Prognostic and predictive role of immune microenvironment in colorectal cancer.

Colorectal cancer (CRC) represents a molecularly heterogeneous disease and one of the most frequent causes of cancer-related death worldwide. The traditional classification of CRC is based on pathomorphological and molecular characteristics of tumor cells (mucinous, ring-cell carcinomas, etc.), analysis of mechanisms of carcinogenesis involved (chromosomal instability, microsatellite instability, CpG island methylator phenotype) and mutational statuses of commonly altered genes (KRAS, NRAS, BRAF, APC, etc.), as well as expression signatures (CMS 1-4). It is also suggested that the tumor microenvironment is a key player in tumor progression and metastasis in CRC. According to the latest data, the immune microenvironment can also be predictive of the response to immune checkpoint inhibitors. In this review, we highlight how the immune environment influences CRC prognosis and sensitivity to systemic therapy.

Failure of immune checkpoint inhibitors for microsatellite instability-positive pancreatic adenocarcinoma with atypical pattern of short tandem repeat mutation.

Microsatellite instability (MSI) is an important biomarker in cancer. While routine methods can detect MSI in certain tumor types, in other tumor types the results may be incorrect due to differences in the MSI loci pattern. Here, we report the case of a patient with pancreatic adenocarcinoma, with confirmed MSI by two independent next-generation sequencing tests, but not by routine methods, who had progression on pembrolizumab. Comparison of the patient's MSI loci patterns with MSI+ colorectal adenocarcinoma samples showed a lower fraction of unstable loci, low resolution of a second peak in the repeat length spectrum of unstable short tandem repeats in the patient's sample, and a lower length of indels (3.7 vs 4.5 base pairs, p < 0.01).

Microsatellite instability (MSI) is typically evaluated to select patients who will most likely benefit from the treatments to make immune system work better (immunotherapy). MSI is difficult to identify in cancer, because its patterns can vary in different tumors. In this article, we describe a case of a pancreatic cancer patient whose tumor, although MSI-positive, did not respond to immunotherapy. We conclude that this can be because the MSI pattern was different from those typically observed in other cancers.

Evidence blocks for effective presentation of genomic findings at molecular tumor boards: Single institution experience.

Genomic profiling, or molecular profiling of the tumor, is becoming a key component of therapeutic decision making in clinical oncology, and is typically carried out via next generation sequencing. However, the interpretation of the results and evaluation of rationale for targeting the uncovered alterations is challenging and requires a deep understanding of cancer biology, genetics, genomics and oncology. Multidisciplinary molecular tumor boards represent a promising strategy in the facilitation of molecularly-informed therapeutic decisions, and usually consist of specialists with various fields of expertise. To effectively communicate the biological and clinical significance of genomic findings, as well as to make molecular tumor board discussions more productive, we developed and implemented evidence blocks into case discussions in our center. We found that this approach facilitated clinicians' understanding of the results of genomic profiling, and resulted in shorter yet more efficient case discussions within the molecular tumor board. Here, we discuss our experience with evidence blocks and how their implementation influenced the molecular tumor board practice.

Evaluation of blood MSI burden dynamics to trace immune checkpoint inhibitor therapy efficacy through the course of treatment.

Analysis of serial liquid biopsy (LB) samples has been found to be a promising approach for the monitoring of tumor dynamics in the course of therapy for patients with colorectal cancer (CRC). Currently, somatic mutations are used for tracing the dynamics of the tumor via LB. However, the analysis of the dynamic changes in the molecular signatures such as microsatellite instability (MSI) is not currently used. We hypothesized that changes in blood MSI burden (bMSI) could be registered using serial LB sampling in the course of immune checkpoint inhibitors (ICI), and that its changes could potentially correlate with treatment outcomes. We report the preliminary findings of the observational trial launched to study (NCT06414304) the dynamics of bMSI in 9 MSI-positive CRC patients receiving ICI. NGS-based MSI testing was performed on both pre-treatment FFPE and serial LB samples. For patients who had detectable bMSI burden in any of the LB samples (n = 8, 89%), median bMSI was 1.4% (range, 0.01-40%). Among patients with detectable MSI in available FFPE samples, median MSI burden was 29.3% (range, 10-40%). bMSI detected in baseline LB and FFPE samples were positively correlated (Pearson's R 0.47). Maximal variant allele frequencies of driver mutations observed in LB were also positively correlated with bMSI burden (Pearson's R 0.7). Patients who had clinical benefit had undetectable bMSI burden at follow-up. Our results provide the rationale for further validation of bMSI as a predictive biomarker of ICI in MSI-positive patients.

Precision oncology strategy in cetuximab-resistant ERRFI1-mutant colon cancer: case report of disease progression on afatinib.

Despite the existence of effective first and second line therapy options for patients with colorectal cancer, heavily treated patients have limited additional therapies. Genomic profiling is a promising tool for guiding subsequent treatment selection. Here, we describe the results of treating a colorectal cancer patient with molecularly-matched therapy based on the results of genomic profiling. The patient received a combination of afatinib and bevacizumab due to the presence of ERRFI1 variant. To our knowledge, this is the first report on the effect of EGFR inhibitors in patients with ERRFI1-altered RAS/BRAF wild-type colorectal adenocarcinoma.

Case Report: Progressive disease of BRCA2-mutant colon adenocarcinoma following talazoparib therapy.

Colorectal cancer (CRC) is currently one of the most common tumor types diagnosed worldwide. In the early stages, the disease responds well to surgical and chemotherapeutic treatment, but in the later stages when therapeutic options are exhausted, comprehensive genomic profiling can guide further treatment decisions. We present the case of a 46-year-old man of Ashkenazi Jewish ancestry who was diagnosed with KRAS-mutated metastatic colorectal cancer. After surgery and progression on standard FOLFOX/FOLFIRI + bevacizumab therapy, as well as on Trifluridine/Tipiracil, comprehensive genomic profiling was performed with the hope of expanding therapeutic options. Following comprehensive tumor molecular profiling via NGS, a discussion of the case was discussed at the local molecular tumor board in order to determine further treatment strategy. An activating variant of KRAS and PIK3CA, FLT3 and SRC amplification and damaging TP53 and APC variants were discarded by MTB as potential targetable biomarkers. The BRCA2 p.S1415fs*4 founder frameshift variant was of interest and the patient was included in the clinical trial investigating the efficacy of a PARP inhibitor talazoparib. Unfortunately, the disease progression was detected within one month of talazoparib treatment and the patient died during the 8th cycle of FOLFIRI + bevacizumab therapy rechallenge.

Microsatellite Instability: A Review of Molecular Epidemiology and Implications for Immune Checkpoint Inhibitor Therapy.

Microsatellite instability (MSI) is one of the most important molecular characteristics of a tumor, which occurs among various tumor types. In this review article, we examine the molecular characteristics of MSI tumors, both sporadic and Lynch-associated. We also overview the risks of developing hereditary forms of cancer and potential mechanisms of tumor development in patients with Lynch syndrome. Additionally, we summarize the results of major clinical studies on the efficacy of immune checkpoint inhibitors for MSI tumors and discuss the predictive role of MSI in the context of chemotherapy and checkpoint inhibitors. Finally, we briefly discuss some of the underlying mechanisms causing therapy resistance in patients treated with immune checkpoint inhibitors.

Utility of public knowledge bases for the interpretation of comprehensive tumor molecular profiling results.

With the growing use of comprehensive tumor molecular profiling (CTMP), the therapeutic landscape of cancer is rapidly evolving. NGS produces large amounts of genomic data requiring complex analysis and subsequent interpretation. We sought to determine the utility of publicly available knowledge bases (KB) for the interpretation of the cancer mutational profile in clinical practice. Analysis was performed across patients who previously underwent CTMP. Independent interpretation of the CTMP was performed manually, and then, the recommendations were compared to ones present in KBs (OncoKB, CIViC, CGI, CGA, VICC, MolecularMatch). A total of 222 CTMP reports from 222 patients with 932 genomic alterations (GA) were identified. For 368 targetable GA identified in 171 (77%) of the patients, 1381 therapy recommendations were compiled. Except for CGA, therapy ESCAT LOE I, II, IIIA and IIIB therapy options were equally represented in the majority of KB. Personalized treatment options with ESCAT LOE I-II were provided for 35 patients (16%); MolecularMatch/CIViC allowed to collect ESCAT I-II treatment options for 34 of them (97%), OncoKB/CGI-for 33 of them (94%). Employing VICC and CGA 6 (17%) and 20 (57%) of patients were left without ESCAT I or II treatment options. For 88 patients with ESCAT level III-B therapy recommendations: only 2 (2%), 3 (3%), 4 (5%) and 6 (7%) of patients were left without options with CIViC, MolecularMatch, CGI and OncoKB, and with VICC-12 (14%). Highest overlap ratio was observed for IIIA (0.81) biomarkers, with the comparable results for LOE I-II. Meanwhile, overlap ratio for ESCAT LOE IV was 0.22. Public KBs provide substantial information on ESCAT-I/R1 biomarkers, but the information on ESCAT II-IV and resistance biomarkers is underrepresented. Manual curation should be considered the gold standard for the CTMP interpretation.

Complete response to talazoparib in patient with pancreatic adenocarcinoma harboring somatic PALB2 mutation: A case report and literature review.

PARP inhibitors have recently emerged as a maintenance treatment option for metastatic pancreatic cancer patients with germline BRCA mutations. However, the possibility of PARP-inhibitor use as a standalone-targeted therapy for patients with various homologous repair pathway alterations remains mostly undetermined. Here we report a clinical case of a 56-year-old woman with pancreatic ductal adenocarcinoma harboring a somatic PALB2 mutation. Following disease progression after 10 cycles of FOLFIRINOX chemotherapy and two cycles of second-line gemcitabine, she was switched to talazoparib and achieved a complete clinical response after 25 months of treatment. The patient remains alive without clinical or radiological signs of disease progression three years after the start of talazoparib with no targeted therapy-related toxicities. This case highlights the role of broad molecular profiling as a window of opportunity to achieve a durable response for selected pancreatic cancer patients while pinpointing our gaps in understanding the whole picture of management of these patients since a new puzzle element represented by PARP inhibitors was introduced to clinical practice.