Trends in Colon and Rectal Cancer Incidence in Australia from 1982 to 2014: Analysis of Data on Over 375,000 Cases.

BACKGROUND: Colorectal cancer is the third most commonly diagnosed cancer in Australia. Emerging evidence from several countries suggests increasing incidence in people aged <50 years. METHODS: We assessed colon and rectal cancer incidence trends in people aged 20+ in Australia from 1982 to 2014. We used data on 375,008 incident cases (248,162 colon and 126,846 rectal). We quantified the annual percentage change (APC) in rates by age group using Joinpoint regression. RESULTS: For people aged <50 years, colon cancer rates increased from the mid-2000s, with the increase in APCs ranging from 1.7% to 9.3% per annum (depending on specific age group); rectal cancer rates increased from the early 1990s, with APCs ranging from 0.9% to 7.1% per annum. For people aged 50 to 69 years, colon and rectal cancer rates decreased from the mid-1990s, with the decrease in APCs in specific age groups ranging from 0.8% to 4.8% per annum (except for colon cancer in those ages 65 to 69 years, where similar rate decreases were observed from 2007). An overall reduction in older persons (>70 years) was estimated at 1.9% to 4.9% per annum for colon cancer from 2010 onward and 1.1% to 1.8% per annum in rectal cancer from the early 2000s onward. CONCLUSIONS: Colon and rectal cancer incidence has increased in people aged <50 years in Australia over the last two decades. However, colon and rectal cancer rates decreased in people aged 50+, likely due to de facto and organized bowel cancer screening. IMPACT: Further research is needed to examine the cause of the increase and to quantify the impact of future trends on the cost-effectiveness of population-based screening for those <50 years.

Revised Australian national guidelines for colorectal cancer screening: family history.

INTRODUCTION: Screening is an effective means for colorectal cancer prevention and early detection. Family history is strongly associated with colorectal cancer risk. We describe the rationale, evidence and recommendations for colorectal cancer screening by family history for people without a genetic syndrome, as reported in the 2017 revised Australian guidelines. Main recommendations: Based on 10-year risks of colorectal cancer, people at near average risk due to no or weak family history (category 1) are recommended screening by immunochemical faecal occult blood test (iFOBT) every 2 years from age 50 to 74 years. Individuals with moderate risk due to their family history (category 2) are recommended biennial iFOBT from age 40 to 49 years, then colonoscopy every 5 years from age 50 to 74 years. People with a high risk due to their family history (category 3) are recommended biennial iFOBT from age 35 to 44 years, then colonoscopy every 5 years from age 45 to 74 years. Changes in management as a result of the guidelines: By 2019, the National Bowel Cancer Screening Program will offer all Australians free biennial iFOBT screening from age 50 to 74 years, consistent with the recommendations in these guidelines for category 1. Compared with the 2005 guidelines, there are some minor changes in the family history inclusion criteria for categories 1 and 2; the genetic syndromes have been removed from category 3 and, as a consequence, colonoscopy screening is now every 5 years; and for categories 2 and 3, screening begins with iFOBT for people aged 40 and 35 years, respectively, before transitioning to colonoscopy after 10 years.

Benefits, Harms, and Cost-Effectiveness of Potential Age Extensions to the National Bowel Cancer Screening Program in Australia.

BACKGROUND: The Australian National Bowel Cancer Screening Program (NBCSP) is rolling out 2-yearly immunochemical fecal occult blood test screening in people aged 50 to 74 years. This study aimed to evaluate the benefits, harms, and cost-effectiveness of extending the NBCSP to younger and/or older ages. METHODS: A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate the fully rolled-out NBCSP and alternative strategies assuming screening starts at 40 or 45 years and/or ceases at 79 or 84 years given three scenarios: (i) perfect adherence (100%), (ii) high adherence (60%), and (ii) low adherence (40%, as currently achieved). RESULTS: The current NBCSP will reduce colorectal cancer incidence (mortality) by 23% to 51% (36% to 74%) compared with no screening (range reflects participation); extending screening to younger or older ages would result in additional reductions of 2 to 6 (2 to 9) or 1 to 3 (3 to 7) percentage points, respectively. With an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS), only screening from 50 to 74 years [incremental cost-effective ratio (ICER): A$2,984-5,981/LYS) or from 45 to 74 years (ICER: A$17,053-29,512/LYS) remained cost-effective in all participation scenarios. The number-needed-to-colonoscope to prevent a death over the lifetime of a cohort in the current NBCSP is 35 to 49. Starting screening at 45 years would increase colonoscopy demand for program-related colonoscopies by 3% to 14% and be associated with 55 to 170 additional colonoscopies per additional death prevented. CONCLUSIONS: Starting screening at 45 years could be cost-effective, but it would increase colonoscopy demand and would be associated with a less favorable incremental benefits-to-harms trade-off than screening from 50 to 74 years. IMPACT: The study underpins recently updated Australian colorectal cancer management guidelines that recommend that the NBCSP continues to offer bowel screening from 50 to 74 years.

Evaluation of the benefits, harms and cost-effectiveness of potential alternatives to iFOBT testing for colorectal cancer screening in Australia.

The Australian National Bowel Cancer Screening Program (NBCSP) will fully roll-out 2-yearly screening using the immunochemical Faecal Occult Blood Testing (iFOBT) in people aged 50 to 74 years by 2020. In this study, we aimed to estimate the comparative health benefits, harms, and cost-effectiveness of screening with iFOBT, versus other potential alternative or adjunctive technologies. A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate a total of 13 screening approaches involving use of iFOBT, colonoscopy, sigmoidoscopy, computed tomographic colonography (CTC), faecal DNA (fDNA) and plasma DNA (pDNA), in people aged 50 to 74 years. All strategies were evaluated in three scenarios: (i) perfect adherence, (ii) high (but imperfect) adherence, and (iii) low adherence. When assuming perfect adherence, the most effective strategies involved using iFOBT (annually, or biennially with/without adjunct sigmoidoscopy either at 50, or at 54, 64 and 74 years for individuals with negative iFOBT), or colonoscopy (10-yearly, or once-off at 50 years combined with biennial iFOBT). Colorectal cancer incidence (mortality) reductions for these strategies were 51-67(74-80)% in comparison with no screening; 2-yearly iFOBT screening (i.e. the NBCSP) would be associated with reductions of 51(74)%. Only 2-yearly iFOBT screening was found to be cost-effective in all scenarios in context of an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS); this strategy was associated with an incremental cost-effectiveness ratio of A$2,984/LYS-A$5,981/LYS (depending on adherence). The fully rolled-out NBCSP is highly cost-effective, and is also one of the most effective approaches for bowel cancer screening in Australia.

Long-term evaluation of benefits, harms, and cost-effectiveness of the National Bowel Cancer Screening Program in Australia: a modelling study.

BACKGROUND: No assessment of the National Bowel Screening Program (NBCSP) in Australia, which considers all downstream benefits, costs, and harms, has been done. We aimed to use a comprehensive natural history model and the most recent information about cancer treatment costs to estimate long-term benefits, costs, and harms of the NBCSP (2 yearly immunochemical faecal occult blood testing screening at age 50-74 years) and evaluate the incremental effect of improved screening participation under different scenarios. METHODS: In this modelling study, a microsimulation model, Policy1-Bowel, which simulates the development of colorectal cancer via both the conventional adenoma-carcinoma and serrated pathways was used to simulate the NBCSP in 2006-40, taking into account the gradual rollout of NBCSP in 2006-20. The base-case scenario assumed 40% screening participation (currently observed behaviour) and two alternative scenarios assuming 50% and 60% participation by 2020 were modelled. Aggregate year-by-year screening, diagnosis, treatment and surveillance-related costs, resource utilisation (number of screening tests and colonoscopies), and health outcomes (incident colorectal cancer cases and colorectal cancer deaths) were estimated, as was the cost-effectiveness of the NBCSP. FINDINGS: With current levels of participation (40%), the NBCSP is expected to prevent 92 200 cancer cases and 59 000 deaths over the period 2015-40; an additional 24 300 and 37 300 cases and 16 800 and 24 800 deaths would be prevented if participation was increased to 50% and 60%, respectively. In 2020, an estimated 101 000 programme-related colonoscopies will be done, associated with about 270 adverse events; an additional 32 500 and 49 800 colonoscopies and 88 and 134 adverse events would occur if participation was increased to 50% and 60%, respectively. The overall number needed to screen (NNS) is 647-788 per death prevented, with 52-59 colonoscopies per death prevented. The programme is cost-effective due to the cancer treatment costs averted (cost-effectiveness ratio compared with no screening at current participation, AUS$3014 [95% uncertainty interval 1807-5583] per life-year saved) in the cost-effectiveness analysis. In the budget impact analysis, reduced annual expenditure on colorectal cancer control is expected by 2030, with expenditure reduced by a cumulative AUS$1·7 billion, AUS$2·0 billion, and AUS$2·1 billion (2015 prices) between 2030 and 2040, at participation rates of 40%, 50%, and 60%, respectively. INTERPRETATION: The NBCSP has potential to save 83 800 lives over the period 2015-40 if coverage rates can be increased to 60%. By contrast, the associated harms, although an important consideration, are at a smaller magnitude at the population level. The programme is highly cost-effective and within a decade of full roll-out, there will be reduced annual health systems expenditure on colorectal cancer control due to the impact of screening. FUNDING: Australia Postgraduate Award PhD Scholarship, Translational Cancer Research Network Top-up scholarship (supported by Cancer Institute NSW) and Cancer Council NSW.

Optimising the expansion of the National Bowel Cancer Screening Program.

OBJECTIVES: To estimate the impact of various expansion scenarios of the National Bowel Cancer Screening Program (NBCSP) on the number of bowel cancer deaths prevented; and to investigate the impact of the expansion scenarios on colonoscopy demand. DESIGN: MISCAN-Colon, a well established, validated computer simulation model for bowel cancer screening, was adjusted to reflect the Australian situation. In July 2013, we simulated the effects of screening over a 50-year period, starting in 2006. The model parameters included rates of participation in screening and follow-up, rates of identification of cancerous and precancerous lesions, bowel cancer incidence, mortality and the outcomes of the NBCSP. Five implementation scenarios, based on biennial screening using an immunochemical faecal occult blood test, were developed and modelled. A sensitivity analysis that increased screening participation to 60% was also conducted. PARTICIPANTS: Australian residents aged 50 to 74 years. MAIN OUTCOME MEASURES: Comparison of the impact of five implementation scenarios on the number of bowel cancer deaths prevented and demand for colonoscopy. RESULTS: MISCAN-Colon calculated that in its current state, the NBCSP should prevent 35 169 bowel cancer deaths in the coming 40 years. Accelerating the expansion of the program to achieve biennial screening by 2020 would prevent more than 70 000 deaths. If complete implementation of biennial screening results in a corresponding increase in participation to 60%, the number of deaths prevented will increase across all scenarios. CONCLUSIONS: The findings strongly support the need for rapid implementation of the NBCSP. Compared with the current situation, achieving biennial screening by 2020 could result in 100% more bowel cancer deaths (about 35 000) being prevented in the coming 40 years.

Costs and cost-effectiveness of full implementation of a biennial faecal occult blood test screening program for bowel cancer in Australia.

OBJECTIVE: To examine the costs and cost-effectiveness of full implementation of biennial bowel cancer screening for Australian residents aged 50-74 years. DESIGN AND SETTING: Identification of existing economic models from 1993 to 2010 through searches of PubMed and economic analysis databases, and by seeking expert advice; and additional modelling to determine the costs and cost-effectiveness of full implementation of biennial faecal occult blood test screening for the five million adults in Australia aged 50-74 years. MAIN OUTCOME MEASURES: Estimated number of deaths from bowel cancer prevented, costs, and cost-effectiveness (cost per life-year gained [LYG]) of biennial bowel cancer screening. RESULTS: We identified six relevant economic analyses, all of which found colorectal cancer (CRC) screening to be very cost-effective, with costs per LYG under $55,000 per year in 2010 Australian dollars. Based on our additional modelling, we conservatively estimate that full implementation of biennial screening for people aged 50-74 years would have gross costs of $150 million, reduce CRC mortality by 15%-25%, prevent 300-500 deaths from bowel cancer, and save 3600-6000 life-years annually, for an undiscounted cost per LYG of $25,000-$41,667, compared with no screening, and not taking cost savings as a result of treatment into consideration. The additional expenditure required, after accounting for reductions in CRC incidence, savings in CRC treatment costs, and existing ad-hoc colonoscopy use, is likely to be less than $50 million annually. CONCLUSIONS: Full implementation of biennial faecal occult blood test screening in Australia can reduce bowel cancer mortality, and is an efficient use of health resources that would require modest additional government investment.

Dependence of colorectal cancer risk on the parent-of-origin of mutations in DNA mismatch repair genes.

Genetic diseases associated with dynamic mutations in microsatellite DNA often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Carriers of germline mutations in mismatch repair (MMR) genes have high risks of colorectal carcinoma (CRC). We investigated whether these risks depend on the parent-of-origin of the mutation. We studied 422 subjects, including 89 MMR gene mutation carriers, from 17 population-based families who were each recruited via a CRC case diagnosed before age 45 years and found to carry a MMR gene mutation. The POE hazard ratio (HR(POE)), defined to be the CRC incidence for carriers with maternally derived mutations divided by the corresponding paternal incidence, was estimated using a novel application of modified segregation analysis. HR(POE) (95% confidence interval) was estimated to be 3.2 (1.1-9.8) for males (P = 0.03) and 0.8 (0.2-2.8) for females (P = 0.5) and the corresponding cumulative risks to age 80 years were 88% (54%-100%) for male carriers with maternally derived mutations and 38-48% for all other carriers. If confirmed by larger studies, these results will have important implications for the etiology of CRC and for the clinical management of MMR gene mutation carriers.

Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes.

PURPOSE: Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes. EXPERIMENTAL DESIGN: Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLH1, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel. RESULTS: The National Cancer Institute five-marker panel system scored 31 (29%) as (NCI)MSI-High, 13 (12%) as (NCI)MSI-Low, and 63 (59%) as (NCI)MS-Stable. The 10-marker panel classified 18 (17%) as (10)MSI-High, 17 (16%) as (10)MSI-Low, and 72 (67%) as (10)MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92%) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all (10)MSI-High cancers and all MLH1 and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100% sensitive). Bat40 was unstable in all MMR gene mutation carriers (100% sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored (10)MSI-Low) from the MLH1 and MSH2 mutation carriers (all scored (10)MSI-High). CONCLUSIONS: In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.

Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study.

BACKGROUND & AIMS: Cancer risks for mismatch repair gene mutation carriers have been derived almost exclusively using families ascertained owing to their strong cancer family history. These may be overestimates, due to analytic problems, and not generalizable. We estimated average cancer risks for mutations identified in population-based early onset colorectal cancer cases (probands) unselected for family history. METHODS: Data were cancer histories and mutation status (carrier, non-carrier, or unknown) of 17 mismatch repair gene mutation carrier probands with colorectal cancer diagnosed before age 45 (8 hMLH1, 4 hMSH2, 4 hMSH6, 1 hPMS2) and their first- and second-degree relatives. We used modified segregation analysis theory, adjusting for the family being ascertained through the proband being an early onset mutation carrier. RESULTS: Eleven carrier probands (64%) were from families meeting the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. The cumulative risk for colorectal cancer (95% confidence interval) to age 70 was 45% (29%-62%) for men and 38% (19%-51%) for women. Corresponding risks were 67% (47%-84%) and 72% (48%-85%) for any hereditary nonpolyposis colorectal cancer-related cancer. Compared with the general population, colorectal cancer incidence for men was approximately 180-fold higher before age 50, but about the same after age 50. For women, incidence was approximately 100-fold higher before age 50 and 7-fold higher thereafter. CONCLUSIONS: For carriers of the mutations in the mismatch repair genes that cause early onset colorectal cancer, colorectal cancer increases rapidly until age 50, and the incidence decreases to general population levels at older ages.

Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer.

PURPOSE: The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. METHODS: We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins. RESULTS: Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. CONCLUSIONS: Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.

Screening and preventive behaviors one year after predictive genetic testing for hereditary nonpolyposis colorectal carcinoma.

BACKGROUND: Prevention benefits from predictive genetic testing for cancer will only be fully realized if appropriate screening is adopted after testing. The current study assessed screening and preventive behaviors during 12 months after predictive genetic testing for hereditary nonpolyposis colorectal carcinoma (HNPCC) in an Australian clinical cohort. METHODS: Participants received predictive genetic testing for HNPCC at one of five Australian familial cancer clinics. Data on self-reported screening behaviors (colonoscopy, and endometrial sampling and transvaginal ultrasound for women) and prophylactic surgery (colectomy, and hysterectomy and bilateral oophorectomy for women) were collected using postal questionnaires before (baseline) and 12 months after receipt of genetic test results. Age, gender, perceived risk of cancer, and cancer-specific distress were assessed as predictors of colonoscopic screening. RESULTS: In the current study, 114 participants returned baseline questionnaires (32 carriers and 82 noncarriers of an HNPCC mutation). Ninety-eight participants also returned a 12-month follow-up questionnaire. Of those > or = 25 years, 73% reported having had a colonoscopy before genetic testing. At follow-up, 71% (15 of 25) of carriers and 12% (8 of 65) of noncarriers reported having a colonoscopy in the 12 months after receipt of test results. The reduction in colonoscopy among noncarriers was statistically significant (P < 0.001). High perceived risk was associated with colonoscopy at baseline. At follow-up, mutation status was the only variable significantly associated with colonoscopy. Among female mutation carriers, 47% reported having transvaginal ultrasonography and 53% endometrial sampling during follow-up. There was low uptake of prophylactic surgery for colorectal, endometrial, or ovarian carcinomas. CONCLUSIONS: The majority of individuals reported appropriate screening behaviors after predictive genetic testing for HNPCC. The small group of noncarriers who had screening after genetic testing might benefit from additional counseling.

After hMSH2 and hMLH1--what next? Analysis of three-generational, population-based, early-onset colorectal cancer families.

The aim of our study was to examine the role of genetic factors on early-onset colorectal cancer after excluding the impact of germline mutations in the two major mismatch repair genes. A total of 131 incident probands, under 45 years at diagnosis of a first primary colorectal cancer selected from the Victorian Cancer Registry, and their first-and second-degree relatives, were interviewed. Germline DNA from all 12 probands with a family history meeting the modified Amsterdam Criteria for Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and a random sample of 31 of the remaining probands was screened for mutations in hMSH2 and hMLH1 via manual sequencing. Germline mutations were identified in 6 of the 131 probands (5%), all from the "HNPCC" families. Of the remaining 125 probands, 51 (41%) reported at least one first-or second-degree relative with colorectal cancer with an excess of colorectal cancer in first-degree relatives (SMR = 2.7, 95% CI = 1.7-4.1, p < 0.001). The lifetime risk to age 70 for first-degree relatives was 8.0% (5.0-12.8%), compared to the Victorian population risk of 3.2% (p = 0.01). The best fitting major gene model was a recessively-inherited risk of 98% to age 70 (95% CI = 24-100%) carried by 0.17% of the population and would explain 15% of all colorectal cancer in cases with a diagnosis before age 45. Early-onset colorectal cancer is strongly familial even after excluding families found to be segregating a mutation in either of the 2 major mismatch repair genes. There is evidence for a role of yet to be identified genes associated with a high recessively-inherited risk of colorectal cancer.

Choice of fecal occult blood tests for colorectal cancer screening: recommendations based on performance characteristics in population studies: a WHO (World Health Organization) and OMED (World Organization for Digestive Endoscopy) report.

OBJECTIVE: There is now strong evidence that screening for colorectal cancer with fecal occult blood tests (FOBTs) is effective in reducing the incidence and mortality of this disease. Various FOBTs are now available with a wide range of evidence supporting their use. The purpose of this study was to review published data on the performance of these FOBTs to provide recommendations for their effective use in screening. METHODS: A joint committee representing the World Health Organization and the World Organization for Digestive Endoscopy was established for this study. A process was designed that would search the literature systematically for evidence of FOBT performance. Criteria for including studies in this paper were established based on study design, cohort size, and performance variables reported. RESULTS: Of the guaiac tests, Hemoccult SENSA had the highest sensitivity for cancer and adenomas but a high test positivity. It had a better readability than the older Hemoccult II test. Immunochemical tests, HemeSelect, FlexSure OBT, and Immudia Hem Sp have acceptable performance characteristics and are easier for participants to use but are more expensive. These tests have been well studied in large cohorts, but only Immudia Hem Sp is commercially available. CONCLUSIONS: At present, there is no extensively studied FOBT that fulfills the needs for all target populations worldwide. Choice of FOBT should take into account population dietary compliance and colonoscopy resources: The more sensitive newer tests should be used if dietary compliance is good (in the case of guaiac tests) and colonoscopy resources are adequate for diagnostic workup of people who test positive. Immunochemical tests remove the difficulties created by diet and drug restrictions and are more amenable to standardized development and quality control.