Individual Cancer Risk Assessment Research Articles

The Use of National Cancer Registry Data for Breast Cancer Family History Assessment in Premenopausal Women.

Background: Population-based cancer registries are the best source of information to measure cancer burden. However, little is done to use this information for individual cancer risk assessment. In this study, we aimed at identifying women at high risk of breast and ovarian cancer using data on family history of cancer from the Israel national cancer registry. Methods: We used the family history assessment tool (FHAT) to score all females, 26 to 45 years of age, in a 2.6-million-member health provider in Israel (Maccabi Healthcare Services). Data on breast, ovarian, prostate, and pancreatic cancer history among the participants and their parents (identified using the national census) were retrieved from the national cancer registry. These data were used to calculate individual FHAT scores. Results: A total of 377,931 eligible women were included in the analysis. A relevant family history of cancer was detected in 20,386 (5.4%), with FHAT scores ranging from 1 to 16. FHAT score was higher in older women and among those with a history of breast cancer. Among women aged 35-39, an FHAT score of 10 or above was associated with an OR of 15.23 (95%CI: 7.41-28.19) for breast cancer compared to women with an FHAT of 0. Conclusions: Using individual-level data from national cancer registries may assist in detecting women with a relevant family history of cancer.

Current situation and prospect of primary prevention of cancer in China

Cancer is a major public health issue that seriously endangers the public health and social development of China. Future initiatives for cancer prevention and control should continue to adhere to the principle of prioritizing prevention, and comprehensively implement related prevention activities nationwide. This is critical to reducing cancer burden in Chinese residents, especially in the low- and middle-income populations and those living in areas that are less economically developed. In the past several decades, the international community has significantly reduced the incidence of related cancers through primary prevention measures such as tobacco control, improved occupational hygiene, and vaccination. China has also implemented a series of exploratory primary prevention measures among high-risk groups of cancer in specific areas including Xuanwei, Qidong, and Linxian, and achieved encouraging results. However, due to the low level of systematic awareness of cancer risk factors and the lack of awareness and ability of self-health management in Chinese residents, it is urgent to develop novel research tools and methods to further reveal the causes of cancer, and establish innovative mechanisms and systems of primary prevention of cancer at population and individual levels. Based on current status of the transformation of cancer spectrum and the development of digital intelligence, it would be beneficial to establish a smart digital system for primary cancer prevention service that can cover the entire population, integrating authoritative popular science education on primary prevention of cancer, individualized cancer risk assessment, and personalized health management assistant. This will improve primary cancer prevention among the Chinese general population and can help the sustainable development of cancer prevention and control in China.

Decision-making and regret in patients with germline CDH1 variants undergoing prophylactic total gastrectomy

IntroductionProphylactic total gastrectomy (PTG) can eliminate gastric cancer risk and is recommended in carriers of a germline CDH1 pathogenic variant. PTG has established risks and potential life-long morbidity. Decision-making regarding...

Development and Internal Validation of a Predictive Model for Individual Cancer Risk Assessment for Thyroid Nodules

The objective of this study was to develop and validate a predictive model for the assessment of the individual risk of malignancy of thyroid nodules based on clinical, ultrasound, and analytic variables. A retrospective case-control study was carried out with 542 patients whose thyroid nodules were analyzed at our endocrinology department between 2013 and 2018 while undergoing treatment for thyroidectomy. Starting with a multivariate logistic regression analysis, which included clinical, analytic, and ultrasound variables, a predictive model for thyroid cancer (TC) risk was devised. This was then subjected to a cross-validation process, using resampling techniques. In the final model, the independent predictors of the risk of malignancy were: being male, age of the extremes, family history of TC, thyroid-stimulating hormone level >4.7 μU/L, presence of autoimmune thyroiditis, solid consistency, hypoechogenicity, irregular or microlobed borders, nodules that are taller than they are wide, microcalcifications, and suspicious adenopathy. With a cut-off point of 50% probability of thyroid cancer, the predictive model had an area under the receiver operating characteristic curve of 0.925 (95% confidence interval 0.898 to 0.952). Finally, using the 10-fold cross-validation method, the accuracy of the model was found to be 88.46%, with a kappa correlation coefficient of 0.62. A predictive model for the individual risk of malignancy of thyroid nodules was developed and validated using clinical, analytic, and ultrasound variables. An online calculator was developed from this model to be used by clinicians to improve decision-making in patients with thyroid nodules.

Reproductive cancer risk factors among relatives of cancer patients in a tertiary oncology center

BackgroundThe aim of this study was to evaluate the prevalence of some gynecological cancer risk factors in a population of female relatives of cancer patients in Hacettepe University Oncology Hospital. Additionally, what are the levels of the women’s awareness /behavior toward available screening tools?MethodsAn individual cancer risk assessment questionnaire has been developed in the Department of Preventive Oncology, which questions the medical history, health behaviors and cancer awareness, as well as their behavior toward available cancer screening tools.ResultsThe mean age of the study population was 45.7 ± 12.2 years. Median age at menarche was 13 years (IQR, 12–14), 6.9% of the women reported their menarche was before age of 12. About 11.1% of the women had intercourse before age of 18. The median age at first delivery was 22 years. Median BMI was 24.9, with 18.3% of population having obesity. Of the women 65% were current/past smokers. Sixty-two percent of the women had never used condom. About 8% of the women were unaware about mammography and 17.7% about the Pap test.ConclusionsThis study has documented high tobacco use, low protective condom use and low rates of physical activity. Percentage of some risk factors like early menarche was lower than what was suggested for general Turkish population. Awareness and behavior of the women were better about mammography when compared to the Pap test. Considering our results, some measures should be put in place to increase people’s awareness, and to modify their behavior toward cancer prevention.

A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s.

N-nitrosamines are a well-established group of environmental carcinogens, which require cytochrome P450 oxidation to exhibit activity. The accepted mechanism of metabolic activation involves formation of α-hydroxynitrosamines that spontaneously decompose to DNA alkylating agents. Accumulation of DNA damage and the resulting mutations can ultimately lead to cancer. New evidence indicates that α-hydroxynitrosamines can be further oxidized to nitrosamides processively by cytochrome P450s. Because nitrosamides are generally more stable than α-hydroxynitrosamines and can also alkylate DNA, nitrosamides may play a role in carcinogenesis. In this report, we describe a general protocol for evaluating nitrosamide production from in vitro cytochrome P450-catalyzed metabolism of nitrosamines. This protocol utilizes a general approach to the synthesis of the relevant nitrosamides and an in vitro cytochrome P450 metabolism assay using liquid chromatography-nanospray ionization-high resolution tandem mass spectrometry for detection. This method detected N'-nitrosonorcotinine as a minor metabolite of N'-nitrosonornicotine in the example study. The method has high sensitivity and selectively due to accurate mass detection. Application of this method to a wide variety of nitrosamine-cytochrome P450 systems will help determine the generality of this transformation. Because cytochrome P450s are polymorphic and vary in activity, a better understanding of nitrosamide formation could aid in individual cancer risk assessment.

Combining aneuploidy and dysplasia for colitis' cancer risk assessment outperforms current surveillance efficiency: a meta-analysis.

Cancer risk assessment for ulcerative colitis patients by evaluating histological changes through colonoscopy surveillance is still challenging. Thus, additional parameters of high prognostic impact for the development of colitis-associated carcinoma are necessary. This meta-analysis was conducted to clarify the value of aneuploidy as predictor for individual cancer risk compared with current surveillance parameters. A systematic web-based search identified studies published in English that addressed the relevance of the ploidy status for individual cancer risk during surveillance in comparison to neoplastic mucosal changes. The resulting data were included into a meta-analysis, and odds ratios (OR) were calculated for aneuploidy or dysplasia or aneuploidy plus dysplasia. Twelve studies addressing the relevance of aneuploidy compared to dyplasia were comprehensively evaluated and further used for meta-analysis. The meta-analysis revealed that aneuploidy (OR 5.31 [95% CI 2.03, 13.93]) is an equally effective parameter for cancer risk assessment in ulcerative colitis patients as dysplasia (OR 4.93 [1.61, 15.11]). Strikingly, the combined assessment of dysplasia and aneuploidy is superior compared to applying each parameter alone (OR 8.99 [3.08, 26.26]). This meta-analysis reveals that aneuploidy is an equally effective parameter for individual cancer risk assessment in ulcerative colitis as the detection of dysplasia. More important, the combined assessment of dysplasia and aneuploidy outperforms the use of each parameter alone. We suggest image cytometry for ploidy assessment to become an additional feature of consensus criteria to individually assess cancer risk in UC.

Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort

This study aims to assess multi-gene panel testing in an ethnically diverse clinical cancer genetics practice. We conducted a retrospective study of individuals with a personal or family history of cancer undergoing clinically indicated multi-gene panel tests of 6-110 genes, from six commercial laboratories. The 475 patients in the study included 228 Hispanics (47.6%), 166 non-Hispanic Whites (35.4%), 55 Asians (11.6%), 19 Blacks (4.0%), and seven others (1.5%). Panel testing found that 15.6% (74/475) of patients carried deleterious mutations for a total of 79 mutations identified. This included 7.4% (35/475) of patients who had a mutation identified that would not have been tested with a gene-by-gene approach. The identification of a panel-added mutation impacted clinical management for most of cases (69%, 24/35), and genetic testing was recommended for the first degree relatives of nearly all of them (91%, 32/35). Variants of uncertain significance (VUSs) were identified in a higher proportion of tests performed in ethnic minorities. Multi-gene panel testing increases the yield of mutations detected and adds to the capability of providing individualized cancer risk assessment. VUSs represent an interpretive challenge due to less data available outside of White, non-Hispanic populations. Further studies are necessary to expand understanding of the implementation and utilization of panels across broad clinical settings and patient populations.

High Smoking Cessation Rates After National Awareness Campaigns and By Comprehensive Treatment Approach

ABSTRACT Aim: Turkey is the 10th country among the most tobacco product consuming countries. By the recent regulations, Turkey became a “Smoke Free Country”, and one of the leading countries to implement WHO's MPOWER package. Turkey is also one of the most successful countries in reducing the smoking rates in the last five years. WHO declared in September 2012 that tobacco use is declining at unprecedented rates in Turkey. Hacettepe University smoking cessation clinic in one of the most comprehensive institutions in Turkey, providing counseling, medical treatment, psychosocial support, individual cancer risk assessment, and screening to the smokers. This study presents the quit rates of a comprehensive approach for smoking cessation between 2010 and 2013, which the most intensive awareness campaigns held in Turkey. Methods: The patient database of HU was used for obtaining the demographic data, and the quit rates for this study. All patients took psychosocial support, individual cancer risk assessment, and screening support when needed, along with their smoking cessation treatment; and followed-up for one year by telephone interviews. Results: A total of 4085 patients with a mean age of 40.3 (SD: 12) years were admitted for smoking cessation treatment. Mean age for initiation of smoking was 18.1 (SD: 5.2) years, 56.4% were men, 70.2% were married, 69.4% were graduated from high school or higher degrees, median Fagerstrom nicotine dependence test score was 6, and mean cigarette consumption was 24.6 (SD: 18.3) pack.years. Nicotine replacement, Bupropion, and Varenicline was used as primary medications in 5.7%, 21.3%, and 50.5% of the patients, respectively. Overall quit rate was 43.6%, relapse rate was 22.3%, and median time to relapse was 14 (95%CI: 12.6-15.4) months. Smoke-free 1-year success rate of the comprehensive treatment was 31.3%. Conclusions: These results indicate that, overall and 1-year smoke-free rates, and the time to relapse after smoking cessation treatment applied in our institution is better than the current literature data. This might be related with the increased awareness level in the community, yet a comprehensive approach is still needed for the successful smoking cessation treatment. Disclosure: All authors have declared no conflicts of interest.

A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS)

Clinical mutation screening of the BRCA1 and BRCA2 genes for the presence of germline inactivating mutations is used to identify individuals at elevated risk of breast and ovarian cancer. Variants identified during screening are usually classified as pathogenic (increased risk of cancer) or not pathogenic (no increased risk of cancer). However, a significant proportion of genetic tests yields variants of uncertain significance (VUS) that have undefined risk of cancer. Individuals carrying these VUS cannot benefit from individualized cancer risk assessment. Recently, a quantitative "posterior probability model" for assessing the clinical relevance of VUS in BRCA1 or BRCA2, which integrates multiple forms of genetic evidence has been developed. Here, we provide a detailed review of this model. We describe the components of the model and explain how these can be combined to calculate a posterior probability of pathogenicity for each VUS. We explain how the model can be applied to public data and provide tables that list the VUS that have been classified as not pathogenic or pathogenic using this method. While we use BRCA1 and BRCA2 VUS as examples, the method can be used as a framework for classification of the pathogenicity of VUS in other cancer genes.

Reading Between the Lines: A Comparison of Responders and Non‐responders to a Family History Questionnaire and Implications for Cancer Genetic Counselling

Family history questionnaires (FHQ) are useful tools for cancer genetic counseling, providing an informational basis for pedigree construction and individualized cancer risk assessment. Reported return rates of mailed FHQs amongst familial cancer clinics that utilize them are lower than desired however, and it is unknown whether patients perceive required completion of a FHQ as a barrier to access of cancer genetics services. This study critically evaluated the use of a mailed FHQ for all routine new patient referrals to a single hereditary cancer clinic in Quebec, Canada. Reasons for response/non-response to a FHQ and the effect of administration of a questionnaire on patients' self-reported level of motivation to pursue genetic counseling, were examined. Of 112 eligible individuals referred during the study period, 86 completed a semi-structured telephone survey; of these, 45% had returned the mailed FHQ prior to the telephone survey (Responders) and 55% had not (Non-responders). Overall, the majority of participants indicated a FHQ is an acceptable and understandable method of collecting family history information. Most prevalent reasons for not returning the FHQ were (bad) timing (56%), and difficulty accessing family history information (46%). Non-response was significantly associated with difficulty in asking relatives for the requested information (p = 0.011), and Non-responders cited fewer overall perceived benefits of cancer genetic counseling as compared with Responders (p < 0.0001). One quarter of Non-responders returned the mailed FHQ following administration of the telephone survey, suggesting implementation of a follow-up prompt is a cost-effective way to increase response.

Consensus Recommendations for Advancing Breast Cancer: Risk Identification and Screening in Ethnically Diverse Younger Women

A need exists for a breast cancer risk identification paradigm that utilizes relevant demographic, clinical, and other readily obtainable patient-specific data in order to provide individualized cancer risk assessment, direct screening efforts, and detect breast cancer at an early disease stage in historically underserved populations, such as younger women (under age 40) and minority populations, who represent a disproportionate number of military beneficiaries. Recognizing this unique need for military beneficiaries, a consensus panel was convened by the USA TATRC to review available evidence for individualized breast cancer risk assessment and screening in young (< 40), ethnically diverse women with an overall goal of improving care for military beneficiaries. In the process of review and discussion, it was determined to publish our findings as the panel believes that our recommendations have the potential to reduce health disparities in risk assessment, health promotion, disease prevention, and early cancer detection within and in other underserved populations outside of the military. This paper aims to provide clinicians with an overview of the clinical factors, evidence and recommendations that are being used to advance risk assessment and screening for breast cancer in the military.

The impact of future technology on cancer care

Globally cancer will increase greatly over the next 20 years because of ageing populations. Minimally invasive surgery will reduce the need for routine organ resection. The application of sophisticated computer systems to radiotherapy planning will allow the precise shaping of beam delivery conforming exactly to the shape of the tumour. The most promising advances will come from the rapidly increasing understanding of the molecular genetics of cancer. This will have considerable impact on prevention, screening, diagnosis and treatment and lead to a golden age of drug discovery. Individual cancer risk assessment will provide messages tailored for individual prevention and have far-reaching public health consequences. Increased consumerism in medicine will produce increasingly informed and assertive patients seeking out novel therapies, bypassing traditional referral pathways through global information networks. This will bring new ethical and moral dilemmas. The cancer future will be created by the interaction of four complex factors: technological success, society’s willingness to pay, future healthcare delivery systems and the financial mechanisms that underpin them.

Hereditary colorectal cancer: clinical consequences of predictive molecular testing.

The continuing increase in knowledge about the genetic basis of carcinogenesis has led to diverse efforts to exploit this knowledge clinically, primarily in the form of predictive genetic testing. In conjunction with family history, gene tests are intended to improve individual cancer risk assessment. The objectives of predictive molecular testing are to identify the disease-causing germline mutation in an index person who has already developed the disease and to distinguish asymptomatic mutation carriers from non-mutation carriers within a given cancer-prone family. At present, genetic testing for colorectal cancer risk, primarily in form of DNA sequencing, is applied in familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). In these inherited colorectal tumor syndromes determining the genetic status may result in an individually tailored surveillance program and prophylactic treatment. The implications of genetic testing for the clinical management of disease, both of mutation and non-mutation carriers, in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer families are discussed.

The future of oncology: more of the same?

R eminiscent of President Kennedy's pledge in the early 1960s to land a man on the moon within the decade, in 1971 US President Richard Nixon declared a war on that was to eradicate the disease within that decade. Researchers and politicians have since become more prudent about the promises they make, but similar euphoric projections continue to be issued in conjunction with announcements of breakthroughs in Today, these are more likely to be targeted at the stock market than at the scientific community, and the public has become increasingly sceptical. In reality, improvement in the cure rate has been minimal over the past 15 years, despite the unprecedented amount of new information about the biology of cancer. The rise in cancer mortality is due more to the higher incidence of neoplasms that occur subsequent to survival of other diseases, and overall longer survival, than to the real, age-adjusted higher incidence of some tumours (eg, melanomas, lymphomas, lung cancers). In the early years of the new millennium a third to a fourth of all deaths will be cancer-related, at least in the developed world. Does this imply that no major therapeutic progress can be expected for the next 10-20 years? Not necessarily. Although the improvement in the cure rate of some tumours Cancer cell in the 1960s and 1970s was due chiefly to technological factors (surgical techniques, highenergy equipment in radiotherapy, the empirical discovery of new drugs such as cisplatin), the next major step forward will probably come from the biological revolution, of which the discovery of the BRCAI and BRCA2 genes in breast cancer is only the beginning. In coming decades, the availability of individual cancerrisk assessment based on molecular genetics will render a much more individualised approach to preventive measures: changes in lifestyle are easier to achieve when people are confronted with a personal as opposed to a population-based risk assessment. The flipside of the coin, however, is the possibility that this evolution will generate more bad than good news. Lifestyle changes can in fact prevent the occurrence of only some tumours, and it is currently impossible to predict when chemopreventive agents are likely to become available (current results with tamoxifen are much too preliminary). Meanwhile, the most immediate consequence of greater clarification of molecular genetics, and of the advent of novel tumour markers, could simply be an increase of anxiety in individuals at risk. Such developments will ultimately lead to an improved cure rate, but they could also dramatically increase the number of cases without a clear localisation of the primary tumour. It is difficult to see how such patients could then be treated with the current cytotoxic chemotherapies, The future of oncology: more of the same?

Molecular mechanisms of radiation oncogenesis.

Resolving the molecular mechanisms of radiation oncogenesis represents an important but daunting challenge in radiation research. This brief review outlines the principal oncogenic mechanisms that need to be considered in the context of radiation effects on the genome, how these might relate to specific gene and chromosomal changes relevant to neoplasia and the possible implications of such knowledge for the modelling of cancer risk. The long-term application of this mechanistic knowledge to the determination of tumour causality and for the assessment of individual cancer risk is also briefly discussed.

The GSTM1 null genotype as a potential risk modifier for squamous cell carcinoma of the lung.

The identification of genetic traits that predispose individuals to environmentally induced cancers is one of the challenges in the assessment of individual cancer risk. For this reason, individual variations in the expression of enzymes involved in biotransformation reactions have been extensively studied. One such polymorphic enzyme is GSTM1, which belongs to the class Mu of glutathione S-transferases (GSTs), and is only expressed in 55-60% of Caucasians. Previous data suggest that smokers lacking GSTM1 activity may be at greater risk of developing lung cancer. In this study, we used a polymerase chain reaction-based method to examine this issue in a Finnish study population. We found that 44% of a control group of 142 individuals lacked the GSTM1 gene, i.e. they had the GSTM1 null genotype; the rest were either homozygous or heterozygous for the expressed GSTM1 alleles. In a group of 36 patients with non-neoplastic pulmonary diseases, an identical distribution was observed. However, among 138 lung cancer patients the distribution of the GSTM1 genotypes deviated from that found in the healthy controls (53% nulled; odds ratio 1.5, 95% confidence interval 0.9-2.3). Furthermore, when the lung cancer patients were analysed by tumour type, a statistically significant increase in the GSTM1 null genotypes (62%; n = 71) was seen in the squamous cell carcinoma group, with an odds ratio of 2.1 (95% confidence interval 1.2-3.8). These data support the suggestion that GSTM1 null genotype may act as a risk modifier in lung cancer.