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Background Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of earlyonset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. MethodsThe IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3•0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.

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Background: Dumon silicone Y-stent is useful for releasing the tracheobronchial stenosis. We often encounter patients with tumors involving the carina between the bronchus to the right upper lobe and bronchus intermedius. However, there has not been ideal stenting for such cases, especially to maintain the patency of the right upper lobe bronchus. We investigated the clinical outcome in patients with malignant tracheobronchial stenosis, especially focused on the patency of right upper lobe bronchus after Y-stent placement. Method: From January 2012 until December 2018, 102 patients who had placed Y-stent on malignant tracheobronchial stenosis in our department were examined retrospectively. This study involved 73 male and 29 female. The mean age was 64 years (range, 30-91 years). Fifty-nine patients had lung cancer, 29 had esophageal cancer, and 14 had other carcinomas. All procedures were carried out in the operating room under general anesthesia, and the stents were implanted via rigid bronchoscopy. The patients were divided into two groups based on the patency of right upper bronchus: patency group (P group, n¼73) and stenosis /occlusion group (S group, n¼29). The clinicopathological features, clinical course, and the survival after stenting of the groups were compared. Result: Stents were implanted and symptoms were resolved in all cases. No operative death occurred. Stent indwelling types were only Y-stent in 69 patients and Y-stent with additional self-expanding metallic stent (SEMS) in 33. Although there was no difference between the two groups in age, gender, preoperative Hugh-Jones classification, hospitalization days, and size of Y-stent, esophageal cancer was significantly more frequent in P group. The total length of placed stent was significantly longer in S group (median 10.5cm) compared to P group (8cm) (p<0.01) and the postoperative Hugh-Jones classification (I or II) in S group (47%) was inferior compared to the P group (72%). After stent placement, 67% of the P group could be treated chemotherapy/radiotherapy to primary disease, while only 43% of the S group was received these because of their poor general condition (p ¼ 0.03).The median survival time (MST) and 1-year survival rate of the two groups was 7 months and 32% (P group), and 2 months and 17% (S group), respectively (p<0.01). Conclusion: The patency of right upper lobe bronchus after Y-stent placement affects not only the improvement of postoperative Hugh-Jones classification but also the administration of subsequent treatment to primary disease and associated to their clinical outcome.

8558 Background: Genetically stratified therapy for malignant mesothelioma (MM) is lacking. MMs frequently harbour loss of chromosome 9p21.3 locus (CDKN2A) associated with shorter survival. CDKN2A encodes the tumour suppressor p16ink4a, an endogenous suppressor of CDK4 and CDK6. Genetic reconstitution of p16ink4a into CDKN2A suppresses MM in preclinical models, underpinning the rationale for targeting of CDK4/6 in p16ink4a negative MM. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis as arm 2 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST2). Methods: Patients with histologically confirmed MM (pleural or peritoneal) were molecularly screened by immunohistochemistry for p16ink4a, BAP1, BRCA1, and PDL1 (Dako 22C3). Patients with p16ink4a negative MM were eligible. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Abemaciclib (Ab) 200mg bd po daily in q21 day cycles. Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Results: Between November 2019 and March 2020, 26 patients with p16ink4a negative MM received at least one dose of Ab. The median age of pts was 67 (range, 64-74) years, 89% were male, 80.8% epithelioid, 84.6% ECOG PS1, > 1 prior systemic therapy 62%. All patients received at least one cycle with 27% completing 6 cycles. No dose reductions occurred in 53.9% of pts. DCR12w: 54% (95% confidence limit (CI), 36% – 71%), DCR24w: 23% (95%CI, 9% – 44%). Best responses (within 24w): partial - 15% (95%CI, 4- 35%), one occurring after 18 weeks; stable disease - 53.8% (33.4 – 73.4%); progression - 7.7% (0.9 – 25.1%). Adverse events (any cause): ≥ grade 3 toxicities affected 5.7% of pts. Conclusions: MiST2 met its primary endpoint, warranting further clinical evaluation of Ab. Whole exome sequencing of the cohort is ongoing to explore genomic correlates of de novo and acquired resistance. Clinical trial information: NCT03654833.