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Ni/photoredox catalysis has emerged as a powerful platform for C(sp2)-C(sp3) bond formation. While many of these methods typically employ aryl bromides as the C(sp2) coupling partner, a variety of aliphatic radical sources have been investigated. In principle, these reactions enable access to the same product scaffolds, but it can be hard to discern which method to employ because nonstandardized sets of aryl bromides are used in scope evaluation. Herein, we report a Ni/photoredox-catalyzed (deutero)methylation and alkylation of aryl halides where benzaldehyde di(alkyl) acetals serve as alcohol-derived radical sources. Reaction development, mechanistic studies, and late-stage derivatization of a biologically relevant aryl chloride, fenofibrate, are presented. Then, we describe the integration of data science techniques, including DFT featurization, dimensionality reduction, and hierarchical clustering, to delineate a diverse and succinct collection of aryl bromides that is representative of the chemical space of the substrate class. By superimposing scope examples from published Ni/photoredox methods on this same chemical space, we identify areas of sparse coverage and high versus low average yields, enabling comparisons between prior art and this new method. Additionally, we demonstrate that the systematically selected scope of aryl bromides can be used to quantify population-wide reactivity trends and reveal sources of possible functional group incompatibility with supervised machine learning.

The direct cyanomethylation of indoles at the 2- or 3-position was achieved via photoredox catalysis. The versatile nitrile synthon is introduced as a radical generated from bromoacetonitrile, a photocatalyst, and blue LED as a light source. The mechanism of the reaction is explored by determination of the Stern-Volmer quenching constants. By combining photophysical data and mass spectrometry to follow the catalyst decomposition, the catalyst ligands were tuned to enable synthetically useful yields of radical coupling products. A range of indole substrates with alkyl, aryl, halogen, ester, and ether functional groups participate in the reaction, affording products in 16-90% yields. The reaction allows the rapid construction of synthetically useful cyanomethylindoles, products that otherwise require several synthetic steps.

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8-35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1-43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8-51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease., (© 2024 Tsimberidou et al.)

Background: Elevated mammographic density (MD) for a woman's age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD)., Methods: ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35-85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest., Results: Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (β: - 0.05, 95% confidence interval (CI): - 0.07, - 0.03) and √DA (β: - 0.08, 95% CI: - 0.12, - 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (β:0.06, 95% CI:0.03, 0.10) and √DA (β:0.06, 95% CI:0.02, 0.10), and lower √NDA (β: - 0.06, 95% CI: - 0.11, - 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD., Conclusions: Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk., (© 2024. The Author(s).)

Tumor-associated macrophages (TAMs) and other myelomonocytic cells are implicated in regulating responsiveness to immunotherapies, including immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis. We have developed an ex vivo high-throughput approach to discover modulators of macrophage-mediated T cell suppression, which can improve clinical outcomes of ICIs. We screened 1,430 Food and Drug Administration (FDA)-approved small-molecule drugs using a co-culture assay employing bone-marrow-derived macrophages (BMDMs) and splenic-derived T cells. This identified 57 compounds that disrupted macrophage-mediated T cell suppression. Seven compounds exerted prominent synergistic T cell expansion activity when combined with αPD-L1. These include four COX1/2 inhibitors and two myeloid cell signaling inhibitors. We demonstrate that the use of cyclooxygenase (COX)1/2 inhibitors in combination with αPD-L1 decreases tumor growth kinetics and enhances overall survival in triple-negative breast cancer (TNBC) tumor models in a CD8 + T cell-dependent manner. Altogether, we present a rationalized approach for identifying compounds that synergize with ICI to potentially enhance therapeutic outcomes for patients with solid tumors., Competing Interests: Declaration of interests S.V.M., L.M.C., D.T., S. Kumar, and A.D. are inventors on the following US Provisional patent application: Combination Therapy for Treatment of Solid Tumors, provisional filed on 04/10/2023, provisional patent application no. 63/495,246. S. Kumar received reagent support and funding from HiberCell, Inc. S. Kummar – consultant/advisory board: Boehringer Ingelheim, SpringWorks Therapeutics, Seagen, Bayer, Genome & Company, Harbour BioMed, BPGbio Therapeutics, Oxford BioTherapeutics, Mundibiopharma, Gilead, EcoR1, and Mirati; PathomIQ (co-founder), Cadila Pharmaceuticals (scientific advisor-spouse), and Arxeon (co-founder-spouse). L.M.C. has received reagent support from Cell Signaling Technologies, Syndax Pharmaceuticals, Inc., ZielBio, Inc., and HiberCell, Inc.; holds sponsored research agreements with Syndax Pharmaceuticals and HiberCell, Inc.; receives research support from the Prospect Creek Foundation, Lustgarten Foundation for Pancreatic Cancer Research, Susan G. Komen Foundation, and the National Foundation for Cancer Research; and is on the advisory board for Carisma Therapeutics, Inc., CytomX Therapeutics, Inc., Kineta, Inc., HiberCell, Inc., Cell Signaling Technologies, Inc., Alkermes, Inc., NextCure, Guardian Bio, Dispatch Biotherapeutics, AstraZeneca Partner of Choice Network (OHSU Site Leader), Genenta Sciences, Pio Therapeutics Pty Ltd., and Lustgarten Foundation for Pancreatic Cancer Research Therapeutics Working Group, Inc. S.V.M. is on the Scientific Advisory Board of Cadila Pharmaceuticals Pvt. Ltd. and is a co-founder of Arxeon, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of antiapoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial., Patients and Methods: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel., Results: ORIC-101 reversed chemoprotection induced by glucocorticoids in vitro and achieved tumor regressions when combined with paclitaxel in both taxane-naïve and -resistant xenograft models. In the phase 1 study, 21 patients were treated in dose escalation and 62 patients were treated in dose expansion. All patients in dose expansion had previously progressed on a taxane-based regimen. In dose escalation, five objective responses were observed. A preplanned futility analysis in dose expansion showed a 3.2% (95% confidence interval, 0.4-11.2) objective response rate with a median progression-free survival of 2 months (95% confidence interval, 1.8-2.8) across all four cohorts, leading to study termination. Pharmacodynamic analysis of tissue and plasma showed GR pathway downregulation in most patients in cycle 1., Conclusions: ORIC-101 with nab-paclitaxel showed limited clinical activity in taxane-resistant solid tumors. Despite clear inhibition of GR pathway signaling, the insufficient clinical signal underscores the challenges of targeting a single resistance pathway when multiple mechanisms of resistance may be in play., Significance: Glucocorticoid receptor (GR) upregulation is a mechanism of resistance to taxane chemotherapy in preclinical cancer models. ORIC-101 is a small molecule GR inhibitor. In this phase 1 study, ORIC-101 plus nab-paclitaxel did not show meaningful clinical benefit in patients who previously progressed on taxanes despite successful GR pathway downregulation., (©2024 The Authors; Published by the American Association for Cancer Research.)

Endoplasmic reticulum (ER) stress induces the repression of protein synthesis throughout the cell. Attempts to understand how localized stress leads to widespread repression have been limited by difficulties in resolving translation rates at the subcellular level. Here, using live-cell imaging of reporter mRNA translation, we unexpectedly found that during ER stress, active translation at mitochondria was significantly protected. The mitochondrial protein ATPase family AAA domain-containing protein 3A (ATAD3A) interacted with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and mediated this effect on localized translation by competing for binding with PERK's target, eukaryotic initiation factor 2 (eIF2). PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact sites. Furthermore, ATAD3A binding attenuated local PERK signaling and rescued the expression of some mitochondrial proteins. Thus, PERK-ATAD3A interactions can control translational repression at a subcellular level, mitigating the impact of ER stress on the cell.

Belinostat was approved in 2014 for the treatment of relapsed or refractory peripheral T-cell lymphoma, however, there was insufficient data to recommend a dose in patients with moderate to severe hepatic impairment. The purpose of this analysis was to characterize the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers and varying degrees of liver dysfunction. A population pharmacokinetic model was therefore developed to describe the parent-metabolite system. The final model was then implemented to assess the effect of liver impairment on each metabolic pathway of belinostat. It was determined that significant pharmacokinetic differences could only be demonstrated in patients with severe hepatic impairment. The final model estimated a 35%-47% reduction in metabolic clearance attributed to UGT1A1/2B7 glucuronidation, CYP2A6/3A4/2C9 metabolism, and β-oxidation. These hepatic impairment effects reduced between-subject variability by only 5%-8% for their respective parameter, with a large amount of remaining unexplained variability. With further validation, this model can be leveraged to assess the need for dose adjustments in this patient population., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Traditionally, immunotherapy agent selection and treatment strategies are guided by biopsy-based histological information. However, biopsies are limited in that they are invasive, provide static information regarding the tumor immune microenvironment, and only sample a small part of one tumor site. The tumor microenvironment is dynamic and heterogenous. As a result, the immune milieu at one site may be distinct from other metastatic sites. These factors make identifying which patients are likely to respond to different immunotherapies and which harbor intrinsic resistance mechanisms difficult to identify based on a biopsy alone. As such, there is significant interest in alternative methodologies that better characterize the tumor immune microenvironment and monitor immunotherapy response. PET imaging potentially offers a non-invasive way to characterize the tumor immune microenvironment at the primary tumor and metastases and allow for longitudinal characterization. Herein, we review pre-clinically and clinically tested T cell-targeted PET radiopharmaceuticals, as T cells have been the dominant immunotherapy target, and their utility in both evaluating response to immunotherapy and in understanding the systemic immune response to treatment with immunotherapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Glazer, Kummar and Mittra.)

Purpose: GS-3583, an FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDC) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell-mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors., Patients and Methods: Multiple escalating doses of GS-3583 (standard 3+3 design) were administered intravenously on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle for up to 52 weeks. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 at each dose level., Results: Thirteen participants enrolled in four dose-escalation cohorts, after which the study was terminated following safety review. Median (range) age was 71 (44-79), and 7 (54%) participants were male. There were no DLTs. Seven participants had grade ≥3 AEs; 2 participants had grade 5 AEs, including a second primary malignancy (acute myeloid leukemia) considered treatment-related. Dose-dependent increase in GS-3583 serum exposure was observed in the dose range of 2-20 mg with GS-3583 accumulation at higher dose levels. Expansions of cDCs occurred at all four doses with a dose-dependent trend in the durability of the cDC expansion., Conclusions: GS-3583 was relatively well tolerated and induced dose-dependent expansion of cDCs in the periphery of patients with advanced solid tumors. However, development of a second primary malignancy provides a cautionary tale for the FLT3 agonist mechanism. See related commentary by Raeder and Drazer, p. 2857., (©2024 The Authors; Published by the American Association for Cancer Research.)

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high ( MSI-H ) or deficient mismatch repair ( dMMR ) solid tumors in 2017. It was later approved for tumor mutational burden-high ( TMB-H ) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase ( NTRK ) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase ( NTRK ) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection ( RET ) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAF V600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.

Background: Mammographic density (MD) has been shown to be a strong and independent risk factor for breast cancer in women of European and Asian descent. However, the majority of Asian studies to date have used BI-RADS as the scoring method and none have evaluated area and volumetric densities in the same cohort of women. This study aims to compare the association of MD measured by two automated methods with the risk of breast cancer in Asian women, and to investigate if the association is different for premenopausal and postmenopausal women., Methods: In this case-control study of 531 cases and 2297 controls, we evaluated the association of area-based MD measures and volumetric-based MD measures with breast cancer risk in Asian women using conditional logistic regression analysis, adjusting for relevant confounders. The corresponding association by menopausal status were assessed using unconditional logistic regression., Results: We found that both area and volume-based MD measures were associated with breast cancer risk. Strongest associations were observed for percent densities (OR (95% CI) was 2.06 (1.42-2.99) for percent dense area and 2.21 (1.44-3.39) for percent dense volume, comparing women in highest density quartile with those in the lowest quartile). The corresponding associations were significant in postmenopausal but not premenopausal women (premenopausal versus postmenopausal were 1.59 (0.95-2.67) and 1.89 (1.22-2.96) for percent dense area and 1.24 (0.70-2.22) and 1.96 (1.19-3.27) for percent dense volume). However, the odds ratios were not statistically different by menopausal status [p difference = 0.782 for percent dense area and 0.486 for percent dense volume]., Conclusions: This study confirms the associations of mammographic density measured by both area and volumetric methods and breast cancer risk in Asian women. Stronger associations were observed for percent dense area and percent dense volume, and strongest effects were seen in postmenopausal individuals., (© 2024. The Author(s).)

Purpose: Talazoparib is an inhibitor of the poly (ADP-ribose) polymerase (PARP) family of enzymes and is FDA-approved for patients with (suspected) deleterious germline BRCA1/2-mutated, HER2‑negative, locally advanced or metastatic breast cancer. Because knowledge of the pharmacodynamic (PD) effects of talazoparib in patients has been limited to studies of PARP enzymatic activity (PARylation) in peripheral blood mononuclear cells, we developed a study to assess tumoral PD response to talazoparib treatment (NCT01989546)., Methods: We administered single-agent talazoparib (1 mg/day) orally in 28-day cycles to adult patients with advanced solid tumors harboring (suspected) deleterious BRCA1 or BRCA2 mutations. The primary objective was to examine the PD effects of talazoparib; the secondary objective was to determine overall response rate (ORR). Tumor biopsies were mandatory at baseline and post-treatment on day 8 (optional at disease progression). Biopsies were analyzed for PARylation, DNA damage response (γH2AX), and epithelial‒mesenchymal transition., Results: Nine patients enrolled in this trial. Four of six patients (67%) evaluable for the primary PD endpoint exhibited a nuclear γH2AX response on day 8 of treatment, and five of six (83%) also exhibited strong suppression of PARylation. A transition towards a more mesenchymal phenotype was seen in 4 of 6 carcinoma patients, but this biological change did not affect γH2AX or PAR responses. The ORR was 55% with the five partial responses lasting a median of six cycles., Conclusion: Intra-tumoral DNA damage response and inhibition of PARP enzymatic activity were confirmed in patients with advanced solid tumors harboring BRCA1/2 mutations after 8 days of talazoparib treatment., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Observational studies show high rates of switching away from cigarettes among adult purchasers of JUUL-brand electronic nicotine delivery system (ENDS); data are needed to evaluate switching with JUUL in randomized general population trials. The association of ENDS flavor availability and switching is pertinent. This study assessed switch rates and smoking reduction among participants randomized to use JUUL in a choice of flavors or tobacco-only, compared to a condition provided smoking-cessation materials. U.S. adults who smoke cigarettes ( N = 837; M age [ SD ] = 45.99 years [11.48]; 18.76 cigarettes/day [ SD = 7.86]; 50.2% female) from an address-based representative panel were randomized to receive JUUL for 6 months (5.0% nicotine; only Virginia Tobacco [ N = 285] or choice of flavors [ N = 281]), or smoking-cessation materials (quit advice [QA]; N = 271). Self-reported past 30-day smoking and cigarette consumption were assessed at 1, 3, and 6 months. Repeated-measure regressions assessed differences in smoking outcomes between groups. Only 2% of participants were planning to quit smoking within 30 days. Across the 6-month intervention, participants randomized to JUUL (vs. QA) had 6.57-fold greater odds of reporting past 30-day switching (95% CI [3.72-11.63]). Participants in the JUUL (vs. QA) group smoked 27% fewer cigarettes/day versus baseline (Rate Ratio [95% CI] = 0.73 [0.68-0.77]). Over half (51.8%) of the Virginia Tobacco group used other flavors (36.7% nontobacco flavors), contaminating randomized flavor-conditions. JUUL flavor groups did not differ in smoking outcomes ( p > .48). Use of JUUL products may support complete switching away from cigarettes, including among those not ready to quit smoking. Results suggest a preference for nontobacco-flavored ENDS among adults who smoke, although smoking outcomes did not differ by flavor. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Larotrectinib, a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas., Methods: Patients (≥18 years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100 mg orally twice daily. Response was investigator-assessed per RECIST v1.1. Data cutoff was July 20, 2021., Results: At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated larotrectinib therapy: two (6%) patients had bone sarcomas, four (11%) had gastrointestinal stromal tumors, and 30 (83%) had soft tissue sarcomas. All patients were evaluable for response and demonstrated an objective response rate of 58% (95% confidence interval, 41-74). Patients responded well to larotrectinib regardless of number of prior lines of therapy. Adverse events (AEs) were mostly grade 1/2. Grade 3 treatment-emergent AEs (TEAEs) occurred in 15 (42%) patients. There were no grade 4 TEAEs. Two grade 5 TEAEs were reported, neither of which were considered related to larotrectinib. Four (11%) patients permanently discontinued treatment due to TEAEs., Conclusions: Larotrectinib demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in adult patients with TRK fusion sarcomas with longer follow-up. These results continue to demonstrate that testing for NTRK gene fusions should be incorporated into the clinical management of adult patients with various types of sarcomas., Plain Language Summary: Tropomyosin receptor kinase (TRK) fusion proteins result from translocations involving the NTRK gene and cause cancer in a range of tumor types. Larotrectinib is an agent that specifically targets TRK fusion proteins and is approved for the treatment of patients with TRK fusion cancer. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. Over half of patients had a durable response to larotrectinib, with no unexpected side effects. These results show that larotrectinib is safe and effective in adult patients with TRK fusion sarcomas., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Mammographic density (MD), after accounting for age and body mass index (BMI), is a strong heritable risk factor for breast cancer. Genome-wide association studies (GWAS) have identified 64 SNPs in 55 independent loci associated with MD in women of European ancestry. Their associations with MD in Asian women, however, are largely unknown., Method: Using linear regression adjusting for age, BMI, and ancestry-informative principal components, we evaluated the associations of previously reported MD-associated SNPs with MD in a multi-ethnic cohort of Asian ancestry. Area and volumetric mammographic densities were determined using STRATUS (N = 2450) and Volpara™ (N = 2257). We also assessed the associations of these SNPs with breast cancer risk in an Asian population of 14,570 cases and 80,870 controls., Results: Of the 61 SNPs available in our data, 21 were associated with MD at a nominal threshold of P value < 0.05, all in consistent directions with those reported in European ancestry populations. Of the remaining 40 variants with a P-value of association > 0.05, 29 variants showed consistent directions of association as those previously reported. We found that nine of the 21 MD-associated SNPs in this study were also associated with breast cancer risk in Asian women (P < 0.05), seven of which showed a direction of associations that was consistent with that reported for MD., Conclusion: Our study confirms the associations of 21 SNPs (19/55 or 34.5% out of all known MD loci identified in women of European ancestry) with area and/or volumetric densities in Asian women, and further supports the evidence of a shared genetic basis through common genetic variants for MD and breast cancer risk., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Atlastins are mechanochemical GTPases that catalyze homotypic fusion of ER tubules. Recent work has demonstrated that tethering and fusion by the three mammalian atlastin paralogs are differentially regulated by their variable N- and C-terminal extensions. These new findings have profound implications for atlastin-mediated homeostasis of the tubular ER network., (© 2023 Altos Labs, Inc.)

Matrix-deprivation stress leads to cell-death by anoikis, whereas overcoming anoikis is critical for cancer metastasis. Work from our lab and others has identified a crucial role for the cellular energy sensor AMPK in anoikis-resistance, highlighting a key role for metabolic reprogramming in stress survival. Protein synthesis is a major energy-consuming process that is tightly regulated under stress. Although an increase in protein synthesis in AMPK-depleted experimentally-transformed MEFs has been associated with anoikis, the status and regulation of protein translation in epithelial-origin cancer cells facing matrix-detachment remains largely unknown. Our study shows that protein translation is mechanistically abrogated at both initiation and elongation stages by the activation of the unfolded protein response (UPR) pathway and inactivation of elongation factor eEF2, respectively. Additionally, we show inhibition of the mTORC1 pathway known for regulation of canonical protein synthesis. We further functionally assay this inhibition using SUnSET assay, which demonstrates repression of global protein synthesis in MDA-MB-231 and MCF7 breast cancer cells when subjected to matrix-deprivation. In order to gauge the translational status of matrix-deprived cancer cells, we undertook polysome profiling. Our data revealed reduced but continuous mRNA translation under matrix-deprivation stress. An integrated analysis of transcriptomic and proteomic data further identifies novel targets that may aid cellular adaptations to matrix-deprivation stress and can be explored for therapeutic intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Warrier, Srinivasan, Chedere and Rangarajan.)

This Perspective surveys the progress and current limitations of nucleophilic fluorination methodologies. Despite the long and rich history of C(sp 3 )-F bond construction in chemical research, the inherent challenges associated with this transformation have largely constrained nucleophilic fluorination to a privileged reaction platform. In recent years, the Doyle group─along with many others─has pursued the study and development of this transformation with the intent of generating deeper mechanistic understanding, developing user-friendly fluorination reagents, and contributing to the invention of synthetic methods capable of enabling radiofluorination. Studies from our laboratory are discussed along with recent developments from others in this field. Fluoride reagent development and the mechanistic implications of reagent identity are highlighted. We also outline the chemical space inaccessible by current synthetic technologies and a series of future directions in the field that can potentially fill the existing dark spaces.

Background: Electronic nicotine delivery systems (ENDS), such as the JUUL system, are nicotine products for adults who currently smoke cigarettes but are looking for an alternative to combustible cigarettes. Sales of ENDS products were legislatively acknowledged and authorized federally in Canada with the Royal Assent of the Tobacco and Vaping Products Act in 2018., Methods: With the unique dataset from a major chain retailer in Canada, we evaluated the impacts of JUUL market entry on cigarette sales across Canada from January 2017 to August 2019 using two-way fixed effects panel regression models by leveraging on the entry time variation at the city level. We conducted various robustness checks and a permutation test to validate our results., Results: Our estimates suggested that JUUL market entry was, on average, significantly correlated with a 1.65% per-month decrease in cigarette sales during the initial months, and with a potentially larger impact on urban areas. Our results were robust across various specifications and tests. These findings implied that JUUL and combustible cigarettes act as economic substitutes during the study time period in Canada., Conclusions: These results suggested that local availability of ENDS products, such as JUUL, has the potential to reduce local cigarette consumption., (© 2023. The Author(s).)

Background: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments., Methods: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival., Results: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%)., Conclusions: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: This study aimed at characterizing indotecan population pharmacokinetics and explore the indotecan-neutropenia relationship in patients with solid tumors., Methods: Population pharmacokinetics were assessed using nonlinear mixed-effects modeling of concentration data from two first-in-human phase 1 trials evaluating different dosing schedules of indotecan. Covariates were assessed in a stepwise manner. Final model qualification included bootstrap simulation, visual and quantitative predictive checks, and goodness-of-fit. A sigmoidal E max model was developed to describe the relationship between average concentration and maximum percent neutrophil reduction. Simulations at fixed doses were conducted to determine the mean predicted decrease in neutrophil count for each schedule., Results: 518 concentrations from 41 patients supported a three-compartment pharmacokinetic model. Body weight and body surface area accounted for inter-individual variability of central/peripheral distribution volume and intercompartmental clearance, respectively. Estimated typical population values were CL 2.75 L/h, Q3 46.0 L/h, and V3 37.9 L. The estimated value of Q2 for a typical patient (BSA = 1.96 m 2 ) was 17.3 L/h, while V1 and V2 for a typical patient (WT = 80 kg) was 33.9 L and 132 L. The final sigmoidal E max model estimated that half-maximal ANC reduction occurs at an average concentration of 1416 µg/L and 1041 µg/L for the daily and weekly regimens, respectively. Simulations of the weekly regimen demonstrated lower percent reduction in ANC compared to the daily regimen at equivalent cumulative fixed doses., Conclusion: The final PK model adequately describes indotecan population pharmacokinetics. Fixed dosing may be justified based on covariate analysis and the weekly dosing regimen may have a reduced neutropenic effect., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Achieving a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved patient outcomes in triple-negative breast cancer (TNBC). Currently, there are no validated predictive biomarkers for the response to NAC in TNBC. We developed and validated a deep convolutional neural network-based artificial intelligence (AI) model to predict the response of TNBC to NAC., Materials and Methods: Whole-slide images (WSIs) of hematoxylin and eosin-stained core biopsies from 165 (pCR in 60 and non-pCR in 105) and 78 (pCR in 31 and non-pCR in 47) patients with TNBC were used to train and validate the model. The model extracts morphometric features from WSIs in an unsupervised manner, thereby generating clusters of morphologically similar patterns. Downstream ranking of clusters provided regions of interest and morphometric scores; a low score close to zero and a high score close to one represented a high or low probability of response to NAC., Results: The predictive ability of AI score for the entire cohort of 78 patients with TNBC ascertained by receiver operating characteristic analysis demonstrated an area under the curve (AUC) of 0.75. The AUC for stages I, II, and III disease were 0.88, 0.73, and 0.74, respectively. Using a cutoff value of 0.35, the positive predictive value of the AI score for pCR was 73.7%, and the negative predictive value was 76.2% for non-pCR patients., Conclusion: To our knowledge, this study is the first to demonstrate the use of an AI tool on digitized hematoxylin and eosin-stained tissue images to predict the response to NAC in patients with TNBC with high accuracy. If validated in subsequent studies, these results may serve as an ancillary aid for individualized therapeutic decisions in patients with TNBC., Competing Interests: Hassan MuhammadEmployment: Pathomiq

Cascade testing for families with BRCA pathogenic variants is important to identify relatives who are carriers. These relatives can benefit from appropriate risk management and preventative strategies arising from an inherited increased risk of breast, ovarian, prostate, melanoma, and pancreatic cancers. Cascade testing has the potential to enable cost-effective cancer control even in low- and middle-income settings, but few studies have hitherto evaluated the psychosocial impact of cascade testing in an Asian population, where the cultural and religious beliefs around inheritance and destiny have previously been shown to influence perception and attitudes toward screening. In this study, we evaluated the short- and long-term psychosocial impact of genetic testing among unaffected relatives of probands identified through the Malaysian Breast Cancer Genetics Study and the Malaysian Ovarian Cancer Study, using validated questionnaires (Hospital Anxiety and Depression Scale and Cancer Worry Scale) administered at baseline, and 1-month and 2-year post-disclosure of results. Of the 305 unaffected relatives from 98 independent families who were offered cascade testing, 256 (84%) completed predictive testing and family history of cancers was the only factor significantly associated with uptake of predictive testing. We found that the levels of anxiety, depression, and cancer worry among unaffected relatives decreased significantly after result disclosure and remained low 2-year post-result disclosure. Younger relatives and relatives of Malay descent had higher cancer worry at both baseline and after result disclosure compared to those of Chinese and Indian descent, whereas relatives of Indian descent and those with family history of cancers had higher anxiety and depression levels post-result disclosure. Taken together, the results from this Asian cohort highlight the differences in psychosocial needs in different communities and inform the development of culture-specific genetic counseling strategies., (© 2022 National Society of Genetic Counselors.)

Aim: Timely recruitment of eligible participants is essential for the success of clinical trials, with insufficient accrual being the leading cause for premature termination of both oncology and non-oncology trials., Methods: In this paper we further elaborate on the challenges for patient participation in oncology trials from physician, patient, healthcare system, and some trial-related perspectives., Results: We present strategies such as use of digital healthcare technologies, real-world data and real-world evidence, decentralized clinical trials, pragmatic trial designs, and supportive services to increase patient participation., Conclusions: Multifaceted measures are necessary to increase patient participation, especially for those who are under-represented in cancer trials., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Soy intake is associated with lower breast cancer risk in observational studies concerning Asian women, however, no randomized controlled trials (RCT) have been conducted among Asian women living in Asia. This three-armed RCT assessed the effects of one-year soy isoflavone (ISF) intervention on mammographic density (MD) change among healthy peri- and postmenopausal Malaysian women. This study was registered at ClinicalTrials.gov (NCT03686098). Participants were randomized into the 100 mg/day ISF Supplement, 50 mg/day ISF Diet, or control arm, and assessed for change in absolute and relative dense area from digital mammograms conducted at enrolment and after 12 months, compared over time across study arms using Kruskal-Wallis tests. Out of 118 women enrolled, 91 women completed the intervention, while 27 women (23%) were lost in follow up. The ISF supplement arm participants observed a larger decline in dense area (−1.3 cm2), compared to the ISF diet (−0.5 cm2) and control arm (−0.8 cm2), though it was not statistically significant (p = 0.48). Notably, among women enrolled within 5 years of menopause; dense area declined by 6 cm2 in the ISF supplement arm, compared to <1.0 cm2 in the control arm (p = 0.13). This RCT demonstrates a possible causal association between soy ISF intake and MD, a biomarker of breast cancer risk, among Asian women around the time of menopause, but these findings require confirmation in a larger trial.

Better understanding of molecular drivers and dysregulated pathways has furthered the concept of precision oncology and rational drug development. The role of DNA damage response (DDR) pathways has been extensively studied in carcinogenesis and as potential therapeutic targets to improve response to chemotherapy or overcome resistance. Treatment with small molecule inhibitors of PARP has resulted in clinical response and conferred survival benefit to patients with ovarian cancer, BRCA-mutant breast cancer, HRD-deficient prostate cancer and BRCA-mutant pancreatic cancer, leading to US Food and Drug Administration (FDA) approvals. However, the observed clinical benefit with single agent PARP inhibitors is limited to few tumor types within the relevant genetic context. Since DDR pathways are essential for repair of damage caused by cytotoxic agents, PARP inhibitors have been evaluated in combination with various chemotherapeutic agents to broaden the therapeutic application of this class of drugs. In this chapter, we discuss the combination of PARP inhibitors with different chemotherapeutics agents, clinical experience to date, lessons learnt, and future directions for this approach., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10 -8 and a Bonferroni-corrected p < 4.6 × 10 -6 , respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors., Patients and Methods: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed., Results: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062)., Conclusions: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633., (©2022 The Authors; Published by the American Association for Cancer Research.)

Objectives: In the fall of 2019, several states in the United States passed emergency bans on the sale of electronic nicotine delivery systems (ENDS), in response to an outbreak of illnesses strongly linked to tetrahydrocannabinol vaping products that received national news coverage. Given that ENDS are potential alternative nicotine products for adult smokers, banning ENDS may have unintended consequences. This study provides evidence of an association between state-level ENDS bans and cigarette sales., Methods: We used difference-in-differences and generalized synthetic control methods to estimate the impacts of the emergency ENDS bans on cigarette sales by comparing treatment states that passed ENDS bans in fall 2019 (Massachusetts, Washington, and Rhode Island), halted states that revoked the announced ENDS bans, and control states., Results: Our results show that cigarette sales in ban states were higher than would have been observed otherwise in the post-ban period. A full ban on ENDS was associated with increased cigarette sales of 7.5% in Massachusetts (P < .01); banning non-tobacco flavored ENDS was associated with 4.6% (P < .1) higher-than-expected cigarette sales. We did not detect statistically significant impacts in halted states, and placebo tests, which randomly assigned control states as treatments, showed no difference in observed cigarette sales in the same period., Conclusions: This study provides evidence that banning ENDS is associated with increased cigarette sales. Future research is needed to determine the long-term impact of these policies., (Copyright © 2022. Published by Elsevier Inc.)

Background: Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk., Methods: Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche., Results: In pooled analyses, later age at menarche was associated with higher per cent density (β √PD  = 0.023 SE = 0.008, P = 0.003) and larger dense area (β √DA  = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (β √DA  = 0.069 SE = 0.028, P = 0.012) and higher per cent density (β √PD  = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups., Conclusions: In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density., (© 2022. The Author(s).)

Background: Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 ( PALB2 ) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population., Methods: Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays., Results: PTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2 . However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks., Conclusion: Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)