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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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 to 25.0% 10-year survival [12]. Even then, the recurrence
rate is high, and about 75.0% of all recurrences are seen
in the first 2 years [2].
Chemotherapy can prolong recurrence-free survival
[4,13], increase resectability of liver metastases [14] and
has an impact on overall survival [15]. Different regimens 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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