Category: 3. Business

  • How US-Japan trade deal impacts auto production, steel demand

    The US-Japan trade deal is likely to be a boon to US-based automotive production but any reduction in imports from Japan may be modest, market observers and analysts told Fastmarkets on Friday July 25.

    Key takeaways

    • US-Japan trade deal reduces tariffs on Japanese cars from 25% to 15%, boosting competition in the US auto market
    • Increased US auto production is expected to drive higher demand for steel, particularly galvanized and cold-rolled coil
    • Japanese automakers may expand US-based production, intensifying competition for the Detroit Three and reshaping market dynamics

    Any rise in US domestic automotive production will, in turn, push up demand for steel but the extent of production gains was still unclear, trade sources said.

    The automotive sector consumes 40% of all flat steel output, principally galvanized and cold-rolled coil, and is responsible for about 40-50% of demand for special bar quality (SBQ) long steel products, according to Phil Gibbs, metals equity analyst at Keybanc Capital Markets.

    Under the trade agreement, completed on July 23, Japan will pay a reduced 15% duty on autos made in Japan and shipped to the US, a reduction from the current 25% tariff rate.

    Sectoral tariffs on imports of Japanese steel will remain at 50%.

    The lower 15% duty on imported Japanese cars and other goods surprised market observers and pleased investors, leading to a big rally in the shares of Japanese auto companies, with a more modest increase in the share prices of the so-called Detroit Three – General Motors, Ford and Stellantis (formerly Chrysler).

    The negotiations

    US President Donald Trump said on July 24 the lower tariff rate emerged from negotiations that were “not easy,” and were resolved with Japan agreeing to provide $550 billion to fund a new US-based strategic industrial investment fund.

    “They gave us $550 billion because they didn’t want to pay [the higher rate of 25% they currently pay],” Trump said during an impromptu press conference on his visit to view construction at the Federal Reserve renovation project.

    The $550 billion will go into a US fund that will make new domestic investments, with 90% of the profits paid to the US and 10% to Japan, Trump said.

    “It’s not a loan or anything. It’s a signing bonus, I called it,” Trump said. “They gave us $550 billion and took down the tariffs a little bit and they agreed to open their economy to everybody.”

    The market opening will remove trade barriers that have prevented the export of US cars to Japan.

    “The opening of the economy is worth more than the $550 billion,” Trump said.

    A White House fact sheet published on July 23 provided more detail. “Longstanding restrictions on US cars and trucks will be [removed], granting US automakers access to the Japanese consumer market,” it said. “US automotive standards will be approved in Japan for the first time.”

    The White House also said: “At President Trump’s direction, these funds will be targeted toward the revitalization of America’s strategic industrial base.” The White House fact sheet included detailed investments in “energy, semiconductors, critical minerals, pharmaceuticals and shipbuilding.”

    The 15% tariff on imports from Japan does, however, come at higher price for buyers of imported Japanese cars, Arthur Wheaton, director of labor studies at Cornell University’s School of Industrial and Labor Relations, said.

    “The good news is that the auto industry strongly prefers certainty, even if more expensive,” Wheaton said. “There may be more attempts to source US-based metals if the price is competitive. With a more definitive price on imported metals, procurement is much less of a headache.”

    Shifts in market share

    Any shift in domestic US production may benefit US-based but foreign-owned automakers rather than the Detroit Three, according to Sam Fiorani, vice president of global vehicle forecasting at AutoForecast Solutions.

    “Additional production by Japanese original equipment manufacturers in the US will likely eat away at market share from the Detroit Three,” Fiorani said.

    He outlined the prospects for each Japanese automaker with production based in the US.

    “Companies such as Toyota and Subaru have struggled for years with capacity in North America and, especially, in the US, but have not found the need to expand their footprints,” he said.

    “Honda does not import many vehicles from outside of North America, and has no reason to add more North American capacity. Nissan already has too much factory space,” Fiorani added. “Smaller automakers such as Subaru and Mazda can’t afford to take big risks. If any automaker [were to] make a new investment, Toyota could open a new plant at some point.”

    More intense competition

    Marick Masters, professor of business at Wayne State University in Detroit, expected the Japan trade deal to intensify competitiveness within the US industry and to lead to an increase in imports into the US of cars made in Japan.

    “The US runs a sizable trade deficit overall, and in the auto sector specifically with Japan. It imports a large number of motor vehicles from Japan and the relatively lower tariffs for Japan on vehicles will encourage further imports,” Masters said.

    “Japan-based auto companies also manufacture a large quantity of vehicles in the US, meaning that they compete directly with US-owned manufacturers on two fronts,” he said. “The announced trade agreement includes substantial Japanese investment in the US economy which will add more to Japan’s industrial capacity in the US.”

    The Detroit Three will face heightened pressure from both new investment in US domestic capacity and increased imports from Japan, according to Masters.

    “The major threat to the US-owned legacy auto companies remains the global acceleration to electrical vehicles, dominated by China, and the competitive disadvantage of the US firms in labor costs, production efficiencies and regulatory and bureaucratic burdens,” he said.

    US production outlook

    AutoForecast Solutions expected US automakers to produce 10.3 million light vehicles in 2025, about the same number as in 2024.

    “Over the next few years, production is expected to slip slightly while manufacturers shift capacity from electric vehicles and toward vehicles with internal combustion engines,” Fiorani said. “Growth beyond the current level isn’t expected before 2028.”

    Fiorani expected Japanese firms to increase US domestic production rather than increase exports from Japan to the US.

    “Japanese automakers spent the past 45 years investing in production facilities in the US and were likely to continue that investment,” Fiorani said.

    “Only a handful of models imported from Japan are in volumes large enough to warrant North American production, so we’re unlikely to see a flood of new local facilities,” he added. “Toyota may look into ways to produce the 4Runner in the US, and Mazda might seek a local source for the CX-5, but those are among the few options.”

    Japan’s automakers have a strategy that makes it more likely that they will continue to export to the US and other nations, according to the analyst.

    “The reason why the imported models are imported is that they need the volume for other countries, especially Japan, to make the business case for production,” Fiorani said. “Forcing many of those models to be produced in the US would stop their sales and eliminate choice for American buyers.

    “Mitsubishi might have to take a hard look at the US market,” he added, “and Subaru buyers may need to pay a bit more for their Outback. Adding tariffs to these niche sectors means more expensive vehicles for consumers.”

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  • Navigating Evolving Treatment Paths With Dato-DXd

    Navigating Evolving Treatment Paths With Dato-DXd

    In an interview with Targeted Oncology, Jacob Sands, MD, medical oncologist at Dana-Farber Cancer Institute, discusses the integration of datopotamab deruxtecan (Dato-DXd; Datroway) into the treatment landscape for EGFR-mutant non–small cell lung cancer (NSCLC).

    The recent FDA approval of Dato-DXdoffers a new therapeutic avenue for patients with EGFR-sensitizing mutations in their tumors who have previously received an EGFR-directed therapy and chemotherapy. This expands the treatment landscape for a subset of patients with NSCLC, providing an additional option for those who have progressed on earlier lines of treatment.

    The field of EGFR-mutated NSCLC has become increasingly intricate, with multiple established and emerging pathways for treatment. In the first-line setting, osimertinib (Tagrisso) has long been a cornerstone, administered as a single agent and generally very well tolerated. Many patients experience remarkable durability of response with osimertinib monotherapy, offering a significant period of disease control.

    However, the treatment paradigm has evolved further with the introduction of combination regimens demonstrating superior efficacy compared to osimertinib alone. One notable regimen is the combination of chemotherapy plus osimertinib, commonly utilizing carboplatin and pemetrexed in conjunction with osimertinib. This combination, often referred to as the FLAURA2 regimen, has shown enhanced progression-free survival benefits.

    Another significant first-line option is the MARIPOSA regimen, which combines amivantamab (Rybrevant) with lazertinib (Lazcluze). This represents a distinct approach, targeting EGFR and MET pathways simultaneously. The choice between these first-line regimens carries significant implications for subsequent lines of therapy, necessitating careful consideration in shared decision-making with patients.

    The sequence of therapies postprogression is highly dependent on the initial first-line treatment. If a patient initially receives amivantamab plus lazertinib and then progresses, the subsequent line of therapy would typically involve chemotherapy.

    Conversely, for patients who initially receive osimertinib plus chemotherapy and subsequently progress, several options exist. One such option, now reinforced by the recent FDA approval, is Dato-DXd.

    For patients who commence treatment with osimertinib alone and then progress, the next line of therapy could be chemotherapy or the MARIPOSA-2 regimen, which combines amivantamab with chemotherapy. Following progression on either of these options, Dato-DXd then becomes a viable treatment option.

    The rapid advancements in the treatment of EGFR-mutated NSCLC have resulted in a diverse array of therapeutic choices that can be strategically integrated into a patient’s treatment journey. This expanded toolkit offers personalized approaches but simultaneously introduces greater complexity into clinical decision-making, particularly regarding the optimal first-line therapy, as this choice directly influences the sequence of subsequent treatments and overall patient outcomes. The increased complexity underscores the importance of multidisciplinary tumor boards and expert consultation to navigate these intricate treatment pathways effectively.

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  • Dollar Extends July Rally After US-EU Trade Deal: Markets Wrap

    Dollar Extends July Rally After US-EU Trade Deal: Markets Wrap

    (Bloomberg) — Wall Street kicked off a pivotal week with the dollar climbing after President Donald Trump reached a tariff deal with the European Union and signs mounted that the US and China will extend their trade truce. Stocks held near a record and bonds edged lower.

    Most Read from Bloomberg

    The start of a week that will set the tone for the rest of the year in markets saw the greenback extending its July rally. The euro dropped the most in over two months. The S&P 500 hovered around 6,400. Treasuries saw small losses before a pair of US debt sales. Oil rose as Trump said he would reduce the deadline for Russia to agree to a truce in Ukraine.

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    In the run-up to the Aug. 1 US tariff deadline, traders will go through a raft of key data from jobs to inflation and economic activity. The big event comes Wednesday, when the Federal Reserve is expected to keep rates unchanged. Then there’s a string of big-tech earnings, with four megacaps worth a combined $11.3 trillion reporting results.

    “This is about as busy as a week can get in the markets,” said Chris Larkin at E*Trade from Morgan Stanley. “This week could make or break that momentum in the near term.”

    US and Chinese officials kicked off two days of talks aimed at extending their tariff truce beyond a mid-August deadline and hashing out ways to maintain trade ties while safeguarding economic security.

    President Trump said he would impose a new deadline of 10-12 days for Russian leader Vladimir Putin to reach a truce with Ukraine, ramping up pressures on Moscow to bring the fighting to a halt.

    “Whether we agree or not with the use of tariffs and the deals announced, we are getting the big ones out of the way which will allow American businesses to adjust and plan, for better or worse,” said Peter Boockvar at the Boock Report. “And we can now focus on how this all plays out.”

    While the dollar’s strength today may reflect the perception that the new EU deal is lopsided in favor of the US, it may also reflect a feeling that America is reengaging with its major allies, according to Thierry Wizman at Macquarie Group.

    “The impact this new reality has on the real economy remains to be seen, although we’re certainly cognizant that the recent data has reinforced the US exceptionalism narrative,” said Ian Lyngen and Vail Hartman at BMO Capital Markets. “At the end of the day, it is simply too soon for the full extent of the new tariff structure to be evident in the data or real economy.”

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  • How Nuclear Technology is Testing Pistachios for Toxins

    How Nuclear Technology is Testing Pistachios for Toxins

    Climate change is expected to accelerate the spread of mycotoxins like aflatoxins and heavy metal contamination in food, which could have devastating consequences for food safety and public health for countries already struggling with food insecurity, 

    As global food systems grow more complex and climate risks intensify, countries will need more portable, affordable and scalable tools such as these, especially in regions where conventional laboratory testing is inaccessible.  

    The IAEA, through its Joint FAO/IAEA Centre of Nuclear Techniques in Food and Agriculture, undertakes research and development to develop nuclear and complementary tools to detect food hazards that threaten food security, trade and public health.  

    Under the Atoms4Food initiative and in cooperation with the FAO, the IAEA has developed cost-effective and portable techniques that allow for the rapid testing of a large number of samples, including field-deployable tools, to support food safety emergency responses. 

    Food safety experts in Seibersdorf are working to extend this type of application to cover more categories of contaminants in other food products based on Member State needs. The FSCL has also adapted the same sensor platform to detect fumonisins (harmful mycotoxins linked to cancer and birth defects) in maize and maize products and toxic metals such as lead in fruit juices. This flexibility makes the technique a powerful tool in enhancing food safety. 

    Vlachou said, “The IAEA is creating resilient and robust interventions to assist food safety stakeholders in countries around the world, maintaining safety and hygiene at required levels to avoid foodborne illnesses.”

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  • DLA Piper continues the expansion of its Real Estate practice with the addition of Devan Popat in Los Angeles

    DLA Piper is pleased to welcome Devan Popat as a Partner in the Real Estate practice. Popat will be based in the Los Angeles office, further bolstering the firm’s real estate capabilities in the region.

    Devan represents clients on a broad range of real estate transactions, including advising investors and sponsors in the formation of real estate joint ventures and all stages of complex development from acquisition, entitlement, equity and debt financing, and construction through stabilization. He represents lenders, including debt funds and insurance companies, in all types of real estate finance transactions, including mortgage, construction, and mezzanine loans; secured and unsecured corporate credit facilities; preferred equity, and other structured financings; as well as co-lending arrangements, participations, workouts, loan sales, and mezzanine foreclosures.

    Notable examples of Devan’s lead counsel experience include counseling a real estate investment firm in a US$250 million joint venture with a South Korean investment management firm to acquire student housing properties; representing a real estate debt fund in the origination of mortgage loans, mezzanine loans, and A/B loans; and advising an investment management firm on establishing a preferred equity investment platform.

    “With a sophisticated practice that includes both equity and credit transactions and assets located throughout the US, Devan is a perfect fit for our global real estate platform. His addition to our group will enhance our ability to continue to provide best-in-class service for our clients investing in California and throughout the country,” said Bryan Connolly, US Chair of the firm’s Real Estate practice.

    “Devan is a highly regarded real estate transactional lawyer, and his addition to our Los Angeles office will provide significant value to our clients both in California and throughout the US,” said Jerry Neuman, head of the firm’s California Real Estate practice.

    Popat’s arrival is a part of the firm’s commitment to the continued growth of its Real Estate practice. In recent months, Real Estate Partners Todd Eisner, Ryan Hanofee, Lewis Goss II, and Warren Seay, Jr. have also joined the firm.

    With more than 200 lawyers in the US real estate sector and more than 500 globally, DLA Piper’s market-leading Real Estate practice offers a full range of real estate services, including acquisitions and sales, single asset, programmatic and operating company joint ventures, real estate fund formation, public and private REITs, financing, cross-border transactions, zoning and development, construction and design, leasing and restructuring and workouts. The firm represents many of the world’s largest and most sophisticated real estate investors, owners, developers and lenders in their most important matters.

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  • Standard DNA Testing May Miss Majority of NUT Carcinomas, Study Finds

    Standard DNA Testing May Miss Majority of NUT Carcinomas, Study Finds

    When a NUT carcinoma is detected, standard-of-care DNA next-generation sequencing (NGS) may be unable to detect upward of 75% of incidences of the disease, according to findings published in Clinical Cancer Research. The study authors suggested that to correctly detect and diagnosis NUT carcinomas, RNA-based fusion testing, NUT immunohistochemistry, and NUTM1 fluorescence in situ hybridization (FISH) must become a routine part of testing. 

    “If a diagnosis of NUT carcinoma is being considered, standard of care DNA-based testing is insufficient and clinicians should consult with pathology colleagues about ordering a better gold standard test such as NUT immunohistochemistry or RNA-based mutation sequencing,” stated co-senior study author Jia Luo, MD, a thoracic oncologist at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute. “Early accurate diagnosis is key to getting patients on the correct treatment and clinical trials.”

    Study Methods and Rationale 

    NUT carcinomas are aggressive, poorly differentiated squamous cell cancers that are typically found in midline structures and are characterized by NUTM1 fusions. The study authors believed that NUT carcinomas are often underdiagnosed and sought to determine the ability of standard NGS for detecting NUTM1 fusions. They also explored other molecular features of NUT carcinomas to aid in future diagnosis. 

    The researchers analyzed NGS reports and medical records from 116 patients with NUT carcinoma who underwent broad-panel NGS (> 80 genes) between 2013 and 2024. 

    Key Study Findings 

    Of the 116 patients, 84.5% had DNA testing completed, 12.1% had circulating tumor DNA (ctDNA) testing completed, and 51.7% had RNA fusion testing. Of the 100 patients with DNA or ctDNA testing, 92.9% had less than a 10 pack-year or never-smoker history, and 58.8% had a BRD4:NUTM1 fusion. The median tumor mutational burden was 1.0 mutation/megabase, and 19.7% had PD-L1 expression ≥ 1%.

    DNA, ctDNA, RNA fusion, NUT immunohistochemistry, and NUTM1 FISH detected NUT carcinoma fusions in 21.6%, 21.4%, 83.9%, 100.0%, and 91.9% of tests, respectively. “These findings warrant immediate change to the diagnostic workflow for patients with suspected NUT carcinoma,” Dr. Luo said, recommending simultaneous testing of both DNA and RNA fusions. 

    Other co-occurring pathogenic mutations were found in the PIK3CA, RET, and FGFR3 genes as well as in the tumor suppressor ATM and BRCA1 genes. Secondary altered genes included LRP1B, MLL2/KMT2D, and FAT1, which were found in more than 5% of all NUT carcinomas. The most common pathways with mutated genes were epigenetic (57%), cell cycle (26%), and DNA repair pathways (24%). 

    “This study characterized the common mutations seen in NUT carcinoma, which will help researchers develop future effective combination treatments,” stated Dr. Luo.

    Disclosure: For full disclosures of the study authors, visit aacrjournals.org.  

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  • Durvalumab Earns FDA Priority Review for Early-Stage Gastric Cancer

    Durvalumab Earns FDA Priority Review for Early-Stage Gastric Cancer

    A significant advancement in the treatment landscape for resectable early-stage gastric and gastroesophageal junction (GEJ) cancers is on the horizon, following the FDA granting priority review and breakthrough therapy designation to durvalumab (Imfinzi).1 This decision underscores the potential for durvalumab to become the first and only perioperative immunotherapy-based regimen in this challenging setting, addressing a critical unmet medical need where disease recurrence remains common despite curative-intent surgery and chemotherapy.

    The supplemental biologics license application (sBLA) for durvalumab is supported by compelling data from the phase 3 MATTERHORN trial (NCT04592913). Results from this global, randomized, double-blind, placebo-controlled study were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) for patients treated with the durvalumab-based perioperative regimen. Specifically, the regimen led to a 29% reduction in the risk of disease progression, recurrence, or death compared with chemotherapy alone (HR, 0.71; 95% CI, 0.58–0.86; P <.001).1,2

    While the estimated median EFS had not yet been reached in the durvalumab arm at the time of the interim analysis, it stood at 32.8 months for the comparator arm, signaling a notable clinical benefit. The estimated EFS rates further highlighted this advantage, with 78.2% of patients in the durvalumab arm being event-free at 1 year compared with 74.0% in the comparator arm. At 24 months, these rates were 67.4% vs 58.5%, respectively, suggesting a growing magnitude of benefit over time. A strong trend favoring overall survival (OS) was also observed (HR, 0.78; 95% CI, 0.62–0.97; P =.025), with formal assessment of OS planned for the final analysis of the trial.

    Gastric/GEJ tumor: ©LASZLO – stock.adobe.com

    Gastric cancer, including GEJ cancer, represents a substantial global health burden, ranking as the fifth most common cancer worldwide and a leading cause of cancer mortality. In 2024, approximately 6500 patients in the US were treated for early-stage and locally advanced gastric or GEJ cancer.1 Despite aggressive treatment approaches involving curative surgery and perioperative chemotherapy, a significant proportion of patients experience disease recurrence within a year, and 5-year survival rates remain suboptimal, with less than half of patients surviving beyond 5 years. The need for more effective treatment strategies is paramount to improve long-term outcomes for these patients.

    The MATTERHORN trial protocol involved a perioperative approach, where patients received durvalumab in combination with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy before surgery, followed by adjuvant durvalumab plus FLOT chemotherapy, and then durvalumab monotherapy after surgery. This comprehensive treatment strategy aims to leverage durvalumab’s mechanism of action as a human monoclonal antibody that binds to the PD-L1 protein, thereby blocking its interaction with PD-1 and CD80. This blockade is designed to counteract tumor immune evasion tactics and restore antitumor immune responses, offering a novel therapeutic avenue for a disease that has seen limited advancements in recent decades.

    The safety profile observed in the MATTERHORN trial was consistent with the known profiles of durvalumab and FLOT chemotherapy, with similar rates of grade 3 or higher adverse events between the treatment and comparator arms. This manageable safety profile is crucial for a regimen intended for a broad patient population undergoing demanding perioperative treatment.1,2

    Regulatory applications for durvalumab in this setting are also under review in the European Union, Japan, and several other countries, indicating a global effort to bring this potential new standard of care to patients worldwide.1 The anticipated FDA action date for the sBLA is in the fourth quarter of 2025, a timeline that underscores the urgency and significance placed on this potential approval by regulatory authorities and the oncology community. If approved, this perioperative durvalumab regimen could redefine the clinical paradigm for patients with resectable early-stage gastric and GEJ cancers, offering a much-needed improvement in the quest for durable remissions and extended survival.

    REFERENCES:
    1. IMFINZI® (durvalumab) granted Priority Review and Breakthrough Therapy Designation in the US for patients with resectable early-stage gastric and gastroesophageal junction cancers. News release. AstraZeneca. July 28, 2025. Accessed July 28, 2025. https://tinyurl.com/yfczjf3h
    2. Janjigian Y, Al-Batran S-E, Wainberg Z, et al. Event-free survival (EFS) in MATTERHORN: a randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). J Clin Oncol. 2025;43(suppl 17):LBA5. doi:10.1200/JCO.2025.43.17_suppl.LBA5

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  • Immune Modulation in Sarcoma: Targeting the Tumor Microenvironment

    Immune Modulation in Sarcoma: Targeting the Tumor Microenvironment

    Explore the latest advancements in sarcoma immunotherapy, focusing on tumor microenvironment modulation and innovative treatment strategies for improved patient outcomes.

    Introduction

    Sarcomas are a varied group of mesenchymal neoplasms that can impact a range of tissues, including bone, cartilage, muscle, nerves, and connective tissues.1 They include soft tissue sarcomas (STS) such as malignant fibrous histiocytoma, liposarcoma, and leiomyosarcoma, as well as primary bone sarcomas like osteosarcoma, Ewing sarcoma, giant cell tumor, and chondrosarcoma.2

    STS have been further categorized into subtypes according to the NCCN classification, including STS of extremity, superficial/trunk, or head and neck; retroperitoneal or intra-abdominal STS; desmoid tumors (aggressive fibromatosis); and rhabdomyosarcoma, to facilitate management.3 Seth M. Pollack, MD, professor at the Feinberg School of Medicine at Northwestern Medicine, gave a lecture at the MedNews Week Keynote Conference focusing on these rare cancers, comprising 1% of all adult malignancies and leading to 5130 deaths in 2022 alone.1,3 The primary sites of STS origin are the extremities (43%), the trunk (10%), viscera (19%), retroperitoneum (15%), and the head and neck (9%).3 The pelvis is the most common site of origin for bone sarcomas, followed by the proximal femur, proximal humerus, distal femur, and ribs.3

    Though traditionally sarcomas have been classified based on morphology and type of tissue they resemble, in recent years they have been classified based on the genetic alteration into sarcomas with specific genetic alterations and sarcomas with complex aneuploidy karyotypes, consisting of numerous losses, gains, and amplifications.4 Pollack brings to light another important classification of sarcomas for the tumor response and clinical efficacy. When categorizing tumors into hot, cold, and variable types, various factors are taken into consideration. This includes details about the cancer cells, the immune characteristics of the tumor, the microenvironment in which the tumor is situated, and the signaling mechanisms involved.5 These factors all play a significant role in determining the classification of tumors. Understanding the immunobiology of these tumors is crucial for the effective application of immunotherapy. This classification is centered on the delicate balance between the tumor’s ability to evade the immune system and the immune system’s coordination and response to the tumor.5

    This unique immunobiology provides a promising opportunity for the use of immunotherapy. Immunotherapy is a type of treatment that focuses on harnessing the body’s own immune system to target and destroy tumors.5 It works by reactivating and maintaining the immune response against the tumor as well as enhancing the body’s natural ability to fight against cancer.

    In this paper, Pollack’s lecture is discussed, and the authors explore the normal tumor microenvironment (TME) and how differences in TME can alter tumor response and patient outcomes. The authors also look at the potential effects of radiation therapy on the TME. Pollack delves into the intricacies of altering the TME to effectively treat sarcomas. Strategies for overcoming TME inhibitory macrophages are investigated to enhance patient outcomes. This is especially important for patients with poor outcomes and involves the implementation of several precision techniques, including immunotherapy (such as T-cell receptor [TCR] therapy, cancer testis antigen [CTA]-targeting cells, and chimeric antigen receptor [CAR] T-cell therapy) and neoadjuvant therapy in combination with radiation treatment (Figure).

    FIGURE. Summary of the key approaches in sarcoma immunotherapy, including the targeting of CTAs such as NY-ESO-1, and the use of CAR T cells, TCR, and interferon gamma to enhance immune responses against tumors

    The Role of the TME and Immune Modulation in Sarcoma Therapy

    Sarcoma cells continually interact with their TME, which includes various cellular (tumor-infiltrating lymphocytes, tumor-associated macrophages, dendritic cells, myeloid-derived suppressor cells, and natural killer [NK] cells) and noncellular (vascular beds and extracellular matrix) components.6 This interaction influences tumor progression and response to treatment. The TME often suppresses antitumor activity, indicated by the scarcity of CD8+ T cells, high levels of immunosuppressive cytokines (TGF-β and IL-10), and an abundance of regulatory T cells (Tregs) and CD206+ macrophages.6 Continuous exposure of T cells to tumor antigens leads to exhaustion, reducing their cytotoxic abilities and proliferation, and expressing multiple inhibitory receptors such as PD-1, TIM-3, and LAG-3.7 Inhibitory T-cell immune checkpoint receptors like PD-1, when interacting with PD-L1, inhibit T-cell function, predicting responses to immune checkpoint inhibitors (ICIs).8,9 Tregs produce immunosuppressive cytokines (IL-10, TGF-β), express coinhibitory molecules (CTLA-4, PD-1, PD-L1), and capture IL-2, inhibiting T-cell responses and promoting tumor immune escape.7

    Not all sarcomas have the same TME composition; some are cold tumors with low tumor mutational burden and PD-L1 expression.9 The TME’s composition and behavior are determined by the genetic makeup of the sarcoma.6 Pollack’s paper “T-Cell Infiltration and Clonality Correlate With Programmed Cell Death Protein 1 and Programmed Death-Ligand 1 Expression in Patients With Soft Tissue Sarcomas” examines the TME in various STS, from simple genetic alterations like liposarcomas and synovial sarcoma to highly mutated complex alterations like undifferentiated pleomorphic sarcomas (UPS) and leiomyosarcoma.8,10The study assessed 760 genes using a NanoString platform, examined PD-1 and PD-L1 expression with immunohistochemistry, and analyzed TCR diversity and clonality using TCR-Vβ sequencing.9

    The study found that STS with complex mutations like UPS have higher PD-1/PD-L1 expression, more T-cell infiltration, higher clonality, and better responses to PD-L1 inhibitors.8,10 This is attributed to complex genetic mutations creating neoantigens that are immunogenic targets for T cells, potentially inhibited by ICIs.10,11 Higher tumor mutational burden increases the likelihood of ICI efficacy. Despite high T-cell infiltration and PD-1/PD-L1 staining, leiomyosarcoma responds poorly to checkpoint inhibitors.8,10 STS with simple mutations, like synovial sarcoma and mixed round-cell liposarcoma, show lower PD-L1 expression, fewer T-cell infiltration markers (CD3D, IL-7 receptor), fewer MHC molecules (HLA-A, HLA-DP), lower clonality, and limited responses to checkpoint inhibitors.8,10

    TCR sequencing identifies TCR diversity and clonality, with high clonality indicating a focused immune response and low clonality suggesting a less targeted response.12 Liposarcomas provided unexpected results; dedifferentiated liposarcomas showed high clonality and low fractions associated with worse outcomes.8,10 Further examination identified favorable markers like B cells and CD4, while macrophages and CD14+ monocytes were linked to poorer outcomes.8,10 Macrophages, both inflammatory (M1) and inhibitory (M2), are critical in the TME of sarcomas, with inhibitory macrophages linked to poorer outcomes in tumors like leiomyosarcoma.8,10

    Pollack also discusses the impact of radiation therapy on the TME postneoadjuvant therapy, noting an upregulation of genes related to antigen presentation, B cells, NK cells, and macrophage markers.8,13 While radiation is crucial for tumor control, it increases inhibitory macrophage populations, complicating treatment.8,13

    Enhancing Antitumor Immune Responses in Sarcoma Through Targeted Modulation of the TME

    Recently, a study on the TME of patients with sarcoma, specifically before and after neoadjuvant therapy, showed that the immune landscape post therapy had significant changes. This was mainly characterized by the increase in antigen presentation molecules such as HLA-DR, B cells, and NK cells, accompanied by an upregulation in gene expression related to antigen presentation and a notable rise in macrophage-related markers.14 While radiation therapy is considered necessary for tumor suppression/control, it was found to potentially increase the number of inhibitory macrophages within the TME.15

    To counteract the difficulty posed by inhibitory macrophages, the study investigated the use of toll-like receptor (TLR) agonists, specifically a TLR4 agonist, GLA, in combination with radiation therapy. This strategy aimed at converting inhibitory macrophages into activating macrophages, hence increasing the antitumor response.16 Results among patients with metastatic sarcoma in the phase 1 trial (NCT02180698) showed that tumors injected with the TLR4 agonist exhibited better responses than the ones treated with radiation. This suggests that TLR4 activation may enhance the effects of radiation by modifying the macrophage phenotype.17

    Surprisingly, the TLR4 agonist was not found to be associated with the TLR4 expression directly on tumor cells but rather with the activation of immune cells within the TME, which aligns with previous studies done in hematologic malignancies where TLR activation targeted immune cells rather than tumor cells.18 The patients who demonstrated strong local reactions to the combined therapy displayed elevated T-cell infiltration and clonal expansion, with
    single-cell sequencing disclosing a Th1 phenotype in expanded T-cell clones. This signifies a strong antitumor immune response. The posttreatment rise in peripheral blood mononuclear cell clonalities among those who responded also suggests systemic immune activation.19

    Additional inquiries into the matter looked at the potential of using trabectedin, along with ICIs such as pembrolizumab, to regulate macrophage activity throughout the body. Trabectedin is a substance that can effectively eliminate macrophages within tumors. It demonstrated encouraging findings among patients displaying a high M2 macrophage gene signature, indicating its double effect on both tumor cells and macrophages.20 The mixture of trabectedin and ICIs showed better progression-free survival and overall survival in patients with liposarcoma or leiomyosarcoma. The fact that higher T-cell clonalities before treatment relate to improved responses, therefore, highlights how crucial it is for an enhanced immune environment before therapy success.21

    In conclusion, the study highlights the intricate interplay between the immune landscape, therapeutic interventions, and tumor responses in patients with sarcoma. By targeting inhibitory macrophages through TLR4 agonists and trabectedin-based strategies, researchers aim to enhance antitumor immune responses and improve treatment outcomes in patients with sarcoma.

    Targeting Cancer Testis Antigens in Sarcoma Immunotherapy

    In the field of sarcoma immunotherapy, tumors expressing high levels of cancer testis antigens (CTAs) can be effectively targeted. CTAs are typically expressed at high levels in the testis, specifically in immature sperm cells located at the periphery of the seminiferous tubules, while mature sperm reside in the center. Notably, fetal organs like the fetal ovary and placenta also exhibit high CTA expression, whereas healthy tissues in children and adults, excluding the testis and placenta, do not. This makes CTAs, such as NY-ESO-1, promising targets for cancer therapies.

    Pollack’s research on synovial sarcoma revealed that all observed cases expressed NY-ESO-1, with approximately 70% showing homogeneous expression of NY-ESO-1 and other CTAs in both synovial sarcoma and myxoid/round cell liposarcoma. Although rare patients may lack NY-ESO-1 or MAGE family antigens, these findings support the potential of CTA-targeted therapies.

    CAR T cells and gene-engineered TCR T cells are central to this discussion. CAR T cells, which are FDA approved for acute lymphoblastic leukemia, leukemia, and lymphoma, target specific cell surface proteins using CD19-specific and CD20-specific constructs. These cells incorporate an SEF from an antibody, linked to molecules such as CD28 or 4-1BB, and a CD3ζ chain to activate the T cell upon target recognition. In contrast, TCR T cells identify intracellular proteins presented on the cell surface by MHC molecules, requiring specific HLA types, such as HLA-A0201. TCRs can be developed for various HLA types, though this process is costly and complex.

    In this study, Pollack cultured NY-ESO-1–specific T cells from patients’ blood. Dendritic cells pulsed with NY-ESO-1 peptide produced a population of NY-ESO-1–specific T cells, which were then used to stimulate the patients’ blood, yielding purified T-cell products for treatment.22

    A pilot study on IL-15–mediated expansion of memory T cells following adoptive cellular therapy with cyclophosphamide conditioning showed clinical benefits such as stable disease and reduction in liver and lung lesions, though progression eventually occurred.23 Sequencing revealed these T cells retained activity but lacked markers of activation and cytokine production.

    Additionally, tumors with low HLA expression pose challenges. Pollack’s team explored interferon gamma to enhance MHC and T-cell presence in tumors.24

    A pilot study demonstrated increased class I expression in over half of the patients, with some developing NY-ESO-1–specific T-cell responses.25 However, a PD-1 inhibitor trial with interferon gamma showed no response, necessitating further research.

    Interferon gamma combined with cellular therapy indicated technical progression in some patients, reducing symptoms and expressing NY-ESO-1, though class I MHC was not expressed.26 A second trial was halted due to fatal myocarditis in patients with advanced synovial sarcomas.

    Approved therapies, such as MAGE-A4 TCR therapy, are under development. Additionally, sarcomas in pet dogs, similar to human sarcomas, led Pollack’s team to create a canine CAR T cell, potentially improving cellular therapy.27

    Another study highlighted TME reprogramming via ketotifen, enhancing nanomedicine-based chemoimmunotherapy in sarcomas.28 Ketotifen reduced tumor stiffness, increased perfusion, and improved therapeutic efficacy when combined with anti–PD-1 and alendronate. This combination increased cytotoxic CD8+ and CD4+T-cell infiltration and decreased regulatory T cells, disrupting tumor-associated macrophage polarization. These findings underscore the potential of ketotifen-induced TME reprogramming to boost nanomedicine-based chemoimmunotherapy efficacy in sarcomas.

    The study highlights the potential of targeting CTAs in sarcoma immunotherapy, with NY-ESO-1 being a particularly favorable target. CAR T cells and TCR T cells offer innovative approaches, though challenges such as low HLA expression and inhibitory TME remain. Combining therapies like interferon gamma and ketotifen with cellular and ICIs shows promise in enhancing antitumor responses and improving patient outcomes. The ongoing development of new therapies, including those for canine sarcomas, highlights the dynamic nature of research in this field.

    New Developments in Sarcoma Immunotherapy

    Since the original lecture referenced in this paper, there have been notable advancements in the field of sarcoma immunotherapy. A key update is the approval of afamitresgene autoleucel, a TCR therapy, for synovial sarcoma, which was officially approved in August 2024. This approval marks a significant milestone in treatment options for this challenging sarcoma subtype, which previously lacked effective immunotherapeutic options. The approval is based on promising clinical data showing improved patient outcomes with afamitresgene autoleucel, offering hope for a more personalized and targeted approach to therapy.29 Therefore, TCR therapy is no longer just a promising treatment but a recognized and approved option for patients with synovial sarcoma. This development significantly impacts the landscape of sarcoma treatment, and it is essential for health care providers to stay informed about these advancements to guide clinical decisions.

    Additionally, recent data presented at the Connective Tissue Oncology Society (CTOS) 2024 Annual Meeting have further expanded our understanding of the TME and its role in modulating immune responses in sarcoma treatment. One important study shared at CTOS, the phase 2 EFTISARC-NEO trial (NCT06128863), has examined the effects of radiation therapy combined with trabectedin chemotherapy in patients with advanced sarcomas. Preliminary results from this trial suggest significant improvements in treatment efficacy, highlighting the potential benefits of this combination therapy in modulating the TME.30 The results underscore the importance of continuing to explore strategies that target both the tumor and its surrounding immune microenvironment, offering a potential avenue for improving patient outcomes and advancing the field of sarcoma therapy. These new data align with the growing body of research emphasizing the crucial role of TME modulation in sarcoma treatment, especially when combined with targeted therapies and immunotherapies.

    Conclusions

    Pollack’s keynote emphasized the importance of continuous learning and adaptation to stay ahead in the ever-evolving field of medicine. Effective immunotherapy, crucial for classification based on genetic alterations and tumor response, includes techniques like TCR therapy, CTA-targeting cells, and CAR T-cell therapy, which have shown results in clinical trials, offering new hope for patients with difficult-to-treat cancers. Health care professionals must stay informed about these advancements to provide the best possible care. A study on patients with sarcoma TME revealed significant changes in the immune landscape post therapy, including increased antigen presentation molecules, gene expression, and macrophage-related markers. Radiation therapy may increase inhibitory macrophages, counteracted by TLR agonists like GLA. Combining trabectedin and ICIs can improve progression-free survival. Targeting CTAs, characterized by high expression in the testis, is effective in immunotherapy for sarcomas, with CAR T cells, FDA approved for various cancers, being used to target synovial sarcomas.

    Overall, immunotherapy has shown optimistic results in treating sarcomas by targeting specific antigens, utilizing CAR T cells, and enhancing the immune response against cancer cells. The recent approval of TCR therapy further expands the options for targeting tumor-specific antigens, offering hope for patients who may not respond to traditional treatments. Combining different therapeutic approaches, such as radiation therapy and ICIs, can enhance treatment effectiveness and improve patient outcomes. Ongoing research explores the potential of combining various immunotherapeutic approaches to further improve outcomes for patients with sarcomas. These advancements in immunotherapy offer new hope for patients, providing alternative options for those who may not respond well to traditional treatments. By targeting specific antigens and enhancing the immune system’s ability to recognize and attack cancer cells, immunotherapy is revolutionizing the approach to this rare type of cancer. With more continued research and clinical trials, the future of sarcoma treatment has potential, leading to more effective and personalized therapies for patients in the years to come.

    Author Contributions

    Conceptualization, JG and HV; methodology, JG and HV; formal analysis, JG, HV, VC, AHA, KI, YL, CHP, and KB; investigation, JG, HV, VC, AHA, KI, YL, CHP, JG, HV, VC, AHA, KI, YL, and CHP; data curation, JG, HV, VC, AHA, KI, YL, and CHP; writing—original draft preparation, JG, HV, VC, AHA, KI, YL, and CHP; writing—review and editing, JG and HV; visualization, JG, HV, VC, AHA, KI, YL, and CHP; supervision, JG and HV; project administration, JG, HV, CHP, and YL. All authors jointly agree on the accuracy of this work and are in favor of submitting it for publication. All authors have read and agreed to the published version of the manuscript.

    Acknowledgments

    We thank Seth M. Pollack, MD, for the opportunity to learn from a global leader in medicine. We are grateful to be part of MedNews Week. We would like to express our sincere gratitude to Jill Gregory for her invaluable assistance in significantly improving the figures of this manuscript.

    Conflicts of Interest

    The authors declare no conflicts of interest.

    References

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    2. Skubitz KM, D’Adamo DR. Sarcoma. Mayo Clin Proc. 2007;82(11):1409-1432. doi:10.4065/82.11.1409
    3. von Mehren M, Kane JM, Agulnik M, et al. Soft tissue sarcoma, version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(7):815-833. doi:10.6004/jnccn.2022.0035
    4. Jain S, Xu R, Prieto VG, Lee P. Molecular classification of soft tissue sarcomas and its clinical applications. Int J Clin Exp Pathol. 2010;3(4):416-428.
    5. Wang L, Geng H, Liu Y, et al. Hot and cold tumors: immunological features and the therapeutic strategies. MedComm (2020). 2023;4(5):e343. doi:10.1002/mco2.343
    6. Jumaniyazova E, Lokhonina A, Dzhalilova D, Kosyreva A, Fatkhudinov T. Immune cells in the tumor microenvironment of soft tissue sarcomas. Cancers (Basel). 2023;15(24):5760. doi:10.3390/cancers15245760
    7. Ando M, Ito M, Srirat T, Kondo T, Yoshimura A. Memory T cell, exhaustion, and tumor immunity. Immunol Med. 2020,43(1):1-9. doi:10.1080/25785826.2019.1698261
    8. Pollack SM. Altering the sarcoma immune microenvironment for effective therapy. Presented at: MedNews Week Keynote Conference;May 27, 2023. Accessed February 2025. Videocast available at: https://tinyurl.com/2nr64mvu
    9. Anastasiou M, Kyriazoglou A, Kotsantis I, et al. Immune checkpoint inhibitors in sarcomas: a systematic review. Immunooncol Technol. 2023;20:100407. doi:10.1016/j.iotech.2023.100407
    10. Pollack SM, He Q, Yearley JH, et al. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas. Cancer. 2017;123(17):3291-3304. doi:10.1002/cncr.30726
    11. Yi M, Qin S, Zhao W, Yu S, Chu Q, Wu K. The role of neoantigen in immune checkpoint blockade therapy. Exp Hematol Oncol. 2018;7:28. doi:10.1186/s40164-018-0120-y
    12. Aran A, Garrigós L, Curigliano G, Cortés J, Martí M. Evaluation of the TCR repertoire as a predictive and prognostic biomarker in cancer: diversity or clonality? Cancers (Basel). 2022;14(7):1771. doi:10.3390/cancers14071771
    13. Goff PH, Riolobos L, LaFleur BJ, et al. Neoadjuvant therapy induces a potent immune response to sarcoma, dominated by myeloid and B cells. Clin Cancer Res. 2022;28(8):1701-1711. doi:10.1158/1078-0432.CCR-21-4239
    14. Smith C, Corvino D, Beagley L, et al. T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical response. J Clin Invest. 2019;129(11):5020-5032. doi:10.1172/JCI128323
    15. Anagnostou V, Smith KN, Forde PM, et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 2017;7(3):264-276. doi:10.1158/2159-8290.CD-16-0828
    16. Achard C, Surendran A, Wedge ME, Ungerechts G, Bell J, Ilkow CS. Lighting a fire in the tumor microenvironment using oncolytic immunotherapy. EBioMedicine. 2018;31:17-24. doi:10.1016/j.ebiom.2018.04.020
    17. Seo YD, Lu H, Black G, et al. Toll-like receptor 4 agonist injection with concurrent radiotherapy in patients with metastatic soft tissue sarcoma: a phase 1 nonrandomized controlled trial. JAMA Oncol. 2023;9(12):1660-1668. doi:10.1001/jamaoncol.2023.4015
    18. Simon Davis DA, Mun S, Smith JM, et al. Machine learning predicts cancer subtypes and progression from blood immune signatures. PLoS One. 2022;17(2):e0264631. doi:10.1371/journal.pone.0264631
    19. Caushi JX, Zhang J, Ji Z, et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature. 2021;596(7870):126-132. doi:10.1038/s41586-021-03752-4
    20. Kyi C, Postow MA. Immune checkpoint inhibitor combinations in solid tumors: opportunities and challenges. Immunotherapy. 2016;8(7):821-837. doi:10.2217/imt-2016-0002
    21. Leng D, Yang Z, Sun H, et al. Comprehensive analysis of tumor microenvironment reveals prognostic ceRNA network related to immune infiltration in sarcoma. Clin Cancer Res. 2023;29(19):3986-4001. doi:10.1158/1078-0432.CCR-22-3396
    22. Jungbluth AA, Chen YT, Stockert E, et al. Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues. Int J Cancer. 2001;92(6):856-860. doi:10.1002/ijc.1282
    23. Kohli K, Yao L, Nowicki TS, et al. IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy. J Immunother Cancer. 2021;9(5):e002232. doi:10.1136/jitc-2020-002232
    24. Mitchell G, Pollack SM, Wagner MJ. Targeting cancer testis antigens in synovial sarcoma. J Immunother Cancer. 2021;9(6):e002072. doi:10.1136/jitc-2020-002072
    25. Zhang S, Kohli K, Black RG, et al. Systemic interferon-γ increases MHC class I expression and T-cell infiltration in cold tumors: results of a phase 0 clinical trial. Cancer Immunol Res. 2019;7(8):1237-1243. doi:10.1158/2326-6066.CIR-18-0940
    26. Schroeder BA, Black RG, Spadinger S, et al. Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy. J Immunother Cancer. 2020;8(1):e000247. doi:10.1136/jitc-2019-000247
    27. Zhang S, Black RG, Kohli K, et al. B7-H3 specific CAR T cells for the naturally occurring, spontaneous canine sarcoma model. Mol Cancer Ther. 2022;21(6):999-1009. doi:10.1158/1535-7163.MCT-21-0726
    28. Charalambous A, Mpekris F, Panagi M, et al. Tumor microenvironment reprogramming improves nanomedicine-based chemo-immunotherapy in sarcomas. Mol Cancer Ther. 2024;23(11):1555-1567. doi:10.1158/1535-7163.MCT-23-0772
    29. Winstead E. FDA approves engineered cell therapy for advanced synovial sarcoma. National Cancer Institute. August 27, 2024. Accessed March 20, 2025. https://tinyurl.com/39nfmdch
    30. Sobczuk P, Rogala P, Mariuk-Jarema A, et al. Preliminary results from the phase 2 EFTISARC-NEO trial of neoadjuvant soluble LAG-3 protein eftilagimod alpha, pembrolizumab, and concurrent radiotherapy in patients with resectable soft tissue sarcoma. Presented at: Connective Tissue Oncology Society 2024 Annual Meeting; November 13-16, 2024; San Diego, CA.

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  • Metformin Fails to Improve Survival in Metastatic Hormone-Sensitive Prostate Cancer

    Metformin Fails to Improve Survival in Metastatic Hormone-Sensitive Prostate Cancer

    Prostate cancer under the microscope: © heitipaves – stock.adobe.com

    A large-scale, randomized, phase 3 trial, part of the STAMPEDE (NCT00268476) platform, has found that adding metformin to standard-of-care treatment in nondiabetic patients with metastatic hormone-sensitive prostate cancer (mHSPC) did not significantly improve overall survival (OS).1

    While the widely used antidiabetic agent did reduce adverse metabolic effects associated with androgen-deprivation therapy (ADT), its primary end point of improved OS was not met in the overall study population.

    These findings provide crucial evidence regarding the utility of metformin in this patient cohort, particularly given previous preclinical data and smaller studies suggesting potential anticancer activity.

    Study Design and Patient Cohort

    The STAMPEDE trial, conducted across 112 hospitals in the United Kingdom and Switzerland, recruited patients with high-risk locally advanced or metastatic adenocarcinoma of the prostate.1,2 This specific analysis focused on nondiabetic patients with metastatic disease, adequate renal function, and a WHO performance status of 0 to 2. Patients were randomized 1:1 to receive either standard of care or standard of care plus metformin 850 mg twice daily. Standard of care typically included ADT, with or without radiotherapy, and with or without docetaxel or an androgen receptor pathway inhibitor (ARPI) such as abiraterone (Zytiga), enzalutamide (Xtandi), or apalutamide (Erleada).

    Between September 5, 2016, and March 31, 2023, a total of 1874 patients with metastatic disease were randomized.1 The median age was 69 years, and the median prostate-specific antigen (PSA) level at baseline was 84 ng/mL. A substantial majority of patients (94%) had newly diagnosed metastatic disease, and 82% received ADT plus docetaxel.

    No Overall Survival Benefit Observed

    The primary end point was OS. After a median follow-up of 60 months, 473 deaths were reported in the standard-of-care group, with a median survival of 61.8 months. In the metformin group, 453 deaths were reported, with a median survival of 67.4 months. The hazard ratio (HR) for OS for the metformin group compared with standard of care was 0.91 (95% CI, 0.80–1.03; P =.15), indicating no statistically significant improvement in overall survival with the addition of metformin.

    Similarly, there was no evidence of an effect on prostate cancer-specific survival in the overall population (HR, 0.97; 95% CI, 0.85–1.12; P =.70). Progression-free survival (PFS) and failure-free survival also showed no significant overall benefit.

    Potential Benefit in High-Volume Disease

    While the overall population did not demonstrate a survival benefit, a prespecified subgroup analysis explored the impact of metformin based on metastatic disease volume, categorized by CHAARTED criteria. In patients with high-volume disease, the HR for OS was 0.79 (95% CI, 0.67–0.94; P =.0072) favoring metformin. Conversely, for patients with low-volume disease, the HR was 0.98 (range, 0.78–1.23; P =.87). Although the P-value for interaction was 0.12, which did not meet strict statistical significance for heterogeneity, this finding warrants further investigation into whether a subset of patients with more aggressive disease might derive some oncological benefit. A similar trend was observed for PFS and metastatic PFS in the high-volume disease subgroup.

    Mitigating Metabolic Adverse Effects of ADT

    A significant secondary finding of the study was metformin’s ability to mitigate the adverse metabolic effects commonly associated with ADT. Patients in the metformin group experienced significantly less weight gain compared with the standard-of-care group. At 104 weeks, patients on standard of care gained a mean of 4.40 kg, while those on metformin gained a mean of 2.00 kg (mean difference, –2.48 kg; 95% CI, –3.55 to –1.41; P <.0001).

    Metformin also led to statistically significant improvements in changes from baseline for fasting glucose, total cholesterol, LDL cholesterol, and HbA1c. These metabolic benefits were consistent across various time points (24, 48, and 104 weeks).

    Safety Profile

    PC-3 human prostate cancer cells: © heitipaves – stock.adobe.com

    The safety profile of metformin was consistent with its known effects. Grade 3 or worse adverse events were reported in 57% of patients in the metformin group compared with 52% in the standard of care group. The most notable difference was in gastrointestinal adverse events, which were more common with metformin. Diarrhea was reported by 65% of patients in the metformin group vs 37% in the standard-of-care group, with grade 3 diarrhea occurring in 5% and 3% of patients, respectively. Nausea was also more frequent in the metformin arm. Other body systems showed no significant differences in grade 3 or worse adverse events. There was 1 drug-related death in the metformin group compared with 6 in the standard-of-care group.

    Implications for Clinical Practice

    The results of the STAMPEDE trial, the first large-scale randomized study of its kind in this population, do not support the routine addition of metformin to the standard of care for all nondiabetic patients with mHSPC for the purpose of improving OS. However, the observed metabolic benefits are noteworthy, as ADT-induced metabolic changes, including weight gain and increased cardiovascular risk, are significant concerns for patients.

    “[The] addition of metformin to standard of care produced clear metabolic benefits irrespective of disease volume, inducing significant and sustained reductions in circulating glucose and HbA1c and total cholesterol and LDL cholesterol concentrations,” study authors wrote. “Additionally, metformin significantly reduced clinically relevant weight gain induced by systemic treatment with ADT. These findings are novel and represent a substantial and potentially valuable treatment benefit for men with this lethal form of prostate cancer. Use of metformin as a supplement to ADT-based standard of care will have to be weighted against side effects, namely [diarrhea].”

    The intriguing signal of potential anticancer effect in patients with high-volume disease warrants further exploration. This may suggest that a more tailored approach, perhaps based on disease characteristics or specific biomarkers, could identify a subset of patients who might benefit from metformin beyond its metabolic effects. Ongoing research stemming from the STAMPEDE platform, including a metabolic substudy, aims to delve deeper into these mechanisms and identify optimal patient selection.

    REFERENCES:
    1. Gillessen S, Murphy L, James ND, et al. Metformin for patients with metastatic prostate cancer starting androgen deprivation therapy: a randomised phase 3 trial of the STAMPEDE platform protocol. Lancet Oncol. 2025 Jul 7:S1470-2045(25)00231-1. doi: 10.1016/S1470-2045(25)00231-1. Online ahead of print.
    2. Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE). ClinicalTrials.gov. Updated April 18, 2023. Accessed July 25, 2025. https://clinicaltrials.gov/study/NCT00268476

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  • NIH researchers develop AI agent that improves accuracy of gene set analysis by leveraging expert-curated databases

    NIH researchers develop AI agent that improves accuracy of gene set analysis by leveraging expert-curated databases

    Monday, July 28, 2025

    Researchers at the National Institutes of Health (NIH) have developed an artificial intelligence (AI) agent powered by a large language model (LLM) that creates more accurate and informative descriptions of biological processes and their functions in gene set analysis than current systems.

    The system, called GeneAgent, cross-checks its own initial predictions—also known as claims—for accuracy against information from established, expert-curated databases and returns a verification report detailing its successes and failures. The AI agent can help researchers interpret high-throughput molecular data and identify relevant biological pathways or functional modules, which can lead to a better understanding of how different diseases and conditions affect groups of genes individually and together.

    AI-generated content is produced by LLMs trained on enormous amounts of text data from across the internet. LLMs use those data to recognize patterns and predict what words might follow each other in a sentence. However, LLMs are not designed to verify truth, meaning AI-generated content can be false, misleading, or fabricated, a phenomenon called AI hallucinations. Additionally, LLMs are prone to circular reasoning—fact-checking their generated results against their own data—which makes them sound more confident in the output even when the information is false.

    Staving off AI hallucinations is important when using LLM tools for gene set analysis—the process of generating collective functional descriptions of grouped genes and their potential interactions. Previous studies that taught LLMs to answer genomic questions or summarize biological processes in a given gene set did not explicitly address hallucinations in the generated content.

    GeneAgent mitigates this issue by taking its own claims and independently comparing them to established knowledge compiled in external, expert-curated databases. The research team first tested GeneAgent on 1,106 gene sets sourced from existing databases with known functions and process names. For each gene set, GeneAgent first generated an initial list of functional claims. It then independently used its self-verification agent module to cross-check these claims against the curated databases and create a verification report that noted whether each of its claims was supported, partially supported, or refuted.

    To best determine its accuracy in the self-verification step, the researchers next brought in two human experts to manually review 10 randomly selected gene sets with a cumulative 132 claims and judge whether GeneAgent’s self-verification reports were correct, partially correct, or incorrect. Of the self-verification reports generated by GeneAgent, the experts determined that 92% of its decisions were correct, indicating high performance in its ability to conduct self-verification, especially when compared to GPT-4. Their detailed review confirmed the model’s effectiveness in minimizing hallucinations and generating more reliable analytical narratives.

    The research team also looked at real-world application of GeneAgent on animal-model gene sets. When applied to seven novel gene sets derived from mouse melanoma cell lines, GeneAgent was able to offer valuable insight into novel functionalities for specific genes. This could mean knowledge discovery for things such as potential new drug targets for diseases like cancer.

    While LLMs such as GeneAgent are still limited by the information they can use and their inability to reason as humans, GeneAgent’s ability for self-driven fact-checking shows remarkable promise in mitigating AI hallucinations.

    About the National Library of Medicine (NLM): NLM is a leader in research in biomedical informatics and data science and the world’s largest biomedical library. NLM conducts and supports research in methods for recording, storing, retrieving, preserving, and communicating health information. It creates resources and tools that are used billions of times each year by millions of people to access and analyze molecular biology, biotechnology, toxicology, environmental health, and health services information. Additional information is available at https://www.nlm.nih.gov.

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

    NIH…Turning Discovery Into Health®

    ​​​​​​​Reference

    Wang, Z., Jin, Q., Wei, CH. et al. GeneAgent: self-verification language agent for gene-set analysis using domain databases. Nat Methods (2025). https://doi.org/10.1038/s41592-025-02748-6

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