Microsatellite Stable Colon Cancer Research Articles

Clinical, pathological, and adjuvant chemotherapy use differences among microsatellite unstable and microsatellite stable colon cancers

BackgroundColon cancers are categorized into mismatch repair deficient/microsatellite unstable (MSI-H) and mismatch repair proficient/microsatellite stable (MSS) cancers. This study aims to compare the disease characteristics and trends in the utilization of cancer therapies across different age groups and stages in these two groups. MethodsMSI-H and MSS colon adenocarcinomas from 2010 to 2016 were identified using the National Cancer Database. We compared patient and disease characteristics between the two groups and evaluated the use of adjuvant chemotherapy across age groups and cancer stages. Within MSI-H and MSS groups, we conducted a landmark analysis after propensity score matching for adjuvant chemotherapy versus no chemotherapy to determine its effect on survival. ResultsOf the 542,368 patients that met inclusion criteria, 120,751 (22%) had mismatch repair results available—out of these 96,928 (80%) had MSS colon cancers while 23,823 (19.7%) had MSI-H cancers. MSI-H disease had a bimodal age distribution (<40 years = 22%; ≥75 years = 26%) and was frequent among females (22%) and non-Hispanic Whites (20%). Among those < 65 years, 15% of low-risk stage 2 MSI-H patients and 40% of high-risk stage 2 MSI-H patients received adjuvant chemotherapy. More than two-thirds of stage 3 patients <65 years received adjuvant chemotherapy in both groups. After conducting propensity-score matching for age, gender, and co-morbidities, we found that adjuvant chemotherapy use had a trend towards lower overall survival (OS) in low-risk stage 2 MSI-H (HR = 1.8 [95% CI, 0.8–4.02]) and high-risk stage 2 MSI-H (HR = 1.42 [95% CI, 0.96–2.12]) groups. Adjuvant chemotherapy significantly improved OS in stage 3 colon cancer patients irrespective of microsatellite status or risk category of disease. ConclusionsMSI-H colon cancer had bimodal age distribution. Among stage 2 MSI-H patients <65 years, a notable proportion received adjuvant chemotherapy. Among MSI-H stage 2 patients, adjuvant chemotherapy use was associated with lower survival while it significantly improved survival for stage 3 patients, irrespective of MSI status.

An invasion front gene expression signature for higher-risk patient selection in stage IIA MSS colon cancer.

Stage II colon cancer (CC) encompasses a heterogeneous group of patients with diverse survival experiences: 87% to 58% 5-year relative survival rates for stages IIA and IIC, respectively. While stage IIA patients are usually spared the adjuvant chemotherapy, some of them relapse and may benefit from it; thus, their timely identification is crucial. Current gene expression signatures did not specifically target this group nor did they find their place in clinical practice. Since processes at invasion front have also been linked to tumor progression, we hypothesize that aside from bulk tumor features, focusing on the invasion front may provide additional clues for this stratification. A retrospective matched case-control collection of 39 stage IIA microsatellite-stable (MSS) untreated CCs was analyzed to identify prognostic gene expression-based signatures. The endpoint was defined as relapse within 5 years vs. no relapse for at least 6 years. From the same tumors, three different classifiers (bulk tumor, invasion front, and constrained baseline on bulk tumor) were developed and their performance estimated. The baseline classifier, while the weakest, was validated in two independent data sets. The best performing signature was based on invasion front profiles [area under the receiver operating curve (AUC) = 0.931 (0.815-1.0)] and contained genes associated with KRAS pathway activation, apical junction complex, and heme metabolism. Its combination with bulk tumor classifier further improved the accuracy of the predictions.

ASO Visual Abstract: Lymph Node Metastases and Associated Recurrence-Free Survival in Microsatellite Stable and Unstable Colon Cancer.

ASO Visual Abstract: Lymph Node Metastases and Associated Recurrence-Free Survival in Microsatellite Stable and Unstable Colon Cancer.

Lymph Node Metastases and Associated Recurrence-Free Survival in Microsatellite Stable and Unstable Colon Cancer.

In contrast to microsatellite stable (MSS) colon cancer, predictors of lymph node metastases and their association with recurrence are not well-defined in microsatellite instability (MSI) colon cancer. A cohort of nonmetastatic colon cancer patients undergoing surgery between 2015 and 2021 were evaluated for predictors of lymph node metastases (LNMs) and their association with recurrence-free survival (RFS). Of 1466 patients included in the analyses, 361 (25 %) had MSI. Compared with MSS, MSI was associated with earlier stage, fewer LNMs in the patients with N1 or N2 disease, and fewer high-risk features. Compared with the T3-T4 MSS patients, the odds ratios for LNM were 0.52 (95% confidence interval [CI], 0.38-0.71) for the T3-T4 MSI patients, 0.27 (95% CI, 0.38-0.71) for the T1-T2 MSS patients, and 0.15 (95 % CI, 0.08-0.26) for the T1-T2 MSI patients. In both groups, LNMs were associated with T category, patient age, and venous, lymphatic, or perineural invasion. In the MSS patients, LNMs were additionally associated with patient sex and histologic grade. Compared with the MSS patients, the MSI patients with N0 and N1 disease had a better 3-year RFS. However, the MSI patients with N2 disease had a lower rate of 3-year RFS than the MSS patients (hazard ratio, 19.75 vs 4.49). In MSI colon cancer, LNMs are 50 % less prevalent, but the factors associated withLNM are like those in MSS colon cancer. The improved prognosis traditionally associated with early-stage MSI colon cancers dissipates with four or more LNMs. These findings should be taken into consideration by clinicians selecting the most appropriate course of treatment for MSI colon cancer.

Prognostic Value of Tumor Size in Colon Cancer-Smaller is Better?

The prognostic value of tumor size in colon cancer remains controversial. This study aimed to reveal the correlation between tumor size and prognosis of colon cancer. A total of 491 patients with colon cancer were included in this study. The correlation of tumor size with prognosis, mismatch repair status, and other clinicopathological characteristics as well as tumor microenvironment was analyzed. For stage IIA microsatellite stable (MSS) colon cancer, tumors sized <3.5cm and ≥5cm were associated with a poorer disease free survival (DFS) compared with tumors sized between 3.5 and 5cm (P = .002). Small tumor size (HR = 5.098, P = .001) and large tumor size (HR = 2.749, P = .029) were found to be independent prognostic factors for stage IIA MSS colon cancer. Moreover, high expression of transgelin (TAGLN), a marker of cancer-associated fibroblasts (CAFs), was found to be an independent prognostic factor for poorer DFS (HR = 9.651, P = .009), which was also associated with smaller tumor size (P = .027). Small (<3.5cm) and large (≥5cm) tumor sizes are associated with decreased DFS in stage IIA MSS colon cancer. Enrichment of TAGLN+ CAFs is associated with decreased DFS and small tumor size.

Identification of a Twelve-microRNA Signature with Prognostic Value in Stage II Microsatellite Stable Colon Cancer.

We aimed to identify and validate a set of miRNAs that could serve as a prognostic signature useful to determine the recurrence risk for patients with COAD. Small RNAs from tumors of 100 stage II, untreated, MSS colon cancer patients were sequenced for the discovery step. For this purpose, we built an miRNA score using an elastic net Cox regression model based on the disease-free survival status. Patients were grouped into high or low recurrence risk categories based on the median value of the score. We then validated these results in an independent sample of stage II microsatellite stable tumor tissues, with a hazard ratio of 3.24, (CI95% = 1.05-10.0) and a 10-year area under the receiver operating characteristic curve of 0.67. Functional analysis of the miRNAs present in the signature identified key pathways in cancer progression. In conclusion, the proposed signature of 12 miRNAs can contribute to improving the prediction of disease relapse in patients with stage II MSS colorectal cancer, and might be useful in deciding which patients may benefit from adjuvant chemotherapy.

Long-Term Response to Sintilimab, Bevacizumab and Chemotherapy in Heavily Pretreated Microsatellite Stable Colon Cancer

Most advanced colorectal cancer patients with proficient DNA mismatch repair or microsatellite stability (MSS) are insensitive to immune checkpoint inhibitor therapy. This report describes a heavily pretreated refractory colon adenocarcinoma patient with MSS. After experiencing four lines of treatment, the patient received the fifth-line therapy with the combined sintilimab, bevacizumaband chemotherapy. She achieved a long-term clinical outcome. The patient's progression-free survival after the fifth-line therapy was approximately 9.3months, and her overall survival was approximately 57months. To the best of our knowledge, this case represents the first report of durable clinical benefit from combination of animmune checkpoint inhibitor, bevacizumab and chemotherapy in a heavily pretreated patient with refractory metastatic colon adenocarcinoma with MSS.

Interference with pathways activated by topoisomerase inhibition alters the surface expression of PD-L1 and MHC I in colon cancer cells.

Topoisomerase inhibitors are clinically used to treat various cancer types, including colorectal cancer. These drugs also activate signaling pathways that modulate cell survival and immune cell functions. Immunotherapy is promising for certain tumors, including microsatellite instable colorectal cancer, but not for microsatellite stable colorectal cancer. The reasons for this lack of responsiveness are largely unknown. Understanding how colorectal cancer cell-surface proteins interact with tumor-resident immune cells may offer an opportunity to identify molecules that, if targeted, may render tumor cells visible to immune cells. The present study used flow cytometry, fluorescent staining and immunoblotting to examine if inhibition of pathways activated by topoisomerase-targeting drugs may modulate the outcomes of treatment through effects on cell cycle arrest and apoptosis, and by altering surface expression levels of programmed death-ligand 1 (PD-L1) or major histocompatibility complex protein I (MHC I). Inhibition of either NF-κB or DNA-damage response (DDR) potently enhanced cell death in combination with topoisomerase inhibition, while only NF-κB inhibition increased MHC I. PD-L1 upregulation was moderately affected by NF-κB or DDR inhibitors, while both topoisomerase inhibitors and DNA damaging agents may enhance the surface expression of MHC I molecules on colon cancer cells. Such enhanced expression of MHC I may be suppressed by inhibitors of ataxia-telangiectasia mutated or checkpoint kinase kinases. Additionally, adaptive tolerance to topoisomerase inhibition caused altered cell cycle response, and reduced the expression levels of both PD-L1 and MHC I on both microsatellite instable and stable colon cancer cell lines. Therefore, targeted modulation of DDR pathways, PD-L1, MHC I or other immune regulators in colon cancer cells may make them more visible to immune cells and enable rational combination of conventional therapy with immunotherapy.

Overexpression of satellite RNAs in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells

Overexpression of satellite RNAs in heterochromatin induces chromosomal instability (CIN) through the DNA damage response and cell cycle checkpoint activation. Although satellite RNAs may be therapeutic targets, the associated mechanisms underlying drug sensitivity are unknown. Here, we determined whether satellite RNAs reflect drug sensitivity to the topoisomerase I inhibitor camptothecin (CPT) via CIN induction. We constructed retroviral vectors expressing major satellite and control viruses, infected microsatellite stable mouse colon cancer cells (CT26) and MC38 cells harboring microsatellite instability, and assessed drug sensitivity after 48 h. Cells overexpressing satellite RNAs showed clear features of abnormal segregation, including micronuclei and anaphase bridging, and elevated levels of the DNA damage marker γH2AX relative to controls. Additionally, overexpression of satellite RNAs enhanced MC38 cell susceptibility to CPT [half-maximal inhibitory concentration: 0.814 μM (control) vs. 0.332 μM (MC38 cells with a major satellite), p = 0.003] but not that of CT26. These findings imply that MC38 cells, which are unlikely to harbor CIN, are more susceptible to CIN-induced CPT sensitivity than CT26 cells, which are characterized by CIN. Furthermore, CPT administration upregulated p53 levels but not those of p21, indicating that overexpression of major satellite transcripts likely induces CPT-responsive cell death rather than cellular senescence.

LIGHT enhanced bispecific antibody armed T-cells to treat immunotherapy resistant colon cancer

Increased tumor infiltrating lymphocytes (TIL) are associated with improved patient responses to immunotherapy. As a result, there is interest in enhancing lymphocyte trafficking particularly to colon cancers since the majority are checkpoint blockade-resistant and microsatellite stable. Here, we demonstrate that activated T-cells (ATC) armed with anti-CD3 x anti-EGFR bispecific antibody increases TIL and mediate anti-tumor cytotoxicity while decreasing tumor cell viability. Furthermore, treatment induces endogenous anti-tumor immunity that resisted tumor rechallenge and increased memory T-cell subsets in the tumor. When combined with targeted tumor expression of the tumor necrosis factor superfamily member LIGHT, activated T-cell proliferation and infiltration were further enhanced, and human colorectal tumor regressions were observed. Our data indicate that tumor-targeted armed bispecific antibody increases TIL trafficking and is a potentially potent strategy that can be paired with combination immunotherapy to battle microsatellite stable colon cancer.SignificanceEnhancing trafficking of tumor infiltrating lymphocytes (TILs) to solid tumors has been shown to improve outcomes. Unfortunately, few strategies have been successful in the clinical setting for solid tumors, particularly for “cold” microsatellite stable colon cancers. In order to address this gap in knowledge, this study combined TNFSF14/LIGHT immunomodulation with a bispecific antibody armed with activated T-cells targeted to the tumor. This unique T-cell trafficking strategy successfully generated anti-tumor immunity in a microsatellite stable colon cancer model, stimulated T-cell infiltration, and holds promise as a combination immunotherapy for treating advanced and metastatic colorectal cancer.

Hypothesis: Mutations and Immunosurveillance in Obesity-Associated Colorectal Cancer.

Tumorigenesis typically requires the accumulation of several driver gene mutations; therefore, there is a mutation threshold for the completion of the neoplastic process. Obesity increases the risk of cancer, and we have proposed that one mechanism whereby obesity raises the risk of microsatellite stable (MSS) colon cancer is by decreasing the mutation threshold. Therefore, obese MSS colon cancer patients should exhibit fewer driver gene mutations compared to normal body-mass index (BMI) patients. Our hypothesis is supported by results from analyses of The Cancer Genome Atlas (TCGA) data, which revealed that cancer genomes of obese MSS colon patients exhibit both fewer somatic mutations and fewer driver gene mutations. These findings could be explained by the high levels of obesity-associated cytokines and factors, the signaling pathways of which substitute for the additional driver gene mutations detected in normal-weight MSS colon cancer patients. Therefore, obesity-induced aberrant cell signaling might cooperate with initiating driver gene mutations to promote neoplastic development. Consistent with this possibility, we observed a lower number of KRAS mutations in high-BMI MSS colon cancer patients. This paper extends our hypothesis to address the interactions between obesity, immune surveillance in neoplastic development, and colorectal cancer (CRC) risk. A better understanding of these interactions will inform future preventive and therapeutic approaches against MSS CRC. We propose that the individual variations in the major histocompatibility class 1 (MHC-1) genotype interact with obesity to shape the tumor mutational landscape. Thus, the efficiency of the immune surveillance mechanisms to select against specific mutations may depend on both the MHC-1 genotype variant and the BMI of an individual. A high BMI is expected to reduce the number of driver gene mutations required to evade the MHC-1 surveillance mechanism and support an accelerated cancer progression.

The role of inflammatory parameters in predicting disease recurrence in patients with stage IIA colon cancer with no high-risk features

ABSTRACT Objective We aimed to investigate the roles of inflammatory parameters, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and C-reactive protein/albumin ratio (CAR), in predicting disease recurrence in patients with stage IIA (T3N0M0) high microsatellite instability and microsatellite-stable colon cancer who had no risk factors associated with relapse. Materials and methods We evaluated 155 patients with colon cancer followed in 3 hospitals in Turkey between February 2009 and March 2020. These patients had stage IIA disease and had no risk factors associated with relapse. None of the patients received adjuvant chemotherapy. NLR, PLR, LMR, and CAR parameters were retrospectively obtained from laboratory results at the time of diagnosis, and their associations with disease recurrence were assessed. Results Over a median follow-up period of 38 months (range: 4–98 months), 11 of the 155 patients experienced relapse or developed metastases. Multivariate Cox analyses revealed that NLRs of ≥3.12 (hazard ratio [HR]: 0.041, 95% confidence interval [CI]: 0.048–0.826, p = 0.006) and CARs of ≥0.027 (HR: 0.199, 95% CI: 0.004–0.404, p = 0.026) were independent prognostic markers predicting relapse. The median 5-year recurrence-free survival rate of patients with NLRs of ≥3.12 at the time of diagnosis was 88.0%; this rate was 100% in patients with NLRs of <3.12 (p < 0.001). Similarly, the median 5-year recurrence-free survival rate of patients with CARs of ≥0.027 at the time of diagnosis was 84.7%; this rate was 95.7% in patients with CARs of <0.027 (p = 0.016). Conclusion In this study, NLR and CAR were found to be independent prognostic markers predicting disease recurrence in patients with stage IIA colon cancer who did not receive adjuvant chemotherapy due to low clinical risk.

Brief Research Report Regional Difference in TRAF2 and TRAF3 Gene Mutations in Colon Cancers.

TRAF2 and TRAF3 genes of tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family are involved in diverse cell signaling, and function as both tumor suppressor gene and oncogene. Alterations of TRAF2 and TRAF3 in colon cancer (CC) along with their regional difference and microsatellite instability (MSI) are largely unknown. In the present study, we analyzed TRAF2 and TRAF3 frameshift mutations in 168 sporadic CCs (100 high MSI (MSI-H) and 68 microsatellite-stable (MSS) CCs). We identified TRAF2 and TRAF3 frameshift mutations in 4 (4%) and 3 CCs (3%) with MSI-H, respectively, but none in 68 cases of MSS CCs. Of the 168 CCs, we analyzed the mutations in multi-regions for 39 CCs (16 MSI-H and 23 MSS CCs), and discovered that 12.5% (2/16) and 6.3% (1/16) of MSI-H CCs exhibited regional difference in TRAF2 and TRAF3 mutations, respectively. In the multi-region samples of 23 MSS CCs, neither TRAF2 nor TRAF3 frameshift mutation was found. In 40% of CCs, both TRAF2 and TRAF3 expressions were increased compared to normal colon cells. Our data indicate that TRAF2 and TRAF3 frameshift mutations and their regional difference as well as altered expressions are present in MSI-H CCs, which could contribute to MSI-H cancer development.

Combination Immunotherapy With LIGHT and Interleukin-2 Increases CD8 Central Memory T-Cells In Vivo

BackgroundThe generation of long-term durable tumor immunity and prolonged disease-free survival depends on the ability to generate and support CD8+ central memory T-cells. Microsatellite-stable colon cancer is resistant to currently available immunotherapies; thus, development of novel mechanisms to increase both lymphocyte infiltration and central memory formation are needed to improve outcomes in these patients. We have previously demonstrated that both interleukin-2 (IL-2) and LIGHT (TNFSF14) independently enhance antitumor immune responses and hypothesize that combination immunotherapy may increase the CD8+ central memory T-cell response. MethodsMurine colorectal cancer tumors were established in syngeneic mice. Tumors were treated with control, soluble, or liposomal IL-2 at established intervals. A subset of animal tumors overexpressed tumor necrosis superfamily factor LIGHT (TNFSF14). Peripheral blood, splenic, and tumor-infiltrating lymphocytes were isolated for phenotypic studies and flow cytometry. ResultsTumors exposed to a combination of LIGHT and IL-2 experienced a decrease in tumor size compared with IL-2 alone that was not demonstrated in wild-type tumors or between other treatment groups. Combination exposure also increased splenic central memory CD8+ cells compared with IL-2 administration alone, while not increasing tumor-infiltrating lymphocytes. In the periphery, the combination enhanced levels of circulating CD8 T-cells and central memory T-cells, while also increasing circulating T-regulatory cells. ConclusionsCombination of IL-2, whether soluble or liposomal, with exposure to LIGHT results in increased CD8+ central memory cells in the spleen and periphery. New combination immunotherapy strategies that support both effector and memory T-cell functions are critical to enhancing durable antitumor responses and warrant further investigation.

Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer.

Understanding molecular features of colon cancer has shed light on its pathogenesis and progression. Over time, some of these features acquired clinical dignity and were incorporated in decision making. Namely, microsatellite instability (MSI) due to mismatch repair of defects, which primarily was adopted for the diagnosis of Lynch syndrome, became recognized as the biomarker of a different disease type, showing a less aggressive behavior. MSI tumors harbor high amounts of tumor infiltrating lymphocytes (TILs) due to their peculiar load in neoantigens. However, microsatellite stable colon cancer may also show high amounts of TILs, and this feature is as well associated with better outcomes. High TIL loads are in general associated with a favorable prognosis, especially in stage II colon cancer, and therein identifies a patient subset with the lowest probability of relapse. With respect to post-surgical adjuvant treatment, particularly in stage III, TILs predictive ability seems to weaken along with the progression of the disease, being less evident in high risk patients. Moving from cohort studies to the analysis of a series from clinical trials contributed to increase the robustness of TILs as a biomarker. The employment of high TIL densities as an indicator of good prognosis in early-stage colon cancers is strongly advisable, while in late-stage colon cancers the employment as an indicator of good responsiveness to post-surgical therapy requires refinement. It remains to be clarified whether TILs could help in identifying those patients with node-positive cancers to whom adjuvant treatment could be spared, at least in low-risk groups as defined by the TNM staging system.

Coexistence of Microsatellite Stable (MSS) and Instable Colorectal Cancer (CRC) Primary Colon Cancers: A Case Report and Brief Review of Literature

Abstract Introduction/Objective Microsatellite stable (MSS) and Instable colorectal cancer (CRC) as primary colon cancers differ in their pathological features and biological behavior including response to treatment. In general, MSI-high CRC has a better prognosis and a more favorable response to treatment. To our knowledge, the co-occurrence of the microsatellite stable and unstable CRCs in the same person has not been reported in the literature. Herein, we present the case report of 78 year African American female who presented to us with this condition. Methods A literature search of publication up to March 2020 in PubMed was conducted on the occurrence of microsatellite stable and unstable CRCs in the same individual. The literature search was limited to English language only. The following words were used in the search engine of PubMed: “Microsatellite stable colorectal cancer + unstable colorectal cancer and colorectal cancer + same patient”. No articles were identified. Results A search using the terms “coexistence of MSS and MSI CRC in the same individual” identified 45 articles. No case report or article discussing the presence of coexisting MSS and MSI CRC in the same individual was identified Conclusion Identification of MSI CRC is important, as MSI may serve as a screening tool for detecting Lynch Syndrome, a prognostic marker for patient outcome, and as a predictive marker for response to chemotherapy and to immunotherapy. Whether coexistence of MSI and MSS favorably affects the prognosis of the disease is unknown.

Adoption of Immune Checkpoint Inhibitors and Patterns of Care at the End of Life.

As immune checkpoint inhibitors (ICIs) have transformed the care of patients with cancer, it is unclear whether treatment at the end of life (EOL) has changed. Because aggressive therapy at the EOL is associated with increased costs and patient distress, we explored the association between the Food and Drug Administration (FDA) approvals of ICIs and treatment patterns at the EOL. We conducted a retrospective, observational study using patient-level data from a nationwide electronic health record-derived database. Patients had advanced melanoma, non-small-cell lung cancer (NSCLC; cancer types with an ICI indication), or microsatellite stable (MSS) colon cancer (a cancer type without an ICI indication) and died between 2013 and 2017. We calculated annual proportions of decedents who received systemic cancer therapy in the final 30 days of life, using logistic regression to model the association between the post-ICI FDA approval time and use of systemic therapy at the EOL, adjusting for patient characteristics. We assessed the use of chemotherapy or targeted/biologic therapies at the EOL, before and after FDA approval of ICIs using Pearson chi-square test. There was an increase in use of EOL systemic cancer therapy in the post-ICI approval period for both melanoma (33.9% to 43.2%; P < .001) and NSCLC (37.4% to 40.3%; P < .001), with no significant change in use of systemic therapy in MSS colon cancer. After FDA approval of ICIs, patients with NSCLC and melanoma had a decrease in the use of chemotherapy, with a concomitant increase in use of ICIs at the EOL. The adoption of ICIs was associated with a substantive increase in the use of systemic therapy at the EOL in melanoma and a smaller yet significant increase in NSCLC.

The adoption of immune checkpoint inhibitors and patterns of care at the end of life.

12027 Background: As immune checkpoint inhibitors (ICIs) have transformed the care of patients with cancer, it is unclear whether treatment at end of life (EOL) has changed. Because aggressive therapy at EOL is associated with increased costs and patient distress, we explored the association between the FDA approvals of ICIs and treatment patterns at EOL. Methods: We conducted a retrospective, observational study using patient-level data from the Flatiron health EHR-derived de-identified database. Patients had advanced melanoma, non-small cell lung cancer (NSCLC) (cancer types with an ICI indication) or microsatellite stable (MSS) colon cancer (a cancer type without an ICI indication) and died between 2013 and 2017. We calculated annual proportions of decedents who received systemic cancer therapy in the final 30 days of life and used logistic regression to model the association between the post-ICI Federal Drug Administration (FDA) approval time period and use of systemic therapy at EOL, adjusting for patient characteristics. We also assessed the use of chemotherapy or targeted/biologic therapies at EOL, before and after FDA approval of ICIs using Pearson Chi Square test. Results: There was an increase in use of EOL systemic cancer therapy in the post-ICI approval period for both melanoma (33.9% to 43.2%, p-value &lt; 0.001) and NSCLC (37.4% to 40.3%, p-value &lt; 0.001). In contrast, the control group of decedents with MSS colon cancer demonstrated no significant increase in use of systemic therapy at EOL. After controlling for patient characteristics, there was a significantly higher odds of receiving systemic treatment at EOL in the post-ICI time period compared to the pre-ICI time period in melanoma (OR 1.42, 95% CI 1.09-1.86, p-value &lt; 0.001) and NSCLC (OR 1.13, 95% CI 1.06-1.20, p value &lt; 0.001), with no significant difference in receipt of systemic therapy in patients with MSS colon cancer. After FDA approval of ICIs, patients with NSCLC and melanoma had a decrease in the use of chemotherapy, with a concomitant increase in use of ICIs at EOL. Decedents with MSS colon cancer did not have a statistically significant change in use of chemotherapy or targeted/biologic therapies during the study period. Conclusions: The adoption of ICIs was associated with a substantive increase in the use of systemic therapy at EOL in melanoma, and a smaller yet significant increase in NSCLC.

Impact of tumor side on clinical outcomes in stage II and III colon cancer with known microsatellite instability status.

4068 Background: Microsatellite instability high (MSI-H) status indicates better prognosis in early stage colon cancer (CC) compared to microsatellite stable (MSS). However, the impact of tumor side, left side (L) versus right side (R), is not described on clinical outcomes based on MSI status. Methods: Patients with pathological stage II and III primary adenocarcinoma of the colon between 2010 and 2015 were identified in the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8140-47, 8210-11, 8220-21, 8260-63, 8480-81, 8490 and C18.0, 18.2,18.3, 18.5,18.6, 18.7. Univariate (UVA) and multivariable (MVA) survival analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on tumor location and treatment received with Log-rank test. Results: A total of 35,071 patients with stage II (n = 17,629) and III (n = 17,442) CC were identified. 51.3% female; 81.5% Caucasian; median age 66 (range, 18-90). Majority of stage II and III tumors were R, 61.2% (n = 10,794) and 56.0% (n = 9,763). MSI-H was more common in stage II compared to III, 23.3% (n = 4,115) vs 18.2% (n = 3,171) (p &lt; 0.0001). Survival was better in stage II MSI-H compared to MSS, 5 year-OS 75.1% vs 71.8% (p = 0.0057). However, stage III CC survival was better in MSS compared to MSI-H, 5-year OS 60.5% vs 58.0% (p &lt; 0.001). In stage II MSI-H CC R was more common than left, 78.3 % (n = 3223) vs 21.7% (n = 892). There was no significant difference in survival between stage II MSI-H L vs R (5-year OS 76.2% vs 74.7%, p = 0.1578). Stage II MSS CC R was more common than L, 56.0% (n = 7571) vs 44.0% (n = 5943), and survival was better in L vs R (5-year OS 73.2% vs 70.8%, p = 0.0029). Stage III MSI-H CC was more common in R than L, 75.6% (n = 2397) vs 24.4% (n = 774) and survival was better in L (5-year OS 62.5% vs 56.5%, p = 0.0026). Stage III MSS CC was more common in R than L, 51.6% (n = 7366) vs 48.4% (n = 6905), and survival was better in L vs R (5-year OS 67.0% vs 54.4%, p &lt; 0.001). Conclusions: Survival was better in left sided tumors compared to right in stage II MSS, stage III MSS and stage III MSI-H CC.

The mutation of homologous recombination repair genetics is a potential biomarker for immunotherapy in microsatellite stable colon cancer.

4076 Background: Patients with microsatellite instability-high (MSI-H) colonic adenocarcinoma (COAD) are always immunotherapy-sensitive for the use immune checkpoint inhibitors, however, the vast majority of COAD patients (85%) are microsatellite stable (MSS). Homologous recombination deficiency (HRD) is demonstrated to be a response predictor to immunotherapies in gynecologic cancers, while limited studies were reported in colon cancer. We focus herein on the mutational pattern of HRR related genes in a large Chinese COAD cohort and further analyze the relationship between HRR-gene mutations and clinical response to immunotherapy in MSS COAD. Methods: The genomic profiling of Genecast cohort which is consisted of 406 Chinese patients with COAD were analyzed in a panel of 543 cancer related genes via next generation sequencing (NGS). The correlation between HRR-gene mutations and tumor immunity or clinical outcome using two COAD genomics datasets (TCGA and MSK-COAD) by the bioinformatic approach. Results: In Genecast Cohort, seventy of 406 (17.2%) patients were identified genomic alterations in HRR-gene, the most frequently mutated genes were ATM (9%), BRCA2 (4%), ATR (3%), RAD50 (3%) and BRIP1 (3%). In MSK-COAD cohort (treated with immune checkpoint inhibitors), HRR-mut group (n = 34) had a significantly better OS than HRR-wt group (n = 50) (log-rank test, P = 0.0087). From the analysis of TCGA cohort, we found that mutations of HRR-gene could increase immune activity in MSS COAD, including increased cytotoxic cells infiltration ( P = 0.035), increased exhausted CD8 T cells infiltration ( P = 0.0098) and higher IFN-g score ( P = 0.03). In contrary, similar results were not found in MSI-H COAD (all P &gt; 0.05). Conclusions: Mutations of HRR-gene could significantly increase immune activity in patients with MSS COAD, implying the feasibility of using HRR-mut as a response predictor of immunotherapy in MSS-COAD.