Trastuzumab deruxtecan versus treatment of physician's choice in previously treated Asian patients with HER2-low unresectable/metastatic breast cancer: subgroup analysis of the DESTINY-Breast04 study.

BACKGROUND: In the global phase 3 DESTINY-Breast04 study (NCT03734029), the anti-human epidermal growth factor 2 (HER2) antibody-drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated a statistically significant improvement in progression-free survival (PFS) and overall survival (OS), with manageable safety compared with treatment of physician's choice (TPC) in patients with HER2-low metastatic breast cancer (mBC) who had received 1-2 prior lines of chemotherapy. METHODS: This subgroup analysis examined the efficacy and safety of T-DXd versus TPC in 213 patients from Asian countries and regions who were enrolled in the DESTINY-Breast04 trial and randomized to T-DXd (n = 147) or TPC (n = 66). RESULTS: Median PFS with T-DXd and TPC was 10.9 and 5.3 months, respectively, in Asian patients with hormone receptor-positive mBC, and 10.9 and 4.6 months, respectively, in the overall Asian population. In both populations, median OS was not reached with T-DXd and was 19.9 months with TPC. The objective response rate was higher with T-DXd versus TPC in all Asian patients. Median treatment duration was 8.4 months with T-DXd and 3.5 months with TPC. The most common grade ≥ 3 drug-related treatment-emergent adverse events in Asian patients treated with T-DXd were neutropenia (16.3%), anemia (12.9%), and leukopenia (11.6%); the incidences of neutropenia and leukopenia were higher with TPC versus T-DXd. Adjudicated drug-related interstitial lung disease or pneumonitis with T-DXd was 14.3%; the majority of events were grade 1-2. CONCLUSIONS: T-DXd demonstrated clinically meaningful survival benefits versus TPC in Asian HER2-low mBC patients, regardless of hormone receptor status, with no new safety signals. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03734029.

Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial.

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3-4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144-fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2-46.1%) and the median PFS was 10.7 (5.3-not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2- mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446 .

Exploring the effect of BRCA1/2 status on chemotherapy-induced hematologic toxicity in patients with ovarian cancer.

OBJECTIVE: BRCA1/2 are integral to the DNA repair mechanism and their germline pathogenic variants (gBRCA) result in a high risk for developing breast and ovarian cancer. Patients with gBRCA mutations showed increased sensitivity to DNA cross-linking agent but might have increased treatment-related toxicities. Thus, we hypothesized that gBRCA mutation ovarian cancer patients who underwent platinum-based chemotherapy might be at higher risk of developing chemotherapy-induced hematologic toxicity. METHODS: This study enrolled 160 patients with ovarian cancer who received frontline platinum-based chemotherapy between 2011 and 2019 in Kyungpook National University Chilgok Hospital. Incidence rate and severity of chemotherapy-induced hematologic toxicity (neutropenia, anemia, thrombocytopenia) was compared for BRCA mutation and wild patients. RESULTS: 160 women, including 62 BRCA1/2 (38 BRCA1, and 25 BRCA2) mutation group, and 98 noncarriers, were analyzed. A higher frequency of G2 anemia was noted in the BRCA -mutant group (22% vs. 1%, p = 0.07). Furthermore, G3 anemia was significantly common among BRCA group (12.9% vs. 3%, p = 0.02). In the subgroup analysis according to BRCA1/2 status, BRCA1 mutated patients showed a significantly higher frequency of G1 anemia than BRCA2 (89% vs. 60%, p = 0.01). In terms of neutropenia and thrombocytopenia, BRCA mutated patients and noncarriers had similar hematologic toxicity. CONCLUSION: Germline BRCA mutations were associated with a higher frequency of G2/3 anemia in ovarian cancer patients who underwent first-line platinum-based chemotherapy. Moreover, the BRCA1 mutation appeared to be more strongly associated with the incidence of chemotherapy-induced anemia. Our findings warrant further investigation in larger, prospective studies to confirm these current findings and determine whether preventive interventions may be necessary.

Long non-coding RNA SOX2OT in tamoxifen-resistant breast cancer.

Hormone receptor (HR)-positive breast cancer can become aggressive after developing hormone-treatment resistance. This study elucidated the role of long non-coding RNA (lncRNA) SOX2OT in tamoxifen-resistant (TAMR) breast cancer and its potential interplay with the tumor microenvironment (TME). TAMR breast cancer cell lines TAMR-V and TAMR-H were compared with the luminal type A cell line (MCF-7). LncRNA expression was assessed via next-generation sequencing, RNA extraction, lncRNA profiling, and quantitative RT-qPCR. SOX2OT overexpression effects on cell proliferation, migration, and invasion were evaluated using various assays. SOX2OT was consistently downregulated in TAMR cell lines and TAMR breast cancer tissue. Overexpression of SOX2OT in TAMR cells increased cell proliferation and cell invasion. However, SOX2OT overexpression did not significantly alter SOX2 levels, suggesting an independent interaction within TAMR cells. Kaplan-Meier plot analysis revealed an inverse relationship between SOX2OT expression and prognosis in luminal A and B breast cancers. Our findings highlight the potential role of SOX2OT in TAMR breast cancer progression. The downregulation of SOX2OT in TAMR breast cancer indicates its involvement in resistance mechanisms. Further studies should explore the intricate interactions between SOX2OT, SOX2, and TME in breast cancer subtypes.

Exploration of MELK as a downstream of Del-1 and druggable targets in triple-negative breast cancer.

PURPOSE: In our previous study, Developmental endothelial locus-1 (Del-1) was a promising predictive marker for breast cancer. However, the downstream targets of Del-1 remain unknown. Here, we sought to discover a druggable target downstream of Del-1 and investigate the mechanism by which it regulates the course of breast cancer. METHODS: To investigate Del-1 downregulation effect on breast cancer, we performed transcriptome analysis using RNA sequencing of Del-1 knockdowned MDA-MB-231 cell line Plus, to investigate the expression of Del-1 and Maternal embryonic leucine zipper kinase (MELK), mRNA levels in eight different triple-Negative Breast Cancer (TNBC) cell lines were analyzed. High-throughput sequencing was performed on total RNA isolated. OTS167 was used for MELK inhibition. The effects of MELK on cell proliferation and invasion were determined using the MTT and Matrigel transwell assays. Furthermore, we examined MELK expression in breast cancer tissue. RESULTS: Del-1 and MELK mRNA expression levels were significantly higher in the TNBC cell lines, MDA-MB-468, HCC-1806, and MBA-MB-231. Knocking down Del-1 with siRNA in HCC-1806 and MBA-MB-231 cells significantly decreased MELK expression and thus suggested a possible relationship between Del-1 and MELK. In MDA-MB-468 cells, a basal-like 1 TNBC cell line, OTS167 significantly inhibited breast cancer cell proliferation and promoted cell apoptosis. To further investigate the relationship between Del-1 and MELK, dual inhibition of both Del-1 and MELK was performed, which significantly reduced the viability of MDA-MB-468 and MBA-MB-231 cells. CONCLUSION: We found that MELK acts downstream of Del-1 and is a promising druggable target, especially in basal-like and mesenchymal stem-like subtype.

Effectiveness of Carboplatin-Prescreening Intradermal Skin Tests to Reduce Unanticipated Immediate Hypersensitivity Reactions: A Comparative Study.

BACKGROUND: Carboplatin administration poses a risk of immediate hypersensitivity reactions (IHRs) that tend to increase with repeated administration and are mostly IgE-mediated. OBJECTIVE: This study evaluated the usefulness of carboplatin-prescreening intradermal skin tests (IDTs). METHODS: Carboplatin-prescreening IDTs were routinely conducted in patients with a history of receiving six or more carboplatin cycles beginning in January 2021. The primary objective was to assess disparities in the incidence of unanticipated IHRs to carboplatin administration. We compared patients in the intervention group (from 2021 to 2022) and those who did not undergo prescreening IDTs under the same conditions (preintervention group, from 2019 to 2020). Secondary objectives included evaluating the sensitivity and specificity of the prescreening IDT and the incidence of carboplatin IHR according to the number of infusion cycles. RESULTS: The intervention group was composed of 67 patients who were administered 347 carboplatin cycles whereas the preintervention group included 96 patients who were administered 464 carboplatin cycles. The risk of unanticipated carboplatin IHRs decreased by 83.2% in the intervention group compared with results in the preintervention group (preintervention group, 3.45%, n = 16 vs intervention group, 0.58%, n = 2; P = .005). The prescreening IDT showed a sensitivity and specificity of 77.78% and 99.41%, respectively. The risk of newly developed IHRs based on the number of carboplatin cycles was less than 1% (cycles 1-5), 2.11% (cycle 6), 3.90% (cycles 7-12), 2.90% (cycles 13-18), and 0.74% (cycles 19 and greater), respectively. CONCLUSIONS: Initiating carboplatin-prescreening IDTs from the seventh cycle on significantly reduced the risk of unanticipated IHRs.

A phase Ia/Ib study of novel anti-ErbB3 monoclonal antibody, barecetamab (ISU104) in refractory solid cancers and monotherapy or in combination with cetuximab in recurrent or metastatic head and neck cancer.

We evaluated the safety, tolerability, pharmacokinetics and antitumor activity of barecetamab monotherapy and combination cetuximab therapy in patients with advanced solid cancers, especially head and neck cancer (HNC). Part 1 was a 3 + 3 dose-escalation study in which 15 patients received barecetamab at 1, 3, 5, 10 and 20 mg/kg intravenously (IV) on days 1 and 28 and weekly in patients with advanced solid cancer. Part 2 was a dose-expansion study including two patient groups with advanced HNC, including six patients receiving barecetamab at 20 mg/kg IV every 3 weeks and 12 patients receiving barecetamab and cetuximab (400 mg/m2 on day 1 followed by 250 mg/m2 every week). No dose-limiting toxicities (DLTs) were observed. Maximum serum target engagement was reached with trough levels of doses ≥3 mg/kg IV weekly. Common adverse drug reactions were diarrhea, stomatitis, dermatitis acneiform and decreased appetite. One durable complete response of more than 17 months was observed, and the overall response and disease control rates were 36.4% (4/11) and 81.1% (9/11), respectively, in the combination therapy group. In conclusion, DLT was not observed in barecetamab at 1 to 20 mg/kg. The recommended phase II dose was determined to be 20 mg/kg triweekly. Barecetamab and in cetuximab combination was well tolerated and demonstrated meaningful antitumor effects.

Cardiac Safety and Efficacy of SB3 Trastuzumab Biosimilar for ERBB2-Positive Early Breast Cancer: Secondary Analysis of a Randomized Clinical Trial.

Importance: Trastuzumab has been the standard of care for the treatment of patients with ERBB2-positive breast cancer; however, cardiac events have been reported. This long-term follow-up study provides clinical evidence supporting the similarity of a trastuzumab biosimilar (SB3) to reference trastuzumab (TRZ). Objective: To compare cardiac safety and efficacy between SB3 and TRZ for patients with ERBB2-positive early or locally advanced breast cancer after up to 6 years of follow-up. Design, Setting, and Participants: This prespecified secondary analysis of a randomized clinical trial, conducted from April 2016 to January 2021, included patients with ERBB2-positive early or locally advanced breast cancer from a multicenter double-blind, parallel-group, equivalence phase 3 randomized clinical trial of SB3 vs TRZ with concomitant neoadjuvant chemotherapy who completed neoadjuvant and adjuvant treatment. Interventions: In the original trial, patients were randomized to either SB3 or TRZ with concomitant neoadjuvant chemotherapy for 8 cycles (4 cycles of docetaxel followed by 4 cycles of fluorouracil, epirubicin, and cyclophosphamide). After surgery, patients continued SB3 or TRZ monotherapy for 10 cycles of adjuvant treatment per previous treatment allocation. Following neoadjuvant and adjuvant treatment, patients were monitored for up to 5 years. Main Outcomes and Measures: The primary outcomes were the incidence of symptomatic congestive heart failure and asymptomatic, significant decrease in left ventricular ejection fraction (LVEF). The secondary outcomes were event-free survival (EFS) and overall survival (OS). Results: A total of 538 female patients were included (median age, 51 years [range, 22-65 years]). Baseline characteristics were comparable between the SB3 and TRZ groups. Cardiac safety was monitored for 367 patients (SB3, n = 186; TRZ, n = 181). Median follow-up was 68 months (range, 8.5-78.1 months). Asymptomatic, clinically significant LVEF decreases were rarely reported (SB3, 1 patient [0.4%]; TRZ, 2 [0.7%]). No patient experienced symptomatic cardiac failure or death due to a cardiovascular event. Survival was evaluated for the 367 patients in the cardiac safety cohort and an additional 171 patients enrolled after a protocol amendment (538 patients [SB3, n = 267; TRZ, n = 271]). No difference was observed in EFS or OS between treatment groups (EFS: hazard ratio [HR], 0.84; 95% CI, 0.58-1.20; P = .34; OS: HR, 0.61; 95% CI, 0.36-1.05; P = .07). Five-year EFS rates were 79.8% (95% CI, 74.8%-84.9%) in the SB3 group and 75.0% (95% CI, 69.7%-80.3%) in the TRZ group, and OS rates were 92.5% (95% CI, 89.2%-95.7%) in the SB3 group and 85.4% (95% CI, 81.0%-89.7%) in the TRZ group. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, SB3 demonstrated cardiac safety and survival comparable to those of TRZ after up to 6 years of follow-up in patients with ERBB2-positive early or locally advanced breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02771795.

Ten-Year Oncologic Outcomes in T1-3N1 Breast Cancer After Targeted Axillary Sampling: A Retrospective Study.

BACKGROUND: Targeted axillary sampling (TAS) is a new surgical concept for the assessment of axillary lymph node status in breast cancer that is hypothesized to be more effective at minimizing postoperative morbidities than axillary lymph node dissection (ALND), provided the metastatic axillary lymph node can be accurately detected without missing data; however, the oncologic outcomes over long-term follow-up have not been sufficiently investigated. This was a retrospective analysis to evaluate the 10-year oncologic outcomes in T1-3N1 breast cancer after TAS. METHODS: Between 2008 and 2013, 230 female patients with cT1-3N1 breast cancer underwent breast and axillary surgery (ALND, n = 171; TAS, n = 59) at our institute. After TAS was applied, additional axillary radiotherapy was performed. Various postoperative complications, including postoperative seroma, lymphedema, and 10-year oncological outcomes, were evaluated and compared between the ALND and TAS groups. RESULTS: Although overall survival during the 10-year follow-up period was better in the TAS group, there was no statistically significant difference in oncologic outcomes, including locoregional recurrence, distant metastasis, and overall survival (p = 0.395, 0.818, and 0.555, respectively). Furthermore, the incidence of lymphedema on the ipsilateral arm was significantly higher in the ALND group (p < 0.001). CONCLUSIONS: The 10-year oncological outcomes of TAS were not inferior to those of conventional ALND in T1-3N1 breast cancers; however, the incidence of lymphedema was significantly higher in the ALND group.

Oncologic necessity for the complete removal of residual microcalcifications after neoadjuvant chemotherapy for breast cancer.

The surgical range of breast cancer that shows pathologic complete response (pCR) without change in microcalcifications after neoadjuvant chemotherapy (NAC) is controversial. This study examined whole breast specimens to evaluate the necessity of mastectomy in those cases. The viability of cancer cells around the residual microcalcification was assessed using prospectively collected breast samples to confirm the presence or absence of cancer cells. A total of 144 patients with breast cancer and diffuse microcalcifications were classified into the reduced mass with no change in residual microcalcification (RESMIN, n = 49) and non-RESMIN (n = 95) groups. Five specimens were prospectively evaluated to assess the presence of viable cancer cells around the microcalcification. Tumor responses to NAC were significantly better with high pCR rates in the RESMIN group (p = 0.005 and p = 0.002). The incidence of human epidermal growth factor receptor 2-positive and triple-negative breast cancers was significantly high in the RESMIN group (p = 0.007). Although five (10.2%) patients had locoregional recurrence in the RESMIN group, no local recurrence in the breast was reported. Although pCR was highly estimated, residual cancers, including ductal carcinoma in situ, remained in 80% cases. Therefore, given the weak scientific evidence available currently, complete removal of residual microcalcifications should be considered for oncologic safety.

Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.

BACKGROUND: Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers. METHODS: We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients. RESULTS: Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events. CONCLUSIONS: In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).

Higher Pathological Complete Response Rate of Less than 10 Total Axillary Lymph Nodes After Axillary Lymph Node Dissection Following Neoadjuvant Chemotherapy in Breast Cancer.

Background: The American Joint Committee on Cancer (AJCC) guideline recommends the evaluation of ≥10 axillary lymph nodes (ALN) in patients with breast cancer to assess the N stage. However, the total ALN count in ALN dissection (ALND) often decreases after neoadjuvant chemotherapy in breast cancer. The authors compared clinicopathological factors and oncological outcomes between <10 vs. ≥10 ALNs after ALND following neoadjuvant chemotherapy in breast cancer. Methods: Data of 159 patients with breast cancer, treated with neoadjuvant chemotherapy and ALND, were reviewed, and the cases were classified into two groups (<10 vs. ≥10 ALN count). The treatment response was determined based on the RECIST 1.1 criteria, and histopathological regression of the tumor was assessed based on the Miller-Payne grading scales. Results: Most of the clinical and pathological factors did not demonstrate any significant differences between the two groups. However, the pathological complete response (pCR) rate in breast lesion and ALNs were the higher trend in the group with <10 ALNs. During the 88-month follow-up period, there was no significant difference in locoregional recurrence, distant metastasis, or overall survival. Conclusions: Although there was a limitation due to different sample sizes, additional axillary surgery may not be necessary even in cases with <10 total ALNs after ALND, following neoadjuvant chemotherapy because the lymph nodes are more likely to have been regressed themselves due to neoadjuvant chemotherapy, and the residual lymph nodes may be absent.

Feasibility of targeted cascade genetic testing in the family members of BRCA1/2 gene pathogenic variant/likely pathogenic variant carriers.

The pathogenic variant (PV) or likely pathogenic variant (LPV) BRCA1/2 gene is strongly associated with hereditary breast or ovarian cancer. Therefore, it is important to screen blood relatives to establish preventive modalities and surveillance. This study evaluated the feasibility of targeted cascade genetic testing for family members of BRCA1/2 gene PV or LPV carriers. We screened 18 families for BRCA1/2 gene status via the conventional cascade genetic test (n = 9) and targeted cascade genetic test (n = 9), which targeted the exon region wherein the index patient showed PV or LPV. The pedigree and clinicopathologic characteristics were reviewed and analyzed. All index patients were diagnosed with breast cancer, while the third family members were all healthy. In the conventional cascade test group, 3 index patients and 3 family members had the BRCA1/2 gene PV or LPV. In the targeted cascade test group, 5 family members had same type of BRCA1/2 gene PV or LPV as their index patients. Two families had an identical string of BRCA1/2 gene PV or LPV. Although the targeted cascade genetic test cannot completely characterize the BRCA1/2 gene, it is sufficient for determining its PV or LPV status. This limited genetic test can be used for family members of PV or LPV carriers.

Evaluation of a Direct Reverse Transcription Loop-Mediated Isothermal Amplification Method without RNA Extraction (Direct RT-LAMP) for the Detection of Lymph Node Metastasis in Early Breast Cancer.

PURPOSE: Assessing lymph node metastasis, tumor-derived DNA, or tumor-derived RNA has previously been studied in place of immunohistochemical assay. Because a direct reverse transcription loop-mediated isothermal amplification method (direct RT-LAMP) has been previously developed in order to rapidly identify viruses in place of RNA extraction, our team hypothesized that a direct RT-LAMP assay can be employed as a substitute in order to detect tumor involvement of lymph nodes within breast cancer patients. MATERIALS AND METHODS: A total amount of 92 lymph nodes removed across 40 patients possessing breast cancer were collected at Kyungpook National University Chilgok Hospital between the months of November 2015 and February 2016. All samples were then evaluated and contrasted via both a direct RT-LAMP assay and routine histopathologic examination. RESULTS: The sensitivity and specificity of the direct RT-LAMP assay were 85.7% and 100%, respectively. The positive predictive value and negative predictive value were 100% and 94.4%, respectively. CONCLUSION: Direct RT-LAMP assay is capable of facilitating the detection of sentinel lymph node metastasis within breast cancer patients intraoperatively possessing an excellent sensitivity via a cost-effective and time-saving manner.

Short-term serial assessment of electronic patient-reported outcome for depression and anxiety in breast Cancer.

PURPOSE: The incidence of depression and anxiety is higher in patients with breast cancer than in the general population. We evaluated the degree of depression and anxiety and investigated the changes in patients with breast cancer during the treatment period and short-term follow-up period. METHODS: Overall, 137 patients with breast cancer were evaluated using the Patient Health Questionnaire 9-item depression scale (PHQ-9) and Generalized Anxiety Disorder scale (GAD-7). The scales were developed as a web-based electronic patient-reported outcome measure, and serial results were assessed before the operation, after the operation, in the post-treatment period, and in the 6-month follow-up period after surgery. RESULTS: The degree of depression and anxiety increased during treatment and decreased at 6-month follow-up, even if there were no statistical differences among the four periods (PHQ-9: p = 0.128; GAD-7: p = 0.786). However, daily fatigue (PHQ-9 Q4) and insomnia (PHQ-9 Q3) were the most serious problems encountered during treatment and at 6-month follow-up, respectively. In the GAD-7, worrying too much (Q3) consistently showed the highest scores during the treatment and follow-up periods. Of the patients, 7 (5.11%) and 11 (8.03%) patients had a worsened state of depression and anxiety, respectively, after treatment compared with before treatment. CONCLUSION: Most factors associated with depression and anxiety improved after treatment. However, factors such as insomnia and worrying too much still disturbed patients with breast cancer, even at 6-month follow-up. Therefore, serial assessment of depression and anxiety is necessary for such patients.

Peritumoral edema in breast cancer at preoperative MRI: an interpretative study with histopathological review toward understanding tumor microenvironment.

Peritumoral edema (PE) of breast cancer at T2-weighted MR images is considered a poor prognostic sign and may represent the microenvironment surrounding the tumor; however, its histopathological mechanism remains unclear. The purpose of the study was to identify and describe detailed histopathological characteristics associated with PE at preoperative breast MRI in breast cancer patients. This retrospective study included breast cancer patients who had undergone preoperative MRI and surgery between January 2011 and December 2012. Two radiologists determined the presence of PE in consensus based on the signal intensity surrounding the tumor at T2-weighted images. The following detailed histopathological characteristics were reviewed by two breast pathologists using four-tiered grades; lymphovascular invasion, vessel ectasia, stromal fibrosis, growth pattern, and tumor budding. Tumor necrosis and tumor infiltrating lymphocytes were assessed using a percent scale. Baseline clinicopathological characteristics, including age and histologic grade, were collected. The associations between detailed histopathologic characteristics and PE were examined using multivariable logistic regression with odds ratio (OR) calculation. A total of 136 women (median age, 49 ± 9 years) were assessed; among them 34 (25.0%) had PE. After adjustment of baseline clinicopathological characteristics that were significantly associated with PE (age, T stage, N stage, histologic grade, and subtype, all Ps < 0.05), lymphovascular invasion (P = 0.009), vessel ectasia (P = 0.021), stromal fibrosis (P = 0.024), growth pattern (P = 0.036), and tumor necrosis (P < 0.001) were also associated with PE. In comparison with patients without PE, patients with PE were more likely to have a higher degree of lymphovascular invasion (OR, 2.9), vessel ectasia (OR, 3.3), stromal fibrosis (OR, 2.5), lesser degree of infiltrative growth pattern (OR, 0.4), and higher portion of tumor necrosis (OR, 1.4). PE of breast cancer at MRI is associated with detailed histopathological characteristics of lymphovascular invasion, vessel ectasia, stromal fibrosis, growth pattern, and tumor necrosis, suggesting a relevance for tumor microenvironment.

Value of accurate diagnosis for metastatic supraclavicular lymph nodes in breast cancer: assessment with neck US, CT, and 18F-FDG PET/CT.

PURPOSE: Neck ultrasonography (US), computed tomography (CT), and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) are all known to be useful imaging modalities for detecting supraclavicular lymph node (SCN) metastasis in breast cancer. The authors compared the diagnostic values of neck US, CT, and PET/CT in the detection of SCN metastasis in breast cancer. METHODS: SCN metastases identified in neck US, CT, or PET/CT during follow-up visits of patients with breast cancer were pathologically confirmed with the use of US-guided fine-needle aspiration cytology. The clinicopathological factors of the patients were analyzed, and the statistical parameters including sensitivity, specificity, positive and negative predictive values, false-positive and false-negative rates, and accuracy of neck US, CT, and PET/CT were compared. RESULTS: Among 32 cases of suspicious SCNs, 24 were pathologically confirmed as metastasis of breast cancer. The sensitivity of US + CT was 91.7%, which was the same as that of PET/CT, while the sensitivity rates of US alone and CT alone were 87.5% and 83.3%, respectively. Accuracy was 99.8% in PET/CT alone and 98.1% in US + CT. The false-negative rate was 0.1% in US + PET/CT, while it was 0.2% in PET/CT and US + CT, 0.3% in US alone and 0.4% in CT alone. CONCLUSION: PET/CT can be the first choice for detecting SCN metastases in breast cancer. However, if PET/CT is unavailable for any reason, US + CT could be a good second option to avoid false-negative results.

MicroRNA-496 inhibits triple negative breast cancer cell proliferation by targeting Del-1.

ABSTRACT: Del-1 has been linked to the pathogenesis of various cancers, including breast cancer. However, the regulation of Del-1 expression remains unclear. We previously reported the interaction between microRNA-137 (miR-137) and the Del-1 gene. In this study, we investigated miR-496 and miR-137 as regulators of Del-1 expression in triple negative breast cancer (TNBC). Del-1 mRNA and miR-496 were measured by quantitative PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3, and T-47D) and tissues from 30 patients with TNBC. The effects of miR-496 on cell proliferation, migration, and invasion were determined with MTT, wound healing, and Matrigel transwell assays, respectively. In MDA-MB-231 cells, miR-496 levels were remarkably low and Del-1 mRNA levels were higher than in other breast cancer cell lines. Luciferase reporter assays revealed that miR-496 binds the 3'-UTR of Del-1 and Del-1 expression is downregulated by miR-496 mimics. Furthermore, miR-496 inhibited the proliferation, migration, and invasion of MDA-MB-231 cells. The effects of miR-496 on cell proliferation were additive with those of miR-137, another miRNA that regulates Del-1 expression. Moreover, in the 30 TNBC specimens, miR-496 was downregulated (P < .005) and the levels of Del-1 in the plasma were significantly elevated as compared with in normal controls (P = .0142). The Cancer Genome Atlas (TCGA) data showed the correlation of miR-496 expression with better overall survival in patients with early TNBC. In in silico and in vitro analyses, we showed that Del-1 is a target of miR-496 in TNBC and thereby affects cancer progression. Our findings suggest that miR-496 and miR-137 additively target Del-1 and act as modulating factors in TNBC. They are potentially new biomarkers for patients with TNBC.