Correlation between postoperative treatment selection and prognosis determined using the Oncotype DX® test data: a retrospective multicenter study in Japan.

PURPOSE: Oncotype DX® is a frequently used multigene assay for hormone receptor-positive breast cancers. However, limited evidence is available regarding its application in Japan owing to the lack of insurance coverage. Therefore, we conducted this large-scale, retrospective study by collecting data from nine Japanese institutes and assessed postoperative treatment choice and prognosis by using Oncotype DX®. METHODS: Six hundred thirty-two patients who underwent breast surgery and whose recurrence score (RS) data were available were included. They were divided into RS 0-25 and RS ≥ 26 groups. The groups were compared in terms of clinicopathological factors, treatment options, and prognosis. RESULTS: After the median follow-up period of 10.1 years, the disease-free survival (DFS) rates were significantly better in the RS 0-25 group (p = 0.02). Per the recurrent event type, there was no significant intergroup difference in locoregional recurrence (p = 0.139). However, a trend toward better distant DFS was observed in the RS 0-25 group (p = 0.08). Overall survival was also significantly better in this group (p = 0.027). Considering chemotherapy use, DFS worsened among chemotherapy-treated patients with an RS of 0-25 and those with an RS ≥ 26 who did not receive chemotherapy (p < 0.001). Seven (1.35%) chemotherapy-treated patients with an RS of 0-25 showed disease recurrence. CONCLUSIONS: This study presents the largest database-derived prognostic data in Japanese patients, utilizing the Oncotype DX® treatment selection. Further studies are needed to determine the impact on treatment choice, considering the clinical risk, and the need for additional postoperative treatment.

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer.

In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.

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.

Baseline interleukin-6 is a prognostic factor for patients with metastatic breast cancer treated with eribulin.

PURPOSE: Eribulin is a unique anti-cancer drug which can improve overall survival (OS) of patients with metastatic breast cancer (MBC), probably by modulating the tumor immune microenvironment. The aim of this study was to investigate the clinical significance of serum levels of immune-related and inflammatory cytokines in patients treated with eribulin. Furthermore, we investigated the association between cytokines and immune cells, such as myeloid-derived suppressor cells (MDSCs) and cytotoxic and regulatory T cells, to explore how these cytokines might affect the immune microenvironment. METHODS: Sixty-eight patients with MBC treated with eribulin were recruited for this retrospective study. The relationship of cytokines, including interleukin (IL)-6, to progression-free survival and OS was examined. CD4+ and CD8+ lymphocyte, MDSCs and regulatory T cell levels were determined in the blood by flow cytometry analysis. RESULTS: In our cohort, patients with high IL-6 at baseline had shorter progression-free survival and OS compared with those with low IL-6 (p = 0.0017 and p = 0.0012, respectively). Univariable and multivariable analyses revealed that baseline IL-6 was an independent prognostic factor for OS (p = 0.0058). Importantly, CD8+ lymphocytes were significantly lower and MDSCs were significantly higher in patients with high IL-6, compared to those with low IL-6. CONCLUSION: Baseline IL-6 is an important prognostic factor in patients with MBC treated with eribulin. Our results show that high IL-6 is associated with higher levels of MDSCs which suppress anti-tumor immunity, such as CD8+ cells. It appears that eribulin is not particularly effective in patients with high IL-6 due to a poor tumor immune microenvironment.

Efficacy of probiotics and trimebutine maleate for abemaciclib-induced diarrhea: A randomized, open-label phase II trial (MERMAID, WJOG11318B).

BACKGROUND: Abemaciclib-induced diarrhea (AID) impairs quality of life (QOL) and treatment adherence in patients with breast cancer. Supportive treatment with loperamide is associated with constipation. We hypothesized that probiotics and trimebutine maleate (TM) would decrease the frequency of AID without causing constipation. METHODS: Hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer patients were randomized into the probiotic Bifidobacterium (A) or probiotic Bifidobacterium and TM (B) groups. Endocrine therapy, Abemaciclib and probiotic Bifidobacterium three times a day for 28 days, was administered to both arms. Arm B was treated with TM upon the onset of diarrhea. The primary endpoint was the percentage of patients who experienced grade ≥2 diarrhea. The secondary endpoints were safety, frequency, and duration of all-grade diarrhea; frequency of emesis and constipation; usage of loperamide; and health-related QOL/patient-reported outcome during the study. We evaluated whether the primary endpoint of each arm exceeded the predetermined threshold. RESULTS: Fifty-one patients completed treatment. Grade 2 diarrhea occurred in 52% and 50% of patients in Arm A and Arm B, respectively. One patient experienced grade 3 diarrhea in each arm. The median duration of grade2 diarrhea was 2 and 2.5day, and only one patient required dose reduction. Grade ≥2 constipation was observed in 4% of Arm A and 3.6% of Arm B. CONCLUSIONS: Probiotic Bifidobacterium or the combination of probiotic Bifidobacterium with TM did not decrease the incidence of grade 2 or greater diarrhea compared with historical control, although the grade 3 or greater diarrhea was reduced. CLINICAL TRIAL REGISTRATION: jRCT (Japan registry of clinical trials). jRCTs031190154.

Intratumoral Tumor Infiltrating Lymphocytes (TILs) are Associated With Cell Proliferation and Better Survival But Not Always With Chemotherapy Response in Breast Cancer.

OBJECTIVE: To investigate the clinical relevance of intratumoral tumor infiltrating lymphocytes (TILs) in breast cancer as measured by computational deconvolution of bulk tumor transcriptomes. SUMMARY BACKGROUND DATA: Commonly assessed TILs, located in tumor stroma without direct contact with cancer cells (stromal TILs), correlate with breast cancer treatment response and survival. The clinical relevance of intratumoral TILs has been less studied partly due to their rarity; however, they may have nonnegligible effects given their direct contact with cancer cells. METHODS: In all, 5870 breast cancer patients from TCGA, METABRIC, GSE96058, GSE25066, GSE163882, GSE123845, and GSE20271 cohorts were analyzed and validated. RESULTS: The intratumoral TIL score was established by the sum of all types of lymphocytes using the xCell algorithm. This score was the highest in triple-negative breast cancer (TNBC) and the lowest in the ER-positive/HER2-negative subtype. It correlated with cytolytic activity and infiltrations of dendritic cells, macrophages, and monocytes, and uniformly enriched immune-related gene sets regardless of subtype. Intratumoral TIL-high tumors correlated with higher mutation rates and significant cell proliferation on biological, pathological, and molecular analyses only in the ER-positive/HER2-negative subtype. It was significantly associated with pathological complete response after anthracycline- and taxane-based neoadjuvant chemotherapy in about half of the cohorts, regardless of the subtype. Intratumoral TIL-high tumors correlated with better overall survival in HER2-positive and TNBC subtypes consistently in 3 cohorts. CONCLUSIONS: Intratumoral TILs estimated by transcriptome computation were associated with increased immune response and cell proliferation in ER-positive/HER2-negative and better survival in HER2-positive and TNBC subtypes, but not always with pathological complete response after neoadjuvant chemotherapy.

An increase in tumor-infiltrating lymphocytes after treatment is significantly associated with a poor response to neoadjuvant endocrine therapy for estrogen receptor-positive/HER2-negative breast cancers.

BACKGROUND: The reason for the poor prognosis of estrogen receptor (ER) + /human epidermal growth factor receptor 2 (HER2)- breast cancer patients with high levels of tumor-infiltrating lymphocytes (TILs) is poorly understood. The association between TILs and response to neoadjuvant endocrine therapy (NET) was examined. METHODS: We recruited 170 patients with ER + /HER2- breast cancer who were treated with preoperative endocrine monotherapy. TILs were evaluated before and after NET, and their changes were noted. Furthermore, T cell subtypes were examined using CD8 and FOXP3 immunohistochemical analyses. Neutrophil and lymphocyte counts in the peripheral blood were analyzed with reference to TIL levels or changes. Responders were defined as Ki67 expression levels ≤ 2.7% after treatment. RESULTS: Post-treatment (p = 0.016), but not pre-treatment (p = 0.464), TIL levels were significantly associated with the response to NET. TIL levels increased significantly after treatment among non-responders (p = 0.001). FOXP3 + T cell counts increased significantly after treatment in patients with increased TILs (p = 0.035), but not in those without increased TILs (p = 0.281). Neutrophil counts decreased significantly after treatment in patients without increased TILs (p = 0.026), but not in patients with increased TILs (p = 0.312). CONCLUSION: An increase in TILs after NET was significantly associated with a poor response to NET. Given that FOXP3 + T-cell counts increased, and neutrophil counts did not decrease in patients with increased TILs after NET, the induction of an immunosuppressive microenvironment was speculated to play a role in the inferior efficacy. These data might partially indicate the involvement of the immune response in the efficacy of endocrine therapy.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In the single-arm, phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan showed robust activity in patients with HER2-positive metastatic breast cancer who were refractory or resistant to trastuzumab emtansine; a population with scarce effective treatments. In DESTINY-Breast02, we aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in this patient population. METHODS: This randomised, open-label, multicentre, phase 3 trial was conducted at 227 sites (hospitals, university hospitals, clinics, community centres, and private oncology centres) in North America, Europe, Asia, Australia, Brazil, Israel, and Türkiye. Eligible patients were aged 18 years or older, had unresectable or HER2-positive metastatic breast cancer, previously received trastuzumab emtansine, disease progression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate renal and hepatic function. Patients were randomly assigned (2:1) to receive trastuzumab deruxtecan (intravenously at 5·4 mg/kg once every 3 weeks) or treatment of physician's choice using block randomisation. Treatment of physician's choice was either capecitabine (1250 mg/m2; orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint was progression-free survival based on blinded independent central review in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03523585. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). 608 (100%) patients were included in the full analysis set. The median age was 54·2 years (IQR 45·5-63·4) in the trastuzumab deruxtecan group and 54·7 years (48·0-63·0) in the treatment of physician's choice group. 384 (63%) patients were White, 603 (99%) were female, and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (8·8-26·0) in the treatment of physician's choice group. Median progression-free survival by blinded independent central review was 17·8 months (95% CI 14·3-20·8) in the trastuzumab deruxtecan group versus 6·9 months (5·5-8·4) in the treatment of physician's choice group (HR 0·36 [0·28-0·45]; p<0·0001). The most common treatment-emergent adverse events were nausea (293 [73%] of 404 with trastuzumab deruxtecan vs 73 [37%] of 195 with treatment of physician's choice), vomiting (152 [38%] vs 25 [13%]), alopecia (150 [37%] vs eight [4%]), fatigue (147 [36%] vs 52 [27%]), diarrhoea (109 [27%] vs 105 [54%]), and palmar-plantar erythrodysaesthesia (seven [2%] vs 100 [51%]). Grade 3 or higher treatment-emergent adverse events occurred in 213 (53%) patients receiving trastuzumab deruxtecan versus 86 (44%) receiving treatment of physician's choice; whereas drug-related interstitial lung disease occurred in 42 (10%; including two grade 5 death events) versus one (<1%). INTERPRETATION: DESTINY-Breast02 shows the favourable benefit-risk profile of trastuzumab deruxtecan in patients with HER2 positive metastatic breast cancer, as previously reported in DESTINY-Breast01, and is the first randomised study to show that one antibody-drug conjugate can overcome resistance to a previous one. FUNDING: Daiichi Sankyo and AstraZeneca.

Copy number alteration is an independent prognostic biomarker in triple-negative breast cancer patients.

BACKGROUND: Next-generation sequencing (NGS) has enabled comprehensive genomic profiling to identify gene alterations that play important roles in cancer biology. However, the clinical significance of these genomic alterations in triple-negative breast cancer (TNBC) patients has not yet been fully elucidated. The aim of this study was to clarify the clinical significance of genomic profiling data, including copy number alterations (CNA) and tumor mutation burden (TMB), in TNBC patients. METHODS: A total of 47 patients with Stage I-III TNBC with genomic profiling of 435 known cancer genes by NGS were enrolled in this study. Disease-free survival (DFS) and overall survival (OS) were evaluated for their association to gene profiling data. RESULTS: CNA-high patients showed significantly worse DFS and OS than CNA-low patients (p = 0.0009, p = 0.0041, respectively). TMB was not associated with DFS or OS in TNBC patients. Patients with TP53 alterations showed a tendency of worse DFS (p = 0.0953) and significantly worse OS (p = 0.0338) compared with patients without TP53 alterations. Multivariable analysis including CNA and other clinicopathological parameters revealed that CNA was an independent prognostic factor for DFS (p = 0.0104) and OS (p = 0.0306). Finally, multivariable analysis also revealed the combination of CNA-high and TP53 alterations is an independent prognostic factor for DFS (p = 0.0005) and OS (p = 0.0023). CONCLUSIONS: We revealed that CNA, but not TMB, is significantly associated with DFS and OS in TNBC patients. The combination of CNA-high and TP53 alterations may be a promising biomarker that can inform beyond standard clinicopathologic factors to identify a subgroup of TNBC patients with significantly worse prognosis.

Relationship between FDG-PET and the immune microenvironment in breast cancer.

OBJECTIVE: To investigate the relationship between fluorodeoxyglucose (FDG) uptake (maximum standardised uptake value [SUVmax]) and immune markers (tumour-infiltrating lymphocytes [TILs] and neutrophil-to-lymphocyte ratio [NLR]) and evaluate the potential prognostic value of any correlations. METHODS: Data from 502 patients with breast cancer, including 346 oestrogen receptor (ER)-positive / human epidermal growth factor receptor 2 (HER2)-negative, 88 HER2-positive, and 68 triple-negative cases, who had undergone surgery were reviewed. Relationships between the clinicopathological factors, SUVmax, TILs, NLR, recurrence-free survival (RFS), and overall survival of all patients and each subtype were evaluated using a Cox proportional hazards model and log-rank test. A sub-analysis of patients divided into low and high TIL groups was also undertaken. RESULTS: High SUVmax was significantly related to high TILs (p < 0.0001). In low TIL (TILs1) group, patients with high SUVmax (≥3.585) had a significantly shorter RFS than those with low SUVmax (<3.585; p < 0.0001). In high TIL (TILs2,3) group, patients with high SUVmax had a shorter RFS than those with low SUVmax without a significant difference (p = 0.35). Multivariate analysis of 502 patients showed high SUVmax, high T status, and nodal metastasis were independent negative predictors of RFS. In 317 TILs-low patients, high SUVmax, high T status, nodal metastasis, and ER-positivity were independent predictors of RFS. In 185 TILs-high patients, nodal metastasis was an independent predictor of RFS. In ER-positive/HER2-negative and HER2-positive subtypes, SUVmax was a significant predictive parameter in the TILs-low but not TILs-high groups. CONCLUSION: FDG uptake may be predictive of immunological features and aggressive features in breast cancer patients.

Lack of impact of the ALDH2 rs671 variant on breast cancer development in Japanese BRCA1/2-mutation carriers.

The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair-defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer-initiating cells in these patients usually undergo loss of the wild-type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients.

Total Lesion Glycolysis Levels as Predictive Indicators in Patients With Metastatic and Recurrent Breast Cancer Undergoing Endocrine Therapy With or Without CDK4/6 Inhibitor.

BACKGROUND/AIM: Endocrine therapy (ET) with or without CDK4/6 inhibitors is the primary treatment choice for patients with estrogen receptor (ER)-positive and HER2-negative subtype of metastatic breast cancer (MBC). We examined the metabolic parameters identified using 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in terms of sensitivity, since no predictive factors exist. PATIENTS AND METHODS: We included 136 patients with MBC treated with ET alone (n=107) or combined with CDK4/6 inhibitor (n=29) and examined using FDG-PET before treatment began. The highest maximum value of the standard uptake value (SUVmax), whole-body metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. RESULTS: Progression-free survival (PFS) was significantly longer in patients with low levels of MTV, TLG, and SUVmax than those with higher levels (median PFS 49.5 vs. 20.7 months, p=0.001 for MTV, 49.5 vs. 20.7 months, p=0.0016 for TLG, 37.0 vs. 20.7 months, p=0.012 for SUVmax). Multivariable analysis revealed that TLG (hazard ratio=6.383, 95% confidence interval=1.167-34.913, p=0.033) was independently and significantly associated with PFS. The relationship between TLG levels and PFS was significant in patients treated with ET with (p=0.0054) and without (p=0.0188) CDK4/6 inhibitor. CONCLUSION: TLG at baseline was a significant predictor for sensitivity to ET alone or combined with CDK4/6 inhibitor. These data may be useful to identify patients that would benefit from ET.

Absolute Lymphocyte Count Is an Independent Prognostic Factor for ER-positive HER2-negative Advanced Breast Cancer Patients Treated With CDK4/6 Inhibitors.

BACKGROUND/AIM: The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer treated with the CDK4/6 inhibitors, abemaciclib and palbociclib. PATIENTS AND METHODS: A total of 83 patients treated with fulvestrant plus abemaciclib or palbociclib were included in this study. Progression-free survival (PFS) and overall survival (OS) were compared in relation to baseline levels of ALC, NLR, PLR and CRP. RESULTS: The cut-off values of ALC, NLR, PLR, and CRP for PFS were determined from the receiver operating characteristic curve using the Youden index for area under the curve and set at 1,212/µl, 1.964, 170 and 0.220 mg/dl, respectively. In the abemaciclib-treated group, ALC-high patients showed significantly better PFS than ALC-low patients (p=0.0151) and multivariate analysis revealed that ALC was an independent prognostic factor for PFS (p=0.0085). In the palbociclib-treated group, there was no significant relationship between any peripheral blood biomarkers and PFS. In both treatment groups, ALC-high patients showed significantly better OS than ALC-low patients (p=0.0169 and 0.0290, respectively). Multivariate analysis revealed ALC was an independent prognostic factor for OS in both abemaciclib- and palbociclib-treated groups (p=0.0112 and 0.0202, respectively). CONCLUSION: ALC is an independent prognostic factor for estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer patients treated with the CDK4/6 inhibitors abemaciclib and palbociclib.

Early assessment of tumor response using 18F-FDG PET/CT after one cycle of systemic therapy in patients with recurrent and metastatic breast cancer.

OBJECTIVE: This study was conducted to evaluate the usefulness of early assessment of tumor response using fluorine-18-fludeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) after one cycle of systemic therapy in patients with recurrent and metastatic breast cancer. SUBJECT AND METHODS: Thirty-three patients with recurrent or metastatic breast cancer underwent 18F-FDG PET/CT before and after one cycle of systemic therapy. Based on the European Organization for Research and Treatment of Cancer (EORTC) criteria, the maximum standardized uptake value (SUVmax) of the same lesions (up to a total of five) noted in the baseline and follow-up scans were summed (maximum of two per organ) as target lesions, and therapeutic response was evaluated. Log-rank and Cox methods were employed to determine progression-free survival (PFS) and overall survival (OS). RESULTS: Complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD) was seen in 2, 16, 11, and 4 patients, respectively. The mean reduction rates of SUVmax between 84 target lesions in 18 responders (CMR/PMR) and 75 target lesions in 15 non-responders (SMD/PMD) were -55.8% (range, -100%- -1.2%) and 0.47% (range, -48.7%- +209.4%), respectively, with a significant difference (P<0.0001). Every lesion site (local lesion, lymph node metastasis, bone metastasis, lung metastasis, and liver metastasis) showed a similar tendency. Thirty patients showed progression, and 17 died due to breast cancer after a median of 38.5 months. Responders showed significantly longer PFS than non-responders (P=0.0038). CONCLUSION: Fluorine-18-FDG PET/CT after one cycle of systemic therapy was able to reflect early metabolic changes regardless of the lesion site, and showed accuracy for early response evaluation and prediction of progression in patients with recurrent or metastatic breast cancer.

Alteration of Trop-2 expression in breast cancer cells by clinically used therapeutic agents and acquired tamoxifen resistance.

BACKGROUND: Sacituzumab govitecan is an antibody-drug conjugate that delivers SN-38, an active metabolite of irinotecan, to the target molecule, trophoblast cell-surface antigen 2 (Trop-2). It is a promising drug for triple-negative breast cancer and is anticipated to be effective for luminal breast cancer. The efficacy of the agent relies on the expression of Trop-2 rather than its intracellular function. However, conditions that alter the Trop-2 expression have not been well investigated. METHODS: We tested a range of clinically related treatments for their effect on Trop-2 expression in cultured breast cancer cell lines. RESULTS: The expression level of Trop-2 differed among cell lines, independent of their subtypes, and was highly variable on treatment with kinase inhibitors, tamoxifen, irradiation, and chemotherapeutic agents including irinotecan. While inhibitors of AKT, RSK, and p38 MAPK suppressed the Trop-2 expression, tamoxifen treatment significantly increased Trop-2 expression in luminal cancer cell lines. Notably, luminal cancer cells with acquired resistance to tamoxifen also exhibited higher levels of Trop-2. We identified transcription factor EB (TFEB) as a possible mechanism underlying tamoxifen-induced elevation of Trop-2 expression. Tamoxifen triggers dephosphorylation of TFEB, an active form of TFEB, and the effect of tamoxifen on Trop-2 was prevented by depletion of TFEB. A luciferase reporter assay showed that Trop-2 induction by TFEB was dependent on a tandem E-box motif within the Trop-2 promoter region. CONCLUSIONS: Overall, these results suggest that the effectiveness of sacituzumab govitecan could be altered by concomitant treatment and that tamoxifen could be a favorable agent for combined therapy.

Low intratumoral genetic neutrophil-to-lymphocyte ratio (NLR) is associated with favorable tumor immune microenvironment and with survival in triple negative breast cancer (TNBC).

Patients with triple negative breast cancer (TNBC) have a poor prognosis. A novel prognostic biomarker may guide management by appropriately selecting patients for particular treatments. Peripheral blood neutrophil-to-lymphocyte ratio (NLR) was reported to associate with cancer progression, thus we hypothesized that intratumor genetic NLR will reflect tumor immune microenvironment (TIME) and breast cancer biology. The intratumoral genetic NLR previously defined as the ratio of CD66b (CEACAM8) and CD8 (CD8A) gene expressions was utilized to analyze total of 2,994 patients from METABRIC, TCGA, GSE21094, GSE22358, GSE25088, GSE32646, and GSE2603 cohorts. Intratumoral genetic NLR did not correlate with cancer stage nor clinical parameters of cancer cell proliferation such as Nottingham histological grade or MKI67 expression levels in neither the METABRIC or TCGA cohorts. Intratumoral genetic NLR-high breast cancer was not associated with pathologic complete response (pCR) after neoadjuvant chemotherapy in 5 independent cohorts with different regimens. Despite these results, intratumoral genetic NLR-high TNBC demonstrated worse disease-free, disease-specific, and overall survival. Intratumoral genetic NLR-low TNBC enriched multiple immune-related gene sets, was associated with higher favorable immune-related scores and with a favorable TIME, whereas no gene sets enriched to NLR-high TNBC. In conclusion, intratumoral genetic NLR-low TNBC was associated with favorable TIME and with better survival.

Investigation of a Novel S-1 Administration Schedule for Treating Metastatic and Recurrent Breast Cancer (KBCOG13).

BACKGROUND/AIM: S-1, a 5-fluorouracil(5-FU) oral anti-cancer drug, has been traditionally used with a schedule of 4-week oral administration followed by 2-week rest for breast cancer treatment. We, herein, aimed to investigate the clinical efficacy and safety of a schedule of 2-week oral administration followed by 1-week rest for patients with metastatic breast cancer. PATIENTS AND METHODS: We enrolled patients with HER2-negative metastatic breast cancer who had not received prior chemotherapy. S-1 was administered consecutively for 2-weeks followed by a 1-week rest. RESULTS: Between September 1, 2013 and August 31, 2016, 32 patients were enrolled. The median follow-up time was 32.1 months. The median progression-free survival (PFS) was 9.4 months. Overall survival (OS) was 41.0 months, time to treatment failure (TTF) was 7.8 months, response rate (RR) was 31.3%, and disease control rate (DCR) was 78.1%. The incidence of grade 3 side-effects was not high. CONCLUSION: The 3-week schedule of S-1 can be considered useful as a treatment for patients with metastatic breast cancer, helping in maintaining a high quality of life.

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 .

Indices of peripheral leukocytes predict longer overall survival in breast cancer patients on eribulin in Japan.

BACKGROUND: It was reported that eribulin regulates the tumor microenvironment, including the immune system, by inducing vascular remodeling. Lymphocyte counts are a critical index of immune response in patients. The non-Asian, global EMBRACE study has suggested that baseline absolute lymphocyte count (ALC) may be a predictor of the survival benefit of eribulin in breast cancer patients. We examined whether the baseline ALC is a potential predictor of overall survival (OS) in Japanese patients with HER2-negative advanced breast cancer treated with eribulin. METHODS: This was a post hoc analysis of data from a post-marketing observational study of eribulin in Japan. The OS by baseline ALC was estimated using the Kaplan-Meier method, with the cut-off value of 1500/µL for ALC. The OS by baseline neutrophil-to-lymphocyte ratio (NLR), a general prognostic index in breast cancer patients, was also estimated, with the cut-off value of 3. RESULTS: The median OS was longer in patients with an ALC of ≥ 1500/µL than in those with an ALC of < 1500/µL (19.4 vs. 14.3 months; hazard ratio [HR]: 0.628; 95% confidence interval [CI]: 0.492, 0.801). Patients with an NLR of ≥ 3 showed shorter OS than those with an NLR of < 3 (13.2 vs. 18.8 months; HR: 1.552; 95% CI 1.254, 1.921), and NLR also separated OS in patients with an ALC of < 1500/µL. CONCLUSIONS: Consistent with the findings of a previous study involving a non-Asian, Western population, our study suggested that baseline ALC may be a predictive factor for the survival benefit of eribulin in Japanese patients.