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SAN ANTONIO – Adding tucatinib (Tukysa) to first-line maintenance therapy with trastuzumab (Herceptin) and pertuzumab (Perjeta) delayed disease progression in patients with HER2-positive metastatic breast cancer, potentially extending time off chemotherapy, according to results from the phase III clinical trial HER2CLIMB-05 presented at the San Antonio Breast Cancer Symposium (SABCS), held December 9-12, 2025.
The results of this study were simultaneously published in the Journal of Clinical Oncology.
HER2-positive breast cancer accounts for approximately 17% of all breast cancer cases and is associated with a five-year survival rate of less than 50% for patients with metastatic disease. Since 2012, the first-line treatment for HER2-positive metastatic breast cancer has remained largely unchanged, consisting of chemotherapy followed by maintenance therapy with dual anti-HER2 monoclonal antibodies, said Erika Hamilton, MD, director of Breast Cancer Research at Sarah Cannon Research Institute (SCRI) in Nashville. Currently, most patients experience disease progression within two years of starting treatment and often have to transition to chemotherapy. “The results of our study show that the addition of tucatinib to the standard of care represents an enhanced first-line maintenance therapy option for patients with HER2-positive metastatic breast cancer, providing an opportunity to prolong time to disease progression and time off chemotherapy,” said Hamilton, who presented this study.
Tucatinib, a selective inhibitor of HER2, has previously shown efficacy in later lines of therapy, including in patients with brain metastases, according to the results from the HER2CLIMB study, Hamilton said. Based on this, the U.S. Food and Drug Administration approved this drug in 2020 for treatment of unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least one prior therapy. “The HER2CLIMB-05 trial was initiated to investigate the efficacy of tucatinib in a first-line maintenance setting in patients with HER2-positive metastatic breast cancer who completed chemotherapy-based induction therapy without disease progression,” she said. “We also wanted to assess whether targeting HER2 both intracellularly, with tucatinib, and extracellularly, with dual blockade with monoclonal antibodies, may potentially improve patient outcomes,” she added.
The trial enrolled 654 patients with HER2-positive advanced breast cancer who had completed four to eight cycles of induction chemotherapy plus trastuzumab and pertuzumab, without disease progression. The patients were randomly assigned to receive either tucatinib or a placebo alongside continued trastuzumab and pertuzumab.
At a median follow-up of 23 months, the patients who received tucatinib had a progression-free survival (PFS) of over two years—an improvement of 8.6 months compared with the patients in the control arm.
Patients with hormone receptor (HR)-negative disease experienced a 44.6% reduction in risk of progression or death, with a 12.3-month improvement in median PFS. Those with HR-positive disease saw a 27.5% reduction in risk of progression or death and a 6.9-month improvement in median PFS.
Among the 12.2% of patients with brain metastases at baseline, tucatinib nearly doubled the median central nervous system-PFS, which is the time taken for the cancer to progress to the brain or death from any cause—from 4.3 months to 8.5 months. “Central nervous system-PFS was a secondary endpoint and this finding is preliminary,” cautioned Hamilton, adding that 54% of the patients in the tucatinib arm remained on study treatment at the data cutoff of this analysis.
These findings suggest that tucatinib may offer broad benefits across diverse patient subgroups, Hamilton said. She emphasized the importance of enhancing HER2 targeting during the maintenance phase, rather than waiting for disease progression. “Prolonging the maintenance phase allows patients to maintain disease control, while extending their time off chemotherapy,” she said. She noted that the results of the HER2CLIMB-05 trial, alongside recent data from the PATINA trial—where incorporating palbociclib (Ibrance) into the treatment regimen for HR-positive, HER2-positive metastatic breast cancer showed a 15-month improvement in PFS—support a shift toward more personalized first-line maintenance strategies for this patient population.
A limitation of this study is the exclusive enrollment of patients who had not progressed after induction therapy, potentially introducing selection bias, Hamilton explained. Another limitation is that the differences in brain imaging frequency and the cessation of routine imaging after systemic progression may have affected the accuracy of central nervous system-PFS assessments.
The study was funded by Seagen, which was acquired by Pfizer in December 2023. Hamilton holds consulting and advisory roles with Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis GmbH, Verascity Science, Theratechnologies, Accutar Biotech, Entos, Fosun Pharma, Gilead Sciences, Jaxx Pharmaceuticals, MphaR, Zentalis, Jefferies, and Tempus. She has received research funding from AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, StemcentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix/Inspirna, Novartis, Mersana, Millennium, TapImmune Inc./Marker Therapeutics, Lilly, Pfizer Inc., Tesaro, Boehringer Ingelheim, H3 Biomedicine/Eisai, Radius Health, Acerta Pharma, MacroGenics, AbbVie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, NuCana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Sutro Biopharma, Zenith Epigenetics, Arvinas, Harpoon Therapeutics, Black Diamond Therapeutics, Orinove, Molecular Templates, Seagen, Compugen, G1 Therapeutics, Karyopharm Therapeutics, Dana-Farber Cancer Institute, Onconova Therapeutics, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, ImmunoGen, Plexxikon, Amgen, Akeso Biopharma, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicines, Treadwell Therapeutics, Jacobio Pharma, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque Therapeutics, BeiGene/BeOne Medicines, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology/Lilly, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, ProfoundBio, Cullinan Oncology/Cullinan Therapeutics, Bristol Myers Squibb, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, and Stemline Therapeutics.
SAN ANTONIO – Patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancers had similar progression-free survival (PFS) whether they were treated with sacituzumab govitecan-hziy (Trodelvy) or standard-of-care chemotherapy as the first treatment after endocrine therapy, according to results from the phase III ASCENT-07 clinical trial presented at the San Antonio Breast Cancer Symposium (SABCS), held December 9-12, 2025.
“HR-positive, HER2-negative breast cancers are typically treated with first-line endocrine therapy, but treatment resistance is common,” said Komal Jhaveri, MD, the Patricia and James Cayne chair for junior faculty; associate attending, Breast Medicine and Early Drug Development Services; and section head of the Endocrine Therapy Research Program at Memorial Sloan Kettering Cancer Center.
“In cases where HR-positive, HER2-negative, metastatic breast cancer has become refractory to endocrine therapy, chemotherapy remains a common standard,” she explained. “Chemotherapy agents have shown marginal survival benefit but are associated with numerous toxicities that can be severe and long-lasting. Therefore, there remains a high unmet need in this setting for additional effective treatments.”
Sacituzumab govitecan-hziy is an antibody-drug conjugate that targets the TROP-2 protein found on the surface of most breast cancer cells to deliver a cytotoxic agent to these cells, as well as to neighboring cells within the tumor microenvironment. One of the therapeutic’s approved indications is for patients with HR-positive, HER2-negative advanced breast cancers that have progressed on or after endocrine therapy and chemotherapy. The approval was based on statistically significant and clinically meaningful PFS and overall survival (OS) data from the phase III TROPiCS-02 clinical trial, said Jhaveri. In that study, patients treated with sacituzumab govitecan-hziy after two or more lines of chemotherapy had a 34% lower risk of disease progression or death and a 3.2-month improvement in OS compared with those treated with another line of chemotherapy.
Those results led Jhaveri and colleagues to ask whether sacituzumab govitecan-hziy would also be beneficial earlier in the treatment course—for patients who had received endocrine therapy but who had not yet been treated with chemotherapy.
To test this, they conducted the ASCENT-07 trial, which enrolled 690 patients with HR-positive, HER2-negative advanced breast cancers who had received prior endocrine therapy and who were candidates for first chemotherapy. Patients were randomly assigned (2:1) to receive either sacituzumab govitecan-hziy or standard-of-care chemotherapy.
The ASCENT-07 trial did not meet its primary endpoint of improved PFS by blinded independent central review. After a median follow-up of 15.4 months, the median PFS was 8.3 months in both arms with a hazard ratio of 0.85.
While data on OS were not mature at the time of this primary analysis, Jhaveri noted that preliminary results suggest a potentially lower risk of death among patients treated with sacituzumab govitecan-hziy. “It will be critical that we continue to follow patients for overall survival to better understand the potential long-term impact of sacituzumab govitecan-hziy in this treatment setting,” she added.
The rates of treatment response were similar between the arms, but numerically higher for patients treated with sacituzumab govitecan-hziy, with 37% of patients experiencing responses to sacituzumab govitecan-hziy and 33% to chemotherapy. The median duration of response was numerically longer with sacituzumab govitecan-hziy than with chemotherapy (12.1 months vs. 9.3 months).
According to Jhaveri, the toxicities associated with sacituzumab govitecan-hziy in this trial were consistent with those observed in previous breast cancer studies. In both arms, the most common grade 3 or higher treatment-related adverse events were neutropenia and leukopenia, with both of these occurring at higher rates among patients treated with sacituzumab govitecan-hziy. Treatment-related adverse events that led to treatment discontinuation were observed in approximately 3% of patients in the sacituzumab govitecan-hziy and 7% in the chemotherapy arm.
“While our study did not meet its primary endpoint of PFS for patients who have not yet received chemotherapy, sacituzumab govitecan-hziy remains a standard of care for HR-positive, HER2-negative metastatic breast cancers after prior endocrine therapy and chemotherapy based on the PFS and overall survival results seen in the TROPiCS-02 study,” said Jhaveri.
“HR-positive, HER2-negative metastatic breast cancer is a highly heterogeneous disease, and this complexity makes it particularly challenging to manage, especially in patients whose disease has already progressed on multiple lines of endocrine therapy,” she added.
The study did not compare the efficacy of sacituzumab govitecan-hziy with trastuzumab deruxtecan (T-DXd; Enhertu), a HER2-targeted antibody-drug conjugate that is now approved for some HR-positive, HER2-negative breast cancers that express enough HER2 to be considered “HER2-low” or “HER2-ultralow.” T-DXd was not approved to treat HER2-low and -ultralow breast cancers in the chemotherapy naïve setting until after enrollment for the ASCENT-07 trial had closed.
“The ASCENT-07 study design and choice of comparator was aligned with treatment guidelines for this line of treatment and disease setting at the time of study planning and conduct,” Jhaveri noted.
The study was sponsored by Gilead Sciences. Jhaveri reports consulting and/or advisory board roles with Novartis, Pfizer, Genentech, Eisai Co., AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Menarini/Stemline Therapeutics, Gilead Sciences, Scorpion Therapeutics/Lilly, Bicycle Therapeutics, Olema Pharmaceuticals, Lilly/Loxo Oncology, Merck, Zymeworks, Halda Therapeutics, Arvinas, and RayzeBio. Jhaveri reports research funding to her institution from Novartis, Genentech, AstraZeneca, Pfizer, Lilly/Loxo Oncology, Zymeworks, Gilead Sciences, Puma Biotechnology, Merck, Scorpion Therapeutics, RayzeBio, Eisai Co., Bicycle Therapeutics, BridgeBio Oncology Therapeutics, and Blueprint Medicines.
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Christmas shopping – some love it, to others it’s a chore and this year for the first time many of us will outsource the annual task of coming up with gift ideas to artificial intelligence.
While traditional internet search, social media – especially TikTok and Instagram – and simply wandering a local high street will still be the main routes to presents for most this year, about a quarter of people in the UK are already using AI to find the right products, according to PricewaterhouseCoopers.
For brands appealing to younger people, the revolution is well under way: the rival advisory firm KPMG says as many as 30% of shoppers aged 25-34 are using AI to find products, compared with 1% of those aged over 65.
Asking a large language model (LLM) such as ChatGPT or Gemini what you should get your father-in-law – rather than typing “whisky” or “socks” into Google or DuckDuckGo – may seem a small change in habits. However, it marks a sea change for retailers accustomed to paying search engines to promote their listings.
LLMs allow users to ask questions in conversational language, perhaps by speaking into their computer or phone. Instead of just providing a list of links, they offer specific suggestions with the potential for big sales for items that are regularly recommended.
The chatbots produce their responses by scraping the internet and inbuilt datasets for relevant information, with some sources given more trusted status than others.
Companies large and small are scrambling to adapt to this new world where the keywords and advertising deals previously central to web marketing hold less importance than the reviewers’ opinions, accurate availability information and product details read by LLMs such as OpenAI’s ChatGPT, Google’s Gemini and Meta’s Llama.
The shake-up may create an opening for independent businesses to cut through online, but some big brands are concerned they will be lost in a wild west where it is unclear how to reach the consumer. Marketers must now appeal not only to shoppers directly but also to their AI bots.
“Retailers can’t buy their way into the search – they have to earn it,” says Emma Ford, the director of digital transformation for PwC UK. “The experience, expertise, authenticity and trustworthiness [of a brand online] help. Sentiment across the internet is really important.”
Several large UK retailers have told the Guardian they already have teams on the case looking at a wide variety of tactics, from making sure they appear in Reddit forums – a key source for some platforms – to responding to reviews on Google or Trustpilot, and ensuring AI models can access the correct product data.
While some say they are being cautious with resources, amid signs certain individual LLMs could disappear as rapidly as they have sprung up, the belief is that this new way of interacting online is here to stay.
Nickyl Raithatha, the chief executive of the online card and gift seller Moonpig, says AI search’s relevance for companies this year is relatively low but his company is well-prepared for rapid change.
He says Moonpig is ensuring its products are picked up in AI search by using generative engine optimisation (GEO) techniques such as “online content with people discussing the best way to make someone happy on Mothers Day” in its own content or on discussions boards and in YouTube videos. He adds: “There is a growing science around this and we are all learning.”
Ford says businesses are still feeling their way into the nuances of how the technology will find and respond to their online presence. Online reviews, for example, are clearly a factor in AI decision-making, but it is not clear how much importance is placed on particular platforms or how they rank against other factors such as reliable availability data, longevity of a brand or secure payment options.
It may be that suppliers that have been around longer and have a broader profile are foregrounded, but their long history of ups and downs could also play against them.
“I do think AI will change retail for the next 20 years,” says Peter Ruis, the managing director of John Lewis. He contends that established brands such as his will benefit from having a strong reputation with the technology in place to sell online, while shoppers could discover they stock items previously assumed to have been available only at a specialist.
In future, industry watchers believe, ChatGPT, Amazon and Google are likely to try to monetise their AI platforms with some form of paid search or featured ads.
More sophisticated “AI agent” models are also being developed – bots that can autonomously perform complex multistage tasks such as seeking out the best deals, placing orders and organising delivery.
For example, it could be possible for these digital secretaries to negotiate offers tailored to particular customers, such as bundling together a number of furniture purchases from various outlets during a move, which have been customised to fit budget, style and delivery preferences, according to the advisory firm McKinsey.
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That could lead retailers into allowing their systems to flex product prices to attract particular searchers.
Organising the return of an unwanted item could also be taken on by AI agents, with one acting on behalf of the shoppers and the other for the retailer.
However, such technology is fraught with potential pitfalls. Retailers will need systems that can cope with a potential flurry of queries and to have clear rules on who might be responsible for glitches such as unwanted purchases made by a bot.
In the US, the online marketplace Etsy was the first to team up with ChatGPT to make it possible to pay for goods via the LLM’s instant checkout service. The e-commerce platform Shopify and the retailers Walmart and Target swiftly followed. While the deals do not appear to prioritise their products in searches, the inclusion of a “buy” button for their goods could put them ahead of the pack.
Anna Bancroft, a partner in PwC’s digital transformation team, points out that under current UK rules it is not possible for an AI bot to make a purchase on behalf of a human, and regulation would need to change for such systems to run without human oversight. She says retailers and shoppers are cautious about giving the robots access to customer data and handling payment.
There are also concerns about agents being susceptible to manipulation, as Microsoft has found in research simulations. Meanwhile, tech retail players are becoming territorial about who gets to crawl whose data.
Last month, Amazon sued the AI company Perplexity over its shopping feature that automates placing orders for users. Amazon accused the startup of covertly accessing customer accounts and disguising AI activity as human browsing. Perplexity hit back, defending users’ right to delegate their shopping to AI agents and calling the suit “a bully tactic to suppress competition”.
In this rapidly shifting landscape, Ford suggests independent retailers may have a chance to shine. “Independents have potential to go faster,” she says, with the ability to respond nimbly without having to sign off large budgets.
Michelle Ovens, the founder of Small Business Britain, which advises independent retailers on how to survive on the changing high street, agrees. “[Independent businesses] don’t necessarily need to spend a lot of money. You don’t necessarily need a big team,” she says.
Ovens advises local shopkeepers to ask AI platforms themselves how best to make sure they can appear. “Be clear about who you are,” she says, with a description making clear that you are an independent specialist, up-to-date pictures and “encourage customers who have got experience of the brand to give a good review”.
However, all of this should not stand ahead of making a website engaging and easy to shop on, Ovens adds. “There will not be a dramatic shift this Christmas. We’ll see change over time and operators will rise to the challenge.”
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