Cancer Risk Assessment Process Research Articles

Hereditary Cancer Risk Assessment and Genetic Testing in the Community-Practice Setting.

To evaluate the feasibility and results of incorporating routine hereditary cancer risk assessment, counseling, and follow-up genetic testing in the community obstetrics and gynecology practice setting without referral to a genetic counselor. This prospective process intervention study was conducted with two obstetrics and gynecology practice groups (five sites). The intervention included baseline process assessment, refinement of clinic-specific patient screening workflows and tools, and training in hereditary cancer risk screening and follow-up. Outcomes related to hereditary cancer assessment and testing were measured during an 8-week postintervention period. Patients and health care providers were surveyed about satisfaction with the process. Data also were collected during the 8 weeks before the intervention to assess the effects of screening process improvements. A total of 4,107 patients were seen during the postintervention period, and 92.8% (3,811) were assessed for hereditary cancer risk. Among those assessed, 906 of 3,811 (23.8%) women met National Comprehensive Cancer Network guidelines for genetic testing, and 813 of 906 (89.7%) eligible patients were offered genetic testing. A total of 165 of 4,107 (4.0%) women completed genetic testing and received a final test result. This represents a fourfold increase over genetic testing immediately before the intervention (1.1%) and an eightfold increase over the previous year (0.5%). Testing identified pathogenic variants in 9 of 165 (5.5%) tested women. All health care providers (15/15) reported that they will continue to use the established hereditary cancer risk assessment process. In addition, 98.8% (167/169) of patients who submitted a sample for genetic testing and completed a patient satisfaction survey stated that they were able to understand the information provided, and 97.6% (165/169) expressed satisfaction with the overall process. It is feasible to incorporate hereditary cancer risk assessment, education, and testing into community obstetrics and gynecology practices. As a result, multigene panel testing identified significant cancer risks that otherwise would not have been recognized.

Epigenetic effects of cadmium in cancer: focus on melanoma.

Cadmium is a highly toxic heavy metal, which has a destroying impact on organs. Exposure to cadmium causes severe health problems to human beings due to its ubiquitous environmental presence and features of the pathologies associated with pro-longed exposure. Cadmium is a well-established carcinogen, although the underlying mechanisms have not been fully under-stood yet. Recently, there has been considerable interest in the impact of this environmental pollutant on the epigenome. Be-cause of the role of epigenetic alterations in regulating gene expression, there is a potential for the integration of cadmium-induced epigenetic alterations as critical elements in the cancer risk assessment process. Here, after a brief review of the ma-jor diseases related to cadmium exposure, we focus our interest on the carcinogenic potential of this heavy metal. Among the several proposed pathogenetic mechanisms, particular attention is given to epigenetic alterations, including changes in DNA methylation, histone modifications and non-coding RNA expression. We review evidence for a link between cadmium-induced epigenetic changes and cell transformation, with special emphasis on melanoma. DNA methylation, with reduced expression of key genes that regulate cell proliferation and apoptosis, has emerged as a possible cadmium-induced epigenetic mechanism in melanoma. A wider comprehension of mechanisms related to this common environmental contaminant would allow a better cancer risk evaluation.

Identifying hereditary cancer: Genetic counseling and cancer risk assessment

The goal of cancer genetic counseling, risk assessment, and testing is to identify individuals and families at risk for hereditary cancer, such that targeted management strategies can be used to reduce associated morbidity and mortality. Involvement of a qualified cancer genetic service provider helps to ensure that at-risk individuals identified and offered appropriate education, risk assessment, genetic testing, and follow-up risk management strategies. There are multiple screening and hereditary risk models available to help the clinician identify who needs to be referred to cancer genetic counseling and to facilitate the cancer risk assessment process. Genetic testing should only be pursued with fully informed consent in the context of pretest counseling to ensure that the individual understands the benefits, risks, and limitations of genetic testing, possible results, and their implications. Incorporating psychosocial assessment throughout the counseling session may assist the individual in their understanding of genetic testing in the context of their support resources and coping mechanisms and may help with decision making. There is a growing public awareness of and interest in cancer genetic testing, as well as increasing complexity of available testing options and results. It is therefore essential that cancer genetic professionals, primary care providers, and oncology practitioners work together to ensure that genetic testing for hereditary cancer syndromes is used in the most appropriate and effective way.

DNA Reactivity as a Mode of Action and Its Relevance to Cancer Risk Assessment

The ability of a chemical to induce mutations has long been a driver in the cancer risk assessment process. The default strategy has been that mutagenic chemicals demonstrate linear cancer dose responses, especially at low exposure levels. In the absence of additional confounding information, this is a reasonable approach, because risk assessment is appropriately considered as being protective of human health. The concept of mode of action has allowed for an opportunity to move off this default position; mutagenicity is now not considered as the driver but rather the mode of action is. In a more precise way, it is the set of key events that define a mode of action that is fundamental in defining the shape of a cancer dose response. A key event is an informative bioindicator of the cancer response and as such should be predictive of the tumor response, at least in a qualitative way. A clear example of the use of key events in cancer risk assessment is for DNA reactive chemicals. A series of such key events is initiated by the production of DNA damage in target cells from direct interaction of the chemical with DNA leading to the production of mutations by misreplication that results in enhanced cell replication. This enhanced cell replication eventually leads to the development of preneoplastic cells and ultimately overt neoplasms. The response of each of these key events to dose of the chemical can inform the cancer dose-response curve shape. Thus, the dose-response curve for any DNA-reactive chemical can be predicted from knowledge of its mode of action and the behavior of the induced key events.

Data and literature gathering in chemical cancer risk assessment

In recent years, chemical cancer risk assessment has faced major challenges: the demand for cancer risk assessment has grown considerably with strict legislation regarding chemical safety, whereas cancer hazard identification has turned increasingly complex due to the rapid development and high publication rate in biomedical sciences. Thus, much of the scientific evidence required for hazard identification is hidden in large collections of biomedical literature. Extensive guidelines have been produced to support cancer risk assessment under these circumstances. We evaluated whether these guidelines support the first, critical step of this task--data and literature gathering--and found that the guidance is vague. We propose ways to improve data and literature gathering for cancer risk assessment and suggest developing a computational literature search and analysis tool dedicated to the task. We describe the first prototype tool we have developed and discuss how it could help to improve the quality, consistency, and effectiveness of cancer risk assessment when developed further. Fully reliable automatic data and literature gathering may not be realistic; the retrieved articles will always need to be examined further by risk assessors. However, our proposal offers a starting point for improved data and literature gathering that can benefit the whole cancer risk assessment process.

An audit of families with unreported or misreported cancers verified through a population-based cancer registry: implications for providing cancer risk assessment and management advice by a Familial Cancer Centre

Background The Cancer Council Victoria manages a populationbased cancer registry, the Victorian Cancer Registry (VCR). All cancer diagnoses in the state of Victoria are notified to this register. As part of the genetic cancer risk assessment process, the Victorian Familial Cancer Centres (FCCs) submit the family history pedigree to the Cancer Council for verification. Each person in the pedigree is checked against the Register. Cancer verification and pathology reports are returned to the FCCs within five days of the submitted request. Since 2002 over eight thousand families have been submitted to the Cancer Council for verification with over 160,000 individuals checked for cancer. 3% of all individuals with no report of cancer had a cancer confirmed, and 4% had a different diagnosis confirmed to what was reported.

Genetic Cancer Risk Assessment

To describe critical elements of cancer risk assessment as identified through professional standards. Professional guidelines, policy statements, and other published literature. The continually increasing integration of genetics/genomics into oncology care mandates that oncology nurses be familiar with the cancer risk assessment process, complexities, and implications for personalized risk reduction and early detection recommendations and for cancer treatment, including targeted therapies. Informed nurses can identify genetic cancer risk factors, educate patients about cancer risk and risk management/treatment strategies, and refer appropriate patients to a cancer genetics nurse or other genetics professional for comprehensive risk assessment.

Implementation of the Suggested Guidelines for Breast Cancer Risk, Genetics, and Risk Assessment: The Critical Need for Educating Practicing Physicians

Implementation of the Suggested Guidelines for Breast Cancer Risk, Genetics, and Risk Assessment: The Critical Need for Educating Practicing Physicians

A Survey of Patients’ Experiences with the Cancer Genetic Counseling Process: Recommendations for Cancer Genetics Programs

In order to promote ongoing quality improvement of not only the Penn State Cancer Genetics Program, but also other cancer risk assessment programs throughout the country, we developed, piloted and conducted a survey to explore patient expectations, experiences, and satisfaction with the cancer genetic counseling process. The comprehensive survey was mailed to 340 eligible patients, 156 (45.9%) of whom returned the completed survey within the allotted time. Responses to closed-ended questions were tallied and open-ended questions were content analyzed. Major findings show that: (1) Patients were seeking cancer-related information and support throughout the cancer risk assessment process and were interested in participating in available research studies; (2) The setting in which patients are seen for cancer risk assessment may pose potential emotional ramifications; (3) Misperceptions regarding insurance discrimination and lack of insurance coverage persist; (4) Patients view the genetic counselor as responsible for updating them about new discoveries. Specific recommendations for cancer genetics programs are included.

A Risk Assessment Perspective: Application of Mode of Action and Human Relevance Frameworks to the Analysis of Rodent Tumor Data

When the United States Environmental Protection Agency (USEPA) published guidelines for carcinogen risk assessment in 1986, it provided essentially no guidance on how to consider mechanistic information. The guidelines simply pointed out that ‘‘The Agency will review each assessment as to the evidence on carcinogenesis mechanisms and other biological or statistical evidence that indicates the suitability of a particular extrapolation model.’’ (USEPA, 1986). At that time, mechanisms of carcinogenesis were largely unknown and empirically difficult to approach. Nonetheless, as mechanistic data became available, the Agency considered it in formulating science policies, e.g., alpha2u-globulin–induced rat renal tumors (USEPA, 1991) and thyroid follicular cell rodent tumors and disruption of thyroid homeostasis (USEPA, 1998) or in chemical-specific assessments, e.g., bladder tumors induced by melamine through formation of urinary calculi (USEPA, 1988). In 1996, the Agency formally proposed to make information on the mode of carcinogenic action a pivotal point of the cancer risk assessment process (USEPA, 1996). Because complete knowledge of how an agent causes cancer is unlikely to exist (certainly for the near term), the 1996 guidelines put forth the notion of understanding mode of action versus mechanism of action. The former being a less detailed biochemical description of events than is meant by mechanism of action. The mode of action is sufficient evidence to draw a reasonable working conclusion concerning the agent’s influence on key processes. The mode of action concept permits information on precursor events to be evaluated and incorporated into the risk assessment process in a realistic way. The most frequent comment about the Agency’s 1996 proposed revision of its cancer risk assessment guidelines was that more guidance was needed on how to evaluate an agent’s mode of action. A few comments raised concern that the new USEPA guidelines would not be public health protective and opposed using mode of action data. In response, in 1999, EPA incorporated a mode of action framework analysis (USEPA, 1999) in conjunction with work by the International Programme for Chemical Safety (IPCS) (SonichMullin et al., 2001). This framework provided assurance that a rigorous and transparent approach would be taken to using mode of action data in the Agency’s cancer risk assessments, and it was well received by the scientific community. The mode of action framework is derived from considerations for causality used in epidemiologic investigations, which were originally articulated by Hill (1965). The Hill criteria were later modified by the U.S. Department of Health and Human Services (USHHS, 1982) and by Faustman et al. (1997) to extend to experimental animal studies. The publication of the USEPA 1999 framework provided an important tool with which the Agency can promote and formalize the use of mode of action data in cancer assessment. Mode of action data have come into play in several ways in EPA risk assessments. It has been critical in informing the dose–response relationship below the experimental observable range of tumors, and thus it is useful in establishing more appropriate guidance levels for environmental contaminants. The Agency’s traditional linear default extrapolation procedure for modeling tumor incidence has been a longstanding and often controversial issue. The 1986 USEPA guidelines provided only one dose–response default, namely the linear extrapolation procedure. The 1999 (and 1996) guidelines advanced this issue by providing two default extrapolation approaches—one linear and and one nonlinear. Application of the nonlinear default extrapolation procedure (typically a margin of exposure analysis or determination of a reference dose/ concentration) is based on the mode of action understanding about the agent. It was acknowledged in the 1999 (1996) guidelines that ‘‘true thresholds’’ are experimentally difficult to This paper does not necessarily reflect the views and policies of the U.S. Environmental Protection Agency. The opinions expressed within this paper reflect the views of the authors. 1 To whom correspondence should be addressed. Fax: þ1-703-5147; E-mail: dellarco.vicki@epamail.epa.gov.

Mechanistic data and cancer risk assessment: The need for quantitative molecular endpoints

The cancer risk assessment process as currently proposed by the U.S. Environmental Protection Agency allows for the use of mechanistic data to inform the low-dose tumor response in humans and in laboratory animals. The aim is to reduce the reliance on defaults that introduce a relatively high level of uncertainty to the risk estimates. The types of data required for this purpose are those that help identify key events in tumor formation following exposure to environmental chemicals. Informative biomarkers of tumor responses could then be developed for describing the shape of a dose-response curve at low doses (i.e., a qualitative assessment) and for predicting tumor frequency at these low doses (i.e., a quantitative assessment). A number of recently developed molecular approaches could aid in the development of qualitatively and quantitatively informative biomarkers. An overview of these with examples of their use is presented. These methods include quantitative gene expression array techniques, quantitative proteomic assays, and the assessment of DNA alterations at the single gene level and at the genome level of detection. It is most likely that a combination of approaches at different levels of cellular organization (i.e., DNA, RNA, and protein) will be the most productive for biomarker development. The rapid progress that is being made will make this tool kit even more applicable for the cancer risk assessment process.