended RAS mutational analyses for metastatic colorectal cancer patients

“…These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have the EGFR pathway is activated, the tumour phenotype becomes more aggressive and may acquire resistance to treatments 22 . RAS oncogenes have a well-established role in cell growth and proliferation, with its three isoforms, mainly neuroblastoma rat sarcomal viral oncogene homologue (NRAS) KRAS and Harvey rat sarcoma viral oncogene homologue (HRAS).…”

Rectal cancer

“…Several correlative studies attempted to elicit molecularly defined subgroups that may benefit from the addition of cetuximab. However, thus far, no single marker or pattern of markers, including EGFR, KRAS, BRAF, PTEN, etc., could be unambiguously identified to have predictive or prognostic value [16,20,21]. One common feature of all the clinical trials reported so far is that the primary endpoint chosen to assess the efficacy of CRT with EGFR inhibitors was the early surrogate endpoint pCR.…”