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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INTRODUCTION

Colorectal cancer is a very common malignancy and a significant health problem [1]. At the time of diagnosis, almost 25.0% of patients have synchronous metastases, and up to 50.0% will experience metastases. The liver is certainly the most common site for metastasis to occur, and about four-fifths of the patients have isolated metastatic disease in the liver [2]. However, a minority of these are initially eligible for surgery. Despite the modern improvement of cancer therapy [3], treatment of metastatic colorectal cancer is still challenging, especially in synchronous presentation. Long-term survival is poorer than in patients with metachronous metastases [4]. In the past decade, some neoadjuvant therapies have improved treatment of stage IV colorectal cancer [5]. Besides the radio and chemotherapy, newly designed biological agents have shown great advance in the management of colorectal disease, particularly in the neoadjuvant setting [6-8]. Because of the different pathways in tumor genesis and tremendous heterogeneity [9], it is necessary to stratify every single neoplastic process. Molecular targeted therapy is based on the specific genetics of every neoplastic process which implies individualized treatment according to detected genetic mutations. The role of some biomarkers, such as the KRAS (Kirsten rat sarcoma) gene mutation, is evaluated in determining molecular targeted therapy [6]. Neoadjuvant chemotherapy response is very important for disease-free and overall survival, and in the era of effective chemotherapy, various criteria for tumor response are established [10]. A complete pathologic response of both primary and secondary tumors, is extremely rare [11]. We present a case of individualized management of metastatic colorectal cancer with a complete pathological response of both primary and secondary tumors. Case Presentation. A 47-year-old female with a few months history of abdominal pain and bloody stools was admitted to our clinic in April 2017. Colonoscopy revealed a large circumferential tumor, 7 cm from the anal verge, and pathological examination of biopsied material diagnosed adenocarcinoma [Figure 1(a)]. Carcinoembryonic antigen (CEA) was 16.3 μ/L and carbohydrate antigen 19-9 (CA19-9) was in the normal range. Computerized tomography (CT) of the abdomen and pelvis showed three metastatic lesions in the liver: in segment three (S3) 42 × 33 mm [Figure 1(b)], in S7 two lesions, one superficial 31 × 19 mm [Figure 1(c)], and the other 33 × 33mm [Figure 1(d)], inseparable from the right hepatic vein; the rectal tumor was in the middle and proximal part of the rectum and distal part of the sigmoid colon, 10 cm in length, 7 cm from the anal verge, calculated on CT scans [Figure 1(e) and (f)]. Clinical tumor-nodemetastasis (TNM) classification was T3d/4, N2, M1, and one lesion of 3 cm was also detected in the spleen but with an unclear diagnosis. The multidisciplinary team decided to start treatment with preoperative chemotherapy. Due to the prediction of bowel obstruction, we first performed a bipolar colostomy. The mutation was detected by genetic analysis of biopsied tumor tissue that was based on real-time polymerase chain reaction (PCR). The detected mutation was on codon 13 (G13X) of the KRAS gene, but we were not able to elucidate the exact mutation type because of the method limitations. Thus, we excluded the possibility of Cetuximab according to our national guidelines. In this situation, we decided to use combined regimen of Oxaliplatin and Capecitabine with the addition of Bevacizumab, which is the only remaining biological agent for colorectal liver metastases at our oncological practice. We did not have the possibility of performing vascular endothelial growth factor (VEGF) expression on the tumor sample, so we were unable to determine tumor tissue sensitivity to Bevacizumab. However, it is widely accepted to include this medicine in the first line therapy. After four cycles of neoadjuvant therapy, we confirmed partial regression on CT scans, according to response evaluation criteria in solid tumors (RECIST), and continued with three more cycles because the patient was in good general condition and therapy was efficient. In November 2017, CT of the thorax, abdomen, and pelvis was done and revealed total regression of the primary rectal tumor [Figure 1 (g) and (h)], and further regression of metastatic lesions (lesion in S3 was 13 × 12 mm) [Figure 1(i)], superficial lesion in S7 was 11 × 8 mm [Figure 1(j)], and in S7 lesion near to the right hepatic vein was 8 × 6 mm [Figure 1(k)]. Tumor markers reached normal values, and the splenic lesion was stable in size. The patient was prepared for the operation, and in January 2018, we performed a low anterior resection of the rectum with total mesorectal excision, colorectal anastomosis, and synchronous liver resection. During the operation, we did not find any signs of dissemination in the abdomen. The rectal tumor was presented as a few centimeter scar. In the liver, we found only the lesion in S3, and another two lesions were not detectable either by palpation or by intraoperative ultrasound. Thus, we performed only a subsegmental liver resection of S3, and because the CT scan detected the splenic lesion, we also performed a splenectomy. The patient recovered from the operation without any complication. Pathological examination showed the complete response of both primary and secondary liver tumors without any positive lymph node (yTNM8: T0, N0 (0/31), M0). Microscopic findings described only fibrosis and mucin in rectal tumor residue [Figure 1(l)] and multiple necrotic nodules surrounded by fibro-vascular septa in the liver specimen [Figure 1(m)]. The splenic tumor was characterized to be a benign sclerotic vascular tumor. In the follow-up period after 4 and 8 months we did not find any sign of malignancy. Four months after the operation, tumor markers were normal, and we found S3 without recurrence on the CT scan [Figure 1(n)] and two lesions in S7 that are described as fibrotic tissue [Figure 1(o) and (p)]. After 8 months, the CT scan did not show any sign of focal lesions in the liver and tumor markers were still in the normal range. Then we performed positronemission tomography (PET) and confirmed that the liver was free of malignancy and pelvis free of recurrent tumors. The patient is still free of recurrent disease.



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