Following initial successes in melanoma treatment, immunotherapy has rapidly become established as a major treatment modality for multiple types of solid cancers, including a subset of colorectal ...cancers (CRCs). Two programmed cell death 1 (PD1)-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in patients with metastatic CRC that is mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H), and have been granted accelerated FDA approval. In contrast to most other treatments for metastatic cancer, immunotherapy achieves long-term durable remission in a subset of patients, highlighting the tremendous promise of immunotherapy in treating dMMR-MSI-H metastatic CRC. Here, we review the clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR-MSI-H CRC. We focus on new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR-MSI-L) and discuss emerging approaches for targeting the immune microenvironment, which might complement immune checkpoint inhibition.
Abstract The last two decades have seen significant advancement in our understanding of colorectal tumors with DNA mismatch repair (MMR) deficiency. The ever-emerging revelations of new molecular and ...genetic alterations in various clinical conditions have necessitated constant refinement of disease terminology and classification. Thus, a case with the clinical condition of hereditary non-polyposis colorectal cancer as defined by the Amsterdam criteria may be one of Lynch syndrome characterized by a germline defect in one of the several MMR genes, one of the yet-to-be-defined “Lynch-like syndrome” if there is evidence of MMR deficiency in the tumor but no detectable germline MMR defect or tumor MLH1 promoter methylation, or “familial colorectal cancer type X” if there is no evidence of MMR deficiency. The detection of these conditions carries significant clinical implications. The detection tools and strategies are constantly evolving. The Bethesda guidelines symbolize a selective approach that uses clinical information and tumor histology as the basis to select high-risk individuals. Such a selective approach has subsequently been found to have limited sensitivity, and is thus gradually giving way to the alternative universal approach that tests all newly diagnosed colorectal cancers. Notably, the universal approach also has its own limitations; its cost-effectiveness in real practice, in particular, remains to be determined. Meanwhile, technological advances such as the next-generation sequencing are offering the promise of direct genetic testing for MMR deficiency at an affordable cost probably in the near future. This article reviews the up-to-date molecular definitions of the various conditions related to MMR deficiency, and discusses the tools and strategies that have been used in detecting these conditions. Special emphasis will be placed on the evolving nature and the clinical importance of the disease definitions and the detection strategies.
The anal canal possesses complex anatomy and histology and gives rise to a variety of tumor types. Challenging issues remain with regard to both the pathologic diagnosis and the clinical management ...of these tumors.
To provide an updated overview of the histogenesis, clinical and pathologic characteristics, diagnostic terminology, and relevant clinical management of the various types of anal canal tumors.
Recent literature on clinical and pathologic characteristics of anal canal tumors.
Although most anal canal tumors are of squamous lineage, a complex variety of other tumors also occurs. Recognition of such diverse tumor entities will allow accurate pathologic diagnosis and most optimal clinical management.
Immune checkpoint inhibition has been shown to generate profound and durable responses in mismatch repair deficient (MMR-D) solid tumors and has elicited interest in detection tools and strategies to ...guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D pancreatic ductal adenocarcinoma (PDAC) and assess the utility of next-generation sequencing (NGS) in providing additional prognostic and predictive information for MMR-D PDAC.
Archival and prospectively acquired samples and matched normal DNA from
= 833 PDAC cases were analyzed using a hybridization capture-based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341 to 468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genome sequencing data. Available germline testing, IHC, and microsatellite instability (MSI) PCR results were reviewed to assess and confirm MMR-D and MSI status.
MMR-D in PDAC is a rare event among PDAC patients (7/833), occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load, and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response, 2 partial responses, 1 stable disease).
An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients.
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Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in ...mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer.
We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.
A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging,
F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.
Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).
Recently discovered DNAJB1-PRKACA oncogenic fusions have been considered diagnostic for fibrolamellar hepatocellular carcinoma. In this study, we describe six pancreatobiliary neoplasms with PRKACA ...fusions, five of which harbor the DNAJB1-PRKACA fusion. All neoplasms were subjected to a hybridization capture-based next-generation sequencing assay (MSK-IMPACT), which enables the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving ≥410 genes (n = 6) and/or to a custom targeted, RNA-based panel (MSK-Fusion) that utilizes Archer Anchored Multiplex PCR technology and next-generation sequencing to detect gene fusions in 62 genes (n = 2). Selected neoplasms also underwent FISH analysis, albumin mRNA in-situ hybridization, and arginase-1 immunohistochemical labeling (n = 3). Five neoplasms were pancreatic, and one arose in the intrahepatic bile ducts. All revealed at least focal oncocytic morphology: three cases were diagnosed as intraductal oncocytic papillary neoplasms, and three as intraductal papillary mucinous neoplasms with mixed oncocytic and pancreatobiliary or gastric features. Four cases had an invasive carcinoma component composed of oncocytic cells. Five cases revealed DNAJB1-PRKACA fusions and one revealed an ATP1B1-PRKACA fusion. None of the cases tested were positive for albumin or arginase-1. Our data prove that DNAJB1-PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, and caution should be exercised in diagnosing liver tumors with DNAJB1-PRKACA fusions as fibrolamellar hepatocellular carcinoma, particularly if a pancreatic lesion is present. Moreover, considering DNAJB1-PRKACA fusions lead to upregulated protein kinase activity and that this upregulated protein kinase activity has a significant role in tumorigenesis of fibrolamellar hepatocellular carcinoma, protein kinase inhibition could have therapeutic potential in the treatment of these pancreatobiliary neoplasms as well, once a suitable drug is developed.
Prior molecular profiling of hepatocellular carcinoma (HCC) has identified actionable findings that may have a role in guiding therapeutic decision-making and clinical trial enrollment. We ...implemented prospective next-generation sequencing (NGS) in the clinic to determine whether such analyses provide predictive and/or prognostic information for HCC patients treated with contemporary systemic therapies.
Matched tumor/normal DNA from patients with HCC (
= 127) were analyzed using a hybridization capture-based NGS assay designed to target 341 or more cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.
WNT/β-catenin pathway (45%) and
(33%) alterations were frequent and represented mutually exclusive molecular subsets. In sorafenib-treated patients (
= 81), oncogenic PI3K-mTOR pathway alterations were associated with lower disease control rates (DCR, 8.3% vs. 40.2%), shorter median progression-free survival (PFS; 1.9 vs. 5.3 months), and shorter median overall survival (OS; 10.4 vs. 17.9 months). For patients treated with immune checkpoint inhibitors (
= 31), activating alteration WNT/β-catenin signaling were associated with lower DCR (0% vs. 53%), shorter median PFS (2.0 vs. 7.4 months), and shorter median OS (9.1 vs. 15.2 months). Twenty-four percent of patients harbored potentially actionable alterations including
(8.5%) inactivating/truncating mutations,
(6.3%) and
(1.5%) amplifications, and
missense mutations (<1%). Six percent of patients treated with systemic therapy were matched to targeted therapeutics.
Linking NGS to routine clinical care has the potential to identify those patients with HCC likely to benefit from standard systemic therapies and can be used in an investigational context to match patients to genome-directed targeted therapies.
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Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We ...identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.
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•Prospective targeted sequencing of 1,134 colorectal cancers in the clinical setting•Few genomic differences between primaries and metastases•Identified CTNNB1 in-frame deletions enriched in microsatellite stable cases•Differences in APC, BRAF, KRAS, and NRAS predict varied survival by tumor laterality
Yaeger et al. perform prospective sequencing of metastatic colorectal cancers (mCRCs). Right-sided primary microsatellite stable mCRCs are associated with increased oncogenic mutations whereas most left-sided tumors lack identifiable genetic mitogenic signaling alterations but highly express mitogenic ligands.
Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer ...fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.
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