Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening.

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25-65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56-1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43-1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14-65) and intervention 43 (95% CI: 25-73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1-0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.

Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial.

Human papillomavirus (HPV)-based cervical cancer screening requires triage of HPV positive women to identify those at risk of cervical intraepithelial neoplasia grade 2 (CIN2) or worse. We conducted a blinded case-control study within the HPV FOCAL randomized cervical cancer screening trial of women aged 25-65 to examine whether baseline methylation testing using the S5 classifier provided triage performance similar to an algorithm relying on cytology and HPV genotyping. Groups were randomly selected from women with known HPV/cytology results and pathology outcomes. Group 1: 104 HPV positive (HPV+), abnormal cytology (54 CIN2/3; 50

Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV FOCAL Randomized Clinical Trial.

Importance: There is limited information about the relative effectiveness of cervical cancer screening with primary human papillomavirus (HPV) testing alone compared with cytology in North American populations. Objective: To evaluate histologically confirmed cumulative incident cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) detected up to and including 48 months by primary HPV testing alone (intervention) or liquid-based cytology (control). Design, Setting, and Participants: Randomized clinical trial conducted in an organized Cervical Cancer Screening Program in Canada. Participants were recruited through 224 collaborating clinicians from January 2008 to May 2012, with follow-up through December 2016. Women aged 25 to 65 years with no history of CIN2+ in the past 5 years, no history of invasive cervical cancer, or no history of hysterectomy; who have not received a Papanicolaou test within the past 12 months; and who were not receiving immunosuppressive therapy were eligible. Interventions: A total of 19 009 women were randomized to the intervention (n = 9552) and control (n = 9457) groups. Women in the intervention group received HPV testing; those whose results were negative returned at 48 months. Women in the control group received liquid-based cytology (LBC) testing; those whose results were negative returned at 24 months for LBC. Women in the control group who were negative at 24 months returned at 48 months. At 48-month exit, both groups received HPV and LBC co-testing. Main Outcomes and Measures: The primary outcome was the cumulative incidence of CIN3+ 48 months following randomization. The cumulative incidence of CIN2+ was a secondary outcome. Results: Among 19 009 women who were randomized (mean age, 45 years [10th-90th percentile, 30-59]), 16 374 (8296 [86.9%] in the intervention group and 8078 [85.4%] in the control group) completed the study. At 48 months, significantly fewer CIN3+ and CIN2+ were detected in the intervention vs control group. The CIN3+ incidence rate was 2.3/1000 (95% CI, 1.5-3.5) in the intervention group and 5.5/1000 (95% CI, 4.2-7.2) in the control group. The CIN3+ risk ratio was 0.42 (95% CI, 0.25-0.69). The CIN2+ incidence rate at 48 months was 5.0/1000 (95% CI, 3.8-6.7) in the intervention group and 10.6/1000 (95% CI, 8.7-12.9) in the control group. The CIN2+ risk ratio was 0.47 (95% CI, 0.34-0.67). Baseline HPV-negative women had a significantly lower cumulative incidence of CIN3+ at 48 months than cytology-negative women (CIN3+ incidence rate, 1.4/1000 [95% CI, 0.8-2.4]; CIN3+ risk ratio, 0.25 [95% CI, 0.13-0.48]). Conclusions and Relevance: Among women undergoing cervical cancer screening, the use of primary HPV testing compared with cytology testing resulted in a significantly lower likelihood of CIN3+ at 48 months. Further research is needed to understand long-term clinical outcomes as well as cost-effectiveness. Trial Registration: isrctn.org Identifier: ISRCTN79347302.

HPV for cervical cancer screening (HPV FOCAL): Complete Round 1 results of a randomized trial comparing HPV-based primary screening to liquid-based cytology for cervical cancer.

Complete Round 1 data (baseline and 12-month follow-up) for HPV FOCAL, a randomized trial establishing the efficacy of HPV DNA testing with cytology triage as a primary screen for cervical cancer are presented. Women were randomized to one of three arms: Control arm - Baseline liquid-based cytology (LBC) with ASCUS results triaged with HPV testing; Intervention and Safety arms - Baseline HPV with LBC triage for HPV positives. Results are presented for 15,744 women allocated to the HPV (intervention and safety combined) and 9,408 to the control arms. For all age cohorts, the CIN3+ detection rate was higher in the HPV (7.5/1,000; 95%CI: 6.2, 8.9) compared to the control arm (4.6/1,000; 95%CI: 3.4, 6.2). The CIN2+ detection rates were also significantly higher in the HPV (16.5/1,000; 95%CI: 14.6, 18.6) vs. the control arm (10.1/1,000; 95%CI: 8.3, 12.4). In women ≥35 years, the overall detection rates for CIN2+ and CIN3+ were higher in the HPV vs. the control arm (CIN2+:10.0/1,000 vs. 5.2/1,000; CIN3+: 4.2/1,000 vs. 2.2/1,000 respectively, with a statistically significant difference for CIN2+). HPV testing detected significantly more CIN2+ in women 25-29 compared to LBC (63.7/1,000; 95%CI: 51.9, 78.0 vs. 32.4/1,000; 95%CI: 22.3, 46.8). HPV testing resulted in significantly higher colposcopy referral rates for all age cohorts (HPV: 58.9/1,000; 95%CI: 55.4, 62.7 vs. CONTROL: 30.9/1,000; 95%CI: 27.6, 34.6). At completion of Round 1 HPV-based cervical cancer screening in a population-based program resulted in greater CIN2+ detection of across all age cohorts compared to LBC screening.

Cancer in First Nations people living in British Columbia, Canada: an analysis of incidence and survival from 1993 to 2010.

BACKGROUND: For First Nations (FN) peoples living in British Columbia (BC), little is known regarding cancer in the population. The aim of this study was to explore cancer incidence and survival in the FN population of BC and compare it to the non-FN population. METHODS: All new cancers diagnosed from 1993 to 2010 were linked to the First Nations Client File (FNCF). Age-standardized incidence rates (ASIR) and rate ratios, and 1- and 5-year cause-specific survival estimates and hazard ratios were calculated. Follow-up end date for survival was December 31, 2011 and follow-up time was censored at a maximum of 15 years. RESULTS: ASIR of colorectal cancer (male SRR = 1.42, 95% CI 1.25-1.61; female SRR = 1.21, 95% CI 1.06-1.38) and cervical cancer (SRR = 1.84, 95% CI 1.45-2.33) were higher overall in FN residents in BC, compared to non-FN residents. Incidence rates of almost all other cancers were generally similar or lower in FN populations overall and by sex, age, and period categories, compared to non-FN residents. Trends in ASIR over time were similar except for lung (increasing for FN, decreasing for non-FN) and colorectal cancers (increasing for FN, decreasing for non-FN). Conversely, survival rates were generally lower for FN, with differences evident for some cancer sites at 1 year following diagnosis. CONCLUSION: FN people living in BC face unique cancer issues compared to non-FN people. Higher incidence and lower survival associated with certain cancer types require further research to look into the likely multifaceted basis for these findings.

Post-Loop Electrosurgical Excision Procedure High-Risk Human Papillomavirus Testing as a Test of Cure: The British Columbia Experience.

OBJECTIVES: To determine whether Hybrid Capture 2 High-Risk HPV DNA Test (HC2) can be used as a test of cure in women treated for cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and allow discharge from colposcopy follow-up with a return to a cytology-based screening program for HC2-negative women. MATERIALS AND METHODS: Data were analyzed for all women who underwent a loop electrosurgical excision procedure between August 1, 2008, and June 30, 2011, and had a valid HC2 result after loop electrosurgical excision procedure and follow-up histopathology result, to determine risk of persistent or recurrent CIN 2+ in HC2-positive and HC2-negative women. RESULTS: Two thousand three hundred forty women had adequate biopsies and valid HC2 results. Of 460 HC2-positive women, 118 (25.7%) were diagnosed with CIN 2+, whereas of 1,880 HC2-negative women, 35 (1.9%) had a subsequent diagnosis of CIN 2+ (p < .0002) yielding a HC2-negative predictive value of 98.1% (95% confidence interval = 97.4-98.7). Of 460 HC2-positive women, 306 initially had negative biopsies. In the subsequent 36 months, 38 of the 306 were diagnosed with CIN 2+. CONCLUSIONS: We conclude that women with a negative HC2 test can safely return to routine annual cytology screening by primary care providers while women who test HC2 positive are at higher risk and should continue to be followed by colposcopy, even if their initial biopsy is negative.

Disease detection and resource use in the safety and control arms of the HPV FOCAL cervical cancer screening trial.

BACKGROUND: The HPV FOCAL Trial is a RCT comparing human papilloma virus (HPV) with Liquid Based Cytology (LBC) screening for cervical cancer. Results are presented for the comparison of the Safety and Control arms after two rounds. METHODS: HPV FOCAL included randomisation of women aged 25-65 into the Safety arm, where they were initially screened with HPV and the Control arm, where they received entry screening with LBC, with both arms screened again with LBC at 24 months. RESULTS: There are 6203 (Safety) and 6075 (Control) women included in this analysis. For the Safety vs Control arms, Round 1 screening resulted in increased detection of cervical intraepithelial neoplasia 2 or worse (CIN2+),15.3 vs 10.4 per 1000, RR=1.48 (95%CI=1.08-2.03) and higher colposcopy referral rates, 5.6% vs 3.2%. LBC screening at 24 months resulted in similar colposcopy referral rates, 1.5% vs 1.9%, and decreased CIN2+ detection, 2.0 vs 4.7 per 1000, RR=0.43 (95%CI=0.21-0.88) in the Safety vs Control arms. CIN2+ detection and colposcopy referral rates declined with increasing age in both arms. One round of HPV screening detected similar levels of CIN2+ as two rounds of LBC screening. INTERPRETATION: CIN2+ detection at 2 years was lower in those screened by HPV, indicating an improved 2-year negative predictive value of the HPV test.

Correlates of women's intentions to be screened for human papillomavirus for cervical cancer screening with an extended interval.

BACKGROUND: High-risk HPV DNA testing has been proposed as a primary tool for cervical cancer screening (HPV-CCS) as an alternative to the Papanicolaou cytology- method. This study describes factors associated with women's intentions to attend cervical cancer screening if high-risk HPV DNA testing (HPV-CCS) was implemented as a primary screening tool, and if screening were conducted every 4 years starting after age 25. METHODS: This online survey was designed using the Theory of Planned Behaviour to assess factors that impact women's intentions to attend HPV-CCS among women aged 25-69 upon exit of the HPV FOCAL trial. Univariate and regression analyses were performed to compare the demographic, sexual history, and smoking characteristics between women willing and unwilling to screen, and scales for intention to attend HPV-CCS. A qualitative analysis was performed by compiling and coding the comments section of the survey. RESULTS: Of the 981 women who completed the survey in full, only 51.4 % responded that they intended to attend HPV-CCS with a delayed start age and extended screening interval. Women who intended to screen were more likely to have higher education (AOR 0.59, 95 % CI [0.37, 0.93]), while both positive attitudes (AOR 1.26, 95 % CI [1.23, 1.30]) and perceived behavior control (AOR 1.06, 95 % CI [1.02, 1.10]) were significant predictors of intention to screen. Among women who provided comments in the survey, a large number of women expressed fears about not being checked more than every 4 years, but 12 % stated that these fears may be alleviated by having more information. CONCLUSIONS: Acceptability of increased screening intervals and starting age could be improved through enhanced education of benefits. Program planners should consider measures to assess and improve women's knowledge, attitudes and beliefs prior to the implementation of new screening programs to avoid unintended consequences.

Reduction in cervical intraepithelial neoplasia in young women in British Columbia after introduction of the HPV vaccine: An ecological analysis.

We report on the rates of cervical intraepithelial neoplasia (CIN) in young women aged 15-22 years of age in British Columbia before and after the introduction of an HPV vaccine program. Rates of cervical intraepithelial neoplasia (CIN) 2+ for each age stratum (15-22) in the calendar years 2004-2012 for the province of British Columbia were obtained from the BC Cancer Agency's population-based cervical cancer program. Incidence rate ratios (IRR) of CIN2+ were described and compared before and after HPV vaccine program introduction in cohorts born in vaccine eligible years, and in non-vaccine eligible years using piece-wise Poisson regression analysis, and adjusted for age. Between 2004 and 2012, rates of CIN2 and CIN2+ in young women aged 15-22 years in the province of British Columbia have decreased overall. After the introduction of the HPV vaccine program, the age adjusted IRR for CIN2+ for young women aged 15-17 years decreased significantly from 0.91 (95% CI: 0.86-0.98 p < 0.01) to 0.36 (95% CI: 0.18-0.73 p < 0.01). During the same time period, no similar reduction was found in young women 18-22 years. After introduction of HPV vaccine program, IRR for CIN2+ in young women 15-17 was significantly reduced for CIN2+ (0.14; 95% CI: 0.04- 0.47; p < 0.01) and CIN2 (0.1; 95% CI: 0.02-0.54; p < 0.01). This ecological analysis shows a significant reduction in CIN2+ lesions in young women aged 15-17 years in British Columbia after the introduction of the HPV vaccine in young women despite vaccine uptake levels below 70%.

Comparison of the Roche cobas® 4800 and Digene Hybrid Capture® 2 HPV tests for primary cervical cancer screening in the HPV FOCAL trial.

BACKGROUND: HPV FOCAL is a randomized trial (ISRCTN79347302, registered 20 Apr 2007) comparing high-risk (hr) HPV testing vs. liquid-based cytology (LBC) for cervical cancer screening of women aged 25-65. We compared the Digene Hybrid Capture® 2 High-Risk HPV DNA Test® (HC2) and the Roche cobas® 4800 HPV Test (COBAS) for primary screening. METHODS: Women (n=6,172) were screened at baseline by HC2 and COBAS and by LBC 24 months later. We assessed HPV genotyping and reflex LBC for colposcopy triage of baseline HPV positive women. RESULTS: Overall HC2/COBAS agreement was 96.1% (kappa 0.75) and positive agreement was 77.5%. Baseline CIN2 and CIN3+ rates based on HPV screening were 8.6/1,000 and 6.6/1,000 respectively; 24 month rates were 0.7/1,000 and 0.4/1,000 (LBC screening). HC2 and COBAS were concordant positive for 91% of round 1 CIN2 and 98% of CIN3+. CIN3+ was significantly associated with HPV 16 (Odds Ratio [OR] 5.11; 95% confidence interval [CI] 2.30, 11.37), but not HPV 18 (OR 2.62; 95% CI 0.73, 9.49), vs. non-HPV 16/18 HPV at baseline. There was no significant association between HPV genotype and CIN2. CIN3+ was significantly more likely for high-grade (OR 5.99; 95% CI 2.53, 14.18), but not low-grade (OR 0.54; 95% CI 0.20, 1.49), vs. negative LBC. No significant association was observed between LBC grade and CIN2. HPV 16 and 18 were associated with 33% of CIN2 and 68% of CIN3+ identified at baseline. CONCLUSIONS: For hrHPV positive women, abnormal reflex LBC is appropriate for colposcopy triage. In addition, immediate referral of women with HPV 16/18 and normal cytology may allow for earlier detection of CIN2+ lesions which would not be detected until after follow-up testing.

Projected Impact of HPV and LBC Primary Testing on Rates of Referral for Colposcopy in a Canadian Cervical Cancer Screening Program.

OBJECTIVE: To estimate the impact of implementing primary human papilloma virus liquid-based cytology (LBC) screening on four-year rates of referral for colposcopy in the British Columbia screening program. METHODS: We used data on referral for colposcopy from an RCT (HPV FOCAL) comparing HPV testing every four years with LBC testing every two years. We also used data from population screening with conventional cytology among women aged 25 to 69. The predicted effect of adoption of either trial protocol on rates of referral for colposcopy was estimated using trial age-specific result and screening result-specific rates weighted by their screening program distribution. The cumulative age-specific rates of referral for colposcopy over four years were calculated. RESULTS: Use of HPV testing initially increased rates of referral for colposcopy in the trial, but over four years the cumulative rates of referral were similar to those for LBC except in women aged 25 to 29, in whom a substantial excess persisted. Four-year rates of referral for colposcopy declined with age in women screened with HPV testing, LBC, and conventional cytology. Extrapolating the trial results to the distribution in the provincial screening program, implementation of either HPV or LBC throughout the provincial population would approximately double the current rates of referral for colposcopy. CONCLUSION: Compared with LBC screening, primary screening for HPV increased rates of referral for colposcopy only among women aged 25 to 29. In contrast to current practice, referral for colposcopy was largely driven by the trial protocol recommendations for the management of abnormal results and not by which screening test was used.

Objectif : Estimer les effets de la mise en œuvre d'un dépistage primaire du virus du papillome humain par cytologie en milieu liquide (CML) sur les taux d'orientation en colposcopie sur quatre ans, dans le cadre du programme de dépistage de la Colombie-Britannique. Méthodes : Nous avons utilisé les données sur l'orientation en colposcopie issues d'un ECR (HPV FOCAL) comparant le dépistage du VPH tous les quatre ans au dépistage par CML tous les deux ans. Nous avons également utilisé des données issues du dépistage populationnel par cytologie conventionnelle mené auprès des femmes de 25 à 69 ans. Le taux d'orientation en colposcopie en fonction de l'âge et le taux d'orientation en colposcopie en fonction des résultats de dépistage ont été pondérés en fonction de la distribution de leurs programmes de dépistage respectifs, ce qui a permis d'estimer l'effet populationnel prévu de l'adoption de l'un ou l'autre des protocoles d'essai en question sur les taux d'orientation en colposcopie. Les taux cumulatifs (en fonction de l'âge) de l'orientation en colposcopie sur quatre ans ont été calculés. Résultats : Le recours au dépistage du VPH a initialement mené à la hausse des taux d'orientation en colposcopie dans le cadre de l'essai; toutefois, sur quatre ans, les taux cumulatifs d'orientation ont été semblables à ceux de la CML, sauf chez les femmes de 25 à 29 ans (chez lesquelles un excès substantiel a persisté). Les taux d'orientation en colposcopie sur quatre ans ont connu une baisse en fonction de l'âge chez les femmes ayant fait l'objet d'un dépistage du VPH, d'une CML et d'une cytologie conventionnelle. En extrapolant les résultats de l'essai à la distribution qui existe au sein du programme provincial de dépistage, nous avons constaté que la mise en œuvre du dépistage du VPH ou de la CML au sein de la population provinciale mènerait au doublement approximatif des taux actuels d'orientation en colposcopie. Conclusion : Par comparaison avec le dépistage par CML, le dépistage primaire du VPH n'a entraîné la hausse des taux d'orientation en colposcopie que chez les femmes de 25 à 29 ans. Contrairement à la pratique actuelle, l'orientation en colposcopie était largement motivée par les recommandations du protocole d'essai en ce qui concerne la prise en charge des résultats anormaux, et non par le test de dépistage utilisé.

Is prostate cancer screening cost-effective? A microsimulation model of prostate-specific antigen-based screening for British Columbia, Canada.

Prostate-specific antigen (PSA) screening for prostate cancer may reduce mortality, but it incurs considerable risk of over diagnosis and potential harm to quality of life. Our objective was to evaluate the cost-effectiveness of PSA screening, with and without adjustment for quality of life, for the British Columbia (BC) population. We adapted an existing natural history model using BC incidence, treatment, cost and mortality patterns. The modeled mortality benefit of screening derives from a stage-shift mechanism, assuming mortality reduction consistent with the European Study of Randomized Screening for Prostate Cancer. The model projected outcomes for 40-year-old men under 14 combinations of screening ages and frequencies. Cost and utility estimates were explored with deterministic sensitivity analysis. The incremental cost-effectiveness of regular screening ranged from $36,300/LYG, for screening every four years from ages 55 to 69 years, to $588,300/LYG, for screening every two years from ages 40 to 74 years. The marginal benefits of increasing screening frequency to 2 years or starting screening at age 40 years were small and came at significant cost. After utility adjustment, all screening strategies resulted in a loss of quality-adjusted life years (QALYs); however, this result was very sensitive to utility estimates. Plausible outcomes under a range of screening strategies inform discussion of prostate cancer screening policy in BC and similar jurisdictions. Screening may be cost-effective, but the sensitivity of results to utility values suggests individual preferences for quality versus quantity of life should be a key consideration.

Women's intentions to self-collect samples for human papillomavirus testing in an organized cervical cancer screening program.

BACKGROUND: Mounting evidence affirms HPV testing as an effective cervical cancer screening tool, and many organized screening programs are considering adopting it as primary testing. HPV self-collection has comparable sensitivity to clinician collected specimens and is considered a feasible option in hard-to-reach women. We explored women's intentions to HPV self-collect for cervical cancer screening from a cohort participating in a Canadian randomized controlled cervical cancer screening trial. METHODS: Women aged 25-65 were invited to complete an online survey assessing intentions to be screened with HPV testing instead of the Pap smear. The survey was based in the Theory of Planned Behaviour and questions were included to assess women's intentions to self-collect for HPV. Demographic characteristics of women who intended to self-collect were compared with those who did not. Demographic and scale variables achieving a p-value <0.1 in the univariate and bivariate analyses were included in the stepwise logistic regression model. The final model was created to predict factors associated with women's intentions to self-collect an HPV specimen for cervical cancer. Odds ratios were calculated with 95% confidence intervals to identify variables associated with a woman's intention to self-collect for cervical cancer screening. RESULTS: The overall survey response rate was 63.8% (981/1538) with 447 (45.6%) reporting they intended to self-collect, versus 534 (54.4%) reporting they did not. In the univariate analysis, women with more than high school education were more likely to self-collect. Women who intended to receive HPV testing versus the Pap smear were 1.94 times as likely to be in favour of self-collection and those who intended to self-collect had significantly higher attitudinal scores towards HPV self-collection. The adjusted odds ratio and 95% confidence interval from the multivariate analysis demonstrated attitude towards self-collection was the only significant variable predicting a woman's intention to self-collect (OR 1.25; 95% CI: 1.22, 1.29). CONCLUSIONS: The primary predictor of a woman's intention to HPV self-collect for cervical cancer screening was her attitude towards the procedure. From a program planning perspective, these results indicate that education and awareness may be significant contributing factors to improving acceptance of self-collection and subsequently, improving screening attendance rates.

Examining breast cancer screening recommendations in Canada: The projected resource impact of screening among women aged 40-49.

OBJECTIVE: To quantify the resource use of revising breast cancer screening guidelines to include average-risk women aged 40-49 years across Canada from 2024 to 2043 using a validated microsimulation model. SETTING: OncoSim-Breast microsimulation platform was used to simulate the entire Canadian population in 2015-2051. METHODS: We compared resource use between current screening guidelines (biennial screening ages 50-74) and alternate screening scenarios, which included annual and biennial screening for ages 40-49 and ages 45-49, followed by biennial screening ages 50-74. We estimated absolute and relative differences in number of screens, abnormal screening recalls without cancer, total and negative biopsies, screen-detected cancers, stage of diagnosis, and breast cancer deaths averted. RESULTS: Compared with current guidelines in Canada, the most intensive screening scenario (annual screening ages 40-49) would result in 13.3% increases in the number of screens and abnormal screening recalls without cancer whereas the least intensive scenario (biennial screening ages 45-49) would result in a 3.4% increase in number of screens and 3.8% increase in number of abnormal screening recalls without cancer. More intensive screening would be associated with fewer stage II, III, and IV diagnoses, and more breast cancer deaths averted. CONCLUSIONS: Revising breast cancer screening in Canada to include average-risk women aged 40-49 would detect cancers earlier leading to fewer breast cancer deaths. To realize this potential clinical benefit, a considerable increase in screening resources would be required in terms of number of screens and screen follow-ups. Further economic analyses are required to fully understand cost and budget implications.

Women's intentions to receive cervical cancer screening with primary human papillomavirus testing.

We explored the potential impact of human papillomavirus (HPV) testing on women's intentions to be screened for cervical cancer in a cohort of Canadian women. Participants aged 25-65 years from an ongoing trial were sent a questionnaire to assess women's intentions to be screened for cervical cancer with HPV testing instead of Pap smears and to be screened every 4 years or after 25 years of age. We created scales for attitudes about HPV testing, perceived behavioral control, and direct and indirect subjective norms. Demographic data and scales that were significantly different (p < 0.1) between women who intended to be screened with HPV and those who did not intend were included in a stepwise logistic regression model. Of the 2,016 invitations emailed, 1,538 were received, and 981 completed surveys for a response rate of 63% (981/1,538). Eighty-four percent of women (826/981) responded that they intended to attend for HPV-based cervical cancer screening, which decreased to 54.2% when the screening interval was extended, and decreased further to 51.4% when screening start was delayed to age of 25. Predictors of intentions to undergo screening were attitudes (odds ratio [OR]: 1.22; 95% confidence interval [CI]: 1.15, 1.30), indirect subjective norms (OR: 1.02; 95% CI: 1.01, 1.03) and perceived behavioral control (OR: 1.16; 95% CI: 1.10; 1.22). Intentions to be screened for cervical cancer with HPV testing decreased substantially when the screening interval was extended and screening started at age of 25. Use of primary HPV testing may optimize the screening paradigm, but programs should ensure robust planning and education to mitigate any negative impact on screening attendance rates.

Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation carriers.

BACKGROUND: Women with mutations in BRCA1 or BRCA2 are at high risk of developing breast cancer and, in British Columbia, Canada, are offered screening with both magnetic resonance imaging (MRI) and mammography to facilitate early detection. MRI is more sensitive than mammography but is more costly and produces more false positive results. The purpose of this study was to calculate the cost-effectiveness of MRI screening for breast cancer in BRCA1/2 mutation carriers in a Canadian setting. METHODS: We constructed a Markov model of annual MRI and mammography screening for BRCA1/2 carriers, using local data and published values. We calculated cost-effectiveness as cost per quality-adjusted life-year gained (QALY), and conducted one-way and probabilistic sensitivity analysis. RESULTS: The incremental cost-effectiveness ratio (ICER) of annual mammography plus MRI screening, compared to annual mammography alone, was $50,900/QALY. After incorporating parameter uncertainty, MRI screening is expected to be a cost-effective option 86% of the time at a willingness-to-pay of $100,000/QALY, and 53% of the time at a willingness-to-pay of $50,000/QALY. The model is highly sensitive to the cost of MRI; as the cost is increased from $200 to $700 per scan, the ICER ranges from $37,100/QALY to $133,000/QALY. CONCLUSIONS: The cost-effectiveness of using MRI and mammography in combination to screen for breast cancer in BRCA1/2 mutation carriers is finely balanced. The sensitivity of the results to the cost of the MRI screen itself warrants consideration: in jurisdictions with higher MRI costs, screening may not be a cost-effective use of resources, but improving the efficiency of MRI screening will also improve cost-effectiveness.

Incidence of breast cancer and estimates of overdiagnosis after the initiation of a population-based mammography screening program.

BACKGROUND: There has been growing interest in the overdiagnosis of breast cancer as a result of mammography screening. We report incidence rates in British Columbia before and after the initiation of population screening and provide estimates of overdiagnosis. METHODS: We obtained the numbers of breast cancer diagnoses from the BC Cancer Registry and screening histories from the Screening Mammography Program of BC for women aged 30-89 years between 1970 and 2009. We calculated age-specific rates of invasive breast cancer and ductal carcinoma in situ. We compared these rates by age, calendar period and screening participation. We obtained 2 estimates of overdiagnosis from cumulative cancer rates among women between the ages of 40 and 89 years: the first estimate compared participants with nonparticipants; the second estimate compared observed and predicted population rates. RESULTS: We calculated participation-based estimates of overdiagnosis to be 5.4% for invasive disease alone and 17.3% when ductal carcinoma in situ was included. The corresponding population-based estimates were -0.7% and 6.7%. Participants had higher rates of invasive cancer and ductal carcinoma in situ than nonparticipants but lower rates after screening stopped. Population incidence rates for invasive cancer increased after 1980; by 2009, they had returned to levels similar to those of the 1970s among women under 60 years of age but remained elevated among women 60-79 years old. Rates of ductal carcinoma in situ increased in all age groups. INTERPRETATION: The extent of overdiagnosis of invasive cancer in our study population was modest and primarily occurred among women over the age of 60 years. However, overdiagnosis of ductal carcinoma in situ was elevated for all age groups. The estimation of overdiagnosis from observational data is complex and subject to many influences. The use of mammography screening in older women has an increased risk of overdiagnosis, which should be considered in screening decisions.

The impact on clinical outcomes and healthcare resources from discontinuing colonoscopy surveillance subsequent to low-risk adenoma removal: A simulation study using the OncoSim-Colorectal model.

OBJECTIVE: To estimate the impact on clinical outcomes and healthcare resource use from recommending that patients with 1-2 low-risk adenomas (LRAs) return to routine fecal immunochemical test (FIT) screening instead of surveillance colonoscopy, from a Canadian provincial healthcare system perspective. METHODS: The OncoSim-Colorectal microsimulation model simulated average-risk individuals eligible for FIT-based colorectal cancer (CRC) screening in Alberta, Canada. We simulated two surveillance strategies that applied to individuals with 1-2 LRAs (<10 mm) removed as part of the average risk CRC screening program: (a) Surveillance colonoscopy (status quo) and (b) return to FIT screening (new strategy); both at 5 years after polypectomy. A 75 ng/mL FIT positivity threshold was used in the base case. The simulations projected average annual CRC outcomes and healthcare resource use from 2023 to 2042. We conducted alternative scenarios and sensitivity analyses on key variables. RESULTS: Returning to FIT screening (versus surveillance colonoscopy) after polypectomy was projected to have minimal impact on long-term CRC incidence and deaths (not statistically significant). There was a projected decrease of one (4%) major bleeding event and seven (5%) perforation events per year. There was a projected increase of 4800 (1.5%) FIT screens, decrease of 3900 (5.1%) colonoscopies, and a decrease of $3.4 million (1.2%) in total healthcare costs per year, on average. The annual colonoscopies averted and healthcare cost savings increased over time. Results were similar in the alternative scenarios and sensitivity analyses. CONCLUSIONS: Returning to FIT screening would have similar clinical outcomes as surveillance colonoscopy but could reduce colonoscopy demand and healthcare costs.

The OncoSim-Breast Cancer Microsimulation Model.

BACKGROUND: OncoSim-Breast is a Canadian breast cancer simulation model to evaluate breast cancer interventions. This paper aims to describe the OncoSim-Breast model and how well it reproduces observed breast cancer trends. METHODS: The OncoSim-Breast model simulates the onset, growth, and spread of invasive and ductal carcinoma in situ tumours. It combines Canadian cancer incidence, mortality, screening program, and cost data to project population-level outcomes. Users can change the model input to answer specific questions. Here, we compared its projections with observed data. First, we compared the model's projected breast cancer trends with the observed data in the Canadian Cancer Registry and from Vital Statistics. Next, we replicated a screening trial to compare the model's projections with the trial's observed screening effects. RESULTS: OncoSim-Breast's projected incidence, mortality, and stage distribution of breast cancer were close to the observed data in the Canadian Cancer Registry and from Vital Statistics. OncoSim-Breast also reproduced the breast cancer screening effects observed in the UK Age trial. CONCLUSIONS: OncoSim-Breast's ability to reproduce the observed population-level breast cancer trends and the screening effects in a randomized trial increases the confidence of using its results to inform policy decisions related to early detection of breast cancer.