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. 2019 Apr;17(4):3890-3898.
doi: 10.3892/ol.2019.10043. Epub 2019 Feb 14.

Tumor response to irinotecan is associated with CYP3A5 expression in colorectal cancer

Emanuel Buck  1 , Martin Sprick  2 , Matthias M Gaida  3 , Carsten Grüllich  4 , Tim Frederik Weber  5 , Esther Herpel  3 , Thomas Bruckner  6 , Ronald Koschny  1
Affiliations

Tumor response to irinotecan is associated with CYP3A5 expression in colorectal cancer

Emanuel Buck et al. Oncol Lett. 2019 Apr.

Abstract

Recently, a tumor-autonomous cytochrome P450 (CYP)-3A5-mediated resistance to cancer therapy has been demonstrated in pancreatic ductal adenocarcinoma. Expression of CYP3A5, which is involved in the degradation of irinotecan, has also been reported in colorectal cancer (CRC). The aim of the present study was to analyze CYP3A5 expression in the normal colon, colon adenoma, CRC and normal tissues, as well as to examine whether CYP3A5 expression in CRC has an impact on tumor response to irinotecan treatment. Immunohistochemistry was used to assess 85 tissue samples from 65 patients with CRC, along with 15 samples of normal colon and 45 samples of colon adenoma (including tubular, tubulovillous, and sessile serrated adenomas), and a tissue microarray (TMA) comprised of 26 different normal tissue types. Expression of CYP3A5 was evaluated with a semi-quantitative score. Tumor response to irinotecan therapy was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. In normal tissues, CYP3A5 was expressed in epithelial cells of the colon, gallbladder, kidney, liver, small intestine, stomach, thyroid gland and tonsil, as well as in nerves. Expression in colon mucosa was heterogeneous, with only weak staining in the minority of specimens. CYP3A5 exhibited markedly higher expression in adenomas compared with normal colon tissues. A statistically significant inverse correlation was identified between CYP3A5 expression in CRC tissues and tumor response to irinotecan therapy. Irinotecan treatment itself did not alter CYP3A5 expression in CRC tissues. As CYP3A5 is involved in the degradation of irinotecan, the significantly higher intratumoral expression of CYP3A5 in patients with CRC who do not respond to irinotecan-based chemotherapy may indicate a causal role of CYP3A5 in tumor resistance.

Keywords: RECIST; colorectal adenoma; colorectal cancer; cytochrome P450 3A5; immunohistochemistry; irinotecan; resistance.

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Figures

Figure 1.
Figure 1.
Examples of semiquantitative scoring of CYP3A5 expression. Magnification, ×400. (A) CYP3A5-negative. (B) CYP3A5-positive with weak staining. (C) CYP3A5-positive with moderate staining. (D) CYP3A5-positive with strong staining. CYP3A5, cytochrome P450 3A5.
Figure 2.
Figure 2.
Assessment of immunohistochemical staining in CYP3A5-positive normal tissues included in TMA. The figure presents the medians, 25 and 75th percentiles, and the minimums and maximums of the scores in CYP3A5-positive normal tissues of TMA. Medians: Colon 0, gallbladder 0, kidney 0, liver 0, small intestine 0, stomach 5, thyroid gland 0, and tonsil 0. *P<0.05 and **P<0.01, as indicated. CYP3A5, cytochrome P450 3A5; TMA, tissue microarrays.
Figure 3.
Figure 3.
Examples of CYP3A5-positive immunohistochemical staining in normal tissues. Magnification, ×100. (A) Colon. (B) Gallbladder. (C) Kidney. (D) Liver. (E) Small intestine. (F) Stomach. (G) Thyroid gland. (H) Tonsil. (I) Ganglion cells. CYP3A5, cytochrome P450 3A5.
Figure 4.
Figure 4.
Assessment of immunohistochemical staining in normal colon and colon adenomas. The figure presents the medians, 25 and 75th percentiles, and the minimums and maximums of the scores in the normal colon (median, 0), sessile serrated adenoma (median, 0), tubular adenoma (median, 10), and tubulovillous adenoma (median, 0). *P<0.05, as indicated.
Figure 5.
Figure 5.
Examples of CYP3A5-positive immunohistochemical staining in the normal colon and colon adenomas. Magnification, ×400. (A) Normal colon. (B) Sessile serrated adenoma. (C) Tubular adenoma. (D) Tubulovillous adenoma. CYP3A5, cytochrome P450 3A5.
Figure 6.
Figure 6.
Assessment of immunohistochemical staining as a function of therapy response under irinotecan treatment. The figure presents the medians, 25 and 75th percentiles, and minimums and maximums of the scores in every category of the tumor response under treatment with irinotecan. Medians in all categories: 0. Analysis included 61 patients; a total of 53 specimens were irinotecan-naïve and 8 were obtained following treatment with irinotecan. *P<0.05, as indicated. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
Figure 7.
Figure 7.
Examples of CYP3A5 immunohistochemical staining in colorectal carcinoma. CRC tissue with best response to irinotecan: CR (responder), at magnification (A) ×100 and (B) ×400. PD (non-responder), at magnification (C) ×100 and (D) ×400. CYP3A5, cytochrome P450 3A5. CR, complete response; PD, progressive disease; CRC, colorectal cancer.
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