Development and internal validation of a multifactorial risk prediction model for gallbladder cancer in a high-incidence country

Since 2006, Chile has been implementing a gallbladder cancer (GBC) prevention program based on prophylactic cholecystectomy for gallstone patients aged 35 to 49 years. The effectiveness of this prevention program has not yet been comprehensively evaluated. We conducted a retrospective study of 473 Chilean GBC patients and 2137 population-based controls to develop and internally validate three GBC risk prediction models. The Baseline Model accounted for gallstones while adjusting for sex and birth year. Enhanced Model I also included the non-genetic risk factors: body mass index, educational level, Mapuche surnames, number of children and family history of GBC. Enhanced Model II further included Mapuche ancestry and the genotype for rs17209837. Multiple Cox regression was applied to assess the predictive performance, quantified by the area under the precision-recall curve (AUC-PRC) and the number of cholecystectomies needed (NCN) to prevent one case of GBC at age 70 years. The AUC-PRC for the Baseline Model (0.44%, 95%CI 0.42-0.46) increased by 0.22 (95%CI 0.15-0.29) when non-genetic factors were included, and by 0.25 (95%CI 0.20-0.30) when incorporating non-genetic and genetic factors. The overall NCN for Chileans with gallstones (115, 95%CI 104-131) decreased to 92 (95%CI 60-128) for Chileans with a higher risk than the median according to Enhanced Model I, and to 80 (95%CI 59-110) according to Enhanced Model II. In conclusion, age, sex and gallstones are strong risk factors for GBC, but consideration of other non-genetic factors and individual genotype data improves risk prediction and may optimize allocation of financial resources and surgical capacity.     

Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre

Background:

Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom.

Methods:

Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level.

Results:

The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76–1.10). The E/O ratios by subgroups of the participant''s relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66–0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2).

Conclusion:

BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level.     

Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx

Although studies have established human papillomaviruses (HPVs) as a risk factor for oral and oropharyngeal cancer, it is not clear whether viral infection affects survival in head and neck malignancies. This investigation examined the relationship between HPV and survival in carcinomas of the oral cavity and oropharynx. Formalin-fixed, paraffin-embedded tumor specimens from 139 newly diagnosed cases were tested for HPVs by PCR and DNA sequencing. Patient and tumor characteristics were obtained from questionnaires, pathology reports and cancer registries. Odds ratios (ORs) and relative risks (RRs) were based on logistic and Cox regression models, respectively. HPVs were detected in 21% of the tumors; 83% were HPV-16. Greater risk of HPV infection was associated with males (OR = 2.9, 95% CI = 1.0-8.6), a history of oral-genital sex (OR = 4.2, 95% CI = 1.5-11.7), and oropharyngeal tumors (OR = 10.4, 95% CI = 3.5-31.2). As tobacco usage increased, the odds of HPV detection decreased (OR = 0.97/pack-year, 95% CI = 0.96-0.99). HPV infected patients had better overall survival (RR = 0.3, 95% CI = 0.1-0.8) than those with HPV-negative tumors. There was an interaction between gender and HPV for overall (p = 0.05) and disease-specific (p = 0.03) survival that suggested that HPV infected males had better prognosis than HPV-negative males, but this was not the case among females. HPV status was identified as an independent prognostic factor in oral and oropharyngeal cancers. This result appeared to be gender-specific, suggesting the need for further study of the interaction between HPV and gender on survival.     

Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer

Smoking and alcohol are well-known etiological factors in tonsillar cancer. However, as in cervical cancer, human papillomavirus (HPV) is currently found in a sizable proportion of tonsillar cancer. Recent reports from the U.S. and Finland show an increase in the incidence of tonsillar cancer, without a parallel rise in smoking and alcohol consumption. This study investigates whether the incidence of tonsillar cancer has also changed in Sweden and whether a possible explanation of the increase is a higher proportion of HPV-positive tonsillar cancer. The incidence of tonsillar cancer between 1970 and 2002 in the Stockholm area was obtained from the Swedish Cancer Registry. In parallel, 203 pretreatment paraffin-embedded tonsillar cancer biopsies taken during 1970-2002 from patients in the Stockholm area were tested for presence of HPV DNA by PCR. The incidence of tonsillar cancer increased 2.8-fold (2.6 in men and 3.5 in women) from 1970 to 2002. During the same period, a significant increase in the proportion of HPV-positive tonsillar cancer cases was observed, as it increased 2.9-fold (p < 0.001). The distribution of HPV-positive cases was 7/30 (23.3%) in the 1970s, 12/42 (29%) in the 1980s, 48/84 (57%) in the 1990s and 32/47 (68%) during 2000-2002. We have demonstrated a highly significant and parallel increase both in the incidence of tonsillar cancer and the proportion of HPV-positive tumors. Hence, HPV may play an important role for the increased incidence of tonsillar cancer. This should definitely influence future preventive strategies as well as treatment for this type of cancer.     

The LLP risk model: an individual risk prediction model for lung cancer

Using a model-based approach, we estimated the probability that an individual, with a specified combination of risk factors, would develop lung cancer within a 5-year period.Data from 579 lung cancer cases and 1157 age- and sex-matched population-based controls were available for this analysis. Significant risk factors were fitted into multivariate conditional logistic regression models. The final multivariate model was combined with age-standardised lung cancer incidence data to calculate absolute risk estimates.Combinations of lifestyle risk factors were modelled to create risk profiles. For example, a 77-year-old male non-smoker, with a family history of lung cancer (early onset) and occupational exposure to asbestos has an absolute risk of 3.17% (95% CI, 1.67-5.95). Choosing a 2.5% cutoff to trigger increased surveillance, gave a sensitivity of 0.62 and specificity of 0.70, while a 6.0% cutoff gave a sensitivity of 0.34 and specificity of 0.90. A 10-fold cross validation produced an AUC statistic of 0.70, indicating good discrimination.If independent validation studies confirm these results, the LLP risk models' application as the first stage in an early detection strategy is a logical evolution in patient care.     

A smoking-based carcinogenesis model for lung cancer risk prediction

Lung cancer is the leading cancer killer for both men and women worldwide. Over 80% of lung cancers are attributed to smoking. In this analysis, the authors propose to use a two-stage clonal expansion (TSCE) model to predict an individual's lung cancer risk based on gender and smoking history. The TSCE model is traditionally fitted to prospective cohort data. Here, the authors describe a new method that allows for the reconstruction of cohort data from the combination of risk factor data obtained from a case-control study, and tabled incidence/mortality rate data, and discuss alternative approaches. The method is applied to fit a TSCE model based on smoking. The fitted model is validated against independent data from the control arm of a lung cancer chemoprevention trial, CARET, where it accurately predicted the number of lung cancer deaths observed.     

Genetic variations in human papillomavirus and cervical cancer outcomes

Cervical cancer is driven by persistent infection of human papillomavirus (HPV), which is influenced by HPV type and intratypic variants, yet the impact of HPV type and intratypic variants on patient outcomes is far less understood. Here, we examined the association of cervical cancer stage and survival with HPV type, clade, lineage, and intratypic variants within the HPV E6 locus. Of 1,028 HPV-positive cases recruited through the CerGE study, 301 were in-situ and 727 were invasive cervical cancer (ICC), with an average post-diagnosis follow-up of 4.8 years. HPV sequencing was performed using tumor-isolated DNA to assign HPV type, HPV 16 lineage, clade, and intratypic variants within the HPV 16 E6 locus, of which nonsynonomous variants were functionally annotated by molecular modeling. HPV 18-related types were more prevalent in ICC compared to in-situ disease and associated with significantly worse recurrence-free survival (RFS) compared to HPV 16-related types. The HPV 16 Asian American lineage D3 and Asian lineage A4 associated more frequently with ICC than with in situ disease and women with an intratypic HPV 16 lineage B exhibited a trend toward worse RFS than those with A, C, or D lineages. Participants with intratypic E6 variants predicted to stabilize the E6–E6AP–p53 complex had worse RFS. Variants within the highly immunogenic HPV 16 E6 region (E14–I34) were enriched in ICC compared to in-situ lesions but were not associated with survival. Collectively, our results suggest that cervical cancer outcome is associated with HPV variants that affect virus-host interactions.     

Construction and assessment of a joint prediction model and nomogram for colorectal cancer

BackgroundColorectal cancer (CRC) is one of the most common tumors in the digestive system, and all its risk factors are not yet known. It is important to identify valuable clinical indicators to predict the risk of CRC.MethodsA total of 227 participants, comprising 162 healthy adults and 65 patients diagnosed with CRC at Tianjin Hospital from January 2017 to March 2022, were included in this study. Electrochemiluminescence was adopted to test the expression levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA199). Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for CRC, and a joint prediction model was then constructed. A nomogram was prepared, and the model was later assessed using the receiver operating characteristic curve and calibration curve.ResultsThe univariate analysis showed that there were statistically significant differences between the two groups in terms of smoking (χ²=8.67), fecal occult blood (χ²=119.41), Helicobacter pylori (H. pylori) infection (χ²=30.87), a history of appendectomy (χ²=5.47), serum total bile acid levels (t=19.80), serum CEA levels (t=37.82), serum CA199 levels (t=6.82), and serum ferritin levels (t=54.31) (all P<0.05). The multiple logistic regression analysis showed that smoking, fecal occult blood, H. pylori infection, a history of appendectomy, serum CEA levels, and serum CA199 levels were independent risk factors for CRC (all P<0.05). Based on the above findings, a joint prediction model was constructed, and the area under the receiver operator characteristic (ROC) curve of the model was 0.842. A nomogram and calibration curve was drawn, and the internal validation results indicated that the model had good diagnostic value.ConclusionsSmoking, fecal occult blood, H. pylori infection, a history of appendectomy, serum CEA levels, and serum CA199 levels are independent risk factors for CRC, and the prediction model based on these factors had good predictive ability.     

Cervical cancer prevention in Australia: Planning for the future

The high rate of coverage that has been achieved to date by the Australian government's Human Papillomavirus (HPV) Vaccination Program has already led to profound reductions in the prevalence of biopsy‐confirmed, high‐grade abnormalities and of vaccine‐preventable HPV types in Australia. Declines in the prevalence of vaccine preventable HPV have occurred not only in vaccinated women but also in unvaccinated women, suggesting a herd‐immunity affect. These declines were anticipated on the basis of modelling and were the major drivers for the changes proposed to the Australian National Cervical Screening Program. The federal and state‐based Australian governments established a “Renewal Steering Committee,” which conducted a literature search and a review of the available evidence to assess its applicability and quality. Together with this information the committee also used modeling to determine the optimal screening pathway for cervical cancer screening and constructed a plan for implementing the changes that will be required to transition from the currently successful screening program to the renewed program. The committee recommended that Australia move to a screening program based on testing every 5 years using an HPV test with partial genotyping with reflex liquid‐based cytology (LBC) triage for HPV‐vaccinated and unvaccinated women ages 25 to 69 years, and an additional exit test for women up to age 74 years. Primary HPV testing and reflex LBC will be funded by government. Symptomatic women outside the screening program will also be able to access government funded testing. The new screening program, to be rolled out in 2017, will also provide a cost‐effective framework for an evaluation of the national HPV vaccination program, enabling ongoing monitoring of HPV genotypes and cervical lesions in screened women. Cancer Cytopathol 2016;124:235–40 . © 2015 American Cancer Society.     

Head and Neck cancers—major changes in the American Joint Committee on cancer eighth edition cancer staging manual

Answer questions and earn CME/CNE The recently released eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual, Head and Neck Section, introduces significant modifications from the prior seventh edition. This article details several of the most significant modifications, and the rationale for the revisions, to alert the reader to evolution of the field. The most significant update creates a separate staging algorithm for high‐risk human papillomavirus‐associated cancer of the oropharynx, distinguishing it from oropharyngeal cancer with other causes. Other modifications include: the reorganizing of skin cancer (other than melanoma and Merkel cell carcinoma) from a general chapter for the entire body to a head and neck‐specific cutaneous malignancies chapter; division of cancer of the pharynx into 3 separate chapters; changes to the tumor (T) categories for oral cavity, skin, and nasopharynx; and the addition of extranodal cancer extension to lymph node category (N) in all but the viral‐related cancers and mucosal melanoma. The Head and Neck Task Force worked with colleagues around the world to derive a staging system that reflects ongoing changes in head and neck oncology; it remains user friendly and consistent with the traditional tumor, lymph node, metastasis (TNM) staging paradigm. CA Cancer J Clin 2017;67:122–137. © 2017 American Cancer Society.     

p73 G4C14-to-A4T14 polymorphism and risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never smokers and never drinkers

BACKGROUND.

The p53 tumor suppressor protein homolog p73 can be inactivated by oncoprotein E6 of human papillomavirus (HPV). Variation in p73 may alter the interaction between the E6 protein and p73 and, thus, alter the risk for HPV‐associated carcinogenesis. It is believed that the p73 G4C14‐to‐A4T14 polymorphism affects p73 function by altering gene expression; however, whether that polymorphism also alters the risk of HPV type 16 (HPV‐16)‐associated squamous cell carcinoma of the oropharynx (SCCOP) is unknown.

METHODS.

The current case‐control study included a case group of 188 non‐Hispanic white patients with newly diagnosed SCCOP and a control group of 349 healthy individuals. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for cases and controls stratified by p73 genotype, age, sex, smoking status, alcohol use, and HPV‐16 status. The effects of p73 genotypes on the risk of HPV‐16‐associated SCCOP were explored with further stratification by smoking and drinking status.

RESULTS.

HPV‐16 seropositivity was associated with an increased risk of SCCOP (adjusted OR, 5.98; 95% CI, 3.89‐9.20), especially among never smokers (adjusted OR, 13.8; 95% CI, 5.91‐32.1), never drinkers (adjusted OR, 14.9; 95% CI, 5.24‐42.4), and individuals with p73 variant genotypes (GC/AT and AT/AT; adjusted OR, 7.96; 95% CI, 3.83‐16.5). Moreover, the risk of HPV‐16‐associated SCCOP for individuals who had p73 variant genotypes was particularly high in never smokers and never drinkers.

CONCLUSIONS.

The p73 G4C14‐to‐A4T14 polymorphism may modulate the risk of HPV‐16‐associated SCCOP, and the p73 variant genotypes may be markers of genetic susceptibility to HPV‐16‐associated SCCOP, particularly in never smokers and never drinkers. Cancer 2008. © 2008 American Cancer Society.     

A risk prediction model for head and neck cancers incorporating lifestyle factors,HPV serology and genetic markers

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.