Podcasts about v600e

BUFFALO, NY- August 14, 2024 – A new #casereport was #published in Oncotarget's Volume 15 on July 17, 2024, entitled, “Rapid but nondurable response of a BRAF exon 15 double-mutated spindle cell sarcoma to a combination of BRAF and MEK inhibitors.” As noted in the introduction of the Abstract, the BRAF V600E substitution predicts a cancer's sensitivity to BRAF inhibitor therapy, though the mutation is rarely found in soft-tissue sarcomas. Researchers Kseniya Sinichenkova, Iliya Sidorov, Nataliya Kriventsova, Dmitriy Konovalov, Ruslan Abasov, Nataliya Usman, Alexander Karachunskiy, Galina Novichkova, Dmitriy Litvinov, and Alexander Druy from the Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology (Ministry of Healthcare of Russian Federation) and the Research Institute of Medical Cell Technologies in Yekaterinburg, Russia, describe a case of undifferentiated spindle cell sarcoma that exhibited primary insensitivity to standard chemotherapy and a pronounced but non-sustained response to BRAF/MEK inhibitors at recurrence. The case presentation involved a 13-year-old girl that was diagnosed with low-grade spindle cell sarcoma of pelvic localization, BRAF exon 15 double-mutated: c.1799T>A p.V600E and c.1819T>A p.S607T in cis-position. “This is the first report of spindle cell sarcoma BRAF V600E/S607T double-mutated, responding to a combination of B-Raf and MEK inhibitors.” DOI - https://doi.org/10.18632/oncotarget.28606 Correspondence to - Kseniya Sinichenkova - ksinichenkova@gmail.com Video short - https://www.youtube.com/watch?v=QWEAaaixPxE Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28606 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, undifferentiated sarcoma, BRAF V600E mutation, low grade spindle cell sarcoma, abdominal cocoon About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY- August 12, 2024 – A new research perspective was published in Oncotarget's Volume 15 on July 16, 2024, entitled, “Targeting the multifaceted BRAF in cancer: New directions.” In cancer patients, BRAF-targeting precision therapeutics are effective against Class I BRAF alterations (p.V600 hotspot mutations) in tumors such as melanoma, thyroid cancer, and colorectal cancer. However, numerous non-Class I BRAF inhibitors are also in development and have been explored in various cancers. Researchers Eamon Toye, Alexander Chehrazi-Raffle, Justin Hwang, and Emmanuel S. Antonarakis from the Masonic Cancer Center, University of Minnesota-Twin Cities, Department of Medicine, University of Minnesota-Twin Cities, Perelman School of Medicine, University of Pennsylvania, and the City of Hope Comprehensive Cancer Center in Duarte, California, discuss the diverse forms of BRAF alterations found in human cancers and the strategies used to inhibit them in patients with cancers of various origins. As part of their conclusion, the researchers highlighted that Class I BRAF inhibitors represent a landmark achievement in precision oncology, as demonstrated by the recent tissue-agnostic FDA approval of dabrafenib/trametinib for patients with metastatic BRAF p.V600E-mutant solid tumors. Additionally, the accelerated approval of tovorafenib for patients with relapsed/refractory BRAF-altered pediatric low-grade glioma underscores the therapeutic potential of this and other next-generation strategies targeting aberrant MAPK signaling. DOI - https://doi.org/10.18632/oncotarget.28612 Correspondence to - Emmanuel S. Antonarakis - anton401@umn.edu, and Justin Hwang - jhwang@umn.edu Video short - https://www.youtube.com/watch?v=3dRWRvOnssc Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28612 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, BRAF, MAPK, pan-cancer, precision oncology, genomics About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Send us a Text Message.Discover the latest breakthroughs from ASCO 2024 with The Oncology Journal Club team!Professor Chris Jackson, who, despite battling the infamous man flu, brings his A-game to dissect the NADINA study. Learn how neoadjuvant ipilimumab and nivolumab are transforming resectable stage 3 melanoma treatment with a remarkable 26 percentage point gain in 12-month event-free survival. Chris shines a spotlight on the innovative design of this trial and its promising implications for reducing treatment duration and financial strain.But that's just the beginning. Dive into the long-term data from the COMBI-AD study, where we explore the enduring effects of dabrafenib and trametinib on melanoma patients with V600 mutations. We'll unpack the nuances between V600E and V600K mutations and discuss how these findings could shift clinical practice towards more effective strategies. Plus, Dr Kate Clarke talks us through the latest on the A-BRAVE study in triple-negative breast cancer and its quest for improved disease-free survival rates.And of course our Host Professor Craig Underhill unpacks the incredible paradigm-shifting data in  lung cancer that could redefine clinical protocols. He also explores the expanding frontier of telehealth in palliative care and its game-changing potential, especially for remote communities. Covering a whopping 17 abstracts, this second ASCO 2024 Special Episode is packed with critical insights and forward-thinking discussions that no oncology professional should miss. Join us for a thought-provoking and entertaining journey through the latest in cancer research and care.For papers, bios and other links visit the Show Notes on our website.For the latest oncology news visit www.oncologynews.com.au.We invite healthcare professionals to join The Oncology Network for free - you'll also receive our free weekly publication The Oncology Newsletter.The Oncology Podcast - An Australian Oncology Perspective

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In the Research Round Up series, ASCO experts and members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, our guests will discuss new research in head and neck cancer, brain tumors, and health equity that was presented at the 2022 ASCO Annual Meeting, held June 3-7 in Chicago, Illinois. First, Dr. Cristina Rodriguez will discuss 2 studies on new treatment options for locally advanced head and neck cancer. Dr. Rodriguez is a medical oncologist at Seattle Cancer Care Alliance, an Associate Professor in the Division of Medical Oncology at the University of Washington, and an Associate Member for solid tumor clinical research at the Fred Hutchinson Cancer Research Center. She is also the Cancer.Net Associate Editor for Head and Neck Cancers. You can view Dr. Rodriguez's disclosures at Cancer.Net. Dr. Rodriguez: Hello. My name is Christina Rodriguez. I'm a medical oncologist with a clinical and research focus on head and neck cancer. And today I'm going to discuss research on head and neck cancer that was presented at the most recent 2022 ASCO Annual Meeting. I don't have any relationship to disclose that pertains to the research that I will talk about today. I'd like to discuss 2 abstracts that I thought were practice changing or practice affirming that really addresses some of the key questions that patients and doctors like me have about the treatment of patients with head and neck cancer. So, as you know, most patients with head and neck cancer present with typically locally advanced disease, and most head and neck cancer patients are treated with the intent of curing them most of the time with the use of radiation either as the main treatment or after surgery. And many clinical trials have shown that when we add a chemotherapy called cisplatin to radiation, we improve curative outcomes for patients. But the first abstract that I will talk about, abstract 6003, asks the question "What do we do for patients who are not candidates for cisplatin chemotherapy?" And we know that a significant proportion of our patients will have other medical problems that could make it difficult for us to give chemotherapy and often will result in complications or more toxicity or in side effects for patients. This clinical trial was carried out in India, and it compared radiation alone for patients with head and neck cancer versus radiation given with a non-cisplatin chemotherapy called docetaxel. What's unique about this clinical trial is that it's specifically focused on patients who were not candidates for cisplatin chemotherapy, something that really hasn't been done for this population. Interestingly enough, they found that when we give docetaxel with radiation in these patients, we find that they do better, they live longer, and they feel better based on quality-of-life questionnaires. So I will say that this study, abstract 6003, tells us that even in patients who are not candidates for cisplatin to be given with radiation, there is an alternative treatment that we can use, such as docetaxel given with radiation, that might still improve patient's cure rates for their head and neck cancer. The second study that I think was another interesting study was a clinical trial that asked the question, "Can we give cisplatin in an alternative manner for patients who are undergoing definitive radiation treatment as their main treatment for head and neck cancer?" Like I mentioned, the clinical trials that led to the use of chemoradiation as a standard use cisplatin given in larger doses every 3 weeks, but there's been concern about how well that approach is tolerated by patients. So this particular clinical trial compared patients receiving radiation as curative intense therapy for head and neck cancer with either the cisplatin given every  3 weeks or the cisplatin given at a lower dose once a week. It's important to know that this trial was done in India, where the population is pretty different from what we see in the United States. These are mostly patients who have HPV-negative cancers, mostly cancers acquired through exposures like tobacco and alcohol. And what they found was that these 2 groups of patients had very similar outcomes. In other words, there didn't seem to be a reduction in the rates of cure when we give chemotherapy every week versus every 3 weeks. And interestingly enough, it looked like from a toxicity or side effect standpoint, the every week seems to be a little bit better tolerated. Patients who got the treatment every 3 weeks also had less need for hospitalization or IV fluids and less utilization of health care resources. I think this is a very interesting finding because it really provides us with what we call high-level data that the weekly administration can work. I think it's important to recognize that the population that it studied for this particular clinical trial really was more an HPV-negative population. That's important to know because the standards for HPV-positive head and neck cancer are generated from larger trials that use cisplatin every 3 weeks. But we are continuing to study this question, and there's actually a large NRG study, HN009, that is asking that question both for the HPV- positive and HPV- negative population. So we are, I think, making strides in terms of asking the questions that allow our patients not only to receive treatment that is highly efficacious but also that limits side effects and toxicity. I will also mention that these trials were completed during the COVID-19 pandemic, which tells you that the dedication of these researchers to complete something like this in such a challenging time is to be commended. That's all I have to say, and thank you for listening to this brief summary of new research in head and neck cancer from the ASCO 2022 Annual Meeting. ASCO: Thank you, Dr. Rodriguez. Next, Dr. Glenn Lesser will discuss 3 studies that looked at new treatments for different types of brain tumors. Dr. Lesser is the inaugural Louise McMichael Miracle Professor and Associate Chief in the section on Hematology and Oncology in the Department of Internal Medicine at Wake Forest Health. He is also the Cancer.Net Associate Editor for Central Nervous System Tumors. You can view Dr. Lesser's disclosures at Cancer.Net.   Dr. Lesser: Hello. My name is Glenn Lesser, and I'm a professor of medical oncology and the director of medical neuro-oncology at the Wake Forest Baptist Comprehensive Cancer Center in Winston-Salem, North Carolina. I'm also the editor of the brain tumor section for ASCO's Cancer.Net. And today, I would like to briefly discuss several clinically relevant research studies involving patients with brain tumors that were presented at this year's ASCO Scientific Program. Of note, I have no disclosures or relationships relevant to the abstracts I'll be discussing today. The first presentation to talk about is a late-breaking abstract presented by Dr. Eric Bouffet, who described the results of a phase II trial of 2 targeted anticancer agents, dabrafenib and trametinib, in pediatric patients with a kind of brain tumor called a low-grade glioma, which harbored something called a BRAF V600E mutation in their tumor DNA. By way of background, gliomas account for about 45% of all pediatric brain tumors, and the majority of these gliomas are low-grade, which include World Health Organization grade 1 and 2 tumors. Common types of pediatric low-grade gliomas include pilocytic astrocytomas, gangliogliomas, and low-grade gliomas that are not otherwise specified. Now, mutations in the BRAF gene are common in certain kinds of cancers, particularly melanoma, and novel oral targeted therapies have been developed to effectively treat these tumors by targeting this mutant BRAF gene. A particular mutation in this gene called a V600E mutation occurs in about 15% to 20% of pediatric low-grade gliomas. The presence of this mutation is thought to lead to an increased risk of progression to a higher grade or a more malignant glioma in these patients, and these mutations in their tumors also predict a less favorable response to chemotherapy. In adults, recent studies in patients with malignant gliomas, papillary craniopharyngiomas, and melanomas containing V600E mutations have shown excellent results, with 1one of several similar 2-drug combinations that target both the V600E mutation and a second pathway that cells use to escape from this BRAF blockade. Now, early pediatric data suggested that one of these pairs of drugs, the combination of dabrafenib and trametinib, was safe and tolerable and had the ability to effectively treat patients whose tumors had the V600E mutation. So with that as background, this study was started and enrolled patients from 12 months to 18 years of age who had a low-grade glioma that contained a BRAF V600E mutation. And it randomized them to receive either the combination of dabrafenib and trametinib, or an older, standard cytotoxic chemotherapy regimen consisting of carboplatin and vincristine. Importantly, these patients were newly diagnosed, and this was the first systemic treatment they got, following their surgery or biopsy. 110 patients were enrolled, with 73 given the new targeted therapy combination and 37 receiving the standard combination. The most common types of tumors that the patients enrolled on this study had included pilocytic astrocytoma, ganglioglioma, and low-grade glioma. The results of this trial were that the patients who received the newer combination, targeted treatment of dabrafenib and trametinib, did substantially better than those who received standard, older cytotoxic chemotherapy. Their overall response rate - that's defined as a complete or partial disappearance of the tumor on MRI scan - was 47% versus 11% in the control arm. When patients who had stable disease by MRI were included, 86% of those on the new combination versus 46% of those patients treated with the older chemotherapy had the so-called best clinical response. Now, a large number of patients responding to dabrafenib and trametinib, remain on treatment and are receiving these drugs with an ongoing imaging and clinical response at the time of this report. Patients receiving the new combination had a median or average progression-free survival of 20 months versus about 7.4 months with the older, standard chemotherapy. The investigators conducting this study also had patients fill out a variety of questionnaires to assess their quality of life while on treatment. Once again, the patients who received dabrafenib and trametinib, on average, experienced an improved quality of life in contrast to those on standard chemo who, on average, had a worse quality of life. The new treatment was also well-tolerated with fewer serious adverse events or side effects when compared with standard chemotherapy. And these side effects were no different than what has been seen in patients without brain tumors who have been treated with this combination, including fevers, headaches, fatigue, skin changes, and lower blood counts. The authors appropriately suggested that these findings demonstrate the importance of molecular testing of these pediatric low-grade glioma tumors at the time of diagnosis and that this combination of dabrafenib and trametinib is a new potential standard of care in those patients who have the BRAF V600E mutant, low-grade tumors. Of note, liquid formulations of these drugs have been developed for those pediatric patients who are unable to swallow capsules or tablets. The second presentation at ASCO highlighted the continued importance of prospective randomized clinical trials in patients with malignant brain tumors. Dr. Jann Sarkaria from the Mayo Clinic presented the long-awaited results of the Alliance for Clinical Trials in Oncology cooperative group phase II/III study of a PARP inhibitor or placebo added to standard temozolomide and radiation in adult patients with newly- diagnosed glioblastoma, and in addition, glioblastomas that had specific molecular finding called MGMT promoter methylation. This change to the DNA of the tumors prevents the MGMT DNA repair enzyme from being made in the tumors and leads to a better outcome with temozolomide treatment. Some very elegant laboratory science had suggested that adding a type of drug called a PARP inhibitor, which also causes defects in DNA repair, could lead to improved killing of glioblastoma tumor cells. So patients with newly- diagnosed glioblastomas, which had MGMT promoter methylation on genomic analysis, were enrolled on this study between December of 2014 and October of 2018. The study was conducted in 2 phases separated by a pre-planned pause after the first group of patients were enrolled, which was the phase II part of the study. This was done in order to allow a preliminary analysis of the outcomes of the treatment arms to make sure that there was a signal of activity that justified moving on to test this treatment in a larger number of patients, the so-called phase III part of the trial. This trial design hopes to minimize the number of patients treated with an inactive drug and save years of drug development time by avoiding large trials that go on for a long time with what turns out to be ineffective drugs. For this trial, 447 patients were eventually treated on this trial. Despite the convincing laboratory evidence and early, promising clinical results that led to the trial moving to the second or phase III portion, the final results showed no statistically significant difference in progression-free or overall survival between the 2 arms, that is, those treated with a PARP inhibitor, and those treated with placebo. I personally was very excited about this study and had hoped that the long wait to hear the results indicated that something good was happening. In addition, several of my patients who were treated on the study did exceedingly well, so I, incorrectly, it turns out, expected positive results from the trial. These negative results are a stark reminder of why we spend lots of time and money and energy performing well-designed clinical trials to determine appropriate treatment strategies for our patients, rather than relying on expert opinion or 1 institution's published experience. This approach turns out to be the best way to fairly test treatment strategies and establish new therapeutic approaches which are truly effective. A final, interesting abstract that was presented at a poster discussion session at ASCO was from the group with the University of Pennsylvania in Philadelphia, and it dealt with the risk of bleeding in patients with brain tumors who had blood clots and were then treated with a newer class of blood thinners or anticoagulants called direct oral anticoagulants, or DOACs for short. It's been known for over 100 years that a variety of types of cancer cause patients to be hypercoagulable, that is, to be predisposed to developing blood clots throughout the venous system. Patients with malignant brain tumors have the highest incidence of all tumors of developing blood clots, which typically occur in the legs, called deep venous thrombosis or DVTs, or in the lungs, called pulmonary emboli or PEs. These clots can lead to a variety of severe and debilitating symptoms, including leg pain, swelling, shortness of breath, heart strain, and even death. For the past 2 to 3 decades, affected patients have typically been treated with a class of medications called low-molecular-weight heparins, which need to be injected under the skin once or twice daily. Over the past decade, a new class of oral anticoagulants called DOACs have generally replaced low-molecular-weight heparins as the primary method of treatment for patients with and without cancer who develop venous blood clots because of their safety, ease of administration, and a lack of requirement for regular blood tests or monitoring. However, little, if any, data has been available to determine the safety of these agents in patients with brain tumors and blood clots, a situation where bleeding into the brain or the brain tumor as a side effect of the anticoagulant could be catastrophic. In fact, this potential risk led to the exclusion of patients with brain tumors from several of the large trials which established the safety of the DOACs. Despite the absence of evidence, the DOACs are now pretty broadly used in brain tumor patients for the reasons described above. So this abstract described a cohort of patients with glioblastoma who developed venous blood clots between 2014 and 2021 while under treatment at Penn. The authors reviewed the medical record to determine the relative efficacy or effectiveness and the toxicity or side effects experienced by patients treated with the low-molecular-weight heparins and with the DOACs, including the rates of bleeding into the brain or the brain tumor. 121 patients were identified who fit these criteria, and the cumulative incidence of clinically significant intracranial hemorrhage, that is, bleeding into the brain or the brain tumor, by 30 days after starting the drugs, was minimal and similar in the 2 groups. When measured at 6 months, 24% of the patients in the low-molecular-weight heparin group had developed intracranial bleeding, and 4 of those patients had died from this bleeding, while none of the 32 patients in the DOAC group experienced this complication. Thus, these investigators felt that their data suggested that there was a lower incidence of clinically important intracranial hemorrhage or bleeding in patients with glioblastoma and venous blood clots who were treated with DOACs as compared to low-molecular-weight heparin. They went on to suggest that the use of DOACs was a safe alternative in patients with glioblastoma. Now clearly, either a prospective trial, a larger trial, or additional retrospective evaluations with a larger number of patients are needed to prove the safety of this approach. But this data is pretty comforting, as the use of these agents is now widespread in patients with high-grade gliomas. The ease of administration of a pill once or twice a day, as compared with potentially lifelong injections once or twice a day, is a major quality of life advantage for our patients. Thank you for listening to this brief summary of new research in neuro-oncology from the 2022 ASCO Annual Meeting. ASCO: Thank you, Dr. Lesser. Finally, Dr. Manali Patel discusses new research focused on reducing disparities in cancer care. Dr. Patel is a medical oncologist and Assistant Professor of Medicine at Stanford University. She is also the Cancer.Net Associate Editor for Health Equity. You can view Dr. Patel's disclosures at Cancer.Net. Dr. Patel: Today I have the privilege of discussing several really exciting research abstracts that were presented at the 2022 ASCO Annual Meeting. My name is Manali Patel. I'm a thoracic oncologist, meaning I take care of patients and try to provide good care delivery for patients with lung cancer. And I also am a researcher focused on health equity. I have no relevant disclosures for any of the studies that I will be presenting today with the exception of one that I was leading. And there were several wonderful abstracts that were presented on describing disparities and the ongoing state of disparities continuing within cancer care delivery. What I was particularly struck by were many of the abstracts that I'm presenting this morning and this podcast that really focus on what we can do as a nation and what we can do individually in our clinics to try to move towards action to overcoming these inequities. The first abstract I want to present was looking at how the Affordable Care Act and changes in the Affordable Care Act led to differences in mortality or deaths by race and ethnicity following the enactment in California. And this particular study looked at greater than 150,000 people who were diagnosed with breast cancer, colorectal cancer, and cervical cancer. And they evaluated death rates from these cancers both before and after the implementation of the Affordable Care Act. And what they found was that the cancer death rates for everyone was much lower after the Affordable Care Act was passed, but specifically for individuals who had self-identified as Hispanic ethnicity, who also identified as Black and who identified as White. And so what this abstract showed me was that at a larger level and a macro level, our policies that are enforced at the national level really do play a role in terms of how we can overcome disparities in cancer. Our group, as I mentioned before, has worked on really trying to integrate community health workers into care. So this abstract paired with local union organizations in Chicago and in Atlantic City to try to help individuals who self-identified as having been from families that were from low-income households and racial and ethnic minorities to communicate their goals and their preferences for care and to also better their relationships with their clinicians as well as to describe their symptoms. And what we found in this randomized trial was that for individuals who received this community health advocate who helped them to better engage with their clinician and who also helped them to describe the symptoms that they were experiencing as well as receive community resources such as food boxes if they were food insecure or be connected to household agencies if they were having difficulties with housing, we found a significant improvement in quality of life, but we also found reductions in the use of the hospital unnecessarily. We also found that this translated into reductions in total cost of care, thereby reducing the amount of out-of-pocket costs these individuals were spending on their cancer care. One of the other abstracts that I thought really was reflective of the many different ways that we can move towards action was an abstract which looked at during the pandemic, trying to reduce the number of times people need to come in for mammograms, their biopsies, and then any further testing that they needed after their biopsy. And this particular study evaluated what was called a same-day biopsy service, which layered on a same-day mammogram reading program. So at this particular institution, they had already implemented when you came in to get your mammogram as a woman or a man, you would have a read on the same day. So you did not have to wait to find out what your results were. And what they did further to push better care was that they layered on on that same day you could get your biopsy. So almost a one-stop shop. And what they found was that for everyone, regardless of race and ethnicity, the time to biopsies decreased by almost half. And the median days, for example, from an abnormal mammogram to obtaining a biopsy, meaning a sample of that tissue, that it decreased from 10 days median to 5 days. And particular patient populations did much better. And so they were able to show that when you do interventions that move the care to provide better care for everyone, everyone benefits, but particularly our patient populations who identify as racial and ethnic minorities who were more likely to experience delays in care, they also received some benefit from this intervention. The last study I want to highlight is work which looked at how to improve specialized services for people who would otherwise not receive those. And this particular study looked at stem cell transplantation for people with blood cancers. And what they found was that these services are often only offered in very tertiary centers, so places that may not be as accessible, large institutions that a lot of people may not have access to receiving care. So what they did was they partnered with this large academic institution so that they could build a pathway for individuals who would otherwise not get stem cell transplantation so that they could have access to those services. And it was really a multipronged approach where they not only educated the clinicians in the community practice about the effort, but they also educated the institution-level clinicians about the effort. They also provided shared medical records, which oftentimes in practice, we don't share our medical records with other clinics. And what they were able to do was to convince these clinics and the institution, let's share the medical records so that then you can have access to seeing what's happening for patients that are diagnosed in the community. And then that way we can both document, we can both have access in the community as well as in the institution where they're receiving the specialized service so that there's better communication. They also provided a navigator for each patient that would help each patient to identify any sort of barriers that they may experience to receiving stem cell transplantation. And then they offered telemedicine, which allowed for individuals to receive specialized services in the comforts of their own home without having to travel after the stem cell transplantation had occurred. And what they found was that usually in the institution, most individuals were more affluent. So they had higher levels of socioeconomic status. But after the intervention, individuals that were referred from this community clinic made it such that the affluence really decreased so that it was showing that people who wouldn't otherwise have access, who had identified as having low income, were now able to receive those services and had been receiving transplantation. I think that these studies really do move us towards a new paradigm of taking action on the many disparities that we know continue to happen. I really appreciate you all for listening to this brief summary of the new research on health equity from the 2022 ASCO Annual Meeting, and I hope to see you next year. ASCO: Thank you, Dr. Patel. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Host: Scott Kopetz, MD, PhD Guest: Rona Yaeger, MD Advances in the diagnosis and treatment of mCRC enable personalized care based on the molecular profile of the tumor to achieve improved outcomes. About 5% to 15% of mCRC patients have a mutation in the proto-oncogene BRAF. BRAF is part of an essential cell signaling pathway, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). The BRAF V600E mutation induces constitutive activation of BRAF, leading to increased cell growth and proliferation downstream. Patients with the V600E mutation have a 2-fold increased risk for mortality compared to patients with wild-type BRAF, suggesting this gene mutation may act not only as a prognostic biomarker but also as a predictive biomarker. Understanding the current research regarding the consequences of the V600E mutation and testing for it can help guide treatment decision-making in patients with BRAF V600E–mutated mCRC. This web-based, on-demand activity will feature an expert panel discussion on the latest trends and emerging research in the treatment of BRAF-mutated mCRC. Expert faculty will review and provide their interprofessional perspectives on testing patients for BRAF mutations, recent and emerging data for combination therapies, appropriate treatment selection, and side effect management.

CME credits: 1.00 Valid until: 02-11-2022 Claim your CME credit at https://reachmd.com/programs/cme/evolving-management-strategies-braf-mutant-metastatic-colorectal-cancer/13015/ Advances in the diagnosis and treatment of mCRC enable personalized care based on the molecular profile of the tumor to achieve improved outcomes. About 5% to 15% of mCRC patients have a mutation in the proto-oncogene BRAF. BRAF is part of an essential cell signaling pathway, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). The BRAF V600E mutation induces constitutive activation of BRAF, leading to increased cell growth and proliferation downstream. Patients with the V600E mutation have a 2-fold increased risk for mortality compared to patients with wild-type BRAF, suggesting this gene mutation may act not only as a prognostic biomarker but also as a predictive biomarker. Understanding the current research regarding the consequences of the V600E mutation and testing for it can help guide treatment decision-making in patients with BRAF V600E–mutated mCRC. This web-based, on-demand activity will feature an expert panel discussion on the latest trends and emerging research in the treatment of BRAF-mutated mCRC. Expert faculty will review and provide their interprofessional perspectives on testing patients for BRAF mutations, recent and emerging data for combination therapies, appropriate treatment selection, and side effect management.

CME credits: 1.00 Valid until: 02-11-2022 Claim your CME credit at https://reachmd.com/programs/cme/evolving-management-strategies-braf-mutant-metastatic-colorectal-cancer/13015/ Advances in the diagnosis and treatment of mCRC enable personalized care based on the molecular profile of the tumor to achieve improved outcomes. About 5% to 15% of mCRC patients have a mutation in the proto-oncogene BRAF. BRAF is part of an essential cell signaling pathway, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). The BRAF V600E mutation induces constitutive activation of BRAF, leading to increased cell growth and proliferation downstream. Patients with the V600E mutation have a 2-fold increased risk for mortality compared to patients with wild-type BRAF, suggesting this gene mutation may act not only as a prognostic biomarker but also as a predictive biomarker. Understanding the current research regarding the consequences of the V600E mutation and testing for it can help guide treatment decision-making in patients with BRAF V600E–mutated mCRC. This web-based, on-demand activity will feature an expert panel discussion on the latest trends and emerging research in the treatment of BRAF-mutated mCRC. Expert faculty will review and provide their interprofessional perspectives on testing patients for BRAF mutations, recent and emerging data for combination therapies, appropriate treatment selection, and side effect management.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.19.211177v1?rss=1 Authors: Nguyen, D., Lin, L. Y., Zhou, J., Kibby, E., Sia, T., Tillis, T., Vapuryan, N., Xu, M.-R., Potluri, R., Shin, Y., Erler, E., Bronkema, N., Boehmler, D., Chung, C., Burkhard, C., Grasso, M., Acevedo, L. A., Marmorstein, R., Fera, D. Abstract: In the MAPK pathway, an oncogenic V600E mutation in B-Raf kinase causes the enzyme to be constitutively active, leading to aberrantly high phosphorylation levels of its downstream effectors, MEK and ERK kinases. The V600E mutation in B-Raf accounts for more than half of all melanomas and ~3% of all cancers and many drugs target the ATP-binding site of the enzyme for its inhibition. Since B-Raf can develop resistance against these drugs and such drugs can induce paradoxical activation, drugs that target allosteric sites are needed. To identify other potential drug targets, we generated and kinetically characterized an active form of B-RafV600E expressed using a bacterial expression system. In doing so, we identified an alpha helix on B-Raf, found at the B-Raf-MEK interface, that is critical for their interaction and the oncogenic activity of B-RafV600E. We performed binding experiments between B-Raf mutants and MEK using pull downs and biolayer interferometry, and assessed phosphorylation levels of MEK as well as its downstream target ERK to show that mutating certain residues on this alpha helix is detrimental to binding and downstream activity. Our results suggest that this B-Raf alpha helix binding site on MEK could be a site to target for drug development to treat B-RafV600E-induced melanomas. Copy rights belong to original authors. Visit the link for more info

Visiting Professors: Lung Cancer Edition — Part 1: Our discussion with Drs Levy and Lobins highlights the following topics as well as cases from Dr Lobins’s practice: Case: A man in his early 60s, a current smoker, with metastatic lung adenocarcinoma and a PD-L1 tumor proportion score (TPS) of 80% experiences a dramatic response to first-line pembrolizumab but a recurrence of small lymphocytic lymphoma (SLL) during therapy (00:00) Activity and tolerability of immune checkpoint inhibitors alone or with chemotherapy as first-line therapy in patients with metastatic non-small cell lung cancer (NSCLC) (02:30) Duration of therapy with immune checkpoint inhibitors (05:28) Perspectives on the effects of recent advances in the management of lung cancer on the practice of oncology (09:16) Potential correlation between recurrence of chronic lymphocytic leukemia or SLL and treatment with anti-PD-1/PD-L1 antibodies (11:02) Case: A woman in her late 50s with a history of autoimmune uveitis is diagnosed with NSCLC and multiple metastases in the brain (13:46) Side effects associated with whole-brain radiation therapy (14:55) Use of immune checkpoint inhibitors for patients with preexisting autoimmune disorders (17:45) Therapeutic options for patients with metastatic NSCLC in the second-line setting (22:05) Results of the Phase III REVEL trial investigating ramucirumab with docetaxel as second-line therapy for patients with metastatic NSCLC (24:16) Activity of ramucirumab in patients with squamous cell NSCLC and those with prior exposure to bevacizumab (25:45) Side effects and tolerability of ramucirumab and bevacizumab (26:46) Case: A man in his early 50s, a current smoker, with metastatic lung adenocarcinoma and a BRAF non-V600E tumor mutation receives first-line carboplatin/pemetrexed/pembrolizumab (29:19) Hemoptysis as a presenting symptom of lung cancer (30:28) Clinical care of patients with metastatic NSCLC and no identified targetable tumor mutations (32:58) Novel agents and approaches under investigation for lung cancer (36:11) Mechanisms of resistance to immunotherapy (39:15) Monitoring for immune-related adverse events in patients receiving immune checkpoint inhibitors (41:31) Case: A woman in her mid-50s with large cell neuroendocrine carcinoma of the lung and a solitary metastasis in the brain (43:20) Perspective on the management of oligometastatic disease (45:55) Therapeutic options for patients with metastatic large cell neuroendocrine carcinoma of the lung (48:10) Management of metastatic small cell lung cancer in the second-line setting (51:07) Case: A man in his early 80s with severe pulmonary fibrosis is diagnosed with metastatic NSCLC (54:40) Challenges in the management of pulmonary fibrosis in elderly patients with lung cancer (58:22) Biologic rationale for and emerging data with immune checkpoint inhibitors in combination with anti-angiogenic agents (1:01:13) Benefits and challenges of integrating early palliative care into the management of metastatic lung cancer (1:03:55) Case: A man in his late 60s with metastatic NSCLC with KRAS and p53 tumor mutations experiences disease progression on multiple lines of therapy (1:06:27) Therapeutic approach for patients with metastatic NSCLC in the late-line setting (1:08:26) Case: A woman in her early 20s initially diagnosed with unresectable Stage III NSCLC with mutations in ROS1 and p53 develops metastatic disease (1:13:22) Activity and tolerability of crizotinib and lorlatinib in patients with metastatic NSCLC and ROS1 tumor mutations (1:15:37) Sequencing therapies for patients with metastatic NSCLC and ROS1 tumor mutations (1:18:23) CME information and select publications  

 Key Takeaways from the 2019 Gastrointestinal Cancers Symposium with Dr. Stephen Leong   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Welcome to the ASCO Daily News podcast. I'm Lauren Davis, and joining me today is Dr. Stephen Long, associate editor of ASCO Daily News. Dr. Long is associate professor in the division of medical oncology and is a translational researcher in the GI and developmental therapeutics programs at the University of Colorado Cancer Center. Dr. Long, welcome to the podcast. Thanks for having me. It's a pleasure to be here. Dr. Long, you've just returned from the Gastrointestinal Cancers Symposium. How was this year's event compared with previous years? First of all, I love you GI ASCO. I always find it informative. And I love the format of the talks and presentation. This year there was no significant practice changing presentations like in years past. However, there were still some excellent presentations and talks. And what were some of the presentations that stood out to you? There were some reports of a couple of clinical trials that sort of intrigued me. One was KEYNOTE-181. This was a phase III study comparing pembrolizumab monotherapy versus standard chemotherapy in patients with local events and metastatic esophageal cancer in the second line setting. They reported a significant improvement in overall survival in patients with PD-L1 combined positive score of greater than 10. And these patients received 9.3 months overall survival compared to 6.7 months for those who received [INAUDIBLE] choice of chemotherapy, which then consists of paclitaxel, docetaxel, or irinotecan. In addition, pembrolizumab was better tolerated and had a better safety profile. What made it really intriguing was of the total 628 patients that were enrolled in the trial, 64% of them had squamous cell carcinoma of the esophagus, which is unusual, especially in a phase II setting. And even though the study had a statistic overall survival benefit, in the squamous cell carcinoma cohort, there was a non-statistical trend in overall survival of 8.2 months versus 7.1 respectively. Pembrolizumab did boost the objective response rate compared with chemotherapy in the PD-L1 CPS greater than 10 and a response rate of 21.5% versus 6.1%. And then squamous cell carcinoma, it was 16.7% versus 7.4%. That leads to a whole bunch of questions. One, should we improve our PD-L1 scoring by including a CPX score greater than 10 and making our predictions based off that? In addition, should pembrolizumab expand its indications to include squamous cell carcinoma, since presently in the United States, pembrolizumab is only approved for adenocarcinoma. Also, there were the reports of the phase II ROAR study, which was looking at biliary tract cancers with BRAF V600E activating mutations. And these patients received a combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. There were 33 patients. And they had an objective response rate of 42%. All of them with partial responses. And 7 of the 14 patients with responses had the responses lasting more than six months. And adding those with stable disease, they had reported a disease control rate of 88%. They looked at survival data. And the median progression free survival in this cohort was 9.2 months with an overall survival of 11.7 months. And to put this into context, usually second line biliary tract cancers we rarely ever see survival being more than five months. And these PFS and overall survival is very comparable to the first line setting for gemcitabine cisplatin, where the original study showed a PFS of eight months and overall survival of 11.7 months. So this potentially could be another treatment option for people with V600E biliary tract cancers. And then there were the preliminary results of a single phase II study at Memorial Sloan Kettering, which was evaluating pembrolizumab in conjunction with trastuzumab HER2 antibody with CAPOX and those with HER2 positive metastatic esophageal gastric adenocarcinoma. They had 32 patients with the overall response rate of 87%. They reported three CRs and 25 partial responses. And then when you factor in the stable disease, they had 100% disease control rate. And all the patients had some degree of tumor regression. The PFS were 11.4 months with an overall survival having not been met after six months. This is extremely exciting, and this has already led to the development of a global phase III study, which will be known as KEYNOTE-811. That's great. That sounds very promising. Were there any research presentations that you were interested in? Oh, yeah. There was a lot of great preclinical work. One of the most intriguing was in pancreatic cancer, where the Canadians did a study known as COMPASS, where they took advanced pancreatic ductal adenocarcinoma, and these patients underwent whole genome sequencing, as well as RNA sequencing of their tumors, prior to the initiation of first line chemotherapy with either modified FOLFIRINOX or gemcitabine and abraxane. Treatment outcomes were then compared to their molecular characteristics. The data suggests that chemotherapy differs depending on the transcription features of the tumor. So for example, the best survival data came out of those patients with the classical ductal adenocarcinoma subtype that were treated with FOLFIRINOX. And they had a median survival of 7.17 months. And when they were compared to the basal-like subtypes and were treated with FOLFIRINOX, they had a median progression free survival of 2.5 months. Now, patients with the basal-like subtype actually had a better response to gemcitabine and abraxane, which had a PFS of 5.65 months compared to the classical subtype, where they had median progression free survival of 4.93 months. So in summary, those with the basal-like subtype actually had a resistance for FOLFIRINOX. In addition, the researchers also mentioned that GATA6 RNA expression significantly correlates to the PDAC classic and basal-like molecular subtype. So it could actually be used as a marker in determining subtypes. And all this put together means that we could potentially identify patients who have a better chance of responding to FOLFIRINOX versus gem abraxane in the first line setting in pancreatic cancer. And obviously there needs to be more work to validate this, but this actually is quite intriguing. Also, there was data from the amino scoring testing, which was looking at its test in high risk stage 2 colorectal cancer patients. And for those who are not familiar, patients with stage colon cancer have a poor prognostic if they had a T4 disease, had fewer than 12 lymph nodes removed, had a point differentiation subtype, and also had evidence of vascular emboli, lymphovascular invasion, perineural invasion, or actually had a presentation of bowel obstruction or bowel perforation. And these patients are often offered adjuvant chemotherapy following curative resection due to their high risk of recurrence. The amino score test measures the density of CT3 positive T cells, as well as cytotoxic CDH cells within and surrounding the tumor to gauge the strength of the host immune response at a tumor site. So therefore a high amino score indicates a high anti-tumor immunity, which correlates with a low risk for disease recurrence. And these investigators looked at 1,130 patients with stage two colon cancers. And their conclusion for time to recurrence was those with high risk disease with high amino scoring compared to those with low risk disease had a very similar five-year survival of 87.4% versus 89.1% respectively. In contrast, if you have a high risk disease and a low amino scoring, your five-year time to recurrence was only 72.2% in the absence of adjuvant therapy. So this could potentially be used as a prognostic tool for those who are high risk stage two in the future. What about education sessions? Were there any that caught your attention? So my favorite was the neuroendocrine session. Neuroendocrine, as most people know, is a pretty rare disease population. However, there has been significant advances in the past few years with new drugs, new understanding of the biology, new diagnostic procedures, as well as testing. And it was a great panel of leading experts to help us navigate the new landscape of neuroendocrine and understanding how we should be approaching this. So that was my favorite session. Were there any other takeaways that were important during the symposium? There were a few other presentations I thought that were quite interesting. The Japanese presented their Prep-02 or JSAP-05 trial. And this was the first study to ever demonstrate the efficacy of neoadjuvant therapy in resectable pancreatic cancer. And their neoadjuvant chemotherapy regimen was a combination of gemcitabine with an oral drug S1. And they showed that it met its primary endpoint of overall survival of 36.72 months in those patients who received neoadjuvant therapy versus 26.65 months in those who went from upfront surgery. And for the Japanese, which tend to do upfront surgery followed by adjuvant chemotherapy in the past, I think this may be a shift in their paradigm, where this could be the new standard in Japan of using neoadjuvant therapy prior to surgery. Also, there was the oral drug trifluridine and tipiracil, which was studied in a phase III metastatic gastric and GE junction adenocarcinoma for those who have received two previous line of therapies. And they were randomized to the drug versus placebo. And it demonstrated a 2.1 survival benefit over placebo. And their main concern was a lot of these patients end up getting gastrectomies. But being an oral drug, could that affect its efficacy? And it seems like this benefit was also seen in those who had a gastrectomy versus those who didn't as well. So this potentially could be another option for those in the third line setting for gastric cancer. However, the big debate is even though it met its overall survival, is 2.1 months clinically significant? And I guess we'll have to have more data regarding safety and tolerability before we can make that decision. There is also the French GRECCAR-6 trial, which was evaluating the optimal time to surgery following chemoradiation for rectal cancer, where patients who underwent neoadjuvant chemoradiation were randomized to waiting 7 or 11 weeks prior to a mesoresection of the rectal cancer. They demonstrated that they had very similar path CR rates between the two. But more interesting, they found that if you had a good disease response to chemoradiation, there was no difference in disease free survival if you waited 7 weeks versus 11 weeks prior to surgery. However, if you were a bad disease responder, you had a poorer disease free survival if you waited more than seven weeks. However, this was not statistically significant. And then the authors concluded that we shouldn't be waiting more than seven weeks prior to surgery following neoadjuvant chemoradiation for rectal surgery. Thank you so much. Again, today my guest has been Dr. Stephen Long. Thank you for being on our podcast today. And to our listeners, thank you for tuning into the ASCO Daily News podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple podcast.  

Background: Colorectal cancers carrying the B-Raf V600E-mutation are associated with a poor prognosis. The purpose of this study was to identify B-Raf(V600E)-mediated traits of cancer cells in a genetic in vitro model and to assess the selective sensitization of B-Raf(V600E)-mutant cancer cells towards therapeutic agents. Methods: Somatic cell gene targeting was used to generate subclones of the colorectal cancer cell line RKO containing either wild-type or V600E-mutant B-Raf kinase. Cell-biologic analyses were performed in order to link cancer cell traits to the BRAF-mutant genotype. Subsequently, the corresponding tumor cell clones were characterized pharmacogenetically to identify therapeutic agents exhibiting selective sensitivity in B-Raf(V600E)-mutant cells. Results: Genetic targeting of mutant BRAF resulted in restoration of sensitivity to serum starvation-induced apoptosis and efficiently inhibited cell proliferation in the absence of growth factors. Among tested agents, the B-Raf inhibitor dabrafenib was found to induce a strong V600E-dependent shift in cell viability. In contrast, no differential sensitizing effect was observed for conventional chemotherapeutic agents (mitomycin C, oxaliplatin, paclitaxel, etoposide, 5-fluorouracil), nor for the targeted agents cetuximab, sorafenib, vemurafenib, RAF265, or for inhibition of PI3 kinase. Treatment with dabrafenib efficiently inhibited phosphorylation of the B-Raf downstream targets Mek 1/2 and Erk 1/2. Conclusion: Mutant BRAF alleles mediate self-sufficiency of growth signals and serum starvation-induced resistance to apoptosis. Targeting of the BRAF mutation leads to a loss of these hallmarks of cancer. Dabrafenib selectively inhibits cell viability in B-Raf(V600E) mutant cancer cells.

Drs. Nate Pennell, Mary Pinder, and Jack West discuss an encouraging study of dabrafenib, a BRAF inhibitor, for the limited number of NSCLC patients with a BRAF V600E mutation.

Drs. Nate Pennell, Mary Pinder, and Jack West discuss an encouraging study of dabrafenib, a BRAF inhibitor, for the limited number of NSCLC patients with a BRAF V600E mutation.

Drs. Nate Pennell, Mary Pinder, and Jack West discuss an encouraging study of dabrafenib, a BRAF inhibitor, for the limited number of NSCLC patients with a BRAF V600E mutation.

Für ein genetisches Modell B-Raf(V600E)-mutierter Darmkrebszellen und korrespondierender Wildtyp-Zellen wurde erstmalig in Deutschland das Somatic Cell Gene Targeting eingesetzt. Dabei konnte demonstriert werden, dass RKO eine Oncogene Addiction bezüglich der BRAF-Mutation aufweist. Als weitere B-Raf(V600E)-abhängige Effekte wurden die Selbstversorgung mit Wachstumssignalen (Self-Sufficiency of Growth Signals) und die Resistenz gegen Apoptose in dem Modell festgestellt. Darüber hinaus war die proliferative Kontaktinhibition in V600E-mutierten Klonen durch eine verstärkte Akt-Phosphorylierung aufgehoben und wurde nach Knockout der mutierten Allele im Wildtyp-Zellklon RBW-1 wieder hergestellt. Somit konnten vier zentrale Merkmale der Onkogenität dem mutierten B-Raf(V600E) zugeordnet werden. Andere onkogene Mechanismen waren dagegen vermutlich aufgrund einer Mutation der PI3-Kinase auch in BRAF-Wildtyp-Zellen noch intakt. So waren das Wachstum unter guten Kulturbedingungen und eine verstärkte Expression des EGF-Rezeptors unter Mangelbedingungen nicht vom BRAF-Mutationsstatus abhängig. Außerdem behielten Wildtyp-Zellen ihre Immortalisierung bei und zeigten weiterhin kein relevantes Auftreten von Seneszenz. Es wurden neue Spleißvarianten des BRAF-Gens gefunden und basal charakterisiert. Die alternativen Transkripte zeigten keine Kinase-Aktivität und waren in einem Ausmaß nachweisbar, das eine physiologische Bedeutung vermuten lässt. Hinsichtlich der Herkunft-Allele alternativer Isoformen und den Ursachen für das Auftreten alternativen Spleißens wurden neue Erkenntnisse gewonnen, die zudem die Interpretation publizierter Daten erleichtern. Es wurde gezeigt, dass die durch E-Cadherin vermittelten Zellkontakte essentiell für die epitheliale Komponente der intestinalen Barriere sind. Darüber hinaus wurde der Einfluss von E-Cadherin auf die Ausreifung sekretierender Zellen im Darm ermittelt und damit ein weiterer entscheidender Mechanismus der Abwehr bakterieller Invasionen aufgeklärt.