BIOMEDICA CRO’s Post

Imagine undergoing cancer treatment and not knowing whether the regimen keeps truly helping you. It is exactly this dilemma that we address in this 'comment and controversies' article published in the Journal of Clinical Oncology. The work was created through an international collaborative group composed of oncologists, cancer researchers, trialists, and pathologists. Notably, one of the authors offers her concrete lived patient perspective which exemplifies the real-world impact of this complex topic – thank you for sharing this: a must read. Briefly, in trials like KEYNOTE-522, the benefits of pre-surgery (neoadjuvant) versus post-surgery (adjuvant) pembrolizumab for event-free survival (EFS) in early-stage diseases remain unclear due to trial designs that do not re-randomize patients after surgery. Current guidelines recommend continuing pembrolizumab after surgery, even though the (post-surgery) benefits are uncertain. Evidence suggests neoadjuvant immunotherapy may be more effective, as shown in melanoma and TNBC trials. However, biomarker research, crucial for predicting who benefits from treatments like pembrolizumab, is hindered by limited tissue access for analysis. This challenge might arise from pharmaceutical companies' reluctance to identify markers that could exclude large patient groups. Effective markers could tailor treatments better, but establishing such approaches is still needed. Tumor-infiltrating lymphocytes (TILs) are promising markers. We provide an outline of these challenges and strategies for optimizing immunotherapy for patients with TNBC. Addressing these issues requires balancing broad trial designs for regulatory approval with detailed, patient-specific information, which regulatory agencies should mandate. Encouraging trials for specific subgroups and refining treatment phases could reduce unnecessary treatments and costs. Marleen Kok, Robbert-Jan Gielen, Sylvia Adams, Priyanka Sharma, Prof. Dr. med. Sibylle Loibl, Erin Reardon, Gabe Sonke, Sabine Linn, Suzette Delaloge, Denis Lacombe Tim Robinson, Sunil Badve, Miguel Martín Justin Balko Michail Ignatiadis Giuseppe Curigliano Antonio C. Wolff Elizabeth Mittendorf Sherene Loi Lajos Pusztai Sara Tolaney and Roberto Salgado Link to pubmed: https://lnkd.in/esFhpDzj Link to Article: https://lnkd.in/eQG9RuFm DOI: 10.1200/JCO.24.00372 #FDA #biomarker #regulatory #drugdevelopment #cancerresearch #Keynote #pembrolizumab #ASCO #JCO #precisiononcology #precisionmedicine #oncology #breastcancer BostonGene The Netherlands Cancer Institute NYU Breast Center Gustave Roussy EORTC - European Organisation for Research and Treatment of Cancer Emory Pathology Instituto de Investigación Sanitaria Gregorio Marañón Vanderbilt University Medical Center Université libre de Bruxelles Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Johns Hopkins Medicine Dana-Farber Cancer Institute Peter MacCallum Cancer Centre Yale Cancer Center

【World's 1st study on treatment of immunotherapy-resistant liver cancer】Immunotherapy is frequently used to combat advanced stage liver cancer that cannot be removed by surgery. However, even with a good initial response, over 80% of patients will subsequently develop resistance to immunotherapy after around seven months of treatment. Finding treatment alternatives for people who are resistant to immunotherapy for liver cancer has been a hot topic of research globally. Two recent studies published by CU Medicine not only contribute to prolonging the lives of liver cancer patients but also provide invaluable data for reference by clinicians and guidelines on liver cancer treatment. CU Medicine collaborated with two research sites in South Korea and conducted the world's first clinical trial to explore the use of a targeted drug in the treatment of immunotherapy-resistant liver cancer. The results showed that the disease at least partly stabilised in over 80% of patients after they started treatment with the targeted agent, with a median survival of 14.3 months. Additionally, the research team also investigated the use of radiotherapy on liver cancer patients who had developed resistance to immunotherapy. They found that the addition of radiotherapy to patients with limited cancer volume in the liver could survive for a median period of 24.5 months without any significant side effects. This is the first case series of patients on whom radiotherapy has been used in the treatment of liver cancer after immunotherapy had failed. The study has been presented at multiple international meetings and recently published in the Journal of Hepatology . Details: https://bit.ly/3vHFywJ Research articles: https://bit.ly/3U6slXy https://bit.ly/3U2uUtU #CUMedicine #LiveCancer #ImmunotherapyResistant #Treatment

💡 New Insights 💡 DRIA signature predicting gastrointestinal cancer therapy response #Gastrointestinal (GI) cancer poses a serious health risk, with a global incidence of 26% and mortality of 35%. Although various treatments including surgery and chemotherapy have been implemented, these have not yielded satisfactory outcomes. The exploration of immune checkpoint inhibitors (ICI) that target specific signalling of #PD-1/PD-L1 has played a significant role as a therapy option for advanced esophagogastric and colorectal #cancer, however this needs to be optimised for GI cancer.   Genomic instability, often caused by increased accumulation of damaged DNA as well as DNA Damage response (DDR) deficiency, is a hallmark trait of cancers. Thus, in the present retrospective study, the authors established a novel DDR-related immune activation (#DRIA) signature, through the detection of a smaller panel of genes (compared to the 44 or 9 gene panel) that can be translated into a clinical assay. The three genes (namely, CXCL10, IDO1 and IFI44L) identified and used in this study, showed a better prediction of therapy efficacy in various cohorts of cancer patients, including GI cancer and pan-cancer. Firstly, the immune characteristics and prognosis of DRIA in GI cancer was evaluated, and the authors noted that the levels of these three genes were increased in DDR-deficient tumours compared to DDR-proficient tumours, thus validating the importance of these genes to be used for DDIR characterisation. Next, the authors further explored the association between DRIA and response to ICI therapy in gastric cancer. The authors evaluated six cohorts of patients, including those for GI cancer, melanoma, urothelial cancer and pan-cancer. They showed that the median DRIA score for patients in the CR/PR (complete or partial response) group was significantly higher than patients in the SD/PD (stable or progressive disease) group. Similarly, the clinical outcome, which is defined as the progression-free survival (PFS) (which is the time from initiation of ICI therapy to the date of disease progression or death), showed that the DRIA-low group had a significantly poorer PFS compared to the DRIA-high  group. Thus, the findings highlighted in the study show that the three-gene signature could positively identify patients with improved response rates and that further exploration of the relationship between DRIA as well as known #clinical #biomarkers may guide clinical application of ICI therapy. Read more: Yan et al., 2023. DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation ( https://lnkd.in/d6vpd8BW ). Cancer Biology and Medicine.

Important paper in Lancet: Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial https://lnkd.in/etSprDin Background Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. Methods In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2–IIB node positive vs stage III–IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Findings Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab–chemoradiotherapy group and 531 to the placebo–chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3–22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab–chemoradiotherapy group versus 57% in the placebo–chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55–0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab–chemoradiotherapy group and 81% in the placebo–chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49–1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab–chemoradiotherapy group and 69% in the placebo–chemoradiotherapy group. Interpretation Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer.

This very exciting study by Dr. Liu and colleagues represents a category of research known as translational research, where breakthroughs in the laboratory are directly applied to patient care, i.e "from bench to bedside". The authors used patient derived xenografts (PDXs) to create an in-vivo model of an aggressive yet under-studied type of pediatric brain tumor called diffuse hemispheric glioma, H3G34-mutant (DHG-H3G34). Guided by preclinical studies, the authors hypothesized that a drug called Ribociclib (an inhibitor of CDK [Cyclin-Dependent Kinase] 4/6) may demonstrate therapeutic benefit in PDX mice. And indeed, their model showed a survival benefit in the mice treated with Ribociclib compared to placebo (for instance, at the 110 day post-treatment point, only 25% of the placebo-treated mice were alive compared to 100% of mice treated with Ribociclib). Furthermore, the authors describe a clinical case in which a 10-year old girl with high grade glioma was refractory to surgery, radiation and two different conventional chemotherapy regimens. In need of a third-line regimen, Ribociclib was chosen based on the genetic profile of the patient's tumor which demonstrated relevant markers, including a methylation profile consistent with DHG-H34G34. The drug was relatively well-tolerated and resulted in 17 months of progression-free survival. The use of therapy guided by molecular tumor markers is becoming more and more prevalent in the world of oncology. Sometimes called "targeted therapies", these treatments are much more specific than traditional chemotherapies, which are globally cytotoxic in general. Targeted therapies such as Ribociclib aim to address the root cause of a cancer cell's aberrant nature, and often have fewer side effects than conventional chemotherapy. Overall I am excited to see what the future holds for targeted therapies in the treatment of aggressive cancers. Although more clinical trials are needed to lend evidence to efficacy and information about side effects (both short-term and long-term), I applaud the authors for their application of translational research and the use of targeted therapy for pediatric high grade glioma. Hopefully the oncology community will continue to see progress in this area and offer more hope for patients in the future. https://lnkd.in/ekiQnAET

ArteraAI is at the 2024 American Society of Clinical Oncology (ASCO) annual meeting presenting 3 works on both our breast cancer and prostate cancer multi-modal AI (MMAI) tests. I'm stunned by our team's velocity - since founding the company about 2.5 years ago, we've produced about 30 scientific works forming the basis of our MMAI tests' evidence, largely with phase III clinical trials. Our breast cancer abstract demonstrates subgroup analysis of prognosis in HR+ HER2- early stage breast cancer. Our prostate cancer abstracts show the extension of our prostate test into oligo-metastatic and metastatic patients. This follows our recent oral presentation (https://lnkd.in/gkwhhEJf) at the 2024 American Urological Association (AUA) annual meeting, validating the first-ever AI biomarker that can stratify metastatic risk in patients with biochemical recurrence after surgery (radical prostatectomy), and in doing so predict therapeutic response to hormone therapy as an adjuvant to salvage radiation. ------- ASCO 2024 Evidence ------ Oral Presentation: Multimodal artificial intelligence models from baseline histopathology to predict prognosis in HR+ HER2- early breast cancer Poster Presentation: Validation of a digital pathology-based multimodal artificial intelligence model in oligometastatic castration-sensitive prostate cancer, including in patients from the STOMP and ORIOLE phase II randomized clinical trials. Poster Presentation: Prognostic validation of a digital pathology-based multi-modal artificial intelligence (MMAI) biomarker in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the CHAARTED trial (ECOG-ACRIN EA3805). #AI #MMAI #biomarkers #prostatecancer #breastcancer #arteraai #asco2024 #aua2024 https://lnkd.in/gTdRbUqQ

💎💎💎Whatsapp!! 💎💎💎 Breast Cancer’s Spread to Brain Could Be Treated by Antibody-Drug Conjugate The results of a prospective window-of-opportunity trial at the University of Texas Health Science Center at San Antonio (UT Health San Antonio) suggest an #antibody_drug #conjugate (#ADC) #treatment that has been effective in treating #breast_cancer may also show promise in addressing breast cancer with #brain metastases (BCBM), or recurrent #glioblastoma (rGBM). The window trial, in which patients undergoing #craniotomy for BCBM or rGBM agreed to receive the drug Sacituzumab Govitecan (SG) before undergoing surgery, found that the novel treatment was well tolerated and showed signs of effectiveness for those whose breast cancer had progressed to brain #tumors. The researchers believe the newly reported data support ongoing investigation in a Phase II #clinical_trial of the drug in recurrent glioblastoma. “We knew that the drug has been effective in the treatment of breast cancer, but its usefulness in the treatment of resulting brain tumors has been unclear,” said Andrew J. Brenner, MD, PhD, professor and chair of neuro-oncology research with Mays Cancer Center at UT Health San Antonio. “Our trial, however, revealed that it could achieve concentrations of #inhibitors inside the tumors sufficient to benefit patients, and with minimal #side_effects, which is very promising for new therapy.” Brenner, who also is a clinical investigator for the Institute for Drug Development at UT Health San Antonio and co-leader of its Experimental and Development Therapeutics Program, is the lead author of the team’s report in Nature Communications, titled “Sacituzumab Govitecan in patients with breast cancer brain metastases and recurrent glioblastoma: a phase 0 window-of-opportunity trial.” In their paper the team concluded, “SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS.” Brain tumors originating from breast cancer are frequent, and treatment for these tumors typically involves #surgery, radiotherapy, and #systemic therapies, though these measures often are unsuccessful. “The prognosis for patients with #malignant brain tumors is grim,” the authors wrote. “In terms of disease burden, brain tumors of breast origin are frequent, accounting for 15 to 25% of #patients with stage IV breast cancer.” ➡ 💎 You can find more pieces of work by clicking here. https://lnkd.in/eSG67K5G https://lnkd.in/eFBq_8E5 https://lnkd.in/eFBq_8E5 https://lnkd.in/dB3s88ei #Breast_Cancer’s #Brain #Antibody_Drug_Conjugate

✍️In this article, UROonco24 steering committee member and ESOU Chair Prof. Morgan Rouprêt (FR) shares some of his personal highlights that he is looking forward to next month when onco-urology experts will meet to discuss the latest developments in genitourinary cancers at the UROonco24 meeting in Budapest, Hungary (Thursday, 20 June to Saturday, 22 June). Prof. Rouprêt: “These highlights underscore UROonco24’s commitment to providing cutting-edge research, practical skills training, and interactive learning opportunities.” ⭐Rapid fire debates – common problems in PCa Prof. Rouprêt: “One of the highly anticipated sessions is ‘Prostate cancer I: Rapid fire debates – common problems in prostate cancer’. The four cases that will be debated include: How best to follow patients with low-risk prostate cancer on active surveillance; Can PSMA PET/CT spare extended pelvic lymph node dissection in high-risk prostate cancer?; Oligometastatic recurrence after primary local treatment detection on PSMA PET/CT: How to treat; and PARPi + ARPI for all patients with metastatic castration resistant prostate cancer?’. These discussions will provide insights into new trials, making it a must-attend for anyone involved in prostate cancer management”. ⭐Update sessions for PCa, BCa, and RCC “The meeting will feature interactive roundtable discussions on prostate, bladder, and kidney cancers. These sessions are designed to deliver comprehensive updates and facilitate active participation from delegates, enabling a deep dive into the latest advancements and challenges in each cancer type.” For prostate cancer, topics include: ‘Enhancing detection of lymph node-positive prostate cancer through molecular imaging, is it worth the effort?’, including results on new trials such as PRIMORDIUM; and ‘De novo metastatic disease in 2024: a matter of staging and sequencing’. For bladder cancer, the cases will cover ‘High grade recurrence after BCG treatment: importance of BCG exposure and available options’; and ‘Good response after neoadjuvant chemotherapy for clinical node disease, when should we go for surgery?’. For renal cancer, topics include: ‘Decision-making for a large localised (ct1Bb) renal mass: Any role of virtual biopsy?’; and ‘Adjuvant pembrolizumab for high-risk ccRCC: How to optimise patient selection and treatment at recurrence.’ ⭐Clinical trial corner UROonco24 is a great avenue for Europe-based urologists to get the latest research and updates from international urological gatherings such as ESMO, ASCO GU, AUA and ASCO. There will be presentations and discussion on the latest onco-urology trials, such as PRIME, EMBARK, RADICALS-RT, PRISMA, NURE-COMBO and KEYNOTE-564. See the full scientific programme in the link below, and register before 6 June, 2024 (23:59 CEST) for the reduced rates 👉https://lnkd.in/eu2ktn3Z

Dual-miRNA triggered DNA nanomachine for breast cancer subtype detection and treatment. The dual-mirna triggered DNA-Au nanomachine based on toehold-mediated strand displacement reactions for controlled release of dox. Breast cancer is the most common malignancy in women, posing a serious threat to female health. Due to the high inter- and intra-tumoral heterogeneity of breast cancer, clinical treatment and prognosis can vary greatly in patients. Currently, chemotherapy is the main systemic treatment for triple-negative breast cancer (TNBC), a common type of breast cancer that does not have any of the receptors that are commonly found in breast cancer. However, treatment with the uniform high-dose chemotherapy regimen without molecular subtyping frequently yields suboptimal efficacy, adding further burden and discomfort to patients. A group of researchers from China outline a new discrimination and treatment approach—a dual-miRNA-triggered DNA-programmed nanomachine capable of imaging endogenous miRNA expressions. This approach makes subtype-based detection possible, thereby regulating drug release for chemotherapy. "For the diagnosis and subtyping of breast cancer, histological examination of puncture biopsy sample is the 'gold standard,' but it is invasive and difficult to realize dynamic monitoring of tumor progression and prognosis for treatment guidance," "Fluorescence imaging techniques are capable of visualizing and monitoring minimal molecular changes occurring at an early stage of cancers with high resolution and sensitivity. However, single miRNA imaging is not suitable for discrimination of cancer cell types." Notably, while previous studies have demonstrated that dual miRNA-triggered drug release can be applied for cancer therapy via the toehold-mediated strand displacement reactions (TSDR), tailored treatments, such as high-dose chemotherapy in TNBC and conventional-dose chemotherapy in other breast subtypes, have not been realized. "We developed a DNA-programmed nanomachine for effective discrimination and tailored treatment of specific breast cancer cell types," "It is a responsive therapy strategy towards the various cell states. This intelligent nanomachine with controlled release of anti-cancer drug in specific cancer cell subtypes can reduce the side effect to normal cells and facilitate the targeted therapy, which is promising as a theranostics nanoplatform in precise medicine." #miRNA #DNA #biopsy #nanomachine #breastcancer #cells #anticancer #TNBC #tumor #TSDR #chemotherapy #dox

The PAM50 classification is the most accurate way to predict the prognosis of patients with locally advanced breast cancer in Latin American patients. Patients with LumA tumors have the best prognosis, while basal tumors have the worst. PS: Under the PAM50 classification, tumors can be assigned to some of the following subtypes: * Luminal A: The subtype with the best prognosis, characterized by the expression of genes related to luminal differentiation and the expression of estrogen and progesterone receptors. These tumors are estrogen receptor (ER) positive and progesterone receptor (PR) positive, meaning they are sensitive to hormone therapy. LumA tumors are also typically HER2 negative, meaning they are not sensitive to drugs that block this gene. These tumors are generally slow growing and have a lower risk of recurrence or metastasis. LumA tumors are usually treated with hormonal therapy, such as tamoxifen or anastrozole, which block the action of estrogen and progesterone. In some cases, chemotherapy or radiation therapy may also be given. The 5-year survival rate for this subtype of breast cancer is between 90% to 99%. * Luminal B: These tumors are similar to Luminal A (they are hormone-sensitive), but they are more prone to metastasize since they have a high degree of cell proliferation. * Her2 positive: Subtype with an intermediate prognosis, characterized by overexpression of the HER2 gene and are sensitive to drugs that block this gene. * Basal-like: Subtype with the worst prognosis, characterized by the expression of genes related to basal cells and the absence of expression of hormone receptors. These tumors are ER and PR negative, meaning they are not sensitive to hormone therapy. Basal tumors are also usually HER2 negative, meaning they are not sensitive to drugs that block this gene, so they are less sensitive to hormonal treatments or drugs that block HER2. These tumors are generally fast growing and have a higher risk of recurrence or metastasis. Basal tumors are usually treated with chemotherapy, as they do not respond to hormone therapy. In some cases, radiation therapy may also be given. The 5-year survival rate for this subtype of breast cancer is around 70%. * Normal-like: These tumors are similar to normal breast tissues and have a good prognosis * Claudin-Low Breast Cancer characterized by low expression of genes related to cell adhesion. It has been recognised to preferentially display a triple-negative phenotype, however only a minority of triple-negative breast cancers are claudin-low. Claudin-low breast cancer is typically negative for ER, PR, HER2, claudin 3, claudin 4, claudin 7 and E-cadherin. Claudin-low tumors were associated with young age of onset, higher tumor grade, larger tumor size, extensive lymphocytic infiltrate and a circumscribed tumor margin. https://lnkd.in/dVjG3TE4