Biomarkers, bundled payments, and colorectal cancer care

Changes in the management of cancers such as colorectal cancer (CRC) are urgently needed, as such cancers continue to be one of the most commonly diagnosed cancers; CRC accounts for 21% of all cancers and is responsible for mortalities second only to lung cancer in the United States. A comprehensive science-driven approach towards markedly improved early detection/screening to efficacious targeted therapeutics with clear diagnostic and prognostic markers is essential. In addition, further changes addressing rising costs, stemming from recent health care reform measures, will be brought about in part by changes in how care is reimbursed. For oncology, the advances in genomics and biomarkers have the potential to define subsets of patients who have a prognosis or response to a particular type of therapy that differs from the mean. Better definition of a cancer's behavior will facilitate developing care plans tailored to the patient. One method under study is episode-based payment or bundling, where one payment is made to a provider organization to cover all expenses associated with a discrete illness episode. Payments will be based on the average cost of care, with providers taking on a risk for overutilization and outliers. For providers to thrive in this environment, they will need to know what care a patient will require and the costs of that care. A science-driven "personalized approach" to cancer care has the potential to produce better outcomes with reductions in the use of ineffectual therapies and costs. This promising scenario is still in the future, but progress is being made, and the shape of things to come for cancer care in the age of genomics is becoming clearer.     

Biomarkers in breast cancer

Biomarkers are measured in the management of breast cancer patients for the following purposes. (1) Early detection of breast cancer: blood tumor markers such as CA 15-3 are useless for this detection because of a low sensitivity. Proteomics profiling has recently been investigated using blood or nipple aspirate fluid for the detection. Measurement of CEA and HER 2 in abnormal nipple discharge has been approved for diagnosis of breast cancer in Japan. (2) Monitoring of breast cancer patients: serum tumor markers are routinely measured for early detection of recurrent diseases, evaluation of therapeutic response and monitoring outcome of patients by a majority of breast cancer experts in Japan. Study results investigated by the Study Group of the Japanese Breast Cancer Society in 2001 are presented with regard to the questionnaire survey on the present status of tumor marker measurement and the clinical study on usefulness of tumor markers for the evaluation for therapeutic response. (3) Prognostic factors: new biomarkers have been investigated to select patients at high risk for distant metastases, which could not be selected by classic prognostic factors. Three prognostic factors (UPA/PAI-1, cyclin E, gene profiling), which were discussed at the 8th St. Gallen International Consensus Meeting last year, are mainly discussed. (4) Predictive factors for therapeutic response: hormone receptors (HR) have been used as reliable predictive factors for response to endocrine therapy. Other biomarkers have been investigated to select patients with tumors HR-positive but unresponsive to endocrine therapy. Current status, clinical significance, problems and future directions on predictive factors for response to cytotoxic chemotherapy are also discussed.     

Biomarkers in bronchopulmonary cancer

Non-small-cell lung cancer (NSCLC) ranks among the neoplasms with the worst prognoses and the highest mortality rates. Several factors, mainly clinical, are known that provide a predictive value on the course of the disease. In the era in which we live, the molecular basis of cancer is studied in depth and several molecular markers have been described that could play a prognostic role or that could predict the probability of responding to the different treatments used. Moreover, some mechanisms have been proposed that could explain primary or acquired resistance to treatment with chemotherapy and to targeted therapies. Knowing all these pathways is very important, as it allows the development of selective therapeutic strategies that minimise toxicity and optimise treatment effectiveness. However, the data obtained yield results that are at times contradictory, prospective studies with biomarkers thus being necessary so that their role can be established with the necessary evidence.     

Biomarkers of depression in cancer patients

BACKGROUND: Inflammation and perturbation of the hypothalamic-pituitary-adrenal (HPA) axis function appears to play a putative role in the etiology of depression. Patients with metastatic cancer demonstrate elevated prevalence rates for depression. The objective of the current study was to illustrate the efficacy of interleukin-6 (IL-6) and HPA axis function as adjuncts to support the diagnosis of depression in cancer patients. METHODS: Plasma concentrations of IL-6 and cortisol were measured in 114 cancer patients with and without depression. The relative diurnal variation of cortisol (cortisol VAR), expressed as a percentage, was calculated. Receiver operating characteristics analysis was performed. RESULTS: Depression was associated with increased plasma concentrations of IL-6 (18.7 pg/mL vs. 2.7 pg/mL; P < .001) and higher cortisol concentrations at 8 AM and 8 PM. The relative cortisol VAR (11.7% vs. 60.6%, respectively; P < .001) was found to be decreased in cancer patients with depression, indicating a disturbed circadian function of the HPA axis. As a biomarker of depression, IL-6 yielded at a cutoff value of 10.6 pg/mL, a sensitivity of 79%, and a specificity of 87% (area under the curve [AUC] = 0.86; 95% confidence interval [95% CI], 0.78-0.94), whereas cortisol VAR demonstrated a sensitivity of 81% and a specificity of 88% (AUC = 0.85; 95% CI, 0.74-0.97) at a cutoff value of 33.5%. CONCLUSIONS: Depression is associated with increased plasma IL-6 concentrations in patients with cancer. These patients demonstrate a dysfunction of the HPA-axis, characterized by a decreased diurnal variation of cortisol. The high sensitivity and specificity of these parameters biomarkers of depression make IL-6 and cortisol VAR helpful tools in the diagnosis of depression in patients with cancer.     

Biomarkers for prostate cancer detection

Since its approval by the US FDA in 1986, prostate-specific antigen (PSA) has been employed to monitor men with a diagnosis of prostate cancer. In 1994, PSA was approved for use in prostate cancer screening and has been employed worldwide. However, due to the limited specificity of PSA for the disease, novel biomarkers are needed for detecting prostate cancer and for determining which cancers need to be treated. This review will discuss the development of new biomarkers for prostate cancer detection and disease prognostication, focusing on recent progress and particular topical issues related to the development and validation of these new markers.     

Biomarkers of inflammation are associated with colorectal cancer risk in women but are not suitable as early detection markers

Initial studies have investigated the association between inflammation and colorectal cancer (CRC) using C‐reactive protein (CRP) as a proinflammatory biomarker and have noted inconsistent results among women. We here report the findings from a large prospective study with repeat measurements of CRP, as well as serum amyloid A (SAA), an additional biomarker of inflammation, and risk of CRC. In the Women's Health Initiative Observational Study, we examined associations of CRP and SAA with CRC using repeat assessments (baseline and 3‐year follow‐up) among 953 matched case–control pairs for CRP and 966 pairs for SAA. Multivariate‐adjusted conditional‐logistic regression models were used with two‐sided tests of significance. Receiver operating characteristic (ROC) curve analysis assessed their utility as early detection markers. Colon cancer risk (odds ratio [OR] and 95% confidence intervals) among women in the highest quintiles of CRP or SAA compared to those in the lowest quintiles was OR_colon/CRP = 1.37 (0.95–1.97, p‐trend = 0.04) and OR_colon/SAA = 1.26 (0.88–1.80, p‐trend = 0.10), respectively. Women with elevated concentrations of both CRP and SAA had an increased risk of OR_colon = 1.50 (1.12–2.00, p‐value = 0.006) compared to those with low concentrations. No positive associations were observed with rectal cancer and weaker associations for CRC overall. Temporal changes in biomarkers more than 3 years did not predict risk. The area under the 6‐month ROC curve for CRP+SAA was 0.62 (95% confidence interval = 0.55–0.68). Elevated inflammatory biomarkers are associated with an increased risk of CRC, mainly colon cancer. Nevertheless, changes in the biomarkers over time do not suggest that they merit consideration as early detection markers for CRC.     

Biomarkers of inherited susceptibility and cancer

The etiology of cancer is likely to involve the effects of inherited genotypes at various points in the multistage process of carcinogenesis. For example, inherited genotypes could influence propensity to be exposed to carcinogens, generation of somatic mutations that initiate tumours, determination of a tumour's natural history or clinical prognosis and response to chemoprevention and treatment. Classes of inherited genotypes involved in multistage carcinogenesis are defined here to help focus the role inherited genotypes may have in the etiology and prevention of cancer. Knowledge of inherited genotype may assist in elucidating the nature and timing of specific genetic events in carcinogenesis, identify exposures that correlate with specific steps in carcinogenesis, lead to the development of risk assessment models and target relevant biochemical pathways for the development of preventive or therapeutic interventions.     

Panitumumab in colorectal cancer

The combination of chemotherapy and targeted therapies is rapidly becoming the standard of care in the treatment of metastatic colorectal cancer. Panitumumab (formerly ABX-EGF) is a fully human antibody developed to target the human epidermal growth factor receptor (EGFR/HER-1), which is expressed in up to 75% of patients with colorectal cancer. As a fully human antibody, panitumumab can be administered without any premedication and few infusion reactions have been reported. It has recently been approved in the USA for the treatment of colorectal cancer as a single agent in the salvage setting. Ongoing studies are being performed to determine whether the addition of panitumumab to standard treatment for metastatic colorectal cancer will improve the survival of these patients.     

Panitumumab in colorectal cancer

The combination of chemotherapy and targeted therapies is rapidly becoming the standard of care in the treatment of metastatic colorectal cancer. Panitumumab (formerly ABX-EGF) is a fully human antibody developed to target the human epidermal growth factor receptor (EGFR/HER-1), which is expressed in up to 75% of patients with colorectal cancer. As a fully human antibody, panitumumab can be administered without any premedication and few infusion reactions have been reported. It has recently been approved in the USA for the treatment of colorectal cancer as a single agent in the salvage setting. Ongoing studies are being performed to determine whether the addition of panitumumab to standard treatment for metastatic colorectal cancer will improve the survival of these patients.     

Intussusception in colorectal cancer

Adult intussusception is a rare occurrence and, unlike in childhood, is usually associated with an underlying tumor. Although computed tomography (CT) imaging can identify an intussusception and point toward a cause, diagnosis is challenging if it is only intermittent. When an intussusception presents in the context of a known bowel cancer, it is possible to attribute nonspecific abdominal symptoms to the malignant process. Herein, we describe 2 cases of retrograde intussusception caused by cecal tumors that were not identified on preoperative CT scanning, only to be found during surgery. Both patients presented with intermittent severe abdominal pain and weight loss, which is not usually a feature of cecal cancer without metastases. These cases highlight the difficulty of diagnosing intermittent adult intussusception and that atypical abdominal pain might herald an otherwise occult colorectal cancer.     

Viruses in colorectal cancer

Increasing evidence suggests that microorganisms might represent at least highly interesting cofactors in colorectal cancer (CRC) oncogenesis and progression. Still, associated mechanisms, specifically in colonocytes and their microenvironmental interactions, are still poorly understood. Although, currently, at least seven viruses are being recognized as human carcinogens, only three of these – Epstein–Barr virus (EBV), human papillomavirus (HPV) and John Cunningham virus (JCV) – have been described, with varying levels of evidence, in CRC. In addition, cytomegalovirus (CMV) has been associated with CRC in some publications, albeit not being a fully acknowledged oncovirus. Moreover, recent microbiome studies set increasing grounds for new hypotheses on bacteriophages as interesting additional modulators in CRC carcinogenesis and progression. The present Review summarizes how particular groups of viruses, including bacteriophages, affect cells and the cellular and microbial microenvironment, thereby putatively contributing to foster CRC. This could be achieved, for example, by promoting several processes – such as DNA damage, chromosomal instability, or molecular aspects of cell proliferation, CRC progression and metastasis – not necessarily by direct infection of epithelial cells only, but also by interaction with the microenvironment of infected cells. In this context, there are striking common features of EBV, CMV, HPV and JCV that are able to promote oncogenesis, in terms of establishing latent infections and affecting p53‐/pRb‐driven, epithelial–mesenchymal transition (EMT)‐/EGFR‐associated and especially Wnt/β‐catenin‐driven pathways. We speculate that, at least in part, such viral impacts on particular pathways might be reflected in lasting (e.g. mutational or further genomic) fingerprints of viruses in cells. Also, the complex interplay between several species within the intestinal microbiome, involving a direct or indirect impact on colorectal and microenvironmental cells but also between, for example, phages and bacterial and viral pathogens, and further novel species certainly might, in part, explain ongoing difficulties to establish unequivocal monocausal links between specific viral infections and CRC.     

Biomarkers as surrogates for cancer development

Biomarkers are routinely applied in the management of chronic diseases to reduce morbidity and mortality through early diagnosis, as well as to assess the necessity for, and responsiveness to, applied interventions. Biomarkers yield mechanistic insights into layers of biologic organization from molecule to organelle, to cell, and finally to cellular organization and tissue. A step-wise approach to the development of tissue-based biomarkers is presented. These biomarkers may serve as molecular targets for scientific inquiry and intervention, as well as approvable endpoints for clinical trials.     

胃癌干细胞标志物

分离鉴定胃癌干细胞需要借助某些特异性的表面标志,包括正常胃干细胞标志、通用的肿瘤干细胞标志和间充质标志等.目前除常见的CD133和CD44分子外,已研究出许多新的胃癌干细胞标志物,对其进行联合检测有望分离出胃癌干细胞,为推进胃癌的治疗提供依据.     

Biomarkers in non-small cell lung cancer prevention.

Identification of biomarkers is one of the most promising approaches for the detection of early malignant or even premalignant lesions with the chance of diagnosing early stages of non-small cell lung cancer that could be treated curatively. Alterations of chromosomes (3p, 5q, 9p), genes (Rb, C-myc, C-mos, hTERT), proteins (p16, p53, K-ras, hnRNP A2/B1, MCM2, EGFR, erbB-2, erbB-3, erbB-4) and others can be found in lung cancer. Some of these occur at early stages of the disease and few could serve as potential screening markers. The actual literature is reviewed and the relevance of the different biomarkers for early lung cancer detection is discussed.