American Association For Cancer Research Research Articles

Assessment of isochromosome 12p and 12p abnormalities in germ cell tumors using fluorescence in situ hybridization, single-nucleotide polymorphism arrays, and next-generation sequencing/mate-pair sequencing

The identification of isochromosome 12p [i(12p)] and 12p gains have significant clinical utility in the diagnosis of germ cell tumors (GCTs). We have summarized the results of fluorescence in situ hybridization (FISH) assays to identify i(12p), performed in a Clinical Laboratory Improvement Amendments (CLIA)-validated setting for 536 specimens. In addition, the American Association for Cancer Research (AACR) Project GENIE registry and The Cancer Genome Atlas (TCGA) data sets were evaluated for chromosome 12p gains, and a limited number of cases were concurrently evaluated using FISH, single-nucleotide polymorphism (SNP) arrays and next-generation sequencing (NGS; including mate-pair sequencing). Specimens submitted for FISH testing were frequently from potential sites of metastases (male: 70.9% and female: 69.3%), and polysomy of chromosome 12 with or without concurrent i(12p) was a frequent finding, seen in 3% (16/536) and 35% (186/536) of cases, respectively. Our analysis suggests that 12p gains are likely to be present in approximately 73% of male GCTand in 32% of female GCT (AACR GENIE, n=555). When comparing TCGA cases of testicular GCT (n=149) to combined cases of sarcoma, colorectal, prostate, and urothelial carcinoma (n=1754), 12p gains had a sensitivity of 77.2% and specificity of 97.3% for GCT. Some advantages of FISH over SNP arrays/NGS include relatively lower cost, rapid turnaround time, the ability to analyze biopsy material with a limited number of tumor cells (50cells), and the ability to distinguish i(12p) from polysomy. The ability to spatially restrict the analysis to cells of interest is critical, as specimens submitted for testing often have low tumor purity. Disadvantages include false negative results due to an inability to detect segmental gains due to FISH probe design. With the availability of numerous testing modalities, including FISH, SNP arrays, and NGS-based assays, a nuanced understanding of the advantages and disadvantages of each methodology, as has been presented in this study, may inform appropriate testing strategies.

Ralph A. Reisfeld, PhD: In Memoriam (1926–2020)

![][1] The sad news that Ralph A. Reisfeld, PhD, passed away on December 6, 2020 reached us early this year, and we would like to reflect on Ralph's long career and distinctive contribution to biomedical science and in particular to the field of cancer research. Ralph was well known

Joseph V. Simone: In Memoriam (1935–2021)

![][1] He was a poet. A prodigious writer. A giant in the world of pediatric oncology. Those of us in the field of cancer research, as well as patients around the globe, owe a tremendous debt of gratitude to Joseph “Joe” Simone. A first-generation American who was born amid the

ES24.02 The Rationale for FDA (and EMA) Regulatory Review of Tobacco Use in Clinical Trials

ES24.02 The Rationale for FDA (and EMA) Regulatory Review of Tobacco Use in Clinical Trials

FP07.12 Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real-World Datasets

Exon 20 insertion mutations (Exon20ins) account for up to 10% of all mutations in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs). Exon20ins specific drugs are in development. Because Exon20ins are molecularly heterogenous, the ability to identify the range of variants is dependent on the test methods used. Real-time polymerase chain reaction (PCR) and next-generation sequencing (NGS) are two molecular tests widely used to identify mutations in the EGFR. We analyzed real-world genomic data to determine the frequency of Exon20ins variants and to assess the ability of PCR and NGS to comprehensively identify them. Two US-based genomic databases were utilized for this analysis. NGS data from US institutions were extracted from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database, version 8.5 (The AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831). The FoundationInsights™ database (Foundation Medicine, Cambridge, MA) was used to obtain EGFR Exon20ins variants in real-world NSCLC samples. Coverage of Exon20ins from commercially available PCR tests (therascreen® and cobas®) was obtained from their instructions for use. The GENIE database included 12,497 patients with NSCLC. A total of 2,316 patients with EGFR mutant lung adenocarcinoma were identified and of these patients, 175 (7.6%) harbored Exon20ins. A total of 40 unique Exon20ins variants were identified. Of the 9 most common Exon20ins variants (≥5 patients), only 4 would have been identified at the protein level using commercially available PCR tests. PCR tests would have identified only 89 (50.9%) of the 175 patients with Exon20ins identified by NGS (Figure). The FoundationInsights™ database included 627 patients with lung adenocarcinomas who harbored Exon20ins and identified 102 unique Exon20ins variants. Of the 17 most common variants (≥5 patients), only 4 would have been identified at the protein level with commercially available PCR tests. PCR tests would have identified just 305 (48.6%) of the 627 patients with Exon20ins identified by NGS (Figure). PCR methods are projected to miss 50% or more of Exon20ins. Reliance on commercially available PCR kit methods may provide insufficient information to support appropriate decision-making for emergent Exon20ins-directed therapies. The large number of insertion variants suggests that NGS platforms, academic or commercially available, would also improve their detection rate by capturing the full breadth of variants that have been identified.

Genetic syndromes predisposing to pediatric brain tumors.

The application of high-throughput sequencing approaches including paired tumor/normal sampling with therapeutic intent has demonstrated that 8%-19% of pediatric CNS tumor patients harbor a germline alteration in a classical tumor predisposition gene (NF1, P53). In addition, large-scale germline sequencing studies in unselected cohorts of pediatric neuro-oncology patients have demonstrated novel candidate tumor predisposition genes (ELP1 alterations in sonic hedgehog medulloblastoma). Therefore, the possibility of an underlying tumor predisposition syndrome (TPS) should be considered in all pediatric patients diagnosed with a CNS tumor which carries critical implications including accurate prognostication, selection of optimal therapy, screening, risk reduction, and family planning. The Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) recently published consensus screening recommendations for children with the most common TPS. In this review, we provide an overview of the most relevant as well as recently identified TPS associated with the most frequently encountered pediatric CNS tumors with an emphasis on pathogenesis, genetic testing, clinical features, and treatment implications.

Leveraging the power for genomics for immuno-oncology

<div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://cdn.insights.bio/uploads/Golub headshot sq.jpg" data-image="1"></div><div class="author-det"> <!--StartFragment--><b>Todd Golub</b> is a founding core member of the Broad Institute and serves as the institute’s chief scientific officer and director of its Cancer Program. He is also the director of the Gerstner Center for Cancer Diagnostics at the Broad Institute. Dr Golub is a world leader in understanding the basis of cancer, by creating and applying tools of genomics. He has made fundamental discoveries in the molecular basis of childhood leukemia, and laid the foundation for the diagnosis and classification of human cancers using gene expression analysis. He also pioneered the development of chemical screening approaches based on gene expression. He joined the faculty of the Dana-Farber Cancer Institute and Harvard Medical School in 1997. At the same time he served as the leader of cancer genomics at the Whitehead Institute/MIT Center for Genome Research, which evolved into the Cancer Program at the Broad Institute. Dr Golub has directed that program since 2004, and is also currently the Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute and professor of pediatrics at Harvard Medical School. He is the recipient of multiple awards, including the Erasmus Hematology Award; the Richard and Hinda Rosenthal Memorial Award and the Outstanding Achievement Award from the American Association for Cancer Research; the Paul Marks Prize for Cancer Research; the E. Mead Johnson Award from the Society for Pediatric Research; and the Judson Daland Prize for Outstanding Achievement in Clinical Investigation from the American Philosophical Society. In 2014, he was elected as a member to the National Academy of Medicine (formerly the Institute of Medicine). Dr Golub has served on the scientific advisory boards of numerous organizations including serving as chair of St. Jude Children’s Research Hospital and the Board of Scientific Advisors of the National Cancer Institute. Golub received his B.A. from Carleton College and his M.D. from the University of Chicago Pritzker School of Medicine. He completed his internship, residency, and fellowship training at Boston Children’s Hospital and the Dana-Farber Cancer Institute.<!--EndFragment--> </div></div></div>

The role of Black people in ending systemic racism in oncology.

Being Black is bad for one's health, but being part of Black in Cancer can help. Analysis of a report published by the American Association for Cancer Research (AACR) in 2020, might present the strongest evidence yet that being Black is currently bad for one's health. The report highlights grievous cancer inequalities, including statistics showing that Black Americans have the highest overall death rate from cancer of any racial or ethnic group in the USA. Using specific examples, prostate cancer death rates in Black men are more than double those of every other racial or ethnic group, and Black women are 40% more likely to die of breast cancer than White women, and twice as likely to die if they are aged older than 50 years.

Takashi Sugimura: In Memoriam (1926–2020)–A Personal Perspective

![][1] Takashi Sugimura was a pioneer in cancer research and a figure recognized internationally for his seminal contributions to the understanding of mutagenicity and chemical carcinogenesis. Rather than focusing on the many accolades, honors, and influential positions that he held,

112th American Association for Cancer Research Annual Meeting. Virtual - April 10-15, 2021

The American Association for Cancer Research (AACR) Annual Meeting is one of the most important events in the field of cancer research, covering all aspects and types. Attendees/ presenters are brought together from all areas in cancer research, including scientists, healthcare professionals, cancer survivors and patients. Due to the global COVID-19 infection pandemic, the 112th Annual Meeting was divided into 2 virtual meetings, the first held April 10-15, and the second part on May 17-21. The first week included oral and poster sessions, under the topic of‘Discovery Science Driving Clinical Breakthroughs’. This report covers some of the highlights from that first week. Copyright © 2021 Clarivate Analytics

Editorial introductions.

Editorial introductions.

Virtual Conferences: Optimizing Oncology Nurses' Experience.

One casualty of the COVID-19 pandemic was in-person professional conferences. Organizations, including the American Society of Clinical Oncology, American Association for Cancer Research, and Oncology Nursing Society, had to quickly pivot and radically transform the delivery of the traditional in-person conference to a virtual offering accessible to thousands of oncology healthcare professionals. However, what may have felt catastrophic has revealed unique opportunities to engage individuals in professional offerings, including those who, because of cost or travel, may not have previously participated. In this article, the authors present insights into how to optimize virtual learning experiences during the COVID-19 pandemic and beyond.

Experts say that funding for cancer research is at risk during the pandemic.

Over the past 5 years, the US Congress has approved an increase of $11.6 billion, or approximately 39%, for the National Institutes of Health (NIH) budget, which has enabled significant research funding. However, with the arrival of the coronavirus disease 2019 (COVID-19) pandemic, experts say that future funding and medical research progress are now at risk. “The consequences of the pandemic on the entire medical enterprise are extremely concerning for the medical research community,” says Jon Retzlaff, MBA, MPA, chief policy officer and vice president of science policy and government affairs for the American Association for Cancer Research. “It's why we've been advocating for $15.5 billion to be included in the next COVID-19 relief supplemental appropriations bill.” The financial challenges that universities and medical centers have been experiencing as well as significant disruptions in laboratory and clinical research during the pandemic have all taken a toll and led to lost research opportunities, he says. Researchers are concerned that they could lose entire germ lines and mouse colonies and that fewer patients have enrolled in clinical trials. Meanwhile, many laboratories and most supplemental government research dollars have been redirected toward COVID-19 research. According to Retzlaff, of the $15.5 billion requested for the NIH, $10 billion is needed to offset the expenses associated with research disruptions that have occurred during the pandemic. At press time—shortly before Election Day—he did not anticipate that Congress would approve a COVID-19 relief appropriations bill until after the presidential election. In addition, he and fellow medical research advocates requested a $3 billion increase in NIH's fiscal year 2021 budget to continue the institutes' robust research efforts. He praises leaders in both the Senate and the House, specifically Senators Roy Blunt of Missouri and Patty Murray of Washington and Representatives Rosa DeLauro of Connecticut and Tom Cole of Oklahoma, for championing NIH support over the past 5 years. Although he is optimistic that the NIH will see another significant increase in fiscal year 2021, he recognizes that many challenges remain. Currently, the National Cancer Institute (NCI) has a 10% success rate, which means that only 1 in 10 reviewed grant applications are being funded. “Prior to the pandemic, the rate of applications being submitted to NCI was at a pace we've never seen—there was incredible momentum and excitement,” Retzlaff says. He adds that, like other private research funders, the American Association for Cancer Research has experienced a reduction in donations, which has left it with a lower funding capacity and has made it even more imperative for the federal government to step in and provide assistance. To that end, approximately 500 people representing nearly every state participated in the virtual Rally for Medical Research Hill Day on September 17, 2020. Participants included health care providers, researchers, clinicians, caregivers, and survivors, who held some 400 meetings with Congressional representatives. The event was the largest and most inclusive since Hill Day first launched in 2013. These groups will continue working to remind Congress that medical research into major diseases needs to remain at the forefront, Retzlaff says. “Cancer and heart disease are still the number 1 and number 2 causes of death, and we can't afford to take our eyes off the ball.”

AACR Cancer Disparities Progress Report 2020: Achieving the Bold Vision of Health Equity for Racial and Ethnic Minorities and Other Underserved Populations.

The American Association for Cancer Research (AACR) is proud to announce the release of the inaugural AACR Cancer Disparities Progress Report. Disparities in health care, including cancer health disparities, are among the most significant form of inequality and injustice. The AACR Cancer Disparities

AACR Cancer Progress Report 2020: Turning Science into Lifesaving Care.

The American Association for Cancer Research (AACR) is proud to announce the release of the AACR Cancer Progress Report 2020 . This 10th edition of the annual report details how research is the backbone of progress across the spectrum of lifesaving cancer care. The full report, and all nine prior

Experts discuss cancer care and research in the age of COVID-19: Findings presented at the American Association for Cancer Research's virtual meeting could shift clinicians' thinking about immunotherapy and point to encouraging changes in the way that clinical trials are being conducted during the pandemic.

Experts discuss cancer care and research in the age of COVID-19: Findings presented at the American Association for Cancer Research's virtual meeting could shift clinicians' thinking about immunotherapy and point to encouraging changes in the way that clinical trials are being conducted during the pandemic.

Editorial introductions

Editorial introductions

Racism and racial inequities in health care rise to the forefront: Amid the country's national reckoning on race, experts are renewing their focus on systemic racism in the health care system.

Racism and racial inequities in health care rise to the forefront: Amid the country's national reckoning on race, experts are renewing their focus on systemic racism in the health care system.

Abstract 6550: WD105, a novel decursin derivative, showed greater growth inhibition and androgen receptor suppression in LNCaP human prostate cancer cells

Abstract Androgen receptor (AR) is a primary target for treatment of prostate cancer (PCa). AR signaling plays a critical function in all stages of PCa. Our previous research demonstrated that decursin and its isomer decursinol angelate, a pair of natural compounds from Angelica gigas Nakai, inhibit AR signaling and suppressed the growth of prostate cancer cells in vitro and in vivo. In this study, we have designed a series of pro-drug conjugates of decursin, based on acid-esterified modification, in order to achieve higher water solubility, stronger cytocidal effect and better AR suppression activity. Twelve novel esterified derivatives of decursin were synthesized from decursinol and characterized by 1H-, 13C-NMR and HR-MS techniques. Among them, WD105 displayed the best solubility. Initial structure-activity relationship (SAR) studies were carried out with a cell growth (CCK8) assay and identifıed WD105 and WD106 as lead compounds with more potency at suppressing LNCaP cell growth than decursin judged by IC50 value. In addition, both WD105 and WD106 induced caspase-mediated cell apoptosis (48h), evidenced by cleavage of PARP, in a concentration-dependent manner. Furthermore, WD105 decreased the transcriptional activity of AR and androgen-induced expression of PSA better than WD106 and decursin when assessed by Western Blot and ELISA. Taken together, these data suggest that WD105 has greater in vitro activity than decursin as an AR targeting lead compound. Future studies will characterize the PK metrics and, if warranted, determine the in vivo antitumor effect of WD105 on the growth of LNCaP-AR xenografts. Citation Format: Wei Wu, Huaiwei Ding, Huiyong Zhang. WD105, a novel decursin derivative, showed greater growth inhibition and androgen receptor suppression in LNCaP human prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6550.

Abstract 6237: Bone-targeted nanoparticle containing protein therapeutics as an effective delivery system for bone metastasis

Abstract Background: Protein drugs are one of the most promising new areas in drug research and development, however, great challenges are still faced in the drug delivery in vivo. Previously, we constructed bone targeted micelles for bone metastases. In order to address the issues of protein delivery in vivo and enhanced cancer bone metastasis treatment, we engineered and evaluated a bone-targeting nanoparticles by using metal organic framework nanoparticles (MOFs), bone-targeting agents (Alendronate) and hyaluronic acid (HA) as materials and a protein toxin as therapeutic. Methods: Alendronate (ALN) were conjugated to HA through PEG as linker and ALN-PEG-HA were obtained. Cytochrome C, as modle proteins, were caged in the MOFs (ZIF-8) by selfassembly of Zn2+ and organic ligands (2-methylimidazole) to form protein-encapsulated nanoparticles (ZIF8-CC). And ALN-PEG-HA were further decorated on the surface of ZIF8-CC nanoparticles via the coordination effect between its carboxyls and metal ions in ZIF-8 to result in active-targeting ALN-HA@ZIF8-CC nanopartilces. The materials and nanoparticles were synthesized and characterized by NMR, FT-IR, TEM, DLS, XRD, TGA and N2 adsorption−desorption isotherms analysis. The in vitro release profiles, stability and cytocompatibility were also studied. Results: The synthesis of ALN-PEG-HA was confirmed by 1H-NMR and FT-IR. TEM, XRD and DLS showed that ALN-HA@ZIF8-CC nanopartilces had been prepared, and the experiment of washing nanoparticles with SDS confirmed that protein was encapsulated in ZIF-8 instead of adsorbed on its surface. TGA and N2 absorption-degradation isotherms analysis also confirmed the formation of the crystal structure and porous structure, respectively. HA coated nanoparticles have good stability while ZIF8-CC were easy to aggregate. The results of in vitro release showed that the nanoparticles have acid sensitive release properties and excellent cell compatibility. In addition, In vitro bone fragment targeting experiment confirmed that nanoparticles have strong bone affinity. Conclusions: Our data demonstrated that bone-targeted protein drug-encapsulated MOFs were constructed. Citation Format: Yimin Niu, Cuicui Gao, Hongbin Yang, Qiang Huo, Andrew Wang, Ming Xu, Yang Liu. Bone-targeted nanoparticle containing protein therapeutics as an effective delivery system for bone metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6237.