Lovedeep Gondara

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

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

Volumetric Radiosurgery for 1 to 10 Brain Metastases: A Multicenter, Single-Arm, Phase 2 Study

PURPOSE Interest is growing in treating multiple brain metastases with radiosurgery. We report on the effectiveness and tolerability of volumetric radiosurgery (VRS). METHODS AND MATERIALS We enrolled patients with a ≥6-month estimated life expectancy and 1 to 10 brain metastases with a diameter of ≤3 cm at 5 cancer centers. Volumetric radiosurgery was delivered in 5 fractions with 98% target coverage, prescribed as 95% of 50 Gy (47.5 Gy in 5 fractions) to the metastases with no margin and 95% of 40 Gy (38 Gy in 5 fractions) to their 2-mm planning target volumes, concurrent with 20 Gy to the whole brain planning target volume. The treatment was delivered with daily image guidance using conventional linear accelerators and volumetric modulated arc therapy. A magnetic resonance imaging scan was obtained every 3 months. The primary endpoint was the 3-month objective response in the brain according to the Response Evaluation Criteria in Solid Tumors, version 1.1. The principal secondary endpoint was 1-year actuarial control of treated metastases. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. The present study is registered with ClinicalTrials.gov (clinicaltrials.gov identifier NCT01046123). RESULTS From July 2010 to May 2013, 60 patients underwent VRS with 47.5 Gy in 5 fractions for 12 metastases in the thalamus and basal ganglia (deep metastases) and 207 non-deep metastases. The median follow-up period was 30.5 months, and the median survival was 10.1 months. For the 43 patients assessable at 3 months, the objective response in the brain was 56%. The treated metastases were controlled in 88% of patients at 1 year and 84% at 3 years. Overall survival did not differ for patients with 4 to 10 versus 1 to 3 metastases (hazard ratio 1.18, P=.6). The crude incidence of severe radionecrosis (grade 3-5) was 25% (3 of 12) per deep metastasis, 1.9% (4 of 219) per non-deep metastasis, and 10% (6 of 60) per patient. CONCLUSIONS For non-deep brain metastases, 47.5 Gy in 5 fractions was tolerable. Volumetric radiosurgery was effective for long-term control of treated brain metastases.

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

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

Using proliferative markers and Oncotype DX in therapeutic decision-making for breast cancer: the B.C. experience.

BACKGROUND Proliferative scoring of breast tumours can guide treatment recommendations, particularly for estrogen receptor (er)-positive, her2-negative, T1-2, N0 disease. Our objectives were to □ estimate the proportion of such patients for whom proliferative indices [mitotic count (mc), Ki-67 immunostain, and Oncotype dx (Genomic Health, Redwood City, CA, U.S.A.) recurrence score (rs)] were obtained.□ compare the indices preferred by oncologists with the indices available to them.□ correlate Nottingham grade (ng) and its subcomponents with Oncotype dx.□ assess interobserver variation. METHODS All of the er-positive, her2-negative, T1-2, N0 breast cancers diagnosed from 2007 to 2011 (n = 5110) were linked to a dataset of all provincial breast cancers with a rs. A 5% random sample of the 5110 cancers was reviewed to estimate the proportion that had a mc, Ki-67 index, and rs. Correlation coefficients were calculated for the rs with ng subcomponent scores. Interobserver variation in histologic grading between outside and central review pathology reports was assessed using a weighted kappa test. RESULTS During 2007-2011, most cancers were histologically graded and assigned a mc; few had a Ki-67 index or rs. The ng and mc were significantly positively correlated with rs. The level of agreement in histologic scoring between outside and central pathology reports was good or very good. Very few cases with a low mc had a high rs (1.8%). CONCLUSIONS Patients with low ng and mc scores are unlikely to have a high rs, and thus are less likely to benefit from chemotherapy. In the context of limited resources, that finding can guide clinicians about when a rs adds the most value.

Aptima HPV Assay versus Hybrid Capture® 2 HPV test for primary cervical cancer screening in the HPV FOCAL trial

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<0.001) 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. 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.

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

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

Comparison of One versus Two Fecal Immunochemical Tests in the Detection of Colorectal Neoplasia in a Population-Based Colorectal Cancer Screening Program

Objective. To determine the positive predictive value (PPV) of two versus one abnormal FIT in the detection of colorectal neoplasia in a Canadian population. Methods. Three communities enrolled in a colorectal cancer (CRC) screening pilot program from 01/2009 to 04/2013 using 2 FITs. Data collected included demographics, colonoscopy, pathology, and FIT results. Participants completed both FITs and had one positive FIT and colonoscopy. PPV of one versus two abnormal FITs was calculated using a weighted-generalized score statistic. A two-sided 5% significance level was used. Results. 1576 of 17,031 average-risk participants, 50–75 years old, had a positive FIT. Colonoscopy revealed 58 (3.7%) cancers, 419 (31.6%) high-risk polyps, and 374 (23.7%) low-risk polyps as the most significant lesion. PPV of one versus two positive FITs for cancer, high-risk polyps, and any neoplasia were 1% versus 8%, 20% versus 40%, and 48% versus 67%, respectively (p value < 0.0001). When the first FIT was negative, the second positive FIT detected 7 CRCs and 98 high-risk polyps. Conclusions. PPV of two positive FITs is superior to one positive FIT for CRC and high-risk polyps. The added value of the second FIT was 12% of total CRCs and 23% of total high-risk polyps.

Performance of a quantitative fecal immunochemical test in a colorectal cancer screening pilot program: a prospective cohort study

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.

Correlating Quantitative Fecal Immunochemical Test Results with Neoplastic Findings on Colonoscopy in a Population-Based Colorectal Cancer Screening Program: A Prospective Study

Background and Aims. The Canadian Partnership Against Cancer (CPAC) recommends a fecal immunochemical test- (FIT-) positive predictive value (PPV) for all adenomas of ≥50%. We sought to assess FIT performance among average-risk participants of the British Columbia Colon Screening Program (BCCSP). Methods. From Nov-2013 to Dec-2014 consecutive participants of the BCCSP were assessed. Data was obtained from a prospectively collected database. A single quantitative FIT (NS-Plus, Alfresa Pharma Corporation, Japan) with a cut-off of ≥10 μg/g (≥50 ng/mL) was used. Results. 20,322 FIT-positive participants underwent CSPY. At a FIT cut-off of ≥10 μg/g (≥50 ng/mL) the PPV for all adenomas was 52.0%. Increasing the FIT cut-off to ≥20 μg/g (≥100 ng/mL) would increase the PPV for colorectal cancer (CRC) by 1.5% and for high-risk adenomas (HRAs) by 6.5% at a cost of missing 13.6% of CRCs and 32.4% of HRAs. Conclusions. As the NS-Plus FIT cut-off rises, the PPV for CRC and HRAs increases but at the cost of missed lesions. A cut-off of ≥10 μg/g (≥50 ng/mL) produces a PPV for all adenomas exceeding national recommendations. Health authorities need to take into consideration endoscopic resources when selecting a FIT positivity threshold.

Correlation between Nottingham grade and Oncotype DX score in breast cancer: Implications for cost-effective incorporation of oncotype in the clinic.

106 Background: Nottingham grading (NG) for breast cancer uses tubule formation (TF), nuclear polymorphism (NP), and mitotic count (MC). The Oncotype Dx recurrence score (RS) is a 21-gene assay that predicts recurrence. Both NG and RS can influence decisions about the use of adjuvant chemotherapy in patients with ER+, HER2-, T1-T2, N0 cancers. The objective was to determine the correlation of overall NG, TF, NP, MC with RS risk group in such patients. This may be useful in guiding the use of Oncotype in specific cases. METHODS 231 patients referred to the BC Cancer Agency between 2007-2011 with ER+, HER2-, T1-T2, N0 breast cancer and an Oncotype were identified. Histologic grading was assessed on the specimen used for Oncotype. Spearmans correlation coefficients, and 95% confidence intervals (CI) were calculated for the RS risk group versus overall NG, TF, NP, and MC. This study adds to the literature as it is one of the largest cohorts examining this topic and focuses on a HER2- patient population. RESULTS There was a significant positive moderate correlation between RS and overall grade (Spearman coefficient 0.47, [95%CI: 0.36, 0.56])(Table 1), and RS and MC (Spearman 0.44, [95%CI: 0.33, 0.54]). There was a significant positive weak correlation between RS and TF (Spearman 0.25, [95%CI: 0.13, 0.37]) and RS and NP (Spearman 0.34, [95%CI: 0.22, 0.45]). None of the patients with low overall NG had a high risk RS. CONCLUSIONS Patients with a low NG are unlikely to have a high risk RS (0 in 231 patients) and very few such patients would benefit from the expense of an Oncotype. Overall NG has a better correlation with RS than TF, MC, or NP components alone. [Table: see text].