Predictive significance of VEGF and HIF-1α expression in metastatic colorectal cancer patients receiving chemotherapy combined with bevacizumab.

e14672 Background: There is no suggested molecular indicator in identifying which patients will benefit from anti-angiogenic treatment in metastatic colorectal cancer. Over expression of vascular endothelial growth factor (VEGF) and Hypoxia Inducible Factor 1-alpha (HIF-1α) are associated with bad prognosis. In this study, VEGF and HIF-1α expression and their clinical significance are studied in tumor tissues of patients with colorectal cancer receiving treatment with bevacizumab. Methods: VEGF and HIF-1α were observed immunohistochemically in primary tumors of 53 patients. The expressions were separated by evaluating low and high of VEGF and HIF-1α expression. We evaluated whether expression of VEGF and HIF-1α can help to predict treatment response, progression free survival (PFS), and overall survival (OS). Results: Fifty-three patients were enrolled in the study. Median age was 55. VEGF was strongly expressed in 30 patients (57%) whilst low expression was observed in 23 of them (43%). When VEGF expression was evaluated in association with therapy response rates; the clinical benefit rate was 38% in the low expression group whereas it was 62% in high expression group. This difference was statistically significant (p=0.01). In the group with strong VEGF expression PFS was 10 months whereas it was 8 months in the low expression group (p=0.009). When evaluated for OS, 26 months versus 15 months was in favor of highly expressed VEGF group (p=0.03). Highly expressed HIF-1α was found in 29 patients (55%), on the other hand low expressed HIF-1α was detected in 24 (%45) patients. For clinical benefit rates, PFS and OS there was no difference between high and low expressed HIF-1α groups. Conclusions: It has been demonstrated that VEGF and HIF-1α expressions are associated with poor prognosis in several tumors, mainly colorectal carcinomas. With the better understanding of carciogenesis and angiogenesis at molecular level, especially VEGF and HIF-1α became target molecules of the therapy. According to results of our study, VEGF expression is a predictive factor in designating the metastatic colorectal cancer treatment.

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Use of VEGF expression to predict for first-line treatment chemotherapy regimen in metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14695 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14695-e14695

Author(s):

Metin Ozkan ◽

Veli Berk ◽

Kemal Deniz ◽

Halit Karaca ◽

Mevlude Inanc ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Metastatic Colorectal Cancer ◽

Survival Rates ◽

First Line ◽

Vegf Expression ◽

Treatment Protocols ◽

Primary Tumors ◽

Study Results ◽

Low Expression

e14695 Background: In metastatic colorectal cancer treatment more successful results are achieved by adding anti-angiogenic therapy to the chemotherapy. Over expression of VEGF in colorectal cancer is known to be a poor prognosis factor but its effects on designating the therapy is not clear. In this study, results of the patients receiving FOLFIRI + Bevacizumab or XELOX + Bevacizumab were compared for VEGF expression. Methods: VEGF was assessed immunohistochemically in primary tumors of the 53 metastatic colorectal cancers. Severity and conformity of VEGF expression was evaluated. Results were used to assess the association with the therapy response, progression free survival (PFS) and overall survival (OS). Results: The median age of the patients was 55 (range, 32-79). In combination with bevacizumab 38 patients received FOLFIRI and 15 patients received XELOX. In 30 patients (57%) there was a strong expression of VEGF and in 23 patients (23%) the expression was weak. In the high VEGF expression group, PFS was 11 months in FOLFIRI receiving patients and 8 months in XELOX receiving ones but in low expression group PFS was 8 months in patients receiving either one of the two treatment protocols. In high expression group, PFS in FOLFIRI-bevacizumab combination receiving patients was different and this difference was statistically significant (p=0.009). Overall survival in FOLFIRI receiving patients with high VEGF expression was 26 months and with low VEGF expression it was 16 months (p=0.04). Median OS was not reached in the XELOX receiving patient group. FOLFIRI regime clinical benefit was 58% in high VEGF expression group whilst it was 34% in low expression group. This difference was not statistically significant but it was close to the significance threshold (p=0.06). There was no association between the therapy responses and VEGF expression of the 15 patients who received XELOX. Conclusions: There is no difference in efficacy between the first line chemotherapy regimens of the metastatic colorectal cancer. In this study, in metastatic colorectal patients with over expressed VEGF first line FOLFIRI-bevacizumab combination led to better response and survival rates.

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Clinical usefulness of mtTFA expression as a predictive marker in colorectal cancer patients treated with FOLFOX

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4059 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4059-4059

Author(s):

Y. Yoshida ◽

J. Hasegawa ◽

R. Nezu ◽

Y. Kim ◽

M. Hirota ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Outcome ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Progression Free Survival ◽

Physical Interaction ◽

Primary Tumors ◽

P53 Expression ◽

Response To Chemotherapy ◽

Colorectal Cancer Patients

4059 Background: We previously reported that mitochondrial transcription factor A (mtTFA; also designated Tfam) preferentially recognizes cisplatin-damaged DNA via physical interaction with p53 and is upregulated by the treatment with cisplatin and 5-FU (Yoshida et al, Cancer Res. 2003). The aim of this study was to evaluate whether expression of mtTFA predicts clinical outcome in patients with metastatic colorectal cancer treated with modified FOLFOX6 (mFOLFOX6). Methods: From January 2006 to April 2008, 59 patients who had metastatic lesions from colorectal cancer treated with mFOLFOX6 at the Osaka Rosai Hospital were included in this study. They consisted of 25 women (42.4%) and 34 men (57.6%), with a median age of 62 years (29–84). Patients were treated with oxaliplatin 85mg/m2 plus leucovorin 200mg/m2 as a 2-h infusion at day 1, followed by 5-FU bolus 400mg/m2 and 46-h continuous infusion of 2400 mg/m2. Treatment was repeated in 2-week intervals for at least 4 cycles. The expressions of mtTFA and p53 of resected primary tumors were examined by immunohistochemistry. Results: Among 59 patients, one complete response and 32 partial responses were observed (response rate, 55.9%) . The positive rates was 44.1% (26/59; CR 1, PR 7, SD/PD 18) for mtTFA and 59.3% (35/59; CR 1, PR 19, SD/PD 15) for p53, respectively. Strong expression of mtTFA was detected in 8 of 33 CR/PR (24.2%) and in 18 of 26 SD/PD (69.2%), indicating that the expression of mtTFA correlated significantly with response to chemotherapy (P<0.01). On the other hand, there was no significant correlation between response to chemotherapy and p53 expression (P=0.82). mtTFA expression was significantly associated with overall survival (P=0.036) and progression free survival (P=0.037). Multivariate analysis revealed that mtTFA expression significantly impacted on OS (Hazard ratio 2.10, P=0.036). Conclusions: Immunohistochemical study of mtTFA may be useful in prediction of the clinical outcome of metastatic colorectal cancer patients treated with FOLFOX. No significant financial relationships to disclose.

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Phosphorylated Akt and MAPK expression in primary tumors and in corresponding metastases and clinical outcome in colorectal cancer patients receiving irinotecan-cetuximab.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14086 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14086-e14086

Author(s):

Riccardo Giampieri ◽

Mario Scartozzi ◽

Elena Maccaroni ◽

Alessandra Mandolesi ◽

Simona Biagetti ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Progression Free Survival ◽

Primary Tumors ◽

Kaplan Meier ◽

Phosphorylated Akt ◽

Line Setting ◽

Colorectal Cancer Patients

e14086 Background: Other than the well-known EGFR pathway activation via the Ras-Raf-MAP-kinase, a possible role of other potential biomarkers could be relevant in determining resistance to anti-EGFR treatment, such as the protein-serine/threonine kinase Akt. We tried to assess the role of Akt and MAPK expression in metastatic colorectal cancer patients and their relationship with outcome for patients receiving Irinotecan-Cetuximab. Methods: Eligible patients were metastatic colorectal cancer patients treated in 2nd or 3rd line setting with a irinotecan-cetuximab based regimen. Patients were tested for K-ras status and subsequently assessed by immunoistochemistry for pAkt and MAPK expression, both in primary tumours and metastases whenever sufficient tissue was available. The role of pAkt and MAPK expression was evaluated for K-ras wild type patients for different likelihood of response, overall survival and progression free survival. Response was evaluated by RECIST criteria. Survival analysis was performed via Kaplan-Meier method. Results: In metastases pAkt correlated with RR (9% vs. 58%, p=0.004), PFS (2.3 months vs.9.2 months p < 0.0001) and OS (6.1 months vs.26.7 months p < 0.0001) and pMAPK correlated with RR (10% vs, 47%, p = 0.002), PFS (2.3 months vs.8.6 months p < 0.0001) and OS (7.8 months vs.26 months p=0.0004). At multivariate analysis pAkt and pMAPK in metastases were able to independently predict PFS. pAkt in metastases independently correlated with RR as well. Conclusions: pAkt and pMAPK expression in metastases may modulate the activity of EGFR-targeted antibodies. We could speculate that in patients with pAkt and pMAPK metastases expression targeting these factors may be crucial.

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NPY Gene Methylation as a Universal, Longitudinal Plasma Marker for Evaluating the Clinical Benefit from Last-Line Treatment with Regorafenib in Metastatic Colorectal Cancer

Cancers ◽

10.3390/cancers11111649 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1649 ◽

Cited By ~ 2

Author(s):

Lars Henrik Jensen ◽

René Olesen ◽

Lone Noergaard Petersen ◽

Anders Kindberg Boysen ◽

Rikke Fredslund Andersen ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Clinical Benefit ◽

Progression Free Survival ◽

Prospective Clinical Study ◽

Line Treatment ◽

Early Effect ◽

Methylated Dna ◽

Colorectal Cancer Patients

There is a need for biomarkers to improve the clinical benefit from systemic treatment of colorectal cancer. We designed a prospective, clinical study where patients receiving regorafenib as last-line treatment had sequential blood samples drawn. Effect and toxicity was monitored. The primary clinical endpoint was progression free survival (PFS). Cell-free circulating tumor (ct) DNA was measured as either the fraction with Neuropeptide Y (NPY) methylated DNA or KRAS/NRAS/BRAF mutated ctDNA. One hundred patients were included from three Danish centers. Among 95 patients who received regorafenib for at least two weeks, the median PFS was 2.1 months (95% confidence interval (CI) 1.8–3.3) and the median overall survival (OS) was 5.2 months (95% CI 4.3–6.5). Grade 3–4 toxicities were reported 51 times, most frequently hypertension, hand-food syndrome, and skin rash. In the biomarker population of 91 patients, 49 could be monitored using mutated DNA and 90 using methylated DNA. There was a strong correlation between mutated and methylated DNA. The median survival for patients with a level of methylated ctDNA above the median was 4.3 months compared to 7.6 months with ctDNA below the median, p < 0.001. The median time from increasing methylated ctDNA to disease progression was 1.64 months (range 0.46–8.38 months). In conclusion, NPY methylated ctDNA was a universal liquid biopsy marker in colorectal cancer patients treated with regorafenib. High baseline levels correlated with short survival and changes during treatment may predict early effect and later progression. We suggest plasma NPY methylation analysis as an easy and universally applicable method for longitudinal monitoring of ctDNA in metastatic colorectal cancer patients.

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