Background: Distinguishing hereditary non-polyposis colorectal cancer (HNPCC) from non-hereditary colorectal cancer (CRC) can increase the life expectancy of HNPCC patients and their close relatives. Aim: To determine the effectiveness, efficiency, and feasibility of a new strategy for the detection of HNPCC, using simple criteria for microsatellite instability (MSI) analysis of newly detected tumours that can be applied by pathologists. Criteria for MSI analysis are: (1) CRC before age 50 years; (2) second CRC; (3) CRC and HNPCC associated cancer; or (4) adenoma before age 40 years. Methods: The efficacy and cost effectiveness of the new strategy was evaluated against current practice. Decision analytic models were constructed to estimate the number of extra HNPCC mutation carriers and the costs of this strategy. The incremental costs and gain in life expectancy for a HNPCC mutation carrier were evaluated by Markov modelling. Feasibility was explored in five hospitals. Results: Using the new strategy, 2.2 times more HNPCC patients can be identified among a CRC population compared with current practice. This new strategy was found to be cost effective with an expected cost effectiveness ratio of J3801 per life year gained. When including the group of siblings and children, the cost effectiveness ratio became J2184 per life year gained. Sensitivity analysis showed these findings to be robust. Conclusions: MSI testing in a selection of newly diagnosed CRC patients was shown to be cost effective and a feasible method to identify patients at risk for HNPCC who are not recognised by family history.
Testing all CRC tumours diagnosed at or below age 70 for LS is cost-effective. Implementation is important as relatives from the large number of LS patients that are missed by current practice, can benefit from life-saving surveillance.
Present guidelines to identify hereditary non-polyposis colorectal cancer (HNPCC) families are criticized for limitations in accuracy. The Amsterdam criteria I and II (AC I and AC II) are used to predict a germline mutation in one of the mismatch repair genes. In families not fulfilling the AC I and AC II criteria, individual indications to test cancer specimens for microsatellite instability (MSI) are guided by the Bethesda Guidelines (BG). Germline mutation testing is then performed in patients who conform to the BG and show MSI. We investigated the sensitivity and specificity of AC I, AC II, and BG. A meta-analysis of studies on the value of the AC I and AC II criteria for predicting germline mutation, as well as a meta-analysis of BG for the detection of MSI was performed. For the AC I, sensitivity varied from 54 to 91% and specificity varied from 62 to 84%. For the AC II, the pooled sensitivity was 78% and specificity ranged between 46 and 68%. Post-test probabilities of a positive test result were 0.61 and 0.46 for the AC I and AC II, respectively. Post-test probabilities of a negative test result were 0.17 and 0.21 for the AC I and AC II, respectively. For the BG, the pooled sensitivity was 89% and pooled specificity was 53%. Post-test probability of a positive test result was 41%, and post-test probability of a negative test result was 9%. The sensitivity and specificity of the Amsterdam criteria for predicting a germline mutation that causes HNPCC is not sufficient. The BG are useful for the detection of MSI in a group of patients suspected of having familial colorectal cancer (CRC), but sensitivity is very low in the total group of newly diagnosed CRC patients. Therefore, a new strategy is needed for the identification of HNPCC.
CRA506 Background: The Dutch MIRROR study is the largest cohort study on pN1mi and pN0(i+) in the SN era with long-term follow-up, central pathology review (6th AJCC-classification), and separate analyses on the use of adjuvant systemic therapy (AST). In patients not receiving AST, pN1mi and pN0(i+) as final N-stage were shown to be independent prognosticators for disease-free survival (SABCS 2008, #23, oral). As a substantial number of patients in the MIRROR study did not undergo cALND or ax RT, we questioned whether this policy was safe in patients with pN1mi(sn) or pN0(i+)(sn). Methods: Patients operated for breast cancer in all Dutch hospitals in the years 1998–2005, having favorable primary tumor characteristics, and having undergone an SN biopsy without macrometastases as final N-stage were included. For this present research question, patients were categorized by their SN-stage. Median follow-up was 4.7 years. The Kaplan-Meier method was used to estimate 5-year axillary recurrence (AR) rates, and Cox regression was used to estimate the hazard ratios (HR). In the analyses, the effect of AST was taken into account. Results: In total, 835 patients with pN0(i-)(sn), 799 patients with pN0(i+)(sn), and 958 patients with pN1mi(sn) were included. AR rates, and HRs on AR are displayed below. Conclusions: Omission of cALND or ax RT in patients with pN1mi(sn) resulted in a significantly higher 5-year AR rate, even after correction for AST, and other patient and tumor characteristics. This indicates that patients with pN1mi(sn) should undergo cALND or ax RT to prevent AR. Support: The Netherlands Organization for Health Research and Development (ZonMw) and the Dutch Breast Cancer Trialists’ Group (BOOG). [Table: see text] No significant financial relationships to disclose.
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