Investigation of the Prognostic and Predictive Value of Thymidylate Synthase, p53, and Ki-67 in Patients With Locally Advanced Colon Cancer

Allegra, Carmen J.; Parr, Allyson; Wold, Lester E.; Mahoney, Michelle R.; Sargent, Daniel J.; Johnston, Patrick G.; Klein, Pamela; Behan, K A; O’Connell, Michael J.; Levitt, Ralph; Kugler, John W.; Tirona, Maria Tria; Goldberg, Richard M.

doi:10.1200/jco.2002.07.080

Cited by 157 publications

(120 citation statements)

References 33 publications

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“…In a recently published study, for example, a significant correlation between protein expression and tumour response in rectal cancer patients was seen only when both staining intensity and staining pattern were considered, with a significant association between high TS expression in tumour biopsies and non-response to therapy (P ¼ 0.04) (Jakob et al, 2005). In our study, we used a four chromagen intensity grade, ranging from 0 to 3, where 0 and 1 were defined as low intensity, and 2 and 3 were defined as high intensity staining, as reported previously (Allegra et al, 2002). The existence of such a high variability supports the demand for a more uniform evaluation of IHC expression.…”

Section: Discussionmentioning

confidence: 95%

Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy

et al. 2007

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We analysed the expression of microsatellite instability, p53, p21, vascular endothelial growth factor and thymidylate synthase (TS) in pretreatment biopsy specimens from 57 locally advanced rectal cancers. The aim of the study was to correlate the expression of these markers with pathological response. Nineteen patients were treated with preoperative concomitant radiotherapy (RT) and fluorouracil/oxaliplatin-based chemotherapy (RCT), while 38 had RT alone. Pathological complete remission (pCR) and microfoci residual tumour (micR) occurred more frequently in patients treated with RCT (P ¼ 0.002) and in N0 tumours (P ¼ 0.004). Among patients treated with RCT, high TS levels were associated with a higher response rate (pCR þ micR; P ¼ 0.015). No such correlation was found in the RT group. The other molecular factors were of no predictive value. Multivariate analysis confirmed a significant interaction between nodal status and the probability of achieving a pathological response (P ¼ 0.023) and between TS expression and treatment, indicating that a high TS level is predictive of a higher pathological response in the RCT subset (P ¼ 0.007). This study shows that lymph node status is the most important predictive factor of tumour response to preoperative treatment. Thymidylate synthase expression assessed immunohistochemically from pretreatment tumour biopsies may be a useful predictive marker of rectal tumour response to preoperative RCT.

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Section: Discussionmentioning

confidence: 95%

Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy

et al. 2007

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“…Although mucinous tumours occur more frequently in the proximal colon, leftsided and rectal mucinous tumours have an overall worse prognosis relative to location-matched nonmucinous tumours (Green et al, 1993). This finding may be at least partially explained by over-expression of both p53 (Lenz et al, 1996) and thymidylate synthase (Allegra et al, 2002) in left-sided tumours, although no previous study has examined expression in the mucinous subset alone. Based on these genetic differences and its more aggressive clinical behaviour, some authors have suggested that mucinous adenocarcinomas should be categorised and treated as a biological entity distinct from other colorectal adenocarcinomas (Consorti et al, 2000).…”

Section: Discussionmentioning

confidence: 98%

Unfavourable expression of pharmacologic markers in mucinous colorectal cancer

Glasgow

Carvalho

et al. 2005

Br J Cancer

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Patients with mucinous colorectal cancer generally have worse prognoses than those with the nonmucinous variety. The reason for this disparity is unclear, but may result from a differential response to adjuvant chemotherapy. We examined known molecular markers for response to common chemotherapy in these two histological subtypes. In all, 21 patients with mucinous and 30 with nonmucinous Dukes C colorectal cancer were reviewed for demographic data and outcome. Total RNA from the tumours and adjacent normal mucosa was isolated and reverse transcribed. Quantitative expression levels of drug pathway genes were determined using TaqMan RT -PCR (5-fluorouracil (5-FU): TYMS, DPYD, ECGF1; oxaliplatin: GSTP1 (glutathione S-transferase pi), ERCC1 and 2; irinotecan: ABCB1, ABCG2, CYP3A4, UGT1A1, CES2, TOP1). Mucinous tumours significantly overexpressed both TYMS and GSTP1 relative to nonmucinous tumours and patient-matched normal mucosa. No significant differences in expression of the remaining markers were found. Mean follow-up was 20 months; 17 patients had recurrent disease. Among patients receiving 5-FU, those with mucinous tumours experienced shorter disease-free survival (DFS) than those with nonmucinous tumours (median DFS 13.8 vs 46.5 months, P ¼ 0.053). Mucinous colorectal cancer overexpresses markers of resistance to 5-FU and oxaliplatin. Likewise, DFS may be decreased in patients with mucinous tumours who receive 5-FU. The presence of mucin should be carefully evaluated in developmental trials of new agents for treating colorectal cancer.

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“…Several retrospective studies have suggested that a number of markers may now define patients with a higher risk of relapse with both stage II and stage III disease. These markers include studies examining 18q LOH, microsatellite instability, and thymidylate synthase [11][12][13][14]. The most promising candidate markers at present are allelic loss of chromosome 18q and microsatellite instability.…”

Section: Molecular Markersmentioning

confidence: 99%

Stage II Colorectal Cancer: To Treat or not to Treat

Johnston¹

2005

The Oncologist

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Investigation of the Prognostic and Predictive Value of Thymidylate Synthase, p53, and Ki-67 in Patients With Locally Advanced Colon Cancer

Abstract: This retrospective investigation failed to demonstrate a significant association between TS, Ki-67, or p53 staining and clinical outcome.

Cited by 157 publications

References 33 publications

Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy

Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy

Unfavourable expression of pharmacologic markers in mucinous colorectal cancer

Stage II Colorectal Cancer: To Treat or not to Treat

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