Nonoperative Management of dMMR/MSI-H Colorectal Cancer following Neoadjuvant Immunotherapy: A Narrative Review.

Immunotherapy with PD-1 blockade has achieved a great success in colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR), and has become the first-line therapy in metastatic setting. Studies of neoadjuvant immunotherapy also report exciting results, showing high rates of clinical complete response (cCR) and pathological complete response. The high efficacy and long duration of response of immunotherapy has prompt attempts to adopt watch-and-wait strategy for patients achieving cCR following the treatment. Thankfully, the watch-and-wait approach has been proposed for nearly 20 years for patients undergoing chemoradiotherapy and has gained ground among patients as well as clinicians. In this narrative review, we combed through the available information on immunotherapy for CRC and on the watch-and-wait strategy in chemoradiotherapy, and looked forward to a future where neoadjuvant immunotherapy as a curative therapy would play a big part in the treatment of MSI-H/dMMR CRC.

Salvage Treatment Using Anti-PD-1/CTLA-4 Immunotherapy After Failure of Neoadjuvant Chemotherapy in Microsatellite Instable Gastroesophageal Carcinoma.

Perioperative chemotherapy is standard treatment for patients with early high-risk gastroesophageal adenocarcinoma independent of molecular subtype. Approximately 8% of gastroesophageal cancers have a microsatellite instable phenotype (MSI-H), and retrospective analyses of neoadjuvant/adjuvant chemotherapy trials suggests no survival benefit in this patient population compared with surgery alone. Patients with advanced MSI-H malignancies obtain durable responses with immunotherapy using anti-programmed cell death protein 1 (PD-1) checkpoint blockade. We describe a case of a patient with an early MSI-H gastroesophageal adenocarcinoma who progressed on neoadjuvant chemotherapy precluding subsequent surgical resection. The patient was subsequently treated with immunotherapy using the anti-PD-1 antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab leading to a complete remission with biopsies of the residual tumor mass and regional lymph nodes revealing no residual tumor. This case highlights the lack of benefit from neoadjuvant chemotherapy in patients with MSI-H gastroesophageal cancers and suggests that perioperative anti-PD-1-based immunotherapy should be further investigated in this patient population. KEY POINTS: This report describes the successful salvage treatment of a patient with an early high-risk MSI-H gastroesophageal carcinoma who progressed through neoadjuvant chemotherapy using combination immunotherapy of the anti-programmed cell death protein 1 (PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab, leading to an ongoing complete remission. The case is in keeping with retrospective analyses of perioperative treatment trials demonstrating a lack of chemotherapy benefit in patients with MSI-H gastroesophageal carcinoma and supports the further investigation of anti-PD-1-based immunotherapy as a treatment modality in this patient population. The case highlights the potential difficulties that may be encountered in the surgical management of patients treated with neoadjuvant immunotherapy with reactive dense fibrotic changes precluding surgical resection.

Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability.

Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8 and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion and vascular invasion (p < 0.05), and with early-stage adenocarcinoma and high budding grade (p < 0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (p < 0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front.

Outcome of Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Mayo Clinic Experience.

BACKGROUND: Deficiencies in the DNA mismatch repair system cause errors during DNA replication, which in turn give rise to microsatellite instability (MSI). The impact of MSI on survival in metastatic colorectal cancer (mCRC) is unclear. This cohort study aims to investigate the prognostic and predictive value of MSI in mCRC prior to the immune therapy era. MATERIALS AND METHODS: A total of 75 MSI-high (MSI-H) mCRC patients (pts) and 75 matched (age, gender, disease sidedness, metachronous/synchronous) microsatellite-stable (MSS) mCRC pts were identified from 1,268 mCRC pts who had MSI/mismatch repair test results at Mayo Clinic Rochester between January 1992 and July 2016. A retrospective review was conducted by using data from electronic medical records. Statistical analyses utilized the Kaplan-Meier method, log-rank test, and Cox proportional hazards models. RESULTS: The MSS group was well matched to the MSI-H group based on age, gender, location, and chronicity of metastatic disease. MSI-H mCRC pts had earlier disease recurrence (median time from initial diagnosis to metastatic disease diagnosis, MSI-H group 12.9 vs. MSS group 20.9 months, p = .034). Median overall survival (OS) was 28.1 and 37.4 months for MSI-H and MSS pts, respectively (p = .99). In total, 94.7% of MSI-H pts and 98.7% of MSS pts had fluoropyrimidine-based chemotherapy for metastatic disease, and there was no difference in OS between these two groups (32.3 vs. 37.4 months, p = .91). Forty-three MSI-H and thirty-nine MSS pts had metastasectomy and/or ablation of metastases (p = .51) with longer median OS compared with pts without metastasectomy (MSI-H: 82.0 vs. 13.9, p < .001; MSS: 69.9 vs. 19.7, p < .001). Age <65 years, BRAF wild type, and metastasectomy were associated with better OS in univariate analysis. Only metastasectomy remained statistically significant in multivariate analysis (p < .001). CONCLUSION: In mCRC, patients with MSI-H tumors have similar, but numerically shorter, median overall survival compared with those with MSS tumors. In both groups, metastasectomy and ablation of metastatic disease should be considered to optimize OS. IMPLICATIONS FOR PRACTICE: This study clearly demonstrated the survival benefits that aggressive metastasectomy provides in selected microsatellite instability-high metastatic colorectal cancer patients. This could be meaningful practice-changing information that has been long awaited.

Dedifferentiated carcinoma with clear cell carcinoma of the endometrium: A case report.

Endometrial dedifferentiated carcinoma consists of a combination of undifferentiated and differentiated carcinomas. To date, clear cell carcinoma components in endometrial dedifferentiated carcinoma have not been reported. We report the first case of endometrial dedifferentiated carcinoma with clear cell carcinoma in a 58-year-old woman. The uterine corpus was completely replaced and enlarged by a heterogeneous mass. The endometrial cut surface showed a yellowish papillary growing mass involving endometrium and deeper myometrium. Microscopically, the three components (endometrioid carcinoma, FIGO grade 1, clear cell carcinoma and undifferentiated carcinoma) were noted with differentiated carcinoma components lining the endometrial cavity, while undifferentiated carcinoma components were identified in deeper endometrium and myometrium. Our histologic diagnosis was supported by the pattern of immunoreactivity. Tumor cells showed loss of expression of MLH1/PMS2 protein and displayed high microsatellite-instability in all three components. Furthermore, all three components including clear cell carcinoma had loss of PTEN and ARID1A expression. Our observations suggest that the three components derived from a monoclonal origin, as the three components had in common specific genetic alterations.

Efficacy and challenges of anti-PD1 in MSI-H mCRC: a case report on concurrent infections and ir-AIHA.

Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated notable efficacy in treating patients with deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) metastatic colorectal cancer (mCRC). However, its clinical application is fraught with challenges and can lead to significant immune-related adverse events (ir-AEs). In this report, we present a complicated case of an mCRC patient with MSI-H and mutations in ß2M and LRP1B proteins, complicated by concurrent bacteremia and liver fluke infection, who received first-line anti-PD1 therapy. The patient exhibited a positive response to anti-PD1 treatment, even in the presence of concomitant antibiotic and anti-parasitic interventions. Additionally, the patient experienced immunotherapy-related autoimmune hemolytic anemia (ir-AIHA), a rare hematological ir-AE, which was effectively treated later on. Immunotherapy represents a pivotal and highly effective approach to tumor treatment. Baseline assessment of the MMR and MSI status is a crucial step before initiating immunotherapy, and regular ongoing assessments during the treatment course can facilitate early recognition of any secondary complications, enabling prompt intervention and ensuring optimal therapeutic outcomes. Overall, a multidisciplinary diagnostic and therapeutic algorithm can help maximize the therapeutic benefits of immunotherapy.

Advanced Appendiceal Cancer with Systematic Metastasis without Gastrointestinal Symptoms Found by Subcutaneous Tumor.

An 86-year-old woman with a subcutaneous nodule in her left axilla visited our hospital. She had no gastrointestinal symptoms, but contrast-enhanced computed tomography revealed a cecal mass and systemic metastasis, including cutaneous, bone, peritoneal dissemination and ascites. Colonoscopy revealed a circumferential, elevated cecal lesion. She underwent right hemicolectomy to prevent colon obstruction. The pathological diagnosis was poorly differentiated adenocarcinoma (por1>tub2>muc) arising from the appendix with a BRAFV600E mutation and microsatellite instability-high. Chemotherapy was administered, and she is currently still alive and undergoing chemotherapy. We describe a rare case of advanced appendiceal cancer without gastrointestinal symptoms diagnosed due to cutaneous metastasis.

Circulating Tumor DNA Testing Overcomes Limitations of Comprehensive Genomic Profiling from Tumor Tissue.

"Liquid biopsy" is an established technique for examining circulating tumor DNA (ctDNA) from a routine blood draw and detecting actionable biomarkers. Nonetheless, ctDNA testing is rarely utilized for patients with newly diagnosed metastatic colorectal cancer (CRC). We report a case in which ctDNA testing uncovered an actionable biomarker that was not detected by comprehensive genomic profiling of tumor tissue. An 81-year-old woman with a remote history of non-Hodgkin's lymphoma presented with primary masses in the ascending colon and sigmoid colon. The ascending colon and sigmoid colon tumors were classified as microsatellite stable (MSS) and mismatch repair proficient (pMMR), and both ctDNA and tissue next-generation sequencing (NGS) from the ascending colon mass were ordered. Because tissue NGS results indicated that the ascending colon tumor was MSS, palliative 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy was started. However, the ctDNA NGS results that arrived after the start of FOLFOX found high microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR) disease with a serine/threonine-protein kinase B-Raf (BRAF V600E ) mutation. To treat both her MSS/pMMR ascending colon and sigmoid colon tumors and MSI-H/dMMR metastatic disease, the immunotherapy nivolumab was added to FOLFOX. After 8 months of combined nivolumab and chemotherapy, the patient's metastatic disease had a complete clinical response. This case highlights the complementary role of ctDNA testing for biomarker identification. By performing simultaneous ctDNA testing at the time of diagnosis, an actionable biomarker was discovered that significantly altered this patient's prognosis and treatment options. Orthogonal testing of key molecular alterations offers significant advantages for identifying actionable biomarkers and improving management of metastatic CRC.

Long-term benefit of immunotherapy in a patient with squamous lung cancer exhibiting mismatch repair deficient/high microsatellite instability/high tumor mutational burden: A case report and literature review.

Genetic mutations that render mismatch repair defective may result in microsatellite instability, which is common in colorectal carcinomas and gastric cancers as well as Lynch syndrome. Mismatch repair deficiency/high microsatellite instability (dMMR/MSI-H) predicts the tumor response to immune checkpoint inhibitors. However, few studies have evaluated the efficacy of immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) patients with dMMR/MSI-H. In this work, we present a patient with advanced squamous lung cancer with dMMR/MSI-H and a high tumor mutational burden (TMB-H) who obtained a long-term benefit from immunotherapy. NSCLC patients with dMMR/MSI-H/TMB-H may thus benefit from immune checkpoint inhibitors.

Clinicopathological characteristics of high microsatellite instability/mismatch repair-deficient colorectal cancer: A narrative review.

Colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) show molecular and clinicopathological characteristics that differ from those of proficient mismatch repair/microsatellite stable CRCs. Despite the importance of MSI-H/dMMR status in clinical decision making, the testing rates for MSI and MMR in clinical practice remain low, even in high-risk populations. Additionally, the real-world prevalence of MSI-H/dMMR CRC may be lower than that reported in the literature. Insufficient MSI and MMR testing fails to identify patients with MSI-H/dMMR CRC, who could benefit from immunotherapy. In this article, we describe the current knowledge of the clinicopathological features, molecular landscape, and radiomic characteristics of MSI-H/dMMR CRCs. A better understanding of the importance of MMR/MSI status in the clinical characteristics and prognosis of CRC may help increase the rates of MMR/MSI testing and guide the development of more effective therapies based on the unique features of these tumors.

Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability.

Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.

Biomarker Landscape in Neuroendocrine Tumors With High-Grade Features: Current Knowledge and Future Perspective.

Neuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2-G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical-pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of KRAS, TP53, and RB1 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.

Complete response of MSI-high metastatic colon cancer following treatment with regorafenib: A case report.

Regorafenib has been demonstrated to prolong survival in patients with metastatic colorectal cancer refractory to standard chemotherapy. However, overall survival is limited to 2.5 months. The present report describes a unique case of metastatic colon cancer, which showed a complete response to regorafenib. A 54-year-old woman was diagnosed with right colon cancer obstruction with peritoneal seeding. The patient underwent laparoscopic right hemicolectomy, and the pathology was T4aN2bM1, moderately differentiated adenocarcinoma with high microsatellite instability (MSI-H) and wild-type KRAS/NRAS. The first-line chemotherapy was fluorouracil, leucovorin and irinotecan with cetuximab. After 12 cycles, recurrence at the anastomotic site was identified. The patient underwent palliative colectomy, and superior mesenteric artery (SMA) lymph node metastases were evident. The patient received second-line chemotherapy of fluorouracil, leucovorin and oxaliplatin with bevacizumab. Progression of metastasis to the right common iliac lymph nodes was detected after only four cycles of therapy. Thereafter, the patient received regorafenib as third-line therapy, starting with 160 mg for two cycles and reducing the dose thereafter, for a total of 17 cycles. The previously confirmed SMA lymph node metastasis had disappeared after the seventh cycle, and the right common iliac lymph node metastasis was not visible on CT after the 16th cycle. The patient decided to terminate regorafenib and has not experienced recurrence 2 years since treatment cessation. This is the first report of refractory metastatic colon cancer with MSI-H showing a complete response to regorafenib. Further studies are required to investigate the efficacy of regorafenib in refractory metastatic colon cancer with MSI-H and to elucidate the mechanism of remission.

Marked improvement of oral intake with nivolumab monotherapy in a patient with microsatellite instability-high gastric cancer with insufficient oral intake.

Although immune checkpoint inhibitors are commonly less effective for patients with a poor general condition, they can be effective and should be considered for poor general conditions in the case of MSI-H tumor.

Occurrence of High Microsatellite-Instability/Mismatch Repair Deficiency in Nearly 2,000 Human Adenocarcinomas of the Gastrointestinal Tract, Pancreas, and Bile Ducts: A Study From a Large German Comprehensive Cancer Center.

INTRODUCTION: Knowledge of the high microsatellite-instability (MSI-H)/mismatch repair deficiency (MMRd) status is of increasing interest for personalized neoadjuvant or adjuvant therapy planning. Only a few studies are available on MSI-H distribution in the Northern European Caucasian patient population. In this study, we focused on a large cohort of tumors of the upper gastrointestinal tract. MATERIALS AND METHODS: Surgical material from a total of 1,965 patients was analyzed for MSI-H/MMRd status (including 1,267 carcinomas of the esophagus or stomach). All tumors were analyzed with an internationally recommended immunohistochemical panel consisting of four antibodies (MLH1, MSH2, PMS2, and MSH6). The results were molecularly objectified. RESULTS: Adenocarcinomas with MSI-H/MMRd were detected with the following distribution: esophagus (1.4%), stomach (8.3%), small intestine (18.2%), large intestine (8.5%), intrahepatic bile ducts (1.9%), and pancreas (0%). In case of gastric tumors with MSI-H/MMRd, neoadjuvant therapy did not influence the prognosis of patients (p = 0.94). Within all tumor entities with MSI-H/MMRd, patients with a UICC stage 4 were also represented. In this advanced stage, 11.7% of patients with MSS tumors were diagnosed compared to 0.5% of patients with MSI-H tumors relative to the entire tumor collective. DISCUSSION: In this study, the proportion of MSI-H/MMRd tumors in the stomach is smaller than would have been expected in knowledge of the data published by TCGA or AGRC. Negative prognostic effects regarding MSI-H status and neoadjuvant therapy as described by the MAGIC study group were not seen in our cohort. The extent to which the MSI-H/MMRd status should be known for neoadjuvant therapy planning must be clarified in prospective studies in the future. At present, there is no convincing data to dispense the neoadjuvant therapy for gastric carcinoma. Due to the very convincing, positive data regarding the response rates of MSI-H tumors to treatment with PD1/PD-L1 inhibitors, every metastatic carcinoma of the gastrointestinal tract should be tested for its MSI-H status.

Successful treatment of metastatic colorectal cancer with synchronous BRAF V600E mutation and dMMR with BGB-A317.

Metastatic colorectal cancer with BRAF mutation is a type of highly invasive malignant tumor with poor prognosis and few treatment options. Here, we report a case of a BRAF-mutant and DNA mismatch-repair deficiency colorectal cancer patient with postoperative recurrence as well as abdominal cavity and pelvic metastasis, whose condition was relieved continuously after treatment with a new anti-PD-1 antibody, BGB-A317.

Management of advanced adenocarcinoma in Indiana Pouch urinary diversion.

Adenocarcinoma is a rare finding following urinary diversion with gastrointestinal segments. This report describes an 80-year-old woman with a history of bladder cancer who subsequently developed a pT4 adenocarcinoma 8 years following her radical cystectomy and Indiana Pouch continent urinary diversion. An en bloc resection of the pouch and affected small bowel was performed and the patient underwent conversion to an ileal conduit diversion. We use this case to highlight a mechanism for possible pathogenesis and the management of adenocarcinoma in urinary diversions including the need for regular surveillance and the surgical approach.

Gastric Cancer in the Era of Precision Medicine.

Gastric cancer (GC) remains the third most common cause of cancer death worldwide, with limited therapeutic strategies available. With the advent of next-generation sequencing and new preclinical model technologies, our understanding of its pathogenesis and molecular alterations continues to be revolutionized. Recently, the genomic landscape of GC has been delineated. Molecular characterization and novel therapeutic targets of each molecular subtype have been identified. At the same time, patient-derived tumor xenografts and organoids now comprise effective tools for genetic evolution studies, biomarker identification, drug screening, and preclinical evaluation of personalized medicine strategies for GC patients. These advances are making it feasible to integrate clinical, genome-based and phenotype-based diagnostic and therapeutic methods and apply them to individual GC patients in the era of precision medicine.