ABSTRACT
INTRODUCTION/BACKGROUND: Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer (PCa). Better biomarkers are needed to predict responses to ICIs. We sought to demonstrate that a panel-based mutational signature identifies mismatch repair (MMR) deficient (MMRd) PCa and is a biomarker of response to pembrolizumab. PATIENTS AND METHODS: Clinico-genomic data was obtained for 2664 patients with PCa sequenced at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering (MSK). Clinical outcomes were collected for patients with metastatic castration-resistant PCa (mCRPC) treated with pembrolizumab at DFCI. SigMA was used to characterize tumors as MMRd or MMR proficient (MMRp). The concordance between MMRd with microsatellite instability (MSI-H) was assessed. Radiographic progression-free survival (rPFS) and overall survival (OS) were collected for patients treated with pembrolizumab. Event-time distributions were estimated using Kaplan-Meier methodology. RESULTS: Across both cohorts, 100% (DFCI: 12/12; MSK: 43/43) of MSI-H tumors were MMRd. However, 14% (2/14) and 9.1% (6/66) of MMRd tumors in the DFCI and MSK cohorts respectively were microsatellite stable (MSS), and 26% (17/66) were MSI-indeterminate in the MSK cohort. Among patients treated with pembrolizumab, those with MMRd (n = 5) versus MMRp (n = 14) mCRPC experienced markedly improved rPFS (HR = 0.088, 95% CI: 0.011-0.70; P = .0064) and OS (HR = 0.11, 95% CI: 0.014-0.80; P = .010) from start of treatment. Four patients with MMRd experienced remissions of >= 2.5 years. CONCLUSION: SigMA detects additional cases of MMRd as compared to MSI testing in PCa and identifies patients likely to experience durable response to pembrolizumab.
Subject(s)
Brain Neoplasms , Colorectal Neoplasms , Neoplastic Syndromes, Hereditary , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Antibodies, Monoclonal, Humanized/therapeutic use , Neoplastic Syndromes, Hereditary/chemically induced , Neoplastic Syndromes, Hereditary/drug therapyABSTRACT
Hereditary cancer syndromes are inherited disorders caused by germline pathogenic variants (PVs) that lead to an increased risk of developing certain types of cancer, frequently at an earlier age than in the rest of the population. The germline PVs promote cancer development, growth and survival, and may represent an ideal target for the personalized treatment of hereditary tumors. PARP inhibitors for the treatment of BRCA and PALB2-associated tumors, immune checkpoint inhibitors for tumors associated with the Lynch Syndrome, HIF-2α inhibitor in the VHL-related cancers and, finally, selective RET inhibitors for the treatment of MEN2-associated medullary thyroid cancer are the most successful examples of how a germline PVs can be exploited to develop effective personalized therapies and improve the outcome of these patients. The present review aims to describe and discuss the personalized systemic therapies for inherited cancer syndromes that have been developed and investigated in clinical trials in recent decades.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Neoplastic Syndromes, Hereditary , Thyroid Neoplasms , Humans , Neoplastic Syndromes, Hereditary/drug therapy , Neoplastic Syndromes, Hereditary/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/drug therapy , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , Germ-Line Mutation , Poly(ADP-ribose) Polymerase InhibitorsABSTRACT
Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder with only a few affected families reported to date. Here, we report a case of familial GISTs harboring a novel germline mutation within exon 18 of KIT. A 58-year-old male patient presented with gastric subepithelial lesions accompanied by cutaneous hyperpigmentation, which were subsequently diagnosed as multinodular GISTs. Endoscopic surgery was initially conducted to remove the larger lesions, and pathological examinations were then conducted for the diagnosis of GISTs. Family history revealed that some other family members had similar cutaneous pigmentations. Whole-exome sequencing was used to search for potential driver mutations, and Sanger sequencing was used for mutation validation. A novel primary driver mutation of KIT (c.G2485C, p.A829P) was detected in these hereditary GISTs, which has been reported in some targeted chemotherapy-resistant GISTs. Cell models were subsequently established for the rapid screening of candidate drugs and exploring potential mechanisms. This mutation could lead to cell proliferation and imatinib resistance by ligand-independent activation of KIT; however, ripretinib administration was identified as an applicable targeted therapy for this mutation. The mutation activated the JAK/STAT3 and MAPK/ERK pathways, which could be inhibited by ripretinib administration. To the best of our knowledge, this is the first report of the KIT-A829P mutation in familial GISTs, complementing the pathogenesis of familial GISTs and providing valuable information for the precision treatment of this disease.
Subject(s)
Drug Resistance, Neoplasm , Gastrointestinal Neoplasms , Gastrointestinal Stromal Tumors , Neoplastic Syndromes, Hereditary , Proto-Oncogene Proteins c-kit , Humans , Male , Middle Aged , Drug Resistance, Neoplasm/genetics , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/genetics , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/genetics , Hyperpigmentation/genetics , Mutation , Neoplastic Syndromes, Hereditary/drug therapy , Neoplastic Syndromes, Hereditary/genetics , Pedigree , Proto-Oncogene Proteins c-kit/genetics , ChinaABSTRACT
Advances in the genetic basis of different tumors have led to identification of tumor vulnerabilities that can be turn into targeted therapies. In this regard, PARP inhibitors cause synthetic lethality with tumors harboring BRCA1 or BRCA2 genetic alterations. On the other hand, tumors with microsatellite instability, either due to germline or sporadic alterations, are candidates for immune checkpoint inhibitors. Finally, patients with von Hippel-Lindau disease who carry a germline alteration in the VHL gene may benefit form belzutifan, a hypoxia-inducible factor 2 alpha inhibitor. Overall, research on the underlying pathological mechanisms of these tumors has provided new therapeutic opportunities that might be expanded to other sporadic tumors with similar biology.
Subject(s)
Neoplastic Syndromes, Hereditary , von Hippel-Lindau Disease , Drug Development , Genomics , Humans , Mutation , Neoplastic Syndromes, Hereditary/drug therapy , Neoplastic Syndromes, Hereditary/genetics , von Hippel-Lindau Disease/genetics , von Hippel-Lindau Disease/pathology , von Hippel-Lindau Disease/therapySubject(s)
Intestinal Polyposis , Neoplastic Syndromes, Hereditary , Adenomatous Polyps , Humans , Intestinal Polyposis/complications , Intestinal Polyposis/congenital , Intestinal Polyposis/drug therapy , Neoplastic Syndromes, Hereditary/complications , Neoplastic Syndromes, Hereditary/drug therapy , Sirolimus/therapeutic use , Stomach NeoplasmsABSTRACT
How to efficiently suspect a germline gene variant(presumed germline pathogenic variant: PGPV)in comprehensive tumor-profiling tests using only cancer tissue(cells)as a sample is an important issue. This is because a few percent are derived from germline variants, which leads to the diagnosis of hereditary tumor syndromes and is useful information for the health management of patients and relatives. Clues include allele frequency, gene type, germline founder mutation, age of onset, present illness and past history, cancer type, family history, and tumor cell proportion. More than 97% of patients want to know such secondary findings before the test, but only about 23% of patients undergo confirmation tests even if PGPV is detected, and it is necessary to improve this in the future.
Subject(s)
Genetic Predisposition to Disease , Germ-Line Mutation , Neoplastic Syndromes, Hereditary , Genomic Medicine , Humans , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/drug therapy , Neoplastic Syndromes, Hereditary/geneticsABSTRACT
Importance: Propranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. However, other less lipophilic ß-blockers, such as nadolol, may be preferable in individuals who experience propranolol unresponsiveness or adverse events. Objective: To document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with IH. Design, Setting, and Participants: This double-blind noninferiority prospective study with a noninferiority margin of 10% compared propranolol with nadolol in infants aged 1 to 6 months with problematic IH. The study was conducted in 2 academic pediatric dermatology centers in Canada between 2016 and 2020. Infants aged 1 to 6 months with a hemangioma greater than 1.5 cm on the face or 3 cm or greater on another body part causing or with potential to cause functional impairment or cosmetic disfigurement. Interventions: Oral propranolol and nadolol in escalating doses up to 2 mg/kg/d. Main Outcomes and Measure: Between-group differences comparing changes in the bulk (size and extent) and color of the IH at week 24 with baseline using a 100-mm visual analog scale. Results: The study included 71 patients. Of these, 36 were treated with propranolol. The mean (SD) age in this group was 3.1 (1.4) months, and 31 individuals (86%) were female. Thirty-five infants were treated with nadolol. The mean (SD) age in this group was 3.2 (1.6) months, and 26 individuals (74%) were female. The difference in IH between groups by t test was 8.8 (95% CI, 2.7-14.9) for size and 17.1 (95% CI, 7.2-30.0) for color in favor of the nadolol group, demonstrating that nadolol was noninferior to propranolol. Similar differences were noted at 52 weeks: 6.0 (95% CI, 1.9-10.1) and 10.1 (95% CI, 2.9-17.4) for size and color improvement, respectively. For each doubling of time unit (week), the coefficient of involution was 2.4 (95% CI, 0.5-4.4) higher with nadolol compared with propranolol. Safety data were similar between the 2 interventions. Conclusions and Relevance: Oral nadolol was noninferior to oral propranolol, indicating it may be an efficacious and safe alternative in cases of propranolol unresponsiveness or adverse events, or when faster involution is required. Trial Registration: ClinicalTrials.gov Identifier: NCT02505971.
Subject(s)
Hemangioma, Capillary/drug therapy , Nadolol/standards , Neoplastic Syndromes, Hereditary/drug therapy , Propranolol/standards , Administration, Oral , Adrenergic beta-Antagonists/adverse effects , Adrenergic beta-Antagonists/pharmacology , Adrenergic beta-Antagonists/standards , Double-Blind Method , Equivalence Trials as Topic , Female , Hemangioma, Capillary/physiopathology , Humans , Infant , Male , Nadolol/adverse effects , Nadolol/pharmacology , Neoplastic Syndromes, Hereditary/physiopathology , Ontario , Propranolol/adverse effects , Propranolol/pharmacology , Prospective Studies , Treatment OutcomeABSTRACT
Tumors arising in the context of Lynch Syndrome or constitutional mismatch repair deficiency are hypermutated and have a good response towards immune-checkpoint inhibitors (ICIs), including α-PD-L1 antibodies. However, in most cases, resistance mechanisms evolve. To improve outcomes and prevent resistance development, combination approaches are warranted. Herein, we applied a combined regimen with an α-PD-L1 antibody and gemcitabine in a preclinical tumor model to activate endogenous antitumor immune responses. Mlh1-/- mice with established gastrointestinal tumors received the α-PD-L1 antibody (clone 6E11; 2.5 mg/kg bw, i.v., q2wx3) and gemcitabine (100 mg/kg bw, i.p., q4wx3) in mono- or combination therapy. Survival and tumor growth were recorded. Immunological changes in the blood were routinely examined via multi-color flow cytometry and complemented by ex vivo frameshift mutation analysis to identify alterations in Mlh1-/--tumor-associated target genes. The combined therapy of α-PD-L1 and gemcitabine prolonged median overall survival of Mlh1-/- mice from four weeks in the untreated control group to 12 weeks, accompanied by therapy-induced tumor growth inhibition, as measured by [18F]-FDG PET/CT. Plasma cytokine levels of IL13, TNFα, and MIP1ß were increased and also higher than in mice receiving either monotherapy. Circulating splenic and intratumoral myeloid-derived suppressor cells (MDSCs), as well as M2 macrophages, were markedly reduced. Besides, residual tumor specimens from combi-treated mice had increased numbers of infiltrating cytotoxic T-cells. Frameshift mutations in APC, Tmem60, and Casc3 were no longer detectable upon treatment, likely because of the successful eradication of single mutated cell clones. By contrast, novel mutations appeared. Collectively, we herein confirm the safe application of combined chemo-immunotherapy by long-term tumor growth control to prevent the development of resistance mechanisms.
Subject(s)
B7-H1 Antigen/genetics , Brain Neoplasms/drug therapy , Colorectal Neoplasms, Hereditary Nonpolyposis/drug therapy , Colorectal Neoplasms/drug therapy , MutL Protein Homolog 1/genetics , Neoplastic Syndromes, Hereditary/drug therapy , Animals , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Brain Neoplasms/blood , Brain Neoplasms/genetics , Brain Neoplasms/immunology , Chemokine CCL4/blood , Colorectal Neoplasms/blood , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms, Hereditary Nonpolyposis/blood , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/immunology , DNA Mismatch Repair/genetics , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Disease Models, Animal , Drug Resistance, Neoplasm/genetics , Humans , Immune Checkpoint Inhibitors/pharmacology , Interleukin-13/blood , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Mice , Myeloid-Derived Suppressor Cells , Neoplastic Syndromes, Hereditary/blood , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/immunology , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Cytotoxic/pathology , Tumor Necrosis Factor-alpha/blood , GemcitabineABSTRACT
BACKGROUND: Mlh1-knock-out-driven mismatch-repair-deficient (dMMR) tumors can be targeted immunologically. By applying therapeutic tumor vaccination, tumor growth is delayed but escape mechanisms evolve, including upregulation of immune-checkpoint molecules (LAG-3, PD-L1). To counteract immune escape, we investigated the therapeutic activity of a combined tumor vaccine-immune-checkpoint inhibitor therapy using α-PD-L1. DESIGN: In this trial, Mlh1-knock-out mice with established gastrointestinal tumors received single or thrice injections of α-PD-L1 monoclonal antibody clone 6E11 (2.5 mg/kg bw, q2w, i.v.) either alone or in combination with the vaccine. Longitudinal flow cytometry and PET/CT imaging studies were followed by ex vivo functional immunological and gene expression assays. RESULTS: 6E11 monotherapy slightly increased median overall survival (mOS: 6.0 weeks vs. control 4.0 weeks). Increasing the number of injections (n = 3) improved therapy outcome (mOS: 9.2 weeks) and was significantly boosted by combining 6E11 with the vaccine (mOS: 19.4 weeks vs. 10.2 weeks vaccine monotherapy). Accompanying PET/CT imaging confirmed treatment-induced tumor growth control, with the strongest inhibition in the combination group. Three mice (30%) achieved a complete remission and showed long-term survival. Decreased levels of circulating splenic and intratumoral myeloid-derived suppressor cells (MDSC) and decreased numbers of immune-checkpoint-expressing splenic T cells (LAG-3, CTLA-4) accompanied therapeutic effects. Gene expression and protein analysis of residual tumors revealed downregulation of PI3K/Akt/Wnt-and TGF-signaling, leading to T cell infiltration, reduced numbers of macrophages, neutrophils and MDSC. CONCLUSIONS: By successful uncoupling of the PD-1/PD-L1 axis, we provide further evidence for the safe and successful application of immunotherapies to combat dMMR-driven malignancies that warrants further investigation.
Subject(s)
Brain Neoplasms/drug therapy , Cancer Vaccines/pharmacology , Colorectal Neoplasms/drug therapy , Gastrointestinal Neoplasms/drug therapy , Immune Checkpoint Inhibitors/pharmacology , Neoplastic Syndromes, Hereditary/drug therapy , Vaccines, Combined/pharmacology , Animals , B7-H1 Antigen/metabolism , Brain Neoplasms/metabolism , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Gastrointestinal Neoplasms/metabolism , Immunotherapy/methods , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/metabolism , Mice , Mice, Knockout , MutL Protein Homolog 1/metabolism , Myeloid-Derived Suppressor Cells/metabolism , Neoplastic Syndromes, Hereditary/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Positron Emission Tomography Computed Tomography/methods , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Wnt Signaling Pathway/drug effectsABSTRACT
BACKGROUND: In the KEYNOTE-177 study, pembrolizumab monotherapy provided statistically significant and clinically meaningful improvements in progression-free survival versus chemotherapy as first-line treatment in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. To further support the efficacy and safety findings of the KEYNOTE-177 study, results of the health-related quality of life (HRQOL) analyses are reported here. METHODS: KEYNOTE-177 is an open-label, randomised, phase 3 trial being done at 192 cancer centres in 23 countries, in patients aged 18 years and older with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had not received previous systemic therapy for metastatic disease. Eligible patients were randomly assigned (1:1) centrally by use of interactive voice response or integrated web response technology to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator's choice chemotherapy (mFOLFOX6 [leucovorin, fluorouracil, and oxaliplatin] or FOLFIRI [leucovorin, fluorouracil, and irinotecan] intravenously every 2 weeks with or without intravenous bevacizumab or cetuximab). Patients and investigators were not masked to treatment assignment. The primary endpoints were progression-free survival (previously reported) and overall survival (data to be reported at the time of the final analysis). HRQOL outcomes were evaluated as prespecified exploratory endpoints. The analysis population comprised all randomly assigned patients who received at least one dose of study treatment and completed at least one HRQOL assessment. HRQOL outcomes were mean change from baseline to prespecified week 18 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scale and item scores, and in the EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L) visual analogue scale and health utility scores; the proportion of patients with improved, stable, or deteriorated scores from baseline to prespecified week 18 in EORTC QLQ-C30 scales and items; and time to deterioration in EORTC QLQ-C30 global health status/quality of life (GHS/QOL), physical functioning, social functioning, and fatigue scores and EORTC QLQ-CR29 urinary incontinence scores. The threshold for a small and clinically meaningful mean difference in EORTC QLQ-C30 score was 5-8 points. This study is registered with ClinicalTrials.gov, NCT02563002 and is ongoing; recruitment is closed. FINDINGS: Between Feb 11, 2016, and Feb 19, 2018, 307 patients were enrolled and randomly assigned to receive pembrolizumab (n=153) or chemotherapy (n=154). The HRQOL analysis population comprised 294 patients (152 receiving pembrolizumab and 142 receiving chemotherapy). As of Feb 19, 2020, median time from randomisation to data cutoff was 32·4 months (IQR 27·7-37·8). Least squares mean (LSM) change from baseline to prespecified week 18 showed a clinically meaningful improvement in EORTC QLQ-C30 GHS/QOL scores with pembrolizumab versus chemotherapy (between-group LSM difference 8·96 [95% CI 4·24-13·69]; two-sided nominal p=0·0002). Median time to deterioration was longer with pembrolizumab versus chemotherapy for GHS/QOL (hazard ratio 0·61 [95% CI 0·38-0·98]; one-sided nominal p=0·019), physical functioning (0·50 [95% CI 0·32-0·81]; one-sided nominal p=0·0016), social functioning (0·53 [95% CI 0·32-0·87]; one-sided nominal p=0·0050), and fatigue scores (0·48 [95% CI 0·33-0·69]; one-sided nominal p<0·0001). INTERPRETATION: Pembrolizumab monotherapy led to clinically meaningful improvements in HRQOL compared with chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These data, along with the previously reported clinical benefits, support pembrolizumab as a first-line treatment option for this population. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Brain Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy , Microsatellite Instability , Neoplastic Syndromes, Hereditary/drug therapy , Quality of Life , Adult , Aged , Brain Neoplasms/genetics , Brain Neoplasms/mortality , Brain Neoplasms/psychology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/psychology , DNA Mismatch Repair , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/mortality , Neoplastic Syndromes, Hereditary/psychologyABSTRACT
Propranolol, a nonselective ß-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Aquaporin 1/metabolism , Hemangioma, Capillary/metabolism , Neoplastic Syndromes, Hereditary/metabolism , Neovascularization, Pathologic/metabolism , Propranolol/pharmacology , Telocytes/metabolism , Animals , Cell Line, Tumor , Cell Movement , Hemangioma, Capillary/drug therapy , Humans , Mice , Neoplastic Syndromes, Hereditary/drug therapy , Neovascularization, Pathologic/drug therapy , Propranolol/therapeutic use , Proteome/genetics , Proteome/metabolism , Receptors, Adrenergic, beta-2/genetics , Receptors, Adrenergic, beta-2/metabolism , Telocytes/drug effects , Telocytes/physiologyABSTRACT
High-grade gliomas, including anaplastic oligodendroglioma, represent the most common malignant neoplasms of the central nervous system in the adult. The standard treatment of anaplastic oligodendroglioma consists of maximum surgical resection, radiotherapy and subsequent chemotherapy. Despite multimodal treatment, theoretically, all cases can relapse. Immune checkpoint inhibitors (ICIs) as pembrolizumab demonstrated promising results in many types of tumors, particularly in the presence of mismatch repair deficiency (MMRd). However, no ICI benefit was demonstrated in high-grade glioma prospective studies, although no biomarker was analyzed. Here, we describe an interesting case of recurrent anaplastic oligodendroglioma with MMRd, reporting a prolonged disease stability during pembrolizumab treatment.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Brain Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy , Neoplastic Syndromes, Hereditary/drug therapy , Oligodendroglioma/drug therapy , Adult , Brain Neoplasms/pathology , Colorectal Neoplasms/pathology , Female , Humans , Neoplasm Recurrence, Local , Neoplastic Syndromes, Hereditary/pathology , Oligodendroglioma/pathologyABSTRACT
The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is defined by germline mutations in the fumarate hydratase (FH) gene and associated with leiomyomas and aggressive renal cell carcinomas with FH deficiency. Here, we comprehensively characterize two new patients with HLRCC syndrome on a morphological, immunohistochemical and genetic level. The patients developed aggressive HLRCC syndrome-associated RCCs, uterine leiomyomas and dermal leiomyomas. One HLRCC syndrome-associated RCC exhibited an unusual morphology with accumulation of "colloid-like" cytoplasmic inclusions, which might serve as a novel sentinel feature to trigger further testing. This case showed partially retained FH expression, initially hampering correct diagnosis. Comprehensive next-generation sequencing analyses of HLRCC syndrome-associated RCC and leiomyomas in our patients revealed divergent genetic changes in the FH gene in different tumors from the same patient. While all leiomyomas (uterine and cutaneous) showed a FH loss of heterozygosity (LOH) as a wildtype allele inactivating event, one HLRCC-RCC showed a second, undescribed NM_000143.3; c.947C>T; p.Ala316Val FH mutation accompanying the preexisting splice site mutation c.378+2T>C. In the other HLRCC syndrome-associated RCC, the FH mutation (NM_000143.3; c.462T>G; p.Asn154Lys with a somatic LOH) represents another variant of unknown significance that we link to HLRCC - and thus classify as likely pathogenic. Due to the specific diagnosis of metastatic HLRCC syndrome-associated RCC, both cases were treated in first line with bevacizumab/erlotinib and showed remarkable and long lasting responses. These findings allow new morphological and molecular insights into the biology of the HLRCC syndrome, corroborate the "second hit" hypothesis of tumor formation in HLRCC patients and may promote a distinct therapeutic approach.
Subject(s)
Fumarate Hydratase/deficiency , Leiomyomatosis/genetics , Neoplastic Syndromes, Hereditary/genetics , Skin Neoplasms/genetics , Uterine Neoplasms/genetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Bevacizumab/administration & dosage , Bevacizumab/therapeutic use , Erlotinib Hydrochloride/administration & dosage , Erlotinib Hydrochloride/therapeutic use , Female , Fumarate Hydratase/genetics , Fumarate Hydratase/metabolism , Humans , Leiomyomatosis/drug therapy , Leiomyomatosis/pathology , Middle Aged , Mutation, Missense , Neoplastic Syndromes, Hereditary/drug therapy , Neoplastic Syndromes, Hereditary/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Uterine Neoplasms/drug therapy , Uterine Neoplasms/pathologyABSTRACT
Poly-ADP-ribose-polymerase inhibitor (PARPi) treatment is indicated for advanced-stage ovarian tumors with BRCA1/2 deficiency. The "BRCAness" status is thought to be attributed to a tumor phenotype associated with a specific epigenomic DNA methylation profile. Here, we examined the diagnostic impact of combined BRCA1/2 sequence, copy number, and promoter DNA methylation analysis, and evaluated whether genomic DNA methylation patterns can predict the BRCAness in ovarian tumors. DNA sequencing of 172 human tissue samples of advanced-stage ovarian adenocarcinoma identified 36 samples with a clinically significant tier 1/2 sequence variants (point mutations and in/dels) and 9 samples with a CNV causing a loss of function in BRCA1/2. DNA methylation analysis of the promoter of BRCA1/2 identified promoter hypermethylation of BRCA1 in two mutation-negative samples. Computational modeling of genome-wide methylation markers, measured using Infinium EPIC arrays, resulted in a total accuracy of 0.75, sensitivity: 0.83, specificity: 0.64, positive predictive value: 0.76, negative predictive value: 0.74, and area under the receiver's operating curve (AUC): 0.77, in classifying tumors harboring a BRCA1/2 defect from the rest. These findings indicate that the assessment of CNV and promoter DNA methylation in BRCA1/2 increases the cumulative diagnostic yield by 10%, compared with the 20% yield achieved by sequence variant analysis alone. Genomic DNA methylation data can partially predict BRCAness in ovarian tumors; however, further investigation in expanded BRCA1/2 cohorts is needed, and the effect of other double strand DNA repair gene defects in these tumors warrants further investigations.
Subject(s)
Adenocarcinoma/genetics , BRCA1 Protein/genetics , BRCA2 Protein/genetics , DNA Methylation , Genes, BRCA1 , Genes, BRCA2 , Molecular Diagnostic Techniques , Neoplastic Syndromes, Hereditary/genetics , Ovarian Neoplasms/genetics , Adenocarcinoma/diagnosis , Adenocarcinoma/drug therapy , Adult , Aged , Antineoplastic Agents/therapeutic use , Area Under Curve , DNA Copy Number Variations , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Female , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , INDEL Mutation , Middle Aged , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/drug therapy , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/drug therapy , Point Mutation , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Predictive Value of Tests , Promoter Regions, Genetic/genetics , ROC Curve , Sensitivity and SpecificityABSTRACT
Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR-MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR-MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).
Subject(s)
Brain Neoplasms/drug therapy , Colonic Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy , Immunotherapy , Microsatellite Instability/drug effects , Neoplastic Syndromes, Hereditary/drug therapy , Animals , Colorectal Neoplasms/pathology , Humans , Immunologic Factors/therapeutic use , Immunotherapy/methodsSubject(s)
Antibiotics, Antineoplastic/administration & dosage , Facial Neoplasms/drug therapy , Neoplastic Syndromes, Hereditary/drug therapy , Sirolimus/administration & dosage , Skin Neoplasms/drug therapy , Administration, Cutaneous , Child , Face , Facial Neoplasms/diagnosis , Facial Neoplasms/pathology , Female , Gels , Humans , Japan , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/pathology , Skin/pathology , Skin Neoplasms/diagnosis , Skin Neoplasms/pathology , Treatment OutcomeSubject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Epigenesis, Genetic/drug effects , Antineoplastic Agents/administration & dosage , Female , Humans , Molecular Targeted Therapy , Neoplastic Syndromes, Hereditary/drug therapy , Neoplastic Syndromes, Hereditary/genetics , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/geneticsABSTRACT
Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic lethality of this enzyme and fumarate hydratase (FH). In the current study, we aimed to validate the effect of genetic and pharmacological inhibition of HO-1 in cells isolated from patients suffering from hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-an inherited cancer syndrome, caused by FH deficiency. Initially, we confirmed that UOK 262, UOK 268, and NCCFH1 cell lines are characterized by non-active FH enzyme, high expression of Nrf2 transcription factor-regulated genes, including HMOX1 and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of HMOX1 resulted in diminished viability and proliferation of cancer cells. Chemical inhibition of HO activity using commercially available inhibitors, zinc and tin metalloporphyrins as well as recently described new imidazole-based compounds, especially SLV-11199, led to decreased cancer cell viability and clonogenic potential. In conclusion, the current study points out the possible relevance of HO-1 inhibition as a potential anti-cancer treatment in HLRCC. However, further studies revealing the molecular mechanisms are still needed.
Subject(s)
Fumarate Hydratase/genetics , Heme Oxygenase-1/antagonists & inhibitors , Heme Oxygenase-1/genetics , Leiomyomatosis/genetics , Leiomyomatosis/therapy , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/therapy , Skin Neoplasms/genetics , Skin Neoplasms/therapy , Uterine Neoplasms/genetics , Uterine Neoplasms/therapy , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Fumarate Hydratase/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Heme Oxygenase-1/metabolism , Humans , Leiomyomatosis/drug therapy , Leiomyomatosis/metabolism , Metalloporphyrins/pharmacology , Neoplastic Syndromes, Hereditary/drug therapy , Neoplastic Syndromes, Hereditary/metabolism , RNA, Small Interfering/pharmacology , RNAi Therapeutics , Skin Neoplasms/drug therapy , Skin Neoplasms/metabolism , Uterine Neoplasms/drug therapy , Uterine Neoplasms/metabolismABSTRACT
Secreting pituitary adenomas are tumors for which few treatment options are available, including surgical treatment and management of hormonal imbalance due to altered pituitary secretion. In case of inoperable relapse, radiotherapy or chemotherapeutic treatment can be considered; the effectiveness of these treatments, however, remains limited. In the immunotherapy era, it is necessary to select patients who can benefit from immunotherapeutic treatment. Mismatch repair deficiency is strongly associated with responsiveness to anti-PD-1 in other cancers and can be detected using immunohistochemistry for MLH1, MSH2, MHS6, and PMS2. In this case report, we report a case of rapid disease progression to pembrolizumab in a patient with a MMRd pituitary adrenocorticotropic hormone (ACTH)-secreting adenoma. For the best of our knowledge, we described for the first time, a poor efficacy of pembrolizumab in a patient with ACTH-secreting pituitary adenoma having mismatch repair deficiency probably caused by high levels of cortisol in this patient. Prospective study should be performed to assess the activity of immune checkpoint inhibitor alone or in association with temozolomide in this subsetting of pituitary adenomas.