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Background: Long-term safety of a single negative human papillomavirus (HPV) test for cervical cancer screening is unclear. The HPV FOr cerviCAL Cancer Trial (FOCAL) was a randomized trial comparing HPV testing with cytology. The FOCAL-DECADE cohort tracked women who received one HPV test during FOCAL, and were HPV negative, for up to 10 years to identify cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) detected through a provincial screening program. Methods: FOCAL participants who received one HPV test, were negative, and had at least one post-FOCAL cervix screen were included (N = 5,537). We constructed cumulative incidence curves of CIN2+/CIN3+ detection, analyzed cumulative risk of detection at intervals post-HPV test, calculated average incidence rates for detection, and compared hazard across ages. Results: Ten years after one negative HPV test, the probability of CIN2+ detection was lower than 1%, with most lesions detected 7 years or later. Average incidence rates of CIN2+/CIN3+ lesions over follow-up were 0.50 [95% confidence interval (CI), 0.31–0.78] and 0.18 (95% CI, 0.07–0.36) per 1,000 person-years, respectively. Hazards were higher for younger ages (nonsignificant trend). Conclusions: Among women with a single negative HPV test, long-term risk of CIN2+ detection was low, particularly through 7 years of follow-up; thus, one negative HPV test appears to confer long-term protection from precancerous lesions. Even 10-year risk is sufficiently low to support extended testing intervals in average-risk populations. Impact: Our findings support the safety of screening policies using HPV testing alone at 5-year or longer intervals.

Background Population-based cancer screening can reduce cancer burden but was interrupted temporarily due to the COVID-19 pandemic. We estimated the long-term clinical impact of breast and colorectal cancer screening interruptions in Canada using a validated mathematical model. Methods We used the OncoSim breast and colorectal cancers microsimulation models to explore scenarios of primary screening stops for 3, 6, and 12 months followed by 6–24-month transition periods of reduced screening volumes. For breast cancer, we estimated changes in cancer incidence over time, additional advanced-stage cases diagnosed, and excess cancer deaths in 2020–2029. For colorectal cancer, we estimated changes in cancer incidence over time, undiagnosed advanced adenomas and colorectal cancers in 2020, and lifetime excess cancer incidence and deaths. Results Our simulations projected a surge of cancer cases when screening resumes. For breast cancer screening, a three-month interruption could increase cases diagnosed at advanced stages (310 more) and cancer deaths (110 more) in 2020–2029. A six-month interruption could lead to 670 extra advanced cancers and 250 additional cancer deaths. For colorectal cancers, a six-month suspension of primary screening could increase cancer incidence by 2200 cases with 960 more cancer deaths over the lifetime. Longer interruptions, and reduced volumes when screening resumes, would further increase excess cancer deaths. Conclusions Interruptions in cancer screening will lead to additional cancer deaths, additional advanced cancers diagnosed, and a surge in demand for downstream resources when screening resumes. An effective strategy is needed to minimize potential harm to people who missed their screening.

ObjectiveTo study participant’s acceptability of and attitudes towards human papillomavirus (HPV) testing compared with cytology for cervical cancer screening and what impact having an HPV positive result may have in future acceptability of screening.DesignCross-sectional online survey of clinical trial participants.SettingPrimary care, population-based Cervix Screening Program, British Columbia, Canada.ParticipantsA total of 5532 participants from the HPV FOCAL trial, in which women received HPV and cytology testing at study exit, were included in the analysis. Median age was 54 years. The median time of survey completion was 3 years after trial exit.Outcome measuresAcceptability of HPV testing for primary cervical cancer screening (primary); attitudes and patient perceptions towards HPV testing and receipt of HPV positive screen results (secondary).ResultsMost respondents (63%) were accepting of HPV testing, with the majority (69%) accepting screening to begin at age 30 years with HPV testing. Only half of participants (54%) were accepting of an extended screening interval of 4–5 years. In multivariable logistic regression, women who received an HPV positive screen test result during the trial (OR=1.41 95% CI 1.11 to 1.80) or were older (OR=1.01, 95% CI 1.00 to 1.02) were more likely to report HPV testing as acceptable.ConclusionsIn this evaluation of acceptability and attitudes regarding HPV testing for cervix screening, most are accepting of HPV testing for screening; however, findings indicate heterogeneity in concerns and experiences surrounding HPV testing and receipt of HPV positive results. These findings provide insights for the development of education, information and communication strategies during implementation of HPV-based cervical cancer screening.Trial registration numbersISRCTN79347302 and NCT00461760.

HPV FOCAL is a randomized trial comparing high-risk HPV [Hybrid Capture 2 (HC2)] vs. liquid-based cytology (LBC) for primary cervical screening.The present study objective was to compare Aptima HPV (AHPV) and HC2 assay performance at the intervention arm baseline and 48 mo. screens in relation to the rates of cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+).Women enrolled after December 2010 (n = 3475) were screened at baseline with both AHPV and HC2 (AHPV was blinded). Women with CIN2+ exited the trial; HC2 negative (-) women and those HC2 positive (+) withCIN2 returned for 48 mo. screening with AHPV, HC2, and LBC.At baseline, 7.2% were AHPV + vs. 8.4% for HC2 (p = 0.06). Round 1 AHPV CIN2+ sensitivity (relative to HC2) was 96.0% (95%CI: 86.5-99.0; p = 0.15) and 100% (95%CI: 82.4-100) for CIN3+. AHPV and HC2 specificities (CIN2) were 94.1% vs. 93.0% respectively (p = 0.05). At 48 mo., 4.8% and 5.2% were AHPV+ and HC2+ respectively (p = 0.41), and both tests had the same CIN2+ and CIN3+ sensitivities (87.5% and 85.0% respectively). AHPV specificity (95.8%) was higher, but not significantly, than HC2 (95.3%; p = 0.38). Of 3226 baseline AHPV- women, 12/2,858 (0.4%) had CIN2+ vs. 13/2821 (0.5%) for the 3184 baseline HC2- women.There was no significant difference in CIN2+ detection for AHPV vs. HC2 at baseline or at 48 mo. Baseline AHPV- and HC2- women had similar CIN2+ rates at 48 mo., demonstrating the safety of a four year screening interval for AHPV- women.

Introduction Projection of the effect of cancer screening interventions are frequently conducted using complex simulation models. It is important that such models demonstrate their ability to replicate observational results on the effect of screening. We present results using the OncoSim-CRC microsimulation model to replicate results from four randomized trials (RCTs) of sigmoidoscopy screening for colorectal cancer (CRC). Methods The published results of four RCTs of sigmoidoscopy were reviewed. Two key outcomes were identified: the intention-to-treat hazard ratios (HR) for CRC incidence and CRC mortality for the screening versus control arms. Each RCT study arm was simulated within OncoSim-CRC using the study specific entry criteria, follow-up and observed participation and compliance rates. The ratio of predicted cases (deaths) between intervention arm and control arm was used to estimate the HRs. Results The RCTs differed in the implementation of sigmoidoscopy screening and only one (PLCO) used more than one cycle. All four RCTs found significant reductions, HR Conclusions OncoSim-CRC predicted reductions in CRC incidence and mortality agreed well with observed in RCTs of sigmoidoscopy screening.

The Canadian Partnership Against Cancer was created in 2007 by the federal government to accelerate cancer control across Canada. Its OncoSim microsimulation model platform, which consists of a suite of specific cancer models, was conceived as a tool to augment conventional resources for population-level policy- and decision-making. The Canadian Partnership Against Cancer manages the OncoSim program, with funding from Health Canada and model development by Statistics Canada. Microsimulation modelling allows for the detailed capture of population heterogeneity and health and demographic history over time. Extensive data from multiple Canadian sources were used as inputs or to validate the model. OncoSim has been validated through expert consultation; assessments of face validity, internal validity, and external validity; and model fit against observed data. The platform comprises three in-depth cancer models (lung, colorectal, cervical), with another in-depth model (breast) and a generalized model (25 cancers) being in development. Unique among models of its class, OncoSim is available online for public sector use free of charge. Users can customize input values and output display, and extensive user support is provided. OncoSim has been used to support decision-making at the national and jurisdictional levels. Although simulation studies are generally not included in hierarchies of evidence, they are integral to informing cancer control policy when clinical studies are not feasible. OncoSim can evaluate complex intervention scenarios for multiple cancers. Canadian decision-makers thus have a powerful tool to assess the costs, benefits, cost-effectiveness, and budgetary effects of cancer control interventions when faced with difficult choices for improvements in population health and resource allocation.

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.

Background Immunochemical faecal testing (FIT) is used in Canada for colorectal cancer (CRC) screening. The threshold for FIT abnormality is under operator control and this study uses a simulation model to predict the effect of threshold selection on outcomes including years-of-life gained, CRC incidence and mortality, and direct health system costs. Method The OncoSim Model was used to predict outcomes of biennial screening between ages 50–74 years in a cohort aged 45 years followed until death for eight FIT threshold values between 50 and 225 ng/ml. The literature on FIT performance was reviewed and seven parameter sets of sensitivity and specificity values by FIT threshold were created to span published variation in test performance in subjects with CRC, adenomas or no colorectal neoplasia. Results Reducing the FIT threshold reduced both projected CRC incidence and mortality for all parameter sets, although cost impacts and cost-effectiveness varied compared to no screening. Biennial FIT was projected to be cost-effective at all thresholds considered with a maximum of CAD$ 5400 per QALY over the seven parameter sets and a maximum of CAD$ 6800 per QALY for a one level change in the eight threshold levels considered. Demand for colonoscopy varied strongly with FIT threshold and was greatest for the lowest threshold (50 ng/ml) but the magnitude varied across the 7 parameter sets. Conclusions Compared to no screening, all thresholds of FIT examined were predicted to be cost-effective in the prevention and management of CRC. Threshold choice strongly influences predicted demand placed upon colonoscopy resources.

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]). 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. [Table: see text] 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

In their report of 10 December 2018, the Canadian Task Force on Preventive Health Care gave a lukewarm endorsement of screening mammography.[...]

Background Globally, cervical screening is moving from cytology (Pap) to HPV-based testing. Cytology-based screening has occurred for decades; therefore, engaging the screened population is critical to success of this significant paradigm shift. HPV FOCAL, a large clinical trial, compared primary HPV testing every 4 years to liquid-based cytology (LBC) every 2 years. Participants were surveyed to assess experiences surrounding HPV screening. Methods Women aged 25–65 (n=19,009) from two urban centres were randomized to control (LBC) or intervention (HPV) arms, and 16,374 women attended 48 month exit with HPV/LBC co-testing. At trial entry, women were provided information about HPV, cervical cancer, HPV testing and results. Women completing exit screening were invited to complete a survey assessing attitudes to HPV vs. Pap testing, screening intervals, and receipt of HPV results. Results Of 14,535 invites sent, 5,532(38%) responders completed some or all of the survey with 63% reporting that HPV vs. Pap testing was acceptable; and 54% willing to have HPV testing every 4–5 yrs vs. a Pap every 3 yrs. Concerns regarding HPV positive results differed by age. More women >50 yrs reported it important for them to know who gave them HPV than younger women (25–34 yrs: 68%; 35–49 yrs: 69%; 50+yrs: 76%). More women 25–34 yrs than >35 yrs would feel judged for having HPV (25–34 yrs: 44%; 35–49 yrs: 36%; 50+yrs: 34%). More women >50 yrs reported being HPV positive would affect the relationship with a sexual partner (25–34 yrs: 36%; 35–49 yrs: 41%; 50+: 45%). Response differences by education will also be presented. Conclusion In this large HPV screening trial, the majority of women reported that HPV vs. Pap testing was acceptable and over half would be willing to have HPV testing every 4–5 yrs. Women had varied concerns regarding HPV positive results and responses varied by age. These findings illustrate the importance of comprehensive, targeted communication strategies prior to implementation of primary HPV screening. Disclosure No significant relationships.

Background In 2008 British Columbia (BC), Canada, implemented a voluntary school-based HPV vaccination program for girls, born 1994 or later, with an average uptake of 63%. Given the long time-lead between infection and malignant disease, effects on cancer incidence will take decades to assess. To evaluate the early impact of the HPV vaccine in BC, ecological trends in cervical intraepithelial neoplasia (CIN) rates were assessed in young women before and after the implementation of the HPV vaccination program. Methods From the population-based cervical cancer screening program database in BC, information on all Pap smears and histopathological abnormalities, in calendar years 2004–2017 in women under age 28 were obtained. Rates of cervical intraepithelial neoplasia (CIN) were calculated as the number of cases divided by the number of cytology specimens for that period. Incidence rate ratios (IRR) comparing pre- and post-vaccination years, adjusted for age and screening year, were calculated by piece-wise Poisson regression analysis. We performed a sensitivity analysis including only women eligible for routine screening. Results The total number of screens in the unvaccinated cohort was 1,417,512 and in the vaccinated cohort 73,343. After the introduction of the HPV vaccination program in BC, a decrease in the incidence of CIN was observed in vaccine-eligible birth cohorts. The adjusted IRR for CIN1, 2 and 3 were respectively 0.60 (95%CI 0.53–0.67), 0.49 (95%CI 0.41–0.57) and 0.39 (95%CI 0.32–0.47). Sensitivity analysis confirmed these findings, also indicating a significant decline in CIN rates in birth cohorts eligible for the HPV vaccination program. Conclusion This study illustrates the population impact of the provincial school-based HPV vaccination program, by an observed decline in rates of CIN since introduction of the program. Further evaluation of the population-based impact includes a linkage between vaccination and screening registry. Disclosure No significant relationships.

Background HPV FOCAL, a large clinical trial conducted within an organized screening program setting, compared high-risk human papillomavirus (HPV) testing (Liquid based cytology (LBC) triage for HPV positives) to LBC for primary screening for cervical cancer. Primary endpoints included detection of high grade cervical intraepithelial neoplasia (CIN) grade 2 or greater (CIN2+) or grade 3 or greater (CIN3+) over 48 months in women 25–65 yrs of age. Methods Over 18,000 women were randomized into the HPV and LBC arms. HPV arm: baseline HPV testing; if HPV negative, exit at 48 months with HPV/LBC co-testing. LBC arm: baseline LBC testing; if LBC negative, screen at 24 months with LBC and exit at 48 months with HPV/LBC co-testing (in LBC arm, 48 months disease detection includes disease found at 24 months). We present 48 month exit CIN2+ results by age for baseline negative women. Results At baseline, in the HPV arm, 8769 were HPV negative and in the cytology arm, 9074 were cytology negative. For all ages, at 48 months significantly more CIN2+ was detected in the LBC vs. HPV arm (10/1000 [95%CI: 8, 12] vs 4/1000 [95% CI: 3,5], respectively, p Conclusion At FOCAL exit where women were co-tested with LBC and HPV, less CIN2+ was detected across all age strata in women who were baseline HPV negative, than in baseline cytology negative women, confirming the safety of a 48 month interval for HPV negative women. In addition, the highest CIN2+ rates were detected in women who were 25–29 yrs at baseline and lowest in those 50+ at baseline, informing for age appropriate HPV-based program planning. Disclosure No significant relationships.

Background Cervical cancer screening programs are switching from Pap screening to high-risk HPV testing. Objectives To compare the Aptima HPV Assay (AHPV) with the Hybrid Capture® 2 High-Risk HPV DNA Test® (HC2) for primary cervical screening. Study design HPV FOCAL is a randomized trial comparing HC2 to liquid-based cytology (LBC) for screening women aged 25–65. AHPV and HC2 were compared at the baseline screen (n = 3473). Genotyping was by the Aptima HPV 16 18/45 Genotype Assay. We assessed HPV genotyping and reflex LBC for colposcopy triage. Results AHPV/HC2 agreement was 96.5% (kappa 0.76); positive agreement was 77.4%. The AHPV positive rate was 7.2% vs. 8.4% for HC2 (p = 0.06). Based on HC2 screening, round 1 CIN2 and CIN3+ rates were 9.2/1000 and 5.2/1000 respectively. Using HC2 as the comparator test, AHPV CIN2+ and CIN3+ relative sensitivities were 0.96 and 1.00 (p = 1.00) respectively. High-grade reflex LBC and HPV 16 infection were significantly associated with CIN3+. AHPV specificity was 0.94 vs. 0.93 (p = 0.05) for HC2. Compared with triage of HC2+ with abnormal cytology or HPV persistence for 12 months, colposcopy referral would be significantly reduced (38.3/1000 vs. 60.8/1000; p Conclusions AHPV vs. HC2 screening had equivalent CIN2+ and CIN3+ detection. Triage of AHPV+ by abnormal reflex LBC and the presence of HPV 16/18/45 would result in a significantly lower colposcopy referral rate with similar CIN2+ and CIN3+ detection rates as the overall HC2+ referral algorithm.

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.

BACKGROUND British Columbia undertook a colorectal cancer screening pilot program in 3 communities. Our objective was to assess the performance of 2-specimen fecal immunochemical testing in the detection of colorectal neoplasms in this population-based screening program. METHODS A prospective cohort of asymptomatic, average-risk people aged 50 to 74 years completed 2 quantitative fecal immunochemical tests every 2 years, with follow-up colonoscopy if the result of either test was positive. Participant demographics, fecal immunochemical test results, colonoscopy quality indicators and pathology results were recorded. Non-screen-detected colorectal cancer that developed in program participants was identified through review of data from the BC Cancer Registry. RESULTS A total of 16 234 people completed a first round of fecal immunochemical testing, with a positivity rate of 8.6%; 5378 (86.0% of eligible participants) completed a second round before the end of the pilot program, with a positivity rate of 6.7%. Of the 1756 who had a positive test result, 1555 (88.6%) underwent colonoscopy. The detection rate of colorectal cancer was 3.5 per 1000 participants. The positive predictive value of the fecal immunochemical test was 4.9% (95% confidence interval [CI] 3.8%-6.0%) for colorectal cancer, 35.0% (95% CI 32.5%-37.2%) for high-risk polyps and 62.0% (95% CI 59.6%-64.4%) for all neoplasms. The number needed to screen was 283 to detect 1 cancer, 40 to detect 1 high-risk polyp and 22 to detect any neoplasm. INTERPRETATION Screening every 2 years with a 2-specimen fecal immunochemical test surpassed the current benchmark for colorectal cancer detection in population-based screening. This study has implications for other jurisdictions planning colorectal cancer screening programs.

Objectives To estimate the impact of increased participation in screening, and of the proposed change from Pap to human papillomavirus screening on the incidence of cervical cancer in British Columbia. Methods For invasive cervical cancer cases diagnosed in British Columbia between 2002 and 2011, data were extracted on age and cancer morphology from the British Columbia Cancer Registry, and Pap screening history was obtained from the British Columbia Cervical Cancer Screening Program database. Only screening performed two to seven years prior to diagnosis was assumed to reduce subsequent risk of cancer. Results from randomized trials of human papillomavirus versus cytology screening and population based estimates of cytology screening were used to estimate the effect of a change in screening test and increases in participation. Results Between 2002 and 2011, there were 1663 cases of cervical cancer reported; 660 (367 squamous and 293 non-squamous) were eligible and screened two to seven years prior to diagnosis. The predicted reduction by changing to human papillomavirus screening was 363 (95% confidence interval = 124–496) representing 22% of all cases. If 50% of subjects not screened two to seven years prior had undergone Pap screening, it is projected that a further 268 cases (16%) could have been prevented; if they had undergone human papillomavirus screening, a further 365 cases (22%) could have been prevented. Conclusions For many women who develop cervical cancer, primary human papillomavirus testing could have substantially reduced their cancer risk. Human papillomavirus rather than Pap testing would further increase the gains from any increases in population screening participation.

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 (7.5/1000; 95% CI: 6.2, 8.9) compared to the control arm (4.6/1000; 95% CI: 3.4, 6.2). The CIN2+ detection rates were also significantly higher in the HPV (16.5/1000; 95% CI: 14.6, 18.6) vs. the control arm (10.1/1000; 95%CI: 8.3, 12.4). In women ≥35yrs, the overall detection rates for CIN2+ and CIN3+ were higher in the HPV vs. the control arm (CIN2+:10.0/1000 vs. 5.2/1000; CIN3+: 4.2/1000 vs. 2.2/1000 respectively, with a statistically significant difference for CIN2+). HPV testing detected significantly more CIN2+ in women 25-29 compared to LBC (63.7/1000; 95%CI: 51.9, 78.0 vs. 32.4/1000; 95%CI: 22.3, 46.8). HPV testing resulted in significantly higher colposcopy referral rates for all age cohorts (HPV: 58.9/1000; 95% CI: 55.4, 62.7 vs. control: 30.9/1000; 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. This article is protected by copyright. All rights reserved.

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.

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, What's new? DNA methylation testing could simplify the triage process for screening HPV+ women for cervical cancer, according to new results from a case‐control study. Most pre‐cancerous cervical lesions do not progress to cancer, so triage is done to identify those lesions more likely to become cancerous and boost screening specificity. Here, the authors tested women in the HPV FOCAL study for baseline methylation using the S5 classifier. Methylation signatures, they found, performed with 93% sensitivity and 18% PPV for CIN3, comparable to the combination of cytology and HPV genotyping (86% sensitivity and 19% PPV).

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

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.

INTRODUCTION: The net benefit of ScreenMam has been questioned in recent literature. We report here the 1975-2010 population-based rates of DCIS, BrINV, and of BrMOR in two regions of Canada, British Columbia [BC] vs the Atlantic Provinces of Canada [Atl.P],with unequal adherence (high in BC, low in Atl.P) to ScreenMam and therapy [Th*] guidelines for BrCa [Ref. 1]. METHODS: Annual age-specific rates of DCIS, BrINV, and BrMOR were obtained for 17 age groups (ages 0-4 to 85+) in BC and Atl.P, and averaged over each 5-year periods [1975-1979 up to 2005-2009]. Four birth cohorts were defined within each region: women who in the 1975-79 were aged 30-34 [COHORT 1]; 35-39 [COHORT 2]; 40-44 [COHORT 3] and 45-49 [COHORT 4]. The rates [cases /100,000 person-years] of DCIS, BrINV and BrMOR in 5 year intervals between 1975 and 2009 were followed within each birth cohort and compared between BC and Atl.P in periods 1975-1984 and 2000-2009 [see Table]. Also, age-standardized rates [ASRs] for BrINV incidence and BrMOR were estimated for the entire population, and for ages 50-65 and 65+. The data were obtained from the Public Health Agency of Canada based on the Canadian Cancer Registry database at Statistics Canada. RESULTS Table 1. Cases / 100,000 person-years, years 1975-84 vs 2000-09. BrCa Incidence [DCIS, BrINV] and mortality in BC vs Atl. P. within four birth-cohorts. BC vs. Atl.P [BC – Atl.P]COHORTS*: 1234IN-SITU1975-842 vs 1 [+1]**4 vs 4 [0]8 vs 5 [+3]13 vs 3 [+10]2000-0950 vs 44 [+6]52 vs 46 [+6]52 vs 41 [+11]50 vs 33 [+17]INVASIVE1975-8442 vs 37 [+5]80 vs 66 [+14]134 vs 106 [+24]181 vs 149 [+32]2000-09271 vs 273 [-2]304 vs 327 [-23]325 vs 344 [-19]341 vs 355 [-14]MORTALITY1975-847 vs 9 [-2]13 vs 14 [-1]28 vs 29 [-1]44 vs 46 [-2]2000-0951 vs 54 [-3]65 vs 68 [-3]72 vs 89 [-17]90 vs 110 [-20]**[x] = Difference Cases / 100,000 person-years, BC vs Atl.P: + or – In BC, the ASR for BrINV incidence increased by 20% between 1985 and 1989, and decreased by 20% between 1990-2007. In the Atl.P, the BrINV rates increased by 40% between 1980 and1998 [i.e.increase to higher extent / over longer time period] and declined by 20% between 1999-2007. Compared to 1975, corresponding ASRs for mortality show a 47% decline in BC vs 30% for Atl.P [for ages 50-65: 52% vs 46%; for ages 65+: 37% vs 5%, respectively.]. CONCLUSIONS: 1. DCIS: Higher rates in BC than in Atl.P in the older cohorts [3 and 4] during 1975-84 likely reflect earlier clinical use of ScreenMam in BC. Substantially higher rates maintained during 2000-09 likely reflect persistent greater usage in BC. 2. BrINV. In every birth cohort, substantially higher rates in BC than in Atl.P during 1975-1984 but substantially lower rates in 2000-2009 are likely due to detection & Th earlier in life in BC. 3. BrMOR. Rates were similar between the two regions within each cohort during 1975-84 but substantially lower in BC for older cohorts [3 and 4] during 2000-09, likely due to earlier detection and Th in BC, concordant with more substantial ASR reduction of BrMOR observed in BC. SUMMARY. In view of more ScreenMam in BC, these data suggest that the higher DCIS, but lower rates of BrINV, and more consistent mortality decline in BC than in Atl.P, could all be related - a likely reflection of earlier detection and earlier therapy. The associations of these interactions will be discussed. *Th : surgery, radiation, Tamoxifen for DCIS; the same + chemotherapy for early BrINV. Ref.1: Cancer Research: December 15, 2009. Citation Format: Joseph Ragaz, Hubert Wong, Hong Qian, Joel Fox, Kenneth Wilson, Andrew Coldman. Population-based rates of in-situ breast cancer [DCIS] invasive breast cancer [BrINV], and breast cancer [BrCa] mortality [BrMOR] over time. A case for screening mammography? [ScreenMam] [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-28.

Several screening methods for colorectal cancer (crc) are available, and some have been shown by randomized trials to be effective. In the present study, we used a well-developed population health simulation model to compare the risks and benefits of a variety of screening scenarios. Tests considered were the fecal occult blood test (fobt), the fecal immunochemical test (fit), flexible sigmoidoscopy, and colonoscopy. Outcomes considered included years of life gained, crc cases and deaths prevented, and direct health system costs. A natural history model of crc was implemented and calibrated to specified targets within the framework of the Cancer Risk Management Model (crmm) from the Canadian Partnership Against Cancer. The crmm-crc permits users to enter their own parameter values or to use program-specified base values. For each of 23 screening scenarios, we used the crmm-crc to run 10 million replicate simulations. Using base parameter values and some user-specified values in the crmm-crc, and comparing our screening scenarios with no screening, all screening scenarios were found to reduce the incidence of and mortality from crc. The fobt was the least effective test, it was not associated with lower net cost. Colonoscopy screening was the most effective test, it had net costs comparable to those for several other strategies considered, but required more than 3 times the colonoscopy resources needed by other approaches. After colonoscopy, strategies based on the fit were predicted to be the most effective. In sensitivity analyses performed for the fobt and fit screening strategies, fobt parameter values associated with high-sensitivity formulations were associated with a substantial increase in test effectiveness. The fit was more cost-effective at the 50 ng/mL threshold than at the 100 ng/mL threshold. The crmm-crc provides a sophisticated and flexible environment in which to evaluate crc control options. All screening scenarios considered in this study effectively reduced crc mortality, although sensitivity analyses demonstrated some uncertainty in the magnitude of the improvements. Where possible, local data should be used to reduce uncertainty in the parameters.

There is little cost-effectiveness evidence for breast cancer screening with mammography in women under the age of 50 years, or over the age of 70 years, and available estimates vary widely. The Canadian Task Force on Preventive Health Care (CTFPHC) took cost-effectiveness into account in their recent recommendations on breast cancer screening, but no data are available from a Canadian setting. We constructed a microsimulation model using data from the Screening Mammography Program of British Columbia (BC) and the BC Cancer Registry. Eight screening strategies with varying age ranges and frequencies were compared to a reference strategy of no screening. Local screening, diagnostic, and treatment costs, and utility weights from the literature were applied to health states. Cost-effectiveness was expressed as incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves, using the results of probabilistic sensitivity analysis. The most cost-effective strategies were biennial screening from ages 50 to 69, with an ICER of $28,921/QALY, and biennial screening from 40 to 69, with an ICER of $86,029/QALY. Screening women ages 40–49 was more cost-effective than screening women ages 70–74, which conflicts with the recommendations of the CTFPHC. There was, however, considerable uncertainty around these cost-effectiveness results. Regardless of willingness-to-pay, no single strategy was significantly more likely to be cost effective than the others. There is value in reducing the uncertainty around these cost-effectiveness estimates, to better inform future screening policy.

Objectives The sensitivity of screening mammography is much lower among women who have dense breast tissue, compared with women who have largely fatty breasts, and they are also at much higher risk of developing the disease. Increasing mammography screening frequency from biennially to annually has been suggested as a policy option to address the elevated risk in this population. The purpose of this study was to assess the cost-effectiveness of annual versus biennial screening mammography among women aged 50–79 with dense breast tissue. Methods A Markov model was constructed based on screening, diagnostic, and treatment pathways for the population-based screening and cancer care programme in British Columbia, Canada. Model probabilities and screening costs were calculated from screening programme data. Costs for breast cancer treatment were calculated from treatment data, and utility values were obtained from the literature. Incremental cost-effectiveness was expressed as cost per quality adjusted life year (QALY), and probabilistic sensitivity analysis was conducted. Results Compared with biennial screening, annual screening generated an additional 0.0014 QALYs (95% CI: −0.0480–0.0359) at a cost of $819 ($ = Canadian dollars) per patient (95% CI: 506–1185), resulting in an incremental cost effectiveness ratio of $565,912/QALY. Annual screening had a 37.5% probability of being cost-effective at a willingness-to-pay threshold of $100,000/QALY. Conclusion There is considerable uncertainty about the incremental cost-effectiveness of annual mammography. Further research on the comparative effectiveness of screening strategies for women with high mammographic breast density is warranted, particularly as digital mammography and density measurement become more widespread, before cost-effectiveness can be reevaluated.

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.

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.

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. 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. 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. 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.

Background British Columbia (BC) introduced a school-based HPV vaccine program in September 2008. As part of the HPV vaccine program evaluation, we determined the type-specific HPV prevalence in a population-based sample of women presenting for routine cervical cancer screening in the province. Methods From June 2010 to February 2011, a total of 1100 physicians from all health regions in BC were invited to return ten sequential cytobrushes used during routine office-based Pap screening to the Provincial Health Services Authority Laboratories for HPV type-specific testing. Client age was the only identifier provided. Specimens were screened by the Digene Hybrid Capture® 2 High-Risk (hr) HPV DNA Test (HC2). HC2 positive specimens were then genotyped using the Roche cobas® 4800 HPV Test, the Roche Linear Array (LA) HPV Genotyping Test and the Digene® HPV Genotyping LQ Test. Results Overall, 12.2% of the 4330 specimens with valid HC2 results were hrHPV positive. Age range was 15–69 (median 39.0). By age group, the proportion HC2 hrHPV positive was: 15–19, 25.7%; 20–24, 33.2%; 25–29, 21.9%; 30–34, 12.6%; 35–39, 9.5%; 40–44, 8.4%; ≥45, 3.4%. Overall hrHPV prevalence was 10.1% by Roche cobas® 4800, 10.5% by Roche LA and 10.3% by Digene LQ. For HPV 16/18, rates by age group by Roche LA were: 15–19, 5.1%/2.8%; 20–24, 9.5%/3.9%; 25–29, 6.2%/1.0%; 30–34, 2.4%/1.7%; 35–39, 1.2%/1.0%; 40–44, 1.6%/0.2%; ≥45, 0.3%/0.2%. Similar HPV 16/18 rates were obtained with the Digene LQ and Roche cobas® 4800 methods. Agreement between the three genotyping methods for HPV 16 and 18 was high. Conclusions Comparable to other evaluations, hrHPV positivity was highest among younger women and HPV 16 was the most frequent genotype detected. These baseline estimates will be useful for monitoring the effectiveness of the HPV vaccine in BC. Type-specific analyses repeated at regular intervals over time may determine whether the use of HPV vaccine results in hrHPV genotype replacement in the province.

Cervical cancer screening programs are switching from Pap screening to high-risk HPV testing.To compare the Aptima HPV Assay (AHPV) with the Hybrid CaptureHPV FOCAL is a randomized trial comparing HC2 to liquid-based cytology (LBC) for screening women aged 25-65. AHPV and HC2 were compared at the baseline screen (n=3473). Genotyping was by the Aptima HPV 16 18/45 Genotype Assay. We assessed HPV genotyping and reflex LBC for colposcopy triage.AHPV/HC2 agreement was 96.5% (kappa 0.76); positive agreement was 77.4%. The AHPV positive rate was 7.2% vs. 8.4% for HC2 (p=0.06). Based on HC2 screening, round 1 CIN2 and CIN3+ rates were 9.2/1000 and 5.2/1000 respectively. Using HC2 as the comparator test, AHPV CIN2+ and CIN3+ relative sensitivities were 0.96 and 1.00 (p=1.00) respectively. High-grade reflex LBC and HPV 16 infection were significantly associated with CIN3+. AHPV specificity was 0.94 vs. 0.93 (p=0.05) for HC2. Compared with triage of HC2+ with abnormal cytology or HPV persistence for 12 months, colposcopy referral would be significantly reduced (38.3/1000 vs. 60.8/1000; p0.001) if AHPV+ women with abnormal LBC and HPV 16/18/45 were referred at baseline. CIN2+ and CIN3+ detection rates were not significantly different for the two strategies.AHPV vs. HC2 screening had equivalent CIN2+ and CIN3+ detection. Triage of AHPV+ by abnormal reflex LBC and the presence of HPV 16/18/45 would result in a significantly lower colposcopy referral rate with similar CIN2+ and CIN3+ detection rates as the overall HC2+ referral algorithm.

Background. The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed about 90% of the worldwide epidemiological evidence on the relation between risk of breast cancer and use of hormone replacement therapy (HRT). Methods. Individual data on 52,705 women with breast cancer and 108,411 women without breast cancer from 51 studies in 21 countries were collected, checked, and analysed centrally. The main analyses are based on 53,865 postmenopausal women with a known age at menopause, of whom 17,830 (33%) had used HRT at some time. The median age at first use was 48 years, and 34% of ever-users had used HRT for 5 years or longer. Estimates of the relative risk of breast cancer associated with the use of HRT were obtained after stratification of all analyses by study, age at diagnosis, time since menopause, body-mass index, parity, and the age a woman was when her first child was born. Findings. Among current users of HRT or those who ceased use 1-4 years previously, the relative risk of having breast cancer diagnosed increased by a factor of 1.023 (95% CI 1.011-1.036; 2p = 0.0002) for each year of use; the relative risk was 1.35 (1.21-1.49; 2p = 0.00001) for women who had used HRT for 5 years or longer (average duration of use in this group 11 years). This increase is comparable with the effect on breast cancer of delaying menopause, since among never-users of HRT the relative risk of breast cancer increases by a factor of 1.028 (95% CI 1.021-1.034) for each year older at menopause. 5 or more years after cessation of HRT use, there was no significant excess of breast cancer overall or in relation to duration of use. These main findings did not vary between individual studies. Of the many factors examined that might affect the relation between breast cancer risk and use of HRT, only a woman's weight and body-mass index had a material effect: the increase in the relative risk of breast dancer associated with long durations of use in current and recent users was greater for women of lower than of higher weight or body-mass index. There was no marked variation in the results according to hormonal type or dose but little information was available about long durations of use of any specific preparation. Cancers diagnosed in women who had ever used HRT tended to be less advanced clinically than those diagnosed in never-users. In North America and Europe the cumulative incidence of breast cancer between the ages of 50 and 70 in never-users of HRT is about 45 per 1000 women. The cumulative excess numbers of breast cancers diagnosed between these ages per 1000 women who began use of HRT at age 50 and used it for 5, 10, and 15 years, respectively, are estimated to be 2 (95% CI 1-3), 6 (3-9), and 12 (5-20). Whether HRT affects mortality from breast cancer is not known. Interpretation. The risk of having breast cancer diagnosed is increased in women using HRT and increases with increasing duration of use. This effect is reduced after cessation of use of HRT and has largely, if not wholly, disappeared after about 5 years. These findings should be considered in the context of the benefits and other risks associated with the use of HRT.

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.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.

We set out to assess the health care resource utilization and cost of cervical cancer from the perspective of a single-payer health care system. Retrospective observational data for women diagnosed with cervical cancer in British Columbia between 2004 and 2009 were analyzed to calculate patient-level resource utilization patterns from diagnosis to death or 5-year discharge. Domains of resource use within the scope of this cost analysis were chemotherapy, radiotherapy, and brachytherapy administered by the BC Cancer Agency, resource utilization related to hospitalization and outpatient visits as recorded by the B.C. Ministry of Health, medically required services billed under the B.C. Medical Services Plan, and prescriptions dispensed under British Columbia&rsquo, s health insurance programs. Unit costs were applied to radiotherapy and brachytherapy, producing per-patient costs. The mean cost per case of treating cervical cancer in British Columbia was $19,153 (standard error: $3,484). Inpatient hospitalizations, at 35%, represented the largest proportion of the total cost (95% confidence interval: 32.9% to 36.9%). Costs were compared for subgroups of the total cohort. As health care systems change the way they manage, screen for, and prevent cervical cancer, cost-effectiveness evaluations of the overall approach will require up-to-date data for resource utilization and costs. We provide information suitable for such a purpose and also identify factors that influence costs.

Background: Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented. Methods: The three arms are: Control arm – liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm – hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm – hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years. Results: A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+. Conclusion: After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.

BACKGROUND: Mammography screening results in false positives that cause anxiety and utilize scarce medical resources for their resolution. Determination of screening recommendations requires knowledge of the population risk of false positives. METHODS: Data were extracted from the Screening Mammography Program of British Columbia and analyzed to determine the influence of personal factors including age, ethnic group and screening history, and the centre where screening was performed, on the likelihood a new screen would result in a false positive and whether a biopsy was required. The resulting probabilities were combined to provide values for lifetime screening algorithms. RESULTS: Age, screen sequence number, history of previous abnormal screens and centre where screening was performed were significantly related to the likelihood a new screen would be a false positive. British Columbia women screened biennially between the ages of 50 and 69 have a projected 41% chance of a false-positive screen and a 5.6% risk of a related biopsy, with the best performing centres having rates of 26% and 3%, respectively. INTERPRETATION: Model projections for BC overall are comparable to other North American estimates. Estimates varied depending upon screening centre attended.

The first organized breast cancer service screening program in Canada was established in 1988 in British Columbia. The pilot project was successful in showing that screening could be conducted at a unit cost of US$38; now US$41. Screening is conducted in dedicated centers and diagnostic work-ups done in the community. The current annual volume is 235,000. Stepwise expansion is ongoing and is determined by community specific service requirements. Prognostic factors of cancers detected consistently exceed internationally recommended targets. Since the inception of the program the age standardized breast cancer mortality rate per 100,000 has dropped in British Columbia from the highest to the lowest in Canada for provinces with similar populations.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1959-5) contains supplementary material, which is available to authorized users.

The most widely used system for grading of endometrial carcinoma is the International Federation of Gynecology and Obstetrics (FIGO) grading system. This grading system requires evaluation of histologic features that are difficult to assess reproducibly. Two hundred and two cases of endometrial carcinoma, treated by hysterectomy, were retrieved from the archives of Vancouver General Hospital (1983-1998). For each tumor, the architectural pattern, nuclear grade, and mitotic index were assessed. The tumor architectural pattern, nuclear grade, and mitotic index were significant predictors of patient outcome (P0.0001 for each, by univariate analysis). There were no prognostic differences between patients having predominantly solid versus papillary tumors, or tumors with mild versus moderate nuclear atypia. The tumors were then classified into high and low grade based on assessment of these three features. The presence of at least two criteria of these three: 1) predominantly papillary or solid growth pattern, 2) mitotic indexor =6/10 high power fields, or 3) severe nuclear atypia, resulted in a tumor being considered high grade. Low-grade tumors satisfied at most one of those criteria. The proposed grading system was found to be an independent predictor of patient outcome when patient survival was adjusted for FIGO stage, patient age, and tumor cell type. It also had more prognostic power than other grading systems tested when it was applied to all tumors, regardless of their cell type; however, the FIGO grading system was superior for prognostication when only carcinomas of endometrioid type were considered. With the FIGO grading system, no significant difference in survival was observed between patients with grade 1 and grade 2 tumors. Combining FIGO grades 1 and 2 results in a binary system (grades 1 and 2 vs. grade 3) that was the most prognostically significant grading system tested, with the additional advantages of being highly reproducible and familiar to practicing pathologists.

Objective: To determine the relationship between the number of initial negative Pap smears and risk of subsequent cervical cancer. Design: A cohort study was conducted using data from the British Columbia Cervical Cancer Screening Program and British Columbia CancerRegistry. The analysis used a random sample (1%) of women aged 20–69 with Pap smears and all cases of invasive cervical cancer diagnosed between 1994 and 1999. Each negative screen defined the beginning of a screening interval and intervals longer than five years were truncated. Thefollowing variables were created for each interval: age at the beginning of the interval, interval length, previous cytological abnormality, previous cervical procedure and number of preceding consecutive negative screens. The relationship between these variables and risk of squamous cervicalcancer was determined using survival analysis methods. Results: A total of 388 cases of invasive cervical cancer (252 squamous) were included in the study from a study population of over 3.3 million Pap smears. The risk of invasive squamous cancer increased with time since the lastnegative screen, history of cytological abnormality and history of cervical therapeutic procedure. Risk was not significantly related to age ( P=0.2) but was highest in women aged 30–49. Multiple consecutive negative pap smears were associated with reduced risk in women with ahistory of moderate atypia ( P Conclusions: Multiple consecutive negative cytology was not associated with reduced risk of invasive cervical cancer in women with no history of cytological abnormality.

There is accumulating evidence that immunohistochemical staining for p53 can identify patients with endometrial carcinoma who have an adverse outcome, but the interpretation of existing data is complicated by differences between studies in the way that p53 immunohistochemistry results have been assessed. In this study, we sought to determine the appropriate cut-off level for stratification of patients with endometrial carcinoma into high- and low-risk groups, based on p53 immunohistochemical staining. A total of 200 cases of endometrial carcinoma treated by hysterectomy were retrieved from the archives of the Department of Pathology, Vancouver General Hospital, from the period 1983 to 1998. Follow-up information was available for all cases. Slides were reviewed and the diagnosis confirmed, tumors graded according to FIGO grading system, and tumor cell type assessed. A tissue microarray consisting of duplicate 0.6-mm cores of tumor was constructed and immunostained for p53. Immunoreactivity for p53 was scored by counting the number of positively stained tumor cell nuclei and expressing this as a percentage of the total number of tumor cell nuclei counted (p53 index). Kaplan-Meier survival curves were constructed and compared by calculation of log-rank statistic, and multivariate analysis was performed by Cox regression modeling. The distribution of p53 index results was bimodal, with most cases having a very low or very high p53 index. The peaks of the bimodal distribution were clearly separated using a p53 index ofor =50%. Immunoreactivity was a significant adverse prognostic indicator of disease-specific survival (p0.0001 by univariate analysis). Patients with strongly p53 immunoreactive tumors (p53 indexor =50%) had a significantly worse outcome than patients with weakly immunoreactive (p53 indexor =5% and50%) or p53-negative (p53 index5%) tumors (p = 0.0001). There was no significant difference between the outcomes for patients in the latter two groups. By multivariate analysis, p53 overexpression was a significant prognostic indicator independent of patient age and tumor stage (p = 0.008) but was not independent when the analysis was extended to include FIGO grade and tumor cell type. p53 immunostaining was of prognostic significance in the subset of patients with endometrioid carcinomas (p = 0.02), but not in patients with clear cell or papillary serous carcinomas. Using a p53 index ofor =50% as a cut-off between positive and negative p53 staining, immunohistochemical staining for p53 is a prognostic indicator in patients with endometrial carcinoma of endometrioid type. p53 immunostaining was not found to be of prognostic significance independent of tumor cell type and grade.

Objectives: To determine the factors that influence risk of cervical cancer after three consecutive negative Pap smears. Methods: A cohort study was conducted using data from the British Columbia Cervical Cancer Screening Program and British Columbia Cancer Registry. Analysis was based on a one percent sample of women aged 20-69 years with Pap smears enriched with all invasive cervical cancer cases diagnosed between 1994-99. Screening intervals, after three negative screens, were created with the following variables: age at beginning of interval, interval length, previous cytologic abnormality and previous cervical procedure. The risk of cervical cancer by histologic type was calculated using survival analysis methods. Results: The sample consisted of 10,509 women, who contributed 28,309 intervals, and 371 cervical cancer cases. The incidence rate of invasive squamous cervical cancer increased with time since last screen up to six years. Women with a history of dysplasia remained at elevated risk for squamous cancer, hazard ratio=2.6 (95% confidence interval [CI]=1.9, 3.4) but age or previous procedure were not related to risk. No relationship between time since last screen and non-squamous cancer risk was found although history of a previous procedure was significant. The marginal effectiveness of Pap smears declined with increasing frequency of use. Conclusions: This study confirmed the preventive effect of Pap smear screening and its dependency on frequency of use. Women with a history of dysplasia, prior to three consecutive negatives, were at increased risk of developing invasive squamous cervical cancer compared with women with no such history.

The aim of this study was to detect neuroendocrine differentiation (NE), to determine its association with major clinicopathological parameters of breast cancer, and to study the prognostic significance of NE differentiation in a group of breast carcinomas by using tissue microarray (TMA) methodology. NE differentiation was studied by using 3 markers, synaptophysin (Syn), chromogranin A (ChA), and neuron-specific enolase (NSE) in a group of 334 patients with breast carcinoma. TMA blocks were made by using duplicate 0.6-mm-diameter tissue cores from each paraffin block. Results of immunostaining were scored on a 4-point scale, that is, as negative, weak, intermediate, and strong immunoreactivity. Positive staining of breast cancers for any of the 3 NE markers was detected in 19.5% of cases. Expression of a single marker was present in 16.2% of cases, and expression of 2 or 3 markers in combination was detected in 3.3% of cases. There was no statistically significant correlation of NE phenotype with tumor morphology, except mucinous carcinoma (3 of 6 cases positive), estrogen receptor, progesterone receptor, or nodal status. A weak correlation was noted between synaptophysin staining and higher tumor grade (P = 0.029). Analysis of disease-specific and overall survival based on up to 20 years of follow-up data showed a correlation between NSE expression and improved disease-specific (P = 0.043) and overall survival (P = 0.03) in univariate but not in multivariate analysis. The expression of Syn and ChA, as well as coexpression of multiple NE markers, had no prognostic significance.