Non-colorectal Cancers Research Articles

S224 Evaluating the Risk of Non-Colorectal Cancers in Individuals With a False Positive Blood-Based Colorectal Cancer Screening Test

S224 Evaluating the Risk of Non-Colorectal Cancers in Individuals With a False Positive Blood-Based Colorectal Cancer Screening Test

998MO Nivolumab and ipilimumab combination treatment in advanced dMMR/MSI-H noncolorectal cancers: Results from the phase II MoST-CIRCUIT study

998MO Nivolumab and ipilimumab combination treatment in advanced dMMR/MSI-H noncolorectal cancers: Results from the phase II MoST-CIRCUIT study

Models and Outcomes of Multidisciplinary Clinics in Colorectal Cancer.

Multidisciplinary clinics (MDCs) represent a potential platform through which high-quality, patient-centered care grounded in interdisciplinary expertise may be delivered for patients with colorectal cancer (CRC). This is increasingly important with the rapidly emerging diagnostic and treatment modalities as well as differential sequences of therapies available. MDCs have been reported to improve various outcomes across numerous non-colorectal cancers; however, data specific to the use of MDCs in CRC are more limited. In this report, we provide a narrative review of the different models of CRC MDCs in the literature and their associations with cancer care outcomes. We found significant heterogeneity in MDC operational logistics as well as reported outcomes across different practice settings. Further research is needed to better understand how MDCs may be optimally structured to meet the unique needs of patients with CRC and how they may affect CRC outcomes.

Microsatellite instability and mismatch repair protein deficiency: equal predictive markers?

Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers of immunotherapies. Most of the pathological guidelines consider MMR protein IHC as the gold standard test to identify cancers with MMR deficiency and recommend molecular MSI tests only in special circumstances or to screen for Lynch syndrome. However, there are data in the literature which suggest that the two test types may not be equal. For example, molecular epidemiology studies reported different rates of deficient MMR (dMMR) and MSI in various cancer types. Additionally, direct comparisons of the two tests revealed relatively frequent discrepancies between MMR IHC and MSI tests, especially in non-colorectal and non-endometrial cancers and in cases with unusual dMMR phenotypes. There are also scattered clinical data showing that the efficacy of immune checkpoint inhibitors is different if the patient selection was based on dMMR versus MSI status of the cancers. All these observations question the current dogma that dMMR phenotype and genetic MSI status are equal predictive markers of the immunotherapies.

A multicenter study evaluating efficacy of immune checkpoint inhibitors in advanced non-colorectal digestive cancers with microsatellite instability

BackgroundOne randomized phase III trial comparing chemotherapy (CT) with immune checkpoint inhibitors (ICI) has demonstrated significant efficacy of ICI in deficient DNA mismatch repair system/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer. However, few studies have compared ICI with CT in other advanced dMMR/MSI-H digestive tumors. MethodsIn this multicenter study, we included patients with advanced dMMR/MSI-H non-colorectal digestive tumors treated with chemotherapy and/or ICIs. Patients were divided retrospectively into two groups, a CT group and an immunotherapy (IO) group. The primary endpoint was progression-free survival (PFS). A propensity score approach using the inverse probability of treatment weighting (IPTW) method was applied to deal with potential differences between the two groups. Results133 patients (45.1/27.1/27.8% with gastric/small bowel/other carcinomas) were included. The majority of patients received ICI in 1st (29.1%) or 2nd line (44.4%). The 24-month PFS rates were 7.9% in the CT group and 71.2% in the IO group. Using the IPTW method, IO treatment was associated with better PFS (HR=0.227; 95% CI 0.147–0.351; p < 0.0001). The overall response rate was 26.3% in the CT group versus 60.7% in the IO group (p < 0.001) with prolonged duration of disease control in the IO group (p < 0.001). In multivariable analysis, predictive factors of PFS for patients treated with IO were good performance status, absence of liver metastasis and prior primary tumor resection, whereas no association was found for the site of the primary tumor. ConclusionsIn the absence of randomized trials, our study highlights the superior efficacy of ICI compared with standard-of-care therapy in patients with unresectable or metastatic dMMR/MSI-H non-colorectal digestive cancer, regardless of tumor type, with acceptable toxicity.

Identification of dMMR in metastatic colorectal and non-colorectal cancers in a private Mexican institution.

177 Background: DNA mismatch repair is a process in which normal cells maintain their original genomic information avoiding errors in mismatched nucleotides or base modifications from recombination processes. The failure of this process could drive carcinogenesis due to increased mutation rate as well as high microsatellite instability. It is estimated that the global average prevalence of dMMR/MSI-H across tumor types and stages is approximately 16%, with higher rates reported for early stages. However, the prevalence for colorectal (CRC) and non-colorectal cancers for this biomarker in Mexico has not been reported. Objective:To explore the prevalence of dMMR in metastatic CRC (mCRC) and non-CRC (gastric, esophageal, and endometrial cancer) from a private Mexican institution. Methods: In this retrospective study, the dMMR status of 215 samples were analyzed from a primary database of stored biopsies from patients diagnosed with metastatic CRC, gastric, esophageal, or endometrial cancers between January 2017 and December 2020. 65 records had information about MMR status. Samples were analyzed using a commercial kit to detect dMMR (BioSb). Prevalence of dMMR was stratified by age and gender and expressed as frequencies. Statistical analysis was conducted in SPSS. Results: dMMR was found in 18.5% (N=27) endometrial cancer cases, 12.7% (N=150) of CRC cases, and 8.3% (N=24) of gastric cancer cases. However, it was not detected in any cases of esophageal cancer (N=14). In CRC, we found a higher percentage of incidence in men than in women, 15.6% (n = 14/90) vs. 8.3% (n = 5/60) respectively. By age groups, the highest total percentage (20%) was observed among those 41-50 years old. The age group with the lowest dMMR rate was 31- 40 yo, with 7.7%. All cases of CRC patients over 91 yo (n=3), were pMMR. Conclusions: Even though this data is not representative for the entire Mexican population, it provides preliminary prevalence dMMR estimates for some key cancers. Additional research is needed to give the limited sample sizes available for non-CRC.

Real-world analyses of BRAF alterations in patients with non-colorectal gastrointestinal cancers.

759 Background: BRAF V600E mutations are present in 5-10% of patients with advanced colorectal cancer (CRC) and associated with poor prognosis. Recently, there was tumor agnostic FDA approval of dabrafenib + trametinib for BRAF V600E mutated solid tumors. However, the frequency of BRAF alterations ( BRAF alt), especially non-V600E, in other gastrointestinal (GI) cancers are not well described. This study characterizes BRAF alt in CRC vs other GI cancers (non-CRC). Methods: De-identified records from 51,560 patients diagnosed with GI cancers were retrospectively analyzed from the Tempus database. The molecular landscape including presence of pathogenic/likely pathogenic BRAF alt was evaluated by panel-based tissue DNA, RNA or ctDNA NGS sequencing (Tempus Labs, Inc.). The frequency of BRAF alt, co-mutations, MSI, TMB and MMR were compared between CRC and (non-CRC) by Chi-squared/Fisher’s Exact or Wilcoxon rank-sum tests. False-discovery rate correction was used for multiple testing. Results: BRAF alt were identified in 8.9% of CRC and 2.2% of non-CRC cohort. BRAF alt frequency varied by tumor type with the highest observed in colon (11%), jejunum (9.6%), intrahepatic bile duct (5.3%), rectal (4.5%), and ampulla of vater (4.5%) and lower in esophageal (0.9%) and gastric (1.6%). BRAF alt CRC had higher frequency of females (57% vs 45%, p &lt;0.001) and older age at diagnosis (67 vs 66 yrs, p=0.029) compared to non-CRC group. Race was also significantly different, with white patients being more predominant in both groups (85% CRC,77% non-CRC). Among the BRAF alt, fusions (12% vs 2.2%, p &lt;0.001) and amplifications (3.1% vs 0.3%, p &lt;0.001) were higher in non-CRC vs CRC (Table). BRAF V600E was most common in all GI tumors, but higher in CRC vs non-CRC (75% vs 27%, q&lt;0.001). Mutations higher in non-CRC vs CRC (q&lt;0.009) included class II (G469A, K601E, BRAF-SND1, and BRAF amplification) and class III (D594N &amp; N581S) BRAF alt. BRAF co-occurring mutations in CRC were TP53 (70%), APC (42%), RNF43 (30%), SMAD4 (22%), and PIK3CA (21%), and in non-CRC: TP53 (52%), CDKN2A (32%), CDKN2B (20%) SMAD4 (17%) and MTAP (16%). Among tissue samples, MSI-H (30% vs 4.%, p &lt;0.001) and TMB-H ≥10 mut/MB (32% vs 6.7%, p &lt;0.001) were more frequent in BRAF alt CRC vs non-CRC. Conclusions: Meaningful differences were found between the groups in terms of demographics, frequency, and type of BRAF alt and co-occurring mutations. In particular, certain BRAF fusions were present in a higher proportion of other GI cancers and could be an important therapeutic target for this patient population.[Table: see text]

Long-term aspirin use and cancer risk: a 20-year cohort study.

Long-term use of aspirin has been shown to reduce colorectal cancer risk, but the association remains inconclusive for individual noncolorectal cancers. We examined the association between long-term aspirin use and cancer risk in Denmark. Using nationwide registries, we followed individuals aged 40-70 years at baseline (January 1, 1997) for cancer diagnoses through 2018. We assessed low-dose (75-150 mg) aspirin use according to continuity, duration, and cumulative amount. In addition, we explored associations with consistent high-dose (500 mg) aspirin use. Using Cox regression, we estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) with aspirin use for overall and site-specific cancer. Among 1 909 531 individuals, 422 778 were diagnosed with cancer during mean follow-up of 18.2 years. Low-dose aspirin use did not reduce the hazard ratio for cancer overall irrespective of continuity and duration of use (continuous use: HR = 1.04, 95% CI = 1.03 to 1.06). However, long-term (≥5 or ≥10 years) use was associated with at least 10% reductions in hazard ratios for several cancer sites: colon, rectum, esophagus, stomach, liver, pancreas, small intestine, head and neck, brain tumors, meningioma, melanoma, thyroid, non-Hodgkin lymphoma, and leukemia. Substantially elevated hazard ratios were found for lung and bladder cancer. In secondary analyses, consistent high-dose aspirin use was associated with reduced hazard ratios for cancer overall (HR = 0.89, 95% CI = 0.85 to 0.93) and for several cancer sites. Long-term low-dose aspirin use was associated with slight to moderately reduced risks for several cancers but not for cancer overall owing to increased risk for some common cancers. Similar or slightly stronger inverse associations were observed for consistent use of high-dose aspirin.

1062P Anti-PD1 efficacy in European patients with advanced MSI-H/MMRd non-colorectal cancers

1062P Anti-PD1 efficacy in European patients with advanced MSI-H/MMRd non-colorectal cancers

ALK, ROS1, RET and NTRK1-3 Gene Fusions in Colorectal and Non-Colorectal Microsatellite-Unstable Cancers.

This study aimed to conduct a comprehensive analysis of actionable gene rearrangements in tumors with microsatellite instability (MSI). The detection of translocations involved tests for 5'/3'-end expression imbalance, variant-specific PCR and RNA-based next generation sequencing (NGS). Gene fusions were detected in 58/471 (12.3%) colorectal carcinomas (CRCs), 4/69 (5.8%) gastric cancers (GCs) and 3/65 (4.6%) endometrial cancers (ECs) (ALK: 8; RET: 12; NTRK1: 24; NTRK2: 2; NTRK3: 19), while none of these alterations were observed in five cervical carcinomas (CCs), four pancreatic cancers (PanCs), three cholangiocarcinomas (ChCs) and two ovarian cancers (OCs). The highest frequency of gene rearrangements was seen in KRAS/NRAS/BRAF wild-type colorectal carcinomas (53/204 (26%)). Surprisingly, as many as 5/267 (1.9%) KRAS/NRAS/BRAF-mutated CRCs also carried tyrosine kinase fusions. Droplet digital PCR (ddPCR) analysis of the fraction of KRAS/NRAS/BRAF mutated gene copies in kinase-rearranged tumors indicated that there was simultaneous co-occurrence of two activating events in cancer cells, but not genetic mosaicism. CRC patients aged above 50 years had a strikingly higher frequency of translocations as compared to younger subjects (56/365 (15.3%) vs. 2/106 (1.9%), p = 0.002), and this difference was particularly pronounced for tumors with normal KRAS/NRAS/BRAF status (52/150 (34.7%) vs. 1/54 (1.9%), p = 0.001). There were no instances of MSI in 56 non-colorectal tumors carrying ALK, ROS1, RET or NTRK1 rearrangements. An analysis of tyrosine kinase gene translocations is particularly feasible in KRAS/NRAS/BRAF wild-type microsatellite-unstable CRCs, although other categories of tumors with MSI also demonstrate moderate occurrence of these events.

Oesogastric cancers and non-colorectal MSI cancers: immunotherapy goes from strength to strength

Oesogastric cancers and non-colorectal MSI cancers: immunotherapy goes from strength to strength

The role of surgery in the management of liver metastases from non-colorectal cancers: A review of the literature

Surgery for non-colorectal liver metastases is nowadays indicated due to advances in surgical techniques and patients multimodal management. The objective of our study is to evaluate the surgical management of liver metastases of non-colorectal cancers in the visceral surgery department of the Mohamed V military hospital in Rabat. This is a retrospective study on a series of 13 resections for non-colorectal liver metastases over a period of 6 years from January 2015 to December 2020. In our series, the average age is 53 years with a prevalence of women (62%). The primary cancer was ducal breast carcinoma 6 times (46.15%). There were 2 cases of stromal tumors (15.38%), 2 cases of neuroendocrine tumors (15.38%), one case of gastric adenocarcinoma, gastric small cell lymphoma, and of adrenocortical carcinoma. Liver metastases were synchronous in 76.92% of cases, metachronous in 23.08% of cases. They were unique in 84.62% of cases, bilobar in 15.38% of cases. The type of liver resection performed was 11 metastasectomy, 3 segmentectomy, 3 bi-segmentectomy. Mortality rate was zero and the morbidity rate was 15.38%. One patient had hepatic recurrence. With a follow-up of 3 to 36 months after resection, only one patient died after 12 months. The management of patients with non-colorectal liver metastases is based on a multimodal approach. Our results show that surgery, when feasible in selected patients, is a safe option and the only possibility for long-term survival. Future advances in chemotherapy, biotherapies and immunotherapy are likely to broaden the indications for surgery.

The differential response to immune checkpoint inhibitors (ICIs) according to mismatch repair alterations in gastrointestinal (GI) non-colorectal cancers (non-CRCs) and the impact of dual vs. monotherapy ICIs on survival in GI (CRC and non-CRC) cancers.

2620 Background: In patients with mismatch repair deficient (dMMR) colorectal cancers (CRCs), we previously reported that loss of expression of MSH2 and MSH6 (MutS co-loss) was associated with better response to ICIs and longer median overall survival (mOS) compared to loss of expression of MLH1 and PMS2 (MutL co-loss). Here, we expanded our analysis and included gastrointestinal (GI) non-CRCs and explored the impact of dual vs. monotherapy ICIs on mOS in GI (CRC and non-CRC) cancers. Methods: Specimens were profiled by next-generation sequencing (592, NextSeq; WES, WTS NovaSeq) (Caris Life Sciences, Phoenix, AZ). MMR/microsatellite instability (MSI) status was determined by immunohistochemistry (IHC) of MMR protein. Real world OS was extracted from insurance claims and calculated using Kaplan-Meier estimates for molecularly defined cohorts from first treatment with ICIs (Nivolumab, Nivo; Ipilumumab, ipi; or Pembrolizumab, pembro) to last contact. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q &lt; 0.05). Results: The GI non-CRC cohort (N= 19,767) included cancers of the esophagus, stomach, gastroesophageal junction, pancreas, bile duct and small bowel with 97 (0.49%) patients having MutS co-loss, and 494 (4.03%) patients having MutL co-loss. MutS co-loss was associated with increased KRAS (45.4% vs 25.2%, q&lt;0.01), CDKN2A (29.2% vs 9.0%), GNAS (27.8% vs 7.8%) and SMAD4 (17.5% vs 5.9%) mutations compared to MutL co-loss. Independent of treatment, MutS co-loss (N=74) had improved mOS compared to MutL co-loss (N=332) (40.4 m vs. 26.2 m, HR = 0.66; (95% CI: 0.46-0.95), P=0.024). In patients treated with ICIs, the mOS in MutS co-loss (N=21) was better compared to MutL co-loss (N=76) (not reached (NR) vs. 25.4 m, HR= 0.23 (95% CI: 0.07-0.75), p=0.008). At 3 years, more than 80% of the patients with MutS co-loss were alive. Of particular importance, when looking at all GI (CRC and non-CRC) patients, the mOS of MutL co-loss treated with ipi/nivo (N=18) trended for better mOS compared to MutL co-loss treated with pembro (N=215) (NR vs. 28.2m (HR=0.39; (95% CI:0.14-1.07), p=0.057), while the mOS of MutS co-loss treated with ipi/nivo (N=6) was not different compared to MutS co-loss treated with pembro (N=44) (NR vs. NR, HR=0.75 (95% CI: 0.094-5.92), p=0.78). Conclusions: In ICI-treated GI non-CRCs, the mOS was longer in MutS co-loss compared to MutL co-loss. In ICI-treated GI (CRC and non-CRC) patients with MutL co-loss, there was a trend for better survival with ipi/nivo compared to pembro. Our data suggest that the MutS vs. MutL status may guide the choice of ICIs regimen (Dual vs. Monotherapy) but more data are needed.

Analysis of Body Mass Index in Early and Middle Adulthood and Estimated Risk of Gastrointestinal Cancer

In a population with significantly increasing rates of individuals with overweight or obesity, understanding the association of obesity with long-term disease risk, such as cancer, is necessary to improve public health. To investigate the association between body mass index (BMI) and gastrointestinal (GI) cancer risk (colorectal cancer [CRC] and noncolorectal GI cancer) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. This retrospective cohort study was a secondary analysis of data from the PLCO Cancer Screening Trial. Participants aged 55 to 74 years were enrolled and randomized to the intervention (screening group) or control group at 10 screening centers between November 8, 1993, and July 2, 2001. The initial analysis of PLCO Cancer Screening Trial data occurred after 13 years of follow-up or December 31, 2009, whichever came first. Participants were reconsented in 2011 and either continued follow-up or refused additional follow-up. For those who reconsented, follow-up for incident cancers continued until December 31, 2014, or death, whichever occurred first. Data analysis for this secondary analysis was performed from April 2022 through November 2022. Body mass index and aspirin use, defined as the frequency of use of aspirin or aspirin-containing substances in the last 12 months. The primary outcomes were the diagnoses of CRC and noncolorectal GI cancer. The association between BMI and cancer (CRC and noncolorectal GI cancer) was assessed using Cox proportional hazards regression modeling. The association between cancer risk and change in BMI was further analyzed at different ages, and an exploratory analysis was performed to evaluate GI cancer risk among aspirin users. This analysis included 135 161 participants (median [range] age, 62 [55-78] years; 67 643 [50.0%] female). Overweight BMI in early adulthood (hazard ratio [HR], 1.23; 95% CI, 1.10-1.37) and overweight BMI in middle adulthood (HR, 1.23; 95% CI, 1.13-1.34) and later adulthood (HR, 1.21; 95% CI, 1.10-1.32) as well as obese BMI in middle adulthood (HR, 1.55; 95% CI, 1.38-1.75) and later adulthood (HR, 1.39; 95% CI, 1.25-1.54) were associated with increased risk of CRC. Similar results were observed for the association with overall GI and non-CRC GI risk and BMI in middle and later adulthood. Maintaining overweight or obese BMI or increasing BMI to overweight or obese in later adulthood was also associated with increased CRC risk. Aspirin use 3 or more times per week did not significantly modify this association. In this secondary analysis of the PLCO Cancer Screening Trial, overweight and obese BMI in early and middle adulthood was associated with an elevated risk of CRC and noncolorectal GI cancers. The results of the current study prompt further exploration into the mechanistic role of obese BMI in carcinogenesis.

The emerging role of circulating tumor DNA in non-colorectal gastrointestinal cancers.

Assays to detect circulating tumor DNA (ctDNA) have multiple clinically important applications in management of multiple types of gastrointestinal cancers. Different methodologies of ctDNA detection have varying sensitivities and potential applications in different contexts. For patients with localized cancers treated for curative intent, ctDNA detection is associated with prognosis in multiple cancer types, and persistent detection of ctDNA after surgical resection is highly concerning for minimal residual disease (MRD) and forebodes impending radiographic and clinical recurrence. CtDNA assays for comprehensive genomic profiling (CGPs) enable genotyping of cancers in the absence of tumor tissue data, and longitudinal testing can also characterize clonal evolution and emergence of putative resistance mechanisms upon treatment with targeted agents. These applications have proven instructive in patients with HER2-amplified gastric and esophageal cancers and in patients with FGFR2 fusion cholangiocarcinomas. In this review, we summarize data supporting the role of ctDNA as a novel predictive and prognostic biomarker and potential impacts on current management of patients with pancreatic, gastroesophageal, and hepatobiliary cancers.

Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Influence of splenic flexure mobilization on postoperative and oncological outcomes following anterior resection.

Splenic flexure mobilization (SFM) during anterior resection is often debated given its increased operative complexity and lack of clear data suggesting oncological benefit. This study aimed to compare postoperative complications and 3-year oncological outcomes in patients undergoing anterior resection with and without SFM. A retrospective single center observational study was performed. Notes review was performed for all patients undergoing anterior resection over a one-year period at a high-volume institution for sigmoid and rectal cancers. Anterior resections performed for benign disease or non-colorectal cancers were excluded. One hundred seventeen patients were included and 49 (41.9%) underwent SFM. 75 (64.1%) cases were completed laparoscopically and 48 (41%) resulted in stoma formation. SFM significantly increased the risk of minor Clavien Dindo Grade 1 postoperative complications (18.4% vs. . 5.9%, P=0.03), however, it had no impact on more major postoperative complications, including anastomotic leaks (4.2% vs. . 7.1%, P=0.52). There were no significant differences in median total lymph node yield (21.0% vs. . 21.1, P=0.57) or R0 resection margin (93.9% vs. . 94.1%, P=0.96). There was a non-significant trend towards lower overall recurrence rates in the SFM group (10.2% vs. . 19.1%, P=0.19). In patients undergoing anterior resection for colorectal cancer, SFM provides no clear oncological benefit, but does increase the likelihood of minor postoperative complications. Whilst a trend towards lower overall recurrence rates was observed in the SFM group, this was not statistically significant. Therefore, SFM should be carefully considered on a case-by-case basis.

Immunogenomic Biomarkers and Validation in Lynch Syndrome.

Lynch syndrome (LS) is an inherited disorder in which affected individuals have a significantly higher-than-average risk of developing colorectal and non-colorectal cancers, often before the age of 50 years. In LS, mutations in DNA repair genes lead to a dysfunctional post-replication repair system. As a result, the unrepaired errors in coding regions of the genome produce novel proteins, called neoantigens. Neoantigens are recognised by the immune system as foreign and trigger an immune response. Due to the invasive nature of cancer screening tests, universal cancer screening guidelines unique for LS (primarily colonoscopy) are poorly adhered to by LS variant heterozygotes (LSVH). Currently, it is unclear whether immunogenomic components produced as a result of neoantigen formation can be used as novel biomarkers in LS. We hypothesise that: (i) LSVH produce measurable and dynamic immunogenomic components in blood, and (ii) these quantifiable immunogenomic components correlate with cancer onset and stage. Here, we discuss the feasibility to: (a) identify personalised novel immunogenomic biomarkers and (b) validate these biomarkers in various clinical scenarios in LSVH.

Frequency and outcomes of BRAF alterations identified by liquid biopsy in metastatic non-colorectal gastrointestinal cancers.

808 Background: The impact of BRAF V600E, a known poor prognostic factor in metastatic colorectal cancer (CRC), has not been assessed broadly in non-CRC gastrointestinal (GI) cancers including pancreatic (PC), gastric/gastroesophageal (GC), hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In view of recent tumor-agnostic approval of a BRAF V600E inhibitor, it is important to determine the prevalence and impact of BRAF alterations on non-CRC GI cancer patients (pts). Methods: Genomic results from pts with PC, GC, HCC, or CCA tested with Guardant360 (G360, Guardant Health) as part of clinical care from June 2019 – June 2022 were retrospectively queried. Prevalence of characterized nonsynonymous BRAF genomic alterations (GA) was analyzed; differences between cancer types was assessed using the Chi-squared test. The GuardantINFORM database with aggregated commercial payer health claims and de-identified records from over 243,000 individuals with G360 results was used to derive real-world overall survival (rwOS), reported in months, calculated from diagnosis of metastatic cancer; differences between cancer types were compared using log-rank tests. Results: 23,069 patients were included: PC:49%; GC:24%; CCA:20%; HCC:6%. Pts were more likely to be male (p&lt;0.01). PC/HCC pts were tested more often at new diagnosis (vs at disease progression) than GC/CCA (p=0.02, p&lt;0.01, respectively). BRAF GAs were identified in 2.9%, comparable to tissue-based datasets (MSK-IMPACT: 2.4%); 21% of BRAF GAs were V600E (0.6% prevalence overall). PC/CCA pts were more likely to have BRAF GAs than the overall cohort (p&lt;0.01); they also had more BRAF V600E GAs (p&lt;0.01). rwOS differed by cancer type and BRAF status (Table). Notably, CCA pts with BRAF V600E had superior rwOS compared to CCA pts without BRAF findings (p=0.02). rwOS is not reported for HCC due to small n. Conclusions: Identification of BRAF GAs and V600E in the non-CRC GI population by liquid biopsy is similar to rates observed in tissue-based testing and may be reliably used to assess BRAF status. BRAF GAs and subtypes have mixed prognostic implications on survival for PC/CCA/GC patients that warrants further exploration. [Table: see text]

Genetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers

Acquired resistance to systemic treatments is inevitable in most cancers, but the genetic basis for this in many cancer types has remained elusive due to constraints in obtaining tissue specimens longitudinally. In the management of gastrointestinal cancers, molecular profiling is conventionally performed at a single time point, although serial evaluations may yield biological insights that inform treatment decisions. We characterize genetic changes in serial liquid biopsies which provide real-time snapshots of tumor genetics and heterogeneity in refractory non-colorectal gastrointestinal cancers, and determine the clinical utility of repeat circulating tumor DNA (ctDNA) testing. In a national cohort of 449 patients with pancreatic, biliary, esophagogastric, and hepatocellular cancers, resistance to conventional therapies is broadly associated with tumor evolution. Emergent ctDNA alterations only detectable at progression occurs in 63% of patients and are frequently associated with treatment actionability. Tumor mutation burden is dynamic in cancers undergoing treatment, but is not associated with time to progression. Objective tumor responses in a case series of patients receiving treatment matched to emergent alterations show that repeat liquid biopsies may have clinical benefit by expanding treatment options in advanced gastrointestinal cancers.