We are pleased to announce the availability of a new release for COSMIC, the Catalogue of Somatic Mutations in Cancer. COSMIC Actionability v8 adds new actionability data to the world’s largest, expert-curated somatic mutation database. The release includes 22 new fully curated somatic genes, 387 new clinical trials, and 166 new oncology drugs.
In this article, we provide a summary of the COSMIC Actionability v8 release highlights.
COSMIC, the Catalogue of Somatic Mutations in Cancer, is an expert-curated database encompassing the wide variety of somatic mutation mechanisms causing human cancer. Owned and maintained by the Wellcome Sanger Institute, COSMIC is exclusively licensed through QIAGEN.
COSMIC’s team of variant scientists manually curates key cancer genes to provide in-depth information on mutation distributions and effects. The team relies on a semi-automated curation process of cancer genomes to provide broad somatic annotations toward target discovery and identification of patterns and signatures. To date, COSMIC contains over 23 million somatic mutations associated with human cancers.
COSMIC Actionability is a standalone product within the COSMIC database that focuses on providing information on the availability and development of drugs targeting somatic mutations in cancer. COSMIC’s certified curation team integrates data from case studies, clinical trials, and regulatory bodies to represent a full picture of the current precision oncology pipeline (from drug development, through safety and clinical phases, to market and repurposing).
Actionability contains information on three core units: mutations, diseases and drugs. By capturing relations between these units, COSMIC’s team identifies existing and upcoming drugs that target specific genetic variants in different cancer types. COSMIC Actionability is a cutting-edge, ‘living-tool’ that provides the most up-to-date data for precision oncology applications.
→ View the full Actionability v8 release notes here.
Learn more about COSMIC and how the industry-leading database can help you identify biomarkers, annotate variants, and explore the etiology of human cancers here.
See first-hand how COSMIC can be used in your lab by downloading sample data here.
The latest release of COSMIC, the Catalogue of Somatic Mutations in Cancer, is now available. In the new update, referred to as v97, there is also a new release of COSMIC Actionability (v7). With the two releases, the world’s largest expert-curated somatic mutation database focuses on blood cancer curation and adds new content, clinical trials, and categories for assessing patient responses in clinical trials.
Here, we provide a summary of the release highlights.
Every four months, COSMIC content and features are updated by the Wellcome Sanger Institute to ensure the database contains the latest findings and evidence. Over the last 5 releases (15 months), COSMIC has increased the number of genomic mutations by over 15%. Here is what’s new in the COSMIC v97 release.
Total genomic variants
Total patient samples
*Of this, 41,161 are whole genome samples
Curated papers
→ View the full COSMIC v97 release notes here.
COSMIC Actionability delivers the latest data on the availability and development of drugs targeting specific somatic mutations in cancer. Actionability covers clinically relevant mutations and alteration types in relevant genes for some of the most frequently sequenced cancer types such as lung, breast, melanoma, ovarian, and colon cancer. Here is what’s new in the Actionability v7 release.
Fully curated genes
*In total, there are 311 genes included
Total variants included
Total clinical trials
*Of this, 3,756 clinical trials have results
→ View the full Actionability v7 release notes here.
Learn more about COSMIC and how the industry-leading database can help you identify biomarkers, annotate variants, and explore the etiology of human cancers here.
See first-hand how COSMIC can be used in your lab and the quality of the database’s content by downloading sample data here.
In oncology research, identifying potentially actionable gene alterations and exploiting cancer’s molecular vulnerabilities is becoming increasingly difficult. Due to the sporadic nature of somatic cancers, the number of variants detected is rapidly rising.
Clinical research labs are tasked with confidently identifying meaningful mutations that could influence or improve decisions at the point of care. To do this, they need ready-access to trusted data to validate biomarkers and better assess their biological and clinical relevance. And this is precisely what the Human Somatic Mutation Database (HSMD) provides.
HSMD can be used to:
HSMD 2.0 comes with over 140,000 new alterations, improved data visualization and new structural variants. The dataset now contains over 419,000 clinical oncology cases and over 1.5 million mutations associated with over 4.2 million relationships from PubMed, drug labels, clinical trials, clinical guidelines and public databases such as gnomAD and HGMD.
Read the statistics sheet.
Many labs struggle with prioritizing clinically- and biologically-relevant variants among the millions of variants detected using NGS. Labs are starting to consolidate smaller panels into one large comprehensive cancer panel to test all cancer types. This presents fresh challenges: interpretation of the data and meeting turnaround times.
Fortunately, with COSMIC’s Cancer Mutation Census and Actionability, labs have the trusted data they need for accurate prioritization at their fingertips.
Here's how.
CMC delivers a score for each variant based on manually-curated information regarding cancer genes and genetic variants. It also provides data on variant frequencies in cancer and non-cancer populations. It utilizes data from many reliable sources, including ClinVar, gnomAD, DNA conservation as reported by GERP, and COSMIC Mutations per AA.
CMC’s algorithmic evaluation of variant significance across the whole set of coding mutations in COSMIC lets you identify variants with the highest potential of biological relevance. The latest version of CMC—v96—describes over 4.9 million somatic variants. It segregates them into four tiers (see Figure 1, below) in order of highest confidence and evidence of driving cancer (Tier 1) to the lowest (Tier 4).
The benefit?
During your NGS data analysis, you can easily match the CMC score to the identified mutations in your NGS test using genomic coordinates, cDNA, or protein change. This lets you rank the mutations in your NGS data according to the CMC score—prioritizing potential biological cancer-driving mutations.
Figure 1. CMC tiers allow you to rapidly classify somatic variants by their potential to drive cancer.
COSMIC Actionability delivers the latest data on the availability and development of drugs targeting specific somatic mutations in cancer. Actionability covers clinically-relevant mutations and alteration types in relevant genes for some of the most frequently sequenced cancer types such as lung, breast, melanoma, ovarian, and colon cancer. This data is updated quarterly; for more information on the latest Actionability release, see below.
With Actionability, you can prioritize clinically-actionable mutations related to your patient’s specific cancer type. This lets you know which of those potentially biologically-relevant mutations are also therapeutically actionable.
Like CMC, Actionability also classifies alterations into four tiers:
Actionability currently covers 62 tier 1, 21 tier 2, 527 tier 3, and 91 tier 4 alterations and alteration types, including those associated with the most common tumor profiling biomarkers and cancer types (see Table 1, below).
Table 1. Genes and cancer types currently included in Actionability data. List of genes adapted from Illumina's TSO500 tumor profiling biomarkers for multiple cancer types [1]. Note: some genes are not yet fully curated, but have been prioritized for curation in Actionability V7 (tentatively launching October 2022).
CMC and Actionability help you rank biologically and clinically relevant mutations easily and efficiently. With the complete set of COSMIC downloadable files, you can further refine the priorities of relevant mutations with the mutational frequency in your patient’s cancer type, as well as resistance mutations.
COSMIC Actionability is updated with new content every quarter. The latest release, V6, contains the following:
See the complete release statistics in Figure 2, below.
Figure 2. COSMIC Actionability V6 release statistics.
Learn more about COSMIC and how the industry-leading database can help you identify biomarkers, annotate variants, and explore the etiology of human cancers here.
See first-hand how COSMIC can be used in your lab and the quality of the database's content by downloading sample data here.
References
The latest COSMIC Actionability release is here with a focus on the ERBB2 gene. Before we delve into the trove of data the new release offers, we explain what COSMIC Actionability is and how it’s designed to support your precision oncology activities.
COSMIC, the Catalogue of Somatic Mutations in Cancer, is an online, expert-curated database encompassing the wide variety of somatic mutation mechanisms causing human cancer. Founded and maintained by the Wellcome Sanger Institute and exclusively licensed through QIAGEN Digital Insights, COSMIC holds details on millions of mutations across thousands of cancer types to help users identify biomarkers and annotate variants.
COSMIC Actionability is a feature within the database that indicates the availability of drugs that target mutations in cancer and tracks the progress of clinical studies towards making new drugs available. These drugs are covered at all stages of development—from early case studies to safety and clinical phases, all the way to market. Actionability data is updated and structured so you can get the latest information on drug repurposing, monitor the drug development landscape and identify emerging biomarkers that may be useful in label expansion.
ERBB2 is an oncogene that encodes a transmembrane protein with tyrosine kinase activity and is involved in pathways that lead to cell growth and differentiation. ERBB2 is also known as human epidermal growth factor receptor 2 (HER2) [1].
ERBB2 gene amplification happens in many different types of cancer. It has been identified in 20% of patients with gastric cancer [2] and about 20% of invasive breast cancer cases [3]. ERBB2 amplification is now a mainstream therapeutic target in breast and gastric cancer and can be easily detected using immunohistochemistry (IHC) techniques.
ERBB2 mutations have only just emerged as a therapeutic target in solid tumors. Historically, and due to how low its occurrence is, ERBB2 mutations have not received as much attention as ERBB2 amplification. Now, newer clinical studies of targeted therapies for ERBB2-mutant cancers are delivering encouraging results in solid tumors, especially breast cancer and non-small cell lung cancer.
Previous clinical trials have indicated that treatment efficacy varies according to the location of the ERBB2 mutation. While ERBB2 mutations appear more often in the tyrosine kinase domain region, there is still some variation in mutational hotspots in different cancer types.
In one study, patients with ERBB2 kinase domain point mutations treated with neratinib (pan-HER tyrosine kinase inhibitor) had a response rate of 21.4%, while patients with exon 20 insertions had a 7.1% response [1]. These variant-specific dissimilarities in clinical outcomes show that a more in-depth understanding of ERBB2 mutations is crucial to developing effective therapies.
Drug discovery and development can be very expensive and slow. Repurposing existing drugs to treat diseases with little to no effective therapies is a valid approach many are starting to take. New candidate therapies based on existing drugs can quickly move through the regulatory process and become more easily embedded into care pathways.
To repurpose drugs safely, effectively and efficiently, data on their failure–why the drugs are not effective or safe, why they have been withdrawn, and why development has been halted—must be readily available for investigation. That’s precisely what COSMIC Actionability provides.
What COSMIC Actionability v5 tells you about drugs for ERBB2 alterations where development has been stopped
Currently, 111 different drug combinations that have been tested in trials on cancer patients with ERBB2 alterations now have the status ‘Terminated’ or ‘Withdrawn’. Of these trials, 3 selected patients with ERBB2 mutations, 78 selected patients with evidence of ERBB2 expression, and 47 specified overexpression.
Out of the 78 combinations tested in trials that selected patients with evidence of ERBB2 expression, reasons for termination were identified for 53. Twenty-five of the trials were terminated due to slow accrual, 9 for lack of efficacy, 6 for safety/toxicity and 10 due to changed business priorities.
Within the group terminated due to lack of efficacy, 7 of them have this reason identified on the ClinicalTrials.gov website. The other 2 had their reason for termination in ASCO postings, which are not available on ClinicalTrials.gov or PubMed.
Again, of the 47 combinations tested in overexpression-selected trials, the reason for termination was identified for 34: 19 for slow accrual, 4 for adverse events or toxicity issues, 4 due to changed business priorities and 3 due to lack of efficacy. One was terminated because the sponsor company decided to suspend the development of the compound, Aderbasib. The reason for the suspension is not available in the download file, but online sources suggest it was because later research contradicted earlier positive results in phase II trials. The press releases are not available anymore.
Label expansion studies are frequently conducted to seek regulatory approval to expand the indications for a drug. Supplementary clinical data is needed to show the drug can safely and effectively treat patient groups other than the ones for which it was initially intended. COSMIC Actionability keeps track of how many trials are currently in development and if you can use an approved drug in other indications.
Which ERBB2-focused trials are currently investigating approved drugs in other indications and their phases
There are 34 combinations in ongoing trials that either selected or plan to correlate efficacy with ERBB2 expression or mutation that are looking at an approved drug combination for another indication. One is approved, but the trial is not complete. One of the trials is in phase III, 24 are in phase II, and 8 are in phase I. In addition, 8 of the 34 trials are repurposing trials looking at gastrointestinal cancers.
With COSMIC Actionability, monitoring the drug development landscape and identifying emerging biomarkers with significant responses is simple and efficient.
Now more than ever, there are multitudes of molecules, biologics, vaccines and innovative therapies at all phases of clinical drug development. COSMIC Actionability allows users to monitor the global, ever- changing landscape of investigational drugs in specific diseases.
Drugs in development, terminated, or withdrawn for ERBB2 amplification in gastric cancers (including GIST at GE junction)
Currently, there are 29 ongoing trial cohorts looking at 25 different drug combinations targeting ERBB2 overexpression in gastrointestinal cancers. Separately, 1 trial was terminated due to changed business priorities, and a further 3 have unknown status.
Are there any ERBB2 point mutations that show significant response with off-label use of FDA-approved therapies?
There are 3 trials looking at FDA-approved drugs for other indications that either select or plan to correlate efficacy with ERBB2 mutations. All the trials are in phase II. One has been terminated due to slow accrual. Another has been completed with an ORR of 19% ─ likely not high enough to take it to phase III. The remaining trial is active but not recruiting, with an ORR of 55% and PFS of 8.2 months, OS of 17.2 months. It has no control, so no statistically significant results, but it is likely to go on to phase III.
COSMIC Actionability is indispensable to investigations focused on drugs targeting specific mutations in cancer. The new release, Actionability v5, focuses on ERBB2 alterations and highlights just how useful COSMIC Actionability can be for any target of choice. With its regularly updated content, you can stay up-to-date on the latest drug developments in the precision oncology space.
Learn more about COSMIC and how the industry-leading database can help you identify biomarkers, annotate variants, and explore the etiology of human cancers here.
See first-hand how COSMIC can be used in your lab and the quality of the database's content by downloading sample data here.
References
While the world showed its support for affected people during Breast Cancer Awareness Month, COSMIC's expert curators were working hard behind the scenes to get information on rare breast cancers ready for the upcoming release later that month.
Breast cancer is still a big global problem
Breast cancer is the most prevalent cancer type worldwide. At the end of 2020, there were 7.8 million women alive who’d been diagnosed with breast cancer in the previous five years. And despite leaps and bounds in detection and treatment, there were still 685,000 deaths from breast cancer in 2020 alone.
Nevertheless, the numbers are still fairly optimistic. Breast cancer mortality in high-income countries has dropped 40% between the 1980s and 2020 - and it’s continuing to drop by around 2-4% in these countries each year. Innovations in treatment and targeted drug therapies, such as trastuzumab to treat HER-2 positive cancers, are showing outstanding results. And let’s be clear, early detection and effective treatment is really the only option. Unlike many common cancers, even if all the risk factors for breast cancer development were controlled, this would only reduce the risk by 30%. A multi-pronged approach is needed- optimize care pathways, facilitate early diagnosis, and provide the right treatment at the right time.
And for treatment-resistant breast cancers? We need to understand what’s driving these cancers at a genetic level and identify targets for the next generation of drugs.
Cue COSMIC as the navigational tool that hosts the data to springboard scientific innovation. COSMIC’s latest release v95 (November 2021) has a special focus on rare female cancers, including the rarer breast cancer subtype with notorious poor outcomes, metaplastic breast cancer (MpBC).
The lowdown on metaplastic breast cancer
Metaplastic breast cancer is a rare and aggressive malignancy. Although the incidence is low (it only accounts for 0.2–5% of all breast cancers), MpBC accounts for a significant proportion of breast-cancer deaths.
MpBCs are usually (but not always) triple-negative - meaning they lack expression of estrogen receptor (ER), progesterone receptor (PR), and HER2. So, some of the revolutions in current treatments are ineffective. Like other triple-negative breast cancers, they’re more likely to present with distant metastasis, but they generally have a worse prognosis than their grade-matched counterparts.
Compared to other cancers, relatively little is known about MpBC, but more studies are happening all the time. Speaking of, time to look at some of the new datasets being incorporated into V95 of COSMIC.
Classification: Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications
When cancer is rare, it can be harder to create clear definitions, classifications, and guidance. This is especially true of MpBC, a cancer literally named for its heterogeneity in cell types. Metaplasia derives from Ancient Greek and means ‘change in form’. In this context, it’s the transformation of one differentiated cell type to another differentiated cell type. The World Health Organisation (WHO) guidelines currently rely on the structure, shape, and organization of the cells to create sub-categories - without any information on molecular causes or clinical guidance.
Caption: Table showing the various WHO classifications of metaplastic breast cancer [1]
But Lakhani et al. decided to look under the hood. Using strength in numbers, they formed the Asia-Pacific MpBC consortium to collect and study 347 MpBCs in depth.
What did the increased numbers provide? Let’s start with genetics. Exome sequencing was performed on 30 of the MpBC cases and found TP53, PTEN, and PIK3CA mutations co-occurring. This countered a long-held concept that TP53/PTEN and PI3CA/PTEN mutations were mutually exclusive.
Moving on to prognosis - the top question that patients have when diagnosed: ‘How bad is it’?’ This study shed a little light. The significant indicators of poor prognosis were large tumor size, loss of cytokeratin expression, EGFR overexpression, and the presence of more than three distinct morphological entities. On the flip side, favorable indicators included fewer morphological components and EGFR negativity.
With these findings, Lakhani et al. suggest minor changes to the WHO classification. The paper ends with the comment that, ‘thousands of samples would need to be reviewed centrally in order to tease out the subtleties required to make any bolder changes to the guidelines’. As more similar data is incorporated into COSMIC datasets, it will enable this scale of analysis.
New targets: Molecular Profiling of the Metaplastic Spindle Cell Carcinoma of the Breast Reveals Potentially Targetable Biomarkers
Having discussed the WHO guidelines more broadly, time to zone in on one of the even rarer subtypes of MbBC, WHO_5: Spindle Cell Carcinoma. This subtype displays the previously mentioned triple-negative characteristic, as well as having an association with resistance to conventional chemotherapy.
Evidently, new tactics are needed. Precision oncology and immuno-oncology could provide some strategies for targeted therapies, but first we need to know if the right mutations and immune markers are present. Gatalica et al. studied this with some promising results.
They used 23 MpBC spindle cell carcinomas and thoroughly analyzed them using immunohistochemistry and DNA/RNA sequencing. And some familiar faces emerge here - PIK3CA, TP53, HRAS, NF1, and PTEN pathogenic gene mutations were identified in the majority (21) of cases. As highlighted by the authors, PIK3CA mutations are particularly relevant because they’ve been classified as strong predictors of response to PIK3CA inhibitors, and several drugs have either been recently approved, or are in the pipeline, for targeting the PI3K pathway, including Piqray (alpelisib).
Finally, onto the immuno-oncology markers. PD1 is a molecular ‘gun’ found on the surface of immune cells - when they spot a threat they attach and fire. Unless the cell in question puts out a defence - PD-L1 - which puts the safety on and prevents firing. Tumors can use PD-L1 as a means of escaping destruction by the immune system, so new drugs have been developed to block PDL1 and PD1 from binding. But there’s an added layer of complexity, if another molecule - PTEN - is present, then it’s indicated that drugs designed to target PD-L1/PD1 will be less effective.
PDL1 and PD1 molecules interacting on surface of cells. PD1 is purple and PDL-1 is yellow.
Back to the research. The study found evidence of PD-L1 expression, but only above the threshold for treatments in two cases. And two cases also had concurrent PTEN expression. So, for biomarkers, there’s promise that targeted therapies could work in some cases, but a thorough analysis would need to be done on a case by case basis.
Power in numbers
It’s promising to see this volume of new studies and big data being gathered for the rarer cancers. And it’s evident that the route forward is in numbers, collaborations, and collating evidence from multiple sources. Seeing the mounting evidence for PIK3CA expression involvement in MpBC is just one example of this. But without a centralized database, curated from thousands of papers that have been read and analyzed by trusted experts (with a passion for their work) it would be easy to miss key cases.
Reach out to the QIAGEN team to get access to this exciting data. Test it out for yourself – the first 100 lines of COSMIC are made available for free download.
[1] McCart Reed AE, Kalaw E, Nones K, Bettington M, Lim M, Bennett J, Johnstone K, Kutasovic JR, Saunus JM, Kazakoff S, Xu Q, Wood S, Holmes O, Leonard C, Reid LE, Black D, Niland C, Ferguson K, Gresshoff I, Raghavendra A, Harvey K, Cooper C, Liu C, Kalinowski L, Reid AS, Davidson M, Pearson JV, Pathmanathan N, Tse G, Papadimos D, Pathmanathan R, Harris G, Yamaguchi R, Tan PH, Fox SB, O'Toole SA, Simpson PT, Waddell N, Lakhani SR. Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications. J Pathol. 2019 Feb;247(2):214-227. doi: 10.1002/path.5184. Epub 2018 Dec 20. PMID: 30350370.
Austin, here we come!
We’re getting AMPed up for the upcoming Association for Molecular Pathology 2015 annual meeting! Held at the Austin Convention Center from November 5-7, AMP offers molecular pathologists the chance to catch up on the latest industry and research developments.
This year, AMP’s theme is “Realizing the Dream of Precision Medicine,” and we couldn’t imagine a more timely topic. Precision medicine is becoming a reality, and we’re proud to be forging the tools for this revolution, particularly where cancer is concerned.
Our theme for AMP is “Insights in Oncology,” and we’ll be focusing on both somatic and hereditary cancers during the show. In addition to several key news announcements, we’ve scheduled a number of activities for AMP attendees. We hope you’ll stop by to hear our speakers and check out our demos. Here are some events where you can find us during AMP:
Workshop:
November 4, 4:00-4:50 p.m.
Austin Convention Center, Grand Ballroom E
“Practical Considerations When Using a Clinical Decision Support System for NGS Variant Analysis, Interpretation, and Reporting”
Speakers: Andrea Ferreira-Gonzalez, PhD, Director Molecular Diagnostics Lab, Chair Molecular Diagnostics Division, Virginia Commonwealth University; Jason D. Peterson, M.S., Genomic Informaticist, Clinical Genomics and Advanced Technology (CGAT), Dartmouth-Hitchcock Medical
Dr. Ferreira-Gonzalez and others will discuss practical aspects involved during the evaluation and use of NGS data analysis tools in the clinical laboratory. Learn about their firsthand experiences with QIAGEN® Clinical Insight – a new, scalable clinical decision support platform intended to assist molecular pathologists in interpreting and reporting NGS variants from any targeted gene panel run on any next-gen sequencing instrument.
Evening reception:
November 4, 6:30 -8:30 p.m.
Hilton Austin, Salon A & B, 500 E 4th St, Austin, TX 78701
Networking event with QIAGEN executives
RSVP required: NATradeshows@qiagen.com
In-booth presentations:
November 5, 3:45-4:00 p.m. and November 6, 9:45-10:00 a.m.
Booth #922 and #923 — QIAGEN Bioinformatics
“Enabling Precision Medicine – Through Scalable NGS Assay Interpretation & Reporting in Oncology”
Speaker: Dan Richards, PhD, VP of Biomedical Informatics, QIAGEN
Next-generation sequencing (NGS) based clinical tests are increasingly being adopted in clinical labs, but there are significant challenges in unraveling the complexity of genetic information to offer actionable insights for healthcare professionals. The time spent on assessment of NGS variants continues to be a rate-limiting step to reporting. To address this issue, in May 2015 the American College of Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) developed and published standards for the classification of sequence variants. The computational assessment of NGS variants according to ACMG and AMP guidelines promises to significantly reduce the amount of time from sequence result analysis to reporting. In this presentation, Dr. Dan Richards will discuss our manual curation and data-driven approach to pathogenicity classification using QIAGEN® Clinical Insight, a clinical decision support software tool developed to streamline the variant interpretation and reporting process for clinical laboratories. QIAGEN Clinical Insight leverages the comprehensive QIAGEN Knowledge Base with over 10 million biomedical findings of curated data to compute classifications based on the ACMG-reported criteria and classification system.
Learn more about QIAGEN Clinical Insight
