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The Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing the efficacy of primary HPV testing to cytology among women in the population‐based Cervix Screening Program in British Columbia, Canada. We conducted a cost‐effectiveness analysis based on the HPV FOCAL trial to estimate the incremental cost per detected high‐grade cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+). A total of 19,009 women aged 25 to 65 were randomized to one of two study groups. Women in the intervention group received primary HPV testing with reflex liquid‐based cytology (LBC) upon a positive finding with a screening interval of 48 months. Women in the control group received primary LBC testing, and those negative returned at 24 months for LBC and again at 48 months for exit screening. Both groups received HPV and LBC co‐testing at the 48‐month exit. Incremental costs during the course of the trial were comparable between the intervention and control groups. The intervention group had lower overall costs and detected a larger number of CIN2+ lesions, resulting in a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of ‐$773 [all costs in 2018 USD]. Cost per detected lesion was sensitive to the costs of sample collection, HPV testing, and LBC testing. The HPV FOCAL Trial results suggest that primary HPV testing every 4 years produces similar outcomes to LBC‐based testing every 2 years for cervical cancer screening at a lower cost., The Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing primary HPV testing to liquid‐based cytology for cervical cancer screening. We conducted a cost‐effectiveness analysis alongside the HPV FOCAL trial. Results showed the intervention group yielded a higher rate of detected cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+) at a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of −$773. Findings suggest that primary HPV testing is cost‐effective compared to liquid‐based cytology.

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.

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.

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.

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.

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: 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.

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

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.

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.

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.

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.

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 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.

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.

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.

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.

British Columbian provincial practice guidelines (PPGs) have recommended breast-conserving surgery (BCS), axillary node dissection, and radiation therapy following BCS for specific subgroups of breast cancer patients. Patient-, disease-, and physician-specific factors associated with these therapies were investigated in nonmetastatic invasive breast cancer patients. Temporal trends in BCS and physicians' experiences with PPGs were also examined. Sources of data for patient, disease, treatment, and treating physician factors included medical records, source documents, and the British Columbia Medical Directory for 967 nonmetastatic invasive breast cancer patients diagnosed in British Columbia in 1995. BCS utilization among 496 patients with pathologically node-negative breast cancer (NNBC) was compared to earlier British Columbian data. Family physicians and surgeons were surveyed in 1997 regarding their experience with PPGs. 57% of "ideal" candidates received BCS; 87% of patients received axillary node dissection; and 95% of women treated with BCS also received radiation therapy. Tumor size, tumor location, and extent of ductal carcinoma in situ (DCIS) were associated with BCS use; age, tumor size, and tumor location were associated with axillary node dissection; and age alone was associated with radiation therapy following BCS. Fifty-four percent of NNBC patients received BCS in 1995, compared to 44% in 1991, with increases seen in most patient-, disease-, and physician-specific comparisons. The increase in BCS, and high proportion completing radiation therapy, are encouraging and may be due in part to greater exposure to PPGs.

Objective To examine population data to see whether survival from breast cancer has improved differentially in screened and unscreened women and examine published studies on mammographic screening to determine whether there is evidence that screening is no longer effective. Methods Data was reviewed on trends in breast cancer specific survival among women participating and not participating in the British Columbia Breast Screening Program. Population studies of mammographic screening published between 2000 and 2010 with breast cancer mortality as the outcome were also reviewed. Results Breast cancer specific survival in British Columbia improved more in screening participants than non-participants, HR = 0.74 (0.58,0.93) between the periods 1990–4 and 2000–4. Among the published studies of mortality between 2000 and 2010 selected from different jurisdictions all had found a reduction in breast cancer mortality although this was not always statistically different from zero. Studies had used a range of designs and evaluative methods which may have contributed to the magnitude of the effect reported. Conclusion No evidence was found in the British Columbia data and the published studies reviewed, that treatment or other changes, had caused mammographic screening to become ineffective.

Screening with mammography has been shown by randomized controlled trials to reduce breast cancer mortality in women aged 40 to 74 years. Estimates from observational studies following screening implementation in different countries have produced varyied findings. We report findings for seven Canadian breast screening programs.Canadian breast screening programs were invited to participate in a study aimed at comparing breast cancer mortality in participants and nonparticipants. Seven of 12 programs, representing 85% of the Canadian population, participated in the study. Data were obtained from the screening programs and corresponding cancer registries on screening mammograms and breast cancer diagnoses and deaths for the period between 1990 and 2009. Standardized mortality ratios were calculated comparing observed mortality in participants to that expected based upon nonparticipant rates. A substudy using data from British Columbia women aged 35 to 44 years was conducted to assess the potential effect of self-selection participation bias. All statistical tests were two-sided.Data were obtained on 2796472 screening participants. The average breast cancer mortality among participants was 40% (95% confidence interval [CI] = 33% to 48%) lower than expected, with a range across provinces of 27% to 59%. Age at entry into screening did not greatly affect the magnitude of the average reduction in mortality, which varied between 35% and 44% overall. The substudy found no evidence that self-selection biased the reported mortality results, although the confidence intervals of this assessment were wide.Participation in mammography screening programs in Canada was associated with substantially reduced breast cancer mortality.

Background: Lung cancer is the most common cause of cancer death in North American women. Because smoking-related changes in the bronchial epithelium and in lung function have not been studied in detail in women, we used fluorescence bronchoscopy-directed biopsy to determine the prevalence of high-grade preinvasive lesions in former and current smokers of both sexes. Methods: Spirometry, white-light bronchoscopy, and fluorescence bronchoscopy were performed in 189 women and 212 men older than 40 years of age who had smoked 20 pack-years or more (pack-years = number of packs of cigarettes smoked per day x number of years of smoking). Results: Carcinoma in situ was found in 1.8% of the subjects, severe dysplasia was found in 6.5%, and moderate dysplasia was found in 14% (all preinvasive lesions). Compared with men, women had a lower prevalence of high-grade preinvasive lesions in the observed airways (14% versus 31%; odds ratio = 0.18; 95% confidence interval = 0.04-0.88), and women with preinvasive lesions had fewer such lesions (two-sided P = .048). The prevalence of preinvasive lesions did not change substantially for more than 10 years after cessation of smoking. Lung function was associated with the prevalence of preinvasive lesions, but the association was weaker in women than in men. If the presence of airflow obstruction was defined by an FEV 1 /FVC (forced expiratory volume in 1 second/forced vital capacity) value of 70% or less, only 56% of the men and 44% of the women with preinvasive lesions had abnormal lung function. Conclusion: In developing strategies for chemoprevention or early detection of lung cancer in high-risk populations, it is important to consider the effect of sex and arbitrarily chosen lung function values on the prevalence of preinvasive airway lesions.

Breast cancer risk estimations are both informative and useful at the population level, with many screening programs relying on these assessments to allocate resources such as breast MRI. This cross-sectional multicenter study attempts to quantify the breast cancer risk distribution for women between the ages of 40 to 79 years undergoing screening mammography in British Columbia (BC), Canada. The proportion of women at high breast cancer risk was estimated by surveying women enrolled in the Screening Mammography Program of British Columbia (SMPBC) for known breast cancer risk factors. Each respondent's 10-year risk was computed with both the Tyrer–Cuzick and Gail risk assessment models. The resulting risk distributions were evaluated using the guidelines from the National Institute for Health and Care Excellence (United Kingdom). Of the 4,266 women surveyed, 3.5% of women between the ages of 40 to 79 years were found to have a high 10-year risk of developing breast cancer using the Tyrer–Cuzick model (1.1% using the Gail model). When extrapolated to the screening population, it was estimated that 19,414 women in the SMPBC are considered to be at high breast cancer risk. These women may benefit from additional MRI screening; preliminary analysis suggests that 4 to 5 additional MRI machines would be required to screen these high-risk women. However, the use of different models and guidelines will modify the number of women qualifying for additional screening interventions, thus impacting the MRI resources required. The results of this project can now be used to inform decision-making groups about resource allocation for breast cancer screening in BC. Cancer Prev Res; 6(10); 1084–92. ©2013 AACR.

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.

PURPOSE The Canadian multicenter trial for advanced non-small-cell lung cancer (NSCLC) reported survival benefit for chemotherapy when best supportive care was compared with vindesine-cisplatin (VP) and the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP). We examined received drug delivery to document dose-intensity (DI) and total dose of drugs given to various groups in this patient population. PATIENTS AND METHODS Plots of cumulatively received chemotherapy against time were used to evaluate drug delivery by regimen, major prognostic factors, and response status. RESULTS Individual CAP patients show a narrow range of received DI, with the median similar to protocol. Drug delivery analysis exposed a wide range of received DI for both drugs in the more intensive VP regimen, and the median received DI was below protocol. The median received DI for cisplatin was still higher for VP than CAP, but only during the first 8 weeks of protocol treatment (20 v 10 mg/m2/wk); thereafter, the ongoing received cisplatin DI was the same (10 mg/m2/wk). The median received DI for cisplatin in each regimen was not influenced by stage, performance status, prior weight loss, sex, or response status. VP-treated patients received a higher total dose of cisplatin than CAP patients (median, 255 mg/m2 v 112.5 mg/m2; P < .0001). Median cisplatin total dose was similar for patients with a chemotherapy response or stable disease and threefold greater than for patients with progressive disease for both regimens. Although patients with chemotherapy response and stable disease had similar survival outcomes for both CAP and VP, the VP regimen had a higher proportion of patients without progressive disease (P = .004), which resulted in an overall survival advantage (P = .01). CONCLUSION The major prognostic factors for advanced NSCLC do not exert their influence on outcome by affecting deliverable chemotherapy DI. Regimen and treatment response determined total dose. Because stable disease patients usually outnumber responding patients in advanced NSCLC trials, controlled studies should be performed that allow assessment of the impact of total received dose on outcome according to response status.

Background. Although smaller variant forms of estrogen receptor (ER) messenger RNA (mRNA) have been detected in breast tumors, neither their prevalence nor their prognostic significance have been evaluated. Similarly, TRPM-2 mRNA, the product of a gene induced principally during the onset of apoptosis, is present in mouse and human breast cancer cell lines, but whether it also occurs in primary breast tumors and is related to disease outcome is unknown. Methods. The relative expression and transcript size of ER mRNA and TRPM-2 mRNA in 126 primary breast tumors were measured by Northern analysis and compared with tumor grade, hormone receptor status, extent of tumor necrosis, and survival. Results. In ER-positive tumors, 64% of the tumors had only the normal 6.5 kb ER mRNA, an additional 9% had the normal plus smaller ER mRNA, and 2% had variant forms. Only 8% of ER-negative tumors had ER mRNA transcripts. There were significant relationships between the occurrence of ER mRNA and low tumor grade, ER-positive receptor status, and better survival. In contrast, TRPM-2 mRNA was found in only 17% of breast tumors, none of which could be grouped with respect to grade, hormone receptor status, or survival. Conclusions. The presence of smaller variant forms of ER mRNA either alone or in association with the normal ER transcript is not indicative of an unfavorable prognosis, whereas TRPM-2 mRNA occurs in many primary breast tumors, but has no apparent relationship to survival.

OBJECTIVE: To estimate outcomes and costs of surveillance strategies after treatment for high-grade cervical intraepithelial neoplasia (CIN). METHODS: A hypothetical cohort of women was evaluated after treatment for CIN 2 or 3 using a Markov model incorporating data from a large study of women treated for CIN, systematic reviews of test accuracy, and individual preferences. Surveillance strategies included initial conventional or liquid-based cytology, human papillomavirus testing, or colposcopy 6 months after treatment, followed by annual or triennial cytology. Estimated outcomes included CIN, cervical cancer, cervical cancer deaths, life expectancy, costs, cost per life-year, and cost per quality-adjusted life-year. RESULTS: Conventional cytology at 6 and 12 months, followed by triennial cytology, was least costly. Compared with triennial cytology, annual cytology follow-up reduced expected cervical cancer deaths by 73% to 77% and had an average incremental cost per life-year gained of $69,000 to $81,000. For colposcopy followed by annual cytology, the incremental cost per life-year gained ranged from $70,000 to more than $1 million, depending on risk. Between-strategy differences in mean additional life expectancy per woman were less than 4 days; differences in mean incremental costs per woman were as high as $822. In the cost-utility analysis, colposcopy at 6 months followed by annual cytology had an incremental cost per quality-adjusted life-year of less than $5,500. Human papillomavirus testing or liquid-based cytology added little to no improvement to life-expectancy with higher costs. CONCLUSION: Annual conventional cytology surveillance reduced cervical cancers and cancer deaths compared with triennial cytology. For high risk of recurrence, a strategy of colposcopy at 6 months increased life expectancy and quality-adjusted life expectancy. Human papillomavirus testing and liquid-based cytology increased costs, but not effectiveness, compared with traditional approaches.

Background In the HPV FOCAL trial, we will establish the efficacy of hr-HPV DNA testing as a stand-alone screening test followed by liquid based cytology (LBC) triage of hr-HPV-positive women compared to LBC followed by hr-HPV triage with ≥ CIN3 as the outcome. Methods/Design HPV-FOCAL is a randomized, controlled, three-armed study over a four year period conducted in British Columbia. It will recruit 33,000 women aged 25-65 through the province's population based cervical cancer screening program. Control arm: LBC at entry and two years, and combined LBC and hr-HPV at four years among those with initial negative results and hr-HPV triage of ASCUS cases; Two Year Safety Check arm: hr-HPV at entry and LBC at two years in those with initial negative results with LBC triage of hr-HPV positives; Four Year Intervention Arm: hr-HPV at entry and combined hr-HPV and LBC at four years among those with initial negative results with LBC triage of hr-HPV positive cases Discussion To date, 6150 participants have a completed sample and epidemiologic questionnaire. Of the 2019 women enrolled in the control arm, 1908 (94.5%) were cytology negative. Women aged 25-29 had the highest rates of HSIL (1.4%). In the safety arm 92.2% of women were hr-HPV negative, with the highest rate of hr-HPV positivity found in 25-29 year old women (23.5%). Similar results were obtained in the intervention arm HPV FOCAL is the first randomized trial in North America to examine hr-HPV testing as the primary screen for cervical cancer within a population-based cervical cancer screening program. Trial Registration International Standard Randomised Controlled Trial Number Register, ISRCTN79347302

Information on the long-term risk of cervical intraepithelial neoplasia (CIN) recurrence among women treated for CIN is limited yet critical for evidence-based surveillance recommendations.We retrospectively identified 37,142 women treated for CIN 1, 2, or 3 from January 1, 1986, through December 31, 2000 (CIN cohort), from the British Columbia Cancer Agency cytology database and linked their records with cancer registry and vital statistics data. Treatment included cryotherapy, loop electrosurgical excision procedure, cone biopsy, and laser vaporization or excision. A comparison cohort contained 71,213 women with normal cytology and no previous CIN diagnosis. Follow-up continued through December 31, 2004. Among women in both cohorts under active surveillance, we compared rates of CIN 2 or 3 (CIN 2/3) and cervical cancer. Cumulative incidence rates of CIN 2/3 and 95% confidence intervals (CIs) were estimated by a life table approach by using annual rates. Cumulative rates of invasive cancer were examined by the person-years method.Overall observed cumulative rates of CIN 2/3 in the first 6 years after treatment were 14.0% (95% CI = 13.84% to 14.15%) for women originally treated for CIN 3, 9.3% (95% CI = 9.09% to 9.42%) for CIN 2, and 5.6% (95% CI = 4.91% to 5.21%) for CIN 1. Annual rates of CIN 2/3 were less than 1% after 6 years. Initial diagnosis, age, and treatment type were associated with a diagnosis of CIN 2/3 after treatment, with 6-year adjusted rates for women aged 40-49 years ranging from 2.6% (95% CI = 1.9% to 3.4%) for treatment of CIN 1 with the loop electrosurgical excision procedure to 34.0% (95% CI = 30.9% to 37.1%) for treatment of CIN 3 with cryotherapy. Overall incidence of invasive cancer (per 100,000 woman-years) was higher in the CIN cohort (37 invasive cancers, 95% CI = 30.6 to 42.5 cancers) than in the comparison cohort (six cancers, 95% CI = 4.3 to 7.7 cancers). Cryotherapy, compared with other treatments, was associated with the highest rate of subsequent disease (adjusted odds ratio for invasive cancer = 2.98, 95% CI = 2.09 to 4.60).Risk of CIN 2/3 after treatment was associated with initial CIN grade, treatment type, and age. Long-term risk of invasive cancer remained higher among women treated for CIN, particularly those treated with cryotherapy.

Objectives The objective of this study was to compare breast cancer outcomes among women subject to different policies on mammography screening frequency. Setting Data were obtained for women participating in the Screening Mammography Programme of British Columbia (SMPBC) for 1988–2005. The SMPBC changed its policy for women aged 50–79 years from annual to biennial mammography in 1997, but retained an annual recommendation for women aged 40–49 years. Methods Breast cancer outcomes were compared for women participating in the programme before and after 1997 for two groups: ages 40–49 and 50–79 years. Results There were data on 658,151 women. Comparing pre-1997 and post-1997, the median interscreen interval increased by 11.1 months in women 50–79 but by only 0.3 months in women aged 40–49. Excluding those detected at initial screen, 6291 breast cancers were identified. Comparing pre-1997 and post-1997: the relative rates (RR) of screen detected cancer increased in women aged 40–49 (RR = 1.32) and the rate of invasive cancers ≥20 mm at diagnosis decreased (RR = 0.83); the rate of cancers with axillary node involvement increased in women aged 50–79 (RR = 1.23). Cancer survival improved after 1997 for women diagnosed at ages 40–49 (hazard ratio = 0.62), but was unchanged for women aged 50–79. Breast cancer mortality rates did not change between the periods in either age group. Conclusion The proximal cancer outcomes considered (staging and survival) improved in women aged 40–49 but this was offset in women aged 50–79 associated with the change in screen frequency. These changes did not result in alterations in breast cancer mortality rates in either age group.

Mucosal squamous cell carcinomas are the most common head and neck malignancies. We hypothesised that over-expression of intracellular signalling proteins and decreased expression of desmoglein molecules would be associated with aggressive tumour behaviour in patients with head and neck squamous cell carcinoma.Seventy-eight cases of head and neck squamous cell carcinoma were immunohistochemically stained for desmoglein 1, desmoglein 2, desmoglein 3, p53, bcl-2, vimentin, cyclin D1, p16, p21, p27, E-cadherin, and E2F-1 in paraffin-embedded tissue blocks in a microarray.The disease-specific survival was 56% at 5 years and 49% at 10 years. Expression of the desmoglein isotypes correlated positively with each other except for desmoglein 2 and desmoglein 3, which did not show a significant correlation. Desmoglein 1 and E-cadherin expression also correlated. On univariate analysis, only expression of desmoglein 1 correlated with patient outcome; lack of expression of desmoglein 1 was associated with a significantly worse disease-specific survival (p = 0.035). Hierarchical clustering analysis identified a subgroup of three patients with an immunophenotype distinct from the other tumours, characterised by co-expression of p16, p27, E2F-1 and bcl-2. Further statistical analysis of the prognostic significance of this small subgroup was not possible, but these three patients are alive and well.Decreased expression of desmoglein 1 is associated with a worse prognosis in head and neck squamous cell carcinoma patients. Examination of an extended panel of immunomarkers revealed a rare subtype of squamous cell carcinoma characterised by the expression of multiple proliferation-associated markers and the anti-apoptotic protein, bcl-2; determination of the prognostic significance of this subgroup will require study of a larger case series.

The authors investigated the relation between diet and histologic types of benign breast disease defined by subsequent risk of breast cancer in a case-control study of volunteers who entered the Vancouver Center of the Canadian National Breast Screening Study between 1983 and 1985. Proliferative benign breast disease (n = 124) was inversely associated with vitamin A supplementation (vitamin A user vs. nonuser, odds ratio (OR) = 0.5) and frequent green vegetable consumption (frequent vs. rare consumption, OR = 0.3), whereas severe atypias and borderline carcinoma in situ (n = 32) were directly associated with frequent meat fats consumption (frequent vs. rare consumption, OR = 3.2) with no association with vitamin A or vegetable consumption. No dietary relations were found for histologic types of benign breast disease at no increased risk for subsequent breast cancer (n = 274). The implications of these findings in relation to the etiology of breast cancer are discussed.