Search

BackgroundExisting evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients.Patients and methodsChemotherapy-receiving breast cancer patients (stages I-III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, interferon-γ and tumor necrosis factor-α] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain.ResultsNinety-nine patients were included (age 50.5 ± 8.4 years; 81.8% Chinese; mean duration of education = 10.8 ± 3.3 years). Higher plasma IL-1β was associated with poorer response speed performance (estimate: -0.78; 95% confidence interval (CI) -1.34 to -0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1β and IL-6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022).ConclusionsWhile elevated concentrations of IL-6 and IL-1β were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes.

Background: The incidence of breast cancer among young Asian women is increasing, yet they remain underrepresented in global data. We analyzed the epidemiology and outcomes of Asian patients with breast cancer <40 years old across different subtypes to identify their clinical unmet needs., Patients and Methods: Female patients aged ≥20 years diagnosed with early breast cancer were analyzed from the prospective cohort of the Asian Breast Cancer Cooperative Group (ABCCG). For comparison, data from the Surveillance, Epidemiology, and End Results Program (SEER) cancer registry were used. Patients were categorized into three age groups: young (<40 years), alleged premenopausal mid-age (40-49 years), and alleged postmenopausal (aged ≥50 years). Multivariable Cox proportional hazards models for survival were adjusted for subtypes, histologic grade, T stage, nodal status, and study centers., Results: A total of 45 021 patients with breast cancer from Asian study centers, 496 332 SEER-White patients, and 18 279 SEER-Asian patients were included in the analysis. The median age at diagnosis was younger in the Asian cohort (51 years) compared with SEER-Whites (62 years) and SEER-Asians (58 years; P < 0.0001). In the young-age group, hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer was more prevalent among Asians and SEER-Asians compared with SEER-Whites (61.2% and 59.8% versus 54.7%). In the Asian population, young patients with HR+/HER2- breast cancer exhibited significantly inferior overall survival than the mid-age group (6-year overall survival 94.4% versus 96.6%; mid-age to young-age group hazard ratio 0.62; P < 0.001). Similarly, young patients in SEER-Whites showed an earlier decline in survival compared with the mid-age group (89.1% versus 94.0%; P < 0.001)., Conclusion: ABCCG-Asian patients with breast cancer <40 years old with HR+/HER2- subtypes were more likely to have worse survival outcomes than their mid-age counterparts. Our study highlights the poorer prognosis of young patients and underscores the need for a tailored therapeutic approach, such as ovarian function suppression, particularly considering ethnic factors., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: A prior pooled analysis of the MONALEESA-2, -3, and -7 trials identified baseline markers predictive of sensitivity or resistance to ribociclib plus endocrine therapy (ET). We report the results of an analysis of paired baseline and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples across the MONALEESA trials., Patients and Methods: Paired baseline and EOT ctDNA samples from MONALEESA-2, -3, and -7 were sequenced using a targeted next-generation sequencing panel. Genes with an EOT alteration prevalence of >5% were included. A McNemar test was carried out on paired samples and adjusted for multiple testing to control the false discovery rate. A Bayesian mixed-effects model was used to adjust for ctDNA fraction at both time points and for study differences., Results: The analysis included 523 paired samples. At EOT, 21 genes had a >5% alteration prevalence. A trend for higher ctDNA fraction at EOT versus baseline (P = 0.08) was observed. Prevalence of alterations was higher at EOT versus baseline in RB1, SPEN, TPR, PCDH15, and FGFR2 in the ribociclib arm; PBRM1 in the placebo arm; and ESR1 in both arms. The mixed-effects model demonstrated that the same trends for increased prevalence of these alterations at EOT were observed after adjusting for ctDNA fraction and that the increased rate of RB1 and SPEN alterations at EOT were specific to ribociclib plus ET. Analysis of ESR1 indicated a similar increase at EOT in both arms. The most common acquired ESR1 mutations at EOT included Y537C/N/S/D, D538G, E380Q, and L536H/R/P/LC. The prevalence of PIK3CA hotspot mutations at baseline and EOT was similar., Conclusions: This analysis identified acquired gene alterations in patients with hormone receptor-positive/human epidermal growth factor receptor-2 negative advanced breast cancer treated with ribociclib plus ET or placebo plus ET. These data may support further studies on acquired resistance mechanisms and inform future systemic interventions in the post-cyclin-dependent kinase 4/6 inhibitor setting., (Copyright © 2024. Published by Elsevier Ltd.)

Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib-tamoxifen in patients with HR+/HER2- advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib-tamoxifen or placebo-tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1-32.4) with palbociclib-tamoxifen and 11.1 months (95% CI, 7.4-14.6) with placebo-tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43-0.85; P = 0.002). Palbociclib-tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44-1.21) with palbociclib-tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib-tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo-tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2- advanced breast cancer, palbociclib-tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib-tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018., (© 2024. The Author(s).)

Purpose: A head-to-head comparison of efficacy between a cyclin-dependent kinase 4/6 inhibitor plus endocrine therapy (ET) versus combination chemotherapy (CT) has never been reported in patients with clinically aggressive hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC)., Methods: In this open-label, multicenter, randomized phase II trial, pre/perimenopausal women with clinically aggressive HR+/HER2- ABC were randomly assigned 1:1 to first-line ribociclib (600 mg once daily; 3 weeks on, 1 week off) plus letrozole/anastrozole and goserelin or investigator's choice of combination CT (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine). The primary end point was progression-free survival (PFS)., Results: Among 222 patients randomly assigned to ribociclib plus ET (n = 112) or combination CT (n = 110), 150 (67.6%) had symptomatic visceral metastases, 41 (18.5%) had rapid disease progression per investigator's judgment, and 31 (14.0%) had symptomatic nonvisceral disease. Overall, 106 (47.7%) patients had investigator-assessed visceral crisis. The median follow-up time was 37.0 months. At data cutoff, 31.3% (ribociclib arm) and 15.5% (CT arm) of patients had completed study treatment and transitioned to post-trial access. The median PFS was 21.8 months (ribociclib plus ET; [95% CI, 17.4 to 26.7]) and 12.8 months (combination CT; [95% CI, 10.1 to 18.4); hazard ratio, 0.61 [95% CI, 0.43 to 0.87]; P = .003. The overall response rates and the median time to response in the ribociclib versus CT arms, respectively, were 66.1% and 61.8% and 4.9 months and 3.2 months (hazard ratio, 0.76 [95% CI, 0.55 to 1.06]). Lower rates of symptomatic adverse events were observed in the ribociclib versus CT arm., Conclusion: First-line ribociclib plus ET showed a significant PFS benefit, similar response rates, and better tolerability over combination CT in patients with clinically aggressive HR+/HER2- ABC.

Background: Although considered a favorable subtype, pure mucinous breast cancer (PMBC) can recur, and evidence for adjuvant therapy is limited. We aimed to compare outcomes of nonmetastatic PMBC with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) to address these uncertainties., Methods: Individual patient-level data from 6 centers on stage I-III hormone receptor-positive and HER2-negative PMBC, IDC, and ILC were used to analyze recurrence-free interval (RFI), recurrence-free survival (RFS), and overall survival (OS), and to identify prognostic factors for PMBC., Results: Data from 20,684 IDC cases, 1,475 ILC cases, and 943 PMBC cases were used. Median follow-up was 6.6 years. Five-year RFI, RFS, and OS for PMBC were 96.1%, 94.9%, and 98.1%, respectively. On multivariable Cox regression, PMBC demonstrated superior RFI (hazard ratio [HR], 0.59; 95% CI, 0.43-0.80), RFS (HR, 0.70; 95% CI, 0.56-0.89), and OS (HR, 0.71; 95% CI, 0.53-0.96) compared with IDC. ILC showed comparable outcomes to IDC. Fewer than half (48.7%) of recurrences in PMBC were distant, which was a lower rate than for IDC (67.3%) and ILC (80.6%). In contrast to RFI, RFS events were driven more by non-breast cancer deaths in older patients. Significant prognostic factors for RFI among PMBC included positive lymph node(s) (HR, 2.42; 95% CI, 1.08-5.40), radiotherapy (HR, 0.44; 95% CI, 0.23-0.85), and endocrine therapy (HR, 0.25; 95% CI, 0.09-0.70). No differential chemotherapy associations with outcomes were detected across PMBC subgroups by nodal stage, tumor size, and age. A separate SEER database analysis also did not find any association of improved survival with adjuvant chemotherapy in these subgroups., Conclusions: Compared with IDC, PMBC demonstrated superior RFI, RFS, and OS. Lymph node negativity, adjuvant radiotherapy, and endocrine therapy were associated with superior RFI. Adjuvant chemotherapy was not associated with better outcomes.

Purpose: The MONALEESA-2, -3, -7 trials demonstrated statistically significant and clinically meaningful progression-free survival and overall survival (OS) benefits with ribociclib plus endocrine therapy (ET) versus ET alone in hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC). Understanding the association of intrinsic subtypes with survival outcomes could potentially guide treatment decisions. Here, we evaluated the association of intrinsic subtypes with OS in MONALEESA-2, -3, -7., Experimental Design: Tumor samples from MONALEESA-2, -3, -7 underwent PAM50-based subtyping. The relationship between subtypes and OS was assessed using univariable and multivariable Cox proportional hazards models. Multivariable models were adjusted for clinical prognostic factors., Results: Overall, 990 tumors (among 2,066 patients) from ribociclib (n = 580) and placebo (n = 410) arms were profiled. Subtype distribution was luminal A, 54.5%; luminal B, 28.0%; HER2-enriched (HER2E) 14.6%; and basal-like, 2.8%; and was consistent across treatment arms. The luminal A subtype had the best OS outcomes in both arms, while basal-like had the worst. Patients with HER2E (HR, 0.60; P = 0.018), luminal B (HR, 0.69; P = 0.023), and luminal A (HR, 0.75; P = 0.021) subtypes derived OS benefit with ribociclib. Patients with basal-like subtype did not derive benefit from ribociclib (HR, 1.92; P = 0.137); however, patient numbers were small (n = 28)., Conclusions: The prognostic value of intrinsic subtypes for OS was confirmed in this pooled analysis of the MONALEESA trials (largest dataset in HR+/HER2- ABC). While basal-like subtype did not benefit, a consistent OS benefit was observed with ribociclib added to ET across luminal and HER2E subtypes., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Recently, HER2-negative breast cancers have been reclassified by protein expression into 'HER2-low' and 'HER2-zero' subgroups, but the consideration of HER2-low breast cancer as a distinct biological subtype with differing prognoses remains controversial. By contrast, non-neutral ERBB2 copy number alteration (CNA) status is associated with inferior survival outcomes compared to ERBB2 CNA-neutral breast cancer, providing an alternative approach to classification., Methods: Here, we investigated the molecular landscape of non-metastatic HER2-negative BCs in relation to ERBB2 CNA status to elucidate biological differences. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) TCGA-BRCA datasets ( n = 1875) were analyzed., Results: Nearly two-fifths of the cohort harbored ERBB2 CNAs (39.4%), which were significantly enriched within hormone receptor-negative (56.1%) than within hormone receptor-positive BCs (35.5%; p < 0.0001). Globally, CNAs across the genome were significantly higher in ERBB2 non-neutral compared to neutral cohorts ( p < 0.0001). Notably, genetic aberrations on chromosome 17 - BRCA1 , NF1 , TP53 , MAP2K4, and NCOR1 - were widespread in the ERBB2 non-neutral cases. While chromosome 17q arm-level alterations were largely in tandem with ERBB2 CNA status, arm-level loss in chromosome 17p was prevalent regardless of ERBB2 gain, amplification, or loss. Differential gene expression analysis demonstrated that pathways involved in the cell cycle, proteasome, and DNA replication were upregulated in ERBB2 non-neutral cases., Conclusion: Classification of HER2-negative BCs according to ERBB2 CNA status reveals differences in the genomic landscape. The implications of concurrent aberrations in other genes on chromosome 17 merit further research in ERBB2 non-neutral BCs., (© The Author(s), 2023.)

Endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the standard first-line treatment for most patients with hormone receptor (HR) positive, human epidermal growth factor receptor (HER2) negative advanced breast cancer. However, resistance to ET and CDK4/6i inevitably ensues. The optimal post-progression treatment regimens and their sequencing continue to evolve in the rapidly changing treatment landscape. In this review, we summarize the mechanisms of resistance to ET and CDK4/6i, which can be broadly classified as alterations affecting cell cycle mediators and activation of alternative signaling pathways. Recent clinical trials have been directed at the targets and pathways implicated, including estrogen and androgen receptors, PI3K/AKT/mTOR and MAPK pathways, tyrosine kinase receptors such as FGFR and HER2, homologous recombination repair pathway, other components of the cell cycle and cell death. We describe the findings from these clinical trials using small molecule inhibitors, antibody-drug conjugates and immunotherapy, providing insights into how these novel strategies may circumvent treatment resistance, and discuss how some have not translated into clinical benefit. The challenges posed by tumor heterogeneity, adaptive rewiring of signaling pathways and dose-limiting toxicities underscore the need to elucidate the latest tumor biology in each patient, and develop treatments with improved therapeutic index in the era of precision medicine., (© 2023. Springer Nature Limited.)

Background: There is increasing interest in the use of liquid biopsies, but data on longitudinal analyses of circulating tumor DNA (ctDNA) remain relatively limited. Here, we report a longitudinal ctDNA analysis of MONALEESASIA, a phase Ib trial evaluating the efficacy and safety of ribociclib plus endocrine therapy (ET) in Asian patients with hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer., Methods: MONALEESASIA enrolled premenopausal and postmenopausal Japanese and postmenopausal non-Japanese Asian patients. All patients received ribociclib with ET (letrozole, fulvestrant, or tamoxifen with goserelin). ctDNA was analyzed using a targeted next-generation sequencing panel of 572 cancer-related genes and correlated by best overall response (BOR)., Results: Five hundred seventy-four cell-free DNA samples from 87 patients were tested. The most frequently altered genes at baseline included PIK3CA (29%) and TP53 (22%). Treatment with ribociclib plus ET decreased ctDNA in most patients at the first on-treatment time point, regardless of dose or ET partner. Patients with partial response and stable disease had lower ctDNA at baseline that remained low until data cutoff if no progressive disease occurred. Most patients with progressive disease as the best response had higher ctDNA at baseline that remained high at the end of treatment. For patients with partial response and stable disease with subsequent progression, ctDNA increased towards the end of treatment in most patients, with a median lead time of 83 days (14-309 days). In some patients with BOR of partial response who experienced disease progression later, specific gene alterations and total ctDNA fraction increased; this was sometimes observed concurrently with the development of new lesions without a change in target lesion size. Patients with alterations in PIK3CA and TP53 at baseline had shorter median progression-free survival compared with patients with wild-type PIK3CA and TP53, 12.7 and 7.3 months vs 19.2 and 19.4 months, respectively (P = .016 and P = .0001, respectively)., Conclusions: Higher ctDNA levels and PIK3CA and TP53 alterations detected at baseline were associated with inferior outcomes. On-treatment ctDNA levels were associated with different patterns based on BOR. Longitudinal tracking of ctDNA may be useful for monitoring tumor status and detection of alterations with treatment implications., Trial Registration: ClinicalTrials.gov NCT02333370 . Registered on January 7, 2015., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Cancer predisposition is most often studied in the context of single cancers. However, inherited cancer predispositions can also give rise to multiple primary cancers. Yet, there is a paucity of studies on genetic predisposition in multiple primary cancers, especially those outside of well-defined cancer predisposition syndromes. This study aimed to identify germline variants associated with dual primary cancers of the breast and lung., Methods: Exome sequencing was performed on germline DNA from 55 Singapore patients (52 [95%] never-smokers) with dual primaries in the breast and lung, confirmed by histopathology. Using two large control cohorts: the local SG10K&#95;Health (n = 9770) and gnomAD non-cancer East Asians (n = 9626); and two additional local case cohorts of early-onset or familial breast cancer (n = 290), and lung cancer (n = 209), variants were assessed for pathogenicity in accordance with ACMG/AMP guidelines. In particular, comparisons were made with known pathogenic or likely pathogenic variants in the ClinVar database, pathogenicity predictions were obtained from in silico prediction software, and case-control association analyses were performed., Results: Altogether, we identified 19 pathogenic or likely pathogenic variants from 16 genes, detected in 17 of 55 (31%) patients. Six of the 19 variants were identified using ClinVar, while 13 variants were classified pathogenic or likely pathogenic using ACMG/AMP guidelines. The 16 genes include well-known cancer predisposition genes such as BRCA2, TP53, and RAD51D; but also lesser known cancer genes EXT2, WWOX, GATA2, and GPC3. Most of these genes are involved in DNA damage repair, reaffirming the role of impaired DNA repair mechanisms in the development of multiple malignancies. These variants warrant further investigations in additional populations., Conclusions: We have identified both known and novel variants significantly enriched in patients with primary breast and lung malignancies, expanding the body of known cancer predisposition variants for both breast and lung cancer. These variants are mostly from genes involved in DNA repair, affirming the role of impaired DNA repair in the predisposition and development of multiple cancers., (© 2023. The Author(s).)

Ethnic or racial differences in breast cancer (BC) survival outcomes have been reported, but current data are largely restricted to comparisons between African Americans and non-Hispanic whites. Most analyses have traditionally been based on self-reported race which may not always be accurate, or are oversimplified in their classification. With increasing globalization, quantification of the genetic ancestry from genomic data may offer a solution to infer the complex makeup from admixture of races. Focusing on the larger and the latest studies, we will discuss recent findings on the differing host and tumor biology that may be driving these disparities, in addition to the extrinsic environmental or lifestyle factors. Socioeconomic disparities with lower cancer literacy may lead to late presentation, poorer adherence to treatment, and other lifestyle factors such as unhealthy diet, obesity, and inadequate physical activity. These hardships may also result in greater allostatic load, which is in turn associated with aggressive BC features in disadvantaged populations. Epigenetic reprogramming may mediate the effects of the environment or lifestyle factors on gene expression, with ensuing differences in BC characteristics and outcome. There is increasing evidence that germline genetics can influence somatic gene alterations or expression, as well as modulate the tumor or immune microenvironment. Although the precise mechanisms remain elusive, this may account for the varying distribution of different BC subtypes across ethnicities. These gaps in our knowledge highlight the need to interrogate the multiomics landscape of BC in diverse populations, ideally in large-scale collaborative settings with standardized methodology for the comparisons to be statistically robust. Together with improving BC awareness and access to good quality health care, a holistic approach with insights of the biological underpinnings is much needed to eradicate ethnic disparities in BC outcomes., Competing Interests: Disclosure YSY is supported by Singapore National Medical Research Council (NMRC) Clinician Scientist Award (MOH-CSAINV18nov-0009) and reports honoraria/personal fees from Novartis, Pfizer, Lilly/DKSH, Astra Zeneca, Eisai, MSD, Specialised Therapeutics, and Roche; travel support from DKSH and Astra Zeneca; and research support from MSD, outside the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Auf der Maur et al. 1 identify neurofibromin 1 (NF1) loss as a mechanism of resistance to PI3K inhibitor in breast cancer cells. NF1 loss leads to enhanced glycolysis, which may be targeted with the antioxidant N-acetyl cysteine (NAC)., Competing Interests: Declaration of interests Y.S.Y. reports honoraria/personal fees from Novartis, Pfizer, Lilly/DKSH, Astra Zeneca, Eisai, MSD, Specialised Therapeutics, and Roche; travel support from DKSH and Astra Zeneca; and research support from MSD, outside the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4-hydroxy-tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6). Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross-ancestry genome-wide association study with well-characterized patients of European, Middle-Eastern, and Asian descent (n = 497) to identify genetic factors impacting active and parent metabolite formation. Genome-wide significant variants were functionally evaluated in an independent liver cohort (n = 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (n = 287, n = 189). Within a single 1-megabase (Mb) region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and metabolic ratio (MR) endoxifen/N-desmethyltamoxifen (minimal P = 5.4E-35 and 2.5E-65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (ρ = 0.35 to -0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (n = 12) plus CYP2D6 activity score (AS) increased the explained variability (~ 9%) compared with AS alone, explaining up to 49% (median R 2 ) and 72% of the variability in endoxifen and MR endoxifen/N-desmethyltamoxifen, respectively. Our findings suggest that the extended CYP2D6 locus at 22q13 is the principal genetic determinant of endoxifen plasma concentration. Long-distance haplotypes connecting CYP2D6 with adjacent regulatory sites and nongenetic factors may account for the unexplained portion of variability., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: This study aimed to investigate the relationship between cardiomegaly and aortic arch calcification (AAC) and overall/cardiovascular mortality in hemodialysis patients., Methods: We conducted a retrospective cohort study and enrolled patients who underwent initial hemodialysis. Cardiomegaly and AAC were determined by chest radiography and classified into four groups according to cross-classification of cardiothoracic ratio (CTR) of 0.5 and lower/higher grade AAC (LGAAC/HGAAC). The relationship between these groups and mortality was then analyzed by Cox proportional hazards model., Results: In multivariate Cox regression analysis, those in CTR ≤ 0.5 and HGAAC [hazard ratio (95% confidence interval): 2.07 (1.14-3.77)], CTR > 0.5 & LGAAC [3.60 (2.07-6.25)] and CTR > 0.5 & HGAAC [3.42 (2.03-5.77)] were significantly associated with overall mortality; while those in CTR > 0.5 & LGAAC [2.81 (1.28-6.19)] and CTR > 0.5 & HGAAC [2.32 (1.09-4.95)] were significantly related to cardiovascular mortality., Conclusion: Combined cardiomegaly and AAC predicted overall and cardiovascular mortality in hemodialysis patients., (© 2022 International Society for Apheresis and Japanese Society for Apheresis.)

TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The identification and characterization of circulating tumor cells (CTCs) are important for gaining insights into the biology of metastatic cancers, monitoring disease progression, and medical management of the disease. The limiting factor in the enrichment of purified CTC populations is their sparse availability, heterogeneity, and altered phenotypes relative to the primary tumor. Intensive research both at the technical and molecular fronts led to the development of assays that ease CTC detection and identification from peripheral blood. Most CTC detection methods based on single-cell RNA sequencing (scRNA-seq) use a mix of size selection, marker-based white blood cell (WBC) depletion, and antibodies targeting tumor-associated antigens. However, the majority of these methods either miss out on atypical CTCs or suffer from WBC contamination. We present unCTC, an R package for unbiased identification and characterization of CTCs from single-cell transcriptomic data. unCTC features many standard and novel computational and statistical modules for various analyses. These include a novel method of scRNA-seq clustering, named deep dictionary learning using k -means clustering cost (DDLK), expression-based copy number variation (CNV) inference, and combinatorial, marker-based verification of the malignant phenotypes. DDLK enables robust segregation of CTCs and WBCs in the pathway space, as opposed to the gene expression space. We validated the utility of unCTC on scRNA-seq profiles of breast CTCs from six patients, captured and profiled using an integrated ClearCell FX and Polaris workflow that works by the principles of size-based separation of CTCs and marker-based WBC depletion., (© 2023 Poonia et al.; Published by Cold Spring Harbor Laboratory Press.)

We present a control and measurement setup for superconducting qubits based on the Xilinx 16-channel radio-frequency system-on-chip (RFSoC) device. The proposed setup consists of four parts: multiple RFSoC boards, a setup to synchronize every digital to analog converter (DAC) and analog to digital converter (ADC) channel across multiple boards, a low-noise direct current supply for tuning the qubit frequency, and cloud access for remotely performing experiments. We also designed the setup to be free of physical mixers. The RFSoC boards directly generate microwave pulses using sixteen DAC channels up to the third Nyquist zone, which are directly sampled by its eight ADC channels between the fifth and the ninth zones.

Purpose: Breast cancer (BC) treatment has shifted from chemotherapy to targeted therapy. Several targeted agents have demonstrated an improvement in survival. Given that national healthcare resources were correlated with the cancer mortality-to-incidence ratio, we compared access to BC drugs in Thailand with that in other Asian countries., Methods: BC experts involved in the Breast International Group (BIG)-Asia in six representative groups for countries or special administrative region (SAR) in Asia (Hong Kong SAR, Japan, Korea, Taiwan, Thailand, and Singapore) were invited to participate in the survey. The questionnaire addressed national health reimbursement schemes, molecular testing for early BC (EBC), availability and accessibility of BC drugs. Accessibility and reimbursement of the drugs were reported based on their listing as essential medicines in the World Health Organization Model List of Essential Medicines (WHO-EML) and their nomination as effective drugs in the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). The study was approved by all participating BIG-Asia organizations in November 2021., Results: Genomic tests for EBC were non-reimbursable in all surveyed territories. Reimbursement and co-payment of BC drugs vary between and within these regions (particularly Thailand). Most drugs in the WHO-EML and ESMO-MCBS (A/B for EBC and 4/5 for advanced BC) were accessible in all surveyed territories. However, the accessibility of effective but costly WHO-EML and ESMO-MCBS drugs was not uniform in Thailand. There was an evident disparity for individuals covered by the Thai Social Security/Universal Health Coverage schemes., Conclusion: Essential BC drugs are generally accessible in selected BIG-Asia countries or SAR. There is a disparity in accessing high-cost drugs in Thailand compared with other Asian territories., Competing Interests: SI received an honorarium from Novartis., (© 2022 Korean Breast Cancer Society.)

Background: HER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC)., Methods: Patients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) (n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH-) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH- status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort (n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS., Results: ABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82-0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76-0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85-0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79-0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83-0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78-0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH- and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59-0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found., Conclusions: HER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC., (© 2022. The Author(s).)

Background: In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known., Methods: Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings., Results: After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed., Conclusions: First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.)., (Copyright © 2022 Massachusetts Medical Society.)

Detection of minimal residual disease in patients with cancer, who are in complete remission with no cancer cells detectable, has the potential to improve recurrence-free survival through treatment selection. Studies analyzing circulating tumor DNA (ctDNA) in patients with solid tumors suggest the potential to accurately predict and detect relapse, enabling treatment strategies that may improve clinical outcomes. Over the past decade, assays for ctDNA detection in plasma samples have steadily increased in sensitivity and specificity. These are applied for the detection of residual disease after treatment and for earlier detection of recurrence. Novel clinical trials are now assessing how assays for "residual disease and recurrence" (RDR) may influence current treatment paradigms and potentially change the landscape of risk classification for cancer recurrence. In this review, we appraise the progress of RDR detection using ctDNA and consider the emerging role of liquid biopsy in the monitoring and management of solid tumors., Competing Interests: Declaration of interests J.C.M.W. and N.R. are inventors/contributors on patents covering methods for ctDNA detection (including WO/2020/104670). P.R. reports institutional research funding from Novartis, Grail/Illumina, ArcherDx/Invitae, Inivata, Epic Sciences, and Tempus; advisory board/honoraria from Novartis, AstraZeneca, Foundation Medicine, Pfizer, Epic Sciences, Inivata, and Natera; and consulting for Tempus. Y.-S.Y. reports honoraria/consultancy from Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, and Specialised Therapeutics and travel support from Pfizer, Eisai, and Roche. S.-J.D. has received research funding from Roche Genentech and Cancer Therapeutics (CTx) CRC and has been an advisory board member for AstraZeneca and Inivata. S.K. serves on the advisory board and is a consultant for Inivata and Natera. N.R. and C.D.M. are officers of Inivata. T.I.M., P.R., E.L.M., R.G., I.T., Y.-S.Y., W.A.R., B.B., A.B., and J.T. served on the advisory board and consulted for Inivata., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Breast cancer (BC) among Asians accounts for ~ 40% of the global BC burden. Differences in BC risk, presentation, tumor biology, and response to treatment exist between Asian and non-Asian patients; however, Asian patients are often under-represented in clinical trials. This narrative review summarizes the efficacy and safety of pharmacological therapies for BC in Asian populations, with a focus on outcomes in Asian versus non-Asian patients treated with chemotherapy, hormone therapy, anti-human epidermal growth factor receptor-2 targeted therapies, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, mammalian target of rapamycin inhibitors, bone-targeted therapies, poly-ADP ribose polymerase, phosphoinositide 3-kinase, and checkpoint inhibitors. While most therapies have demonstrated comparable efficacy and safety in Asian and non-Asian patients with BC, differences that are largely attributed to pharmacogenetic variations between populations exist. Pharmacogenetic differences may contribute to a reduced clinical benefit of tamoxifen, whereas improved clinical outcomes have been reported with tyrosine kinase inhibitors and CDK4/6 inhibitors in Asian versus non-Asian patients with BC. In particular, Asian patients have an increased incidence of hematological toxicities, including neutropenia, although adverse events can be effectively managed using dose adjustments. Recent trials with CDK4/6 inhibitors have increased efforts to include Asians within study subsets. Future clinical trials enrolling higher numbers of Asian patients, and an increased understanding of differences in patient and tumor genetics between Asians and non-Asians, have the potential to incrementally improve the management of BC in Asian patients., (© 2021. The Author(s).)

Purpose: Data are sparse for oral selective estrogen receptor (ER) degraders (SERD) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study., Patients and Methods: A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n = 77) or with ribociclib (arm B; n = 78) or alpelisib (arm C; n = 43) in heavily pretreated adults with histologically confirmed ER-positive breast cancer and prior disease progression. Arm A received LSZ102 200-900 mg/day; arm B, LSZ102 200-600 mg/day plus ribociclib 300-600 mg/day; arm C, LSZ102 300-450 mg/day plus alpelisib 200-300 mg/day. Key outcomes were dose-limiting toxicities (DLT) in the first 28-day treatment cycle, adverse events (AE), laboratory parameters, pharmacokinetics, biopsy ER protein, and investigator-assessed clinical response (RECIST v1.1)., Results: The most common AEs were gastrointestinal. Treatment-related serious AEs occurred in 10% of participants (19/198), mostly in arm C [10/43 (23%)]. DLTs occurred in: arm A, 5% (4/77); arm B, 3% (2/78); and arm C, 19% (8/43). LSZ102 exposure was slightly greater than dose proportional. On-treatment biopsy ER reductions were observed, with a trend toward an LSZ102 dose response. Objective response rates (95% confidence interval) were: arm A, 1.3% (0.0-7.0); arm B, 16.9% (9.3-27.1); and arm C, 7.0% (1.5-19.1), and clinical benefit rates 7.8% (2.9-16.2), 35.1% (24.5-46.8), and 20.9% (10.0-36.0), respectively., Conclusions: LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use., (©2021 The Authors; Published by the American Association for Cancer Research.)

Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states.

Purpose: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein., Methods: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m 2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m 2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety., Results: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity., Conclusion: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted., Clinical Trial Registration: NCT01808573., (© 2021. The Author(s).)

Introduction: Circulating tumor cells (CTCs) and cell-free tumor DNA (ctDNA) are tumor components present in circulation. Due to the limited access to both CTC enrichment platforms and ctDNA sequencing in most laboratories, they are rarely analyzed together., Methods: Concurrent isolation of ctDNA and single CTCs were isolated from lung cancer and breast cancer patients using the combination of size-based and CD45-negative selection method via DropCell platform. We performed targeted amplicon sequencing to evaluate the genomic heterogeneity of CTCs and ctDNA in lung cancer and breast cancer patients., Results: Higher degrees of genomic heterogeneity were observed in CTCs as compared to ctDNA. Several shared alterations present in CTCs and ctDNA were undetected in the primary tumor, highlighting the intra-tumoral heterogeneity of tumor components that were shed into systemic circulation. Accordingly, CTCs and ctDNA displayed higher degree of concordance with the metastatic tumor than the primary tumor. The alterations detected in circulation correlated with worse survival outcome for both lung and breast cancer patients emphasizing the impact of the metastatic phenotype. Notably, evolving genetic signatures were detected in the CTCs and ctDNA samples during the course of treatment and disease progression., Conclusions: A standardized sample processing and data analysis workflow for concurrent analysis of CTCs and ctDNA successfully dissected the heterogeneity of metastatic tumor in circulation as well as the progressive genomic changes that may potentially guide the selection of appropriate therapy against evolving tumor clonality., Competing Interests: ST is the current employee of Sysmex and ex-employee of Clearbridge mFluidics Pte Ltd. YL is ex-employee of Biolidics Ltd. CL is a cofounder and shareholder of Biolidics Ltd. The remaining 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 © 2021 Kong, Liu, Tan, Tai, Phua, Poh, Yeo, Chua, Haw, Ling, Ng, Tan, Loh, Tan, Ng, Ang, Toh, Lee, Lim, Lim, Hillmer, Yap and Lim.)

Purpose: Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center., Patients and Methods: Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made., Results: One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors., Conclusion: Individualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology., Competing Interests: Aaron C. Tan Honoraria: Amgen, Thermo Fisher Scientific Travel, Accommodations, Expenses: ASLAN Pharmaceuticals, Illumina Tira J. Tan Stock and Other Ownership Interests: Immunomedics Honoraria: AstraZeneca, Roche/Genentech Consulting or Advisory Role: AstraZeneca, Lilly, Pfizer, DKSH, Novartis Speakers' Bureau: Novartis Research Funding: Bayer, Novartis, AstraZeneca, Odonate Therapeutics, Synthon Travel, Accommodations, Expenses: AstraZeneca, Eisai Matthew C. H. Ng Honoraria: MSD Oncology, Taiho Pharmaceutical, ASLAN Pharmaceuticals, Lilly Consulting or Advisory Role: MSD Oncology, Bristol Myers Squibb, Novartis, Merck Speakers' Bureau: Lilly Research Funding: ASLAN Pharmaceuticals Travel, Accommodations, Expenses: MSD Oncology, Taiho Pharmaceutical, Bristol Myers Squibb David W. M. Tai Honoraria: Bristol Myers Squibb, Eisai Consulting or Advisory Role: Bristol Myers Squibb, Eisai Speakers' Bureau: Ipsen, Bristol Myers Squibb, Eisai, Roche Research Funding: Bristol-Myers Squibb, Sirtex Medical, Novartis. Justina Y. C. Lam Honoraria: AstraZeneca Consulting or Advisory Role: AstraZeneca Research Funding: Bayer, Merus, Bristol Myers Squibb Travel, Accommodations, Expenses: Lilly Bien-Soo Tan Research Funding: Boston Scientific Rebecca Alexandra Dent Honoraria: Roche/Genentech, AstraZeneca, Pfizer, MSD Consulting or Advisory Role: Roche, Pfizer, Merck, Eisai, AstraZeneca, Novartis Travel, Accommodations, Expenses: Roche, Pfizer, Amgen, Merck Yoon-Sim Yap Honoraria: Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, Inivata Consulting or Advisory Role: Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, Inivata Travel, Accommodations, Expenses: Pfizer, AstraZeneca, Eisai, Lilly, Roche, Novartis Iain B. H. Tan Honoraria: Amgen, Roche, Merck Serono, MSD Consulting or Advisory Role: Amgen, Roche, Merck Serono, MSD, Novartis Research Funding: MSD Travel, Accommodations, Expenses: Merck Serono, Amgen Su Pin Choo Honoraria: Bristol Myers Squibb, AstraZeneca Consulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Bayer, MSD Oncology, Eisai, Roche Travel, Accommodations, Expenses: Taiho Pharmaceutical, Bristol Myers Squibb Chee-Keong Toh Stock and Other Ownership Interests: Nektar Consulting or Advisory Role: Merck, Bristol Myers Squibb/Celgene, Astellas Pharma, MSD Oncology, Roche, DKSH, Natera, Eisai, Pfizer Speakers' Bureau: Ipsen, AstraZeneca, Merck, Astellas Pharma Mohamad Farid Honoraria: Bayer Consulting or Advisory Role: Bayer N. Gopalakrishna Iyer Consulting or Advisory Role: InvitroCue Patents, Royalties, Other Intellectual Property: A device and method of providing lighting during surgeries in deep and narrow cavities Inventors: N. C. Tan, W. S. Tan, M. H. Chew, H. K. Tan, P. Sunkeri, R. S. L. Lieu, F. W. L. Loke, N. G. Iyer. PCTSG2016-050231. Licensed to Vivo Surgical Pte Ltd Wan Teck Lim Consulting or Advisory Role: Roche, AstraZeneca, MSD Oncology, Novartis, Boehringer Ingelheim Research Funding: Bristol Myers Squibb Travel, Accommodations, Expenses: AstraZeneca, Taiho Pharmaceutical Daniel S. W. Tan Honoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, Pfizer Consulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer Research Funding: Novartis, GlaxoSmithKline, AstraZeneca Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche No other potential conflicts of interest were reported.Aaron C. Tan Honoraria: Amgen, Thermo Fisher Scientific Travel, Accommodations, Expenses: ASLAN Pharmaceuticals, Illumina Tira J. Tan Stock and Other Ownership Interests: Immunomedics Honoraria: AstraZeneca, Roche/Genentech Consulting or Advisory Role: AstraZeneca, Lilly, Pfizer, DKSH, Novartis Speakers' Bureau: Novartis Research Funding: Bayer, Novartis, AstraZeneca, Odonate Therapeutics, Synthon Travel, Accommodations, Expenses: AstraZeneca, Eisai Matthew C. H. Ng Honoraria: MSD Oncology, Taiho Pharmaceutical, ASLAN Pharmaceuticals, Lilly Consulting or Advisory Role: MSD Oncology, Bristol Myers Squibb, Novartis, Merck Speakers' Bureau: Lilly Research Funding: ASLAN Pharmaceuticals Travel, Accommodations, Expenses: MSD Oncology, Taiho Pharmaceutical, Bristol Myers Squibb David W. M. Tai Honoraria: Bristol Myers Squibb, Eisai Consulting or Advisory Role: Bristol Myers Squibb, Eisai Speakers' Bureau: Ipsen, Bristol Myers Squibb, Eisai, Roche Research Funding: Bristol-Myers Squibb, Sirtex Medical, Novartis. Justina Y. C. Lam Honoraria: AstraZeneca Consulting or Advisory Role: AstraZeneca Research Funding: Bayer, Merus, Bristol Myers Squibb Travel, Accommodations, Expenses: Lilly Bien-Soo Tan Research Funding: Boston Scientific Rebecca Alexandra Dent Honoraria: Roche/Genentech, AstraZeneca, Pfizer, MSD Consulting or Advisory Role: Roche, Pfizer, Merck, Eisai, AstraZeneca, Novartis Travel, Accommodations, Expenses: Roche, Pfizer, Amgen, Merck Yoon-Sim Yap Honoraria: Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, Inivata Consulting or Advisory Role: Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, Inivata Travel, Accommodations, Expenses: Pfizer, AstraZeneca, Eisai, Lilly, Roche, Novartis Iain B. H. Tan Honoraria: Amgen, Roche, Merck Serono, MSD Consulting or Advisory Role: Amgen, Roche, Merck Serono, MSD, Novartis Research Funding: MSD Travel, Accommodations, Expenses: Merck Serono, Amgen Su Pin Choo Honoraria: Bristol Myers Squibb, AstraZeneca Consulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Bayer, MSD Oncology, Eisai, Roche Travel, Accommodations, Expenses: Taiho Pharmaceutical, Bristol Myers Squibb Chee-Keong Toh Stock and Other Ownership Interests: Nektar Consulting or Advisory Role: Merck, Bristol Myers Squibb/Celgene, Astellas Pharma, MSD Oncology, Roche, DKSH, Natera, Eisai, Pfizer Speakers' Bureau: Ipsen, AstraZeneca, Merck, Astellas Pharma Mohamad Farid Honoraria: Bayer Consulting or Advisory Role: Bayer N. Gopalakrishna Iyer Consulting or Advisory Role: InvitroCue Patents, Royalties, Other Intellectual Property: A device and method of providing lighting during surgeries in deep and narrow cavities Inventors: N. C. Tan, W. S. Tan, M. H. Chew, H. K. Tan, P. Sunkeri, R. S. L. Lieu, F. W. L. Loke, N. G. Iyer. PCTSG2016-050231. Licensed to Vivo Surgical Pte Ltd Wan Teck Lim Consulting or Advisory Role: Roche, AstraZeneca, MSD Oncology, Novartis, Boehringer Ingelheim Research Funding: Bristol Myers Squibb Travel, Accommodations, Expenses: AstraZeneca, Taiho Pharmaceutical Daniel S. W. Tan Honoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, Pfizer Consulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer Research Funding: Novartis, GlaxoSmithKline, AstraZeneca Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

There are many differences between Asian regions in terms of the regulatory requirements and operational procedures in conducting international academic clinical trials for the approval of new drugs. The National Cancer Center Hospital in Japan has launched an international investigator-initiated registration-directed trial (IIRDT) in Japan, Korea, Taiwan, and Singapore, aiming at obtaining pharmaceutical approval in participating regions. Differences in regulatory and operational procedures were identified while coordinating the trial. In Japan, regulatory authority reviews should be performed after approval by institutional review boards for IIRDT, whereas in other regions these can be done in parallel. There were disparities in Good Manufacturing Practice-related documents between regions. Several differences were found regarding investigational product (IP) management, specifically concerning labeling, import/export procedures, and customs clearance costs. On the other hand, safety reporting procedures were relatively well-harmonized in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH-E2A). Regions also differed in per-patient costs, due to varying regulations for academic registration-directed trials. In conclusion, the observed differences among Asian regions should be harmonized to facilitate international academic trials in Asia and thus resolve unmet patient needs worldwide. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? International clinical trials have become common because they make it possible to accrue patients faster and obtain new drug approval in wider areas. However, pharmaceutical regulatory differences hinder the efficient conduct of international clinical trials, especially in academia. WHAT QUESTION DID THIS STUDY ADDRESS? We conducted an academic international clinical trial on new drug applications in four Asian countries and clarified pharmaceutical regulatory differences and operational difficulties. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study identified differences between countries in terms of regulatory affairs, institutional review board (IRB) review processes, investigational new drug (IND) dossiers, investigational product (IP) management procedures, and clinical trial costs, while safety reporting procedures were relatively harmonized. Japan utilizes investigator-initiated registration-directed trials, an advanced regulatory system for new drug application by academia, but the other countries do not. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Harmonization of pharmaceutical regulations and trial initiation procedures, and regulatory reform of clinical trial costs are important to accelerate academic international clinical trials for new drug applications., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Profiling of circulating tumor DNA (ctDNA) may offer a non-invasive approach to monitor disease progression. Here, we develop a quantitative method, exploiting local tissue-specific cell-free DNA (cfDNA) degradation patterns, that accurately estimates ctDNA burden independent of genomic aberrations. Nucleosome-dependent cfDNA degradation at promoters and first exon-intron junctions is strongly associated with differential transcriptional activity in tumors and blood. A quantitative model, based on just 6 regulatory regions, could accurately predict ctDNA levels in colorectal cancer patients. Strikingly, a model restricted to blood-specific regulatory regions could predict ctDNA levels across both colorectal and breast cancer patients. Using compact targeted sequencing (<25 kb) of predictive regions, we demonstrate how the approach could enable quantitative low-cost tracking of ctDNA dynamics and disease progression.

Arteriovenous fistula (AVF) is prone to early dysfunction and relates to poor outcome. However, little is known about the role of early AVF dysfunction as an independent risk factor for death in hemodialysis patients. A retrospective cohort study was performed using data of patients who underwent initial AVF surgery at a single institution. Demographic, clinical, biochemistry and AVF parameters were extracted from the electronic records, and the association between these variables and mortality was analyzed by Cox proportional hazards model. A total of 501 patients on hemodialysis (63.4 ± 12.7 years, 57.3% male) were included, and the median observation period was 3.66 years. In multivariate analysis, early failure of AVF (hazard ratio (95% confidence interval): 1.54 (1.06-2.24); p = 0.023) was associated with overall mortality but not cardiovascular mortality. Other identified predictors of overall mortality included older age, peripheral artery disease (PAD), cardiomegaly, higher white blood cell (WBC) count and corrected calcium level, and lower total cholesterol level, while predictors of cardiovascular mortality included older age, coronary artery disease (CAD), PAD and lower hemoglobin level. In conclusion, patients with early AVF failure were associated with increased risk of overall mortality.

Acquired multidrug resistance in tumors is a big challenge in cancer therapy. As an important physical stimulus in the tumor microenvironment, elevated interstitial fluid pressure has been reported to inhibit drug delivery and promote metastasis in solid tumors. However, the direct influence of this fluid pressure on anticancer drug resistance remains unclear. Here, we develop a pressurized in vitro circulating tumor cell (CTC) culture platform for anticancer drug screening. By using human breast cancer cell line MCF-7 and MDA-MB-231, we find that doxorubicin resistance can be increased by up to 2.5 times under 30 mmHg culture condition, through ABCC1 overexpression that reduces intracellular doxorubicin concentration. A similar chemoresistance change is also observed in clinical metastatic circulating tumor cells samples. These findings provide a new insight into the chemoresistance mechanism of metastatic human breast cancer cells and elucidate the significance of abnormal hydrostatic pressure in cancer progression.

Background: Percutaneous transluminal angioplasty (PTA) has generally replaced surgical procedures to treat arteriovenous fistula (AVF) dysfunction, but the predictors of post-intervention patency are highly variable. This study aimed to determine predictors of primary patency following PTA of dysfunctional AVF., Materials and Methods: Retrospective analysis of first-time PTA of 307 AVF in 307 patients (171 males, mean age 64.3 ± 12.4 years). Demographic, clinical, anatomical and medication variables were reviewed and subjected to univariate and multivariate Cox regression analysis., Results: The post-intervention primary patency rates at 6, 12, 24, and 36 months were 76.3%, 58.3%, 43.2%, and 38.2%, respectively. The higher aortic arch calcification (AAC) grade patients were older, had higher incidence of comorbidities and cardiomegaly, and younger AVF age, but their dialysis vintage term was shorter and diastolic blood pressure was lower, and the maximum diameter of balloon angioplasty was mostly ≤ 6 mm, and had lower phosphorus level and less calcium-containing phosphate binder use. In multivariate Cox proportional hazard analysis, the presence of higher AAC grade [hazard ratio (95% confidence interval): (1.46 (1.02-2.09); p = 0.037)] and stenosis at upper arm [1.76 (1.16-2.67); p = 0.008] were associated with shorter post-intervention primary patency., Conclusion: In conclusion, higher AAC grade and anatomic factor related to the location of AVF (upper arm) were the important predictors of AVF dysfunction after PTA. These results could assist in tailoring surveillance programs and performing appropriate interventions for risky AVF.

Background: Socioeconomic status (SES) is likely to affect survival in breast cancer patients. Housing value is a reasonable surrogate for SES in Singapore where most residents own their own homes, which could be public (subsidised) or private housing. We evaluated effects of housing value and enhanced medical subsidies on patients' presentation, treatment choices, compliance and survival in a setting of good access to healthcare., Methods: A retrospective analysis of breast cancer patients treated in a tertiary hospital cluster from 2000 to 2016 was performed. Individual-level Housing value Index (HI) was derived from each patient's address and then grouped into 3 tiers: HI(high)(minimal subsidy), HI(med)(medium subsidy) and HI(low)(high subsidy). Cox regression was performed to evaluate the associations between overall survival (OS) and cancer-specific survival (CSS) with HI and various factors., Findings: We studied a multiracial cohort of 15,532 Stage 0-IV breast cancer patients. Median age was 53.7 years and median follow-up was 7.7 years. Patients with lower HI presented with more advanced disease and had lower treatment compliance. On multivariable analysis, compared to HI(high) patients, HI(med) patients had decreased OS (HR=1.14, 95% CI 1.05-1.23) and CSS (HR=1.15, 95% CI 1.03-1.27), and HI(low) patients demonstrated reduced OS (HR=1.16, 95% CI 1.01-1.33). Ten-year non-cancer mortality was higher in lower HI-strata. Enhanced medical subsidy approximately halved treatment noncompliance rates but its receipt was not an independent prognostic factor for survival., Interpretation: Despite good healthcare access, lower-HI patients have poorer survival from both cancer and non-cancer causes, possibly due to delayed health-seeking and poorer treatment compliance. Enhanced subsidies may mitigate socioeconomic disadvantages., Funding: None., Competing Interests: We declare no competing interests., (© 2020 The Author(s). Published by Elsevier Ltd.)

Analysis of circulating cell-free DNA (cfDNA) has opened new opportunities for characterizing tumour mutational landscapes with many applications in genomic-driven oncology. We developed a customized targeted cfDNA sequencing approach for breast cancer (BC) using unique molecular identifiers (UMIs) for error correction. Our assay, spanning a 284.5 kb target region, is combined with a novel freely-licensed bioinformatics pipeline that provides detection of low-frequency variants, and reliable identification of copy number variations (CNVs) directly from plasma DNA. We first evaluated our pipeline on reference samples. Then in a cohort of 35 BC patients our approach detected actionable driver and clonal variants at low variant frequency levels in cfDNA that were concordant (77%) with sequencing of primary and/or metastatic solid tumour sites. We also detected ERRB2 gene CNVs used for HER2 subtype classification with 80% precision compared to immunohistochemistry. Further, we evaluated fragmentation profiles of cfDNA in BC and observed distinct differences compared to data from healthy individuals. Our results show that the developed assay addresses the majority of tumour associated aberrations directly from plasma DNA, and thus may be used to elucidate genomic alterations in liquid biopsy studies.

Purpose: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens., Methods: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m 2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m 2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL)., Results: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = . 0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = . 2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = . 043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = . 1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups., Conclusion: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Purpose: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies., Patients and Methods: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy., Results: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB ( n = 9) included multiple cycles of NK cells (1 × 10 7 /kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 10 7 /kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment., Conclusions: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials., (©2020 American Association for Cancer Research.)