Evolutionary histories of breast cancer and related clones.

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.

Non-surgical ablation for breast cancer: an emerging therapeutic option.

Non-surgical ablation is emerging as an alternative local therapy option for patients with early-stage breast cancer and encompasses two main types of percutaneous therapeutic procedures: radiofrequency ablation and cryoablation. Both techniques involve obliteration of a spherical lesion and feasibility studies have shown that complete tumour ablation is achievable with good or excellent cosmetic results. Although few clinical studies have directly compared non-surgical ablation with conventional surgical resection, observational studies indicate that clinical outcomes are favourable with acceptable rates of local control and no detriment to long-term survival. There remain outstanding issues with these percutaneous ablative techniques that require resolution before they could be incorporated into routine clinical practice. Hence, a consensus meeting was convened to discuss the challenges of non-surgical ablation and clarify indications for its use alongside clinical management pathways. In this Policy Review we will address some of the broader biological aspects of non-surgical ablation, including immune-modulatory effects and potential novel applications for the future.

Genomic and transcriptomic profiling of pre- and postneoadjuvant chemotherapy triple negative breast cancer tumors.

Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG-22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)-high (HRD score ≥ 42) tumors with higher pCR rates. When HRD-high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2-mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53-positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e-7), which was also the only common gene between HRD-high and -low tumors with pCR/quasi-pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD-high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients.

Time-series blood cytokine profiles correlate with treatment responses in triple-negative breast cancer patients.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype. Partly due to its heterogeneity, it is currently challenging to stratify TNBC patients and predict treatment outcomes. METHODS: In this study, we examined blood cytokine profiles of TNBC patients throughout treatments (pre-treatment, during chemotherapy, pre-surgery, and 1 year after the surgery in a total of 294 samples). We analyzed the obtained cytokine datasets using weighted correlation network analyses, protein-protein interaction analyses, and logistic regression analyses. RESULTS: We identified five cytokines that correlate with good clinical outcomes: interleukin (IL)-1α, TNF-related apoptosis-inducing ligand (TRAIL), Stem Cell Factor (SCF), Chemokine ligand 5 (CCL5 also known as RANTES), and IL-16. The expression of these cytokines was decreased during chemotherapy and then restored after the treatment. Importantly, patients with good clinical outcomes had constitutively high expression of these cytokines during treatments. Protein-protein interaction analyses implicated that these five cytokines promote an immune response. Logistic regression analyses revealed that IL-1α and TRAIL expression levels at pre-treatment could predict treatment outcomes in our cohort. CONCLUSION: We concluded that time-series cytokine profiles in breast cancer patients may be useful for understanding immune cell activity during treatment and for predicting treatment outcomes, supporting precision medicine. TRIAL REGISTRATION: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with the unique trial number UMIN000023162. The association Japan Breast Cancer Research Group trial number is JBCRG-22. The clinical outcome of the JBCRG-22 study was published in Breast Cancer Research and Treatment on 25 March 2021. https://doi.org/10.1007/s10549-021-06184-w .

Comparison of cisplatin-based versus standard preoperative chemotherapy in patients with operable triple-negative breast cancer: propensity score matching and inverse probability of treatment weighting analysis.

PURPOSE: The efficacy of carboplatin is non-equivalent to that of cisplatin (CDDP) for various tumor types in curative settings. However, the role of CDDP in operable triple-negative breast cancer (TNBC) patients remains unknown. We conducted a multicenter observational study to examine the effects of CDDP added to preoperative chemotherapy in patients with TNBC. METHODS: This retrospective study consecutively included previously untreated patients with stage I-III TNBC treated with preoperative chemotherapy with or without CDDP. The primary endpoint was distant disease-free survival (DDFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to minimize confounding biases in comparisons between the two groups. RESULTS: A total of 138 patients were enrolled in the study. Of these, 52 were in the CDDP group and 86 in the non-CDDP group. DDFS was significantly better in the CDDP group than in the non-CDDP group (unadjusted hazard ratio (HR) 0.127 and p < 0.001, PSM HR 0.141 and p < 0.003, IPTW HR 0.123 and p = < 0.001). Furthermore, among the patients with residual cancer burden (RCB) class II/III, DDFS was better in the CDDP group than in the non-CDDP group (unadjusted HR 0.192 and p = 0.013, PSM HR 0.237 and p = 0.051, IPTW HR 0.124 and p = 0.059). CONCLUSION: Our study showed that CDDP-containing regimens achieved favorable prognoses in patients with operable TNBC, especially for the RCB class II/III population. Confirmative studies are warranted to elucidate the role of CDDP in TNBC treatment.

Fosfomycin as salvage therapy for persistent methicillin-resistant Staphylococcus aureus bacteremia: A case series and review of the literature.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia can be persistent and refractory; however, the optimal approach for its treatment has not been determined. Although fosfomycin (FOM) has been shown to have synergistic effects with anti-MRSA agents in vitro, clinical experience with FOM combination therapy is limited. Thus, we present cases of persistent MRSA bacteremia that improved with the addition of FOM. In case 1, a 48-year-old man with prosthetic vascular graft infection developed persistent MRSA bacteremia despite vancomycin (VCM) and daptomycin (DAP) administration. On day 46, after the first positive blood culture, we added FOM to DAP. The blood culture became negative on day 53. In case 2, an 85-year-old woman presented with pacemaker-related MRSA bacteremia. She was treated with VCM, followed by DAP and DAP plus rifampicin. However, the bacteremia persisted for 32 days because of difficulties in immediate pacemaker removal. After adding FOM to DAP, the blood culture became negative on day 38. In case 3, a 57-year-old woman developed persistent MRSA bacteremia due to pulmonary valve endocarditis and pulmonary artery thrombosis after total esophagectomy for esophageal cancer. The bacteremia continued for 50 days despite treatment with DAP, followed by VCM, VCM plus minocycline, DAP plus linezolid (LZD), and VCM plus LZD. She was managed conservatively because of surgical complications. After adding FOM to VCM on day 51, the blood culture became negative on day 58. FOM combination therapy may be effective in eliminating bacteria and can serve as salvage therapy for refractory MRSA bacteremia.

Predicting invasive disease-free survival in ER-positive, HER2-negative early breast cancer using the PAM50 risk-of-recurrence score: a retrospective analysis using single-center long-term follow-up data of postmenopausal Japanese patients.

BACKGROUND: The prognostic value of the risk-of-recurrence (ROR) score calculated using PAM50 has been validated using clinical trials and patient cohorts. This study aimed to investigate the prognostic value of the PAM50 ROR score in Japanese patients with early breast cancer using long-term follow-up data. METHODS: We enrolled postmenopausal patients with ER-positive, HER2-negative, stage I-II breast cancer who had undergone surgery at the Kyoto University Hospital between 2008 and 2014. The intrinsic subtype and ROR score were calculated using PAM50. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: We enrolled 146 patients, of whom 47 (32%) patients had node-positive disease, and 36 (25%) had received neoadjuvant or adjuvant chemotherapy. The proportions of intrinsic subtypes for luminal A, luminal B, HER2-enriched, and basal-like subtypes were 67%, 27%, 3%, and 2%, respectively. The median follow-up duration was 8.4 (range 6.3-10.0) years, and 21 IDFS events were observed. Based on the ROR score, 37%, 33%, and 30% of the patients were classified as low, intermediate, and high risks, respectively. Patients in the high-risk group had a significantly worse 8-year IDFS rate than those in the low-to-intermediate-risk groups (75.1% vs. 91.6%, p = 0.04). The same trend was observed in patients with and without neoadjuvant or adjuvant chemotherapy. CONCLUSIONS: Using long-term follow-up data, this study showed that the ROR score can predict the prognosis of ER-positive, HER2-negative early breast cancer in Japanese postmenopausal patients. Further investigations are required to confirm the prognostic value of the ROR score in Asian populations.

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.

A risk-based subgroup analysis of the effect of adjuvant S-1 in estrogen receptor-positive, HER2-negative early breast cancer.

PURPOSE: The Phase III POTENT trial demonstrated the efficacy of adding S-1 to adjuvant endocrine therapy for estrogen receptor-positive, HER2-negative early breast cancer. We investigated the efficacy of S-1 across different recurrence risk subgroups. METHODS: This was a post-hoc exploratory analysis of the POTENT trial. Patients in the endocrine-therapy-only arm were divided into three groups based on composite risk values calculated from multiple prognostic factors. The effects of S-1 were estimated using the Cox model in each risk group. The treatment effects of S-1 in patients meeting the eligibility criteria of the monarchE trial were also estimated. RESULTS: A total of 1,897 patients were divided into three groups: group 1 (≤ lower quartile of the composite values) (N = 677), group 2 (interquartile range) (N = 767), and group 3 (> upper quartile) (N = 453). The addition of S-1 to endocrine therapy resulted in 49% (HR: 0.51, 95% CI: 0.33-0.78) and 29% (HR: 0.71, 95% CI 0.49-1.02) reductions in invasive disease-free survival (iDFS) events in groups 2 and 3, respectively. We could not identify any benefit from the addition of S-1 in group 1. The addition of S-1 showed an improvement in iDFS in patients with one to three positive nodes meeting the monarchE cohort 1 criteria (N = 290) (HR: 0.47, 95% CI: 0.29-0.74). CONCLUSIONS: The benefit of adding adjuvant S-1 was particularly marked in group 2. Further investigations are warranted to explore the optimal usage of adjuvant S-1.

An exploratory study for tuft cells in the breast and their relevance in triple-negative breast cancer: the possible relationship of SOX9.

BACKGROUND: Breast cancer is highly heterogeneous, suggesting that small but relevant subsets have been under-recognized. Rare and mainly triple-negative breast cancers (TNBCs) were recently found to exhibit tuft cell-like expression profiles, including POU2F3, the tuft cell master regulator. In addition, immunohistochemistry (IHC) has identified POU2F3-positive cells in the normal human breast, suggesting the presence of tuft cells in this organ. METHODS: Here, we (i) reviewed previously identified POU2F3-positive invasive breast cancers (n = 4) for POU2F3 expression in intraductal cancer components, (ii) investigated a new cohort of invasive breast cancers (n = 1853) by POU2F3-IHC, (iii) explored POU2F3-expressing cells in non-neoplastic breast tissues obtained from women with or without BRCA1 mutations (n = 15), and (iv) reanalyzed publicly available single-cell RNA sequencing (scRNA-seq) data from normal breast cells. RESULTS: Two TNBCs of the four previously reported invasive POU2F3-positive breast cancers contained POU2F3-positive ductal carcinoma in situ (DCIS). In the new cohort of invasive breast cancers, IHC revealed four POU2F3-positive cases, two of which were triple-negative, one luminal-type, and one triple-positive. In addition, another new POU2F3-positive tumor with a triple-negative phenotype was found in daily practice. All non-neoplastic breast tissues contained POU2F3-positive cells, irrespective of BRCA1 status. The scRNA-seq reanalysis confirmed POU2F3-expressing epithelial cells (3.3% of all epithelial cells) and the 17% that co-expressed the other two tuft cell-related markers (SOX9/AVIL or SOX9/GFI1B), which suggested they were bona fide tuft cells. Of note, SOX9 is also known as the "master regulator" of TNBCs. CONCLUSIONS: POU2F3 expression defines small subsets in various breast cancer subtypes, which can be accompanied by DCIS. The mechanistic relationship between POU2F3 and SOX9 in the breast warrants further analysis to enhance our understanding of normal breast physiology and to clarify the significance of the tuft cell-like phenotype for TNBCs.

Ultrafast Dynamic Contrast-Enhanced MRI of the Breast: From Theory to Practice.

The development of ultrafast dynamic contrast-enhanced (UF-DCE) MRI has occurred in tandem with fast MRI scan techniques, particularly view-sharing and compressed sensing. Understanding the strengths of each technique and optimizing the relevant parameters are essential to their implementation. UF-DCE MRI has now shifted from research protocols to becoming a part of clinical scan protocols for breast cancer. UF-DCE MRI is expected to compensate for the low specificity of abbreviated MRI by adding kinetic information from the upslope of the time-intensity curve. Because kinetic information from UF-DCE MRI is obtained from the shape and timing of the initial upslope, various new kinetic parameters have been proposed. These parameters may be associated with receptor status or prognostic markers for breast cancer. In addition to the diagnosis of malignant lesions, more emphasis has been placed on predicting and evaluating treatment response because hyper-vascularity is linked to the aggressiveness of breast cancers. In clinical practice, it is important to note that breast lesion images obtained from UF-DCE MRI are slightly different from those obtained by conventional DCE MRI in terms of morphology. A major benefit of using UF-DCE MRI is avoidance of the marked or moderate background parenchymal enhancement (BPE) that can obscure the target enhancing lesions. BPE is less prominent in the earlier phases of UF-DCE MRI, which offers better lesion-to-noise contrast. The excellent contrast of early-enhancing vessels provides a key to understanding the detailed pathological structure of tumor-associated vessels. UF-DCE MRI is normally accompanied by a large volume of image data for which automated/artificial intelligence-based processing is expected to be useful. In this review, both the theoretical and practical aspects of UF-DCE MRI are summarized. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 2.

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).

Switch maintenance endocrine therapy plus bevacizumab after bevacizumab plus paclitaxel in advanced or metastatic oestrogen receptor-positive, HER2-negative breast cancer (BOOSTER): a randomised, open-label, phase 2 trial.

BACKGROUND: Anticancer treatment regimens typically cause unpleasant side-effects. We aimed to investigate the benefit of switch maintenance endocrine therapy plus bevacizumab after fixed cycles of first-line induction chemotherapy with weekly paclitaxel plus bevacizumab in patients with oestrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer. METHODS: BOOSTER was a prospective, open-label, multicentre, randomised, controlled, phase 2 study done in 53 hospitals in Japan. Eligible patients were women aged 20-75 years, with an Eastern Cooperative Oncology Group performance status of 0-1, who had not received chemotherapy for ER-positive, HER2-negative advanced or metastatic breast cancer. All patients received four to six cycles (in which 4 weeks of treatment constitute one cycle) of weekly paclitaxel plus bevacizumab induction therapy (weekly paclitaxel 90 mg/m2, administered intravenously on days 1, 8, and 15 of each cycle, plus bevacizumab 10 mg/kg administered intravenously on days 1 and 15 of each cycle; first registration). Patients with a complete response, partial response, or stable disease after induction therapy (responders) were then randomly assigned (1:1) using the randomisation enrolment form to either continue weekly paclitaxel plus bevacizumab or switch to maintenance endocrine therapy (an aromatase inhibitor or fulvestrant with or without ovarian-function suppression) plus bevacizumab. Randomisation was stratified by induction therapy period, response to induction therapy, age, history of endocrine therapy, and study site. Patients could receive weekly paclitaxel plus bevacizumab reinduction if they had disease progression with maintenance endocrine therapy plus bevacizumab. The primary endpoint was time to failure of strategy (TFS). Efficacy and safety analyses were done in all treated patients (full analysis set). This study is registered with ClinicalTrials.gov, NCT01989780, and registration and follow-up are closed. FINDINGS: Between Jan 1, 2014, and Dec 31, 2015, we enrolled 160 patients who began weekly paclitaxel plus bevacizumab induction therapy. 125 (78%) patients (responders) were randomly assigned to endocrine therapy plus bevacizumab (n=62; n=61 in the full analysis set) or weekly paclitaxel plus bevacizumab (n=63; n=63 in the full analysis set). Among 61 patients in the switch maintenance endocrine therapy plus bevacizumab group, 32 (52%) were reinitiated on weekly paclitaxel plus bevacizumab. At a median follow-up of 21·3 months (IQR 13·0-28·2), TFS was significantly longer in the endocrine therapy plus bevacizumab group than in the weekly paclitaxel plus bevacizumab group (median 16·8 months [95% CI 12·9-19·0] vs 8·9 months [5·7-13·8]; hazard ratio 0·51 [0·34-0·75]; p=0·0006). The most common grade 3-4 non-haematological adverse events after randomisation were proteinuria (in ten [16%] of 61 patients in the endocrine therapy plus bevacizumab group vs eight [13%] of 63 patients in the weekly paclitaxel plus bevacizumab group), hypertension (six [10%] vs six [10%]), and peripheral neuropathy (one [2%] vs six [10%]). One treatment-related death was reported in the weekly paclitaxel plus bevacizumab group (duodenal ulcer perforation). INTERPRETATION: Switch to maintenance endocrine therapy plus bevacizumab with the possibility of weekly paclitaxel reinduction if needed is an efficacious alternative, with a better safety profile, to continuing weekly paclitaxel plus bevacizumab in patients with ER-positive, HER2-negative advanced or metastatic breast cancer who have responded to induction therapy. FUNDING: Chugai Pharmaceutical. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer. METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969. FINDINGS: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis. INTERPRETATION: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer. FUNDING: Public Health Research Foundation (Japan), Taiho Pharmaceutical.

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.

Exploring Primordial Black Holes from the Multiverse with Optical Telescopes.

Primordial black holes (PBHs) are a viable candidate for dark matter if the PBH masses are in the currently unconstrained "sublunar" mass range. We revisit the possibility that PBHs were produced by nucleation of false vacuum bubbles during inflation. We show that this scenario can produce a population of PBHs that simultaneously accounts for all dark matter, explains the candidate event in the Subaru Hyper Suprime-Cam (HSC) data, and contains both heavy black holes as observed by LIGO and very heavy seeds of supermassive black holes. We demonstrate with numerical studies that future observations of HSC, as well as other optical surveys, such as LSST, will be able to provide a definitive test for this generic PBH formation mechanism if it is the dominant source of dark matter.

Cryosurgery for primary breast cancers, its biological impact, and clinical outcomes.

Recently, a number of new minimally invasive image-guided percutaneous ablation treatments, including cryoablation, radiofrequency ablation, microwave ablation, high-intensity focused ultrasound, laser ablation, and irreversible electroporation have been developed. Several studies have shown the feasibility and safety of these cryoablation therapies for the treatment of benign breast tumors and small invasive breast cancer. Although the complete response rate of cryoablation for breast cancer is reported to be relatively good, most studies enrolled a small number of patients, and so reliable conclusions could not be drawn. In this review, we introduce the mechanisms of action of cryoablation, and summarize the current literature on the efficacy and safety of cryoablation for breast cancer. Cryoablation also induces an immunomodulatory effect, which is an interesting topic of research in the era of immune checkpoint inhibitors. Cryoablation for primary tumor may enhance the treatment effect of immune checkpoint inhibitors in patients with breast cancer. Further investigations of this new therapeutic strategy are needed.

Prediction of postoperative disease-free survival and brain metastasis for HER2-positive breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab using a machine learning algorithm.

PURPOSE: This study aimed to develop mathematical tools to predict the likelihood of recurrence after neoadjuvant chemotherapy (NAC) plus trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: Data of 776 patients from a multicenter retrospective cohort study were collected. All patients had HER2-positive breast cancer and received NAC plus trastuzumab between 2001 and 2010. Two mathematical tools using a machine learning method were developed to predict the likelihood of disease-free survival (DFS) (DFS model) and brain metastasis (BM) (BM model) within 5 years after surgery. For validation, bootstrap analyses were conducted. The area under the receiver operating characteristics curve (AUC) was calculated to examine the discrimination. RESULTS: The AUC values were 0.785 (95% CI 0.740-0.831, P < 0.001) for the DFS model and 0.871 (95% CI 0.830-0.912, P < 0.001) for the BM model. Patients with low-risk DFS or BM events, as predicted by the models, showed better 5-year DFS and BM rates than those with high-risk DFS or BM events (89% vs. 61% for the DFS model, P < 0.001; 99% vs. 87% for the BM model, P < 0.001). These models maintained discrimination abilities in both luminal and non-luminal subtypes, providing prognostic information independent of pathological response. Bootstrap validation confirmed the high generalization abilities of the models. CONCLUSIONS: The DFS and BM models have a high accuracy to predict prognosis among HER2-positive patients treated with NAC plus trastuzumab. Our models can help optimize adjuvant therapy and postoperative surveillance.

Effectiveness of neo-adjuvant systemic therapy with trastuzumab for basal HER2 type breast cancer: results from retrospective cohort study of Japan Breast Cancer Research Group (JBCRG)-C03.

PURPOSE: While human epidermal growth factor receptor 2 (HER2) target therapies have significantly improved the prognosis of patients with HER2-enriched breast cancer, differing clinical benefits and gene expression analyses suggest a divergent HER2 subgroup. We aimed to investigate whether the basal HER2 subtype of breast cancer has distinguished characteristics. METHODS: We performed a substudy by using data from a retrospective multi-institutional cohort of JBCRG-C03. Between 2001 and 2011, we identified 184 eligible patients who received concurrent neo-adjuvant chemotherapy (NAC) with trastuzumab for hormone receptor-negative and HER2-positive breast cancer. We defined basal HER2 subtype breast cancer as HER2-positive, ER/PgR-negative, and basal markers (EGFR, CK14 or CK5/6) positive by immunohistochemistrical evaluation. The pathologic complete response (pCR) and disease-free survival (DFS) rates were compared between the two subtypes. RESULTS: A total of 127 (69.0%) patients achieved pCR after NAC and 29 (15.8%) patients experienced events of DFS within a 42 month median follow-up period (interquartile range 26-58 months). Although the basal HER2 subtype was related with poor DFS (3 year DFS: non-basal HER2, 95.0%; basal HER2, 86.9%; adjusted HR 3.4; 95% CI 1.2-14.5), neither the subtype (pCR: non-basal HER2, 75%; basal HER2, 66.7%; adjusted OR 0.60; 95% CI 0.27-1.28) nor the degree of expression of basal markers was significantly related with the pCR rate. CONCLUSION: Basal HER2 phenotype showed poor DFS, but equivalent pCR rate after concurrent neo-adjuvant chemotherapy with trastuzumab. A different treatment approach to basal-HER2 type is needed even for cases that achieved adequate clinical response after NAC.