Daily Archives: August 9, 2021

Media Advisory

Thursday, August 5, 2021

Mutation in a single gene appears to account for a form of male infertility in which men fail to produce sperm, according to an international study funded in part by the National Institutes of Health. Males with the condition, known as non-obstructive azoospermia, fail to produce any sperm, even though they do not have any obstruction in the ducts through which sperm are released. The gene, PNLDC1, codes for an enzyme that processes a class of non-coding ribonucleic acids (RNA) so they can function. These non-coding RNAs are not involved in making proteins but are believed to be involved in various functions that occur during spermatogenesis the process by which cells in the testes produce sperm cells. The findings may provide insight into how sperm is produced and may one day lead to information helpful for the diagnosis and treatment of non-obstructive azoospermia. Similarly, greater understanding of the genes function may contribute to the development of new methods of male contraception.

The study was conducted by an international team of researchers and appears in The New England Journal of Medicine. Funding from NIHs Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) was provided to two authors institutions, the University of Utah School of Medicine, Salt Lake City (Kenneth I. Aston, Ph.D.) and Oregon Health and Science University, Portland (Donald F. Conrad, Ph.D.).

In the search for the genetic foundations of the condition, the researchers sequenced the exomes protein coding regions of the genome of 924 men with non-obstructive azoospermia. They found that four of the men had mutations in the PNLDC1 gene. Analysis of testicular tissue from the men showed that spermatagonia (sperm producing cells) failed to complete meiotic cell division and develop sperm cells. The authors theorized that other genes coding for enzymes involved in processing non-coding RNAs also might be involved in infertility due to azoospermia.

Stuart B. Moss, Ph.D., Health Scientist Administrator, NICHD Fertility and Infertility Branch, is available for comment.

Nagirnaja, L. Variant PNLDC1, Defective piRNA Processing, and Azoospermia. New England Journal of Medicine. 2021.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD leads research and training to understand human development, improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all. For more information, visit https://www.nichd.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

###

Go here to read the rest:
funded study discovers gene involved in male infertility - National Institutes of Health

Limb-girdle muscular dystrophy type 2A is the most common form of LGMD, accounting for a third of LGMD diagnoses

Sareptas unrivaled portfolio of investigational gene therapies for LGMD offers the potential to address six LGMD subtypes, which together represent more than 70% of all known LGMDs

CAMBRIDGE, Mass., Aug. 04, 2021 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today announced that upon completion of a number of preclinical and safety studies, it had executed an exclusive license agreement for an investigational gene therapy candidate, calpain 3 (CAPN-3), to treat Limb-girdle muscular dystrophy type 2A (LGMD2A), developed by the Abigail Wexner Research Institute at Nationwide Childrens Hospital (Nationwide Childrens).

LGMDs represent a group of distinct genetic neuromuscular diseases with a generally common set of symptoms, including progressive, debilitating weakness and wasting that begins in muscles around the hips and shoulders before progressing to muscles in the arms and legs. Many LGMD sub-types are significantly life-limiting and often life-ending diseases. Also known as calpainopathy, LGMD2A is caused by mutations in the CAPN-3 gene and is the most common type of LGMD, accounting for almost a third of cases.

Treatment plans for LGMD2A are currently limited to physical therapy, assistive devices and surgery for complications. Were excited about the opportunity to transform patient care for this significantly life-limiting disease by advancing the CAPN-3 program following extensive pre-clinical work by the team at Nationwide Childrens. Preclinical research conducted to date has provided early proof of concept for CAPN-3 in LGMD2A and supports further advancement, said Louise Rodino-Klapac, Sareptas executive vice president and chief scientific officer. We intend to build off the knowledge we have gained from our lead investigational gene transfer programs for Duchenne muscular dystrophy and LGMD2E, as the CAPN-3 program also uses the AAVrh74 vector to address another well-characterized genetic disease. Sareptas commitment and research investment in LGMD is unparalleled and we continue to work towards advancing all of our LGMD programs as quickly as possible.

Story continues

Like SRP-9001, Sareptas lead investigational gene transfer therapy for Duchenne muscular dystrophy, and the Companys five other LGMD programs, the LGMD2A program uses the AAVrh74 vector, designed to systematically and robustly deliver treatment to skeletal muscle, including the diaphragm, making it an ideal candidate to treat muscle disease.

The preclinical work on the CAPN-3 program in LGMD2A has been led by Zarife Sahenk, M.D., Ph.D., attending neurologist at Nationwide Childrens, Director of Clinical and Experimental Neuromuscular Pathology at The Research Institute at Nationwide Childrens and Professor of Pediatrics, Pathology and Neurology at The Ohio State University College of Medicine.

About Limb-girdle Muscular DystrophyLimb-girdle muscular dystrophies are genetic diseases that cause progressive, debilitating weakness and wasting that begins in muscles around the hips and shoulders before progressing to muscles in the arms and legs. Sareptas six LGMD gene therapy programs in development include LGMD2E, LGMD2D, LGMD2C, LGMD2B, LGMD2L and LGMD2A, which together represent more than 70 percent of known LGMD cases.

About Sarepta TherapeuticsSarepta is on an urgent mission: engineer precision genetic medicine for rare diseases that devastate lives and cut futures short. We hold leadership positions in Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophies (LGMDs), and we currently have more than 40 programs in various stages of development. Our vast pipeline is driven by our multi-platform Precision Genetic Medicine Engine in gene therapy, RNA and gene editing. For more information, please visit http://www.sarepta.com or follow us on Twitter, LinkedIn, Instagram and Facebook.

Internet Posting of InformationWe routinely post information that may be important to investors in the 'For Investors' section of our website at http://www.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us.

Forward-Looking StatementsThis press release contains "forward-looking statements." Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "will," "intends," "potential," "possible" and similar expressions are intended to identify forward-looking statements. These forward-looking statements include statements regarding the potential benefits of the licensing agreement; the design of the AAVrh74 vector to systematically and robustly deliver treatment to skeletal muscle, including the diaphragm, making it an ideal candidate to treat muscle disease; the potential of our portfolio of investigational gene therapies for LGMD to address six LGMD subtypes, which together represent more than 70% of all known LGMDs; and our plan to continue to advance all of our LGMD programs as quickly as possible.

These forward-looking statements involve risks and uncertainties, many of which are beyond our control. Known risk factors include, among others: the expected benefits and opportunities related to the licensing agreement may not be realized or may take longer to realize than expected due to challenges and uncertainties inherent in product research and development. In particular, activities under the license may not result in any viable treatments suitable for commercialization due to a variety of reasons, including any inability of the parties to perform their commitments and obligations under the agreement; success in preclinical trials does not ensure that later clinical trials will be successful; Sarepta may not be able to execute on its business plans and goals, including meeting its expected or planned regulatory milestones and timelines, clinical development plans, and bringing its product candidates to market, due to a variety of reasons, many of which may be outside of Sareptas control, including possible limitations of company financial and other resources, manufacturing limitations that may not be anticipated or resolved for in a timely manner, regulatory, court or agency decisions, such as decisions by the United States Patent and Trademark Office with respect to patents that cover Sareptas product candidates and the COVID-19 pandemic; even if Sareptas programs result in new commercialized products, Sarepta may not achieve the expected revenues from the sale of such products; if the actual number of patients living with LGMD2A is smaller than estimated, Sareptas revenue and ability to achieve profitability may be adversely affected; and those risks identified under the heading Risk Factors in Sareptas most recent Annual Report on Form 10-K for the year ended December 31, 2020, and most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) as well as other SEC filings made by the Company which you are encouraged to review.

Any of the foregoing risks could materially and adversely affect the Companys business, results of operations and the trading price of Sareptas common stock. For a detailed description of risks and uncertainties Sarepta faces, you are encouraged to review the SEC filings made by Sarepta. We caution investors not to place considerable reliance on the forward-looking statements contained in this press release. Sarepta does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof.

Source: Sarepta Therapeutics, Inc.

Investor Contact: Ian Estepan, 617-274-4052iestepan@sarepta.com

Media Contact: Tracy Sorrentino, 617-301-8566tsorrentino@sarepta.com

Read the original:
Sarepta Therapeutics Executes Licensing Agreement for Gene Therapy Program from Nationwide Childrens Hospital to Treat Limb-Girdle Muscular Dystrophy...

A large new study scanned the genes of hundreds of thousands of women near the age of menopause and turned up hundreds of genetic signals that the researchers said might help predict and prevent early menopause, as well as treat infertility and improve womens reproductive health in the future.

The study, published in Nature, identified 290 genetic variants, many of them part of a pathway that repairs DNA, associated with the age at which women enter menopause. Researchers also found that changing the levels of two of these DNA repair genes delayed menopause in mice. The study broadens the understanding of how genes, specifically those in the DNA-damage response pathway, could influence the reproductive life span in women.

The average age at which women start menopause is about 51 years, and is brought on by a decrease of ovarian reserve, the capacity to produce healthy eggs. But there is significant variation in the age of menopause onset, determined by genetics and environmental factors. Although the environmental factors that influence menopause, like smoking and chemotherapy, are well-studied, the genetic factors had remained a black box.

advertisement

Studying the underlying biology and genetics of menopause has proven difficult because a womans supply of eggs are mostly formed before birth and studying it in adult humans often means taking a sample of ovarian tissue. If you were studying muscle or skin, you can take a biopsy of those tissues, said Anna Murray, a geneticist at the University of Exeter in the U.K. and author of the new study. Nobodys going to biopsy a womans ovaries its very precious tissue.

To get around these difficulties, researchers looked to genetic studies called genome-wide association studies, or GWAS. Two such previous studies had identified around 60 genetic regions associated with the timing of menopause.

advertisement

Now the multi-institutional team looked at the genes of a much larger group of women, about 200,000, between 40 and 60 years old, and found nearly 300 genetic signals associated with menopause timing. Similar to the results of their previous studies, many of the genetic regions they identified are involved in processes that respond to DNA damage to maintain cells health or induce cell death if necessary. Still, the researchers were surprised by how prevalent this pathway was in their findings. I dont know if other traits have found this level of enrichment for one particular process, said Murray.

Using the identified variants, the authors produced a risk score to see if they could predict which individuals were likely to have premature ovarian insufficiency, which occurs when women reach menopause before the age of 40. Although it was a weak predictor, the risk score identified women who started menopause by 40 better than smoking status.

Two DNA-repair genes, Chek1 and Chek2, stood out for their strong association with menopause timing. Women who lacked a working Chek2 protein had menopause three and a half years later than those who had normal Chek2, and female mice bred without the Chek2 gene had more eggs than normal mice when they were older, effectively extending their reproductive life span.

On the other hand, introducing a copy of the Chek1 gene into the mice also extended their reproductive life span, but by enabling production of more eggs after birth, which took longer to deplete. These different mechanisms really highlight the complexity in the processes that go into the ovarian reserve, said Rong Li, cell biologist at Johns Hopkins University and professor of the National University of Singapore who studies cellular processes of development.

In the future, researchers hope these findings could lead to therapeutics to extend fertility in women, though it may not be a straightforward process, Murray said. While early menopause was associated with increased risk of type 2 diabetes and worse bone health, it was also associated with decreased risk of breast and ovarian cancer. To avoid detrimental effects of delaying menopause, researchers suggest that therapeutics could be used in the short-term like targeting certain genes to enhance egg production during IVF cycles, for example.

Targeting DNA-repair genes with treatments could also have unintended consequences. Li suggests that other genes may be better targets. [DNA-damage response genes] are a bit scary to manipulate because [by inhibiting them] you could get cancer, said Li, who was not involved with the study but has collaborated with Perry. Other pathways might be better and safer targets for intervention.

More simply, the findings could also be used to provide women with more information about the approximate age when they would get menopause. Predictions about menopause age could inform women of their risk of developing conditions like breast cancer and help their decisions about when to have children, which could help them avoid unnecessary procedures, like infertility treatments.

But because most of the study was done on women of European ancestry, the findings need to be replicated in different populations, said Corrine Welt, an endocrinologist at the University of Utah who studies the genetics of early menopause and who was not involved in the study. When the study did look at women from East Asian ancestry, it found that many of the genetic signals held up but the size of the effect of these genetic regions on menopause timing was different than those in women with European ancestry.

Murray hopes future studies could improve menopause age prediction by also including non-genetic factors that are known to influence ovarian reserve like smoking. Researchers are hopeful that womens reproductive health is finally getting the attention it deserves, which could open the door for more studies and ultimately better health outcomes.

I think with studies like this, we are making a lot of headway, said Welt. Lets study all the female reproductive problems with genetics, because, unfortunately, its been an underserved aspect of medicine.

See more here:
Study finds genetic signals that might be used to predict early menopause - STAT

Every week there are numerous scientific studies published. Heres a look at some of the more interesting ones.

Getting the Inner Ear to Regenerate

Investigators at Keck School of Medicine of USC identified a natural barrier to the inners sensory cells ability to regenerate. This ability is lost in hearing and balance disorders. There are two major types of sensory cells in the inner each, which is the cochlea: hair cells that receive sound vibrations and supporting cells that have structural and functional roles. When damage occurs to the hair cells, such as from loud noises or some prescription drugs, in older mammals the hearing loss is permanent. But in young laboratory mice, in the first few days of life, they can still repair the hair cells via transdifferentiation, which allows for the recovery of hearing. Mice lose this after about a week, and so do humans, probably before birth.

Permanent hearing loss affects more than 60% of the population that reaches retirement age, said Neil Segil, professor in the Department of Stem Cell Biology and Regenerative Medicine, and the USC Tina and Rick Caruso Department of Otolaryngology Head and Neck Surgery. Our study suggests new gene engineering approaches that could be used to channel some of the same regenerative capability present in embryonic inner ear cells.

In the supporting cells of the cochlea in newborn mice, they found that the hair cell genes were suppressed by loss of H3K27ac, an activating molecule, and the presence of H3K27me3, a repressive molecule. But the hair cell genes of the mouse supporting cells were primed to activate when in the presence of H3K4me1. But with age, the supporting cells lose HeK4me1, leaving that primed state. But if they added a drug to prevent the loss of H3K4me1, the supporting cells stayed primed for transdifferentiation. The researchers believe this opens the possibility of using drugs or gene editing to make epigenetic modifications that could restore hearing.

Early COVID-19 Symptoms Vary Among Age Groups and Between Men and Women

A study out of King's College London found significant differences between age group symptoms in people 16 years to 59 years and 60 to 80 years and over for COVID-19. They also found different early symptoms between men and women. The study evaluated 18 symptoms and found the most important symptoms for early detection of COVID-19 overall were loss of smell, chest pain, persistent cough, abdominal pain, blisters on the feet, eye soreness and unusual muscle pain. But in people over 60, loss of smell lost significance and was not relevant in people over 80. Other early symptoms such as diarrhea were key in the 60 and older groups, while fever was not an early feature in any age group, although it is a known symptom. Men were more likely to report shortness of breath, fatigue, chills and shivers. Women were more likely to report loss of smell, chest pain and persistent cough.

Cardiosphere-Derived Exosomes to Treat Acute Trauma

Capricor Therapeutics and the U.S. Army Institute of Surgical Research published research on cardiosphere-derived exosomes (CDC-EVs) that showed they can attenuate kidney damage and promote new blood vessel formation in a preclinical model of acute trauma. The research is a way of developing ways to stabilize wounded warriors in the field. An exosome is a type of extracellular vesicle that contains proteins, DNA and RNA of the cells that secrete them. They can be taken up by cells that are at a distance, and affect their cell function and behavior. Cardiosphere-derived cells are a cardiac progenitor cell population that has been shown to have cardiac regenerative properties and may be able to improve heart function in some cardiac diseases. The goal of this study was to show that CDC-EVs could help in a rat model of acute traumatic coagulopathy induced by polytrauma and hemorrhagic shock. The data suggests early deliver could improve outcomes.

Too Much Sugar Negatively Affects Mitochondrial Function

Investigators with the Van Andel Research Institute found that surplus sugar can cause mitochondrial, the energy manufacturers of our cells, to become less efficient and decrease energy output. They found that too much cellular glucose, which is directly associated with the amount of sugar in the diet, affected lipid (fat) composition throughout the body, which affects the integrity of mitochondria. Too much sugar decreased the concentration of polyunsaturated fatty acids (PUFAs) in the mitochondrial membrane, making mitochondria less efficient. They were able to reverse the effect in mice by feeding them a low-sugar ketogenic diet.

New Target for Aggressive Cancers

Researchers with the Wellcome Trust Sanger Institute, University of Cambridge and Harvard University identified a protein that plays a major role in transforming normal tissue into cancer. They believe this will be a potential new target for certain aggressive cancers. Using CRISPR-Cas9 gene editing to screen cancer cells, they identified the METTL1 gene, which produces the RNA-modifying METTL1 protein. Mutations in the METTL1 gene lead to higher levels of the METTL1 protein, which causes cells to replicate faster and become cancerous, which creates highly aggressive tumors. When inhibiting the METTL1 protein by knocking out the gene, it halted cancer cell growth while leaving the normal healthy cells unharmed.

The Achilles Heel of Ovarian Cancer

Scientists at UT Southwestern Medical Center discovered that ovarian cancers massively amplify NMNAT-2, an enzyme that makes NAD+. NAD+ is a substrate for a family of enzymes known as PARPS, which modify proteins with ADP-ribose from NAD+. One of the PARPs, PAR-16, uses NAD+ to modify ribosomes, which are the machinery in the cell that synthesizes proteins.

We were able to show that when ribosomes are mono(ADP-ribosyl)ated in ovarian cancer cells, the modification changes the way they translate mRNAs into proteins, said W. Lee Kraus, professor of Obstetrics and Gynecology and Pharmacology and a member of the Harold C. Simmons Comprehensive Cancer Center. The ovarian cancers amplify NMNAT-2 to increase the levels of NAD+ available for PARP-16 to mono(ADP-ribosyl)ate ribosomes, giving them a selective advantage by allowing them to fine-tune the levels of translation and prevent toxic protein aggregation. But that selective advantage also becomes their Achilles heel. Theyre addicted to NMNAT-2, so inhibition or reduction of NMNAT-2 inhibits the growth of the cancer cells.

At this time, there are no PARP-16 inhibitors in clinical trials, but there are labs working to develop PARP-16 inhibitors.

See the article here:
Research Roundup: Getting the Inner Ear to Regenerate and More - BioSpace

Introduction

Pancreatic ductal adenocarcinoma (PDAC) ranks among the top leading causes of cancer deaths in the Western world and, in contrast to other tumor entities of the gastrointestinal tract like colorectal cancer, its incidence is rising.1,2 The dismal prognosis of this cancer type is caused by late diagnosis mostly in advanced stages with no chance for curative resection, a very high relapse rate and resistance to most of the tested therapies and targeted drugs.35 Current cancer statistics show a five year survival rate of only 5-10 % with no meaningful improvements during the last 20 years.6

Integrated analysis of the genomic landscape has identified four commonly mutated genes, namely KRAS, TP53, SMAD4, and CDKN2A.79 Given the aforementioned late detection rate, lack of reliable biomarkers and aggressive biology of PDAC, there is a strong need for finding new biomarkers to guide decision-making in the clinical management of patients affected by this type of cancer. One non-invasive and promising tool for early detection, predicting tumor recurrence and monitoring treatment responses as well as resistance is the analysis of circulating tumor DNA (ctDNA). CtDNA is a relatively small and highly variable fraction of circulating cell-free DNA (cfDNA), which is primarily composed of germline DNA that originates from normal cells.10,11 Assessment of ctDNA derived from the primary tumor and metastatic sites, which can be isolated from the peripheral blood provides a real-time picture of the tumor burden and treatment escape mechanism.12,13 Several studies have shown that ctDNA can be used to analyze somatic sequence alterations in various cancers through Next-Generation Sequencing (NGS).1419 In the case of PDAC, a majority of studies report a very high overlap (>50%) of detected mutations between bulk tumor and ctDNA.2026 However, the detection rate for the most frequently mutated gene KRAS largely varies in recently published reports ranging from 21.1% to almost 100%.2036 It is clear that patient selection and related factors such as disease stage as well as the methods, which were used to isolate and analyze the ctDNA are crucial factors for the practical applicability of liquid biopsy in this disease. To date, liquid biopsy for PDAC is not routinely used in the clinic but potential applications range from using it as a prognostic biomarker for survival to monitoring treatment responses and disease recurrence as well as identifying molecular targets for personalized therapy.37 Therefore our aim was to assess the clinical applicability of two commercially available NGS gene panels to detect the most frequent mutations in ctDNA from two consecutive blood samples in patients with non-resectable locally advanced or metastatic PDAC who underwentsystemic treatment.

This is a single-center, prospective, observational study including patients with histologically proven non-resectable PDAC, which was either locally advanced or metastasized and who underwent a systemic treatment at the Medical University of Vienna between 05/2016 and 05/2018. The electronic medical history was queried for patient demographics, performance status, date of diagnosis, date of advanced disease, diagnosis and carbohydrate antigen 199 (CA199) level at baseline, treatment details and survival data. ECOG (Eastern Cooperative Oncology Group) performance status was derived, if not stated explicitly, from the medical history including comorbidities and overall assessment of the treating physician. Recurrent PDAC after resection of curative intent was stated as stage IV disease. The here presented data analysis received prior approval by the ethical committee of the Medical University of Vienna (EK 274/2011) and was performed according to Helsinki criteria of good scientific practice. Written consent of the study participants was obtained after they were informed about the study purpose and prior to study commencement.

Peripheral blood from patients was collected in cell-free DNA collection tubes (Roche) at day one of the first administration of the systemic chemotherapy regimen as well as 46 weeks after the first blood sample. Blood samples were proceeded within 12 hours of collection via a 2-step centrifugation protocol. First, plasma was separated from the other blood components by centrifugation at 2000 x g for 20 minutes. After transferring the upper plasma layer to a new conical tube, it was respun at 3200 x g for 30 minutes to remove cell debris. Subsequently the resulting plasma supernatant was stored at 20 C in 10 mL cryotubes (VWR) until DNA isolation. Circulating DNA isolation from 510 mL plasma was performed on the Chemagic 360 Instrument (Perkin Elmer) with the isolation kit CMG-1111 (chemagic cfDNA 10k Kit special H12) according to manufacturers instruction. Cell-free DNA was eluted in ~40 L elution buffer. DNA quantification was performed with Qubit dsDNA HS Assay Kit (Invitrogen) according to the instructions provided by the manufacturer and purity was determined by Agilent 2200 TapeStation System. Cell-free DNA was stored at 20 C until further analysis.

Genomic DNA was isolated from formalin fixed, paraffin embedded (FFPE) tissue sections using GeneRead DNA FFPE Kit (Qiagen) according to the user manual. DNA quantification was performed with Qubit dsDNA HS Assay Kit (Invitrogen) according to the instructions provided by the manufacturer and purity was determined by Agilent 2200 TapeStation System. Genomic DNA was stored at 20 C until further analysis.

Library preparation was conducted using the Illumina TruSight Tumor 15 covering 15 genes, which are frequently mutated in solid tumors. Subsequent sequencing of pooled libraries was performed in several runs on the MiniSeq Illumina platform using MiniSeq High Output Reagent Kit (300-cycles). Data analysis was conducted using on-instrument Local Run Manager (LRM) Software with TruSight Tumor 15 analysis module. Passed-filter reads were aligned to human reference genome UCSC hg19 using banded Smith Waterman algorithm. Variants were called using Somatic Variant Caller developed by Illumina. All vcf-datasets were annotated using the Illumina VariantStudio 3.0 Software. Across all samples, several hotspot codons were manually evaluated using the Integrative Genomics Viewer (IGV) for potential low-abundance variants (0.1> VAF <2.0%). Annotated plasma variants had to have allele frequencies above a background threshold of the mean of our control samples (three different non-PDAC cfDNA samples).

Library preparation was conducted using AmpliSeq Library PLUS with AmpliSeq Cancer HotSpot Panel v2 for Illumina. This panel is designed to amplify 207 amplicons covering hotspot regions of 50 genes with known association to cancer. Final libraries were sequenced together using MiniSeq High Output Reagent Kit (300-cycles). Data analysis was conducted using DNA Amplicon workflow via Basespace Sequence Hub. The NGS data alignment was performed with Burrows-Wheeler Aligner (BWA) and subsequently Somatic Variant Caller was used. Variant annotation was performed with Illumina VariantStudio 3.0 Software. Across all samples, several hotspot codons were manually evaluated using the Integrative Genomics Viewer (IGV) for potential low-abundance variants (0.1> VAF <2.0%). Annotated plasma variants had to have allele frequencies above a background threshold of the mean of our control samples (HD701 and HD729 Reference Standards (Horizon)).

Descriptive statistics were calculated as mean, median or percentages as appropriate. Correlation between variant allele frequencies (VAF) between the two panels was calculated with Spearman correlation coefficient. The threshold for statistical significance was set at a p-value of less than 0.05.

A total of 21 patients with histologically proven PDAC were included in this study. Table 1 lists patient and tumor characteristics. There were 12 female (57.1%) and nine male (42.9%) patients. The median age at time of diagnosis of advanced disease was 64.3 years (interquartile range (IQR) 57.968.9 years). Three patients (14.3%) presented with locally advanced (unresectable) disease and 18 patients (85.7%) had metastasis at time of study inclusion. There were eight patients (38.1%) with a prior surgical resection. The median CA 199 levels were 481.5 kU/l (IQR 59.43355.0 kU/l). Levels of CA 199 were within the normal range in three patients (14.3%) and above in 18 patients (85.7%). The primary site of metastatic disease was liver (n = 11; 52.4%) followed by peritoneum (n = 5; 23.8%) and lung (n = 4; 19%). There were three patients (14.3%) with locally advanced disease, while 14 patients (66.7%) had one organ affected by metastatic spread and four patients (19%) had two or over two metastatic sites. The ECOG performance status was zero in 17 patients (81%) and one in four patients (19%).

Table 1 Characteristics of Patients and Tumors

In general, the amount of cfDNA, which can be obtained from plasma is relatively small compared to genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. Moreover, the fraction of cfDNA that originates from tumor cells (ctDNA) is extremely low. First, we analyzed quantity and quality of our cfDNA, which has been isolated using a magnetic bead-based protocol applicable for higher plasma volumes. All samples were isolated successfully and compared to other studies we revealed a considerably high mean cfDNA value of 1.9 ng/L (range 0.494.76 ng/L) in a volume of ~40 L.33,38,39 One sample yielded 53 ng/L cfDNA, which is substantially higher than the cfDNA amount of other samples and therefore not included into the mean-calculation. Due to the high concentration of DNA, we wanted to exclude contamination with high-molecular weight genomic DNA (gDNA) wherefore we performed fragment size analysis with the TapeStation System. CfDNA is highly fragmented and shows a size distribution of ~ 130 bp-180 bp. Generally, fragments higher than 1000 bp are considered as gDNA. The average cfDNA peak of our samples was around 180 bp and shows that there is little to no genomic DNA contamination (see quality control of representative PDAC samples in Supplementary Figure S1). Even the quality of the cfDNA sample with 53 ng/L was sufficient for NGS (Supplementary Figure S2). In summary, we conclude that all our samples were suitable for downstream applications such as NGS without any adaptation, which usually are necessary in cases of low cfDNA yields.

In a next step, we analyzed a total of 42 samples from 21 PDAC patients using a small gene panel containing 15 genes with a high coverage and high sensitivity. Paired-end sequencing resulted in average 3.84 Mio passed filter reads per sample and mean amplicon coverage of 23.086. The ctDNA variant detection limit depends on the background signal of our control samples. The control samples revealed allelic frequencies of 00.21%.

Sixteen out of 21 sequenced patients (76.2%) exhibited at least one variant (see Figure 1A). The number of gene mutations per patient ranged from 1-3 in at least one time point. The identified variants revealed allelic frequencies of 0.122% and were distributed over the following six cancer-related genes: KRAS (n = 14; 66.6%), TP53 (n = 7; 33.3%), PIK3CA (n = 2; 9.5%), EGFR (n = 1; 4.8%), MET (n = 1; 4.8%), PDGFRA (n = 1; 4.8%) (see Figure 1B). All detected variants with known or likely pathogenic effect are listed in detail in Supplementary Table S1. In all 16 patients at least one mutation was detected at baseline level. In eight of 16 patients (50%) all baseline variants were still found in the follow-up sample at varying percentages. In two patients (12.5%) (#3 and #15) one baseline mutation was also present in the follow-up sample at varying frequencies while a new mutation was identified in the subsequent sample and appeared during therapy. In patient #7 two baseline variants were also present with very low allele frequency in the consecutive sample while a TP53 variant disappeared. In the remaining five patients (31.3%) the baseline mutation was not detectable in the second sample. In summary, our 15-gene panel was sufficient to identify at least one tumor-associated mutation in 76.2% of our cases, which was suitable for follow-up monitoring.

Figure 1 Comparison between GP15 and GP50. Ratio of patients with at least one detectable mutation versus no detectable mutation according to the two panels (A). Absolute numbers of mutations detected with the two panels (B). Venn diagrams showing the number of patients with shared or exclusive mutations detected by the two panels (C). Correlation between variant allele frequency (VAF) between the two panels, r = Pearson r, P = p-value (D).

Since KRAS, TP53, SMAD4, and CDKN2A are known driver genes for PDAC and GP15 does not cover the latter two, all 42 samples were concomitantly analyzed with a larger panel containing 50 genes, which automatically leads to lower coverage and thus lower sensitivity. Paired-end sequencing resulted in average 1.08 Mio passed filter reads per sample and mean amplicon coverage of 4370. The detection limit of cfDNA variants depends on the background signal of our control samples, which revealed allelic frequencies of 00.149%. Sixteen out of 21 sequenced patients (76.2%) exhibited at least one variant (see Figure 1A). The number of gene mutations per patient ranged from 1-4 in at least one time point. The identified variants revealed allelic frequencies of 0.1723% and were distributed over the following five cancer-related genes: KRAS (n = 10; 47.6%), TP53 (n = 9; 42.8%), SMAD4 (n = 5; 23.8%), CDKN2A (n = 2; 9.5%), PIK3CA (n = 1; 4.8%) (see Figure 1B). All detected variants with known or likely pathogenic effect are listed in detail in Supplementary Table S2. In patient #5 a mutation was only detectable in the consecutive sample, but not at baseline. In six patients the baseline variants were still found in the follow-up sample at varying percentages. In patient #4 one baseline mutation was also present in the consecutive sample while an additional mutation disappeared during therapy. In patient #2 the baseline mutations were not detectable during therapy, but a new variant emerged in the follow-up sample reflecting different subclones. In the remaining seven patients the detected baseline mutation disappeared under therapy. In summary, with this 50-gene panel we were able to detect at least one tumor-associated mutation in 76.2% of our cases, even if the variant-frequency of some mutations is very low.

As stated above, KRAS and TP53 are the two most commonly mutated genes in PDAC. The overlap for these two genes in our samples analyzed with GP15 and GP50 is shown in Figure 1C. Moreover, a strong correlation of the variant allele frequency (VAF) for KRAS (Pearson r (r) = 0.9868, p =< 0.0001) and TP53 (r = 0.9854, p = 0.0001) between the two sequencing panels for all analyzed samples was observed (see Figure 1D).

When comparing GP15 results with GP50, nine out of 21 patients (43.2%) revealed the same results regarding the GP15 genes. Five patients showed additional KRAS-mutations with GP15, which were not detectable with GP50 because of the low variant-frequency. Patients #3 and #5 had, among others, PIK3CA and MET mutations, respectively. These gene regions are not covered by GP50 and therefore were not detected. In two patients (#17 and #19) a low-frequency TP53 mutation was detected with GP50 (Figure 1C), which was found by GP15 as well, but hadto be excluded because the allele frequency was not above the background threshold.

As aforementioned, SMAD4 and CDKN2A are frequently mutated genes in PDAC, but both genes are not covered by GP15. In this sense, in five GP15-positive cases additional variants in SMAD4 and CDKN2A were detected with GP50. Moreover, in one GP15-negative patient (#6) we could identify SMAD4 and CDKN2A mutations, even though they are low-frequency variants.

Ultimately, we have summarized the GP15 results with the two genes SMAD4 and CDKN2A, which were analyzed with GP50. Overall, 24 different variants with known or likely pathogenic effects were detected. The most commonly altered variants were KRAS p.G12D (n = 5), KRAS p.G12V (n = 3), KRAS p.G12R (n = 3) and the low-frequency variant CDKN2A p.Y129C (n = 2). All detected variants and the individual response to therapy are listed in detail in Table 2. In summary, four out of 21 (19.04%) cases revealed no pathogenic variants. It has been shown in previous studies that a therapy response is associated with a decreasing or unchanged mutant allele frequency, whereas an increase of ctDNA is associated with refractory disease.38,40,41 As a result, in seven of 21 (33.33%) PDAC patients the observed ctDNA dynamics suggests a correlation between ctDNA levels and response/non-response to cancer treatment. In ten of 21 (47.62%) patients a discordance of genetic and clinical data was observed (Table 2).

Table 2 Mutational Profile of 21 PDAC Patients (GP15 Results Combined with GP50 SMAD4 and CDKN2A Results). Paired-End Sequencing Resulted in a Mean Amplicon Coverage of 23.086 (GP15) and 4370 (GP50), respectively.

Depending on the availability, FFPE tissue samples of the primary tumor (n = 8) or liver metastasis (n = 3) were retrieved. To compare the mutations of the primary (FFPE) and recurrent tumor (which is represented by the ctDNA) the GP15 was used. In tissue DNA, alterations in KRAS were observed in all (n = 11) and in TP53 in 81% (n =9) of the available samples. In five (45.45%) patients blood-tissue mutational profiles were fully concordant (Table 3). KRAS and TP53 mutations were detectable in the tumor tissue of three (27.27%) patients, while ctDNA analysis only revealed the KRAS mutation in the respective sample (partially concordant mutational profiles). The remaining three (27.27%) patients only had detectable TP53 and/or KRAS mutations in the primary tumor or liver metastases but not in the corresponding ctDNA analysis with the GP15. Overall, genomic concordance rate between tissue DNA and ctDNA analyses was 65.22%, which means that 15/23 mutations that were present in the primary tumor/metastatic site could also be detected in ctDNA. More precisely, concordance rate was 72.72% for KRAS and 44.44% for TP53.

Table 3 Comparison of Mutations of cfDNA (Baseline) and Primary Tumor Sample/Metastatic Site of Eleven PDAC Patients

Liquid biopsy is increasingly recognized as a versatile tool for the detection of disease relapse and treatment monitoring of cancer patients.42,43 However, the plethora of potential methods, ranging from PCR-based techniques to NGS-based systems, complicates the comparison between different studies and ultimately limits the conclusions, which could be drawn on their clinical utility. Due to declining costs, the wide availability and the possibility to simultaneously detect multiple different mutations, NGS-based methods have also become very popular when analyzing low input samples like ctDNA from blood plasma of cancer patients. Given that a substantial proportion of patients, even if they present with metastatic disease, have unexpectedly low amounts of ctDNA,44 it is important to consider that the coverage of the used sequencing panel is mostly determined by the number of analyzed genes. The aim of this study was to assess the clinical applicability of two commercially available NGS gene panels (15 versus 50 genes), to detect the most frequent mutations in ctDNA from two consecutive blood samples in patients with advanced PDAC, which undergo systemic treatment.

Generally, the amount of total cfDNA, which can be isolated from plasma is quite small. Most studies give remarkably little detail about the quantity of cfDNA, which they have gained with their chosen DNA extraction methods. Some few studies reported about cfDNA levels in PDAC patients, which are much lower than our yield.33,38,39 By using a bead-based isolation approach applicable for higher plasma volumes, we were able to obtain relatively high mean cfDNA values (1.9 ng/L in a volume of ~40 L) with minimal genomic DNA contamination. These samples were suitable for NGS without any adaptation. The cfDNA sample collected at the second time point of patient #10 revealed a concentration of 53 ng/L, much higher than our mean value. Such a high value suggests the assumption that genomic DNA contamination is present; even so the quality control displayed a characteristic profile of cfDNA (Supplementary Figure 2). Therefore, this sample was used for further analysis without any concerns. A non-malignant pathological process leading to the release of high amounts of cfDNA into the blood stream4547 cannot be the only explanation since KRAS p.G12V variant allele frequency was almost unchanged in both samples (Table 2) despite of 20x cfDNA concentration differences (2.51 ng/L versus 53.0 ng/L).

To the best of our knowledge, we present here for the first time results of this promising isolation approach. Some downstream applications require high levels of cfDNA, therefore our results could be of interest for the medical and biobanking communities.

With our 15-gene panel at least one tumor-associated mutation in 76.16% of the patients in our cohort could be identified. With our 50-gene panel we were able to detect in 76.16% of the cases a mutation as well; even though the mutation-positive cases are slightly different. Differences are mainly caused by the number of assessed genes, amplicon coverages and amplicon positions. Variant allele frequency of some mutations detected with the 50-gene panel is very low. Although we have used controls to determine the background threshold, these results are still not reliable enough for routine clinical practice, as with the TP53 low-frequency variants in patients #17 and #19. One possible option to overcome this issue is to combine NGS results with droplet digital PCR just for specific low-frequency mutations.31 Since droplet digital PCR is a more sensitive method,48,49 it would help to validate true positive low-level mutations detected by NGS.

Despite the same detection rate of 76.16% for at least one mutation, the 15-gene panel seems to be more informative (five additional KRAS mutations were detected), sensitive and reliable based on our results in respect of routine clinical practice.

During tumorigenesis KRAS mutations are among the first to occur and consequently they are seen as founder mutations.32335052 Correspondingly, KRAS is the most frequently mutated gene in patients with PDAC. In accordance with these studies, we also predominantly detected mutations in KRAS, more precisely in codon 12.31 In general, therapy response is associated with a decreasing or unchanged mutant allele frequency, whereas an increase of ctDNA is associated with refractory disease.38,40,41 With both our panels we were able to observe changes of the ctDNA allele frequencies under therapy. In 33.33% (7/21) of our cases a correlation between mutational frequency and therapy response assessed by CT-scans can be assumed. For example in patient #14 the mutational frequencies of both detected mutations dropped and correspondingly the follow-up CT-scan showed that the tumor lesions were not progressing. Furthermore, it can be hypothesized that both mutations originate from the same tumor clone because of the similar allele frequency (Table 2). In contrast, in 47.62% (10/21) of our cases a discordance of genetic and clinical data was observed. Patient #4 revealed a KRAS and TP53 mutation and the allele frequency of both decreased during therapy, which would indicate a therapy response. Contrary to this, disease reassessment by CT-scan revealed a disease progression. Based on such findings we propose that it is important to be cautious with the interpretation of mutation frequencies in respect to clinical response. Furthermore, in patients #12 and #17 baseline mutations were not detectable during therapy, although disease reassessment showed a stable disease. Regarding the radiological response evaluation, it should be considered that standard imaging methods cannot always reliably distinguish between vital tumor tissue and fibrotic masses, which could complicate the assessment of treatment responses.

In eleven of 21 patients (52.38%) primary tissue or metastatic sites were analyzed for comparison. In 5/11 patients sequencing analysis revealed a complete blood-tissue concordance of the mutational landscape and in 3/11 patients there was a partial concordance. In the latter case (#8, #11 and #21), KRAS mutations are presented in both analyses, whereas TP53 mutations were not detectable in ctDNA. One possible explanation for the absence of TP53 mutations could be a different clonal composition of the tumor in further treatment lines compared to the primary tumor. Treatment could have eradicated most of these clones during first line treatment.53 In patients #18 and #20 KRAS and TP53 mutations were detected only in the tissue of the primary tumor or metastasis but missing in ctDNA analyses. A reason for the discrepancy in the mutational profile between tissue and ctDNA might be low ctDNA levels in these samples, a limitation, which has been described in patients who are under treatment.39,53,54 In summary, the genomic concordance rate between tissue and ctDNA in our cohort was 65.22% for all mutations and in particular 72.72% for KRAS, which is higher than the rates reported by a previous study from Patel et al.25 These results emphasize the potential of ctDNA as a biomarker in PDAC and underline the promising cfDNA-isolation technique.

Limitations of this study are the relatively small number of included patients and that blood samples were only collected early in the treatment course, which would miss potential outgrowing tumor clones that arise shortly before therapy response evaluation. We decided to collect blood samples early in the treatment course because we speculated to be able to anticipate the treatment response before radiological reassessment would be performed. Our results demonstrate that by following these early ctDNA dynamics we were successful in predicting the clinical outcome in about half of all patients with a detectable mutation at baseline. In the other half of the patients treatment responses were not predictable. The selection of the NGS sequencing panels was based on the covered genes, however at the time of study initiation no PDAC-specific product suitable for ctDNA was available. We would highly encourage the development of a commercially available NGS sequencing panel optimized for ctDNA analysis in PDAC, which focuses only on a limited number of genes that are typically mutated in this disease, like KRAS, TP53, CDKN2A, SMAD4, and KDM6A. With this gene panel it would be possible to simultaneously assess multiple genes to maximize the rate of patients with at least one mutation, which can be monitored during therapy while maintaining a sufficiently high coverage essential for detecting low-abundance ctDNA.

This study demonstrates the feasibility of using an NGS-based analyzing method for ctDNA in PDAC patients undergoing a palliative chemotherapy. Ourresults underscore the importance of precise DNA isolation to yield high quality samples for further ctDNA analysis and the selection of a gene panel with a high coverage. Further validation of our findings, with a specifically for this purpose developed NGS-based gene panel, in a larger patient cohort is warranted.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

We want to thank Robert Brettner for the processing of plasma samples and Sarah Szaffich for her great technical support. Thanks to Dr. Judith Stift for the estimation of the tumor-harboring areas on HE stained FFPE tissue slices. All sequencing was performed in cooperation with the Core Facility Genomics of the Medical University Vienna. This work was supported by the Fonds der Stadt Wien fr innovative interdisziplinre Krebsforschung.

This research received no external funding.

GWP: Personal financial interests: Merck Serono, Roche, Amgen, Sanofi, Lilly, Servier, Taiho, Bayer, Halozyme, BMS, Celgene, Pierre Fabre, Shire, Institutional financial interests Clinical trials: Celgene, Array, Servier, Bayer, BostonBiomedical, Merck, BMS. All other authors declare no conflict of interest.

1. Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:29132921. doi:10.1158/0008-5472.CAN-14-0155

2. Malvezzi M, Bertuccio P, Rosso T, et al. European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women? Ann Oncol. 2015;26:779786. doi:10.1093/annonc/mdv001

3. Balachandran VP, Beatty GL, Dougan SK. Broadening the impact of immunotherapy to pancreatic cancer: challenges and opportunities. Gastroenterology. 2019;156:20562072. doi:10.1053/j.gastro.2018.12.038

4. Neesse A, Bauer CA, Ohlund D, et al. Stromal biology and therapy in pancreatic cancer: ready for clinical translation? Gut. 2019;68:159171. doi:10.1136/gutjnl-2018-316451

5. Singhi AD, Koay EJ, Chari ST, et al. Early detection of pancreatic cancer: opportunities and challenges. Gastroenterology. 2019;156:20242040. doi:10.1053/j.gastro.2019.01.259

6. Kleeff J, Korc M, Apte M, et al. Pancreatic cancer. Nat Rev Dis Primers. 2016;2:16022. doi:10.1038/nrdp.2016.22

7. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399405. doi:10.1038/nature11547

8. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495501. doi:10.1038/nature14169

9. Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:4752. doi:10.1038/nature16965

10. Jahr S, Hentze H, Englisch S, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61:16591665.

11. Crowley E, Di Nicolantonio F, Loupakis F, et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10:472484. doi:10.1038/nrclinonc.2013.110

12. Li L, Zhang J, Jiang X, et al. Promising clinical application of ctDNA in evaluating immunotherapy efficacy. Am J Cancer Res. 2018;8:19471956.

13. Alix-Panabieres C, Pantel K. Real-time liquid biopsy: circulating tumor cells versus circulating tumor DNA. Ann Transl Med. 2013;1:18. doi:10.3978/j.issn.2305-5839.2013.06.02

14. Murtaza M, Dawson SJ, Tsui DW, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013;497:108112. doi:10.1038/nature12065

15. Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:11991209. doi:10.1056/NEJMoa1213261

16. Aravanis AM, Lee M, Klausner RD. Next-generation sequencing of circulating tumor DNA for early cancer detection. Cell. 2017;168:571574. doi:10.1016/j.cell.2017.01.030

17. Madsen AT, Winther-Larsen A, McCulloch T, et al. Genomic profiling of circulating tumor DNA predicts outcome and demonstrates tumor evolution in ALK-positive non-small cell lung cancer patients. Cancers (Basel). 2020;12. doi:10.3390/cancers12040947

18. Kurihara S, Ueda Y, Onitake Y, et al. Circulating free DNA as non-invasive diagnostic biomarker for childhood solid tumors. J Pediatr Surg. 2015;50:20942097. doi:10.1016/j.jpedsurg.2015.08.033

19. Ikeda S, Lim JS, Kurzrock R. Analysis of tissue and circulating tumor DNA by next-generation sequencing of hepatocellular carcinoma: implications for targeted therapeutics. Mol Cancer Ther. 2018;17:11141122. doi:10.1158/1535-7163.Mct-17-0604

20. Zill OA, Greene C, Sebisanovic D, et al. Cell-free DNA next-generation sequencing in pancreatobiliary carcinomas. Cancer Discov. 2015;5:10401048. doi:10.1158/2159-8290.Cd-15-0274

21. Kinugasa H, Nouso K, Miyahara K, et al. Detection of K-ras gene mutation by liquid biopsy in patients with pancreatic cancer. Cancer. 2015;121:22712280. doi:10.1002/cncr.29364

22. Sefrioui D, Blanchard F, Toure E, et al. Diagnostic value of CA19.9, circulating tumour DNA and circulating tumour cells in patients with solid pancreatic tumours. Br J Cancer. 2017;117:10171025. doi:10.1038/bjc.2017.250

23. Perdomo Zaldivar E, Inga E, Cano T, et al. K-Ras mutation in liquid biopsy and tumor tissue correlation in patients with pancreatic cancer. Ann Oncol. 2019;30:iv84. doi:10.1093/annonc/mdz155.304

24. Wang Z-Y, Ding X-Q, Zhu H, et al. KRAS mutant allele fraction in circulating cell-free DNA correlates with clinical stage in pancreatic cancer patients. Front Oncol. 2019;9. doi:10.3389/fonc.2019.01295

25. Patel H, Okamura R, Fanta P, et al. Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer. J Hematol Oncol. 2019;12:130. doi:10.1186/s13045-019-0824-4

26. Ako S, Nouso K, Kinugasa H, et al. Utility of serum DNA as a marker for KRAS mutations in pancreatic cancer tissue. Pancreatology. 2017;17:285290. doi:10.1016/j.pan.2016.12.011

27. Perets R, Greenberg O, Shentzer T, et al. Mutant KRAS circulating tumor DNA is an accurate tool for pancreatic cancer monitoring. The Oncologist. 2018;23:566572. doi:10.1634/theoncologist.2017-0467

28. Pishvaian MJ, Joseph Bender R, Matrisian LM, et al. A pilot study evaluating concordance between blood-based and patient-matched tumor molecular testing within pancreatic cancer patients participating in the Know Your Tumor (KYT) initiative. Oncotarget. 2017;8:8344683456. doi:10.18632/oncotarget.13225

29. Earl J, Garcia-Nieto S, Martinez-Avila JC, et al. Circulating tumor cells (Ctc) and kras mutant circulating free Dna (cfdna) detection in peripheral blood as biomarkers in patients diagnosed with exocrine pancreatic cancer. BMC Cancer. 2015;15:797. doi:10.1186/s12885-015-1779-7

30. Chen H, Tu H, Meng ZQ, et al. K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer. Eur J Surg Oncol. 2010;36:657662. doi:10.1016/j.ejso.2010.05.014

31. Le Calvez-kelm F, Foll M, Wozniak MB, et al. KRAS mutations in blood circulating cell-free DNA: a pancreatic cancer case-control. Oncotarget. 2016;7:7882778840. doi:10.18632/oncotarget.12386

32. Takai E, Totoki Y, Nakamura H, et al. Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer. Sci Rep. 2015;5:18425. doi:10.1038/srep18425

33. Adamo P, Cowley CM, Neal CP, et al. Profiling tumour heterogeneity through circulating tumour DNA in patients with pancreatic cancer. Oncotarget. 2017;8:8722187233. doi:10.18632/oncotarget.20250

34. Hadano N, Murakami Y, Uemura K, et al. Prognostic value of circulating tumour DNA in patients undergoing curative resection for pancreatic cancer. Br J Cancer. 2016;115:5965. doi:10.1038/bjc.2016.175

35. Del Re M, Vivaldi C, Rofi E, et al. Early changes in plasma DNA levels of mutant KRAS as a sensitive marker of response to chemotherapy in pancreatic cancer. Sci Rep. 2017;7:7931. doi:10.1038/s41598-017-08297-z

36. Cohen JD, Javed AA, Thoburn C, et al. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. Proc Natl Acad Sci U S A. 2017;114:1020210207. doi:10.1073/pnas.1704961114

37. Buscail E, Maulat C, Muscari F, et al. Liquid biopsy approach for pancreatic ductal adenocarcinoma. Cancers. 2019;11:852.

38. Wei T, Zhang Q, Li X, et al. Monitoring tumor burden in response to FOLFIRINOX chemotherapy via profiling circulating cell-free DNA in pancreatic cancer. Mol Cancer Ther. 2019;18:196203. doi:10.1158/1535-7163.Mct-17-1298

39. Pietrasz D, Pcuchet N, Garlan F, et al. Plasma circulating tumor DNA in pancreatic cancer patients is a prognostic marker. Clin Cancer Res. 2017;23:116123. doi:10.1158/1078-0432.Ccr-16-0806

40. Cheng H, Liu C, Jiang J, et al. Analysis of ctDNA to predict prognosis and monitor treatment responses in metastatic pancreatic cancer patients. Int J Cancer. 2017;140:23442350. doi:10.1002/ijc.30650

41. Siravegna G, Mussolin B, Buscarino M, et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med. 2015;21:795801. doi:10.1038/nm.3870

42. Pantel K, Alix-Panabieres C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol. 2019;16:409424. doi:10.1038/s41571-019-0187-3

43. Kilgour E, Rothwell DG, Brady G, et al. Liquid biopsy-based biomarkers of treatment response and resistance. Cancer Cell. 2020;37:485495. doi:10.1016/j.ccell.2020.03.012

44. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra224224ra224. doi:10.1126/scitranslmed.3007094

45. Kustanovich A, Schwartz R, Peretz T, et al. Life and death of circulating cell-free DNA. Cancer Biol Ther. 2019;20:10571067. doi:10.1080/15384047.2019.1598759

46. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11:426437. doi:10.1038/nrc3066

47. Volik S, Alcaide M, Morin RD, et al. Cell-free DNA (cfDNA): clinical Significance and utility in cancer shaped by emerging technologies. Mol Cancer Res. 2016;14:898908. doi:10.1158/1541-7786.Mcr-16-0044

48. Postel M, Roosen A, Laurent-Puig P, et al. Droplet-based digital PCR and next generation sequencing for monitoring circulating tumor DNA: a cancer diagnostic perspective. Expert Rev Mol Diagn. 2018;18:717. doi:10.1080/14737159.2018.1400384

49. Yang X, Zhuo M, Ye X, et al. Quantification of mutant alleles in circulating tumor DNA can predict survival in lung cancer. Oncotarget. 2016;7:2081020824. doi:10.18632/oncotarget.8021

50. Kanda M, Matthaei H, Wu J, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology. 2012;142:730733.e739. doi:10.1053/j.gastro.2011.12.042

51. Hruban RH, Wilentz RE, Kern SE. Genetic progression in the pancreatic ducts. Am J Pathol. 2000;156:18211825. doi:10.1016/S0002-9440(10)65054-7

52. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:18011806. doi:10.1126/science.1164368

53. Berger AW, Schwerdel D, Ettrich TJ, et al. Targeted deep sequencing of circulating tumor DNA in metastatic pancreatic cancer. Oncotarget. 2018;9:20762085. doi:10.18632/oncotarget.23330

54. Vidal J, Muinelo L, Dalmases A, et al. Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients. Ann Oncol. 2017;28:13251332. doi:10.1093/annonc/mdx125

Read more:
Bead-based Isolation of Circulating Tumor DNA - CMAR | CMAR - Dove Medical Press

Some sections of our DNA are genes, which are instructions for building proteins, while other sections called enhancers regulate which genes are switched on or off, when, and in which tissue. New research from the University of Copenhagen and the Karolinska Institutet provides evidence of a functional link between epigenetic rewiring of enhancers to control their activity after exercise training and the modulation of disease risk in humans.

Exercise training rewires the enhancers in regions of our DNA that are known to be associated with the risk to develop disease. Image credit: Sasin Tipchai.

Regular physical activity decreases the risk of multiple common disorders such as cardiovascular disease, type 2 diabetes, cancer, and neurological conditions, along with the overall risk of mortality, said Professor Romain Barrs from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen and colleagues.

The beneficial effects of exercise training on human health are partially driven by adaptations of the skeletal muscle tissue.

Exercise-induced adaptations include coordinated changes in the expression of genes controlling substrate usage and metabolic efficiency in skeletal muscle.

In addition to the adaptations that occur within skeletal muscle cells, exercise exerts systemic effects on whole-body homeostasis by triggering the release of soluble factors from the muscle that signal to distal tissues, such as brain, liver, and adipose tissue.

The mechanisms by which training-induced adaptations of skeletal muscle orchestrate positive effects at the whole-body level are poorly understood.

We hypothesized that endurance exercise training remodels the activity of gene enhancers in skeletal muscle and that this remodeling contributes to the beneficial effects of exercise on human health.

For the study, the researchers recruited eight healthy Caucasian men (mean age 23 years) and put them through a six-week endurance exercise program.

They collected a biopsy of their thigh muscle before and after the exercise intervention and examined if changes in the epigenetic signature of their DNA occurred after training.

They discovered that after completing the endurance training program, the structure of many enhancers in the skeletal muscle of the young men had been altered.

By connecting the enhancers to genetic databases, the scientists found that many of the regulated enhancers have already been identified as hotspots of genetic variation between individuals.

Our findings provide a mechanism for the known beneficial effects of exercise, Professor Barrs said.

By connecting each enhancer with a gene, we further provide a list of direct targets that could mediate this effect.

The authors speculate that the beneficial effects of exercise on organs distant from muscle, like the brain, may largely be mediated by regulating the secretion of muscle factors.

In particular, they found that exercise remodels enhancer activity in skeletal muscle that are linked to cognitive abilities, which opens for the identification of exercise training-induced secreted muscle factors targeting the brain.

Our data provides evidence of a functional link between epigenetic rewiring of enhancers to control their activity after exercise training and the modulation of disease risk in humans, said Dr. Kristine Williams, also from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen.

The findings are published in the journal Molecular Metabolism.

_____

Kristine Williams et al. Epigenetic rewiring of skeletal muscle enhancers after exercise training supports a role in the whole-body function and human health. Molecular Metabolism, published online July 10, 2021; doi: 10.1016/j.molmet.2021.101290

Continued here:
Study: Physical Exercise Improves Health of Brain and Other Organs through Epigenetic Changes | Medicine, Physiology - Sci-News.com

Dr. Tadataka Tachi Yamada/Photo Courtesy of Getty Images.

In the midst of the biggest global health crisis in a generation, the world has lost one of its premier global public health advocates. Dr. Tadataka Tachi Yamada, a former GlaxoSmithKline and Takeda Pharmaceutical executive, early gene therapy backer, and philanthropist, passed away on Wednesday of natural causes at the age of 76.

Born in Japan,Yamada eventually moved to the United States and trained as a gastroenterologist. He began his impactful career in academia where he rose to Chief of the Division of Gastroenterology and chair of the Department of Internal Medicine at the University of Michigan. He then made the pivot to the Life Sciences, becoming the Chairman of Research and Development for GSK.

Yamada made the decision to move into industry to make a more direct impact on patients.

Youre working in the laboratory; youre doing research thats pretty basic. And you feel like this work is going to actually have an impact on patients somewhere down the line, but youre never sure, and youre pretty distant from any direct effect on patients, he said in a 2012 interview with the Journal of Clinical Investigation (JCI). When I went, I realized that these people were really serious and had a very difficult task. Making medicines is maybe the hardest task in biomedical science.

Yamada might be best known and remembered for his philanthropic efforts in the development of vaccines for malaria and meningitis. In 2009, he left GSK to join the Bill & Melinda Gates Foundation as executive director of the Global Health program.

In 2013, Yamada heard the industry calling again, joining Takeda as EVP and Chief Medical and Scientific Officer where he shepherded the launch of Takeda Vaccines, which is in the late stages of developing just the second vaccine for the mosquito-borne virus, dengue fever.

In recent years, Yamada founded or co-founded a series of biopharma companies committed to developing vaccines and therapeutics for the diseases closest to his heart. These include Icosavax, Inc., which is focused on developing safe and effective vaccines against infectious diseases, and Passage Bio, a clinical-stage genetic medicines company in the CNS space which he co-founded in 2017 with gene therapy pioneer, Dr. James Wilson.

We are deeply saddened by the sudden passing of Tachi, a visionary leader in our field and co-founder of Passage Bio, said Passage president and CEO, Bruce Goldsmith, Ph.D. We are forever grateful for the vision, scientific experience, and strategic influence that he shared to establish our company. He has left a lasting legacy with his generous contribution to our industry, and specifically to Passage Bio and the patients we serve. We will continue to honor and build upon Tachis legacy.

Prior to his death, Yamada was a venture partner with Frazier Healthcare and served as chair of the board of directors at the Clinton Health Access Initiative.

Dr. Tachi Yamada was an extraordinary scientist and leader who used his brilliant mind and kind, good heart to improve the lives of millions of people, former president Bill Clinton said in a statement. Tachi brought a world of experience, knowledge, and good judgement to CHAI. He inspired us all to help more people and save more lives.

Tributes also poured in from Alnylam Pharmaceuticals CEO, John Maraganore and Dr. Peter Singer, special advisor toDirector General Tedros Adhanom Ghebreyesus at the World Health Organization (WHO).

View post:
The World Takes Another Hit with Loss of Global Health Giant Dr. Tachi Yamada - BioSpace

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the pivotal Phase III POLARIX trial investigating Polivy (polatuzumab vedotin) in combination with Rituxan (rituximab) plus cyclophosphamide, doxorubicin and prednisone (R-CHP) versus Rituxan plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) met its primary endpoint by demonstrating significantly improved and clinically meaningful progression-free survival in people with previously untreated diffuse large B-cell lymphoma (DLBCL). Safety outcomes were consistent with those seen in previous trials.

Since 40% of people with DLBCL relapse after initial therapy, achieving meaningful treatment effects in the front-line setting has the potential to be transformative, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. This Polivy regimen is the first in two decades to improve progression-free survival in DLBCL compared to the standard of care, and we look forward to sharing these results with health authorities to bring this important potential new treatment option to patients as soon as possible.

Todays POLARIX results will be presented at an upcoming medical meeting and submitted to health authorities as part of Genentechs commitment to transforming the treatment of DLBCL by providing options tailored to patient and healthcare professional needs. Genentech would like to thank all investigators, academic partners and people with DLBCL who participated in the study.

Currently, Polivy is used as an off-the-shelf, fixed-duration treatment option in the relapsed or refractory (R/R) DLBCL setting, and is approved in combination with bendamustine and Rituxan for the treatment of R/R DLBCL in more than 60 countries worldwide, including in the EU and in the U.S. Genentech continues to explore areas of unmet need where Polivy has the potential to deliver benefit, with ongoing studies investigating combinations of Polivy with the CD20xCD3 T cell-engaging bispecific antibodies mosunetuzumab and glofitamab, with Venclexta (venetoclax), which is being developed by AbbVie and Genentech, and with Rituxan in combination with gemcitabine and oxaliplatin in the Phase III POLARGO study.

About the POLARIX study

POLARIX [NCT03274492] is an international Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy, safety and pharmacokinetics of Polivy (polatuzumab vedotin) plus Rituxan (rituximab), cyclophosphamide, doxorubicin and prednisone (R-CHP) versus Rituxan, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in people with previously untreated diffuse large B-cell lymphoma (DLBCL). Eight-hundred and seventy-nine patients were randomized 1:1 to receive either Polivy plus R-CHP plus a vincristine placebo for six cycles, followed by Rituxan for two cycles; or R-CHOP plus a Polivy placebo for six cycles, followed by two cycles of Rituxan. The primary outcome measure is progression-free survival as assessed by the investigator using the Lugano Response Criteria for malignant lymphoma. POLARIX is being conducted in collaboration with The Lymphoma Study Association (LYSA) and The Lymphoma Academic Research Organisation (LYSARC).

About Polivy (polatuzumab vedotin-piiq)

Polivy is a first-in-class anti-CD79b antibody-drug conjugate (ADC). The CD79b protein is expressed specifically in the majority of B cells, an immune cell impacted in some types of non-Hodgkins lymphoma (NHL), making it a promising target for the development of new therapies. Polivy binds to CD79b and destroys these B cells through the delivery of an anti-cancer agent, which is thought to minimize the effects on normal cells. Polivy is being developed by Genentech using Seagen ADC technology and is currently being investigated for the treatment of several types of NHL.

About DLBCL

DLBCL is the most common form of non-Hodgkins lymphoma (NHL), accounting for about one in three cases of NHL. DLBCL is an aggressive (fast-growing) type of NHL. While it is generally responsive to treatment in the frontline, as many as 40% of patients will relapse or have refractory disease, at which time salvage therapy options are limited and survival is short. Approximately 150,000 people worldwide are estimated to be diagnosed with DLBCL each year.

Polivy U.S. Indication

Polivy is a prescription medicine used with other medicines, bendamustine and a rituximab product, to treat diffuse large B-cell lymphoma in adults who have progressed after at least two prior therapies.

The accelerated approval of Polivy is based on a type of response rate. There are ongoing studies to confirm the clinical benefit of Polivy.

Important Safety Information

Possible serious side effects

Everyone reacts differently to Polivy therapy, so its important to know what the side effects are. Some people who have been treated with Polivy have experienced serious to fatal side effects. A patients doctor may stop or adjust a patients treatment if any serious side effects occur. Patients must contact their healthcare team if there are any signs of these side effects.

Side effects seen most often

The most common side effects during treatment were

Polivy may not be for everyone. A patient should talk to their doctor if they are

These may not be all the side effects. Patients should talk to their healthcare provider for more information about the benefits and risks of Polivy treatment.

Report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Please visit http://www.Polivy.com for the full Prescribing Information for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, were investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit http://www.gene.com/hematology.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

See the article here:
Phase III Study Shows Genentech's Polivy Plus R-CHP Is the First Regimen in 20 Years to Significantly Improve Outcomes in Previously Untreated...

Aug. 3, 2021 05:00 UTC

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has accepted the companys supplemental Biologics License Application (sBLA) and granted Priority Review for Tecentriq (atezolizumab) as adjuvant treatment following surgery and platinum-based chemotherapy for people with non-small cell lung cancer (NSCLC) whose tumors express PD-L11%, as determined by an FDA-approved test. The FDA is reviewing the application under the Real-Time Oncology Review pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible. The FDA is expected to make a decision on approval by December 1, 2021.

New treatment options are urgently needed in early-stage non-small cell lung cancer to help the nearly 50% of people who currently experience a recurrence following surgery, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. Tecentriq is the first cancer immunotherapy to show a clinically meaningful benefit in the adjuvant lung cancer setting, and were working closely with the FDA to bring this significant advancement to patients as quickly as possible.

This application is based on disease-free survival (DFS) results from an interim analysis of the Phase III IMpower010 study, the first and only Phase III study of a cancer immunotherapy to demonstrate positive results in the adjuvant lung cancer setting. The study showed that treatment with Tecentriq following surgery and platinum-based chemotherapy reduced the risk of disease recurrence or death (DFS) by 34% (hazard ratio [HR]=0.66, 95% CI: 0.50-0.88) in people with Stage II-IIIA NSCLC whose tumors express PD-L11%, compared with best supportive care (BSC). In this population, median DFS was not yet reached for Tecentriq compared with 35.3 months for BSC. Follow-up on the IMpower010 trial will continue with planned analyses of DFS in the overall intent-to-treat (ITT) population, including Stage IB patients, which at the time of analysis did not cross the threshold, and overall survival (OS) data, which were immature at the time of interim analysis. Safety data for Tecentriq were consistent with its known safety profile and no new safety signals were identified. Results from the IMpower010 trial were presented at the 2021 ASCO Annual Meeting.

About the IMpower010 study

IMpower010 is a Phase III, global, multicenter, open-label, randomized study evaluating the efficacy and safety of Tecentriq compared with BSC, in participants with Stage IB-IIIA NSCLC (UICC 7th edition), following surgical resection and up to 4 cycles of adjuvant cisplatin-based chemotherapy. The study randomized 1,005 people with a ratio of 1:1 to receive either Tecentriq (up to 16 cycles) or BSC. The primary endpoint is investigator-determined DFS in the PD-L1-positive Stage II-IIIA, all randomized Stage II-IIIA and ITT Stage IB-IIIA populations. Key secondary endpoints include OS in the overall study population, ITT Stage IB-IIIA NSCLC.

About lung cancer

According to the American Cancer Society, it is estimated that more than 235,000 Americans will be diagnosed with lung cancer in 2021, and NSCLC accounts for 80-85% of all lung cancers. Today, about half of all people with early lung cancer still experience a cancer recurrence following surgery, but treating lung cancer early, before it has spread, may help prevent the disease from returning and provide people with the best opportunity for a cure.

About Tecentriq (atezolizumab)

Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1. Tecentriq is designed to bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the re-activation of T cells. Tecentriq may also affect normal cells.

Tecentriq U.S. Indications

Tecentriq is a prescription medicine used to treat adults with:

A type of lung cancer called non-small cell lung cancer (NSCLC).

A type of lung cancer called small cell lung cancer (SCLC).

It is not known if Tecentriq is safe and effective in children.

Important Safety Information

What is the most important information about Tecentriq?

Tecentriq can cause the immune system to attack normal organs and tissues in any area of the body and can affect the way they work. These problems can sometimes become severe or life threatening and can lead to death. Patients can have more than one of these problems at the same time. These problems may happen anytime during their treatment or even after their treatment has ended.

Patients should call or see their healthcare provider right away if they develop any new or worse signs or symptoms, including:

Lung problems

Intestinal problems

Liver problems

Hormone gland problems

Kidney problems

Skin problems

Problems can also happen in other organs.

These are not all of the signs and symptoms of immune system problems that can happen with Tecentriq. Patients should call or see their healthcare provider right away for any new or worse signs or symptoms, including:

Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:

Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if patients undergo transplantation either before or after being treated with Tecentriq. A healthcare provider will monitor for these complications.

Getting medical treatment right away may help keep these problems from becoming more serious. A healthcare provider will check patients for these problems during their treatment with Tecentriq. A healthcare provider may treat patients with corticosteroid or hormone replacement medicines. A healthcare provider may also need to delay or completely stop treatment with Tecentriq if patients have severe side effects.

Before receiving Tecentriq, patients should tell their healthcare provider about all of their medical conditions, including if they:

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of Tecentriq when used alone include:

The most common side effects of Tecentriq when used in lung cancer with other anti-cancer medicines include:

Tecentriq may cause fertility problems in females, which may affect the ability to have children. Patients should talk to their healthcare provider if they have concerns about fertility.

These are not all the possible side effects of Tecentriq. Patients should ask their healthcare provider or pharmacist for more information about the benefits and side effects of Tecentriq.

Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

Report side effects to Genentech at 1-888-835-2555.

Please see http://www.Tecentriq.com for full Prescribing Information and additional Important Safety Information.

About Genentech in cancer immunotherapy

Genentech has been developing medicines to redefine treatment in oncology for more than 35 years, and today, realizing the full potential of cancer immunotherapy is a major area of focus. With more than 20 immunotherapy molecules in development, Genentech is investigating the potential benefits of immunotherapy alone, and in combination with various chemotherapies, targeted therapies and other immunotherapies with the goal of providing each person with a treatment tailored to harness their own unique immune system.

In addition to Genentechs approved PD-L1 checkpoint inhibitor, the companys broad cancer immunotherapy pipeline includes other checkpoint inhibitors, individualized neoantigen therapies and T cell bispecific antibodies. For more information visit http://www.gene.com/cancer-immunotherapy.

About Genentech in lung cancer

Lung cancer is a major area of focus and investment for Genentech, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have five approved medicines to treat certain kinds of lung cancer and more than 10 medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210802005854/en/

Originally posted here:
FDA Grants Priority Review to Genentech's Tecentriq as Adjuvant Treatment for Certain People With Early Non-small Cell Lung Cancer - BioSpace