Thymidylate Synthase Protein Expression in Primary Colorectal Cancer Compared with the Corresponding Distant Metastases and Relationship with the Clinical Response to 5-Fluorouracil

• Published in: Clinical cancer research Vol. 6; no. 12; pp. 4797 - 4802
• Main Authors: ASCHELE, Carlo, DEBERNARDIS, Domizia, TUNESI, Gianni, MALEY, Frank, SOBRERO, Alberto
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-12-2000
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adult; Aged; Antimetabolites, Antineoplastic - therapeutic use; Biological and medical sciences; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Female; Fluorouracil - therapeutic use; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Immunohistochemistry; Male; Medical sciences; Middle Aged; Neoplasm Metastasis; Recombinant Proteins - metabolism; Rectal Neoplasms - drug therapy; Rectal Neoplasms - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Thymidylate Synthase - biosynthesis; Treatment Outcome; Tumor Suppressor Protein p53 - biosynthesis; Tumors; Antineoplastic agent; Rectal disease; Prognosis; Gene product; Tumoral tissue; Metastasis; Intestinal disease; Colon; Fluorouracil; Human; Enzyme; Transferases; Treatment efficiency; Fluoropyrimidine derivatives; Malignant tumor; Gene expression; Thymidylate synthase; In vitro; Colonic disease; Chemotherapy; Treatment; Methyltransferases; Rectum; Digestive diseases; Pyrimidine derivatives; Predictive factor; Comparative study
• ISSN: 1078-0432; 1557-3265

Thymidylate synthase (TS) expression in colorectal cancer metastases has
been shown to predict for the clinical response to 5-fluorouracil.
Because primary tumors may easily provide accessible sources of tissue
for marker analysis, we have investigated the stability of TS
expression between primary colorectal cancer and the corresponding
distant metastases and compared their relative ability to predict
response to chemotherapy on a series of 27 patients homogeneously
treated with biochemically modulated fluorouracil for advanced
disease. By immunohistochemistry, high levels of TS expression
were observed in 19 of 27 (70%) primary tumors and in 13 of 27 (48%)
metastatic samples. Overall, TS levels observed in primary tumors did
not correlate with those measured in the corresponding metastases
( r = 0.30, P = 0.13), with
higher TS levels in primary tumors in 8 of 10 discordant cases.
Accordingly, the degree of TS immunoreactivity was significantly higher
in primary tumors compared with the corresponding metastases (mean TS
score 3.8; median, 4 versus 2.8; median 3;
P = 0.001). Response rates after chemotherapy for
metastatic disease were similar for patients with low and high TS
levels in their primary tumors (37% versus 53%,
P = 0.47). In contrast, response rates were 71%
and 23% in patients with low and high TS in metastatic samples
( P = 0.012), respectively. In summary, TS levels
measured in primary colorectal cancer do not reflect those observed in
the corresponding metastases and cannot be used to predict their
response to chemotherapy. The basis for the higher TS content of
primary colorectal cancer compared with the corresponding metastases
needs clarification.