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Cancer of the Colon and Rectum: Prognostic Factors and Early Detection
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal cancer (CRC) is one of the most common causes of death from malignant disease. Nevertheless, no ideal screening method exists and there is a lack of prognostic and predictive factors to support clinical decisions and to aid the development of a more individualized treatment for patients with CRC. The aim of this thesis was to investigate early detection, prognostic and predictive factors of CRC. In the first paper, a novel method to collect cells for DNA quantification from the rectal mucosa was investigated. The sensitivity and specificity of this test to detect CRC or any pathology in colon and rectum were ultimately too low to be acceptable. In the second paper, the prognostic value of growth differentiation factor 15 (GDF 15) was evaluated in patients curatively operated for colorectal cancer. GDF 15 expression was demonstrated to be associated with a negative prognosis in patients with stages I-III and III disease. In the third paper, the prognostic value of BRAF, PIK3CA KRAS and MSI was evaluated in a cohort of patients with CRC stratified by disease and recurrence. The results indicated that patients with CRC stage III without recurrence have a higher frequency of BRAF mutation compared to stage III patients with recurrence. In the fourth paper, histopathological predictors of pathologic complete response (pCR) as well as the association between pre-treatment carcinoembryonic antigen (CEA) levels and pCR in non-smoking and smoking patients receiving preoperative chemo-radiotherapy for rectal cancer were evaluated. Only in non-smokers was a low CEA level significantly associated with pCR, suggesting that the predictive value of CEA for pCR in rectal cancer in smokers can be limited. In sum, this research has investigated a new method for CRC detection and further evaluated the clinical use of prognostic and predictive markers in CRC.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 83 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 706
Keyword [en]
colorectal cancer screening predictive markers prognostic markers
National Category
Surgery
Identifiers
URN: urn:nbn:se:uu:diva-159142ISBN: 978-91-554-8166-7 (print)OAI: oai:DiVA.org:uu-159142DiVA: diva2:442592
Public defence
2011-11-04, Hedstrand salen, Akademiska sjuhuset, ing. 70 bv, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-10-14 Created: 2011-09-22 Last updated: 2012-06-14Bibliographically approved
List of papers
1. Microsatellite instability, KRAS, BRAF and PIK3CA mutations in patients operated for stage II and III colorectal cancer
Open this publication in new window or tab >>Microsatellite instability, KRAS, BRAF and PIK3CA mutations in patients operated for stage II and III colorectal cancer
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The aims of this study were to molecularly characterize tumors from disease stage II and III colorectal cancer (CRC) patients with regard to BRAF, PIK3CA, KRAS mutations and microsatellite instability (MSI) status, and to compare the frequency of the mutations in patients stratified by disease recurrences.

Material and methods

BRAF, PIK3CA, KRAS mutations and MSI status were analyzed in fresh frozen tumors from patients with CRC. The analyzed tissue was selected from curatively treated patients with disease stage II and III. These patients were stratified for disease recurrence; stage II without recurrence (n=19) and with recurrence (n=18) and stage III without recurrence (n=17) and stage III with recurrence (n=19).

 

 

Results

 

No major difference in frequency of mutations in BRAF, KRAS, PIK3CA and MSI was demonstrated between patients with or without recurrence or disease stages II-III. Occurrence of any of the analyzed mutations (BRAF, KRAS and PIKC3A) was more frequent when the tumor was localized in the colon (98%) versus the rectum (2%) (p=0.015). MSI tumors demonstrated a high frequency of BRAF mutations (63%) and a low frequency of KRAS mutations (1%). Tumors of patients without recurrence revealed higher frequency of MSI (p=0.038). BRAF mutations were more abundant in patients with stage III disease without recurrence (n=7) compared to stage III patients with recurrence (n=2). Patients with stage III disease and BRAF mutation had a better cancer specific survival, compared with patients in stage III without BRAF mutation (p=0.043).

 

Conclusion

 

The results indicate that patients with CRC stage III without recurrence have a higher frequency of BRAF mutation compared to stage III patients with recurrence, moreover those patients with stage III disease and BRAF mutation have better prognosis than those with stage III disease and no BRAF mutation.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-159140 (URN)
Available from: 2011-09-22 Created: 2011-09-22 Last updated: 2011-11-04
2. Pathological Complete Response after long-course Neoadjuvant Chemoradiation Therapy for Rectal Cancer: Predictive factors and the impact of smoking status
Open this publication in new window or tab >>Pathological Complete Response after long-course Neoadjuvant Chemoradiation Therapy for Rectal Cancer: Predictive factors and the impact of smoking status
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: The standard treatment for patients diagnosed with rectal cancer is surgery, and, depending on the clinical stage of the tumor, it is frequently combined with preoperative chemo-radiation therapy (CRT). Preoperative CRT results in pathologic complete response (pCR) in about 10-30% of patients.  Accurate prediction of that response could avoid surgery. The aim of this study was to identify clinical and histopathological predictors of pCR as well as the association between pre-treatment CEA levels and pCR in non-smoking and smoking patients receiving preoperative CRT for rectal cancer.

Methods: One thousand and two hundred and thirty patients diagnosed between 1998 and 2009 with primary rectal adenocarcinoma without any evidence of distant metastasis and operated with a radical total mesorectal excision (TME) resection were identified. A total of 449 patients remained for inclusion in the study after excluding patients with any of the following: no neoadjuvant CRT (n=720) history of pelvic radiation treatment (n=2), previous transanal endoscopic microsurgery or polypectomy of the primary lesion (n=15), concurrent malignant tumor (n=14), and no information about pre- or post-treatment T stage in the chart (n=30). The clinical tumor stage and size were assessed by endorectal ultrasound, MRI, CT, flexible sigmoidoscopy/colonoscopy, chest X-ray and PET-CT. Pathologic complete response was defined as absence of viable tumor cells in the rectal wall and in any of the resected lymph nodes. CRT consisted of a 5-fluorouracil-based regimen and external beam radiation with a mean radiation dose of 50 Gy given over a mean of 5.6 weeks.

Results: Ninety-one patients (20%) achieved pCR and 85 patients (19%) had only microscopic residual disease left at the time of surgery. In patients with pCR, pretreatment tumor size was smaller, 4.2 cm (95% C.I 3.8-4.6 cm) vs. 4.8 cm (95% C.I 4.6-5.0 cm), and pretreatment CEA was significantly lower, 3.4 ng/ml (95% C.I 2.3-4.6 ng/mL) vs. 10.0 ng/mL (95% C.I 7.5-12.5 ng/ml), when compared to the group with no pCR. When stratifying for smoking status, CEA was significantly associated with pCR only in the group with non-smokers (p=0.018). When adjusting for number of cigarettes smoked per week in the multivariate analysis, CEA was no longer significantly associated with pCR.

Conclusions: In non-smokers a low CEA level are significantly associated with pCR. The predictive value of CEA in smokers can be limited and further studies needs to evaluate the impact of smoking on the predictive value of CEA for pCR in rectal cancer.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-159141 (URN)
Available from: 2011-09-22 Created: 2011-09-22 Last updated: 2011-11-04
3. Growth differentiation factor 15: a prognostic marker for recurrence in colorectal cancer
Open this publication in new window or tab >>Growth differentiation factor 15: a prognostic marker for recurrence in colorectal cancer
Show others...
2011 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, no 10, 1619-1627 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor beta superfamily and has been associated with activation of the p53 pathway in human cancer. The aim of this study was to assess the prognostic value of GDF15 in patients with colorectal cancer (CRC). METHODS: Immunohistochemistry and tissue microarrays were used to analyse GDF15 protein expression in 320 patients with CRC. In a subgroup of 60 patients, the level of GDF15 protein in plasma was also measured using a solid-phase proximity ligation assay. RESULTS: Patients with CRC with moderate to high intensity of GDF15 immunostaining had a higher recurrence rate compared with patients with no or low intensity in all stages (stages I-III) (HR, 3.9; 95% CI, 1.16-13.15) and in stage III (HR, 10.32; 95% CI, 1.15-92.51). Patients with high plasma levels of GDF15 had statistically shorter time to recurrence (P = 0.041) and reduced overall survival (P = 0.002). CONCLUSION: Growth differentiation factor 15 serves as a negative prognostic marker in CRC. High expression of GDF15 in tumour tissue and high plasma levels correlate with an increased risk of recurrence and reduced overall survival.

Keyword
GDF15, colorectal cancer, prognostic markers, MIC-1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-154348 (URN)10.1038/bjc.2011.112 (DOI)000290471600014 ()21468045 (PubMedID)
Available from: 2011-05-31 Created: 2011-05-31 Last updated: 2017-12-11Bibliographically approved
4. Can DNA sampling from the rectal mucosa be a novel tool for the detection of colorectal cancer?
Open this publication in new window or tab >>Can DNA sampling from the rectal mucosa be a novel tool for the detection of colorectal cancer?
Show others...
2010 (English)In: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 25, no 9, 1071-1078 p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: The objective was to evaluate a new method for DNA sampling from the rectal mucosa for the detection of colorectal cancer or any clinically significant pathology in the colon and rectum. METHODS: This prospective cohort study included patients scheduled for colonoscopy (group 1, n = 185) or colonic resection because of suspected colorectal cancer (group 2, n = 62). A test instrument with a balloon-holding end was introduced through a proctoscope into the rectum to collect exfoliated cells, from which DNA was isolated and quantified. RESULTS: The detection of colorectal cancer in group 1 showed a sensitivity for the DNA cut-off levels 1.5, 2, and 2.5 microg/ml of 100%, 80%, and 60%, and a specificity of 37%, 46%, and 56%, respectively. In group 2, for the same cut-off levels, the sensitivity was 73%, 61%, and 55%, and the specificity was 67%, 67%, and 67%, respectively. CONCLUSIONS: This novel technique is a safe and easy way of collecting DNA from the rectal mucosa. The sensitivity and specificity of the test were too low to be acceptable for a screening test. The low sensitivity and specificity in this study could be explained by the diversity within the study groups as many patients presented with long-term history of colorectal disease and surgical interventions in the past.

Keyword
Colon cancer, Rectal cancer, Screening, Fecal DNA, Exfoliated colonocyte collection
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-133091 (URN)10.1007/s00384-010-0979-5 (DOI)000280578500005 ()20563588 (PubMedID)
Available from: 2010-11-02 Created: 2010-11-02 Last updated: 2017-12-12Bibliographically approved

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