Rosa Gallego

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

Metalloproteinase 7 (MMP‐7) plays an important role in tumor growth, invasion and dissemination, and is secreted to the media. Because of the close implication of MMP‐7 in cancer biology, we sought to define the prognostic significance of serum levels of MMP‐7 in metastatic colorectal cancer (CRC) and explore its possible impact in the daily clinical practice. MMP‐7 expression was determined by enzyme‐linked immunoabsorbent assay. We assessed serum MMP‐7 levels in 87 healthy controls, 96 patients with nonmetastatic CRC and 120 patients with advanced CRC. Clinical information was gathered from patient files. Cox proportional hazards model was used to assess survival. MMP‐7 and the variables associated with prognosis were entered and a backward elimination method was employed to adjust the model. Inclusion criteria was p ≤≤≤≤ 0.05 and exclusion criteria was p ≥≥≥≥ 0.10. Advanced CRC patients have a significant higher mean serum MMP‐7 levels (13.4 ng/ml) than those in nonmetastatic CRC (5.5 ng/ml; p < 0.001) and healthy controls (4.2 ng/ml; p < 0.001). In metastatic patients, after adjusting for other prognostic variables, MMP‐7 (entered as a continuous variable) is associated with decreased survival (HR 1.016, IC 95% 1.002–1.031). Serum MMP‐7 levels are significantly elevated in patients with advanced CRC. In conclusion, MMP‐7 is an independent prognostic factor for survival in advanced CRC. In our sample, the risk of death associated to MMP‐7 increase is much higher than the risk of death associated to lactate dehydrogenase elevation.

FAS/FAS Ligand Ratio: A Marker of Oxaliplatin-Based Intrinsic and Acquired Resistance in Advanced Colorectal Cancer

Purpose: Oxaliplatin-5-fluorouracil combinations have increased responses in first-line therapy up to 40% in advanced colorectal cancer. Unfortunately, those patients who will respond are unknown and initially sensitive patients become rapidly resistant to current therapies. FAS (CD95) and FAS ligand (FASL; CD95L) have been implicated in chemosensitivity through leading to apoptosis in response to DNA-damaging drugs. Whereas the proapoptotic role of FAS and FASL is well characterized, the function of their soluble forms as predictors of chemosensitivity remains unknown. Patients and Methods: Blood samples were obtained from 68 patients with advanced colorectal cancer who received oxaliplatin-5-fluorouracil combinations in first-line therapy. Computed tomographic scans were done every 3 months and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. ELISA soluble FAS and soluble FASL analysis were done before treatment and every 3 months until disease progression. Ratios between soluble FAS and soluble FASL were established and its values and variations through time were related to treatment responses. Results: We found a significant increase in soluble FAS levels and a significant decrease in FASL at 3 months compared with baseline (13.2 versus 10.02 ng/mL; P = 0.0001; 0.07 versus 0.14 ng/mL; P = 0.007, respectively). A significant increase in the soluble FASL levels up to 9 months (fourth to fifth extractions; 0.26 ng/mL) of therapy compared with first to third extractions (0.11 ng/mL; P = 0.003) was also found. A random effect regression statistical model determined that >1.2-fold increase in soluble FAS/soluble FASL ratio was a marker of chemosensitivity (P = 0.001). Conclusions: These data strongly indicate that an increment of soluble FAS/soluble FASL ratio after treatment could be an excellent marker of chemosensitivity in colorectal cancer. On the other hand, a decreased ratio after treatment can be a predictor of chemoresistance despite an initial response.

Toxicity of combined treatment of adjuvant irradiation and interferon α2b in high-risk melanoma patients

Surgically resected stage III melanoma patients commonly receive adjuvant therapy with interferon (IFN) &agr;2b. For those patients with high-risk features of draining node recurrence, radiation therapy can also be considered as a treatment option. The purpose of this retrospective study was to assess the efficacy and radiation-related toxicity of this combined therapy. Eighteen patients receiving adjuvant IFN&agr;2b therapy during radiation therapy, or within 1 month of its completion, were reviewed retrospectively and analysed for outcome. Radiation was delivered at 600 cGy dose per fraction, in 16 out of 18 patients, twice a week, and at 200 cGy dose per fraction in two patients five times a week. Total radiation dose and number of fractions were as follows: 30 Gy/5 fr (n=8), 36 Gy/6 fr (n=8) and 50 Gy/25 fr (n=2). The percentage of disease-free patients, with no local recurrence, at 3 years was 88%. In 10 patients, IFN&agr;2b was administered concurrently with radiotherapy; in three, within 30 days before or after radiation; and in five, more than 30 days after radiation. All the patients experienced acute skin reactions, grade I on the Radiation Therapy Oncology Group (RTOG) scale. Late radiation-related toxicity was seen in one patient with grade III (RTOG) skin reaction and two with grade IV (RTOG) radiation-induced myelitis. Concurrent use of adjuvant radiotherapy and IFN&agr;2b might enhance radiation-induced toxicity, and special care should be taken when the spinal cord is included in the radiation field.

RAC1b overexpression correlates with poor prognosis in KRAS/BRAF WT metastatic colorectal cancer patients treated with first-line FOLFOX/XELOX chemotherapy

INTRODUCTION Chemotherapy is the principal treatment in metastatic colorectal cancer (mCRC) patients. RAC1b, a RAC1 spliced variant, is over-expressed in colorectal cancer (CRC), and impairs apoptosis by activation of nuclear-factor-KB. Since RAC1b has been associated with the BRAF(V600E) mutation, associated with poor prognosis in CRC, we evaluated the role of RAC1b expression as a predictor of chemotherapy efficacy in mCRC. METHODS We analysed KRAS and BRAF mutation, microsatellite instability and RAC1b expression in 157 mCRC patients treated with FOLFOX/XELOX in first-line therapy. RESULTS KRAS mutations were detected in 46 patients (34%), 10 patients were BRAF mutant (7%) and 79 were WT for both, KRAS and BRAF (59%). RAC1b overexpression was found in 30 patients (19%). In the multivariate analysis, BRAF mutational status was a poor prognostic factor for overall survival (OS); hazard ratio (HR), 2.78 (95% confidence interval (CI), 1.35-5.72; p=0.0057). RAC1b overexpression was a poor survival factor for OS (HR, 2.35; 95% CI, 1.2-4.59; p=0.01) and progression-free survival (PFS) (HR, 2.4; 95% CI, 1.2-4.78; p=0.01) in KRAS/BRAF WT mCRC patients. CONCLUSIONS RAC1b overexpression constitutes a marker of poor prognosis in KRAS/BRAF WT mCRC patients treated with first-line FOLFOX/XELOX therapy.

Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation

AIM To evaluate the long-term results of conventional chemoradiotherapy and laparoscopic mesorectal excision in rectal adenocarcinoma patients without adjuvant therapy. METHODS Patients with biopsy-proven adenocarcinoma of the rectum staged cT3-T4 by endoscopic ultrasound or magnetic resonance imaging received neoadjuvant continuous infusion of 5-fluorouracil for five weeks and concomitant radiotherapy. Laparoscopic surgery was planned after 5-8 wk. Patients diagnosed with ypT0N0 stage cancer were not treated with adjuvant therapy according to the protocol. Patients with ypT1-2N0 or ypT3-4 or N+ were offered 5-fluorouracil-based adjuvant treatment on an individual basis. An external cohort was used as a reference for the findings. RESULTS One hundred and seventy six patients were treated with induction chemoradiotherapy and 170 underwent total mesorectal excision. Cancer staging of ypT0N0 was achieved in 26/170 (15.3%) patients. After a median follow-up of 58.3 mo, patients with ypT0N0 had five-year disease-free and overall survival rates of 96% (95%CI: 77-99) and 100%, respectively. We provide evidence about the natural history of patients with localized rectal cancer achieving a complete response after preoperative chemoradiation. The inherent good prognosis of these patients will have implications for clinical trial design and care of patients. CONCLUSION Withholding adjuvant chemotherapy after complete response following standard neoadjuvant chemoradiotherapy and laparoscopic mesorectal excision might be safe within an experienced multidisciplinary team.

Chemotherapy for elderly patients with advanced colorectal carcinoma.

There is an increasing need to redefine treatment strategies in elderly patients with advanced colorectal carcinoma since they constitute more than 50% of newly diagnosed patients. Taking into account that the vast majority of clinical trials in advanced colorectal carcinoma include patients up to 75 years old, it seems reasonable to consider those patients over 75 years as elderly. In general, 20% of patients have favorable factors (fewer than four liver nodules less than 5 cm in size) and are suitable for local treatments (surgery or local-ablative therapies). Additionally, 40% of patients have poor performance status or are severely disabled owing to geriatric syndromes and/or comorbid diseases (advanced stage) that preclude any treatment strategies. The remainder of patients (fit elderly patients not suitable for radical treatments) constitute the focus of this review.

Whole brain irradiation and temozolomide based chemotherapy in melanoma brain metastases

IntroductionWhole brain irradiation (WBRT) remains a recommended treatment for patients with brain metastases from malignant melanoma in terms of symptom palliation, especially when extracranial systemic disease is present. Temozolomide (TMZ) has shown efficacy in the treatment of metastatic melanoma. The objective was to evaluate the potential benefit in survival of two different schedules of total dose and fractionation (20 Gy/5 fractions vs 30 Gy/10 fractions) and further TMZ based chemotherapy.Materials and methodWe have conducted a retrospective study in a group of twenty-one patients (RTOG Recursive Partitioning Analysis class II) of the use of WBRT with 20 Gy/5 fractions (n=11) and 30 Gy/10 fractions (n=10). All patients received further TMZ based chemotherapy administered as a single chemotherapeutic agent or in combination with chemo-immunotherapy.ResultsPrognostic variables such as: age, Karnofsky performance status, extracranial metastases and number of brain metastases, were analyzed in both groups of treatment without statistically significant differences. The median survival time (MST) for WBRT 20 Gy group was 4 months (CI 95%: range 2–6 months) and for WBRT 30 Gy group was 4 months (CI 95%: range 0–7 months) without statistically significant differences (Log rank p=0.74). There was one complete response and two partial responses.ConclusionsThe results suggest that MST was not significantly affected by the total dose/fractionation schedule.

Co-expression of matrix metalloproteinase-7 (MMP-7) and phosphorylated insulin growth factor receptor I (pIGF-1R) correlates with poor prognosis in patients with wild-type KRAS treated with cetuximab or panitumumab: a GEMCAD study.

Background: By transactivacion, phosphorylated insulin growth factor receptor I (IGF-1R) can activate epidermal growth factor receptor (EGFR). MMP-7, produced by colorectal cancer cells, also can activate IGF-1R by degrading IGFBP-3 and releasing IGF-I. Methods: A cohort of patients (pts) with advanced colorectal cancer (CRC), under second- or third-line treatment with cetuximab or panitumumab, was tested using immunohistochemistry for expression of the activated form of IGF-1R (p-IGF-1R) and MMP-7. KRAS and BRAF mutation status was determined by sequencing and allelic discrimination analysis, respectively. Analyses were performed in primary CRC tumor samples or metastases, and the association of immunohistochemistry findings, mutational results, and treatment outcomes was investigated in both univariate and multivariate analyses. Results: Expression of activated IGF-1R and MMP-7 was observed in 51 and 49% of pts, respectively. Co-expression of MMP-7 and pIGF-1R (double positivity, DP) was observed in 28 pts (25%). There was no association between KRAS or BRAF mutational status and DP (p=0.52). Pts with DP responded more poorly to first-line chemotherapy (p=0.005) and to anti-EGFR treatment (p=0.01) than non-DP pts. In wild type (WT) KRAS pts, those with DP have poorer PFS (2.7 months vs. 3.5m, p=0.036; HR 1.98, 95% CI 1.05-3.75) and OS (6.4 months vs. 8.6 m, p=0.010; HR 2.33, 95%CI 1.23-4.43) in the adjusted multivariate analysis. Conclusions: Our study suggests that concomitant expression of MMP-7 and activation of p-IGF-1R (DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR. See commentary: MMP7 and activation of IGF-1R: A new insight into anti-EGFR therapeutic resistance in metastatic colorectal cancer

Prognostic Role of Plasma Insulin-Like Growth Factor (IGF) and IGF-Binding Protein 3 in Metastatic Colorectal Cancer

To the Editors: Fuchs et al. ([1][1]) report convincing evidence documenting the predictive and prognostic capacity of a single baseline determination of insulin-like growth factor-binding protein 3 (IGFBP3) and IGF-I plasma levels in advanced colorectal cancer patients undergoing first-line

Design and endpoints of clinical and translational trials in advanced colorectal cancer. a proposal from GROUP Español Multidisciplinar en Cancer Digestivo (GEMCAD).

Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.