Recent research suggests that brain anatomy may help identify the most effective pharmacological treatment for each individual with bipolar disorder and reduce trial-and-error prescribing. We aimed to investigate whether brain anatomy predicts whether a medication is currently prescribed or has been discontinued, as a proxy for treatment effectiveness. The rationale is that medications that provide clinical benefit without unacceptable side effects are likely to be continued, whereas those with limited benefit or poor tolerability are typically discontinued. We used T1-weighted MRI from twelve ENIGMA-BD cohorts (n = 2462; 473 individuals with BD [61% female, age 18-73] and 1989 controls) to derive regional cortical thickness and surface area and subcortical volumes. Site differences were harmonized using ComBat models fitted on controls' data. Within cross-validation, models were trained to first adjust for cumulative dose and other covariates and then predict medication status. On test sets, current prescription (vs. discontinuation) of lithium was predicted by greater cortical thickness and reduced surface area, whereas current prescription (vs. discontinuation) of antidepressants and atypical antipsychotics was predicted by greater cortical thickness. Predictive regions for atypical antipsychotics were generally consistent across subgroups of age, gender, illness duration, and history of psychosis, and in the largest site, and differed from those associated with cumulative effects of medication on the cortex. Predictions were poor for subcortical volumes and for antiepileptic mood stabilizers and typical antipsychotics. These findings provide preliminary support that cortical anatomy may help inform future development of biomarkers for treatment selection, pending validation in longitudinal studies.

Canada’s Drug Agency (CDA-AMC) recommends that Braftovi, in combination with cetuximab and modified leucovorin (folinic acid), fluorouracil, and oxaliplatin (mFOLFOX6), be reimbursed by public drug plans for the treatment of patients with metastatic colorectal cancer (mCRC) with a BRAF V600E gene mutation, as detected by a validated test, if certain conditions are met. Evidence from 1 clinical trial showed that Braftovi, in combination with cetuximab and mFOLFOX6, results in improved progression-free and overall survival in patients with mCRC with a BRAF V600E gene mutation, compared with the trial investigator’s choice of chemotherapy, with or without bevacizumab. The pan-Canadian Oncology Drug Review Expert Review Committee determined that adding Braftovi to cetuximab plus mFOLFOX6, demonstrates acceptable clinical value compared with chemotherapy with or without bevacizumab in patients with mCRC with a BRAF V600E gene mutation, and addresses the need identified by both patients and clinicians for more effective therapy to delay disease progression and extend survival. This determination was enough for the pan-Canadian Oncology Drug Review Expert Review Committee to recommend that Braftovi be reimbursed for this indication. Given that Braftovi is expected to be an alternative to chemotherapy with or without bevacizumab, acceptable clinical value refers to added value over chemotherapy with or without bevacizumab. Braftovi, in combination with cetuximab and mFOLFOX6, should only be covered for adult patients with mCRC with a confirmed BRAF V600E mutation. Patients should have good performance status and should not have active or symptomatic cancer in the brain or spinal cord. Braftovi should not be covered for patients who have received prior drug treatments for mCRC, or oxaliplatin treatment before (neoadjuvant) or after (adjuvant) surgery, if they experienced disease progression during treatment or recurrence within 6 months of completing it. Braftovi, in combination with cetuximab and mFOLFOX6, should only be reimbursed if the patient is under the care of a clinician who has expertise in managing mCRC and the cost of Braftovi is reduced. Treatment should be discontinued if the cancer worsens or if the patient experiences unacceptable side effects. Important budget impact considerations must be addressed for health systems to be able to adopt Braftovi.

Canada’s Drug Agency (CDA-AMC) recommends that Tevimbra be reimbursed by public drug plans, in combination with gemcitabine and platinum chemotherapy, for the first-line treatment of adult patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) if certain conditions are met. Evidence from 1 clinical trial showed that Tevimbra, in combination with gemcitabine-cisplatin in the first-line setting, improved progression-free survival (PFS) and overall survival (OS) compared with gemcitabine-cisplatin alone in patients with recurrent or metastatic NPC. The pan-Canadian Oncology Drug Review Expert Review Committee (pERC) determined that adding Tevimbra to gemcitabine plus platinum chemotherapy provides acceptable clinical value compared with gemcitabine plus platinum chemotherapy alone for the first-line treatment of recurrent or metastatic NPC. pERC also determined that Tevimbra in combination with gemcitabine and platinum chemotherapy addresses the need identified by both patients and clinicians for a more effective first-line therapy to delay disease progression and extend survival. These determinations were enough for pERC to recommend that Tevimbra be reimbursed. Given that Tevimbra is expected to be used as an add-on to gemcitabine plus platinum chemotherapy, acceptable clinical value reflects its added benefit over gemcitabine plus platinum chemotherapy alone. Tevimbra in combination with gemcitabine plus platinum chemotherapy should only be covered for adults with recurrent or metastatic NPC that cannot be treated with surgery or curative radiation and who have not received any previous systemic treatment for the condition. Patients should have good performance status and should not have active or uncontrolled cancer in the brain or significant autoimmune disease. Tevimbra in combination with gemcitabine plus platinum chemotherapy should only be reimbursed if the patient is under the care of a clinician who has expertise in managing NPC and side effects of immunotherapy and the cost of Tevimbra is reduced. Treatment should be discontinued if the patient experiences disease progression or unacceptable side effects. Important organizational implications must be addressed for health systems to be able to adopt Tevimbra.

Abstract Background: Metastatic triple-negative breast cancer (mTNBC) is one of the most challenging forms of breast cancer to treat due to profound heterogeneity and drug resistance. There have been very limited advancements in approval of targeted treatment regimens that are not chemotherapy-based for mTNBC in the past decade. Kinases are tractable therapeutic targets, but while kinase inhibitors have improved outcomes in many metastatic solid tumors including other breast cancer subtypes, they have not improved patient outcomes in TNBC clinical trials. We posit this is because we do not leverage understanding of complex kinase signaling networks and how we utilize kinase inhibitors in TNBC is not optimized. Further, high doses of kinase inhibitors to achieve cytotoxicity have unacceptable side effects for patients limiting real-world use. Chronic stress states such as those initiated by hypoxia, poor nutrient delivery and higher metabolic demands promote pro-metastatic transcriptional programs in TNBC. Our preclinical research and secondary analyses from clinical trial data reveal stress kinase signaling networks, and not individual pathways, drives TNBC metastatic transformation. Our central hypothesis is the RKIP/BACH1 signaling axis is a regulator of the chronic stress response to suppress TNBC metastasis and can be leveraged to produce biomarkers for risk stratification and a novel combination regimens. Methods: Prior work showed activation of the physiologic metastasis suppressor RKIP effectively reduced TNBC metastasis in cell line models through inhibition of stress MAPK networks (p38, JNK, ERK1/2, MLK) resulting in decreased transcription of the pro-metastatic transcription factor BACH1. We utilized mass spectrometry-based techniques with a kinase inhibitor system (MIB-MS) to characterize the activity of kinase signaling networks in heavily treated mTNBC organoids and examined kinase networks prominent in BACH1-high TNBC from publicly available phosphoproteomics datasets. We utilize live/dead, proliferation assays and transwell invasion assays to test efficacy of our stress kinase inhibitor regimen. Results: We show that combinations of 3 kinase inhibitors used in early phase clinical trials (Ralimetinib (p38), JNK-in-8 (JNK) or FDA approved (Trametinib (MEK & ERK1/2)) inhibit stress kinase networks, pro-motility gene expression and TNBC cell invasion. Low dose inhibition of multiple kinase nodes of networks, rather than single kinase nodes, more effectively reduces oncogenic signaling output and prevents compensatory signaling activation and potentiates suppression of organoid tumor initiating capacity when used in combination with chemotherapy. Using patient-derived organoids that recapitulate heterogeneous mTNBC molecular characteristics we successfully generated stable BACH1-knockout organoids which will be used to further identify BACH1-dependent critical kinase networks. Conclusions: Inhibition of these stress kinase networks should enable effective reprogramming of metastatic or high-risk cancers to more benign states and make tumors more susceptible to approved anti-proliferative therapies such as chemotherapy or immunotherapy while limiting toxicities from kinase inhibitors using a low-dose, multi-drug combination approach. Citation Format: M. Matossian, M. Bungert, C. Nguyen, G. Yerradoddi, M. East, D. Okumu, R. Nanda, G. Johnson, M. Rosner. Targeting Pro-Metastatic Stress Kinase Networks in Triple-Negative Breast Cancer Using Patient-Derived Models [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-03-25.

Cancer is a group of dynamic diseases characterized by uncontrollable growth and spread of cells. The heterogenic nature of cancer hinders the abolishment of cancer resulting in a narrow therapeutic index, the capacity of drug efflux, multidrug resistance, and unacceptable side effects. The major challenge in the treatment of malignancies is multidrug resistance (MDR). A novel platform, nanoscale delivery system, concluding desirable applications for the treatment of cancer with targeted and controlled release of drugs, reducing the number of side effects and systemic toxicity. Recent studies emphasize that combining 2 or more nanocarrier-mediated therapies may produce complementary therapeutic effects, perhaps resulting in improved outcomes of cancer current therapies like deterioration of drug resistance. Therefore, in this article, we scrutinize the recent advancement addressing combination therapy by combining nanoparticles with anticancer drugs. It briefly concludes a thorough overview of cancer, tumor or solid resistant tumors, the mechanism of resistant tumors, current therapies for the treatment of solid tumors, and their challenges. It also covers various types of nanoparticles used in cancer treatment, the usage of nanocarriers in resistant tumors, and nanocarrier-based combinatorial therapy for the treatment of resistant tumors as well as its benefits. However, this approach still needs to be improved for clinical applications.

Gut microbiome metabolites in lung cancer: The emerging importance of short-chain fatty acids.

Canada’s Drug Agency recommends that Itovebi in combination with palbociclib (PAL) and fulvestrant (FUL) be reimbursed by public drug plans for the treatment of adult patients with endocrine-resistant, PIK3CA-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer, following recurrence on or after completing adjuvant endocrine treatment, only if certain conditions are met. Itovebi in combination with PAL and FUL should only be covered to treat adults with hormone receptor–positive, HER2-negative breast cancer that has spread to nearby tissue or lymph nodes (locally advanced), or to other parts of the body (metastatic); has come back after hormone (endocrine) therapy; and has an abnormal PIK3CA Patients should also have good performance status. Itovebi in combination with PAL and FUL should not be covered if the patient has been previously treated for hormone receptor–positive, HER2-negative metastatic breast cancer with mutations in the PIK3CA gene, or if they have uncontrolled diabetes. Itovebi in combination with PAL and FUL should be prescribed by, then managed under the care of, health care professionals with expertise in managing advanced or metastatic breast cancer. Reimbursement of Itovebi should be discontinued if the cancer becomes worse or there are unacceptable side effects. Price reductions exceeding 90% in the cost of Itovebi as part of the combination regimen with CDK4/6 inhibitor and FUL would be required to achieve an incremental cost-effectiveness ratio below $50,000 per quality-adjusted life-year gained, relative to therapies currently in use.

Canada’s Drug Agency (CDA-AMC) recommends that Opdivo plus Yervoy be reimbursed by public drug plans for the first-line treatment of adult patients with unresectable or advanced hepatocellular carcinoma (HCC) if certain conditions are met. The pan-Canadian Oncology Drug Review Expert Review Committee (pERC) determined that Opdivo plus Yervoy demonstrates acceptable clinical value versus tyrosine kinase inhibitors (TKIs) (sorafenib and lenvatinib), and immunotherapies (atezolizumab plus bevacizumab, and durvalumab plus tremelimumab) in adults with HCC at an advanced stage when it can no longer be surgically removed (unresectable or advanced). This determination was enough for pERC to recommend that Opdivo plus Yervoy be reimbursed. Given that Opdivo plus Yervoy is expected to be an alternative to TKIs or currently available immunotherapies, acceptable clinical value refers to at least comparable value versus TKIs and immunotherapies. Evidence from a clinical trial (CheckMate 9DW) showed that treatment with Opdivo plus Yervoy likely results in patients living longer (improved overall survival [OS]) compared with sorafenib and lenvatinib at 24 months in patients with unresectable or advanced HCC. Evidence from an indirect treatment comparison suggested better OS with Opdivo plus Yervoy compared to other immunotherapies (atezolizumab plus bevacizumab, and durvalumab plus tremelimumab) after 6 months in adults with unresectable or advanced HCC. Opdivo plus Yervoy was considered an alternative immunotherapy option that may offer a clinical benefit for some patients beyond 6 months of treatment. A key limitation of the evidence is the absence of information identifying which patients are at a higher risk of death in the first 6 months of treatment. Opdivo plus Yervoy should only be covered for the first-line treatment of adults with unresectable or advanced HCC who have Child-Pugh score class A and good performance status. Opdivo plus Yervoy should not be covered if the patient has been previously treated for unresectable or advanced HCC. Opdivo plus Yervoy should be prescribed by and managed under the care of clinicians with expertise in managing unresectable or advanced HCC. Reimbursement should be for a maximum of 2 years of treatment. Reimbursement should be discontinued if the cancer becomes worse or there are unacceptable side effects. The total treatment cost of Opdivo plus Yervoy should not exceed that of treatment with the least costly immunotherapy comparator. Important economic feasibility must be addressed for health systems to be able to adopt Opdivo plus Yervoy due to the magnitude of uncertainty in the budget impact.

Fedora preliminary analysis of a Phase II study evaluating the tolerability, safety and activity of fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis.

The Formulary Management Expert Committee (FMEC) recommends that cabozantinib be reimbursed for adult patients with locally advanced or metastatic extrapancreatic or pancreatic neuroendocrine tumours who have received at least 1 prior therapy, provided certain conditions are met. Cabozantinib may be initiated in patients for the treatment of metastatic extrapancreatic or pancreatic neuroendocrine tumours if the following conditions are met: the tumour grade is consistent with WHO tumour grade 1 to 3; there is histological documentation of neuroendocrine tumour of pancreatic, gastrointestinal, lung, thymus, other, or unknown primary site; there is disease progression or unacceptable side effects after at least 1 prior therapy other than somatostatin analogue; and there is good performance status. A price reduction for cabozantinib may be required.

Background: Outbreaks of Zaire ebolavirus are an ongoing public health threat associated with high case fatality rates. The US Advisory Committee on Immunization Practices (ACIP) recommends preexposure vaccination with rVSV∆G-ZEBOV-GP Ebola vaccine (Brand name: Ervebo), which is effective in preventing disease caused by Zaire ebolavirus, to people at high risk for occupational exposure. We describe the perceptions and desire to be vaccinated with Ervebo among a subset of eligible US healthcare workers (HCWs). Methods: We conducted a cross-sectional online anonymous survey during March-October 2024, distributed to eligible HCWs at three Regional Emerging Special Pathogen Treatment Centers (RESPTCs): NYC Health + Hospitals/Bellevue, University of Texas Medical Branch, and Denver Health & Hospital Authority. Results: There were 66 responses (40% response rate), with the majority aged 30-49 years (63%), female (65%), and either a physician (42%) or nurse (27%). The majority (56%) had received some form of education on Ebola vaccines, most commonly through informational sheets or pamphlets (60%). Thirty-four (51%) were interested in (n=30) or already vaccinated with (n=4) Ervebo. Among those interested or already vaccinated, 44% would choose to receive the vaccine immediately, while 24% would get vaccinated if there were a case of Ebola virus disease (EVD) in the US. Among those not interested or unsure (n=32), most were concerned about risks of spreading the vaccine viral vector (44%), insufficient knowledge about the vaccine (31%), and unacceptable side effects (31%). Among all respondents, the most common concerns about adverse events included potential for a serious side effect (64%) and risk of arthritis (36%). Forty seven percent of respondents were concerned about the potential for spread of the vaccine virus vector. Respondents most frequently wanted more education on potential side effects (67%) and the risk of spreading the vaccine virus vector (59%). Among those not interested in vaccination or unsure (n=32), some may be convinced to accept vaccination if there were an EVD outbreak in the US (44%), if they better understood the risks and benefits of vaccination (34%), and if they better understood the vaccine safety (31%). Conclusion: During a period with no EVD outbreaks, a majority (51%) of eligible HCWs surveyed at three US RESPTCs were interested in or had received Ervebo. A significant proportion (24%) prefer to postpone vaccination until there is a case of EVD in the US. Deployment of Ervebo to eligible US HCWs may be optimized by addressing concerns identified in this study.

Transarterial chemoembolization (TACE) is an effective locoregional treatment for unresectable hepatocellular carcinoma (HCC). Arterial administration can enhance local drug concentrations while reducing systemic toxicity. The potential synergistic effects of combining locoregional treatments with systemic therapy in advanced HCC warrant further investigation. This phase 2 study (NCT04796025) aimed to evaluate the efficacy and safety of TACE combined with intra-arterial infusion of sintilimab and bevacizumab in patients with advanced HCC. Eligible patients received TACE on demand plus intra-arterial infusion of sintilimab and bevacizumab for four cycles. Maintenance therapy included intravenous administration of sintilimab and bevacizumab until disease progression or unacceptable side effects. The primary outcome was the objective response rate (ORR) based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). A total of 34 patients (median age, 53 years [IQR 45-59]; 33 men) were enrolled. With a median follow-up of 10.3 months (IQR 5.8-15.6), our results showed a favorable ORR of 70.6%. The median PFS was calculated as 6.0 months (95% CI 4.8 - not reached), and the median OS was 12.2 months (95% CI 9.3 - not reached). Common treatment-related adverse events (any grade) included elevated alanine transaminase (17.6%), abdominal pain (14.7%), elevated aspartate aminotransferase (11.8%), and hypertension (11.8%). Grade 3 adverse events included hypertension (2.9%) and gastrointestinal hemorrhage (8.8%). No serious treatment-related adverse events were observed. TACE combined with sintilimab and bevacizumab has demonstrated a favorable ORR and promising efficacy in advanced HCC, with manageable side effects.

Current interventions for endometriosis mainly involve hormone therapies but have limited efficacy and unacceptable side effects due to the lack of selectivity to distinguish between endometriosis and endometrial tissues. Elucidating the molecular mechanism underlying the rapid growth of endometrial-like stromal cells, one of the main components of endometriotic lesions, will pave a path for more effective treatment of endometriosis. In the current study, we utilized transcriptome sequencing to compare the transcriptional profiles of endometrial-like stromal cells from endometriosis and endometrial tissues and demonstrated that Homeobox C4 (HOXC4) is preferentially expressed in endometriotic lesions. HOXC4 is indispensable for the proliferation of stromal cells from endometriosis, but not those from endometrial tissues. Mechanistically, HOXC4 acts as a transcription factor to promote the expression of Slit Guidance Ligand 2 (SLIT2) and thereby increases the p38 MAPK activity via the SLIT2 receptor roundabout guidance receptor 1 (ROBO1). Considering the essential role of the p38 MAPK activity in facilitating the development of ectopic endometrium, our findings strongly support the idea of HOXC4, as well as the SLIT2-ROBO1 axis, being potential therapeutic targets for endometriosis.

Corticosteroids remain the cornerstone of sarcoidosis treatment but are associated with significant toxicities and impaired quality of life. Second-line and third-line treatments include hydroxychloroquine or immunosuppressants (methotrexate, azathioprine, leflunomide and mycophenolate mofetil), and anti-TNF-α agents (infliximab and adalimumab), respectively. The latest identification of significant key cellular pathways in sarcoidosis pathogenesis has led to the development of new therapeutic strategies described in this review. JAK inhibitors, mainly tofacitinib, exhibited encouraging results in case reports, small retrospective series, and two prospective open-label trials for skin and pulmonary sarcoidosis. mTOR inhibitors demonstrated efficacity in one cross-over study on skin involvement. Promising findings were obtained with efzofitimod, an inhibitor of neuropilin-2 receptor, in a pilot study on pulmonary sarcoidosis, which needs to be confirmed. Other drugs with potentially relevant mechanisms of action have been used in case reports or small series or are under investigation: CTLA-4 inhibitors, IL-6 inhibitors, NLRP3 inflammasome inhibitors, GM-CSF inhibitors, PDE-4 inhibitors, and statins. There is very little data available on antifibrotic agents for fibrotic pulmonary sarcoidosis. Despite many challenges, well designed studies are warranted to investigate new therapeutic options in sarcoidosis, particularly in patients with refractory forms or unacceptable side-effects with third-line treatment.

During menopause, the majority of women experience hot flashes (HF) that have a significant negative impact on sleep and quality of life. Current HF therapies are either ineffective or associated with unacceptable side effects. Digital health technologies offer a novel opportunity to fill this treatment gap with just-in-time thermal interventions through wearable devices. Thermal interventions have shown promise in reducing the negative impact of HFs. We hypothesized that HF event onsets can be accurately and reliably predicted from physiological signals prior to a person's perception of the events. This study investigated the feasibility of using skin conductance (SC) to predict the onset of HF events before they are subjectively perceived. 62 women who were experiencing HFs and self-reported being in peri- or postmenopause were recruited. Data collection consisted of three remotely conducted 48-h sessions. During each session, SC from the lateral torso was measured continuously and participants logged the precise timing of each perceived HF event onset. We developed new features to identify characteristics of SC signals before HFs were perceived. The best performing model trained with these features identified 82% of HF events on average 17 s before the onset with less than 2% false-positive rate. Among the identified events, the model predicted 69% of HF events before onset. This study demonstrates the feasibility of predicting HF event onsets before subjective perception. Future studies should investigate both multimodal prediction as well as user acceptance and effectiveness of just-in-time thermal interventions.

Abstract Estrogens play a crucial role in regulating the growth and differentiation of glandular cells in the breast. Tamoxifen blocks the effect of estrogens through binding to the estrogen receptor thereby altering downstream signaling. Tamoxifen was approved by the U.S. Food and Drug Administration (FDA) in 1977 for the treatment of breast cancer. In 1997 the FDA accepted tamoxifen for prevention of breast cancer. Theapproval for prevention was based on results from several large randomized controlled trials targeting women aged 35 years or older with a 5-year breast cancer risk of 1.67% or higher. Despite tamoxifen’s success in reducing the recurrence risk of breast cancer, its systemic side effects have led to generally low acceptance. Also, the effect is heterogeneous because tamoxifen acts as a pro-drug that needs to be metabolization in the liver, primarily via the CYP2D6 enzyme. The most potent metabolite is endoxifen. Recent studies have shown that breast cancer patients who are poor or ultrarapid metabolizers have a worse outcome than intermediate and normal metabolizers. Poor metabolizers have too low endoxifen levels, while ultrarapid metabolizers often discontinue therapy due to unacceptable side effects. Additionally, common medications, such as selective serotonin reuptake inhibitors, influence CYP2D6 activity, altogether leading to a heterogeneity in tamoxifen efficacy. Endoxifen has been proposed as an alternative, not needing activation and not influenced by drug interactions. It has been shown that tamoxifen-induced mammographic density decrease is strongly associated with tamoxifen therapy response. Thus, a change in mammographic density could be used for evaluating the effect of endoxifen and / or tamoxifen. A density decrease could also theoretically be used to increase the sensitivity of a mammogram since density influences the ability to identify breast cancer on a mammogram. The ATOS-016R trial is a phase 2, randomized, double-blinded, placebo-controlled, study of oral (Z)-endoxifen (2 mg, 1 mg, and placebo; 80 women in each arm) in premenopausal women with measurable breast density. The trial invited women aged 40-55 years from three hospitals in Stockholm, Sweden. The primary objective is to determine if six months of daily (Z)-endoxifen can lead to a relative reduction in mammographic breast density area (cm2). The secondary objective is to assess the safety and tolerability of daily oral (Z)-endoxifen. The exploratory objectives are to: i) determine if daily oral (Z)-endoxifen for a maximum of six months results in at least a one-category reduction in the BI-RADS scale, ii) study the durability of (Z)-endoxifen effect on breast density response at 24 months post-standard of care screening mammogram, and iii) evaluate the levels of endoxifen over time and correlate endoxifen values to density change. Standard of care mammograms was used for the screening mammogram. Two study mammograms (each equivalent to the radiation dose of half a normal mammogram) was performed at 3 and 6 months. Clinical labs, vital signs, adverse events, and responses to questionnaires was used to assess safety and tolerability. The study was launched in December 2021, and the end of follow-up for the last of the 240 women is scheduled for June 14, 2024. Early results are expected in the fall of 2024. The ATOS-016R trial is a follow-up study to the KARISMA Low Dose Tamoxifen trial presented at SABCS in December 2023. In that trial, we showed that substantially lower doses of tamoxifen (2.5 mg) reduced mammographic density to the same extent as the established 20 mg dose. Severe side effects were reduced but reports of menopausal-like side effects associated with tamoxifen exposure were still substantial. Citation Format: Per Hall, Stephen Nash, Magnus Bäcklund, Jenny Bergqvist, Mattias Hammarström, Mikael Eriksson, Steven Quay, Kamila Czene. Primary breast cancer prevention using oral endoxifen [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS16-05.

e16302 Background: TACE is recommended as the standard of care for patients with BCLC-B stage hepatocellular carcinoma (HCC). However, the BCLC-B stage HCC is a very heterogeneous disease, especially for patients beyond the up-to-seven criteria. The prognosis shows great diversity depending on the treatment strategy. TACE combined with the anti-VEGF antibody therapy improves the clinical prognosis of patients and gains survival benefits. Intra-arterial infusion of bevacizumab has not been evaluated previously. This study aimed to evaluate the safety and efficacy of TACE combined with intra-arterial infusion of bevacizumab for BCLC-B-stage HCC beyond up-to-seven criteria. Methods: This prospective single-arm phase II study recruited five patients with HCC. The main inclusion criteria: a confirmed HCC based on the ALSLD with either pathological or imaging findings; aged ≥18 years; Barcelona Clinic Liver Cancer (BCLC) stage B and sum of the number of tumors and the largest tumor diameter (cm) exceeding 7; no previous systemic/locoregional anticancer treatment; Child-Pugh score ≤7. Patients were treated with TACE (30-40mg of pirarubicin, 30-40mg of lobaplatin, and lipiodol) plus Bevacizumab (15mg/kg, intra-arterial infusion, d1, Q3W) for four cycles, followed by maintenance therapy with Bevacizumab (15mg/kg, intravenously, d1, Q3W) to a maximum total cycle of eighteen unless any evidence of disease progression or unacceptable side effects. The primary endpoint was objective response rate (ORR) (assessed with mRECIST v1.1). The secondary endpoints included overall survival (OS), progression-free survival (PFS) and safety. Results: From March 2023 to April 2024, 5 patients with a median age of 69 years (range:51 -72) were enrolled. There were 4 (80%) patients with HBV infection, and 4 (80%) patients were classified as Child-Pugh A class. The ORR was 60% with 3 PR and 1 PD. The median follow-up was 14.0 months (95%CI, 5.7-22.4) and the median PFS was 5.7 months (0.4-10.9). The median OS was not reached. Adverse events included grade 2 hypertension (1 case) and mild gingival bleeding (1 case). There were no treatment-related serious adverse events. Conclusions: TACE combined with arterial infusion of bevacizumab in patients with BCLC-B stage HCC beyond up-to-seven criteria demonstrates promise as an effective treatment approach. Clinical trial information: NCT05883176 . Patient characteristics. Characteristics Patients (n = 5) Gender Female 2 (40%) Male 3 (60%) Age (years) 69.0 (51.0-72.0) HBV Negative 1 (20%) Positive 4 (80%) Child-Pugh stage A 4 (80%) B 1 (20%) AFP (ng/ml) 779.8 (11.0-6930.8) Maximum diameter of tumor 102.0 (78.5-113.0)

Metastatic triple-negative breast cancer (mTNBC) remains one of the most challenging forms of breast cancer to treat due to profound heterogeneity; chemotherapy-based regimens continue to be the mainstay of treatment. Kinases are attractive therapeutic targets, but while kinase inhibitors have improved outcomes in many metastatic solid cancers including HER2/Neu-amplified and kinase-driven hormone receptor positive breast cancers kinase inhibitors have not shown durable efficacy in mTNBC and many have failed in clinical trials. Furthermore, the high doses of kinase inhibitors to achieve cytotoxicity have unacceptable side effects for patients limiting real-world use. Preclinical research and secondary analyses from clinical trial data from our group and others demonstrate important differences in how kinase signaling networks, and not individual pathways, drive TNBC metastatic transformation compared to other breast cancer subtypes. Chronic stress states such as those initiated by hypoxia, poor nutrient delivery and higher metabolic demands promote pro-metastatic transcriptional programs in TNBC. Our research focuses on identifying and targeting regulators of the chronic stress response to suppress TNBC metastasis. Our previous work showed that activation of the physiologic metastasis suppressor RKIP effectively reduced TNBC metastasis in cell line models through inhibition of stress MAPK networks (p38, JNK, ERK1/2, MLK) resulting in decreased transcription of the pro-metastatic transcription factor BACH1. We demonstrated that low dose inhibition of multiple kinase nodes of networks, rather than single kinase nodes, more effectively reduces oncogenic signaling output and prevents compensatory signaling activation. Here we take the next step to translate this concept into the clinic. We show that combinations of kinase inhibitors used in early phase clinical trials (Ralimetinib (p38), JNK-in-8 (JNK) or FDA approved (Trametinib (MEK & ERK1/2)) can inhibit stress kinase networks, pro-motility gene expression and TNBC cell migration. Using patient-derived organoids that recapitulate heterogeneous TNBC molecular characteristics we successfully generated stable BACH1-knockout TNBC organoids. We utilized mass spectrometry-based techniques with a kinase inhibitor system (MIB-MS) and proteomics to characterize the activation state of kinase signaling networks in organoids and are investigating the effect of metastatic inhibitors on these pathways. Inhibition of these stress kinase networks should enable effective reprogramming of metastatic or high-risk cancers to more benign states and make tumors more susceptible to approved anti-proliferative therapies such as chemotherapy or immunotherapy while limiting toxicities from kinase inhibitors using a low-dose, multi-drug combination approach. Citation Format: Margarite D. Matossian, Ali Yesilkanal,Michael East, Denis Okumu, Geetha P. Yerradoddi, Rita Nanda, Gary Johnson, Marsha R. Rosner. Targeting pro-metastatic stress networks in triple-negative breast cancer using patient-derived models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1310.

Development of novel GI-centric prostaglandin E2 receptor type 4 (EP4) agonist prodrugs as treatment for ulcerative colitis and other intestinal inflammatory diseases.

Ensartinib for advanced or metastatic non-small-cell lung cancer with MET exon 14 skipping mutations (EMBRACE): amulti-center, single-arm, phase 2 trial.