Genomic Landscape of Circulating Tumor DNA in Patients With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-2-Negative Metastatic Breast Cancer Treated With Abemaciclib: Data From the SCRUM-Japan Cancer Genome Screening Project.

PURPOSE: To understand the mutational landscape of circulating tumor DNA (ctDNA) and tumor tissue of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer (MBC) treated with abemaciclib + endocrine therapy (ET). METHODS: Blood samples for ctDNA and/or tissue samples were collected from abemaciclib-treated patients with HR+/HER2- MBC enrolled in the SCRUM-Japan MONSTAR-SCREEN project. Blood samples were collected before abemaciclib initiation (baseline) and at disease progression/abemaciclib discontinuation (post abemaciclib treatment). Clinical and genomic characteristics including neoplastic burden (measured by shedding rate and maximum variant allele frequency [VAF]) were assessed at baseline. Genomic alterations in ctDNA were compared in paired baseline and post abemaciclib treatment samples. RESULTS: All patients (N = 97) were female (median age, 57 years [IQR, 50-67]). In baseline ctDNA (n = 77), PIK3CA (37%), TP53 (28%), ESR1 (16%), and GATA3 (11%) were the most frequently mutated genes. Baseline tissue samples (n = 79) showed similar alteration frequencies. Among patients with baseline ctDNA data, 30% had received previous ET. ESR1 alteration frequency (35% v 8%; P < .01), median shedding rate (3 v 2), and maximum somatic VAF (4 v 0.8; both P < .05) were significantly higher in ctDNA from patients with previous ET than those without previous ET. In paired ctDNA samples (n = 33), PIK3CA and ESR1 alteration frequencies were higher after abemaciclib treatment than at baseline, though not statistically significant. Among the post-treatment alterations, those newly acquired were detected most frequently in FGF3/4/19 (18%); PIK3CA, TP53, CCND1, and RB1 (all 15%); and ESR1 (12%). CONCLUSION: We summarized the ctDNA and cancer tissue mutational landscape, including overall neoplastic burden and PIK3CA and ESR1 hotspot mutations in abemaciclib-treated patients with HR+/HER2- MBC. The data provide insights that could help optimize treatment strategies in this population.

Risk factors for recurrence in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer in Japan: a systematic literature review and meta-analysis.

BACKGROUND: The clinicopathological factors indicating risk of recurrence are used to guide the choice of perioperative therapy in patients with breast cancer. Although several risk factors for recurrence have been reported in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer in Japan, there has been no systematic review quantifying potential risk factors. METHODS: We performed a systematic literature review and meta-analysis using the MEDLINE, Embase, Cochrane CENTRAL, and Japan Medical Abstract Society databases to identify risk factors for recurrence in HR+/HER2- early breast cancer in Japan. The primary outcome was relapse-free or disease-free survival (RFS/DFS), and the secondary outcomes were overall survival and breast cancer-specific survival (BCSS). RESULTS: Searches identified 42 eligible publications. Meta-analyses identified lymph node metastasis (hazard ratio: 2.76 [95% confidence interval: 1.97-3.88]), large tumor size (1.67 [1.24-2.23]), high histological grade (1.50 [1.04-2.16]), and high nuclear grade (2.02 [1.61-2.54]) as risk factors for RFS/DFS. Lymph node metastasis (2.43 [1.28-4.63]), large tumor size (1.80 [1.24-2.62]), and high histological grade (2.02 [1.44-2.84]) were also risk factors for overall survival, and high progesterone status was a possible favorable prognostic factor for BCSS (0.20 [0.10-0.42]). CONCLUSIONS: Identified risk factors were consistent with the previous reports, and this study provides quantitative summary of risk factors for HR+/HER2- early breast cancer recurrence in Japan. (PROSPERO Registration ID, CRD42022338391.).

Association of Neutrophil-to-Lymphocyte Ratio and Absolute Lymphocyte Count With Clinical Outcomes in Advanced Breast Cancer in the MONARCH 2 Trial.

BACKGROUND: Established prognostic factors for treatment response to cyclin-dependent kinases 4 and 6 inhibitors are currently lacking. We aimed to investigate the relationship of pretreatment neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) to abemaciclib outcomes. PATIENTS AND METHODS: This was a post hoc analysis of data from MONARCH 2, a phase III study of abemaciclib or placebo plus fulvestrant in hormone-receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer that progressed on endocrine therapy. Patients were divided into high and low categories based on baseline NLR (cutoff: 2.5) and ALC (cutoff: 1.5 × 109/L). The association of baseline NLR and ALC with progression-free survival (PFS) and overall survival (OS) was explored using Cox models and Kaplan-Meier estimates. Tumor response and safety were also examined. RESULTS: NLR and ALC data were available for 645 patients (abemaciclib: N = 426; placebo: N = 219). Low-baseline NLR or high-baseline ALC was consistently associated with positive PFS and OS trends; low-baseline NLR subgroups also showed trends for better response. The abemaciclib treatment effect against placebo was observed regardless of baseline NLR or ALC. Univariate analyses showed baseline NLR and ALC were prognostic of PFS and OS. Baseline NLR remained significant in the multivariate model (P < .0001). No unexpected differences in safety were observed by baseline NLR or ALC. CONCLUSION: Baseline NLR was independently prognostic of PFS and OS. Low-baseline NLR was associated with numerically better efficacy outcomes, but the benefit of adding abemaciclib to fulvestrant was similar irrespective of baseline NLR status.

Patient characteristics, treatment patterns, and outcomes of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer patients prescribed cyclin-dependent kinase 4 and 6 inhibitors: large-scale data analysis using a Japanese claims database.

PURPOSE: The aim was to understand real-world cyclin-dependent kinase (CDK) 4 and 6 inhibitor use in Japan. METHODS: This retrospective observational study used a Japanese administrative claims database and included patients with presumptive hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) prescribed CDK4 and 6 inhibitor therapy between December 2017 and March 2021. Patient characteristics, treatment patterns, and selected clinical and safety outcomes were descriptively summarized. Time to discontinuation (TTD) and chemotherapy-free survival (CFS) were examined using Kaplan-Meier estimates. RESULTS: The study cohort (N = 6442) was predominantly female (99.4%; median [range] age 64 [26-99] years) with records of metastases (79.6%) within 1 year prior to initiating CDK4 and 6 inhibitor therapy. In total, 4463 (69.3%) and 1979 (30.7%) were prescribed palbociclib and abemaciclib, respectively, as their first CDK4 and 6 inhibitor, most commonly in combination with fulvestrant (n = 3801; 59.0%). Overall, 3756 patients initiated a subsequent anticancer treatment, of whom 748 (19.9%) initiated a different CDK4 and 6 inhibitor in combination with the same or different endocrine therapy. Median TTD (95% confidence interval) was 9.7 (9.3, 10.1) months for the first CDK4 and 6 inhibitor therapy. Median CFS was 26.1 (24.6, 27.8) months. Incidence of clinically relevant diarrhea was higher after abemaciclib initiation (9.8%) than after palbociclib initiation (1.5%). More patients experienced dose reduction with palbociclib (69.3%) than with abemaciclib (53.0%). CONCLUSION: The data provide insights into current clinical practices for CDK4 and 6 inhibitor use in Japan that could help establish future treatment strategies for ABC.

Real-World Patient Characteristics, Treatment Patterns, and Outcomes of HR+, HER2- Early Breast Cancer Patients in Japan: An Analysis with National Database(NDB).

Real-world evidence for clinical outcomes and treatment patterns in patients with hormone receptor-positive(HR+)and human epidermal growth factor receptor 2-negative(HER2-)early breast cancer(EBC)in Japan is limited. We aimed to provide recent evidence in this population using the National Database of Health Insurance Claims and Specific Health Check-ups of Japan(NDB). Adults ≥20 years old who were diagnosed with HR+/HER2- breast cancer and underwent breast resection surgery were followed up. Patient characteristics and treatment patterns were evaluated. Durations of overall post-operative endocrine therapy(ET)and luteinizing hormone-releasing hormone(LH-RH)agonist therapy, and time to metastasis/recurrence after surgery were analyzed using Kaplan-Meier method. Overall, 294,904 patients were included. Cyclophosphamide and tamoxifen were the most common peri-operative chemotherapeutic and ET drugs. Median(95% confidence interval[CI])duration of post-operative ET and LH-RH agonist therapy was 5.01(5.01-5.01)years and 2.13 (2.12-2.14)years, respectively. Five-year cumulative rate(95% CI)of any recurrence was 8.6%(8.5-8.7), visceral metastasis being the most common. Nation-wide treatment patterns were described, which were consistent with guideline recommendations for patients with HR+, HER2- EBC. Further discussion is required to delay metastasis/recurrence and improve clinical outcomes(Fig. 1: Plain language summary of the study).

Safety in Japanese Advanced Breast Cancer Patients Who Received Abemaciclib in MONARCH 2 and MONARCH 3: Assessment of Treatment-Emergent Neutropenia, Diarrhea, and Increased Alanine Aminotransferase and Aspartate Aminotransferase Levels.

Purpose: Our objective was to gain a better understanding of the safety of abemaciclib in Japanese patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Patients and Methods: Treatment-emergent adverse events (TEAEs) were assessed in pooled Japanese subpopulation data from two phase 3 studies assessing abemaciclib/placebo in combination with fulvestrant (MONARCH 2; M2) or non-steroidal aromatase inhibitors (MONARCH 3; M3). For common, clinically relevant TEAEs, event characteristics and management were summarized by study. Results: In the Japanese safety subpopulation (abemaciclib: N=101; placebo: N=46), all patients experienced ≥1 TEAE (Grade ≥ 3: abemaciclib, 71.3%; placebo, 23.9%; no Grade 5). Clinically relevant TEAEs that were more frequent in abemaciclib-treated Japanese patients compared to the overall safety populations included diarrhea (any grade, 95.0%; Grade ≥ 3, 12.9%), neutropenia (any grade, 75.2%; Grade 3-4, 35.6%), increased alanine aminotransferase (ALT; any grade, 39.6%; Grade 3-4, 14.9%), and increased aspartate aminotransferase (AST; any grade, 37.6%; Grade 3-4, 8.9%). Diarrhea was Grade ≤3 and successfully managed with medications (≥87%) and dose reductions (≤25%) and/or omissions (≤23.3%). Most Grade ≥2 diarrhea occurred in the first treatment cycle, declining thereafter. Neutropenia, the most common Grade ≥3 TEAE in abemaciclib-treated Japanese patients, was generally manageable with dose omissions (M2: 42.0%; M3: 23.1%) and/or reductions (M2: 16%; M3: 15.4%). Neutrophil counts plateaued after Cycle 2, recovering to pretreatment levels after discontinuation of abemaciclib. Hepatic events were managed with medication (≤21%) and dose adjustments (≤33.3%), with most Grade ≥2 events occurring in early treatment cycles. Discontinuation of any study treatment in Japanese patients occurred more frequently due to increased ALT/AST (M2: 9.1%/10.5%; M3: 16.7%/10.5%) compared with diarrhea (M2: 0%; M3: 2.8%) or neutropenia (M2: 0%; M3: 3.8%). Conclusion: Abemaciclib was well tolerated in Japanese patients in MONARCH 2 and MONARCH 3, with common, clinically relevant TEAEs manageable with appropriate interventions.

Real-World Insurance Claims Analysis of Venous Thromboembolism in Japanese Patients with Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD), which encompasses both ulcerative colitis (UC) and Crohn's disease (CD), is a risk factor for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). AIM: To investigate the incidence of, and risk factors for, VTE in patients with IBD in Japan. METHODS: This was a retrospective, non-interventional study in patients with IBD from the Japan Medical Data Center claims database. Incidence rates (IRs; unique patients with events per 100 patient-years) were calculated for VTE, DVT, and PE among the IBD, UC, and CD cohorts. Odds ratios of potential risk factors were calculated by univariate and multivariate analyses in a nested case-control design. RESULTS: Overall, 16 273 patients with IBD were included: 13 585 with UC and 3443 with CD. VTE events occurred in 1.3%, 1.2%, and 1.9% of patients with IBD, UC, and CD, respectively. In patients with IBD, UC, and CD, IRs of VTE were 0.45, 0.40, and 0.64, respectively, IRs of DVT were 0.42, 0.38, and 0.61, respectively, and IRs of PE were 0.07, 0.07, and 0.11, respectively. In patients with IBD, treatment history (immunomodulators), cardiovascular risk (hypertension, high-density lipoprotein or diabetes mellitus, and history of coronary artery disease or heart failure), malignancy, and undergoing major surgery were identified as potential risk factors for VTE in the multivariate analysis, with similar risk factors reported for patients with UC and CD. CONCLUSIONS: This large study provides insight into the incidence and risk factors for VTE in patients with IBD from Japan.

Japanese subgroup analysis of the phase 3 MONARCH 3 study of abemaciclib as initial therapy for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.

BACKGROUND: This was a Japanese subpopulation analysis of MONARCH 3, a randomized, double-blind, placebo-controlled phase 3 study of abemaciclib plus nonsteroidal aromatase inhibitors (NSAIs) for initial therapy for advanced breast cancer (ABC). METHODS: Eligibility included postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative ABC who had no prior systemic therapy in the advanced disease setting. Patients (N = 493) were randomized 2:1 to receive abemaciclib or placebo (150 mg) plus either 1 mg anastrozole or 2.5 mg letrozole (physician's choice). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), pharmacokinetics (PK), safety, and health-related quality of life (HRQoL). RESULTS: In Japan, 53 patients were randomized (abemaciclib, n = 38; placebo, n = 15). At final PFS analysis (November 3, 2017), median PFS was 29.1 and 14.9 months in the abemaciclib and placebo groups, respectively (hazard ratio 0.537; 95% confidence interval 0.224-1.289). ORR in measurable disease was 62.1 and 50.0% in the abemaciclib and placebo groups, respectively. The Japanese PK profile was comparable to that of the overall population. Consistent with prior studies, the most frequent adverse events reported were diarrhea (abemaciclib: any grade, 94.7%; grade ≥ 3, 10.5%; placebo: any grade, 46.7%; grade ≥ 3, 0%) and neutropenia (abemaciclib: any grade, 68.4%; grade ≥ 3, 21.1%; placebo: any grade, 0%). HRQoL outcomes were generally similar between treatments except for the diarrhea score, which favored placebo. CONCLUSIONS: Consistent with findings in the overall population, abemaciclib plus NSAI was an effective initial treatment in the Japanese subpopulation, with a manageable safety profile. CLINICAL TRIAL REGISTRATION: NCT02246621; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02246621 .

Validation of a claims-based algorithm to identify cases of ulcerative colitis in Japan.

BACKGROUND AND AIM: The prevalence of ulcerative colitis (UC) is increasing in Japan. Validated claims-based definitions are required to investigate the epidemiology of UC and its treatment and disease course in clinical practice. This study aimed to develop a claims-based algorithm for UC in Japan. METHODS: A committee of epidemiologists, gastroenterologists, and internal medicine physicians developed a claims-based definition for UC, based on diagnostic codes and claims for UC treatments, procedures (cytapheresis), or surgery (postoperative claims). Claims data and medical records for a random sample of 200 cases per site at two large tertiary care academic centers in Japan were used to calculate the positive predictive value (PPV) of the algorithm for three gold standards of diagnosis, defined as physician diagnosis in the medical records, adjudicated cases, or registration in the Japanese Intractable Disease Registry (IDR). RESULTS: Overall, 1139 claims-defined UC cases were identified. Among 393 randomly sampled cases (mean age 44; 48% female), 94% had received ≥ 1 systemic treatment (immunosuppressants, tumor necrosis factor inhibitors, corticosteroids, or antidiarrheals), 7% had cytapheresis, and 7% had postoperative claims. When physician diagnosis was used as a gold standard, PPV was 90.6% (95% confidence interval [CI]: 87.7-93.5). PPV with expert adjudication was also 90.6% (95% CI: 87.7-93.5). PPVs with enrollment in the IDR as gold standard were lower at 41.5% (95% CI: 36.6-46.3) due to incomplete case registration. CONCLUSIONS: The claims-based algorithm developed for use in Japan is likely to identify UC cases with high PPV for clinical studies using administrative claims databases.

Development of KAM score to predict metastasis and worse survival in breast cancer.

Some may think that prediction of metastasis is meaningless since metastatic breast cancer is currently incurable. We argue that effective identification of developing metastasis will enable us to design and conduct clinical trials specifically targeting those patients at high risk. The current study sought to generate the KAM score by 4 genes (BRSK2, EYA1, SIGLEC15, and AGTR1) overexpressed in primary breast cancer that developed metastasis to bone compared with matched controls without metastasis longer than 10 years. A high KAM score was prognostic of poor overall (OS), disease free survival (DFS), and disease specific survival (DSS) in the METABRIC, and OS in the GSE96058 cohorts. A high KAM score was significantly associated with clinical aggressiveness, such as high American Joint Committee Cancer (AJCC) stage, lymph node metastasis, Nottingham pathological grade, and triple negative breast cancer (TNBC). Subgroup analysis revealed that a high KAM score was associated with worse OS in ER-positive/HER2-negative breast cancer in both cohorts. A high KAM breast cancer enriched all 5 cell proliferation-related gene sets of the Hallmark collection and interferon (IFN)-γ response gene sets. Furthermore, a high KAM breast cancer was significantly infiltrated with a high fraction of not only anti-cancer but also pro-cancer immune cells and associated with high level of cytolytic activity. Finally, a high KAM breast cancer was significantly associated with lung metastasis. In conclusion, we developed KAM score using 4 gene expressions that predict lung metastasis and patient survival in breast cancer.

[Development of CDK4 & 6 Inhibitor Abemaciclib in Breast Cancer].

Abemaciclib is a selective cyclin-dependent kinase(CDK)4 & 6 inhibitor, which induces G1 cell cycle arrest and tumour growth inhibition. Abemaciclib has been developed for use in hormone receptor positive(HR+)breast cancer, dosed daily in combination with endocrine therapy. In a phase Ⅲ clinical trial, MONARCH 2, for women with HR+ and human epidermal growth factor receptor 2 negative(HER2-)advanced breast cancer who progressed after endocrine therapy, abemaciclib in combination with fulvestrant significantly improved not only progression-free survival and objective response rate but also overall survival, and demonstrated a tolerable safety profile. Another phase Ⅲ clinical trial, MONARCH 3, for women with HR+ and HER2- advanced breast cancer, abemaciclib in combination with nonsteroidal aromatase inhibitor as an initial therapy also significantly improved progression-free survival and objective response rate. This review presents the rationale for the use of CDK4 & 6 inhibitors in the treatment of breast cancer, background on the development of abemaciclib, clinical data focusing on phase Ⅲ studies of abemaciclib, and information on ongoing clinical studies of abemaciclib.

Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and with better clinical outcomes in triple negative breast cancer.

Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival.

Extracellular acidity in tumor tissue upregulates programmed cell death protein 1 expression on tumor cells via proton-sensing G protein-coupled receptors.

Acidity in the tumor microenvironment has been reported to promote cancer growth and metastasis. In our study, we examined a potential relation between extracellular acidity and expression level of the immune checkpoint molecule programmed cell death protein 1 (PD-L1) in murine squamous cell carcinoma (SCC) and melanoma cell lines. PD-L1 expression in the tumor cells was upregulated by culturing in a low pH culture medium. Tumor-bearing mice were allowed to ingest sodium bicarbonate, resulting in neutralization of acidity in the tumor tissue, a decrease in PD-L1 expression in tumor cells and suppression of tumor growth in vivo. Proton-sensing G protein-coupled receptors, T-cell death-associated gene 8 (TDAG8) and ovarian cancer G-protein-coupled receptor 1 (OGR1), were upregulated by low pH, and essentially involved in the acidity-induced elevation of PD-L1 expression in the tumor cells. Human head and neck SCC RNAseq data from the Cancer Genome Atlas also suggested a statistically significant correlation between expression levels of the proton sensors and PD-L1 mRNA expression. These findings strongly suggest that neutralization of acidity in tumor tissue may result in reduction of PD-L1 expression, potentially leading to inhibition of an immune checkpoint and augmentation of antitumor immunity.

A systematic literature review of prognostic factors in patients with HR+/HER2- advanced breast cancer in Japan.

BACKGROUND: Breast cancer is the most prevalent cancer in women in Japan and the fifth in mortality. This systematic review summarized the evidence for prognostic factors for patients with HR+/HER2- advanced and metastatic breast cancer in Japan. METHODS: MEDLINE and EMBASE were searched with keywords 'breast neoplasms' AND 'Japan' AND 'advanced' or equivalent, and Japan Medical Abstract Society database with 'breast cancer' AND 'advanced/metastatic' for publications from January 2010 to October 2019. ASCO, ESMO, ABC4 abstracts and WHO website were hand searched. The endpoints of interest were overall survival, progression-free survival, tumour response and post-progression survival. Factors were evaluated based on the consistency in direction and the strength (hazard ratios) of association. RESULTS: Searches identified 4530 publications, of which 27 were eligible. All were observational studies. Among the endpoints, overall survival was the most commonly assessed (n = 22) and evaluated further. Ki-67 expression, progesterone receptor expression status, tumour grade and lymph node metastases were consistently associated with poor overall survival in univariate analysis but not in multivariate analysis. Short disease-free interval, the number of metastatic organs and liver metastasis were consistently associated with poor overall survival in both of univariate and multivariate analysis. The association was strong for liver metastasis (hazard ratio ≥2.8 in the majority of studies) and moderate for disease-free interval and the number of metastatic organs (hazard ratio 1.3-2.8 in the majority of studies). CONCLUSIONS: Disease-free interval, the number of metastatic organs and liver metastasis were identified as independent prognostic factors for overall survival. These findings may help clinical decision-making to improve outcomes in patients with HR+/HER2- advanced and metastatic breast cancer.

Oligometastasis scoring system for predicting survival of patients with colorectal liver metastasis after hepatectomy.

BACKGROUND: Oligometastasis, the presence of a small number of resectable metastatic tumors, usually has favorable outcomes. Here we examined whether the novel oligometastatic score (OLGS), which divides the number of colorectal liver metastases (CRLMs) by the time from colorectal resection to liver recurrence, better predicts CRLM patient survival than the commonly used clinical risk score. METHODS: A total of 143 patients who underwent curative hepatectomy for CRLMs between 2007 and 2018 were analyzed. We investigated their clinical characteristics and outcomes using OLGS. RESULTS: Of the 143 CRLM patients, 70 had synchronous CRLMs and 73 had metachronous CRLMs. Patients with metachronous CRLMs were divided into OLGS-low (n = 59) and OLGS-high (n = 14) subgroups. The 5-year overall survival (OS) rates after hepatectomy differed significantly between the subgroups (p < .001). In the multivariate Cox model, a high OLGS was an independent predictor of 5-year OS (p < .001), and the hazard ratio (HR) of the OLGS-high group (HR = 7.171) was higher than that of the high clinical risk score group (HR = 4.337). CONCLUSION: The OLGS, a simple and handy scoring system, better predicts the 5-year OS of patients with CRLMs after hepatectomy and warrants prospective validation.

Altered Expression of Secreted Mediator Genes That Mediate Aggressive Breast Cancer Metastasis to Distant Organs.

Heterogeneity is the characteristic of breast tumors, making it difficult to understand the molecular mechanism. Alteration of gene expression in the primary tumor versus the metastatic lesion remains challenging for getting any specific targeted therapy. To better understand how gene expression profile changes during metastasis, we compare the primary tumor and distant metastatic tumor gene expression using primary breast tumors compared with its metastatic variant in animal models. Our RNA sequencing data from cells revealed that parental cell and the metastatic variant cell are different in gene expression while gene signature significantly altered during metastasis to distant organs than primary breast tumors. We found that secreted mediators encoding genes (ANGPTL7, MMP3, LCN2, S100A8, and ESM1) are correlated with poor prognosis in the clinical setting as divulged from METABRIC and TCGA-BRCA cohort data analysis.

Japanese subpopulation analysis of MONARCH 2: phase 3 study of abemaciclib plus fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that progressed on endocrine therapy.

BACKGROUND: This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). METHODS: Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety. RESULTS: In Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380-1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390-1.463). CONCLUSIONS: Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population. CLINICAL TRIAL REGISTRATION: NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703 .

Chirality induction on non-chiral dye-linked polysilsesquioxane in nanohelical structures.

We demonstrate the direct induction of chirally arranged organic dye-linked polysilsesquioxane through a sol-gel transcription using a chiral supramolecular template. The chiral arrangement was confirmed by using electronic and vibrational circular dichroism and circularly polarized luminescence spectroscopies.

Immune Cytolytic Activity for Comprehensive Understanding of Immune Landscape in Hepatocellular Carcinoma.

Cytolytic activity score (CYT), defined by granzyme A and perforin expression, is a useful marker for underlying immunity. We hypothesized that CYT-high hepatocellular carcinomas (HCCs) have stronger immunogenicity and favorable tumor microenvironments, which would result in better clinical outcomes, using the cancer genome atlas (TCGA) cohort with 371 patients with HCC. We found CYT-high HCCs were associated with higher expressions of the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3), well-known mutagenic enzymes. Further, higher numbers of anti-cancer immune cells, such as CD8+ T cells and M1 macrophages, were infiltrated in CYT-high HCCs. Major T cell exhaustion markers were expressed significantly higher in CYT-high HCCs, likely as a negative feedback loop. Additionally, CYT-high HCCs strongly enriched gene sets related with enhanced immune activity. With strong immunity, patients with CYT-high HCCs had significantly longer disease-specific survival (DSS) and overall survival (OS) (p = 0.03 and <0.01). Furthermore, when the OS is stratified by exhaustion marker expressions, the CYT-high/exhaustion-low group had the best and CYT-low/exhaustion-high groups had the worst OS. Lastly, high CYT was an independent protective factor for prognosis. In conclusion, CYT-high HCCs were associated with enhanced immunity and better survival. Our findings suggest that proper identification of tumor-immune microenvironments could stratify the patients for appropriate treatments.

Orthotopic Implantation Achieves Better Engraftment and Faster Growth Than Subcutaneous Implantation in Breast Cancer Patient-Derived Xenografts.

Patient-Derived Xenograft (PDX) is now accepted as a murine model that better mimics human cancer when compared to a conventional cancer cell-line inoculation model. Some claim the advantage of orthotopic site implantation of patient tumor (OS) over ectopic implantation into the subcutaneous space (SQ); however, there has been no study that describes a head-to-head comparison of oncological differences between these two models to date. We hypothesize that OS tumors re-transplant and grow better than SQ tumors and are therefore a better model to evaluate tumor aggressiveness. Breast cancer PDXs were generated using the tumors derived from 11 patients into NOD scid gamma (NSG) mice. We used six ER(+)HER2(-) tumors and five triple negative (TN) tumors for a total of 11 tumors. Five PDX lines grew for an overall engraftment rate of 45%. We present our OS implantation method in detail. The re-transplantation rate of TN tumors in each transplant site was significantly higher in OS when compared to SQ tumors (70.1% vs. 32.1%, p < 0.01). OS tumors grow significantly faster than SQ tumors. Similarly, OS tumors demonstrated significantly more mitotic figures and Ki-67 positive cells than SQ tumors. The tumor re-transplantation rate significantly increased by the second and third generations with the OS method. The time from implantation to development of a palpable tumor dramatically decreased after the first passage. PDX of ER(+) tumors demonstrated significantly lower engraftment rates and slower tumor growth than TN tumors, which remarkably improved by the first passage. Orthotopically implanted PDX tumors showed better re-transplantation rates, greater tumor size, and more significant growth compared to the subcutaneously implanted model.