Introduction
In a retrospective analysis of two randomized phase III trials in mCRC patients treated first line with oxaliplatin, fluoropyrimidine with and without Bevacizumab (the AIO KRK 0207 and R091 trials) we evaluated the association of high microsatellite instability (MSI-H), immunoscore (IS) and PD-L1 expression in relation to overall survival (OS).
Methods
In total, 550 samples were analysed. Immunohistochemical analysis of the MMR proteins and additionally fragment length analysis was performed, molecular examinations via allele-discriminating PCR in combination with DNA sequencing. Furthermore PD-L1 and IS were assessed.
Results
MSI-H tumors were more frequent in right sided tumors (13.66% vs. 4.14%) and were correlated with mutant BRAF (p = 0.0032), but not with KRAS nor NRAS mutations (MT). 3.1% samples were found to be PD-L1 positive, there was no correlation of PDL1 expression with MSI-H status, but in a subgroup analysis of MSI-H tumors the percentage of PD-L1 positive tumors was higher than in MSS tumors (9.75% vs. 2.55%). 8.5% of samples showed a positive IS, MSI-H was associated with a high IS. The mean IS of the pooled population was 0.57 (SD 0.97), while the IS of MSI-H tumors was significantly higher (mean of 2.4; SD 1.4; p =< 0.0001).
Discussion
Regarding OS in correlation with MSI-H, PD-L1 and IS status we did not find a significant difference. However, PD-L1 positive mCRC tended to exhibit a longer OS compared to PD-L1 negative cancers (28.9 vs. 22.1 months).
Colorectal cancer is one of the leading malignancies and still accounts for almost 25 000 deaths in Germany each year. Although there is accumulating data on the molecular basis, treatment and clinical outcome of patients within clinical trials evidence from the real-world setting is mostly lacking. We started the molecular registry trial Colopredict Plus in 2013 to collect clinical and molecular data from a real-world cohort of patients with early colon cancer stage II and III in 70 German colon cancer centers focusing on the prognostic impact of high microsatellite instability. In this interim report, we characterize a clinical cohort of 2615 patients, of whom 1787 tissue probes were analyzed. Microsatellite status was assessed using immunhistochemistry and fragment length analysis, with a concordance of 91.4 %. These established histopathological methods are sensitive and cost-effective. The median age was 72 years, significantly higher compared to clinical trial populations, with a median Charlson Comorbidity Index of 3. The stage-dependent incidence of microsatellite instability was 23.7 % and was associated with female gender, BRAF-mutation, UICC stage II and localization in the right colon. Survival calculated in disease free, relapse free and overall survival significantly differed between MSI-H and MSS, in favor of MSI-H patients. Multivariate age-adjusted analyses of relapse-free survival, disease-free survival, and overall survival highlighted microsatellite instability as a robust and positive prognostic marker for early colon cancer independent of age.
3543 Background: Numerous trials have examined the prognostic and predictive value of the LPT in mCRC, but little is known about the predictive value of LPT on different maintenance strategies. We analyzed progression-free survival (PFS) and overall survival (OS) from start of maintenance according to LPT in patients (pts) from the AIO KRK 0207 trial. Methods: Following a 24-week standard induction 471 pts were randomized to FP/Bev, Bev mono or no treatment with 454 pts being evaluable for PFS. Right sided primary tumors were defined as located in the caecum, ascending colon, transverse colon up to the splenic flexure; left colon was defined as splenic flexure, descending and sigmoid colon and rectum. Results: Data on LPT was available in 414 pts. for PFS (91%). LPT was left sided (LPTl) in 291 (70%) and right-sided (LPTr) in 123 (30%) of pts, respectively (remaining pts: status was either unknown, n = 37 or LPT was located in both regions, n = 3). Median PFS1 was 3.9 months (mos.) for LPTr and 5.3 mos. for LPTl (p = 0.11; HR 1.19, 95%CI 0.96 - 1.48). Analyses on PFS did not demonstrate a major predictive impact of LPT on the efficacy of the three maintenance strategies. The pairwise comparison of treatment arms showed a better PFS for FP/Bev vs no treatment independent from LPT (left: p < 0.0001; HR = 2.39, 95%CI 1.73-3.31; right: p = 0.011; HR 1.78, 95%CI 1.14-2.80). In addition, Bev mono vs no treatment was superior in LPTl (p = 0.0032; HR 1.54, 95%CI 1.15-2.06) with less difference in LPTr (p = 0.17; HR 1.36, 95%CI 0.87-2.14). Analysis for OS (429 evaluable pts) confirmed the strong prognostic impact of LPT (left vs right: 24.0 vs 16.7 months; p < 0.0001; HR = 1.65, 95%CI 1.32 - 2.06), but without major interaction between LPT and maintenance arms. The impact related to RAS mutational status will be reported. Conclusions: The strong prognostic factor of the LPT is confirmed in pts with mCRC undergoing Ox/FP/Bev induction therapy while there seems to be no major predictive impact of LPT on different maintenance strategies. Clinical trial information: EudraCT-Nr: 2008-007974-39.
e15086 Background: High microsatellite instability (MSI-H) is a prognostic marker in resected colon cancer (CC) identified in post-hoc analysis of multiple trials. However, validation in real-life cohorts and its association with clinical and molecular markers is lacking. Methods: In Sep 2013 we started a platform trial in 49 German cancer centers recruiting patients with UICC stage II and III CC diagnosed between 2008 to 2016. MSI was tested by immunohistochemistry (IHC) of mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. In case of any loss of protein expression (IHC neg), fragment length analysis (FLA) was performed, defining MSI high tumors (MSI-H) and MS stable tumors (MSS). Besides, mutations in known prognostic factors for CC such as RAS, BRAF, PI3K and others were determined by next generation sequencing (NGS). Results: By end of 2016, 1249 patients have been recruited into the trial: median age 73yrs., stage II/III: 686/563 pts. So far, tissue was analysed in 512 pts. Of these, 182 pts. were IHC neg with 116 pts. tested MSI-H upon FLA (22.7%). Median age was 73yrs., female/male: 260/252 pts., stageII/III: 292/220 pts. Association of MS status with clinical factors is shown in Table 1. Upon NGS analysis we found 16.3% BRAF mutations, 39% KRAS mutations, 2.8% NRAS mutations and 22.6% PI3K mutations. MSI-H status was significantly associated with BRAF mutation and wildtype status of RAS. Conclusions: We found a higher percentage of MSI-H cancers in our registry compared to reported data from randomised trials, possibly related to a higher median age in this real-life cohort. MSI-H was associated with female sex, primary tumor site, and distinct molecular markers and should therefore be considered a heterogeneous subgroup of CC. Updated analysis including NGS data and survival will be presented at the meeting. Clinical trial information: AIO- KRK-0413, DKRS:00004305. [Table: see text]
e16241 Background: Clinical guidelines and their adherence are important instruments to ensure quality in diagnosis and treatment, especially when treating rare diseases like pancreatic neuroendocrine tumors (PanNET). However, data on guideline adherence and its impact on outcome in PanNET is limited. Methods: Cases of PanNET according to 2017 WHO definition at our university hospital between 2010 and 2019 were retrospectively identified. Adherence to ENETS guideline 2007/2012 and the German S2k guideline was evaluated among four categories (diagnostics: chromogranin A (CgA) testing, somatostatin receptor imaging, discussion in an interdisciplinary tumor board; pathology: reporting of grading, Ki67 and synaptophysin expression; surgical treatment; systemic treatment including aftercare). Guideline adherence within these categories was valued with one point per fulfilled criterion and a final score between 0-8 points was calculated. Data was analyzed using Student’s t-test, Chi-square test and Spearman’s correlation coefficient test. Results were considered significant at α = 0.05. Results: Overall, 115 patients (47% female) with a diagnosis of PanNET were identified. Mean age was 61 (±13.5) years. Mean overall survival (OS) was 45 months, mean recurrence free survival (RFS) was 47 months. During the study period 21 patients (18%) had died, 6 patients (5%) were lost-to-follow-up and 11 patients (10%) had a recurrent disease after initially curative resection. 24 patients (21%) presented with metastatic disease upon diagnosis. Guideline adherence concerning pathology reports (97%) as well as systemic (91%) and surgical treatment (75%) was high, while complete adherence in diagnostic modalities was low (5%). However, the latter was mainly driven by lack of CgA testing (31%), and somatostatin receptor imaging (11%) not being performed on initial diagnosis, but in most cases during follow-up. Subsequently, complete guideline adherence (8/8) across all categories was rare (3%). However, a higher overall score was associated with survival (p = 0.032, V = 0.321). Long term survivors had a higher mean overall adherence score (5.6 vs. 6.1; p = 0.05). In addition, the composite score of surgical and systemic therapy was significantly correlated with RFS (ρ = 0.254, p = 0.016). Conclusions: The quality in diagnosis and treatment of PanNET in our cohort was high. These are the first data to demonstrate a positive impact of guideline adherence on survival and RFS in PanNET.
3595 Background: MSI-H is an established prognostic marker in early colon cancer. Moreover, MSI-H, tumor immune cell infiltration and PD-L1 expression are also discussed as potential predictive biomarkers for immunotherapy. However, little is known about the prognostic value of these biomarkers and their association among each other in mCRC. Methods: We analyzed samples from pts. with mCRC uniformly treated with a FP and Ox within two randomized AIO trials (KRK 0207 and RO91). MS status was assessed by immunohistochemistry (IHC) of mismatch repair proteins and subsequent fragment length analysis in case of protein loss or incoherent results. PD-L1 expression was determined by IHC (1% expression threshold). Tumor lymphocytic infiltration (CD8 and CD45RO) was scored according to the immunoscore (IS) concept by Galon et al (J Transl Med 2016). Results: 41/550 cases (7.5%) displayed MSI-H. The mean IS of the total population was 0.57 (SD 0.97), the IS of MSI-H pts. was significantly higher (mean of 2.4; SD 1.4; p≤0.0001). 17 cases were PD-L1 positive (pos.) (3 %), only four of these were MSI-H. MSI-H status was significantly correlated with a higher IS, but not with PD-L1 expression (table 1). There was no difference in median overall survival (mOS) between MSI-H and MS stable (MSS) pts. (mOS MSI-H/MSS: 17.6/22.5 months (mos.), log rank: p=0.85), PD-L1 negative (neg.) and pos. pts. (mOS PD-L1 neg./pos.: 22.1/28.9 mos., log rank: p=0.49) and IS high or low pts. (mOS IS high/low: 21.1/22.1mo., log rank: p=0.25). Conclusions: In contrast to early stage colon cancer, none of these parameters was prognostic in mCRC patients. Panel-sequencing with a total of 35 genes including RAS, BRAF and POL-E on cases with PD-L1 expression, high IS or MSI-H status to further characterize these cases will be reported. Clinical trial information: AIO-R091, AIO-KRK-0207: EudraCT-Nr: 2008-007974-39. [Table: see text]
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