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Oncologists’ Guide to Genomics

Stay current on the latest trends in genomics and molecular diagnostics for oncology.

Tuesday, May 21, 2019

By Catlin Nalley

A team of researchers from the Wellcome Sanger Institute and Open Targets recently conducted one of the largest CRISPR screens of cancer genes to date (Nature 2019; The research is supported, in part, by Stand Up To Cancer (SU2C), specifically the SU2C–Dutch Cancer Society Tumor Organoids Dream Team.

The investigators utilized CRISPR technology to disrupt genes in over 300 cancer models from 30 cancer types and discovered thousands of key genes crucial for cancer's survival. A new system was then developed to prioritize and rank 600 drug targets that show the most promise for development into treatments.

"The development of new anti-cancer drugs remains extremely challenging. The vast majority of new therapies ultimately fail during clinical development and the range of new drug targets entering industry pipelines is actually on the decline," noted co-lead study author Mathew J. Garnett, PhD, from the Wellcome Sanger Institute. "This creates an extremely costly and inefficient process, which ultimately negatively impacts our ability to make the best medicines for patients.

"We reasoned that a more rigorous, systematic, and robust target identification at the beginning of drug development could help expand the range of targets, improve success rates, and accelerate the development of new therapies," he noted. "The use of functional genomics strategies, using technologies such as CRISPR screens, that effectively identify and prioritize candidate targets in tumors is one possible solution to this problem."

Study Details

To comprehensively catalogue genes required for cancer cell fitness, the researchers performed 941 CRISPR-Cas9 fitness screens in 339 cancer cell lines, targeting 18,009 genes. Following quality control, the final analysis set included 324 cell lines from 30 different cancer types across 19 different tissues, according to study authors.

The researchers focused on common cancers, including lung, colon, and breast, as well as cancers such as pancreatic where new treatments are urgently needed.

"We used CRISPR gene-editing technology to systematically 'deconstruct' cancer genomes by deleting each gene, one by one, in 324 cancer cell lines from 30 cancer types," explained Garnett. "This identified genes which were selectively required for the fitness of cancer cells in defined molecular contexts.

"These represent vulnerabilities in cancer cells which could be targeted therapeutically," he continued. "We integrated this information with genomic datasets from patients and information on the tractability of candidate targets for drug development to generate ranked lists of new targets for multiple cancer types.

"We identified over 600 candidate drug targets across multiple different cancer types. Some of these were associated with a genomic change in tumor cells, so called genomic biomarkers, that could be useful in selecting patients who would respond to a new therapy."

Amongst the targets, researchers identified and verified a striking dependency on the gene Werner syndrome helicase in cancers cells with a deficiency in a DNA repair process called mismatch repair, according to Garnett.

"This DNA repair defect occurs in a high proportion of colon, stomach, and endometrial cancers," he explained. "In contrast, loss of Werner had no effect in cells that do not have a mismatch repair defect. This is an extremely exciting finding and suggests that Werner could be a good drug target specifically in the setting of cancers which have a defect in this DNA repair process."

Garnett noted that the identification of Werner as a target in a defined subset of cancers is "likely to lead to drug development programs targeting this protein."

Implications, Next Steps

This research provides a rigorous and unbiased framework for the identification of candidate cancer drug targets, Garnett told Oncology Times. "We anticipate our work will lead to a broader range and more effective set of candidate drug targets in the future—which could help improve development success rates and bring patient benefit."

While the research lays the foundation for this approach, there is still more work to be done, Garnett noted. "We believe there could be benefits to expanding this approach across a larger and more diverse set of cancer types. For example, some specific tissues or histo-pathological subtypes are poorly represented in the current set of results. This means we can't identify new targets for these patients.

"There is also a huge amount of work to be done to follow up the candidate targets we have discovered, and we are very excited about the prospect of Werner as a new drug target. Overall, this study is part of a larger effort called the Cancer Dependency Map, which aims to systematically identify vulnerabilities in cancer cells which could be used to guide the development of new cancer medicines.

"We believe this will be important for translating our increasingly deep understanding of the genetics of cancer into improved treatments for patients," Garnett concluded.

Catlin Nalley is associate editor.

Friday, April 19, 2019

By Catlin Nalley

Seventy-four percent of patients with pancreatic cancer die within 1 year of diagnosis and 91 percent will succumb to their disease within 5 years. A lack of early detection and a need for more effective treatment approaches both factor into the low survival rates among these patients.

"The majority of patients with pancreatic cancer present with advanced or metastatic disease," noted Aatur Singhi, MD, PhD, Assistant Professor of Pathology at the University of Pittsburgh. "So, how do we treat these patients?"

To improve survival rates and address these challenges, researchers sought to create a more personalized approach by utilizing genetic signatures to better match drugs to patients (Gastroenterology 2019; doi:10.1053/j.gastro.2019.02.037).

"We have seen a paradigm shift in other cancers, such as breast and lung, where we utilize genomic information to direct targeted therapies," said senior author Nathan Bahary, MD, PhD, Associate Professor of Medicine at the University of Pittsburgh and Clinical Oncologist at UPMC Hillman Cancer Center. "However, to date, this hasn't really been the case for pancreatic cancer.

"Patients who have specific molecular alterations and are able to get directed treatments up front rather than in later lines of therapy often have a survival advantage," he continued. "It behooves us to bring pancreatic cancer into the 21st century as well, and that paper offers a guide on how it can be done."

Study Details

Researchers performed targeted genomic profile analyses of 3,594 pancreatic ductal adenocarcinomas (PDAC) samples from an international cohort.

"We did a comprehensive, targeted sequencing analysis of genomic alterations that are known to occur in all types of cancers," explained Singhi, lead author of the study. "We are focused on a targeted approach because we want to increase the sensitivity. Looking for alterations that truly have a corresponding drug analog that is utilized in therapy [is important]. These are much more valuable than looking at an obscure gene we know nothing about."

The researchers also evaluated for gene fusions. "We isolated RNA and identified specific gene fusions that can occur in certain cancers that we know can be targeted in pancreatic cancer as well," Singhi said.

Tumor mutation burden (TMB) and microsatellite instability (MSI) status also were assessed. "It is known that patients with MSI in their cancer as well as those with a high TMB are potentially susceptible to immunotherapy," Singhi explained.

Key Findings

Researchers found that 17 percent of pancreatic cancers have genomic alterations that could be targeted by existing chemotherapies.

Data showed that the most frequently altered genes in PDAC tissues included KRAS, TP53, CDKN2A, and SMAD4KRAS mutations were detected in 88 percent of samples.

Among PDACs without KRAS mutations, researchers "found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets; n=132; 4%), as well as gene fusions (n=51), gene amplifications (n=35), genes with missense mutations (n=30), and genes that contain deletions (n=16)."

Among PDAC samples evaluated for MSI (n=2,563) and TMB (n=1,021), MSI-H and/or TMB-H phenotypes were detected in 0.5 percent of samples, according to study authors.

Researchers also found evidence of heritable genes, including some in the BRCA family associated with breast cancer, which can predispose whole families to pancreatic cancer. "Understanding the hereditary aspects of pancreatic cancer is extremely important," Singhi noted. "We found a significant number of patients had germline alterations in the DNA repair genes, the same genes that are associated with breast cancer, ovarian cancer, and other neoplasms."

Additionally, the newly discovered biomarkers from this study can be added to the PancreaSeq platform, a clinical molecular test previously developed by Singhi and colleagues. This platform evaluates common pancreatic cysts and identifies which cases may lead to cancer.

Overall, this study highlights potential treatment approaches for patients as well as new directions for pancreatic cancer research. "These findings shed light on certain avenues and pathways for future study," noted Bahary. "For instance, a lot of these genes fall in the category of DNA damage response and may have common pathways of treatment or may give you common pathways to leverage immune therapy, which until now has not worked particularly well for pancreatic cancer."

Ongoing Research

This study lays the foundation for continued investigation of pancreatic cancer and the authors plan to continue sequencing additional patients.

"We have sequenced more than 4,000 to date and are still going through the data," noted Singhi. "We are also inputting identified biomarkers into early detection assays, like PancreaSeq, in an effort to improve the way we evaluate patients as well as early detection of the disease."

Study authors also plan to take a closer look at other pancreatic neoplasms beyond PDAC. The next area of study will involve the comprehensive genome of pancreatic neuroendocrine tumors—the second most common pancreatic cancer, according to Singhi.

"Every pancreatic cancer is different, and performing molecular profiling of each patient's tumor could help determine the best treatment options," he noted, in a statement.

"Rather than blindly giving patients the same chemotherapy, we want to tailor a patient's chemo to their tumor type," Singhi concluded. "A one-size-fits-all approach isn't going to work. Therefore, we would like to make molecular profiling standard of care for patients with pancreatic cancer."

Catlin Nalley is associate editor.

Wednesday, March 20, 2019

By Veda N. Giri, MD

Germline genetic testing for prostate cancer is undergoing immense expansion. Prostate cancer has long been recognized to have a substantial hereditary component.

Familial clustering of prostate cancer has been recognized for many years, with a working definition of hereditary prostate cancer encompassing generational prostate cancer with multiple cases in a nuclear family, and/or early-onset prostate cancer (Genetics of Prostate Cancer (PDQ) NCI: Urol 1993;150(3):797-802). Furthermore, higher rates of prostate cancer have been observed in families with hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) (Genetics of Prostate Cancer (PDQ) NCI: Oncol 2016;43(5):560-565).

Multiple genes have been identified to predispose to inherited prostate cancer, including BRCA1, BRCA2, HOXB13, and the DNA mismatch repair genes (Genetics of Prostate Cancer (PDQ) NCI: Oncol 2016;43(5):560-565; J Clin Oncol2018;36(4):414-424). In addition, a substantial rate of germline mutations in DNA repair genes was reported in men with metastatic prostate cancer of approximately 12 percent (N Engl J Med 2016;375:443-453).

Prior to 2017, guidelines were limited regarding genetic testing for men with prostate cancer and were focused only on BRCA1/2 testing for men meeting strict family history criteria or having metastatic disease. Therefore in 2017, an international consensus conference was convened to develop a comprehensive framework for genetic testing for men with prostate cancer encompassing which men to test, which genes to test, and how testing may impact prostate cancer screening, early-stage management, and treatment for metastatic disease (J Clin Oncol 2018;36(4):414-424).

The consensus statement expanded upon consideration of BRCA testing to include testing for other genes on multigene panels such as DNA mismatch repair genes and HOXB13 in specific scenarios (J Clin Oncol 2018;36(4):414-424).

Shortly thereafter, the NCCN Prostate Cancer guideline significantly expanded to include consideration of genetic testing of all men with metastatic prostate cancer and men in the higher disease risk categories (high risk, very high risk, and regional disease) regardless of family history (NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Prostate (Version 4.2018)).

For men with very low-to-unfavorable, intermediate risk disease, consideration of genetic testing was recommended based upon family history of prostate cancer, particularly if men were diagnosed at age less than 60 or had family cancer history suggestive of HBOC or LS. Genes to test in the guideline include BRCA1, BRCA2, ATM, PALB2, DNA mismatch repair genes (particularly with correlating molecular analysis), and FANCA (NCCN Guidelines: Prostate (Version 4.2018)).

In the current era of clinical genetic testing, multiple genes are now available for genetic testing of men with prostate cancer, not only for BRCA1, BRCA2, HOXB13, DNA mismatch repair genes, and ATM, but also for several genes with varying levels of data regarding association to prostate cancer risk and/or aggressiveness, such as CHEK2, PALB2, and NBN (J Clin Oncol 2018;36(4):414-424).

Analyzing Real-World Data

Given the expansion of genetic testing guidelines, prevalence estimates in clinical cohorts of men with prostate cancer undergoing genetic testing are needed to gain an understanding of the burden of potential inherited prostate cancer and implications of germline testing for prostate cancer management, treatment, and cascade genetic testing in families.

Giri et al. published the first analysis of real-world genetic data among men with prostate cancer undergoing germline testing with the goal to estimate prevalence of genetic mutations overall and particularly in DNA repair genes (such as BRCA1, BRCA2, ATM, PALB2, NBN, and the DNA mismatch repair genes) that are informing therapeutic and clinical trial options (Prostate 2019; doi:10.1002/pros.23739). A secondary goal was to identify predictors of germline mutations in DNA repair genes that may help identify which men with prostate cancer in particular should be referred for genetic evaluation.

The study team from Sidney Kimmel Cancer Center at Thomas Jefferson University analyzed de-identified data from 1,328 men with prostate cancer who had undergone germline genetic testing. ICD-10 billing codes were used to identify a personal diagnosis of prostate cancer and family cancer history. Gleason score was extracted manually from information provided on testing forms.

The prevalence of genetic mutations was 15.6 percent overall and 10.9 percent in DNA repair genes. BRCA2 mutations were the most commonly identified (4.5%), followed by mutations in CHEK2 (2.2%), ATM (1.8%), BRCA1 (1.1%), PMS2(0.6%), MSH2 (0.5%), NBN (0.2%), MLH1 (0.2%), and EPCAM (0.1%). Selected additional DNA repair gene mutations included PALB2 (0.5%), RAD50 (0.4%), BRIP1 (0.2%), RAD51C (0.2%), and RAD51D (0.1%).

Furthermore, family history of breast cancer was significantly associated with an approximate two-fold increased risk of germline DNA repair mutations in men with prostate cancer. In addition, Gleason score ≥8 was significantly associated with mutations in DNA repair genes compared to Gleason scores of 6-7. Of note, the rate of variants of uncertain significance (VUS) in this cohort was 37.2 percent.

Practice Implications

The findings by Giri et al. have several implications. First, this was the first study to report on the prevalence of germline mutations in men with prostate cancer undergoing clinical genetic testing with an overall mutation rate of 15.6 percent. An even more recent study by Nicolosi et al. conducted also in the same dataset reported a germline variant rate of 17.2 percent (JAMA Oncol 2019; doi:10.1001/jamaoncol.2018.6760), confirming the initial findings by Giri et al. and adding support that men with prostate cancer do indeed have substantial rates of germline mutations in a spectrum of cancer risk genes.

Second, the genetic landscape is coming into clearer view showing that men with prostate cancer may harbor mutations in a spectrum of genes such as BRCA1, BRCA2, CHEK2, ATM, PALB2, DNA mismatch repair genes, and additional genes involved in DNA repair. These genes have potential therapeutic and clinical trial implications for men particularly with metastatic, castration-resistant prostate cancer (mCRPC) (N Engl J Med 2015;373(18):1697-1708, N Engl J Med2015;372:2509-2520).

For example, the FDA has granted olaparib Breakthrough Therapy designation for BRCA1/2- or ATM-positive mCRPC based on phase II data (N Engl J Med 2015;373(18):1697-1708). Recently, rucaparib was also granted Breakthrough Therapy designation for men with BRCA1/2-positive mCRPC following at least one androgen receptor-directed therapy and taxane-based chemotherapy based on phase II data from the TRITON2 study.

Genetically informed clinical trial options are also rapidly expanding for men with mCRPC (JCO Precis Oncol 2018; doi:10.1200/PO.18.00060). Additionally, genetic results will likely increasingly be factored into active surveillance discussions particularly if the genetic mutations inform risk for aggressive disease (NCCN Guidelines: Prostate (Version 4.2018), Eur Urol 2017;71(5):740-747, Eur Urol 2018; doi:10.1016/j.eururo.2018.09.021).

Furthermore, this spectrum of germline mutations is in cancer risk genes that confer additional cancer risks for men with prostate cancer. For example, men with BRCA2 mutations are also at risk for male breast cancer, pancreatic cancer, and melanoma where guidelines-based management exist or may require high-risk consultation (NCCN Guidelines: Genetic/Familial High-risk Assessment: Breast and Ovarian (Version 2.2019)). These recommendations to reduce additional cancer risks are important to impart, particularly for men with early-stage prostate cancer and many of whom will enter survivorship.

Third, family history of breast cancer or higher Gleason may be useful in identification of men with prostate cancer for genetic counseling and genetic testing referral, according to the results published (Prostate 2019; doi:10.1002/pros.23739). While other studies have reported that family history and Gleason score could not fully stratify men with prostate cancer for presence of germline mutations (JAMA Oncol 2019; doi:10.1001/jamaoncol.2018.6760), predictors of germline mutations—particularly in DNA repair genes—can be helpful to streamline efforts to refer appropriate men with prostate cancer for genetic evaluation to inform therapeutic options and cascade testing. Further data are needed in this context.

Fourth, the spectrum of genetic mutations in men with prostate cancer informs cascade genetic testing of male and female blood relatives to determine if they carry the genetic mutation and to guide cancer screening and risk reduction recommendations.

Finally, the report by Giri et al. shows that the rate of VUS is approximately 37 percent, which is important to discuss with men considering genetic testing. While VUS are reported to patients in their clinical results, there are no management changes based upon VUS at the time of report. Over time a small minority of these VUS are reclassified to "mutation" (JAMA 2018;320(12):1266-1274), and therefore men need to understand this potential for reclassification in the future and keep in touch with their ordering provider. Prior work by the Giri research team has shown that a subset of men may misinterpret "VUS" as "mutations" at the time of reporting, raising the need to reinforce understanding of VUS at disclosure of genetic results (Prostate 2019; doi:10.1002/pros.23535).

In summary, genetic evaluation of men with prostate cancer is a rapidly growing field that is capitalizing on advances in genetic sequencing and it is now in need of data-driven genetic testing guidelines for optimal evaluation and management.

The publication by Giri et al. provides the first insights into the real-world landscape of genetic testing for men with prostate cancer with implications for genetic testing referral, precision therapy, and cascade testing in families.

VEDA N. GIRI, MD, is Associate Professor of Medical Oncology, Cancer Biology, and Urology, and Director of Cancer Risk Assessment and Clinical Cancer Genetics at Sidney Kimmel Cancer Center at Jefferson Health, Philadelphia.

Wednesday, February 20, 2019

By Catlin Nalley

Relapse is a major challenge when it comes to the treatment of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS); oncologists are constantly searching for ways to combat this issue while improving their understanding of disease mechanisms.

"We have learned a lot about AML and MDS thanks to advances in DNA-sequencing," noted Christopher R. Cogle, MD, Professor of Medicine at the University of Florida. "And one of the things we have learned through this effort is that these diseases are much more genetically complex than we previously thought.

"With this new appreciation for the number and variety of genomic abnormalities, we are beginning to see individual AML and MDS cases as unique diseases loosely connected to one another."

Despite an increased understanding of the genomic makeup of these diseases, response rates, especially in the relapsed/refractory setting, remain poor. "In patients with relapsed or refractory AML or MDS we are seeing response rates of around 20 percent," Cogle noted. "There is an urgent need for new therapeutics or intelligently repurposed older drugs."

Recognizing the need for a deeper understanding of the complexities of these diseases, Cogle and his team pursued a new approach. "We sought to utilize computational means to interpret the high number and wide variety of abnormalities that are presenting in our MDS and AML clinic."

After finding the right software partner and validating the accuracy of the technology through retrospective analysis, the iCare1 prospective clinical study was launched. Findings from this trial were recently presented at the 2018 ASH Annual Meeting (Abstract 3086).

Study Details

Researchers utilized a genomics-informed computational biology modeling (CBM) technique to improve their understanding of the mechanisms of response or relapse after chemotherapy treatment among AML and MDS populations and to hypothesize new treatment approaches.

The investigators recruited 120 patients with AML and MDS to assess the accuracy of CBM prediction through the comparison of computer predictions of treatment response and actual clinical outcomes. Of these patients, 96 had full genomic testing profiles.

Conventional cytogenetics, whole exome sequencing, and array CGH were used to conduct genomic profiling. Disease-specific protein network maps for each patient were created by inputting somatic gene mutations into the CBM program, Cogle explained.

A digital library of FDA-approved drugs was generated for the technology by "programming each agent's mechanism of action determined from published literature," researchers outlined. "Digital drug simulations of the patient's choice of therapy were tested at varying doses and predicted efficacy of the drugs were measured as a function of a disease inhibition score, defined as the degree to which disease pathways and phenotypes (cell proliferation and viability) were mathematically returned to a mutation-free state."

Based on length of follow-up and minimum treatment exposure threshold, 50 patients were eligible for evaluation. Among these patients, 61 treatments were administered. Researchers reported that the CBM maps of relapsed samples from these patients "accurately matched the patient's nonresponse of treatment at relapse in 90 percent of patients and identified mechanisms for chemoresistance."

"By applying this computational biology method and digital drug simulation we found several things," Cogle noted. "Chief amongst them is the capability of this computational method to be employed in the clinic and provide highly accurate predictions of treatment response in our AML and MDS patients."

Implications, Next Steps

Using computers in oncology is an emerging area not only in research, but also for clinical application, noted Cogle. However, he emphasized the importance of comprehensive testing of these methods before marketing to patients with cancer.

"The iCare1 study and the work preceding it represents, firsthand, the kind of stepwise, rigorous clinical trial testing that should be done for predictive methods," Cogle elaborated. "We are not only demonstrating a feasible and accurate computational method, but we are also highlighting a path towards responsible technology development."

While the next step for the computational model tested in iCare1 is to assess it in a randomized clinical trial, Cogle and his team are also focused on educating physicians and patients about this type of technology so they are "empowered to appreciate the results that come out of computational predictions.

"Computational oncology is called a 'black box' only by those who don't know how to open the box and read what's inside," Cogle said. "My group is committed to assisting physicians and patients to better understand the methods being used so that they can determine whether or not it is an appropriate application for their case."

Looking forward, Cogle stressed the important role computational oncology will play in the field of oncology. "Interpreting one gene mutation can be challenging and time consuming, interpreting multiple gene mutations is sometimes impossible in our busy practice setting," he noted. "We have to embrace computational oncology because of limitations not only on our time, but also on our human cognitive capacity to parallel process the tangle of abnormalities that we find in cells of our cancer patients.

"Results like the ones coming out of the iCare1 study are encouraging and demonstrate that we now have access to technology that is not only feasible, but also accurately predicts treatment response."

Catlin Nalley is associate editor.

Friday, January 18, 2019

By Catlin Nalley

Recently reported data from the Angiosarcoma Project identified immune checkpoint inhibition as potentially actionable for angiosarcomas of the head, face, neck, or scalp (HFNS).

Launched by the Broad Institute in March 2017 in collaboration with Dana-Farber Cancer Institute, the Angiosarcoma Project is a patient-partnered genomics study. Patients are involved throughout the length of the project, including design, build, launch, and accrual.

Patient-reported data, medical records, archival tumor tissue, saliva, and blood samples are collected from individuals across the U.S. and Canada who have agreed to contribute to this study. This allows researchers to develop a comprehensive resource to facilitate discoveries for this rare disease.

"Angiosarcoma is an exceedingly rare cancer affecting about 300 patients a year in the U.S., has a high mortality rate, and has no standard of care; because of its rarity, there is a dearth of scientific discoveries that can lead to clinical impact," said Corrie A. Painter, PhD, Associate Director of Operations and Scientific Outreach at Broad Institute of MIT and Harvard, in a statement. "It is important to develop novel approaches for working with patients who are geographically dispersed and who may never have the opportunity to participate in a large-scale prospective research effort because they have such a rare disease."

Building the Project

The Angiosarcoma Project ( was developed following the success of an initial endeavor in the metastatic breast cancer space.

"The Metastatic Breast Cancer Project was launched in October 2015 and it has been very successful from a number of different metrics, including patient enthusiasm," Painter told Oncology Times. "Given the positive responses to this project, we wanted to extend the ability to work with patients affected with other cancers."

The team hypothesized that they could utilize the same platform for a rare cancer and achieve the same results they saw in a major disease. And, as a survivor of angiosarcoma, Painter knew this was a very engaged community. Posting to an online support group, Painter gauged their interest in donating left over tissue and medical records to cancer research. "Within 1 hour, 90 patients expressed their desire to participate," she recalled. "This was the rationale behind the project."

Social media remains a critical aspect of the project. "The Angiosarcoma Working Group" on Facebook is used to communicate findings and connect with patients, according to Painter. "This group represents a mixture of people—patients, researchers, doctors, and caregivers—who are highly invested in research for angiosarcoma and have come together to work on this project."

Initial Findings

Data from the initial analysis were recently presented at the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival.

Researchers performed whole exome sequencing of approximately 20,000 genes on tumor and matched germline DNA. Several genes, known to be altered in angiosarcoma, were identified in the samples, including KDR and TP53, according to study findings. Of the 321 patients registered to date, 21 percent had angiosarcomas of HFNS.

"When first reviewing the data, we noticed outliers on the tumor mutation burden (TMB) graph. We also noted that all of those cases in the first data release matched patients who had angiosarcomas of HFNS," Painter explained. "We hypothesized that the high TMB was caused by UV damage and there could potentially be a UV signature in the DNA."

From the initial cohort of 12 patients, all three with angiosarcoma of HFNS had high TMB (10 mutations per MB) and dominant UV light signature, according to the researchers.

"Our work suggests that patients with angiosarcoma of HFNS have a high mutational burden and UV light signature, and therefore may respond to checkpoint inhibition," Painter observed.

Given the potential impact of this finding, the research team sought to identify additional patients. Painter and colleagues found an additional 56 patients with angiosarcoma of HFNS who provided treatment details.

Of these patients, two had previously received immune checkpoint inhibitors. Both patients had refractory metastatic HFNS angiosarcoma and reported undergoing off-label anti-PD1 therapy, according to investigators. "Both had complete or near-complete responses following immunotherapy, and currently report stable or no evidence of disease."

Angiosarcomas of HFNS represent the largest demographic of people affected by the disease, therefore, Painter noted, these initial findings could have far-reaching implications for a significant number of patients with this rare cancer.

Looking beyond this patient population, the Angiosarcoma Project has broad implications for cancer research as a whole, especially when it comes to rare diseases. "This study serves as proof of principle that patient-partnered genomics efforts can democratize cancer research for exceedingly rare cancers," Painter noted.

Ongoing Discovery

Painter and her team plan to continue the momentum of this project. "We are still building it out in terms of samples and sequencing them," she noted. "We are getting ready to write up our findings. Additionally, we continue to look at the data and see what other insights we can gather."

And their plans go well beyond the angiosarcoma space. "Based on the success of both the Metastatic Breast Cancer and Angiosarcoma projects, we have also built and launched the Metastatic Prostate Cancer Project as well as the Gastroesophageal Cancer Project," noted Painter. "All of these have been appreciated by both the patient and scientific community. As a result we have been able to rollout an official non-profit, Count Me In (

"Our ambition is to launch projects in all major cancers and most, if not all, rare cancers as well," she continued. "Through these projects, we are going to be able to provide the biomedical community with data that will lead to discoveries across a spectrum of cancers that have had significant barriers to get patients together or the funding to actually do the type of deep analysis that we hope to make freely available.

"It is our hope that this will jumpstart a number of different labs on their way toward making discoveries that will impact the lives of patients living with cancer both today and in the future."

The Angiosarcoma Project and others like it underscore the important role patients play.

"Being a patient myself I can say, with certainty, that nobody cares more about the success of a project like this than the people who are directly impacted by it," Painter noted. "As dedicated as I was as a scientist, there was an end of the day. It may have been late, but I went to sleep and didn't have nightmares about it. When you are a patient it is 24/7 and so you will do everything in your power to drive progress.

"If scientists can find more ways to include patients, I think all of us will benefit," she concluded. "I cannot wait to see what happens when we have more established roads between scientists and patients; we are at an inflection point that is going to change everything."

Catlin Nalley is associate editor.