IMPACT OF GENETICS ON NEOADJUVANT THERAPY WITH COMPLETE PATHOLOGICAL RESPONSE IN METASTATIC COLORECTAL CANCER: CASE REPORT AND REVIEW OF THE LITERATURE
Bulajic P1, Bidzic N1,*, Djordjevic V1, Ceranic M1,2, Basaric D1,2, Pesic V3, Djordjevic-Pesic J4
*Corresponding Author: Nemanja Bidzic, M.D., Clinic for Digestive Surgery, Clinical Center of Serbia, Koste Todorovica 6, Belgrade 11000, Serbia. Tel. +381-11-306-5957. Fax: +381-11-306-5967. E-mail: nemanja bidzic@yahoo.com
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DISCUSSION

Today standard therapy for metastatic colorectal cancer certainly comprise both surgery and chemotherapy. Outcomes of surgery alone include death in almost 30.0% of patients during the first 2 years. Chemotherapy has not yet achieved a long-term cure [2,4], hence, surgery is still necessary for cure. With combined treatment, more than 50.0% of the patients can reach a 5-year survival and up of cytotoxic agents are in use (FOLFOX, CAPOX, FOLFIRI, and FOLFOXIRI). New biological therapy added to cytotoxic regimens may enhance therapeutic efficiency, especially in the neoadjuvant setting [16,17]. Chemotherapy, with or without targeted therapy, is recommended for synchronous colorectal liver metastases because they have a less favorable cancer biology [13,16] and expected survival than metachronous, particularly in late metachronous metastases [2]. It is of great importance to identify patients at-risk of recurrence and the patients who will receive a benefit from neoadjuvant therapy. Earlier clinical and pathological risk scores are used to estimate prognosis after surgery and to evaluate eligibility for surgery [4]. In the era of modern systemic chemotherapy regimens, these risk scores have low efficiency in clinical decision-making [18,19]. Colorectal cancer is a heterogeneous disease with several possible pathways responsible for carcinogenesis and a lot of genetic mutations. Different genetic and chromosomal alterations are described: microsatellite instability, loss of heterozygosity of chromosome 18, mutations in p53, RAS and RAF mutations (9). Thus, various tumor biology is possible and subsequently, different responses to neoadjuvant therapy. Molecular biomarkers are now being incorporated in risk stratification and treatment decision due to developing a personalized or individualized treatment [20]. Testing of cancer genetic profile has a leading role in the new concept of personalized medicine, and some of these are widely accepted and frequently used in molecular targeted therapy [21]. Evaluated molecular targeted therapy for metastatic colorectal cancer includes Bevacizumab and Cetuximab. Bevacizumab is a monoclonal antibody inhibitor of VEGF, which is the product of the same-named gene and has a crucial role in angiogenesis and tumor growth [7,8]. Cetux- imab is a monoclonal antibody inhibitor of epidermal growth factor receptor (EGFR) which is very effective in the therapy of KRAS wild-type cancers but with no effect on KRAS mutations [6,21], except in the specific mutation on codon 13 (G13D), which is probably associated with some response to Cetuximab [22]. In the present case, we detected a mutation on codon 13 but without differentiation of the exact mutation type, and we did not know if it was a G13D mutation. Even then, the results of recent studies were not so strong to incorporate the Cetuximab for G13D, especially in a neoadjuvant setting [22]. We decided to use cytotoxic neoadjuvant therapy (CAPOX) and to add Bevacizumab as the only remaining biological agent for colorectal liver metastases, which were previously evaluated as a potent neoadjuvant regimen. There is a possibility for estimation of VEGF expression in the tumor sample, but in our oncological practice it is not routinely used for colorectal cancer as the majority of patients have good therapeutic results [8,16,17]. After seven cycles of CAPOX and Bevacizumab, we achieved an extraordinary response: more than 70.0% regression of metastatic lesions and complete regression of the primary tumor, according to RECIST. Carcinoembryonic antigen and CA19-9 were normal. Postoperative histopathology revealed complete primary and secondary tumor response without any evidence of malignancy [Figure 1(l) and 1(m)]. The complete pathological response has been reported, but most of the authors have presented cases with staged surgery for synchronous metastatic disease and input neo-adjuvant treatment after resection of the primary tumor and before resection of secondary tumors [23-25]. In one case, it was even a reverse or liver-first approach but also achieving complete response in primary and metastatic tumors [26]. The primary tumor was locally advanced (cT3d/4, N2) and surgery as a first-line treatment would not be a proper decision because of the risk of local recurrence. On the other hand, pelvic radiotherapy has a complete response in 10.0 to 20.0% cases but has many side effects [27]. In this case, we had to treat both primary and metastatic tumors and achieving a positive effect on neoadjuvant treatment we achieved a chance for a synchronous resection. Vanishing metastases and impossibility to detect liver lesions intraoperatively after neoadjuvant treatment have been described. The reason is the same echogenicity of the lesion and normal liver parenchyma [28]. Concordance between imaging and pathological examination particularly in bevacizumab-containing neoadjuvant therapy is poor and so visible lesions on imaging can be without malignant cells on histopathology [29]. Natural history of undetectable lesions after neoadjuvant chemotherapy in case of complete pathological response of the other lesions has not yet been elucidated. We performed CT scans, tumor markers and PET after 8 months and all pointed to recurrence-free status. Complete disappearance of primary and secondary lesions makes this case unique.



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