Drug-resistant profiles of extracellular vesicles predict therapeutic response in TNBC patients receiving neoadjuvant chemotherapy.

BACKGROUND: Predicting tumor responses to neoadjuvant chemotherapy (NAC) is critical for evaluating prognosis and designing treatment strategies for patients with breast cancer; however, there are no reliable biomarkers that can effectively assess tumor responses. Therefore, we aimed to evaluate the clinical feasibility of using extracellular vesicles (EVs) to predict tumor response after NAC. METHODS: Drug-resistant triple-negative breast cancer (TNBC) cell lines were successfully established, which developed specific morphologies and rapidly growing features. To detect resistance to chemotherapeutic drugs, EVs were isolated from cultured cells and plasma samples collected post-NAC from 36 patients with breast cancer. RESULTS: Among the differentially expressed gene profiles between parental and drug-resistant cell lines, drug efflux transporters such as MDR1, MRP1, and BCRP were highly expressed in resistant cell lines. Drug efflux transporters have been identified not only in cell lines but also in EVs released from parental cells using immunoaffinity-based EV isolation. The expression of drug resistance markers in EVs was relatively high in patients with residual disease compared to those with a pathological complete response. CONCLUSIONS: The optimal combination of drug-resistant EV markers was significantly efficient in predicting resistance to NAC with 81.82% sensitivity and 92.86% specificity.

On-treatment derived neutrophil-to-lymphocyte ratio and survival with palbociclib and endocrine treatment: analysis of a multicenter retrospective cohort and the PALOMA-2/3 study with immune correlates.

BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been established as a standard treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC); however, predictive biomarkers with translational relevance have not yet been elucidated. METHODS: Data from postmenopausal women who received the CDK4/6 inhibitor palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (N = 221; exploratory cohort). Pre- and on-treatment neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR; neutrophil/[leukocyte-neutrophil]) were correlated with survival outcomes. Data from the PALOMA-2 (NCT01740427) and PALOMA-3 studies (NCT01942135) involving patients treated with endocrine treatment with or without palbociclib were also analyzed (validation cohort). Prospectively enrolled patients (N = 20) were subjected to immunophenotyping with circulating immune cells to explore the biological implications of immune cell dynamics. RESULTS: In the exploratory cohort, palbociclib administration significantly reduced leukocyte, neutrophil, and lymphocyte counts on day 1 of cycle 2. Although the baseline dNLR was not significantly associated with progression-free survival (PFS), higher on-treatment dNLRs were associated with worse PFS (hazard ratio = 3.337, P < 0.001). In the PALOMA-2 validation cohort, higher on-treatment dNLRs were associated with inferior PFS in patients treated with palbociclib and letrozole (hazard ratio = 1.498, P = 0.009), and reduction in the dNLR after treatment was predictive of a survival benefit (hazard ratio = 1.555, P = 0.026). On-treatment dNLRs were also predictive of PFS following palbociclib and fulvestrant treatment in the PALOMA-3 validation cohort. Using flow cytometry analysis, we found that the CDK4/6 inhibitor prevented T cell exhaustion and diminished myeloid-derived suppressor cell frequency. CONCLUSIONS: On-treatment dNLR significantly predicted PFS in patients with HR-positive, HER2-negative ABC receiving palbociclib and endocrine treatment. Additionally, we observed putative systemic immune responses elicited by palbociclib, suggesting immunologic changes upon CDK4/6 inhibitor treatment.

Early experience of robotic axillary lymph node dissection in patients with node-positive breast cancer.

BACKGROUND: Robotic surgical systems enable surgeons to perform precise movement in the surgical field using high-resolution 3D vision and flexible robotic instruments. We aimed to evaluate the feasibility and safety of performing axillary lymph node dissection using a robotic surgical system in patients with node-positive breast cancer. METHODS: Thirty-two women with breast cancer who underwent robot-assisted nipple-sparing mastectomy (RNSM) and level I/II axillary lymph node dissection were analyzed. Patients were divided into two groups: RNSM with conventional axillary lymph node dissection (CALND) vs. RNSM with robotic axillary lymph node dissection (RALND). Clinicopathological features and surgical outcomes were analyzed. RESULTS: The median age of the patients was 44 (range 20-59) years. Eleven patients underwent RALND. None of the clinicopathologic features differed between the two groups. There were no statistically significant differences in surgical outcomes, except for the final incision size, between the two groups. The proportion of cases with an incision ≤ 40 mm was 63.6% in the RALND group and 36.4% in the CALND group (p = 0.020). CONCLUSION: RALND can be safely performed in RNSM. RNSM with RALND is comparable to RNSM with CALND in terms of early surgical outcomes. The incision size can be reduced when using RALND.

Distinct Prognosis of Minimal Residual Disease According to Breast Cancer Subtype in Patients with Breast or Nodal Pathologic Complete Response After Neoadjuvant Chemotherapy.

PURPOSE: Few studies have reported on patient prognosis according to residual cancer burden after neoadjuvant chemotherapy (NAC). Herein, we evaluated the survival of patients based on residual disease after NAC to identify subpopulations with distinct prognoses. METHODS: We retrospectively reviewed 728 patients treated with NAC from 2010 to 2017. Patients were divided into four subgroups depending on post-surgical residual disease according to the staging system: pathological complete response (pCR) (ypT0/TisN0), minimal residual disease (MRD) (ypT1mi/T1aN0 or ypT0/Tis ypN0i+/N1mic), node-only pCR (≥ ypT1b ypN0), and breast-only pCR (ypT0/Tis ≥ ypN1a). Clinicopathological characteristics and survival outcomes were analyzed by adjusting for factors affecting survival. RESULTS: Overall, 50.4% (n = 367) of patients achieved pCR, with the MRD group accounting for 16.5% (n = 120). Although age and clinical stage were not different among the study groups, histologic grade, subtypes, chemotherapy response, and local treatment showed differences. Event-free survival (EFS) and overall survival (OS) demonstrated no significant difference between the pCR and MRD groups. In the multivariate analysis, pCR status was the only significant factor in EFS, and no statistical difference was noted between the pCR and MRD groups. However, clinical stage, pCR status, and subtype significantly affected the OS. MRD showed favorable outcomes in terms of both EFS and OS in all subtypes, except for those with triple-negative breast cancer (TNBC). CONCLUSION: Patients with MRD showed outcomes comparable to those of patients who achieved pCR and may be candidates for de-escalation of post-NAC treatment, except for those with a TNBC subtype.

Oncologic Outcomes in Nipple-sparing Mastectomy with Immediate Reconstruction and Total Mastectomy with Immediate Reconstruction in Women with Breast Cancer: A Machine-Learning Analysis.

BACKGROUND: This study used a single-institution cohort, the Severance dataset, validated the results by using the surveillance, epidemiology, and end results (SEER) database, adjusted with propensity-score matching (PSM), and analyzed by using a machine learning method. To determine whether the 5-year, disease-free survival (DFS) and overall survival (OS) of patients undergoing nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) are not inferior to those of women treated with total mastectomy/skin-sparing mastectomy (TM/SSM). METHODS: The Severance dataset enrolled 611 patients with early, invasive breast cancer from 2010 to 2017. The SEER dataset contained data for 485,245 patients undergoing TM and 14,770 patients undergoing NSM between 2000 and 2018. All patients underwent mastectomy and IBR. Intraoperative, frozen-section biopsy for the retro-areolar tissue was performed in the NSM group. The SEER dataset was extracted by using operation types, including TM/SSM and NSM. The primary outcome was DFS for the Severance dataset and OS for the SEER dataset. PSM analysis was applied. Survival outcomes were analyzed by using the Kaplan-Meier method and Cox proportional hazard (Cox PH) regression model. We implemented XGBSE to predict mortality with high accuracy and evaluated model prediction performance using a concordance index. The final model inspected the impact of relevant predictors on the model output using shapley additive explanation (SHAP) values. RESULTS: In the Severance dataset, 151 patients underwent NSM with IBR and 460 patients underwent TM/SSM with IBR. No significant differences were found between the groups. In multivariate analysis, NSM was not associated with reduced oncologic outcomes. The same results were observed in PSM analysis. In the SEER dataset, according to the SHAP values, the individual feature contribution suggested that AJCC stage ranks first. Analyses from the two datasets confirmed no impact on survival outcomes from the two surgical methods. CONCLUSIONS: NSM with IBR is a safe and feasible procedure in terms of oncologic outcomes. Analysis using machine learning methods can be successfully applied to identify significant risk factors for oncologic outcomes.

Effect of a 1-year tailored exercise program according to cancer trajectories in patients with breast cancer: study protocol for a randomized controlled trial.

BACKGROUND: Patients with breast cancer undergo various treatments according to their tumor subtype and cancer stages within 1 year after being diagnosed. Each treatment may cause treatment-related symptoms that have negative impacts on patients' health and quality of life (QoL) The symptoms can be mitigated when exercise interventions are appropriately applied to patients' physical and mental conditions. Although many exercise programs were developed and implemented during this period, the effects of tailored exercise programs according to symptoms and cancer trajectories on patients' long-term health outcomes have not yet been fully elucidated. Therefore, this randomized controlled trial (RCT) aims to investigate the effect of tailored home-based exercise programs on short-term and long-term physiological outcomes in patients with breast cancer. METHODS: This 12-month RCT includes 96 patients with (stages 1-3) breast cancer randomly assigned to the exercise or control groups. Participants in the exercise group will receive an exercise program tailored to their phase of treatment, type of surgery, and physical function. During post-operative recovery, exercise interventions will be emphasized to improve shoulder range of motion (ROM) and strength. During chemoradiation therapy, exercise intervention will focus on improving physical function and preventing loss of muscle mass. Once chemoradiation therapy is completed, exercise intervention will focus on improving cardiopulmonary fitness and insulin resistance. All interventions will be home-based exercise programs supplemented with once-monthly exercise education and counseling sessions. The main outcome of the study is fasting insulin level at baseline, 6 months, and 1 year post-intervention. Our secondary outcomes include shoulder ROM and strength at 1 month and 3 months, body composition, inflammatory markers, microbiome, QoL, and physical activity levels at 1 month, 6 months, and 1 year post-intervention. CONCLUSION: This trial is the first tailored home-based exercise oncology trial to better understand the comprehensive phase-dependent short- and long-term effects of exercise on shoulder function, body composition, fasting insulin, biomarkers, and microbiome. The results of this study will inform the development of effective exercise programs tailored to the needs of patients with breast cancer post-operatively. TRIAL REGISTRATION: The protocol for this study is registered with the Korean Clinical Trials Registry (KCT0007853).

Robot-assisted Nipple-sparing Mastectomy With Immediate Breast Reconstruction: An initial Experience of the Korea Robot-endoscopy Minimal Access Breast Surgery Study Group (KoREa-BSG).

OBJECTIVE: The aim of this study was to present the results of early experience of robot-assisted nipple sparing mastectomy (RANSM). BACKGROUND: RANSM improves cosmetic outcomes over conventional nipple-sparing mastectomy. However, data on the feasibility and safety of the RANSM are limited. METHODS: Patients who underwent RANSM with immediate breast reconstruction as part of the Korea Robot-endoscopy Minimal Access Breast Surgery Study Group (KoREa-BSG) from November 2016 to January 2020 were enrolled. clinicopathologic characteristics, perioperative complications, and operation time were collected. RESULTS: Overall, 73 women underwent 82 RANSM procedures conducted by 11 breast surgeons at 8 institutions. The median patient age was 45.5 years old (20-66 years), and 52 (63.4%) patients were premenopausal. Invasive breast cancer was noted in 55 cases (40 cases were stage i, 11 cases were stage ii, and 4 cases were stage iii, respectively) and ductal carcinoma in-situ was recorded in 20 cases. Of those, 3 patients with BRCA1/2 mutation carriers underwent contralateral risk-reducing RANSM. The median length of hospitalization was 12.0 days (5.0-24.0 days). The incision location was the mid-axillary line and the median incision length was 50.0 mm (30.0-60.0 mm). Median total operation time, median total mastectomy time, and median reconstruction time was 307.0 minutes (163.0-796.0 minutes), 189.5 minutes (97.5-325.0 minutes), and 119.5 minutes (45.0-689.0 minutes). Only 2 cases (2.5%) required reoperation. Nipple ischemia was found in 9 cases (10.9%) but only 1 case (1.2%) required nipple excision given that 8 cases (9.7%) resolved spontaneously. Skin ischemia was observed in 5 cases (6.1%) and only 2 (2.4%) cases needed skin excision whereas 3 cases (3.6%) resolved spontaneously. There was no conversion to open surgery orcases of mortality. The mean time for mastectomy among surgeons who performed more than 10 cases was 182.3 minutes (± 53.7, minutes) and 195.4 minutes (± 50.4, minutes). CONCLUSION: This was the first report of RANSM conducted in the KoREa-BSG. RANSM is technically feasible and acceptable with a short learning curve. Further prospective research to evaluate surgical and oncologic outcomes is needed.

Surgical and Oncologic Outcomes of Robotic and Conventional Nipple-Sparing Mastectomy with Immediate Reconstruction: International Multicenter Pooled Data Analysis.

BACKGROUND: Robotic nipple-sparing mastectomy (RNSM) has been developed to reduce conspicuous scar and increase the quality of life in women. This study aimed to evaluate the surgical and oncologic outcomes of RNSM with immediate breast reconstruction (IBR) compared with conventional nipple-sparing mastectomy (CNSM). PATIENTS AND METHODS: This international multicenter, pooled analysis of individual patient-level data enrolled a total of 755 procedures in 659 women (609 had breast cancer and 50 underwent risk-reducing mastectomy) who underwent nipple-sparing mastectomy with IBR. Surgical and oncologic outcomes, including 30-days postoperative (POD 30d) complication rate, nipple necrosis rate, grade of Clavien-Dindo classification, disease-free survival, and overall survival, were evaluated. Propensity score-matched analyses were performed to adjust for confounding factors. RESULTS: The median age of both the RNSM and CNSM groups was 45 years. The RNSM group had lower body mass index (BMI) and a higher proportion of benign disease compared with the CNSM group. POD 30d complications and postoperative complication grade III rates were lower in the RNSM group than in the CNSM group (p < 0.05). The nipple necrosis rate was 2.2% and 7.8% for RNSM and CNSM, respectively (p = 0.002). After propensity score matching, significantly lower rates of POD 30d complications, nipple necrosis, and postoperative complication grade III occurred in the RNSM group than in the CNSM group (all p < 0.05). Oncologic outcomes were not significantly different between the two groups. CONCLUSION: RNSM can provide better cosmetic results with favorable surgical and oncologic outcomes for women with early breast cancer or BRCA mutation.

Analysis of robot-assisted nipple-sparing mastectomy using the da Vinci SP system.

BACKGROUND: As patients tend to be diagnosed with breast cancer at an early stage, the demand for better cosmetic outcomes has increased. Several studies revealed that robot-assisted nipple-sparing mastectomy (RNSM) shows favorable outcomes. The aim of the study was to reveal the feasibility of RNSM using the da Vinci single-port (SP) system with a minimal incision, hidden in the arm. METHODS: From 2018 to 2021, 81 cases (70 patients) were retrospectively reviewed. Clinicopathologic characteristics, operative outcomes, and postoperative complications were evaluated. The operative outcomes were analyzed using the Mann-Whitney U test. RESULTS: The median age was 42 years (range, 26-60 years). Bilateral RNSM was performed in 11 (27.2%) patients. The median size of the initial skin incision was 40 mm (range, 20-55 mm). Immediate reconstruction with direct-to-implant was performed in 54 (66.7%) patients and deep inferior epigastric perforator (DIEP) flaps in 15 (18.5%) patients. Postoperative complications of Clavien-Dindo Classification III occurred in six (7.5%) patients. Patients reconstructed with a DIEP flap had large breasts with more severe ptosis, yet grade III complications did not occur. CONCLUSIONS: RNSM using the SP system can be applied for curative and risk-reducing mastectomy, regardless of breast size or ptosis grade.

Blood Test for Breast Cancer Screening through the Detection of Tumor-Associated Circulating Transcripts.

Liquid biopsy has been emerging for early screening and treatment monitoring at each cancer stage. However, the current blood-based diagnostic tools in breast cancer have not been sufficient to understand patient-derived molecular features of aggressive tumors individually. Herein, we aimed to develop a blood test for the early detection of breast cancer with cost-effective and high-throughput considerations in order to combat the challenges associated with precision oncology using mRNA-based tests. We prospectively evaluated 719 blood samples from 404 breast cancer patients and 315 healthy controls, and identified 10 mRNA transcripts whose expression is increased in the blood of breast cancer patients relative to healthy controls. Modeling of the tumor-associated circulating transcripts (TACTs) is performed by means of four different machine learning techniques (artificial neural network (ANN), decision tree (DT), logistic regression (LR), and support vector machine (SVM)). The ANN model had superior sensitivity (90.2%), specificity (80.0%), and accuracy (85.7%) compared with the other three models. Relative to the value of 90.2% achieved using the TACT assay on our test set, the sensitivity values of other conventional assays (mammogram, CEA, and CA 15-3) were comparable or much lower, at 89%, 7%, and 5%, respectively. The sensitivity, specificity, and accuracy of TACTs were appreciably consistent across the different breast cancer stages, suggesting the potential of the TACTs assay as an early diagnosis and prediction of poor outcomes. Our study potentially paves the way for a simple and accurate diagnostic and prognostic tool for liquid biopsy.

Axillary response according to neoadjuvant single or dual human epidermal growth factor receptor 2 (HER2) blockade in clinically node-positive, HER2-positive breast cancer.

Incorporating dual human epidermal growth factor receptor 2 (HER2) blockade into neoadjuvant systemic therapy (NST) led to higher response in patients with HER2-positive breast cancer. However, axillary response to treatment regimens, including single or dual HER2 blockade, in patients with clinically node-positive breast cancer remains uncertain. Our study aimed to examine the pathologic axillary response according to the type of NST, that is, single or dual HER2 blockade. In our study, 546 patients with clinically node-positive, HER2-positive breast cancer who received NST followed by axillary surgery were retrospectively selected and divided into three groups: chemotherapy alone, chemotherapy + trastuzumab and chemotherapy + trastuzumab with pertuzumab. The primary outcome was the axillary pathologic complete response (pCR). Among 471 patients undergoing axillary lymph node dissection, the axillary pCR rates were 43.5%, 74.5% and 68.8% in patients who received chemotherapy alone, chemotherapy + trastuzumab and chemotherapy + trastuzumab with pertuzumab, respectively. There was no difference in axillary pCR rates between patients who received single or dual HER2 blockade (P = .379). Among patients receiving chemotherapy + trastuzumab, patients without breast pCR had the greatest risk for residual axillary metastases (relative risk, 9.8; 95% confidence interval, 3.2-14.9; P < .0001). In conclusion, adding trastuzumab to chemotherapy increased the axillary pCR rate in patients with clinically node-positive, HER2-positive breast cancer; furthermore, dual HER2-blockade with trastuzumab and pertuzumab did not elevate the axillary response compared with trastuzumab alone. Breast pCR could be a strong predictor for axillary pCR in clinically node-positive patients treated with HER2-targeting therapy.

Multi-miRNA panel of tumor-derived extracellular vesicles as promising diagnostic biomarkers of early-stage breast cancer.

Extracellular vesicles (EV) have been emerging as potential biomarkers for disease monitoring. In particular, tumor-derived EV (TDE) are known to carry oncogenic miRNA, so they can be used for diagnosis of early cancer by analyzing the expression levels of EV-miRNA circulating in the blood. Here, using our novel microfluidic device, we rapidly and selectively isolate cancerous EV expressing breast cancer-derived surface markers CD49f and EpCAM within 2 minutes. Based on seven candidates of miRNA nominated from The Cancer Genome Atlas (TCGA) database, the expression levels of miRNA in TDE were validated in a total of 82 individuals, including 62 breast cancer patients and 20 healthy controls. Among seven candidates, four miRNAs (miR-9, miR-16, miR-21, and miR-429) from the EV were highly elevated in early-stage breast cancer patients compared with healthy donors. The combination of significant miRNAs from specific EV has high sensitivities of 0.90, 0.86, 0.88, and 0.84 of the area under the receiver operating characteristic curve (AUC) in each subtype (luminal A, luminal B, HER-2, and triple-negative) of early-stage breast cancer. Our results suggest that the combination of four miRNA signatures of specific EV could serve as a sensitive and specific biomarker and enable early diagnosis of breast cancer using liquid biopsy.

Risk of Lymphedema Following Contemporary Treatment for Breast Cancer: An Analysis of 7617 Consecutive Patients From a Multidisciplinary Perspective.

OBJECTIVE: The aim of this study was to identify the comprehensive risk factors for lymphedema, thereby enabling a more informed multidisciplinary treatment decision-making. SUMMARY BACKGROUND DATA: Lymphedema is a serious long-term complication in breast cancer patients post-surgery; however, the influence of multimodal therapy on its occurrence remains unclear. METHODS: We retrospectively collected treatment-related data from 5549 breast cancer patients who underwent surgery between 2007 and 2015 at our institution. Individual radiotherapy plans were reviewed for regional nodal irradiation (RNI) field design and fractionation type. We identified lymphedema risk factors and used them to construct nomograms to predict individual risk of lymphedema. Nomograms were validated internally using 100 bootstrap samples and externally using 2 separate datasets of 1877 Asian and 191 Western patients. RESULTS: Six hundred thirty-nine patients developed lymphedema during a median follow-up of 60 months. The 3-year lymphedema incidence was 10.5%; this rate increased with larger irradiation volumes (no RNI vs RNI excluding axilla I-II vs RNI including axilla I-II: 5.7% vs 16.8% vs 24.1%) and when using conventional fractionation instead of hypofractionation (13.5% vs 6.8%). On multivariate analysis, higher body mass index, larger number of dissected nodes, taxane-based regimen, total mastectomy, larger irradiation field, and conventional fractionation were strongly associated with lymphedema (all P < 0.001). Nomograms constructed based on these variables showed good calibration and discrimination internally (concordance index: 0.774) and externally (0.832 for Asian and 0.820 for Western patients). CONCLUSIONS: Trimodality breast cancer treatment factors interact to promote lymphedema. Lymphedema risk can be decreased by deintensifying node dissection, chemotherapy regimen, and field and dose of radiotherapy. Deescalation strategies on a multidisciplinary basis might minimize lymphedema risk.

Hormone Receptor Subtype in Ductal Carcinoma in Situ: Prognostic and Predictive Roles of the Progesterone Receptor.

BACKGROUND: We investigated the prognostic and predictive roles of the hormone receptor (HRc) subtype in patients with ductal carcinoma in situ (DCIS). We focused on identifying the roles of the progesterone receptor (PR) independent of estrogen receptor (ER) status. METHODS: Nationwide data of 12,508 female patients diagnosed with DCIS with a mean follow-up period of 60.7 months were analyzed. HRc subtypes were classified as ER-/PR-, ER-/PR+, ER+/PR-, and ER+/PR+ based on ER and PR statuses. The Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The ER+/PR+ group showed better prognoses than the ER+/PR- and ER-/PR- groups in the patients who received tamoxifen therapy (p = .001 and p = .031, respectively). HRc subtype was an independent prognostic factor (p = .028). The tamoxifen therapy group showed better survival than the patients who did not receive tamoxifen, but only in the ER+/PR+ subgroup (p = .002). Tamoxifen therapy was an independent prognostic factor (HR, 0.619; 95% CI, 0.423 - 0.907; p = .014). PR status was a favorable prognostic factor in patients with DCIS who received tamoxifen therapy (p < .001), and it remained a prognostic factor independent of ER status (HR, 0.576; 95% CI, 0.349 - 0.951; p = .031). CONCLUSION: The HRc subtype can be used as both a prognostic and predictive marker in patients with newly diagnosed DCIS. Tamoxifen therapy can improve overall survival in the ER+/PR+ subtype. PR status has significant prognostic and predictive roles independent of ER status. Testing for the PR status in addition to the ER status is routinely recommended in patients with DCIS to determine the HRc subtype in clinical settings. IMPLICATIONS FOR PRACTICE: The hormone receptor (HRc) subtype was an independent prognostic factor, and the estrogen receptor (ER)+/progesterone receptor (PR) + subtype showed a better survival in patients with ductal carcinoma in situ (DCIS) who received tamoxifen therapy. PR was an independent prognostic factor independent of ER, and PR was a favorable prognostic factor in patients with DCIS who received tamoxifen therapy. The HRc subtype could be used as both a prognostic and predictive marker in patients with newly diagnosed DCIS. Testing of PR status in addition to ER status is routinely recommended for patients with DCIS to determine the HRc subtype in clinical settings.

Chronological Trends of Breast Ductal Carcinoma In Situ: Clinical, Radiologic, and Pathologic Perspectives.

BACKGROUND: Because no prior studies have evaluated the chronological trends of ductal carcinoma in situ (DCIS) despite the increasing number of surgeries performed for DCIS, this study analyzed how the clinical, radiologic, and pathologic characteristics of DCIS changed during a 10-year period. METHODS: Of 7123 patients who underwent primary breast cancer surgery at a single institution from 2006 to 2015, 792 patients with pure DCIS were included in this study. The chronological trends of age, symptoms, method for detecting either mammography or ultrasonography, tumor size, nuclear grade, comedonecrosis, and molecular markers were calculated using Poisson regression for all patients and asymptomatic patients. RESULTS: During 10 years, DCIS surgery rates significantly increased (p < 0.001). Despite the high percentage of DCIS detected on mammography, the detection rate for DCIS by mammography significantly decreased (97.3% in 2006 to 67.6% in 2015; p = 0.025), whereas the detection rate by ultrasound significantly increased (2.7% to 31.0%; p < 0.001). Conservation surgery rates (odds ratio [OR], 1.058), low-to-intermediate nuclear grade rates (OR, 1.069), and the absence of comedonecrosis (OR, 1.104) significantly increased over time (all p < 0.05). Estrogen receptor (ER) negativity (OR, 0.935) and human epidermal growth factor receptor 2 (HER2) positivity rates (OR, 0.953) significantly decreased (all p < 0.05). The same trends were observed for the 613 asymptomatic patients. CONCLUSION: The rate of DCIS detected on ultrasound only significantly increased during 10 years. Low-to-intermediate nuclear grade rates significantly increased, whereas ER negativity and HER2 positivity rates significantly decreased during the same period. These findings suggest that DCIS detected on screening ultrasound is less aggressive than DCIS detected on mammography.

Tumor-Specific miRNA Signatures in Combination with CA19-9 for Liquid Biopsy-Based Detection of PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the most aggressive malignancies and has high mortality and poor survival rates. Therefore, there is an urgent need to discover non-invasive biomarkers for early detection before PDAC reaches the incurable stage. We hypothesized that liquid biopsy of PDAC-derived extracellular vesicles (PDEs) containing abundant microRNAs (miRNAs) could be used for early diagnosis of PDAC because they can be selectively enriched and because they are biologically stable. We isolated PDEs by immunocapture using magnetic beads, and we identified 13 miRNA candidates in 20 pancreatic cancer patients and 20 normal controls. We found that expression of five miRNAs, including miR-10b, miR-16, miR-155, miR-429, and miR-1290, was markedly higher in PDEs. Furthermore, the miRNA signatures along with serum carbohydrate antigen 19-9 (CA19-9) were optimized by logistic regression, and the miRNA signature and CA19-9 combination markers (CMs) were effective at differentiating PDAC patients from normal controls. As a result, the CMs represented a high sensitivity (AUC, 0.964; sensitivity, 100%; specificity, 80%) and a high specificity (AUC, 0.962; sensitivity, 85.71%; specificity, 100%). These findings suggest that five miRNAs expressed in PDEs and CA19-9 are valuable biomarkers for screening and diagnosis of pancreatic cancer by liquid biopsy.

Characteristics and prognosis of 17 special histologic subtypes of invasive breast cancers according to World Health Organization classification: comparative analysis to invasive carcinoma of no special type.

BACKGROUND: Breast cancer is a heterogeneous disease with various histopathologic subtypes. Except for invasive carcinoma of no special type (NST), other subtypes are rare with limited data. The purpose of this study was to analyze the characteristics and prognosis of special histopathologic subtypes of breast cancer compared to NST. METHODS: A total of 136,140 patients were analyzed using the Korean Breast Cancer Society Registry database between January 1996 and March 2019. The clinicopathologic features and survival outcomes of special type breast carcinoma were compared with those of NST. RESULTS: The prevalence of special subtypes other than NST was 13.7% (n = 18,633). Compared to NST, patients with lobular, medullary, metaplastic, and micropapillary carcinoma had larger tumors (p < 0.001). Patients with mucinous, tubular, medullary, metaplastic, and cribriform carcinoma presented with less node metastasis (p < 0.001), contrary to patients with micropapillary carcinoma. Patients with lobular, mucinous, tubular, papillary, and cribriform carcinoma presented as luminal A subtype much more often (p < 0.001). Micropapillary carcinoma included more luminal B subtype (p < 0.001). Typically, medullary and metaplastic carcinoma included more triple-negative subtypes (p < 0.001). In survival analysis, only medullary (Hazard Ratio (HzR) 0.542, 95% CI 0.345 to 0.852, p = 0.008) and metaplastic carcinoma (HzR 1.655, 95% CI 1.317 to 2.080, p < 0.001) showed significantly different overall survival from NST by multivariate analysis. CONCLUSION: Breast cancer had distinct clinicopathologic features according to histopathologic subtype. However, special types of breast cancer had similar survival outcomes compared to NST when adjusting for other prognostic factors, except for metaplastic carcinoma and medullary carcinoma.

Correction to: Palbociclib use with grade 3 neutropenia in hormone receptor-positive metastatic breast cancer.

In the original publication of the article, under the Results section, subheading "Patient survival", the second sentence that reads as "The 6-month PFS was 92.4%, 81.8%, and 93.3% and the one-year PFS was 72.0%, 88.9%, and 78.9% in Groups 1-3, respectively." should read as "The 6-month PFS was 82.8%, 75.0%, and 68.0% and the one-year PFS was 77.0%, 62.0%, and 63.8% in Groups 1-3, respectively.".

Palbociclib use with grade 3 neutropenia in hormone receptor-positive metastatic breast cancer.

PURPOSE: Neutropenia is the most common toxicity of CDK4/6 inhibitors, causing frequent dose interruptions. However, CDK4/6 inhibitor-induced neutropenia shows a benign clinical course in contrast to that caused by chemotherapy. Here, we investigated the safety of a new dose scheme for palbociclib, which avoids dose delays or reductions due to afebrile grade 3 neutropenia. METHODS: A consecutive cohort of ER( +)/HER2( -) advanced breast cancer patients who received palbociclib between 2017 and 2018 was analyzed. The patients were classified into Group 1 (patients who maintained palbociclib dose with afebrile grade 3 neutropenia), Group 2 (patients who experienced any dose modification with afebrile grade 3 neutropenia), and Group 3 (patients without afebrile grade 3 neutropenia). The primary endpoint was febrile neutropenia incidence; other toxicities were compared with those of the PALOMA-2 trial. RESULTS: Among the 107 patients, 54.2%, 22.4%, and 23.4% were classified into Groups 1, 2, and 3, respectively. There was no febrile neutropenia in Groups 1 and 2 during palbociclib treatment. Group 1 showed higher incidence of thrombocytopenia (all-grade, 32.8%; grade 3-4, 8.6%) than Group 2 and the PALOMA-2 data, but there was no bleeding related to thrombocytopenia. Group 1 showed higher incidence of all-grade non-hematologic adverse events than Group 2; only one grade 3 non-hematologic toxicity was observed in Group 1. There were no treatment-related hospitalizations or deaths in Group 1. CONCLUSIONS: Thus, omitting palbociclib dose modification with afebrile grade 3 neutropenia is safe and tolerable without febrile neutropenia events. This scheme could be useful to avoid unnecessary reductions in palbociclib doses in future practice.

Intermediate HER2 expression is associated with poor prognosis in estrogen receptor-positive breast cancer patients aged 55 years and older.

PURPOSE: An antibody-drug conjugate targeting HER2, DS8201, has shown clinical activity against breast cancer with low-level HER2 expression. We aimed to evaluate the prognostic impact of intermediate HER2 expression in estrogen receptor (ER)+ early breast cancer (EBC) and metastatic breast cancer (MBC) cohorts. METHODS: We analyzed prospectively collected data from EBC and MBC cohorts at Yonsei Cancer Center. Patients with HER2 immunohistochemistry (IHC) 0 ~ 1+ were assigned to the HER2-negative group, and patients with IHC 2+ and in situ hybridization (ISH)-negativity were assigned to the HER2-intermediate group. After the exclusion of HER2 IHC 3+ or ISH+ patients, a total of 2657 EBC and 535 MBC patients were analyzed. RESULTS: In total, 654 (24.6%) EBC and 166 (31.0%) MBC patients were classified in the HER2-intermediate group. The HER2-intermediate patients more frequently tended to have progesterone receptor (PR)-negativity and higher nuclear grade in the EBC cohort, and showed a higher proportion of patients aged ≥ 55 years compared with the HER2-negative group in the MBC cohort. The HER2-intermediate patients showed significantly poorer recurrence-free survival (RFS) compared to the HER2-negative patients in the EBC cohort (p = 0.044). Notably, intermediate HER2 expression predicted poorer RFS in EBC patients aged ≥ 55 years (hazard ratio 1.95; p = 0.042) in multivariate Cox analysis but did not affect RFS in those aged < 55 years. In line with the EBC cohort results, intermediate HER2 expression predicted poorer overall survival (OS) in MBC patients aged ≥ 55 (hazard ratio 1.45; p = 0.044) without affecting OS of those aged < 55 years. CONCLUSION: Intermediate HER2 expression is an independent predictor of poor prognosis in both ER+ EBC and MBC patients aged ≥ 55 years. The clinical efficacy of new HER2-targeting antibody-drug conjugates needs to be validated in this high-risk subset of ER+ breast cancer patients.