Risk of prostate, breast and colorectal cancer after skin cancer diagnosis.

Ultraviolet radiation is the major cause of skin cancer, but promotes vitamin D synthesis, and vitamin D has been inversely related to the risk of several common cancers including prostate, breast and colorectum. We therefore computed the incidence of prostate, breast and colorectal cancer following skin cancer using the datasets of the Swiss cancer Registries of Vaud and Neuchâtel. Between 1974 and 2005, 6,985 histologically confirmed squamous cell skin cancers, 21,046 basal cell carcinomas and 3,346 cutaneous malignant melanomas were registered, and followed up to the end of 2005 for the occurrence of second primary cancer of the prostate, breast and colorectum. Overall, 680 prostate cancers were observed versus 568.3 expected (standardized incidence ratio (SIR) = 1.20; 95% confidence interval (CI): 1.11-1.29), 440 breast cancers were observed versus 371.5 expected (SIR = 1.18; 95% CI: 1.08-1.30) and 535 colorectal cancers were observed versus 464.6 expected (SIR = 1.15; 95% CI: 1.06-1.25). When basal cell, squamous cell and skin melanoma were considered separately, all the SIRs for prostate, breast and colorectal cancers were around or slightly above unity. Likewise, the results were consistent across strata of age at skin cancer diagnosis and location (head and neck versus others), and for male and female colorectal cancers. These findings, based on a population with a long tradition of systematic histologic examination of all surgically treated skin lesions, do not support the hypothesis that prostate, breast and colorectal cancer risk is decreased following skin cancer.

Dépistage du cancer colorectal: surveillance après résection de polypes coliques ou d'un cancer colorectal [Colorectal cancer screening: follow-up of patients with adenomatous and colorectal cancer]

Les différentes méthodes de dépistage du cancer colorectal sont présentées et commentées. Nos recommandations restent inchangées : à partir de 50 ans, une coloscopie de dépistage est indiquée chez les personnes saines sans risque particulier de développer un cancer colorectal. Les acquisitions de 2007 : lors d'une conférence de consensus interdisciplinaire, de nouvelles recommandations suisses ont été élaborées pour le suivi de patients opérés d'un cancer colorectal ou après polypectomie colorectale. The different methods of colorectal cancer screening are discussed. Our recommendations had not changed: we recommend as colorectal cancer screening a colonoscopy at the age of 50 years in all healthy persons with average risk for colorectal cancer. A 2007 interdisciplinary consensus conference revised the Swiss recommendations for the follow-up of patients with operated colorectal cancer or after polypectomy

p27 and Skp2 immunoreactivity and its clinical significance with endocrine and chemo-endocrine treatments in node-negative early breast cancer.

BACKGROUND: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. PATIENTS AND METHODS: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. RESULTS: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. CONCLUSIONS: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cancer.

The "reversed" treatment approach for synchronous liver metastases and colorectal cancer. Feasability and first results

Background: The « reversed treatment» approach inverts the treatment sequence of¦advanced synchronous colorectal liver metastases - i.e. the liver metastasis is¦treated first, followed by resection of the primary tumor. Chemotherapy is performed¦before and after liver surgery. We recently started to use a reversed treatment¦approach in selected patients. The aim of this study is to critically assess this new¦treatment modality.¦Methods: Nine patients (7 male, 2 female, mean age 62 years) benefited from this¦new treatment between November 2008 and May 2010. The data were collected¦retrospectively.¦Results: All patients responded to the neoadjuvant chemotherapy. The median¦number of liver metastases was 6 (range 1 - 22). The median size of the largest liver¦metastases was 4.3 cm (range 2.6 - 13 cm). Three patients had portal vein¦embolization prior to liver surgery. Two patients could not complete the treatment.¦One had to undergo emergency surgery for occluding colonic tumor. The second one¦showed liver recurrence before starting the adjuvant chemotherapy. The seven¦patients who completed the treatment are still alive after a median time of 27 months¦(range 17 - 37 months). Seven of them had recurrence (1 rectal, 6 liver). The median¦disease-free survival was 9 months (range 0 - 17 months).¦Conclusion: Based on our preliminary experiences, the reversed strategy shows¦encouraging results for the treatment of advanced synchronous colorectal liver¦metastases in well selected patients. The treatment was generally well tolerated and¦long term survival seems to be prolonged.

Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis.

BACKGROUND: Resection of lung metastases (LM) from colorectal cancer (CRC) is increasingly performed with a curative intent. It is currently not possible to identify those CRC patients who may benefit the most from this surgical strategy. The aim of this study was to perform a systematic review of risk factors for survival after lung metastasectomy for CRC. METHODS: We performed a meta-analysis of series published between 2000 and 2011, which focused on surgical management of LM from CRC and included more than 40 patients each. Pooled hazard ratios (HR) were calculated by using random effects model for parameters considered as potential prognostic factors. RESULTS: Twenty-five studies including a total of 2925 patients were considered in this analysis. Four parameters were associated with poor survival: (1) a short disease-free interval between primary tumor resection and development of LM (HR 1.59, 95 % confidence interval [CI] 1.27-1.98); (2) multiple LM (HR 2.04, 95 % CI 1.72-2.41); (3) positive hilar and/or mediastinal lymph nodes (HR 1.65, 95 % CI 1.35-2.02); and (4) elevated prethoracotomy carcinoembryonic antigen (HR 1.91, 95 % CI 1.57-2.32). By comparison, a history of resected liver metastases (HR 1.22, 95 % CI 0.91-1.64) did not achieve statistical significance. CONCLUSIONS: Clinical variables associated with prolonged survival after surgery for LM in CRC patients include prolonged disease-free interval between primary tumor and metastatic spread, normal prethoracotomy carcinoembryonic antigen, absence of thoracic node involvement, and a single pulmonary lesion.

Nodal staging in colorectal cancer: should distant lymph nodes be recovered in surgical specimens?

To assess the value of sampling lymph nodes located far sidelong colorectal cancer specimens, we analyzed retrospectively surgical specimens from 345 colorectal cancer patients. The mesocolic and perirectal fat was divided into 2 fractions: close to (<5 cm) and distant from (>5 cm) the tumor. Tumors were located in the cecum (n = 61), ascending colon (n = 29), transverse colon (n = 31), descending colon (n = 27), sigmoid colon (n = 108), and rectum (n = 89). The median number of lymph nodes sampled was 17 in both fractions (range, 4-66), 12 (range, 0-46) in the close fraction, and 3 (range, 0-33) in the distant fraction. There were 169 pN0, 104 pN1, and 72 pN2 cases. The pN staging was accurate in all cases except 10 based on the close fraction alone; of these, 6 were upstaged from pN0 to pN1 and 4 from pN1 to pN2 when the distant fraction was considered. Among pN1-upstaged cases, 5 were rectal (3/5 with neoadjuvant radiotherapy) and 1 colonic. In the colon, we found that lymph node location is more important than lymph node number because metastatic lymph nodes were present mostly in the peritumoral area. This suggests that lymph nodes should be initially recovered from the pericolic fat close to the tumor. If there are less than 4 positive lymph nodes and less than 12 lymph nodes examined in total, additional lymph nodes should be retrieved from the distal fraction for potential upstaging. In the rectum, systematic sampling of close and distant lymph nodes is mandatory because in rare cases, metastases are detected only in distant lymph nodes, particularly in patients who have undergone neoadjuvant radiotherapy.

An EORTC phase I itudy of bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer.

The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.

p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer.

Mutations of the TP53 and Ki-ras genes have been reported to be of prognostic importance in colorectal carcinomas. An increased intracellular concentration of the p53 protein, although not identical to, is sometimes seen in tumours with TP53 mutation and has been correlated with poor prognosis in some tumour types. Previous colorectal cancer studies, addressing the prognostic importance of Ki-ras mutation and TP53 aberrations, yielded contradictory results. The aim of this study was to determine in a clinically and therapeutically homogeneous group of 122 sporadic Dukes' B colorectal carcinomas with a median follow-up of 67 months (3-144 months) whether or not p53 protein expression, TP53 mutation and K-ras mutation correlated with prognosis. p53 staining was performed by immunohistochemistry, using the monoclonal antibody DO7 on paraffin-embedded tissue. Mutations in exons 5-8 of the TP53 gene and in codons 12 and 13 of the K-ras gene were assayed in paraffin-embedded tissue by the single-strand conformation polymorphism (SSCP) assay. Nuclear p53 staining was found in 57 (47%) tumours. Aberrant migration patterns indicating mutation of the TP53 gene were found in 39 (32%) tumours. Forty-six carcinomas (38%) showed a mutation of the Ki-ras codons 12 or 13. In a univariate analysis, patients with wild-type TP53 status showed a trend towards better survival, compared with those with mutated TP53 (log-rank test, P = 0.051). Likewise, tumours immunohistochemically positive for p53 showed a worse prognosis than p53-negative tumours (P = 0.010). The presence or absence of mutations in Ki-ras did not correlate with prognosis (P = 0.703). In multivariate analysis, only p53 immunoreactivity emerged as an independent marker for prognosis hazard ratio (HR) = 2.16, 95% confidence interval (CI) 1.12-4.11, P = 0.02). Assessment of p53 protein expression is more discriminative than TP53 mutation to predict the outcome of Dukes' stage B tumours and could be a useful tool to identify patients who might benefit from adjuvant therapy.

Metabolic syndrome is associated with colorectal cancer in men.

AIM OF THE STUDY: We assessed the relation between metabolic syndrome (MetS) and its components and colorectal cancer. METHODS: We analysed data from a multicentre case-control study conducted in Italy and Switzerland, including 1378 cases of colon cancer, 878 cases of rectal cancer and 4661 controls. All cases were incident and histologically confirmed. Controls were subjects admitted to the same hospitals as cases with acute non-malignant conditions. MetS was defined according to the International Diabetes Federation criteria. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated by multiple logistic regression models, including terms for major identified confounding factors for colorectal cancer. RESULTS: With reference to each component of the MetS, the ORs of colorectal cancer in men were 1.27 (95% CI, 0.95-1.69) for diabetes, 1.24 (95% CI, 1.03-1.48) for hypertension, 1.14 (95% CI, 0.93-1.40) for hypercholesterolaemia and 1.26 (95% CI, 1.08-1.48) for overweight at age 30. The corresponding ORs in women were 1.20 (95% CI, 0.82-1.75), 0.87 (95% CI, 0.71-1.06), 0.83 (95% CI, 0.66-1.03) and 1.06 (95% CI, 0.86-1.30). Colorectal cancer risk was increased in men (OR=1.86; 95% CI, 1.21-2.86), but not in women (OR=1.13; 95% CI, 0.66-1.93), with MetS. The ORs were 2.09 (95% CI, 1.38-3.18) in men and 1.15 (95% CI, 0.68-1.94) in women with > or =3 components of the MetS, as compared to no component. Results were similar for colon and rectal cancers. CONCLUSION: This study supports a direct association between MetS and both colon and rectal cancers in men, but not in women.

A colorectal cancer classification system that associates cellular phenotype and responses to therapy.

Colorectal cancer (CRC) is a major cause of cancer mortality. Whereas some patients respond well to therapy, others do not, and thus more precise, individualized treatment strategies are needed. To that end, we analyzed gene expression profiles from 1,290 CRC tumors using consensus-based unsupervised clustering. The resultant clusters were then associated with therapeutic response data to the epidermal growth factor receptor-targeted drug cetuximab in 80 patients. The results of these studies define six clinically relevant CRC subtypes. Each subtype shares similarities to distinct cell types within the normal colon crypt and shows differing degrees of 'stemness' and Wnt signaling. Subtype-specific gene signatures are proposed to identify these subtypes. Three subtypes have markedly better disease-free survival (DFS) after surgical resection, suggesting these patients might be spared from the adverse effects of chemotherapy when they have localized disease. One of these three subtypes, identified by filamin A expression, does not respond to cetuximab but may respond to cMET receptor tyrosine kinase inhibitors in the metastatic setting. Two other subtypes, with poor and intermediate DFS, associate with improved response to the chemotherapy regimen FOLFIRI in adjuvant or metastatic settings. Development of clinically deployable assays for these subtypes and of subtype-specific therapies may contribute to more effective management of this challenging disease.

Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial.

BACKGROUND: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial. METHODS: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. RESULTS: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy. CONCLUSIONS: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.

Combined radioimmunotherapy and radiotherapy of liver metastases from colorectal cancer: a feasibility study.

BACKGROUND: A combination of radioimmunotherapy (RIT) and radiotherapy (RT) should allow one to increase the dose of radiation targeting a particular tumour without the concomitant increase of toxic side effects. This might be obtained if the dose limiting side effect of each individual radiation therapy concerned different organs. METHODS: Six patients with limited liver metastatic disease from colorectal cancer were treated with 6.9 GBq (range 4.7 to 8.4 GBq) 131I-labelled anti-CEA MAb F(ab')2 fragments combined with 20 Gy RT to the liver. Both treatments were given in close association, according to timing schedules evaluated in animals that gave the best results. RESULTS: Reversible bone marrow and liver toxicity was observed in 6 and 5 patients, respectively. Three patients who first received 20 Gy RT to the liver, showed a significant platelet drop upon completion of RT. Repeat computerized tomography (CT) after 2 months showed a minor response in 1 patient and stable disease in 3 patients. CONCLUSION: The study shows potential ways of combining RIT and RT, suggesting that this combination is feasible for the treatment of liver metastases.

Colorectal cancer detection: how well do appropriateness criteria perform?

Comment on: Hassan C, Di Giulio E, Pickhardt PJ, Zullo A, Laghi A, Kim DH, Iafrate F, Morini S. Cost effectiveness of colonoscopy, based on the appropriateness of an indication. Clin Gastroenterol Hepatol. 2008 Nov;6(11):1231-6.

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

BACKGROUND: Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. PURPOSE: To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. METHODS: From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. RESULTS: The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. LIMITATIONS: Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. CONCLUSIONS: BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.