Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection. We found that six prominent somatic cancer ...variant knowledgebases were highly disparate in content, structure and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting. We developed a framework for harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations. We demonstrated large gains in overlap between resources across variants, diseases and drugs as a result of this harmonization. We subsequently demonstrated improved matching between a patient cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 33% per individual knowledgebase to 57% in aggregate. Our analyses illuminate the need for open, interoperable sharing of variant interpretation data. We also provide a freely available web interface (search.cancervariants.org) for exploring the harmonized interpretations from these six knowledgebases.
The impact of tumour mutational burden (TMB) on outcome with molecularly matched therapy is unknown. Higher TMB could predict resistance to molecularly matched therapy through co-occurring driver ...mutations.
One hundred and four patients with advanced cancers underwent molecular profiling in the DKTK-MASTER program. Fifty-five patients received systemic therapy excluding immunotherapy. Patients with molecularly matched (n = 35) or non-molecularly informed therapy (n = 20) were analysed for TMB and survival. Results were validated in an independent cohort of patients receiving molecularly matched (n = 68) or non-molecularly informed therapy (n = 40). Co-occurring driver mutations and TMB were analysed in the exploratory cohort and The Cancer Genome Atlas (TCGA) datasets.
Patients were stratified by the median TMB of 1.67 mutations per Megabase (mut/Mb) of 35 patients receiving molecularly matched therapy into TMB-high or TMB-low groups. Median overall survival (4 months 95% CI, 3.3-7.6 versus 12.8 months 95% CI, 10-not reached, p < 0.001) and progression-free survival (1.8 months 95% CI, 1.1-3.7 versus 7.9 months 95% CI, 2.8-17.0, p = 0.003) were significantly shorter in the TMB-high group compared to the TMB-low group. In the validation cohort, shorter OS and PFS were identified in the TMB-high group (TMB cut-off of 4 mut/Mb) treated with molecularly matched therapy. No differences were observed in patients receiving non-molecularly informed systemic therapy. A significant correlation between co-occurring driver mutations and TMB (n = 104, r = 0.78 95% CI, 0.68-0.85, p < 0.001) was found in the exploratory cohort as well as the majority (24/33) of TCGA studies.
A high TMB was associated with unfavourable outcome in patients receiving molecularly matched therapy, indicating untargeted resistance pathways. Therefore, TMB should be further investigated as a predictive biomarker in precision oncology programs.
Background Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. ...Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards. Methods High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0-1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically. Results A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician's choice. Conclusions Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts. Keywords: Precision oncology, Whole-exome sequencing, RNA-sequencing, Clinical interpretation, Targeted therapy, Molecular tumor board
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A subgroup of salivary duct carcinoma (SDC) harbor overexpression of the androgen receptor (AR), and co-occurring mutations in the
- and
-genes. The impact of genomic complexity on targeted treatment ...strategies in advanced cancer is unknown.
We analyzed molecular and clinical data from an institutional molecular tumor board (MTB) to identify AR+,
/
co-mutated SDC. Follow-up was performed within the MTB registrational study or retrospective chart review after approval by the local ethics committee. Response was assessed by the investigator. A systematic literature search was performed in MEDLINE to identify additional clinically annotated cases.
4 patients with AR+
/
co-mutated SDC and clinical follow-up data were identified from the MTB. An additional 9 patients with clinical follow-up were identified from the literature. In addition to AR overexpression and
and
-alterations, PD-L1 expression and Tumor Mutational Burden > 10 Mutations per Megabase were identified as additional potentially targetable alterations. Among evaluable patients, androgen deprivation therapy (ADT) was initiated in 7 patients (1 Partial Response (PR), 2 Stable Disease (SD), 3 Progressive Disease (PD), 2 not evaluable), tipifarnib was initiated in 6 patients (1 PR, 4 SD, 1 PD). One patient each was treated with immune checkpoint inhibition (Mixed Response) and combination therapies of tipifarnib and ADT (SD) and alpelisib and ADT (PR).
Available data further support comprehensive molecular profiling of SDC. Combination therapies, PI3K-inhibitors and immune therapy warrant further investigation, ideally in clinical trials. Future research should consider this rare subgroup of SDC.
Abstract A patient with gastrointestinal stroma tumor (GIST) and KIT p.V559D and BRAF p.G469A alterations was referred to our institutional molecular tumor board (MTB) to discuss therapeutic ...implications. The patient had been diagnosed with B-cell chronic lymphocytic leukemia (CLL) years prior to the MTB presentation. GIST had been diagnosed 1 month earlier. After structured clinical annotation of the molecular alterations and interdisciplinary discussion, we considered BRAF/KIT co-mutation unlikely in a treatment-naïve GIST. Discordant variant allele frequencies furthermore suggested a second malignancy. NGS of a CLL sample revealed the identical class 2 BRAF alteration, thus supporting admixture of CLL cells in the paragastric mass, leading to the detection of 2 alterations. Following the MTB recommendation, the patient received imatinib and had a radiographic response. Structured annotation and interdisciplinary discussion in specialized tumor boards facilitate the clinical management of complex molecular findings. Coexisting malignancies and clonal hematopoiesis warrant consideration in case of complex and uncommon molecular findings.
Targeted therapies for metastatic uveal melanoma have shown limited benefit in biomarker-unselected populations. The Treat20 Plus study prospectively evaluated the feasibility of a precision oncology ...strategy in routine clinical practice.
Fresh biopsies were analyzed by high-throughput genomics (whole-genome, whole-exome, and RNA sequencing). A multidisciplinary molecular and immunologic tumor board (MiTB) made individualized treatment recommendations based on identified molecular aberrations, patient situation, drug, and clinical trial availability. Therapy selection was at the discretion of the treating physician. The primary endpoint was the feasibility of the precision oncology clinical program.
Molecular analyses were available for 39/45 patients (87%). The MiTB provided treatment recommendations for 40/45 patients (89%), of whom 27/45 (60%) received ≥1 matched therapy. First-line matched therapies included MEK inhibitors (n = 15), MET inhibitors (n = 10), sorafenib (n = 1), and nivolumab (n = 1). The best response to first-line matched therapy was partial response in one patient (nivolumab based on tumor mutational burden), mixed response in two patients, and stable disease in 12 patients for a clinical benefit of 56%. The matched therapy population had a median progression-free survival and overall survival of 3.3 and 13.9 months, respectively. The growth modulation index with matched therapy was >1.33 in 6/17 patients (35%) with prior systemic therapy, suggesting clinical benefit.
A precision oncology approach was feasible for patients with metastatic uveal melanoma, with 60% receiving a therapy matched to identify molecular aberrations. The clinical benefit after checkpoint inhibitors highlights the value of tumor mutational burden testing.
•Demonstration of the feasibility of precision oncology for advanced uveal melanoma.•Complete whole-genome and RNA sequencing data were generated for 87% of patients.•Following treatment recommendations, 60% of patients received ≥1 matched therapy.•First-line therapies included inhibitors of MEK, MET, sorafenib, and nivolumab.•Clinical benefit rate in 56% of patients with one partial response under nivolumab.
Immune checkpoint inhibition leads to response in some patients with head and neck squamous cell carcinoma (HNSCC). Robust biomarkers are lacking to date. We analyzed viral status, gene expression ...signatures, mutational load and mutational signatures in whole exome and RNA‐sequencing data of the HNSCC TCGA dataset (n = 496) and a validation set (DKTK MASTER cohort, n = 10). Public single‐cell gene expression data from 17 HPV‐negative HNSCC were separately reanalyzed. APOBEC3‐associated TCW motif mutations but not total single nucleotide variant burden were significantly associated with inflammation. This association was restricted to HPV‐negative HNSCC samples. An APOBEC‐enriched, HPV‐negative subgroup was identified, that showed higher T‐cell inflammation and immune checkpoint expression, as well as expression of APOBEC3 genes. Mutations in immune‐evasion pathways were also enriched in these tumors. Analysis of single‐cell sequencing data identified expression of APOBEC3B and 3C genes in malignant cells. We identified an APOBEC‐enriched subgroup of HPV‐negative HNSCC with a distinct immunogenic phenotype, potentially mediating response to immunotherapy.
What's new?
Head and neck squamous cell carcinoma (HNSCC) is sometimes susceptible to immune checkpoint inhibitors, and biomarkers are needed to help identify which tumors are most likely to respond. Using the Cancer Genome Atlas, these authors evaluated 496 HSNCCs by HPV status, gene expression signatures, mutational load, and mutational signatures. They found that increased inflammation was associated with APOBEC3‐induced mutations in HPV‐negative cancers. This newly identified APOBEC‐enriched, HPV‐negative subgroup showed higher immune checkpoint expression, and also more mutations in immune‐evasion pathways, suggesting this may be a way to identify candidates for immune checkpoint inhibitor therapy.
Reliable and reproducible interpretation of molecular aberrations constitutes a bottleneck of precision medicine. Evidence-based decision management systems may improve rational therapy ...recommendations. To cope with an increasing amount of complex molecular data in the clinical care of patients with cancer, we established a workflow for the interpretation of molecular analyses.
A specialized physician screened results from molecular analyses for potential biomarkers, irrespective of the diagnostic modality. Best available evidence was retrieved and categorized through establishment of an in-house database and interrogation of publicly available databases. Annotated biomarkers were ranked using predefined evidence levels and subsequently discussed at a molecular tumour board (MTB), which generated treatment recommendations. Subsequent translation into patient treatment and clinical outcomes were followed up.
One hundred patients were discussed in the MTB between January 2016 and May 2017. Molecular data were obtained for 70 of 100 patients (50 whole exome/RNA sequencing, 18 panel sequencing, 2 immunohistochemistry (IHC)/microsatellite instability analysis). The MTB generated a median of two treatment recommendations each for 63 patients. Thirty-nine patients were treated: 6 partial responses and 12 stable diseases were achieved as best responses. Genetic counselling for germline events was recommended for seven patients.
The development of an evidence-based workflow allowed for the clinical interpretation of complex molecular data and facilitated the translation of personalized treatment strategies into routine clinical care. The high number of treatment recommendations in patients with comprehensive genomic data and promising responses in patients treated with combination therapy warrant larger clinical studies.
•Evidence-based, flexible workflow for the clinical interpretation of molecular data.•Application to complex data including whole-exome sequencing and RNA-Sequencing in clinical routine.•Initiation of targeted treatment in 39% of patients.•Promising responses in a subset of patients.•Standardisation of precision oncology workflows could help improve prospective trials.
Targeted Therapy of Head and Neck Cancer Rieke, Damian T; Klinghammer, Konrad; Keilholz, Ulrich
Oncology research and treatment,
01/2016, Letnik:
39, Številka:
12
Journal Article
Recenzirano
Head and neck squamous cell carcinoma (HNSCC) is one of the most common solid cancers worldwide. It is mainly caused by exposure to tobacco smoke and alcohol as well as infection with the human ...papilloma virus (HPV). The prognosis is poor, especially once it recurs or metastasizes. Current therapeutic options include surgery, radio- and chemotherapy. Epidermal growth factor receptor (EGFR) inhibitors are so far the only targeted agents that have been approved in head and neck cancer. Primary or secondary resistance is frequent or will eventually develop. Several driver mutations and other genomic aberrations have been described in HNSCC including EGFR overexpression and amplification. Yet, no predictive biomarkers for the application of EGFR inhibitors have been identified. Further targeted agents are in development for HNSCC, of which inhibitors of the PI3K pathway are the closest to clinical application. In recent years, the incidence of HPV-driven HNSCC has risen in Western countries. HPV-positive and -negative HNSCC are distinct molecular tumor entities, and consequences for targeted therapies have been discussed. This review looks at approved and investigational targeted treatment strategies as well as potential predictive biomarkers such as the HPV status to guide treatment.
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