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
page: 75
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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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