Objective

To test the effect of novel representations of randomness on risk perceptions, worry, and subjective uncertainty about individualized colorectal cancer risk estimates.

Methods

A Web-based factorial experiment was conducted, in which 225 adults aged 40 years and older were provided with hypothetical individualized colorectal cancer risk estimates, using 5 different textual and visual representations varying in expressed randomness. Outcome measures were perceived cancer risk, cancer worry, and subjective uncertainty about cancer risk; the moderating effect of dispositional optimism was also examined.

Results

Representational format was significantly associated with subjective uncertainty about cancer risk, but not with perceived cancer risk or worry. A format using software-based animation to express randomness dynamically led to the highest subjective uncertainty, although a static visual non-random format also increased uncertainty. Dispositional optimism moderated this effect; between-format differences in uncertainty were significant only for participants with low optimism.

Conclusion

Representing randomness in individualized estimates of cancer risk increases subjective uncertainty about risk. A novel dynamic visual format produces the greatest effect, which is moderated by individual differences in optimism.

Practice Implications

Novel representations of randomness may be effective in improving people’s understanding of the essential uncertainty pertaining to individualized cancer risk estimates.

Advances in genomics and related fields are promising tools for risk assessment, early detection, and targeted therapies across the entire cancer care continuum. In this commentary, we submit that this promise cannot be fulfilled without an enhanced translational genomics research agenda firmly rooted in the population sciences. Population sciences include multiple disciplines that are needed throughout the translational research continuum. For example, epidemiologic studies are needed not only to accelerate genomic discoveries and new biological insights into cancer etiology and pathogenesis, but to characterize and critically evaluate these discoveries in well defined populations for their potential for cancer prediction, prevention and response to treatments. Behavioral, social and communication sciences are needed to explore genomic-modulated responses to old and new behavioral interventions, adherence to therapies, decision-making across the continuum, and effective use in health care. Implementation science, health services, outcomes research, comparative effectiveness research and regulatory science are needed for moving validated genomic applications into practice and for measuring their effectiveness, cost effectiveness and unintended consequences. Knowledge synthesis, evidence reviews and economic modeling of the effects of promising genomic applications will facilitate policy decisions, and evidence-based recommendations. Several independent and multidisciplinary panels have recently made specific recommendations for enhanced research and policy infrastructure to inform clinical and population research for moving genomic innovations into the cancer care continuum. An enhanced translational genomics and population sciences agenda is urgently needed to fulfill the promise of genomics in reducing the burden of cancer.

Background

Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with incident HF/CM.

Methods

We conducted a population-based, retrospective cohort study of 12 500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities.

Results

Among 12 500 women (mean age = 60 years, range = 22–99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemotherapy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/CM was higher in patients treated with anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR = 1.49, 95% CI = 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR = 4.12, 95% CI = 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR = 7.19, 95% CI = 5.00 to 10.35).

Conclusions

Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety.

Purpose

The Study of Tamoxifen and Raloxifene (STAR) demonstrated that raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer (IBC) in postmenopausal women and had lower risks of thromboembolic events, endometrial cancer, and cataracts but had a nonstatistically significant higher risk of noninvasive breast cancer. There is a need to summarize the risks and benefits of these agents.

Patients and Methods

Baseline incidence rates of IBC and other health outcomes, absent raloxifene and tamoxifen, were estimated from breast cancer chemoprevention trials; the Surveillance, Epidemiology and End Results Program; and the Women's Health Initiative. Effects of raloxifene and tamoxifen were estimated from STAR and the Breast Cancer Prevention Trial. We assigned weights to health outcomes to calculate the net benefit from raloxifene compared with placebo and tamoxifen compared with placebo.

Results

Risks and benefits of treatment with raloxifene or tamoxifen depend on age, race, breast cancer risk, and history of hysterectomy. Over a 5-year period, postmenopausal women with an intact uterus had a better benefit/risk index for raloxifene than for tamoxifen. For postmenopausal women without a uterus, the benefit/risk ratio was similar. The benefits and risks of raloxifene and tamoxifen are described in tables that can help identify groups of women for whom the benefits outweigh the risks.

Conclusion

We developed a benefit/risk index to quantify benefits from chemoprevention with tamoxifen or raloxifene. This index can complement clinical evaluation in deciding whether to initiate chemoprevention and in comparing the benefits and risks of raloxifene versus tamoxifen.

The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice.The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality.Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction.A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines.These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

Background

Guidelines from the American Cancer Society recommend annual breast MRI screening for women with a projected lifetime risk of ≥20% based on risk models that use family history. Since MRI screening is costly and has limited specificity, estimates of the numbers of U.S. women with breast cancer risk ≥20% would be useful.

Methods

We used data from the 2000 and 2005 National Health Interview Survey and the National Cancer Institute’s (NCI) Breast Cancer Risk Assessment Tool (i.e. Gail Model 2 with a revision for African Americans) to calculate estimates of U.S. women by age and race/ethnicity categories with a lifetime absolute breast cancer risk of ≥20%. Distributions of 5-year and lifetime absolute risk of breast cancer are compared across demographic groups.

Results

We estimated that 1.09% (95% CI = 0.95% to 1.24%) of women aged 30–84 years have a lifetime absolute breast cancer risk of ≥20%, which translates to 880,063 U.S. women eligible for MRI screening. The 5-year risks are highest for White non-Hispanics and lowest for Hispanics. The lifetime risks decrease with age and are generally highest for White non-Hispanics, lower for African American non-Hispanic and lowest for Hispanics.

Conclusion

We provide national estimates of the number of U.S. women who would be eligible for MRI breast screening and distributions of 5-year and lifetime risks of breast cancer using the NCI Breast Cancer Risk Assessment Tool.

Impact

These estimates inform the potential resources and public health demand for MRI screening and chemo-preventive interventions that might be required for U.S. women.

Objective

To examine the effects of communicating uncertainty regarding individualized colorectal cancer risk estimates, and to identify factors that influence these effects.

Methods

Two web-based experiments were conducted, in which adults aged 40 years and older were provided with hypothetical individualized colorectal cancer risk estimates differing in the extent and representation of expressed uncertainty. The uncertainty consisted of imprecision (otherwise known as “ambiguity”) of the risk estimates, and was communicated using different representations of confidence intervals. Experiment 1 (n=240) tested the effects of ambiguity (confidence interval vs. point estimate) and representational format (textual vs. visual) on cancer risk perceptions and worry. Potential effect modifiers including personality type (optimism), numeracy, and the information’s perceived credibility were examined, along with the influence of communicating uncertainty on responses to comparative risk information. Experiment 2 (n=135) tested enhanced representations of ambiguity that incorporated supplemental textual and visual depictions.

Results

Communicating uncertainty led to heightened cancer-related worry in participants, exemplifying the phenomenon of “ambiguity aversion.” This effect was moderated by representational format and dispositional optimism; textual (vs. visual) format and low (vs. high) optimism were associated with greater ambiguity aversion. However, when enhanced representations were used to communicate uncertainty, textual and visual formats showed similar effects. Both the communication of uncertainty and use of the visual format diminished the influence of comparative risk information on risk perceptions.

Conclusions

The communication of uncertainty regarding cancer risk estimates has complex effects, which include heightening cancer-related worry—consistent with ambiguity aversion—and diminishing the influence of comparative risk information on risk perceptions. These responses are influenced by representational format and personality type, and the influence of format appears to be modifiable and content-dependent.

The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

Background

Tamoxifen can reduce the risk of developing invasive estrogen-receptor positive (ER+) breast cancer by 49%, but it is unknown how many women in the U.S. are taking tamoxifen for primary prevention of breast cancer.

Methods

Data from the years 2000 and 2005 National Health Interview Surveys (NHIS) were analyzed to estimate the prevalence of tamoxifen use among U.S. women for primary chemoprevention of breast cancer.

Results

In 2000, approximately 0.2 percent of U.S. women aged 40 to 79 without a personal history of breast cancer took tamoxifen for chemoprevention (95% CI 0.13-0.31). In 2005, the prevalence was approximately 0.08% (95% CI 0.03-0.17).

Conclusion

The prevalence of tamoxifen use for primary prevention of breast cancer was very low in the years 2000 and 2005. Possible explanations for the low uptake are explored.

Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled “Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation” on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.

Purpose

Given the high incidence of colorectal cancer (CRC), and the availability of procedures that can detect disease and remove precancerous lesions, there is a need for a model that estimates the probability of developing CRC across various age intervals and risk factor profiles.

Methods

The development of separate CRC absolute risk models for men and women included estimating relative risks and attributable risk parameters from population-based case-control data separately for proximal, distal, and rectal cancer and combining these estimates with baseline age-specific cancer hazard rates based on Surveillance, Epidemiology, and End Results (SEER) incidence rates and competing mortality risks.

Results

For men, the model included a cancer-negative sigmoidoscopy/colonoscopy in the last 10 years, polyp history in the last 10 years, history of CRC in first-degree relatives, aspirin and nonsteroidal anti-inflammatory drug (NSAID) use, cigarette smoking, body mass index (BMI), current leisure-time vigorous activity, and vegetable consumption. For women, the model included sigmoidoscopy/colonoscopy, polyp history, history of CRC in first-degree relatives, aspirin and NSAID use, BMI, leisure-time vigorous activity, vegetable consumption, hormone-replacement therapy (HRT), and estrogen exposure on the basis of menopausal status. For men and women, relative risks differed slightly by tumor site. A validation study in independent data indicates that the models for men and women are well calibrated.

Conclusion

We developed absolute risk prediction models for CRC from population-based data, and a simple questionnaire suitable for self-administration. This model is potentially useful for counseling, for designing research intervention studies, and for other applications.

Objective

To explore laypersons’ responses to the communication of uncertainty associated with individualized cancer risk estimates and to identify reasons for individual differences in these responses.

Design

A qualitative study was conducted using focus groups. Participants were informed about a new colorectal cancer risk prediction model, and presented with hypothetical individualized risk estimates using presentation formats varying in expressed uncertainty (range v. point estimate). Semistructured interviews explored participants’ responses to this information.

Participants and Setting

Eight focus groups were conducted with 48 adults aged 50 to 74 residing in 2 major US metropolitan areas, Chicago, IL and Washington, DC. Purposive sampling was used to recruit participants with a high school or greater education, some familiarity with information technology, and no personal or immediate family history of cancer.

Results

Participants identified several sources of uncertainty regarding cancer risk estimates, including missing data, limitations in accuracy and source credibility, and conflicting information. In comparing presentation formats, most participants reported greater worry and perceived risk with the range than with the point estimate, consistent with the phenomenon of “ambiguity aversion.” However, others reported the opposite effect or else indifference between formats. Reasons suggested by participants’ responses included individual differences in optimism and motivations to reduce feelings of vulnerability and personal lack of control. Perceptions of source credibility and risk mutability emerged as potential mediating factors.

Conclusions

Laypersons’ responses to the communication of uncertainty regarding cancer risk estimates differ, and include both heightened and diminished risk perceptions. These differences may be attributable to personality, cognitive, and motivational factors.

Unrealistically optimistic or pessimistic risk perceptions may be associated with maladaptive health behaviors. This study characterized factors associated with unrealistic optimism (UO) and unrealistic pessimism (UP) about breast cancer. Data from the 2005 National Health Interview Survey were analyzed (N=14,426 women). After accounting for objective risk status, many (43.8%) women displayed UO, 12.3% displayed UP, 34.5% had accurate risk perceptions (their perceived risk matched their calculated risk), and 9.5% indicated “don’t know/no response.” Multivariate multinomial logistic regression indicated that UO was associated with higher education and never smoking. UP was associated with lower education, lower income, being non-Hispanic Black, having ≥3 comorbidities, current smoking, and being overweight. UO was more likely to emerge in younger and older than in middle-aged individuals. UO and UP are associated with different demographic, health, and behavioral characteristics. Population segments that are already vulnerable to negative health outcomes displayed more UP than less vulnerable populations.