Translational Research In Oncology

Scientists' debut 'reverse metabolomics,' a groundbreaking approach to advancing microbiome research. They use the technique to discover hundreds of new human molecules, and a new biomarker and therapeutic target for inflammatory bowel disease. UC San Diego scientists' debut "reverse metabolomics," a groundbreaking approach to advancing microbiome research. They use the technique to discover hundreds of new human molecules, and a new biomarker and therapeutic target for inflammatory bowel disease. In recent years, microbiome research has started to shift its focus from the microbes themselves to the molecules they produce. After all, it's these molecules that directly interact with human cells to influence a person's health. But trying to identify which molecules are being made by a person's microbiome is quite challenging. A typical metabolomics study can only characterize about 10% of the molecular data from a human microbiome sample. In a new study published on December 5, 2023 in Nature, microbiome experts at University of California San Diego debut a new approach they call "reverse metabolomics." The technique combines organic synthesis, data science and mass spectrometry to better understand what molecules are being secreted by the microbiome and how they affect human health. In their first application of reverse metabolomics, the scientists found hundreds of molecules that had never been observed in the human body before. Using this novel data, they were able to identify a new metabolomic signature for inflammatory bowel disease (IBD). The authors say these molecules could someday serve as a biomarker for diagnosing IBD, or as a potential therapeutic target to help treat the disease. "We know the microbiome is important, but we don't know what kinds of molecules the microbes produce or how influential they are in the human body," said senior author Pieter C. Dorrestein, PhD, professor at Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego. "Reverse metabolomics helps us evaluate whether specific molecules can be found in the samples, predict which microbes are producing them, and relate these metabolomic signatures to health and disease." In a typical metabolomics study, researchers will use a tool called mass spectrometry to look for different molecules in a sample. In this technique, each molecule has its own "barcode" that it can be identified by. Still, scientists need to know what these barcodes represent to describe the contents of a sample, which remains challenge. In the new study, researchers in the Dorrestein Lab took a backward approach. First author Emily C. Gentry, PhD, now an assistant professor at Virginia Tech, used organic synthesis to first produce thousands of different synthetic molecules from four classes of interest, and then defined each of their barcodes. The researchers then utilized publicly available metabolomics data including the ones previously collected through the Crohn's & Colitis Foundation and searched for the new barcodes in that data. The findings revealed 145 of the synthesized bile acids were present in biological samples from public data, 139 of which had never been described before. "If you read a biology textbook, none of these molecules will be in it," said Dorrestein. "Not only are they new to our understanding of human physiology, they're entirely new to science, which is pretty amazing." Gentry and colleagues then compared the metabolomic signatures of samples from different patient populations and found a strong association between a synthesized class of microbial molecules -- bile amidates -- and IBD. This association was then validated across multiple cohorts, supporting the idea that these molecules are likely involved in the pathology of IBD. Looking closer, the scientists noticed that certain bile amidates were elevated in patients with Crohn's disease specifically when they had active symptoms, but this was not the case for patients with ulcerative colitis. Patterns like these could one day be used to help differentiate and diagnose specific types of IBD. The researchers then began to explore how these molecules might be influencing gut health. Additional experiments showed that several bile amidate compounds may promote gut inflammation by dysregulating T cell function. For example, one microbial compound produced a six-fold increase of a key cytokine known to be involved in the pathogenesis of Crohn's disease. "We're using organic synthesis and data science to better understand how our bodies work on a molecular level," said Gentry. "We're also one of the first studies to discover new human molecules using publicly available metabolomics data. As more metabolomics data becomes publicly available, reverse metabolomics will become even more informative." The authors say the molecules they've described could one day inspire new therapeutics for treating IBD. For example, patients might be treated with pills containing live microbes that secrete specific molecules, or drugs that inhibit the enzymes these disease-associated molecules interact with. "This is a remarkable achievement derived from our precision nutrition initiative, in which Dr. Dorrestein previously demonstrated that reverse metabolomics could identify food metabolites associated with disease severity in patients with IBD," said Andrés Hurtado-Lorenzo, PhD, senior vice president of Translational Research & IBD Ventures at the Crohn's & Colitis Foundation. "Now, this groundbreaking work has further progressed to discovering new metabolites that hold potential for both diagnostic and therapeutic applications in IBD." Co-authors of the study include: Morgan Panitchpakdi, Pedro Belda-Ferre, Marvic Carrillo Terrazas, Hsueh-han Lu, Simone Zuffa, Julian Avila-Pacheco, Damian R. Plichta, Allegra T. Aron, Mingxun Wang, Alan K. Jarmusch, Mashette Syrkin-Nikolau, Brigid Boland, Amy Hemperly, Niels Vande Casteele, Hiutung Chu, Rob Knight and Dionicio Siegel at UC San Diego; Stephanie L. Collins, Fuhua Hao and Andrew D. Patterson at The Pennsylvania State University; Allison K. Stewart and Erin S. Baker at North Carolina State University; Tingting Yan and Frank J. Gonzalez at National Institutes of Health; Hera Vlamakis, Clary B. Clish and Ramnik J. Xavier at Broad Institute of MIT and Harvard; and Ashwin N. Ananthakrishnan at Massachusetts General Hospital. The study was funded, in part, by the National Institutes of Health (grants R01GM107550, R01AI67860, U01 DK119702, R00DK110534, P30ES025128, P42ES027704, P42 ES031009, T32DK007202 and ES103363-01), the Collaborative Microbial Metabolite Center (grant R01DK13611701), the Crohn's & Colitis Foundation (grant 675191), the Center for Computational Mass Spectrometry (grant P41GM103484), a cooperative agreement with the United States Environmental Protection Agency (STAR RD84003201), the Pennsylvania Department of Health, the Tombros Foundation, the National Academies of Sciences, the Gordon and Betty Moore Foundation and the Howard Hughes Medical Institute Graduate Fellowships.

Funding was provided on the basis of strong interim data successfully supporting the company’s innovative approach targeting the TREM-1 pathway to treat chronic inflammatory conditions. PARIS--(BUSINESS WIRE)-- Inotrem, an advanced clinical stage biotech company specialized in immunotherapies for acute and chronic inflammatory syndromes, announced today it received the second milestone-based funding from the American Crohn’s & Colitis Foundation’s IBD Ventures program. After initial support in December 2022, continuation of funding follows a thorough review of Inotrem’s interim data, successfully supporting the proof of concept of the company’s antibody program (INO-02). This program targets the TREM-1 pathway for Inflammatory Bowel Disease (IBD) and develops a biomarker-based personalized approach to identify the patients most likely to benefit from the treatment. The Crohn’s & Colitis Foundation, the leading nonprofit organization with the mission of curing Crohn’s disease and ulcerative colitis, decided to continue funding based on Inotrem’s successful achievement of the planned interim milestones. Launched in January 2023, the R&D project was designed to last over 12 months and will be a cornerstone in the preparation of Inotrem’s first-in-human clinical trial for INO-02. Inotrem’s antibody program targeting chronic inflammatory indications, such as IBD, is the company’s second asset next to nangibotide, dedicated to the treatment of acute inflammatory diseases (septic shock, Covid-19, myocardial infarction). Based on its cutting-edge proprietary technology platform and strong scientific leadership around the TREM-1 pathway, Inotrem has built a diversified drug portfolio targeting several inflammatory indications for which there are today no or limited specific treatment. “The continuous support of The Crohn’s & Colitis Foundation is a strong recognition of the potential of our therapeutic approach targeting the TREM-1 pathway and eloquently speaks to Inotrem’s ability to deploy its vision and strategy,” says Sven Zimmermann, CEO of Inotrem. “After our stringent evaluation, Inotrem has met predetermined research milestone expectations. We are looking forward to continuing this fruitful collaboration to advance our common quest for cures and the improvement of the quality of life of patients affected by inflammatory bowel diseases,” says Andrés Hurtado-Lorenzo PhD, SVP of Translational Research & IBD Ventures at The Crohn’s & Colitis Foundation. About Inotrem Inotrem S.A. is a biotechnology company specialized in immunotherapy for acute and chronic inflammatory syndromes. The company has developed a new concept of immunomodulation that targets the TREM-1 pathway to control unbalanced inflammatory responses. Through its proprietary technology platform, Inotrem has developed the first-in-class TREM-1 inhibitor, nangibotide, with potential applications in life-threatening immune dysregulations caused by severe infections such as septic shock and severe forms of COVID-19. In parallel, Inotrem has also launched an antibody-based program to develop a new therapeutic modality targeting chronic inflammatory diseases. The company was founded in 2013 by Dr Jean-Jacques Garaud, a former head of research and early development at the Roche Group, Prof. Sébastien Gibot and Dr Marc Derive. Inotrem is supported by leading European and North American investors Inotrem is part of the French Tech 120, a government program dedicated to support the development of fast-growing startups. About the American Crohn’s & Colitis Foundation’s IBD Ventures The Crohn's & Colitis Foundation is the leading non-profit organization focused on both research and patient support for inflammatory bowel disease (IBD), with the mission of curing Crohn's disease and ulcerative colitis, and of improving the quality of life of the millions of Americans living with IBD. The Foundation’s work is dramatically accelerating the research process through investment in research initiatives, while also providing extensive educational and support resources for patients and their families, medical professionals, and the public. IBD-Ventures is a dedicated funding mechanism to support product-oriented research and development programs. For more information, visit crohnscolitisfoundation.org, call 888-694-8872, or email info@crohnscolitisfoundation.org. View source version on businesswire.com: Contacts Media contact for Inotrem Anne REIN Strategies & Image (S&I) anne.rein@strategiesimage.com +33 6 03 35 92 05 Source: Inotrem View this news release online at:

Kisqali is the first and only CDK4/6 inhibitor to demonstrate a consistent, clinically meaningful benefit across a broad population of patients with HR+/HER2- early breast cancer, regardless of disease stage, menopausal or nodal status1 Results were also consistent across all secondary endpoints, including distant disease-free survival and recurrence-free survival, with a trend for improved overall survival*1 The safety profile of Kisqali was favorable at 400 mg with low rates of symptomatic adverse events and limited treatment modifications when administered up to three years1 Collectively, NATALEE results have the potential to more-than-double the number of patients who could benefit from treatment with a CDK4/6 inhibitor in the adjuvant setting2 EAST HANOVER, N.J., June 2, 2023 /PRNewswire/ -- Novartis today presents positive primary endpoint data from the pivotal Phase III NATALEE trial at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. Data showed that Kisqali® (ribociclib) plus endocrine therapy (ET), compared to ET alone, lowered the risk of cancer recurrence by 25.2% in patients with stage II and III hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (HR=0.748; 95% CI: 0.618, 0.906; p=0.0014) along with a consistent, clinically meaningful invasive disease-free survival (iDFS) benefit across key pre-specified subgroups (see table below)1. Experience the full interactive Multichannel News Release here: Kisqali iDFS benefit across key pre-specified subgroups1: Kisqali data across all secondary efficacy endpoints was also consistent, including distant disease-free survival (DDFS) (26% risk reduction) and recurrence-free survival (RFS) (28% risk reduction), with a trend for improvement in overall survival (OS) (HR=0.759; 95% CI: 0.539, 1.068)*1. The safety profile of Kisqali at 400 mg was favorable with low rates of symptomatic adverse events (AEs) and limited need for dose modifications when administered up to three years1. The most frequently reported AEs of special interest (grade 3 or higher) were neutropenia (43.8%) and liver-related AEs (e.g. elevated transaminases) (8.3%)1. Grade 3 or higher QT interval prolongation and diarrhea were low for Kisqali at 1.0% and 0.6%, respectively1. "These landmark results will fundamentally change how we treat patients with stage II and III HR+/HER2- early breast cancer who are in need of new, well-tolerated options that prevent their cancer from coming back," said Dennis J. Slamon, M.D., Director of Clinical/Translational Research, UCLA Jonsson Comprehensive Cancer Center and Chairman and Executive Director of Translational Research In Oncology (TRIO) and NATALEE trial lead investigator. "Addressing this unmet need across such a broad patient population could help streamline treatment decisions for healthcare providers and keep many more at-risk patients cancer-free without disrupting their daily lives." "Patients diagnosed with HR+/HER2- early breast cancer remain at risk of cancer recurrence, given that one-third of patients diagnosed with stage II and more than half of those diagnosed with stage III will unfortunately experience a return of their cancer," said Shreeram Aradhye, M.D., President, Global Drug Development and Chief Medical Officer, Novartis. "The compelling data from NATALEE highlight the potential of Kisqali to reduce the risk of cancer recurrence in this at-risk population, including node-negative patients, while maintaining a favorable safety profile. These potentially practice-changing results reinforce the unique and well-established profile of Kisqali as a proven treatment in HR+/HER2- metastatic breast cancer." "After an early breast cancer diagnosis, patients live with a persistent and lifelong worry that their cancer will return," said Fran Visco, President, National Breast Cancer Coalition, and member of the NATALEE Steering Committee. "The National Breast Cancer Coalition partners with industry and scientists to help find treatments that will make certain that does not happen. Educated patient advocate participation in all phases of research, especially in designing and implementing clinical trials, is critical to making certain patients have meaningful options, and we are grateful that Novartis welcomed our collaboration and participation in all aspects of the NATALEE trial." Novartis plans to submit these Phase III data to regulatory authorities in the US and Europe before end of year. About NATALEE NATALEE is a global Phase III multi-center, randomized, open-label trial to evaluate the efficacy and safety of Kisqali with ET as adjuvant treatment versus ET alone in patients with HR+/HER2- EBC, being conducted in collaboration with TRIO1. The adjuvant ET in both treatment arms was a non-steroidal aromatase inhibitor (NSAI; anastrozole or letrozole) and goserelin if applicable1. The primary endpoint of NATALEE is iDFS as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria1. A total of 5,101 adult patients with HR+/HER2- EBC across 20 countries were randomized in the trial1. Results showed Kisqali plus ET, compared to ET alone, lowered the risk of cancer recurrence by 25.2% (HR=0.748; 95% CI: 0.618, 0.906; p=0.0014), along with consistent clinically meaningful iDFS benefit across key pre-specified subgroups: AJCC Tumor Stage II (HR=0.761; 95% CI: 0.525, 1.103), AJCC Tumor Stage III (HR=0.740; 95% CI: 0.592, 0.925), node-negative disease (HR=0.630; 95% CI: 0.341, 1.165), node-positive disease (HR=0.771; 95% CI: 0.630, 0.944), pre-menopausal women and men (HR=0.722; 95% CI: 0.530, 0.983), post-menopausal women (HR=0.781; 95% CI: 0.613, 0.997)1. Kisqali data across all secondary efficacy endpoints was also consistent, including DDFS (26% risk reduction) and RFS (28% risk reduction), with a trend for improvement in OS (HR=0.759; 95% CI: 0.539, 1.068)*1. Median study duration of follow up was 34 months (range 21-48 months) with clinical benefits observed after approximately two years1. NATALEE explored a lower starting dose (400 mg) of Kisqali than the dose approved for treatment in metastatic breast cancer (MBC) (600 mg) with the goal to minimize disruptions to patient quality of life without compromising efficacy. The safety profile of Kisqali at 400 mg was favorable with low rates of symptomatic AEs and limited need for dose modifications when administered up to three years1. The most frequently reported AEs of special interest (grade 3 or higher) were neutropenia (43.8%) and liver-related AEs (e.g. elevated transaminases) (8.3%)1. Grade 3 or higher QT interval prolongation and diarrhea were low for Kisqali at 1.0% and 0.6%, respectively1. *Results based on pre-specified interim analysis for OS at time of primary iDFS analysis; additional follow up is planned to obtain more mature OS data1. About Early Breast Cancer More than 90% of patients diagnosed with breast cancer have EBC3. Despite standard-of-care adjuvant therapy, approximately one-third of those diagnosed with stage II and more than half of those diagnosed with stage III HR+/HER2- EBC experience cancer recurrence4,5. The risk of recurrence continues over decades with more than half of breast cancer recurrences occurring five or more years after diagnosis4,6. For many of these patients, there are currently no targeted therapeutic options outside of the standard chemotherapy and ET7. About Kisqali® (ribociclib) Kisqali has consistently demonstrated OS benefit while preserving or improving quality of life across three Phase III trials in MBC8-19. Updates to the NCCN Guidelines® for breast cancer, released in January 2023, recommend ribociclib (Kisqali) as the only Category 1 preferred CDK4/6 inhibitor for first-line treatment of patients with HR+/HER2- MBC when combined with an aromatase inhibitor (AI)20. Additionally, Kisqali has the highest rating of any CDK4/6 inhibitor on the ESMO Magnitude of Clinical Benefit Scale, achieving a score of five out of five for first-line pre-menopausal patients with HR+/HER2- advanced breast cancer21. Further, Kisqali in combination with either letrozole or fulvestrant has uniquely, among other CDK4/6 inhibitors, received a score of four out of five for post-menopausal patients with HR+/HER2- advanced breast cancer treated in the first line22. Kisqali has been approved in 99 countries worldwide, including by the United States Food and Drug Administration (FDA) and the European Commission. In the U.S., Kisqali is approved for the treatment of adult patients with HR+/HER2- advanced or MBC in combination with an AI as initial ET or fulvestrant as initial ET or following disease progression on ET in post-menopausal women or in men. In the EU, Kisqali is approved for the treatment of women with HR+/HER2- advanced or MBC in combination with either an AI or fulvestrant as initial ET or following disease progression. In pre- or peri-menopausal women, the ET should be combined with a luteinizing hormone-releasing hormone agonist19. Novartis is committed to continuing to study Kisqali in breast cancer. Novartis is collaborating with SOLTI, which is leading the HARMONIA study to test whether Kisqali changes tumor biology to enable a better response to ET compared to Ibrance®** (palbociclib) for patients with HR+/HER2-, HER2-enriched subtype23 MBC, and with the Akershus University Hospital in Norway on the NEOLETRIB trial, a neoadjuvant Phase II trial studying the effects of Kisqali in HR+/HER2- EBC to discover the potentially unique underlying mechanism of action24. Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals. Please see full Prescribing Information for Kisqali, available at Indications KISQALI® (ribociclib) is a prescription medicine used to treat adults with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer that has gotten worse or has spread to other parts of the body (metastatic), in combination with: an aromatase inhibitor as the first endocrine-based therapy; or fulvestrant as the first endocrine-based therapy or following disease progression on endocrine therapy in postmenopausal women or in men. It is not known if KISQALI is safe and effective in children. Important Safety Information What is the most important information I should know about KISQALI? KISQALI may cause serious side effects, including: Lung problems. KISQALI may cause severe or life-threatening inflammation of the lungs during treatment that may lead to death. Tell your health care provider right away if you have any new or worsening symptoms, including: trouble breathing or shortness of breath cough with or without mucus chest pain Severe skin reactions. Tell your health care provider or get medical help right away if you get severe rash or rash that keeps getting worse; reddened skin; flu-like symptoms; skin pain/burning; blistering of the lips, eyes, or mouth; or blisters on the skin or skin peeling, with or without fever. Heart rhythm problems (QT prolongation). KISQALI can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Your health care provider should check your heart and do blood tests before and during treatment with KISQALI. Tell your health care provider right away if you have a change in your heartbeat (a fast or irregular heartbeat), or if you feel dizzy or faint. Liver problems (hepatobiliary toxicity). KISQALI can cause serious liver problems. Your health care provider should do blood tests to check your liver before and during treatment with KISQALI. Tell your health care provider right away if you get any of the following signs and symptoms of liver problems: yellowing of your skin or the whites of your eyes (jaundice) dark or brown (tea-colored) urine feeling very tired loss of appetite pain on the right side of your stomach area (abdomen) bleeding or bruising more easily than normal Low white blood cell counts (neutropenia). Low white blood cell counts are very common during treatment with KISQALI and may result in infections that may be severe. Your health care provider should check your white blood cell counts before and during treatment with KISQALI. Tell your health care provider right away if you have signs and symptoms of low white blood cell counts or infections such as fever and chills. Your health care provider may tell you to decrease your dose, temporarily stop, or completely stop taking KISQALI if you develop certain serious side effects during treatment with KISQALI. What should I tell my health care provider before taking KISQALI? Before you take KISQALI, tell your health care provider if you: have any heart problems, including heart failure, irregular heartbeats, and QT prolongation have ever had a heart attack have a slow heartbeat (bradycardia) have problems with the amount of potassium, calcium, phosphorus, or magnesium in your blood have fever, chills, or any other signs or symptoms of infection have liver problems have any other medical conditions are pregnant, or plan to become pregnant. KISQALI can harm your unborn baby If you are able to become pregnant, your health care provider should do a pregnancy test before you start treatment with KISQALI. Females who are able to become pregnant and who take KISQALI should use effective birth control during treatment and for at least 3 weeks after the last dose of KISQALI. Talk to your health care provider about birth control methods that may be right for you during this time. If you become pregnant or think you are pregnant, tell your health care provider right away. are breastfeeding or plan to breastfeed. It is not known if KISQALI passes into your breast milk. Do not breastfeed during treatment with KISQALI and for at least 3 weeks after the last dose of KISQALI Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. KISQALI and other medicines may affect each other, causing side effects. Know the medicines you take. Keep a list of them to show your health care provider or pharmacist when you get a new medicine. What should I avoid while taking KISQALI? Avoid eating grapefruit and avoid drinking grapefruit juice during treatment with KISQALI since these may increase the amount of KISQALI in your blood. The most common side effects of KISQALI include: decreased white blood cell counts decreased red blood cell counts abnormal liver function tests infections nausea increased kidney function test tiredness decreased platelet counts diarrhea vomiting headache constipation hair loss cough rash back pain low blood sugar level KISQALI may cause fertility problems if you are male and take KISQALI. This may affect your ability to father a child. Talk to your health care provider if this is a concern for you. Tell your health care provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of KISQALI. For more information, ask your health care provider or pharmacist. Call your doctor for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800-FDA-1088. Please see accompanying full Prescribing Information including Patient Information. Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "may," "could," "would," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. 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For questions about the site or required registration, please contact [email protected]. References Slamon D, Stroyakovskiy D, Yardley D, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer: primary results from the Phase III NATALEE trial. Presented at the American Society of Clinical Oncology Annual Meeting, June 2, 2023. Chicago, USA. Data on File. Novartis. Iqbal J, Ginsburg O, Rochon PA, Sun P, Narod SA. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States [published correction appears in JAMA. 2015 Jun 9;313(22):2287]. JAMA. 2015;313(2):165-173. doi:10.1001/jama.2014.17322 Pan H, Gray R, Braybrooke J, et al; EBCTCG. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846. doi:10.1056/NEJMoa1701830 Pan H, Gray R, Braybrooke J, et al; EBCTCG. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846;(suppl). doi:10.1056/NEJMoa1701830 Gomis R, Gawrzak S. Tumor cell dormancy. Mol Oncol. 2017;11(1):62-78. American Cancer Society. Treatment of breast cancer stages I-III. Revised April 12, 2022. Accessed on September 15, 2022. Yardley DA, Yap YS, et al. Pooled exploratory analysis of survival in patients (pts) with HR+/HER2- advanced breast cancer (ABC) and visceral metastases (mets) treated with ribociclib (RIB) + endocrine therapy (ET) in the MONALEESA (ML) trials. Poster presented at the European Society of Medical Oncology Congress. September 9-13, 2022. Paris, France. Neven P, Fasching PA, et al. Updated overall survival (OS) results from the first-line (1L) population in the Phase III MONALEESA-3 trial of postmenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with ribociclib (RIB) + fulvestrant (FUL). Mini oral presented at the European Society for Medical Oncology Breast Cancer Congress. May 4, 2022. Paris, France. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. New England Journal of Medicine. 2022;386(10):942-950. doi:10.1056/NEJMoa2114663 Hortobagyi, et al. Overall survival (OS) results from the phase III MONALEESA (ML)-2 trial of postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib. Proffered paper presented at the European Society of Medical Oncology Congress, September 16-21, 2021. Lugano, Switzerland. Im S-A, Lu Y-S, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. New England Journal of Medicine. 2019;381(4):307-316. doi:10.1056/nejmoa1903765 Slamon DJ, Neven P, Chia S, et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. New England Journal of Medicine. 2020;382(6):514-524. doi:10.1056/NEJMoa1911149 Slamon, DJ, Neven P, Chia S, et al. Overall survival (OS) results of the Phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor 2–negative (HER2−) advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). Presented at the European Society of Medical Oncology Congress, September 29, 2019, Barcelona, Spain. Slamon D, Neven P, Chia S, et al. Updated overall survival (OS) results from the Phase III MONALEESA-3 trial of postmenopausal patients (pts) with HR+/HER2− advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB. 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