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Hot Topics of the Day are picked by experts to capture the latest information and publications on public health genomics and precision health for various diseases and health topics. Sources include published scientific literature, reviews, blogs and popular press articles.

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286 hot topic(s) found with the query "Cancer genomics"

Clinical Value of Molecular Targets and FDA-Approved Genome-Targeted Cancer Therapies.
Ariadna Tibau et al. JAMA Oncol 2024 4 (Posted: Apr 05, 2024 9AM)

From the abstract: "What is the validity of the molecular targets and clinical benefits of US Food and Drug Administration–approved genome-targeted cancer drugs based on the results of pivotal clinical trials? In this cohort study, 50 molecular-targeted drugs covering 84 indications were identified. Using an international grading system to evaluate molecular targetability strength (European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets) and a scale to assess clinical benefit in genome-targeted cancer therapies (European Society for Medical Oncology Magnitude of Clinical Benefit Scale), 24 indications (29%) supported high-benefit genomic-based cancer treatments. The therapeutic benefit grading frameworks used in this study can help stakeholders identify therapies with the greatest clinical potential. "

Deep learning in cancer genomics and histopathology
M Unger et al, Genome Medicine, March 27, 2024 (Posted: Mar 27, 2024 1PM)

From the abstract: " Histopathology and genomic profiling are cornerstones of precision oncology and are routinely obtained for patients with cancer. Traditionally, histopathology slides are manually reviewed by highly trained pathologists. Genomic data, on the other hand, is evaluated by engineered computational pipelines. In both applications, the advent of modern artificial intelligence methods, specifically machine learning (ML) and deep learning (DL), have opened up a fundamentally new way of extracting actionable insights from raw data, which could augment and potentially replace some aspects of traditional evaluation workflows. "

Understanding perceptions of tumor genomic profile testing in Black/African American cancer patients in a qualitative study: the role of medical mistrust, provider communication, and family support
CC Luck et al, J Comm Genetics, Feb 16, 2024 (Posted: Feb 16, 2024 4PM)

From the abstract: "Tumor genomic profiling (TGP) examines genes and somatic mutations specific to a patient’s tumor to identify targets for cancer treatments but can also uncover secondary hereditary (germline) mutations. Most patients are unprepared to make complex decisions related to this information. Black/African American (AA) cancer patients are especially at risk because of lower health literacy, higher levels of medical mistrust, and lower awareness and knowledge of genetic testing. But little is known about their TGP attitudes or preferences. "

Forget lung, breast or prostate cancer: why tumour naming needs to change The conventional way of classifying metastatic cancers according to their organ of origin is denying people access to drugs that could help them.
F Andre et al, Nature, January 31, 2024 (Posted: Feb 01, 2024 9AM)

From the article: " Over the past century, the two main approaches to treating people with cancer — surgery and radiation — have focused on where in the body the tumour is. This has led to medical oncologists and other health-care providers, regulatory agencies, insurance companies, drug firms — and patients — categorizing cancers according to the organ in which the tumour originated. Yet there is a growing disconnect between classifying cancers in this way and developments in precision oncology, which uses the molecular profiling of tumour and immune cells to guide therapies."

Landmark national study supports use of whole genome sequencing in standard cancer care
Genomics England, January 2023 (Posted: Jan 14, 2024 10AM)

From the website: "In the largest study of its kind, scientists today report how combining health data with whole genome sequence (WGS) data in patients with cancer can help doctors provide more tailored care for their patients. The research shows that linking WGS data to real-world clinical data can identify changes in cancer DNA that may be relevant for an individual patient’s care, for example by helping identify what treatment might work best for them based on their cancer. "

Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme
A Sosinsky et al, Nature Medicine, January 11, 2024 (Posted: Jan 11, 2024 7AM)

From the abstract: "We analyzed WGS data from 13,880 solid tumors spanning 33 cancer types, integrating genomic data with real-world treatment and outcome data, within a secure Research Environment. Incidence of somatic mutations in genes recommended for standard-of-care testing varied across cancer types. For instance, in glioblastoma multiforme, small variants were present in 94% of cases and copy number aberrations in at least one gene in 58% of cases, while sarcoma demonstrated the highest occurrence of actionable structural variants (13%). "

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.
William C Chen et al. Nat Med 2023 11 (Posted: Nov 10, 2023 7AM)

From the abstract: "Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N?=?1856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared to all other systems tested (N?=?9) in the clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). "

Headway against Brain Tumors with Molecular Targeting of IDH-Mutant Gliomas.
David Schiff et al. N Engl J Med 2023 8 (7) 653-654 (Posted: Aug 21, 2023 8AM)

Machine learning for genetics-based classification and treatment response prediction in cancer of unknown primary.
Intae Moon et al. Nat Med 2023 8 (Posted: Aug 08, 2023 8PM)

Cancer of unknown primary (CUP) is a type of cancer that cannot be traced back to its primary site and accounts for 3–5% of all cancers. Established targeted therapies are lacking for CUP, leading to generally poor outcomes. We developed OncoNPC, a machine-learning classifier trained on targeted next-generation sequencing (NGS) data from 36,445 tumors across 22 cancer types from three institutions. Oncology NGS-based primary cancer-type classifier (OncoNPC) achieved a weighted F1 score of 0.942 for high confidence predictions (=0.9 ) on held-out tumor samples, which made up 65.2% of all the held-out samples

Universal genetic testing may improve risk stratification and treatment for rare and lethal cancer
L Ramsey, News Medical, July 27, 2023 (Posted: Jul 30, 2023 10AM)

Esophageal adenocarcinoma (EAC) is a highly lethal cancer, with a five-year survival rate of less than 20 percent. Although a precursor lesion to EAC, called Barrett's esophagus (BE), is present in roughly seven percent of middle-aged adults, less than one percent of BE patients will progress to EAC, making it difficult to determine which individuals are at risk of developing this deadly cancer. To better understand why only a small fraction of individuals with BE develop EAC, investigators used genomic databases to identify genetic drivers associated with EAC. The found that nine percent of EAC patients harbor mutations in cancer-predisposing genes, shedding light on the causes of progression to the disease and new possibilities for screening and treatment.

Comprehensive Genomic Profiling Identifies Targeted Therapies for Advanced Cancer Patients
Genomeweb, July 18, 2023 (Posted: Jul 24, 2023 11AM)

How the Y chromosome makes some cancers more deadly for men
H Ledford, Nature, June 21, 2023 (Posted: Jun 22, 2023 7AM)

Two studies address cancers that are particularly aggressive in men: colorectal cancer and bladder cancer. One study finds that the loss of the entire Y chromosome in some cells — which occurs naturally as men age — raises the risk of aggressive bladder cancer and could allow bladder tumours to evade detection by the immune system2. The other finds that a particular Y-chromosome gene in mice raises the risk of some colorectal cancers spreading to other parts of the body.

Feasibility and Value of Genomic-Profiling in Cancer of Unknown Primary: Real-World Evidence from Prospective Profiling Study.
Ryan W Huey et al. J Natl Cancer Inst 2023 5 (Posted: May 21, 2023 8AM)

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (10/2016-09/2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients; of which GAs with FDA approved genomically-matched therapy were seen in 25 (40.9%) cases

The Potential Contribution of Cancer Genomics Information to Community Investigations of Unusual Patterns of Cancer: A Workshop
NASEM Workshop, April 13, 2023 (Posted: Mar 09, 2023 8PM)

The National Academies of Sciences, Engineering, and Medicine will hold a virtual, 1-day public workshop on the Potential Contribution of Cancer Genomics Information to Community Investigations of Unusual Patterns of Cancer on April 13, 2023 to explore the state of the science with regard to the identification of genomic and epigenomic biomarkers of environmental exposures associated with cancers, with emphasis on pediatric cancers.

Advancing CAR T cell therapy through the use of multidimensional omics data.
Jingwen Yang et al. Nature reviews. Clinical oncology 2023 1 (Posted: Feb 02, 2023 6AM)

In this Review, we summarize the multidimensional cellular and molecular profiling technologies that have been used to advance our mechanistic understanding of CAR T cell therapies. In addition, we discuss current applications and potential strategies leveraging multi-omics data to identify optimal target antigens and other molecular features that could be exploited to enhance the antitumour activity and minimize the toxicity of CAR T cell therapy.

Disparities According to Genetic Ancestry in the Use of Precision Oncology Assays.
Douglas A Mata et al. The New England journal of medicine 2023 1 (3) 281-283 (Posted: Jan 25, 2023 8AM)

Modern oncology care relies on the assessment of tumor genomic profiles. Although it is known that there are racial and ethnic disparities in cancer outcomes, evidence regarding disparities in access to this increasingly important step in cancer diagnosis and treatment is lacking.1 We examined the use of next-generation sequencing assays according to genetic ancestry of patients in a large cancer genomics database.

Optimized detection of homologous recombination deficiency improves the prediction of clinical outcomes in cancer
FP Villatoro et al, NPJ Precision Oncology, December 29, 2022 (Posted: Dec 31, 2022 7AM)

Assessment of Two Commercial Comprehensive Gene Panels for Personalized Cancer Treatment
AL Ottestad et al, J Per Med, December 26, 2022 (Posted: Dec 26, 2022 11AM)

Analysis of tumor DNA by next-generation sequencing (NGS) plays various roles in the classification and management of cancer. This study aimed to assess the performance of two similar and large, comprehensive gene panels with a focus on clinically relevant variant detection and tumor mutation burden (TMB) assessment. Comparable results were obtained using OCAP and TSO500, suggesting that both panels could be applied to screen patients for enrolment in personalized cancer treatment trials.

Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.
Lee Jessica K et al. NPJ precision oncology 2022 12 (1) 91 (Posted: Dec 12, 2022 6AM)

We performed a pan-cancer analysis of KRAS-altered samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% of adult pan-cancer samples had KRAS alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, and prevalence was similar in liquid biopsies.

Avelumab Plus Talazoparib in Patients With BRCA1/2- or ATM-Altered Advanced Solid Tumors: Results From JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial.
Schram Alison M et al. JAMA oncology 2022 11 (Posted: Nov 18, 2022 6AM)

Is the combination of avelumab and talazoparib effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type? In this phase 2b nonrandomized controlled trial with 200 patients, neither the BRCA1/2 nor ATM cohort met the prespecified target of an objective response rate of 40% across cancer types. Durable clinical activity was observed in patients with BRCA1/2-associated tumor types (eg, ovarian, breast, prostate, and pancreatic cancers) vs those with non–BRCA-associated cancer types; a notable exception were patients with BRCA1/2-altered uterine leiomyosarcoma, who had prolonged responses to treatment.

Spatial genomics maps the structure, nature and evolution of cancer clones.
Lomakin Artem et al. Nature 2022 11 (Posted: Nov 10, 2022 6AM)

Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour. We developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers.

Cancer drugs are closing in on some of the deadliest mutations
H ledford, Nature, October 25, 2022 (Posted: Oct 25, 2022 10AM)

The protein KRAS, mutated in many cancers, was deemed ‘undruggable’. Now scientists are hoping to save lives with a batch of new compounds that target it. The KRAS protein sits at the centre of a spiderweb of crucial cellular pathways. It has a role in governing cell proliferation, cell death and many things in between. The KRAS protein cycles between two conformations, switching from an ‘off’ state to an ‘on’ state when it binds to the signalling molecule GTP. Mutations associated with cancer make the protein more likely to linger in its ‘on’ state,and can be found in nearly every type of tumour.

Cancer research needs better databases- Progress on one of the world’s biggest killers will stall without big registries linking scattered records.
T. S. Karin Eisinger-Mathason, Nature, October 25, 2022 (Posted: Oct 25, 2022 10AM)

The ideal cancer registry would aggregate information from millions of consenting participants; include populations of different ancestry and socio-economic status; collect information going forwards from the time of cancer diagnosis — including imaging, tissue samples and genetic data; and capture participants’ histories by automatically linking to their complete medical records. With these detailed profiles, we could trace cancer diagnoses, health effects and risk of death back to potential risk factors.

MatchMiner: an open-source platform for cancer precision medicine
H Klein et al, NPJ Precision Oncology, October 7, 2022 (Posted: Oct 08, 2022 7AM)

To facilitate enrollment onto PM trials, we developed MatchMiner, an open-source platform to computationally match genomically profiled cancer patients to PM trials. Here, we describe MatchMiner’s capabilities, outline its deployment at Dana-Farber Cancer Institute (DFCI), and characterize its impact on PM trial enrollment. We measured time from genomic sequencing report date to trial consent date for the 166 MMC compared to trial consents not facilitated by MatchMiner (non-MMC). We found MMC consented to trials 55 days (22%) earlier than non-MMC. MatchMiner has enabled our clinicians to match patients to PM trials and accelerated the trial enrollment process.

The current state of the art and future trends in RAS-targeted cancer therapies.
Punekar Salman R et al. Nature reviews. Clinical oncology 2022 8 (Posted: Aug 27, 2022 6AM)

Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.

Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity.
Möhrmann Lino et al. Nature communications 2022 8 (1) 4485 (Posted: Aug 03, 2022 6AM)

The benefit of molecularly-informed therapies in cancer of unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and methylome analysis in 70 CUP patients to reveal substantial mutational heterogeneity with TP53, MUC16, KRAS, LRP1B and CSMD3 being the most frequently mutated known cancer-related genes.

Proteome and phosphoproteome signatures of recurrence for HPV+ head and neck squamous cell carcinoma
T Kaneko et al, Comm Medicine, July 30, 2022 (Posted: Jul 31, 2022 7AM)

To gain insights into the mechanisms of recurrence and to inform patient stratification and personalized treatment, we compared the proteome and phosphoproteome of recurrent and non-recurrent tumors by quantitative mass spectrometry. We observe significant differences between the recurrent and non-recurrent tumors in cellular composition, function, and signaling. The recurrent tumors are characterized by a pro-fibrotic and immunosuppressive tumor microenvironment (TME) featuring markedly more abundant cancer-associated fibroblasts, extracellular matrix (ECM), neutrophils, and suppressive myeloid cells.

Systematic pan-cancer analysis of mutation-treatment interactions using large real-world clinicogenomics data.
Liu Ruishan et al. Nature medicine 2022 6 (Posted: Jul 01, 2022 8AM)

We perform a large-scale computational analysis of 40,903 US patients with cancer who have detailed mutation profiles, treatment sequences and outcomes derived from electronic health records. We systematically identify 458 mutations that predict the survival of patients on specific immunotherapies, chemotherapy agents or targeted therapies across eight common cancer types. We further characterize mutation–mutation interactions that impact the outcomes of targeted therapies.

Genome-wide mapping of somatic mutation rates uncovers drivers of cancer
MA Sherman et al, Nature Biotechnology, June 20, 2022 (Posted: Jun 20, 2022 6PM)

We use deep neural networks to map cancer-specific mutation rates genome-wide at kilobase-scale resolution. These estimates are then refined to search for evidence of driver mutations under positive selection throughout the genome by comparing observed to expected mutation counts. We mapped mutation rates for 37 cancer types and applied these maps to identify putative drivers within intronic cryptic splice regions, 5' untranslated regions and infrequently mutated genes. Our high-resolution mutation rate maps, available for web-based exploration, are a resource to enable driver discovery genome-wide.

Prevalence of Germline Findings Among Tumors From Cancer Types Lacking Hereditary Testing Guidelines
TA Yap et al, JAMA Network Open, May 20, 2022 (Posted: May 21, 2022 2PM)

In this cross-sectional study including records from 34?642 patients, approximately 7% of patients with cancer harbored pathogenic or likely pathogenic germline variants. The prevalence of pathogenic or likely pathogenic germline findings was highest in bladder and lung cancers. The findings of this study suggest that paired tumor/normal sequencing has the potential added benefit of identifying germline findings, especially in cancer types, such as bladder and lung, in which germline testing may not be indicated without a suspicious family history of cancer.

Paired Tumor-Germline Testing as a Driver in Better Cancer Care
JW Henson et al, JAMA Network Open, May 20, 2022 (Posted: May 21, 2022 2PM)

Paired tumor-germline testing can lead to better treatment choices. Hereditary cancer syndromes are caused by inactivated tumor suppressor genes. By comparison, activated oncogenes are poorly tolerated during embryonic development. Variant tumor suppressor genes and their inactive protein products are more challenging to target than are activated oncogenes. Attention thus turns from the gene itself to the aberrant downstream molecular pathway and subsequent effects of the pathway. Two notable examples are the use of checkpoint inhibitors to target high tumor mutation burdens from tumors related to a defective mismatch repair pathway (ie, Lynch syndrome when originating in germline) and poly adenosine diphosphate ribose polymerase inhibitors to exploit single-strand breaks from tumors related to the homologous repair/BRCA pathway (ie, hereditary breast and ovarian cancer syndrome when originating in germline).

Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management
AJ Cooper et al, Nature Rev Clin Oncology, May 2022 (Posted: May 14, 2022 11AM)

The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies.

Largest study of whole genome sequencing data reveals new clues to causes of cancer
Genomics England, April 21, 2022 (Posted: Apr 23, 2022 9AM)

DNA analysis of thousands of tumours from NHS patients has found a ‘treasure trove’ of clues about the causes of cancer, with genetic mutations providing a personal history of the damage and repair processes each patient has been through. Because of the vast amount of data provided by whole genome sequencing, the researchers were able to detect patterns in the DNA of cancer or ‘mutational signatures’, that provide clues about whether a patient has had a past exposure to environmental causes of cancer such as smoking or UV light, or has internal, cellular malfunctions.

Pan-cancer prognostic genetic mutations and clinicopathological factors associated with survival outcomes: a systematic review
J Kaubryte et al, NPJ Precision Oncology, April 22, 2022 (Posted: Apr 22, 2022 0PM)

Genetic studies included 210,802 patients and identified 440 gene mutations associated with cancer survival, including genes TP53, BRCA1, BRCA2, BRAF, KRAS, BIRC5. We generated a comprehensive knowledge base of biomarkers that can be used to tailor treatment according to patients’ unique genetic and clinical characteristics. Our pan-cancer investigation uncovers the biomarker landscape and their combined influence that may help guide health practitioners and researchers across the continuum of cancer care from drug development to long-term survivorship.

Early detection of cancer
D Crosby et al, Science, March 18, 2022 (Posted: Mar 22, 2022 11AM)

Many types of cancer are detected at an advanced stage, when treatment options are limited and prognosis is poor. Being able to detect cancers early can substantially improve survival, but this approach comes with challenges, including the possibility of overdiagnosis and overtreatment, which can harm people who would not have developed overt malignancy. In this review, we discuss the importance of cancer early detection and the main challenges that need to be overcome to better understand the early events in tumorigenesis that are detectable in screening tests. The results of these tests can then be reliably interpreted to determine whether an individual requires treatment.

Diversity in cancer genomics research is a matter of equity and scientific discovery.
Pal Tuya et al. Genetics in medicine : official journal of the American College of Medical Genetics 2021 12 (Posted: Mar 07, 2022 9AM)

Promoting diversity to advance genomics research is an ethical issue to ensure that populations beyond those of European descent benefit equally from the advances as highlighted in a new study which shows that polygenic risk scores (PRSs) constructed from single-nucleotide variations (SNVs, formerly singe nucleotide polymorphisms [SNPs]) increase the discriminatory ability to predict cancer risks in individuals of European but not of African ancestry. Their findings underscore the potential for PRS to widen existing health disparities because of the paucity of data in populations of non-European descent,

The ‘war on cancer’ isn’t yet won- The US National Cancer Act of 1971 has fostered tremendous progress in our understanding of the biology that underlies cancer. However, scientific and social challenges remain.
Nature editorial January 19, 2022 (Posted: Jan 19, 2022 2PM)

Over the past 50 years, scientists have made remarkable progress in understanding this complexity through projects carried out by basic and clinical researchers working ever-more closely. The Cancer Genome Atlas and Pan-Cancer Analysis of Whole Genomes projects have revealed both the complexity of cancer and important clues to new treatments. Discoveries made during basic research on the cell cycle have led to the development of anticancer drugs that target certain cell-cycle proteins. Last year, the FDA approved a drug for some non-small cell lung cancers that disables a mutant form of the KRAS protein.

Assessment of tumour-agnostic therapies in basket trials
A Popat et al, Lancet Oncology, Jan 2022 (Posted: Dec 31, 2021 7AM)

Overall survival for oncology drugs approved for genomic indications
A Haslam et al, EJC, January 2022 (Posted: Dec 23, 2021 10AM)

We found 53 drugs approved for 92 unique indications from 2006 to 2020. We found that 50 drugs (55%) approved for a genomic indication had a randomized study evaluating OS benefit, and of those, only 22 demonstrated an improvement in OS. Similarly, 52 drugs (57%) evaluated PFS benefit, and 51 of these studies demonstrated an improvement in PFS. Drugs approved for BRAF V600 melanoma demonstrated an improvement in OS more often than drugs approved for ALK non–small cell lung cancer. The median improvement in OS was 4.7 months.

Computational analysis of cancer genome sequencing data
IC Ciriano et al, Nature Rev Genetics, December 10, 2021 (Posted: Dec 11, 2021 8AM)

Distilling biologically meaningful information from cancer genome sequencing data requires comprehensive identification of somatic alterations using rigorous computational methods. As the amount and complexity of sequencing data have increased, so has the number of tools for analysing them. Here, we describe the main steps involved in the bioinformatic analysis of cancer genomes, review key algorithmic developments and highlight popular tools and emerging technologies. These tools include those that identify point mutations, copy number alterations, structural variations and mutational signatures in cancer genomes.

Trends in Use of Next-Generation Sequencing in Patients With Solid Tumors by Race and Ethnicity After Implementation of the Medicare National Coverage Determination
DM Sheinson et al, JAMA Network Open, December 10, 2021 (Posted: Dec 10, 2021 4PM)

In this cohort study of 92?687 patients with lung, breast, colon, and skin cancer, national coverage decision implementation was associated with a slower rate of increase in next-generation sequencing use for patients with patient assistance programs compared with Medicare beneficiaries. Implementation of the NCD was not associated with narrowing of racial and ethnic disparities among Medicare beneficiaries alone or the overall insured population.

Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study.
Sicklick Jason K et al. Genome medicine 2021 10 (1) 155 (Posted: Oct 10, 2021 7AM)

Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0-15). Fifty-four treated patients (71%) received = 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R2 = 0.92; P = 0.01), and high (= 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01-10.83), P = 0.048], PFS [HR 0.55 (0.28-1.07), P = 0.08], and OS [HR 0.42 (0.21-0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups.

Deep learning in cancer diagnosis, prognosis and treatment selection.
Tran Khoa A et al. Genome medicine 2021 9 (1) 152 (Posted: Sep 29, 2021 6AM)

In this review, we provide an overview of emerging deep learning techniques and how they are being applied to oncology. We focus on the deep learning applications for omics data types, including genomic, methylation and transcriptomic data, as well as histopathology-based genomic inference, and provide perspectives on how the different data types can be integrated to develop decision support tools.

Estimating the predictive power of silent mutations on cancer classification and prognosis
T Gutman et al, NPJ Genomic Medicine, August 12, 2021 (Posted: Aug 12, 2021 7AM)

In the current study, based on the analysis of 9,915 cancer genomes and approximately three million mutations, we provide a comprehensive quantitative evaluation of the predictive power of various types of silent and non-silent mutations over cancer classification and prognosis. The results indicate that silent-mutation models outperform the equivalent null models in classifying all examined cancer types and in estimating the probability of survival 10 years after the initial diagnosis.

Limited evolution of the actionable metastatic cancer genome under therapeutic pressure
J van de Haar et al, Nature Medicine, August 9, 2021 (Posted: Aug 09, 2021 11AM)

Our data demonstrate that there is limited evolution of the actionable genome of treated metastases. A single WGS analysis of a metastatic biopsy is generally sufficient to identify SOC genomic biomarkers and to identify investigational treatment opportunities.

Clinical Outcomes of Molecular Tumor Boards: A Systematic Revi
KL Larson et al, JCO Precision Oncology, July 2021 (Posted: Jul 19, 2021 7AM)

In studies reporting response rates, patients receiving MTB-recommended therapy had overall response rates ranging from 0% to 67%. In the only trial powered on clinical outcome and including a control group, the group receiving MTB-recommended therapy had significantly improved rate of progression-free survival compared with those receiving conventional therapy.

Collaborating with Central Cancer Registries for Public Health Genomics
CDC, July 2021 Brand (Posted: Jul 04, 2021 7AM)

Central cancer registries make up a comprehensive national network of population-based cancer surveillance to monitor cancer cases at local, state, and national levels. This CDC guide provides examples of how state health departments have collaborated with cancer registries to inform and implement activities in cancer genomics to meet the special needs of people at risk of hereditary cancers.

Molecular cancer screening: in search of evidence
S Raoof et al, Nature Medicine, July 2, 2021 (Posted: Jul 03, 2021 7AM)

Cancer screening with germline genetic sequencing and liquid biopsy could facilitate early cancer detection. But testing if these technologies reduce the burden of cancer mortality will require rethinking how clinical trials are run.

Personal regulome navigation of cancer
HY Chang et al, Nat Rev Cancer, June 2021 (Posted: Jun 30, 2021 7AM)

Homing in on genomic instability as a therapeutic target in cancer
CM BIelski et al, Nat Comms, June 16, 2021 (Posted: Jun 17, 2021 9AM)

Mining mutation contexts across the cancer genome to map tumor site of origin
S Chakraborty et al, Nat Comms, May 24, 2021 (Posted: May 25, 2021 7AM)

The landscape and driver potential of site-specific hotspots across cancer genomes
RI Juul et al, NPJ Genomic Medicine, May 13, 2021 (Posted: May 14, 2021 8AM)

Here we detect, categorize, and characterize site-specific hotspots using 2279 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes project and provide a resource of annotated hotspots genome-wide. We investigate the excess of hotspots in both protein-coding and gene regulatory regions and develop measures of positive selection and functional impact for individual hotspots.

Biomarker approach harnessed in trials of personalized medicine for bladder cancer
N Dizman et al, Nature Medicine, May 3, 2021 (Posted: May 03, 2021 0PM)

A multi-arm clinical trial reports results of testing a strategy for the treatment of bladder cancer that uses standard immunotherapy plus biomarker assessment and targeted therapies.

Digital Display Precision Predictor: the prototype of a global biomarker model to guide treatments with targeted therapy and predict progression-free survival
V Lazar et al, NPJ Precision Oncology, April 28, 2021 (Posted: Apr 29, 2021 7AM)

We present the algorithm, Digital Display Precision Predictor (DDPP), aiming to identify transcriptomic predictors of treatment outcome. For example, 17 and 13 key genes were derived from the literature by their association with MTOR and angiogenesis pathways, respectively, and their expression in tumor versus normal tissues was associated with the progression-free survival (PFS) of patients treated with everolimus or axitinib (respectively) using DDPP

Predictive Biomarkers: Progress on the Road to Personalized Cancer Immunotherapy
LE Emmens, JNCI, April 2021 (Posted: Apr 18, 2021 7AM)

Can mRNA vaccines be used in cancer care?
D Carter, MD Anderson, January 2021 (Posted: Apr 12, 2021 7AM)

Patients' and Oncologists' Knowledge and Expectations Regarding Tumour Multigene Next Generation Sequencing: A Narrative Review.
Shirdarreh Melika et al. The oncologist 2021 (Posted: Apr 09, 2021 10AM)

Patients generally had positive attitudes towards tumour NGS despite relatively little knowledge of test-related genetics concepts, but their expectations often exceeded the reality of low clinical utility. Patients with higher education and greater genetics knowledge had more realistic expectations and a more altruistic view of the role of NGS. Attitudes towards disclosure of secondary findings were highly variable. Oncologists had poor to moderate genomic literacy.

Clinical cancer genomic profiling.
Chakravarty Debyani et al. Nature reviews. Genetics 2021 3 (Posted: Mar 26, 2021 8AM)

We discuss ongoing efforts to enhance the clinical utility of tumor genomic profiling by integrating tumor and germline analyses, characterizing allelic context and identifying mutational signatures that influence therapy response. We also discuss the potential clinical utility of more comprehensive whole-genome and whole-transcriptome sequencing and ultra-sensitive cell-free DNA profiling platforms.

Predictive and prognostic transcriptomic biomarkers in soft tissue sarcomas
E Merry et al, NPJ Precision Oncology, March 5, 2021 (Posted: Mar 08, 2021 7AM)

Structural variant detection in cancer genomes: computational challenges and perspectives for precision oncology
I van Belzen et al, NPJ Precision Oncology, March 5, 2021 (Posted: Mar 08, 2021 7AM)

Cancer is generally characterized by acquired genomic aberrations in a broad spectrum of types and sizes, ranging from single nucleotide variants to structural variants (SVs). At least 30% of cancers have a known pathogenic SV used in diagnosis or treatment stratification. However, research into the role of SVs in cancer has been limited due to difficulties in detection.

Single-cell RNA sequencing: one step closer to the clinic- Single-cell RNA-sequencing can help in the prediction of drug resistance in patients with multiple myeloma
RS Pistofidis et al, Nature Medicine, March 4, 2021 (Posted: Mar 06, 2021 7AM)

The NCI Genomic Data Commons.
Heath Allison P et al. Nature genetics 2021 2 (Posted: Feb 26, 2021 8AM)

The National Cancer Institute (NCI) Genomic Data Commons (GDC) contains more than 2.9 petabytes of genomic and associated clinical data from more than 60 NCI-funded and other contributed cancer genomics research projects. The GDC consists of five applications over a common data model and a common application programming interface.

Precision Medicine in Oncology-Toward the Integrated Targeting of Somatic and Germline Genomic Aberrations.
Yap Timothy A et al. JAMA oncology 2021 2 (Posted: Feb 26, 2021 8AM)

The successful practice of precision medicine requires the clinical integration of a trifecta of (1) molecular testing of patients, (2) interpretation of molecular profiling results and identification of matched therapies, and (3) treatment of patients with molecularly targeted agents and other therapies. Each of these key areas is complex and requires myriad considerations that are dependent on available technology, expertise, infrastructure, funding, and clinical need.

Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors.
Cobain Erin F et al. JAMA oncology 2021 2 (Posted: Feb 26, 2021 8AM)

What is the clinical utility of genomic profiling for patients with advanced solid tumors? In this cohort study of 1015 patients who underwent integrative genomic profiling, a high rate of pathogenic germline variants and a subset of patients who derive substantial clinical benefit from sequencing information were identified.

Exploiting KRAS-mediated metabolic reprogramming as a therapeutic target.
Bootsma Sanne et al. Nature genetics 2021 Jan (1) 9-10 (Posted: Jan 09, 2021 0PM)

Half of all colorectal cancers bear KRAS-activating mutations that affect the metabolic dependencies of cancer cells and drive resistance to commonly used drugs. A new study provides insights into KRAS-driven metabolic rewiring and identifies a new therapeutic target for KRAS-mutant cancers

The association between tumor mutational burden and prognosis is dependent on treatment context.
Valero Cristina et al. Nature genetics 2021 Jan (Posted: Jan 06, 2021 8AM)

We analyzed 10,233 patients with 17 cancer types before/without treatment or after treatment. In non-ICI-treated patients, higher TMB was not associated with better prognosis; in fact, in many cancer types, higher TMB was associated with poorer survival, in contrast to ICI-treated patients in whom higher TMB was associated with longer survival.

Tumor Mutation Burden and Cancer Treatment
MJ Fusco et al, JAMA Oncology Patient Page, December 17, 2020 (Posted: Dec 18, 2020 8AM)

Tumor mutation burden (TMB) can be measured using next-generation sequencing of tumor tissue. Cancers with high TMB may be more likely to respond to immune checkpoint inhibitors. Studies are now evaluating measuring TMB from circulating tumor DNA in the plasma, making it potentially possible to test TMB from blood in the future.

KRAS inhibitors at last
H Stower, Nature Medicine, December 78, 2020 (Posted: Dec 08, 2020 8AM)

Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment
DA Wheeler et al, Cancer Cell, November 2020 (Posted: Nov 27, 2020 2PM)

Genomics of 110 patients with exceptional response to therapy profiled. Plausible molecular mechanisms related to therapy identified in ~23% of cases. Proposed mechanisms involve DNA damage, signaling, and the immune response. Synthetic lethality with temozolomide in tumors with a defective DNA damage response.

Investigational KRAS Inhibitor Tested for Advanced Solid Tumors
J Abbasi, JAMA, NoOvember, 10 2020 (Posted: Nov 11, 2020 11AM)

No dose-limiting toxic effects or treatment-related deaths occurred with sotorasib, an experimental drug that targets the cancer-causing KRAS p.G12C genetic variant, in a phase 1 trial involving patients with heavily treated advanced solid tumors.

The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk.
Balmain Allan et al. Nature genetics 2020 Oct (Posted: Oct 29, 2020 11AM)

In a concept supported by decades-old data from mouse tumor models, non-mutagenic tumor-promoting agents have been posited to activate the proliferation of dormant mutated cells, thus generating actively growing lesions, with the promotion stage as the rate-limiting step in tumor formation.

Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial
H Hayashi et al, JAMA Oncology, October 15, 2020 (Posted: Oct 16, 2020 7AM)

This phase 2 nonrandomized clinical trial of such site-specific treatment in 97 patients with cancer of unknown primary site revealed a 1-year survival probability of 53.1%, with a durable response to targeted therapy being observed in patients with actionable genetic alterations.

The role of genomics in global cancer prevention
O Ginsburg et al, Nature Rev Clin Oncology, September 2020 (Posted: Sep 29, 2020 8AM)

In this Review, we present the relevant history and emerging frontiers of cancer genetics and genomics from the perspective of global cancer prevention. We highlight the importance of local context in the adoption of new technologies and emergent evidence, with illustrative examples from worldwide.

Implementing Cancer Genomics in State Health Agencies: Mapping Activities to an Implementation Science Outcome Framework.
Green Ridgely Fisk et al. Public health genomics 2020 Sep 1-12 (Posted: Sep 18, 2020 9AM)

We identified state health agency activities addressing hereditary breast and ovarian cancer and Lynch syndrome by reviewing project narratives from Centers for Disease Control and Prevention Cancer Genomics Program funding recipients, leading discussions with state health agencies, and conducting an environmental scan.

Association of mismatch repair status with survival and response to neoadjuvant chemo(radio)therapy in rectal cancer
SB Ye, NPJ Precision Oncology, September 8, 2020 (Posted: Sep 09, 2020 9AM)

Prior reports have indicated that defective mismatch repair (MMR) has a favorable impact on outcome in colorectal cancer patients treated with surgery, immunotherapy, or adjuvant chemotherapy. Here we report that dMMR was associated with improved disease-free survival (DFS) (P?=?0.034) in patients receiving neoadjuvant chemotherapy (NCT).

Comparison of Tissue-Based Molecular Markers in Younger versus Older Patients with Colorectal Neoplasia
PJ Limburg et al, CEBP, August 2020 (Posted: Sep 01, 2020 8AM)

Selpercatinib Aimed at RET -Altered Cancers.
Kurzrock Razelle et al. The New England journal of medicine 2020 Aug (9) 868-869 (Posted: Aug 27, 2020 7AM)

A remarkable increase has occurred in the number of highly targeted drugs that have efficacy in patients with advanced cancers that harbor specific genomic alterations.

Development of a Machine Learning Model for Survival Risk Stratification of Patients With Advanced Oral Cancer
YJ Tseng et al, JAMA Network Open, August 21, 2020 (Posted: Aug 25, 2020 7AM)

In this 15-year cohort study of 334 patients, a risk stratification model using comprehensive clinicopathologic and genetic data accurately differentiated the high-risk group from the low-risk group in postoperative cancer-specific and locoregional recurrence–free survival for patients with advanced oral cancer.

Molecules in the blood of older people promote cancer spread
H Wang et al, Nature News, August 19, 2020 (Posted: Aug 21, 2020 9AM)

A molecule produced by the metabolism of proteins and fats has been found to accumulate in the blood of older people, and to endow cancer cells with the ability to spread from one site in the body to others.

Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers
H Kim et al, Nature Genetics, August 17, 2020 (Posted: Aug 18, 2020 8AM)

Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification.

Integrating genetic and non-genetic determinants of cancer evolution by single-cell multi-omics
AS Nam et al, Nat Rev Genetics, August 17, 2020 (Posted: Aug 17, 2020 8AM)

n this Review, we discuss emerging analytic and experimental technologies for single-cell multi-omics that enable the capture and integration of multiple data modalities to inform the study of cancer evolution. These data show that cancer results from a complex interplay between genetic and non-genetic determinants of somatic evolution.

Discovery through clinical sequencing in oncology
MTA Donoghue et al, Nat Cancer, August 10, 2020 (Posted: Aug 11, 2020 7AM)

Beyond its role in driving clinical-trial enrollments and guiding therapy in individual patients, large-scale clinical genomics in oncology also represents a rapidly expanding research resource for translational scientific discovery.

Better Biomarkers for Surgeons Treating Cancer
DL Bartlett, JAMA Surgery, June 10, 2020 (Posted: Jun 12, 2020 8AM)

MutSpot: detection of non-coding mutation hotspots in cancer genomes
YA Guo et al, NPJ Genomic Medicine, June 5, 2020 (Posted: Jun 06, 2020 6AM)

Recurrence and clustering of somatic mutations (hotspots) in cancer genomes may indicate positive selection and involvement in tumorigenesis. MutSpot performs genome-wide inference of mutation hotspots in non-coding and regulatory DNA of cancer genomes. MutSpot performs feature selection across hundreds of epigenetic and sequence features.

Germline Testing In Advanced Cancer Can Lead to Targeted Tx
R Nelson, Medscape, June 2, 2020 (Posted: Jun 03, 2020 7AM)

From 7% to nearly 9% of patients with advanced cancer were found to harbor a germline variant with targeted therapeutic actionability in the first study of its kind. The study involved 11,975 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019.

Genomics-guided pre-clinical development of cancer therapies
HE Francies et al, Nature Cancer, May 2020 (Posted: May 26, 2020 7AM)

We consider the evidence that supports genomics-guided drug development and review the concept of oncogene addiction, including recent findings that inform this therapeutic approach. We consider non-oncogene addiction and how this synthetic-lethal paradigm could expand the range of new therapies, particularly for currently undruggable cancers.

Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden.
Qing Tao et al. Nature communications 2020 May (1) 2438 (Posted: May 17, 2020 7AM)

Assessment of the Value of Tumor Variation Profiling Perceived by Patients With Cancer
P Butow et al, JAMA Network Open, May 14, 2020 (Posted: May 17, 2020 7AM)

In this survey study of 777 patients with advanced cancer, 689 individuals (89%) indicated that they would have tumor molecular profiling for as little as a 1% actionable return rate, but fewer were willing to pay for it.

Progress in refining the clinical management of cancer of unknown primary in the molecular era
E Rassy et al, Nature Rev Clin Oncology, April 2020 (Posted: May 12, 2020 9AM)

In this Review, we discuss the clinical management of cancer of unknown primary (CUP) in the era of precision medicine. We focus on the advances in understanding the biology of CUP, the implications for the diagnosis and classification of CUP according to the tissue of origin and the shift away from empirical therapy towards tailored therapy.

Insights From a Temporal Assessment of Increases in US Private Payer Coverage of Tumor Sequencing From 2015 to 2019
JR Trosman et al, Value in Health, May 2020 (Posted: May 08, 2020 9AM)

Temporal analyses revealed trends of payer coverage for tumor sequencing. This included an increase but continued variability in coverage over 3.5 years, the possible contribution of CMS decision to the pace of private payers’ coverage, and the impact of using a third-party policy on coverage timing, and the importance of small payers in early adoption.

A catalogue of cancer-driving mutations in healthy tissue
Nature News, April 22, 2020 (Posted: Apr 23, 2020 8AM)

A study of cancer-associated mutations in normal endometrial glands of the uterus has now been performed using whole-genome sequencing. The analysis sheds light on the early changes that lead to invasive disease.

Role of RNA modifications in cancer
I Barbieri et al, Nature Reviews Cancer, April 2020 (Posted: Apr 23, 2020 8AM)

Microbiome genomics for cancer prediction
L Adlung et al, Nature Cancer, April 2020 (Posted: Apr 22, 2020 8AM)

Although cancer genomics is a powerful tool to understand cancer and develop diagnostic tools, the contribution of the microbiome in cancer diagnosis and clinical assessment is much less studied. Several authors provide their respective views on how studying cancer metagenomes could facilitate identification, diagnosis and staging of different tumor types.

Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer
JAMA Oncology, March 12, 2020 (Posted: Mar 14, 2020 6AM)

Is germline variant status of BRCA1/2 and non-BRCA1/2 breast cancer predisposition genes associated with higher response rates in patients enrolled in the GeparOcto trial?

Genetic Counseling and Germline Testing in the Era of Tumor Sequencing: A Cohort Study
S Klek et al, JNCI Cancer Spectrum (Posted: Mar 10, 2020 8AM)

A clinical approach to detecting germline pathogenic variants from tumor-only sequencing
OC Bersoy et al, JNCI Cancer Spetrum, March 2020 (Posted: Mar 10, 2020 8AM)

Whole tumor genomes across cancers.
et al. Nature genetics 2020 Mar (3) 241 (Posted: Mar 08, 2020 10AM)

This impressively large project, comprising many working groups focusing on various molecular or genetic features of cancer, has generated valuable data for the cancer research community that will continue to be mined for many years to come.

The Challenges of Optimizing Biomarkers To Guide Clinical Decision Making
SM Hewitt JNCI, March 4, 2020 (Posted: Mar 06, 2020 8AM)

Tumor Mutational Burden From Tumor-Only Sequencing Compared With Germline Subtraction From Paired Tumor and Normal Specimens
K Parikh et al, JAMA Network Open, February 28, 2020 (Posted: Mar 01, 2020 8AM)

In this cohort study of 50 tumor samples comparing tumor mutation burden (TMB) calculated using 3 filtering approaches with germline-subtracted TMB, no strong association was found between TMB calculated using any filtering method and germline-subtracted TMB.

The pan-cancer landscape of prognostic germline variants in 10,582 patients.
Chatrath Ajay et al. Genome medicine 2020 Feb (1) 15 (Posted: Feb 20, 2020 10AM)

Germline variants are predictive of outcome in cancer patients and specific germline variants can improve patient outcome predictions beyond predictions made using clinical factors alone.

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Disclaimer: Articles listed in Hot Topics of the Day are selected by Public Health Genomics Branch to provide current awareness of the scientific literature and news. Inclusion in the update does not necessarily represent the views of the Centers for Disease Control and Prevention nor does it imply endorsement of the article's methods or findings. CDC and DHHS assume no responsibility for the factual accuracy of the items presented. The selection, omission, or content of items does not imply any endorsement or other position taken by CDC or DHHS. Opinion, findings and conclusions expressed by the original authors of items included in the Clips, or persons quoted therein, are strictly their own and are in no way meant to represent the opinion or views of CDC or DHHS. References to publications, news sources, and non-CDC Websites are provided solely for informational purposes and do not imply endorsement by CDC or DHHS.
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