HIF pathway and c-Myc as biomarkers for response to sunitinib in metastatic clear-cell renal cell carcinoma.

BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) is a heterogeneous disease with a different clinical behavior and response to targeted therapies. Differences in hypoxia-inducible factor (HIF) expression have been used to classify von Hippel-Lindau gene (VHL)-deficient ccRCC tumors. c-Myc may be driving proliferation in HIF-2α-expressing tumors in a growth factor-independent manner. OBJECTIVE: To explore the HIF-1α, HIF-2α and c-Myc baseline expression as potential predictors of sunitinib outcome as well as the effectiveness and safety with sunitinib in patients with metastatic ccRCC in routine clinical practice. METHODS: This was an observational and prospective study involving 10 Spanish hospitals. Formalin-fixed, paraffin-embedded primary tumor samples from metastatic ccRCC patients who received sunitinib as first-line treatment were analyzed. Association between biomarker expression and sunitinib treatment outcomes was evaluated. Kaplan-Meier method was applied to measure progression-free survival (PFS) and overall survival. RESULTS: Eighty-one patients were included: median PFS was 10.8 months (95% CI: 7.4-13.5 months), median overall survival was 21.8 months (95% CI: 14.7-29.8 months) and objective response rate was 40.7%, with 7.4% of patients achieving a complete response. Molecular marker staining was performed in the 69 available tumor samples. Significant association with lower PFS was identified for double c-Myc/HIF-2α-positive staining tumors (median 4.3 vs 11.5 months, hazard ratio =2.64, 95% CI: 1.03-6.80, P=0.036). A trend toward a lower PFS was found in positive c-Myc tumors (median 5.9 vs 10.9 months, P=0.263). HIF-1α and HIF-2α expression levels were not associated with clinical outcome. CONCLUSION: These preliminary results suggest that predictive subgroups might be defined based on biomarkers such as c-Myc/HIF-2α. Further validation with more patients will be needed in order to confirm it. Outcomes with sunitinib in metastatic ccRCC in daily clinical practice resemble those obtained in clinical trials.

Usefulness of bone turnover markers as predictors of mortality risk, disease progression and skeletal-related events appearance in patients with prostate cancer with bone metastases following treatment with zoledronic acid: TUGAMO study.

BACKGROUND: Owing to the limited validity of clinical data on the treatment of prostate cancer (PCa) and bone metastases, biochemical markers are a promising tool for predicting survival, disease progression and skeletal-related events (SREs) in these patients. The aim of this study was to evaluate the predictive capacity of biochemical markers of bone turnover for mortality risk, disease progression and SREs in patients with PCa and bone metastases undergoing treatment with zoledronic acid (ZA). METHODS: This was an observational, prospective and multicenter study in which ninety-eight patients were included. Patients were treated with ZA (4 mg every 4 weeks for 18 months). Data were collected at baseline and 3, 6, 9, 12, 15 and 18 months after the beginning of treatment. Serum levels of bone alkaline phosphtase (BALP), aminoterminal propeptide of procollagen type I (P1NP) and beta-isomer of carboxiterminal telopeptide of collagen I (ß-CTX) were analysed at all points in the study. Data on disease progression, SREs development and survival were recorded. RESULTS: Cox regression models with clinical data and bone markers showed that the levels of the three markers studied were predictive of survival time, with ß-CTX being especially powerful, in which a lack of normalisation in visit 1 (3 months after the beginning of treatment) showed a 6.3-times more risk for death than in normalised patients. Levels of these markers were also predictive for SREs, although in this case BALP and P1NP proved to be better predictors. We did not find any relationship between bone markers and disease progression. CONCLUSION: In patients with PCa and bone metastases treated with ZA, ß-CTX and P1NP can be considered suitable predictors for mortality risk, while BALP and P1NP are appropriate for SREs. The levels of these biomarkers 3 months after the beginning of treatment are especially important.

Biochemical markers of bone turnover and clinical outcome in patients with renal cell and bladder carcinoma with bone metastases following treatment with zoledronic acid: The TUGAMO study.

BACKGROUND: Levels of bone turnover markers (BTM) might be correlated with outcome in terms of skeletal-related events (SRE), disease progression, and death in patients with bladder cancer (BC) and renal cell carcinoma (RCC) with bone metastases (BM). We try to evaluate this possible correlation in patients who receive treatment with zoledronic acid (ZOL). METHODS: This observational, prospective, and multicenter study analysed BTM and clinical outcome in these patients. Serum levels of bone alkaline phosphatase (BALP), procollagen type I amino-terminal propeptide (PINP), and beta-isomer of carboxy-terminal telopeptide of type I collagen (ß-CTX) were analysed. RESULTS: Patients with RCC who died or progressed had higher baseline ß-CTX levels and those who experienced SRE during follow-up showed high baseline BALP levels. In BC, a poor rate of survival was related with high baseline ß-CTX and BALP levels, and new SRE with increased PINP levels. Cox univariate analysis showed that ß-CTX levels were associated with higher mortality and disease progression in RCC and higher mortality in BC. Bone alkaline phosphatase was associated with increased risk of premature SRE appearance in RCC and death in BC. CONCLUSION: Beta-isomer of carboxy-terminal telopeptide of type I collagen and BALP can be considered a complementary tool for prediction of clinical outcomes in patients with BC and RCC with BM treated with ZOL.

Hepatic resection in breast cancer metastases: should it be considered standard treatment?

A 34-year-old woman was diagnosed in October 1994 with a stage I breast cancer and treated with conservative surgery, locoregional radiotherapy and adjuvant chemotherapy. Nonetheless, 47 months after the initial diagnosis, an isolated liver metastasis was diagnosed in segments VII and VIII. A subsegmentectomy was performed, and chemotherapy with doxorubicin and paclitaxel was given for five cycles. High-dose chemotherapy with peripheral stem cell rescue was then administered and tamoxifen hormonal therapy was begun. Now, 54 months after the liver recurrence, the patient remains free of disease. Isolated liver metastases from breast cancer are rare and should be treated with surgical resection if possible, in the context of multimodality programs with hormonal and chemotherapy. According to the small series published in the literature, an improvement of 27-57 months in median survival rates can be expected when such treatment replaces standard therapies, although a selection bias cannot be excluded.

Central nervous system metastases of a pulmonary epitheloid haemangioendothelioma.

The case of a 55-yr-old male with a right pleural effusion and multiple bilateral nodules is reported. A diagnostic thoracothomy was necessary to obtain a definitive histological diagnosis. During the postoperative course, the subject's neurological condition deteriorated and multiple cerebral mass lesions were discovered. The pathological analysis of both lung and cerebral tumours revealed an atypical endothelial cell proliferation; vascular immunohistochemical markers, such as factor VIII and CD34, were strongly positive. His general condition remained poor and the patient died 18 months after the initial diagnosis. The final diagnosis was pulmonary epitheloid haemangioendothelioma with synchronous central nervous system dissemination, the first time the authors believe that association has been reported. Little is known of the prognosis and treatment of these tumours, due to their rarity. Negative prognostic factors appear to be the presence of symptoms, pleural effusion or multifocal presentations. Treatment should include surgical resection if possible; chemotherapy appears to have little effect. Watchful waiting is an acceptable option, especially in asymptomatic patients.

Lethal toxicity after 5-fluorouracil chemotherapy and its possible relationship to dihydropyrimidine dehydrogenase deficiency: a case report and review of the literature.

5-fluorouracil (5-FU) is a chemotherapeutic agent widely used in the treatment of solid malignancies, especially in colorectal cancer. A characteristic note seen with its use is the considerable interindividual variation in the incidence and severity of the toxicities seen among patients. We report the case of a 55-year old woman who presented with severe, lethal toxicity to standard doses of 5-fluorouracil (5-FU) and folinic acid. We discuss the known clinical determinants of toxicity. We also discuss the possible molecular factors implicated in the variable toxicity seen to 5-FU, especially in regards to dihiyropyrimidine dehydrogenase, a pivotal enzyme in the metabolism of 5-FU.