Characteristics and risk factors of axillary lymph node metastasis of microinvasive breast cancer.

PURPOSE: To select patients who would benefit most from sentinel lymph node biopsy (SLNB) by investigating the characteristics and risk factors of axillary lymph node metastasis (ALNM) in microinvasive breast cancer (MIBC). METHODS: This retrospective study included 1688 patients with MIBC who underwent breast surgery with axillary staging at the Asan Medical Center from 1995 to 2020. RESULTS: Most patients underwent SLNB alone (83.5%). Seventy (4.1%) patients were node-positive, and the majority had positive lymph nodes < 10 mm, with micro-metastases occurring frequently (n = 37; 55%). Node-positive patients underwent total mastectomy and axillary lymph node dissection (ALND) more than breast-conserving surgery (BCS) and SLNB compared with node-negative patients (p < 0.001). In the multivariate analysis, independent predictors of ALNM included young age [odds ratio (OR) 0.959; 95% confidence interval (CI) 0.927-0.993; p = 0.019], ALND (OR 11.486; 95% CI 5.767-22.877; p < 0.001), number of lymph nodes harvested (≥ 5) (OR 3.184; 95% CI 1.555-6.522; p < 0.001), lymphovascular invasion (OR 6.831; 95% CI 2.386-19.557; p < 0.001), presence of multiple microinvasion foci (OR 2.771; 95% CI 1.329-5.779; p = 0.007), prominent lymph nodes in preoperative imaging (OR 2.675; 95% CI 1.362-5.253; p = 0.004), and hormone receptor positivity (OR 2.491; 95% CI 1.230-5.046; p = 0.011). CONCLUSION: Low ALNM rate (4.1%) suggests that routine SLNB for patients with MIBC is unnecessary but can be valuable for patients with specific risk factors. Ongoing trials for omitting SLNB in early breast cancer, and further subanalyses focusing on rare populations with MIBC are necessary.

Oncological Safety of Skipping Axillary Lymph Node Dissection in Patients with Clinical N0, Sentinel Node-Positive Breast Cancer Undergoing Total Mastectomy.

OBJECTIVE: This study aimed to determine whether sentinel lymph node biopsy (SLNB) alone could afford oncological outcomes comparable with axillary lymph node dissection (ALND) in patients with early breast cancer without palpable lymphadenopathy who underwent total mastectomy (TM) and were SLN-positive. METHODS: This study analyzed clinical data of 6747 patients with breast cancer who underwent TM between 2014 and 2018 in two tertiary hospitals in Korea. Overall, 643 clinical stage T1-3 N0 patients who did not receive neoadjuvant therapy and had one to two metastatic SLNs at the time of surgery were included. Propensity score matching was performed between the SLNB alone and ALND groups, adjusting for clinical T stage and number of metastatic SLNs. In total, 237 patients were allocated to each group. RESULTS: Mean number of metastatic SLNs was 1.2 for the SLNB group and 1.6 for the ALND group. With a median follow-up of 65.0 months, 5 year disease-free survival was 90.8% for the SLNB group and 93.9% for the ALND group (hazard ratio [HR] 1.35, 95% confidence interval [CI] 0.70-2.58; p = 0.36). 5 year ipsilateral locoregional recurrence-free survival (LRRFS) was not significantly different between the two groups (95.1% and 98.3% for the SLNB and ALND groups, respectively) [HR 1.86, 95% CI 0.69-5.04; p = 0.21]. In the SLNB group, patients who received radiation therapy (RT) showed superior 5 year LRRFS than patients who did not receive RT (100% vs. 92.9%; p = 0.02). CONCLUSION: Collectively, our findings suggest that SLNB could afford comparable outcomes to ALND in patients with early breast cancer and one to two metastatic SLNs who underwent TM. Importantly, RT could decrease locoregional recurrence in patients who underwent SLNB alone.

Comparison of long-term oncological outcomes after central lumpectomy versus nipple-sparing breast-conserving surgery for centrally located breast cancer: a propensity score-matched study.

PURPOSE: To compare the oncological safety of nipple-sparing breast-conserving surgery (BCS) versus central lumpectomy for centrally located breast cancer (CLBC). METHODS: Patients who underwent BCS for CLBC at Asan Medical Center from 2007 to 2018 were reviewed retrospectively. The oncological outcomes of nipple-sparing BCS (NS-BCS) and central lumpectomy were compared using univariate and multivariate Cox regression analyses and compared again after 1:1 propensity score matching (PSM). RESULTS: The study included 306 patients who underwent NS-BCS and 106 patients who underwent central lumpectomy (median follow-up: 111 months). On multivariate analysis, central lumpectomy had a lower risk of local recurrence compared to NS-BCS, albeit without statistical significance (HR 0.14, 95% CI 0.02-1.24; p = 0.077). There was no significant difference in the risk of death (HR 0.14, 95% CI 0.01-1.68, p = 0.12). After PSM, each group had 106 patients. The 5-year and 10-year local recurrence-free survival rates were 94.2% and 92.9% for NS-BCS, and 99.1% and 99.1% for central lumpectomy, respectively (p = 0.031). There were no significant differences in overall survival, regional recurrence-free survival, or distant recurrence-free survival. Fifteen patients (4.9%) who underwent NS-BCS had ipsilateral breast tumor recurrence (IBTR), of which 40% were in the nipple-areolar complex and previous surgical sites. One patient (0.9%) who underwent central lumpectomy experienced an IBTR in a different quadrant. CONCLUSION: NS-BCS showed more local recurrence than central lumpectomy. When deciding whether to spare the nipple during BCS in CLBC, patients should be sufficiently informed about the risk of IBTR.

Characterization of temperature-dependent subcritical water hydrolysis pattern of strong and floury rice cultivars and potential utilizations of their hydrolysates.

This study investigated the effects of subcritical water (SW) temperatures on the hydrolysis pattern and characteristics of hydrolysates prepared with strong rice (SR) and floury rice (FR). The characteristics of the hydrolysates were generally dependent on the rice cultivar in the SW temperature range of 150-250 °C, while the cultivar dependence was diminished at temperatures greater than 300 °C. Based on brix and reducing sugar content, an optimal production of rice hydrolysates was obtained at a SW temperature range of 200-250 °C. However, thermal conversion of sugar into acids, 5-hydroxymethylfurfural (HMF) and furfural was manifested at 250 °C. The rice hydrolysates prepared at 250 âˆ¼ 300 °C had the highest antioxidant activity with strong umami intensity, but they suppressed the growth of prebiotics. Therefore, the present study demonstrated that controlling the SW temperature is crucial to improve rice hydrolysis efficiency and to regulate the physiological activity of the hydrolysates.

Implementation of BRCA Test among Young Breast Cancer Patients in South Korea: A Nationwide Cohort Study.

Purpose: To investigate the frequency of BRCA testing and related factors among young breast cancer patients (age < 40 years) in South Korea. Materials and Methods: We conducted a nationwide retrospective cohort study using data from the Health Insurance Review and Assessment claims. Newly diagnosed breast cancer patients younger than 40 were included. Annual BRCA testing ratios (number of BRCA test recipients / the number of patients undergoing breast cancer surgery in each year) were analyzed by region and health care delivery system. We investigated the location of breast cancer diagnosis and BRCA testing. Results: From January 2010 to December 2020, there were 25,665 newly diagnosed young breast cancer patients, of whom 12,186 (47.5%) underwent BRCA testing. The BRCA testing ratios increased gradually from 0.084 (154/1,842) in 2010 to 0.961 (1,975/2,055) in 2020. Medical aid (vs. health insurance) and undergoing surgery in metropolitan cities or others (vs. Seoul), general hospitals, and clinics (vs. tertiary hospitals) were associated with a lower likelihood of BRCA testing. While 97.8% of the patients diagnosed in Seoul underwent BRCA testing in Seoul, 22.9% and 29.2% of patients who were diagnosed in metropolitan areas and other regions moved to Seoul and underwent BRCA testing, respectively. Conclusion: The frequency of BRCA testing has increased over time in South Korea, with Seoul showing a particularly high rate of testing. About one-quarter of patients diagnosed with breast cancer outside of Seoul moved to Seoul and underwent BRCA testing.

Diagnostic yield of contrast-enhanced abdominal staging CT in patients with initially diagnosed breast cancer.

PURPOSE: To estimate the diagnostic yield (DY) of abdominal staging CT for detecting breast cancer liver metastasis (BCLM) in patients with initially diagnosed breast cancer and to determine the indications for abdominal staging CT. METHODS: Patients with newly diagnosed breast cancer who underwent abdominal CT as an initial staging work-up between January 2019 and December 2020 were retrospectively analyzed. DY was calculated and analyzed according to patient age, type of treatments, histologic type, histologic grade, lymphovascular invasion, Ki-67 status, hormone receptor status, subtype, and the American Joint Committee on Cancer anatomical staging. RESULTS: A total of 2056 patients (mean age, 51 ± 11 years) were included. The DY of abdominal staging CT for detecting BCLM was 1.1 % (22 of 2056). DY was significantly higher in stage III than in stage I or II cancers (3.9 % [18 of 467] vs. 0 % [0 of 412] or 0.4 % [4 of 1158], respectively, p < .001), and in human epidermal growth factor receptor-2 (HER2)-enriched cancers than in luminal or triple negative cancers (2.9 % [16 of 560] vs. 0.4 % [4 of 1090] or 0.5 % [2 of 406], respectively, p < .001). CONCLUSIONS: The DY of abdominal staging CT for detecting BCLM was low among all patients with initially diagnosed breast cancer. However, although abdominal staging CT for detecting BCLM is probably unnecessary in all patients, it can be clinically useful in patients with stage III or human epidermal growth factor receptor-2-enriched breast cancers.

Clinical Efficacy of Mobile App-Based, Self-Directed Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease: Systematic Review and Meta-Analysis.

Background: Pulmonary rehabilitation is well known to improve clinical symptoms (including dyspnea), quality of life, and exercise capacity in patients with chronic obstructive pulmonary disease (COPD). However, researchers have reported difficulties in practicing center-based pulmonary rehabilitation. Recently, mobile app-based pulmonary rehabilitation has become available in clinical practice. We investigated the clinical outcomes of mobile app-based pulmonary rehabilitation in patients with COPD. Objective: The objective of our study was to evaluate the clinical efficacy of mobile app-based pulmonary rehabilitation versus conventional center-based pulmonary rehabilitation for patients with COPD, using a systematic review and meta-analysis. Methods: A systematic search of the literature published between January 2007 and June 2023 was performed, using the PubMed, Embase, Cochrane, and CINAHL databases to identify relevant randomized controlled trials involving patients with COPD. Pulmonary rehabilitation programs needed to provide an exercise program on a smartphone app. Study outcomes, including exercise capacity, symptom scores, quality of life, and hospitalization, were evaluated. The meta-analysis evaluated mean differences in 6-minute walk test distances (6MWDs), COPD Assessment Test (CAT) scores, modified Medical Research Council (mMRC) dyspnea scale scores, St. George Respiratory Questionnaire (SGRQ) scores, and risk ratios for hospitalization resulting from disease exacerbation. Results: Of the 1173 screened studies, 10 were included in the systematic review and 9 were included in the meta-analysis. Further, 6 studies were multicenter studies. There were a total of 1050 participants, and most were aged ≥65 years. There were discrepancies in the baseline participant characteristics, smartphone apps, interventions, and study outcomes among the included studies. In the meta-analysis, 5 studies assessed 6MWDs (mean difference 9.52, 95% CI -3.05 to 22.08 m), 6 studies assessed CAT scores (mean difference -1.29, 95% CI -2.39 to -0.20), 3 studies assessed mMRC dyspnea scale scores (mean difference -0.08, 95% CI -0.29 to 0.13), 2 studies assessed SGRQ scores (mean difference -3.62, 95% CI -9.62 to 2.38), and 3 studies assessed hospitalization resulting from disease exacerbation (risk ratio 0.65, 95% CI 0.27-1.53). These clinical parameters generally favored mobile app-based pulmonary rehabilitation; however, a statistically significant difference was noted only for the CAT scores (P=.02). Conclusions: Despite some discrepancies in the baseline participant characteristics and interventions among studies, mobile app-based pulmonary rehabilitation resulted in favorable exercise capacity, symptom score, quality of life, and hospitalization outcomes when compared with conventional pulmonary rehabilitation. In the meta-analysis, the CAT scores of the mobile app-based pulmonary rehabilitation group were significantly lower than those of the control group (P=.02). In real-world practice, mobile app-based pulmonary rehabilitation can be a useful treatment option when conventional center-based pulmonary rehabilitation is not feasible.

21-gene expression assay and clinical outcomes of premenopausal patients with hormone receptor-positive breast cancer.

The prognostic role of the recurrence score (RS) based on the 21-gene expression assay in premenopausal women is not well delineated, and we investigated the association of outcomes and the RS in premenopausal patients who had 21-gene expression assay at Asan Medical Center, Seoul, Korea, between June 2005 and July 2018. Invasive breast cancer-free survival (IBCFS) by STEEP version 2.0 was compared according to the RS and clinical risk factors. A total of 554 patients were included in our study and 116 patients (20.9%) had age <40 years, 238 patients (43.0%) had luminal B subtype (Ki67 ≥ 20%), and 83 patients (15.0%) had RS >25. All patients received adjuvant tamoxifen ± chemotherapy. Overall, patients with RS >25 showed trend toward worse IBCFS from multivariable analysis (adjusted HR 1.89 [95% CI: 0.95-3.73], P = .069). When comparing outcomes according to age and luminal subtypes, patients with luminal B subtype and age <40 years (n = 60) showed significantly worse outcomes compared to the others (luminal A or luminal B + age ≥40 years, n = 494; adjusted HR 2.95 [95% CI: 1.49-5.82], log-rank P < .001). Among patients with luminal B subtype and age <40 years, there was no significant association observed between IBCFS and the RS (log-rank P = .51). In conclusion, while RS >25 showed association with poor outcomes in premenopausal women, it may have less prognostic significance among those with luminal B subtype and age <40 years.

Long-term outcome in patients with nodal-positive breast cancer treated with sentinel lymph node biopsy alone after neoadjuvant chemotherapy.

PURPOSE: Sentinel lymph node biopsy (SLNB) has yet to be accepted as the standard staging procedure in node positive (cN1) breast cancer patients who had clinical complete response in the axilla (cN0) following neoadjuvant chemotherapy (NAC), due to the presumed high false negative rate associated with SLNB in such scenario. This study aimed to determine whether there is a significant difference in the axillary recurrence rate (ARR) and long-term survival in this group of patients, receiving SLNB alone versus axillary lymph node dissection (ALND). METHODS: A retrospective cohort of cN1 patients who were rendered cN0 by NAC from January 2014 to December 2018 were identified from the Asan Medical Center database. Patients' characteristics and outcomes were collected and analyzed. RESULTS: 902 cN1 patients treated with NAC and turned cN0 were identified. 477 (52.9%) patients achieved complete pathological response in the axilla (ypN0). At a median follow up of 65 months, ARR was 3.2% in the SLNB only group and 1.8% in the ALND group (p = 0.398). DFS and OS were significantly worse in patients with ALND as compared to patients with SLNB only (p = 0.011 and 0.047, respectively). We noted more patients in the ALND group had T3-4 tumor. In the subgroup analysis, we showed that in the T1-2 subgroup (n = 377), there was no statistically significant difference in DFS and OS (p = 0.242 and 0.671, respectively) between SLNB only and ALND group. CONCLUSION: Our findings suggest that cN1 patients who were converted to ypN0 following NAC may be safely treated with SLNB only.

Age-Related Incidence and Peak Occurrence of Contralateral Breast Cancer.

Importance: Young patients with breast cancer have higher risk for developing contralateral breast cancer (CBC) and have epidemiologic characteristics different from those of older patients. Objective: To examine the incidence and peak occurrence of CBC according to age at primary breast cancer (PBC) surgery. Design, Setting, and Participants: This cohort study included patients who were diagnosed with and underwent surgery for unilateral nonmetastatic breast cancer at Asan Medical Center, Korea, between January 1, 1999, and December 31, 2013, with follow-up through December 31, 2018. Data were analyzed from December 1, 2021, through April 30, 2023. Patients were divided into 2 groups according to their age at surgery for PBC: younger (≤35 years) vs older (>35 years). Main Outcomes and Measures: The main outcomes were cumulative incidence and hazard rate of CBC in the entire study population and in subgroups divided by cancer subtype, categorized according to hormone receptor (HR) and ERBB2 status. Results: A total of 16 251 female patients with stage 0 to III breast cancer were analyzed; all patients were Korean. The mean (SD) age was 48.61 (10.06) years; 1318 patients (8.11%) were in the younger group, and 14 933 (91.89%) were in the older group. Median follow-up was 107 months (IQR, 79-145 months). Compared with the older group, the younger group had significantly higher incidence of CBC (10-year cumulative incidence, 7.1% vs 2.9%; P < .001) and higher risk (hazard ratio, 2.10; 95% CI, 1.62-2.74) of developing CBC. The hazard rate, which indicates risk for developing CBC at a certain time frame, differed according to the subtype of primary cancer. In patients with the HR+/ERBB2- subtype, the risk increased continuously in both age groups. In patients with the triple negative subtype, the risk increased until approximately 10 years and then decreased in both age groups. Meanwhile, in the HR-/ERBB2+ subtype, risk peaked earlier, especially in the younger group (1.7 years since first surgery in the younger group and 4.8 years in the older group). Conclusions and Relevance: In this cohort study, patients aged 35 years or younger with breast cancer had a higher risk of developing CBC than older patients. Moreover, young patients with the HR-/ERBB2+ subtype tended to have a shorter interval for developing CBC. These findings might be useful in guiding treatment decisions, such as contralateral prophylactic mastectomy.

Post-insertion technique to introduce targeting moieties in milk exosomes for targeted drug delivery.

BACKGROUND: Recently, increased attention has been given on exosomes as ideal nanocarriers of drugs owing to their intrinsic properties that facilitate the transport of biomolecular cargos. However, large-scale exosome production remains a major challenge in the clinical application of exosome-based drug delivery systems. Considering its biocompatibility and stability, bovine milk is a suitable natural source for large-scale and stable exosome production. Because the active-targeting ability of drug carriers is essential to maximize therapeutic efficacy and minimize side effects, precise membrane functionalization strategies are required to enable tissue-specific delivery of milk exosomes with difficulty in post-isolation modification. METHODS: In this study, the membrane functionalization of a milk exosome platform modified using a simple post-insertion method was examined comprehensively. Exosomes were engineered from bovine milk (mExo) with surface-tunable modifications for the delivery of tumor-targeting doxorubicin (Dox). The surface modification of mExo was achieved through the hydrophobic insertion of folate (FA)-conjugated lipids. RESULTS: We have confirmed the stable integration of functionalized PE-lipid chains into the mExo membrane through an optimized post-insertion technique, thereby effectively enhancing the surface functionality of mExo. Indeed, the results revealed that FA-modified mExo (mExo-FA) improved cellular uptake in cancer cells via FA receptor (FR)-mediated endocytosis. The designed mExo-FA selectively delivered Dox to FR-positive tumor cells and triggered notable tumor cell death, as confirmed by in vitro and in vivo analyses. CONCLUSIONS: This simple and easy method for post-isolation modification of the exosomal surface may be used to develop milk-exosome-based drug delivery systems.

Factors in Parenting Stress in Young Patients With Breast Cancer and Implications for Children's Emotional Development: The PSYCHE Study.

Importance: The number of patients with breast cancer who have children is substantial. However, the emotional burden of this disease and its implication for childhood development remain largely unknown. Objective: To investigate the clinical factors in parenting stress in mothers with breast cancer and the association of maternal depression and parenting stress with their children's emotional development. Design, Setting, and Participants: This cross-sectional study involved a survey of females with stage 0 to 3 breast cancer and was conducted from June 2020 to April 2021 in Seoul, South Korea. Participants were aged 20 to 45 years and completed the Center for Epidemiologic Studies Depression-Revised scale and basic questionnaires on demographic and clinical characteristics. Participants with children completed the Korean Parenting Stress Index Short Form (K-PSI-SF), Child Behavior Checklist, Junior Temperament and Character Inventory, and Children's Sleep Habits Questionnaire. Exposure: Having children in patients with breast cancer. Main Outcomes and Measures: Multivariable logistic and linear regression analyses were performed to investigate the association between maternal depression and parenting stress. Results: A total of 699 females (mean [SD] age, 39.6 [4.6] years) were included, of whom 499 had children (mean [SD] age of children, 8.0 [2.7] years). Depression was more common in patients with children (odds ratio [OR], 2.25; 95% CI, 1.01-5.05) and patients who had gonadotropin-releasing hormone treatment (OR, 1.68; 95% CI, 1.15-2.44). Disease duration was inversely associated with depression (OR, 0.85; 95% CI, 0.76-0.96). Cancer-related factors were not associated with the K-PSI-SF score. Having children aged 6 years or older (ß = 3.09; 95% CI, 0.19-5.99); being the sole primary caregiver (ß = -3.43; 95% CI, -5.87 to -0.99); and reporting certain temperament (eg, novelty seeking: ß = 0.58; 95% CI, 0.46-0.71), emotional problems (eg, anxious/depressed: ß = 8.09; 95% CI, 3.34-12.83), and sleeping pattern (eg, bedtime resistance: ß = 0.57; 95% CI, 0.15-0.99) subscale scores in their children were associated with parenting stress. Depression and parenting stress were correlated (ß = 0.56; 95% CI, 0.45-0.66; P < .001). The emotional challenges encountered by children of mothers with breast cancer were not significantly different from reference values. Conclusions and Relevance: This study found that in patients with breast cancer, child-related factors and depression were significantly associated with parenting stress, but breast cancer-related factors were not correlated. The findings suggest that mothers with breast cancer are susceptible to both depression and parenting stress and that tailored counseling and support are needed.

Survival Outcomes in Premenopausal Patients With Invasive Lobular Carcinoma.

Importance: The disparate prognostic implications between invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) have been demonstrated. However, information on premenopausal patients remains insufficient. Objective: To examine long-term survival outcomes of ILC and IDC in premenopausal patients using national databases. Design, Setting, and Participants: This cohort study used the Surveillance, Epidemiology, and End Results (SEER), Korean Breast Cancer Registry (KBCR), and Asan Medical Center Research (AMCR) databases to identify premenopausal patients with stage I to III ILC or IDC between January 1, 1990, and December 31, 2015. The median follow-up time was 90 (IQR, 40-151) months in the SEER database, 94 (IQR, 65-131) months in the KBCR database, and 120 (IQR, 86-164) months in the AMCR database. Data were analyzed from January 1 to May 31, 2023. Main Outcomes and Measures: The primary outcome was breast cancer-specific survival (BCSS), which was analyzed according to histological type, and the annual hazard rate was evaluated. Survival rates were analyzed using a log-rank test and a Cox proportional hazards regression model with time-varying coefficients. Multivariable analysis was performed by adjusting for tumor characteristics and treatment factors. Results: A total of 225 938 women diagnosed with IDC or ILC and younger than 50 years were identified. Mean (SD) age at diagnosis was 42.7 (5.3) years in the SEER database, 41.8 (5.5) years in the KBCR database, and 41.8 (5.5) years in the AMCR database. In terms of race (available for the SEER database only), 12.4% of patients were Black, 76.1% were White, 11.0% were of other race (including American Indian or Alaska Native, Asian, and Native Hawaiian or Other Pacific Islander), and 0.5% were of unknown race). Patients with ILC had better BCSS in the first 10 years after diagnosis than those with IDC (hazard ratios [HRs], 0.73 [95% CI, 0.68-0.78] in the SEER database, 1.20 [95% CI, 0.91-1.58] in the KBCR database, and 0.50 [95% CI, 0.29-0.86] in the AMCR database), although BCSS was worse after year 10 (HRs, 1.80 [95% CI, 1.59-2.02] in the SEER database, 2.79 [95% CI, 1.32-5.88] in the KBCR database, and 2.23 [95% CI, 1.04-4.79] in the AMCR database). Similar trends were observed for hormone receptor-positive tumors (HRs, 1.55 [95% CI, 1.37-1.75] in the SEER database, 2.27 [95% CI, 1.01-5.10] in the KBCR database, and 2.12 [95% CI, 0.98-4.60] in the AMCR database). Considering the annual hazard model of BCSS, IDC events tended to decline steadily after peaking 5 years before diagnosis. However, the annual peak event of BCSS was observed 5 years after diagnosis for ILC, which subsequently remained constant. Conclusions and Relevance: These findings suggest that premenopausal women with ILC have worse BCSS estimates than those with IDC, which can be attributed to a higher late recurrence rate of ILC than that of IDC. Histological subtypes should be considered when determining the type and duration of endocrine therapy in premenopausal women.

Design of siRNA Bioconjugates for Efficient Control of Cancer-Associated Membrane Receptors.

Research on siRNA delivery has seen tremendous growth over the past few decades. As one of the major delivery strategies, siRNA bioconjugates offer the potential to enhance and extend the pharmacological properties of siRNAs while minimizing toxicity. In this paper, we suggest the development of a siRNA conjugate platform with peptides and proteins that are ligands of target receptors for cancer treatment. The siRNA bioconjugates target and block the receptor membrane proteins, enter the cells through receptor-mediated endocytosis, and inhibit the expression of that same target membrane receptor, thereby doubly controlling the function of the membrane proteins. The three kinds of bioconjugates targeting CD47, PD-L1, and EGFR were synthesized via two different copper-free click chemistry reactions. Results showed the cellular uptake of each conjugate, reduction of target gene expression, and efficient functional control of receptor proteins. This platform provides an effective approach for regulating membrane proteins in various diseases beyond cancer.

Survival After Development of Contralateral Breast Cancer in Korean Patients With Breast Cancer.

Importance: Contralateral breast cancer (CBC) is the most frequently diagnosed primary cancer in patients with breast cancer. Although many studies have reported survival after the development of CBC, results have been inconsistent. Objective: To investigate whether the development of CBC is associated with survival among patients with breast cancer. Design, Setting, and Participants: This cohort study was conducted at the Asan Medical Center, Korea, among patients who were diagnosed with primary unilateral, nonmetastatic, stage 0 to III breast cancer between 1999 and 2013 and followed up through 2018. The median (IQR) follow-up was 107 (75-143) months. Patients were categorized into CBC and no-CBC groups by whether they developed CBC during the follow-up period. Data were analyzed from November 2021 to March 2023. Exposure: Development of CBC. Main outcomes and measures: Survival rates of CBC and no-CBC groups were compared using a time-dependent Cox proportional hazard model in the entire study population and in subgroup analyses by interval of CBC development and subtype of the primary breast cancer. Results: Among 16 251 patients with breast cancer (all Asian, specifically Korean; mean [SD] age, 48.61 [10.06] years), 418 patients developed CBC. There was no significant difference in overall survival between CBC and no-CBC groups (hazard ratio, 1.166; 95% CI, 0.820-1.657). Patients who developed CBC within 1.5 years after the surgery of the primary breast cancer had a higher risk for overall death during the study period (hazard ratio, 2.014; 95% CI, 1.044-3.886), and those who developed CBC after 1.5 years showed no significant difference in survival compared with the no-CBC group. Patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (ERBB2, formerly HER2)-negative breast cancer had a higher risk for overall death in the CBC group (hazard ratio, 1.882; 95% CI, 1.143-3.098) compared with the no-CBC group. Conclusions and Relevance: This study found that development of CBC in patients with breast cancer was not associated with survival but that early development of CBC after diagnosis of the primary breast cancer or development of CBC in patients with HR-positive/ERBB2-negative breast cancer was associated with survival. These results may provide valuable information for patients seeking advice on opting for contralateral prophylactic mastectomy.

Enhancing the reliability of particulate matter sensing by multivariate Tobit model using weather and air quality data.

Low-cost particulate matter (PM) sensors have been widely used following recent sensor-technology advancements; however, inherent limitations of low-cost monitors (LCMs), which operate based on light scattering without an air-conditioning function, still restrict their applicability. We propose a regional calibration of LCMs using a multivariate Tobit model with historical weather and air quality data to improve the accuracy of ambient air monitoring, which is highly dependent on meteorological conditions, local climate, and regional PM properties. Weather observations and PM2.5 (fine inhalable particles with diameters ≤ 2.5 µm) concentrations from two regions in Korea, Incheon and Jeju, and one in Singapore were used as training data to build a visibility-based calibration model. To validate the model, field measurements were conducted by an LCM in Jeju and Singapore, where R2 and the error after applying the model in Jeju improved (from 0.85 to 0.88) and reduced by 44% (from 8.4 to 4.7 µg m-3), respectively. The results demonstrated that regional calibration involving air temperature, relative humidity, and other local climate parameters can efficiently correct the bias of the sensor. Our findings suggest that the proposed post-processing using the Tobit model with regional weather and air quality data enhances the applicability of LCMs.

Ki-67, 21-Gene Recurrence Score, Endocrine Resistance, and Survival in Patients With Breast Cancer.

Importance: Both high 21-gene recurrence score (RS) and high Ki-67 level are poor prognostic factors in patients with estrogen receptor (ER)-positive ERBB2-negative (ER+/ERBB-) breast cancer; however, a discrepancy between the 2 has been noted. Survival differences according to these 2 biomarkers are not well known. Objective: To assess the associations between RS and Ki-67 expression and between Ki-67 expression and recurrence-free survival in patients with ER+/ERBB- breast cancer with low RS. Design, Setting, and Participants: This cohort study included women treated for ER+/ERBB2- breast cancer who underwent the 21-gene RS test from March 2010 to December 2020 in 2 hospitals in Korea. Exposures: Recurrence score and Ki-67 level. Main Outcomes and Measures: A Cox proportional hazards regression model was used to examine the association of Ki-67 with recurrence-free survival (RFS), while a binary logistic regression model was used to examine the association between Ki-67 and secondary endocrine resistance. High Ki-67 expression was defined as 20% or greater, and low genomic risk as an RS of 25 or less. Secondary endocrine resistance was defined as breast cancer recurrence that occurred after at least 2 years of endocrine therapy and during or within the first year after completing 5 years of adjuvant endocrine therapy. Results: A total of 2295 female patients were included (mean [SD] age, 49.8 [9.3] years), of whom 1948 (84.9%) were in the low genomic risk group and 1425 (62.1%) had low Ki-67 level. The median follow-up period was 40 months (range, 0-140 months). The RS and Ki-67 level had a moderate correlation (R = 0.455; P < .001). Of the patients with low Ki-67 level, 1341 (94.1%) had low RS, whereas 607 of 870 patients with high Ki-67 level (69.8%) had low RS. In patients with low RS, the RFS differed significantly according to Ki-67 level (low Ki-67, 98.5% vs high Ki-67, 96.5%; P = .002). Among the 1807 patients with low genomic risk who did not receive chemotherapy, high Ki-67 level was independently associated with recurrence (hazard ratio, 2.51; 95% CI, 1.27-4.96; P = .008). Recurrence after 3 years differed significantly according to Ki-67 level (low Ki-67, 98.7% vs high Ki-67, 95.7%; P = .003), whereas recurrence within 3 years did not differ (low Ki-67, 99.3% vs high Ki-67, 99.3%; P = .90). In addition, Ki-67 was associated with secondary endocrine resistance in patients with low RS who did not receive chemotherapy (odds ratio, 2.49; 95% CI, 1.13-5.50; P = .02). Conclusions and Relevance: In this cohort study of patients with ER+/ERBB2- breast cancer, a moderate correlation was observed between Ki-67 and RS, and high Ki-67 level in patients with low genomic risk was associated with increased risk of secondary endocrine resistance.

Survey of clinicians on the use of adjuvant therapy for premenopausal women with breast cancer.

PURPOSE: Considering prognostic and anatomic stages in early-stage premenopausal patients with breast cancer, clinicians decide on performing the multigene assay, adjuvant chemotherapy, or ovarian function suppression (OFS). This decision is also based on genetic information related to hormone receptor-positive and human epidermal growth factor receptor 2 negative results. We aimed to determine the tendency to use adjuvant therapy in clinical practice. METHODS: From April to May 2022, clinicians of the Korean Breast Cancer Society responded to a web-based survey. The survey included 62 multiple-choice questions mainly on decision-making under different pathologic conditions. RESULTS: Among 92 responding clinicians, 91.3% were breast surgeons. For 35-year-old patients (pT2N0 and Ki-67 50% profile), 96.8% of clinicians selected chemotherapy, whereas 50.7% selected chemotherapy for patients with pT1N0, Ki-67 10%, and without Oncotype Dx (ODX). Only 35.6% selected chemotherapy for 47-year-old patients with the same profiles, while 84.3% and 49.1% chose chemotherapy with ODX recurrence score 21 and 16, respectively. More clinicians selected tamoxifen (TMX) plus OFS than aromatase inhibitor (AI) plus OFS for 5 years of endocrine therapy in patients with adjuvant chemotherapy regardless of genomic and clinical risks. However, for the same patients without adjuvant chemotherapy, more clinicians selected AI plus OFS. A longer duration of additional OFS and TMX was selected in patients with high clinical and genomic risks, and the duration of OFS was relatively shorter in older patients. CONCLUSION: The decision regarding adjuvant therapy should be made considering clinical and genomic risks and age, and clinicians should consult with patients about adverse effects and compliance.

The Impact of a Mobile Support Group on Distress and Physical Activity in Breast Cancer Survivors: Randomized, Parallel-Group, Open-Label, Controlled Trial.

BACKGROUND: While mobile health apps have demonstrated their potential in revolutionizing health behavior changes, the impact of a mobile community built on these apps on the level of physical activity and mental well-being in cancer survivors remains unexplored. OBJECTIVE: In this randomized controlled trial, we examine the effects of participation in a mobile health community specifically designed for breast cancer survivors on their physical activity levels and mental distress. METHODS: We performed a single-center, randomized, parallel-group, open-label, controlled trial. This trial enrolled women between 20 and 60 years of age with stage 0 to III breast cancer, an Eastern Cooperative Oncology Group performance status of 0, and the capability of using their own smartphone apps. From January 7, 2019, to April 17, 2020, a total of 2,616 patients were consecutively screened for eligibility after breast cancer surgery. Overall, 202 patients were enrolled in this trial, and 186 patients were randomly assigned (1:1) to either the intervention group (engagement in a mobile peer support community using an app for tracking steps; n=93) or the control group (using the app for step tracking only; n=93) with a block size of 10 without stratification. The mobile app provides a visual interface of daily step counts, while the community function also provides rankings among its members and regular notifications encouraging physical activity. The primary end point was the rate of moderate to severe distress for the 24-week study period, measured through an app-based survey using the Distress Thermometer. The secondary end point was the total weekly steps during the 24-week period. RESULTS: After excluding dropouts, 85 patients in the intervention group and 90 patients in the control group were included in the analysis. Multivariate analyses showed that patients in the intervention group had a significantly lower degree of moderate to severe distress (B=-0.558; odds ratio 0.572; P<.001) and a higher number of total weekly step counts (B=0.125; rate ratio 1.132; P<.001) during the 24-week period. CONCLUSIONS: Engagement in a mobile app-based patient community was effective in reducing mental distress and increasing physical activity in breast cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov NCT03783481; https://classic.clinicaltrials.gov/ct2/show/NCT03783481.

Waiting Time for Breast Cancer Treatment in Korea: A Nationwide Cohort Study.

PURPOSE: This study aimed to analyze the waiting time for initial treatment after breast cancer diagnosis and determine the factors influencing treatment delay in South Korea. METHODS: This nationwide retrospective cohort study was conducted using the Health Insurance Review and Assessment data. The participants were classified according to the regions where their biopsy and treatment were performed (Seoul-Seoul, Metro-Metro, Other-Other, Metro-Seoul, Other-Seoul). Waiting time was analyzed according to regional subgroup, year of diagnosis, and type of treatment. Multivariable logistic regression models were constructed to identify the factors associated with treatment delay (after 30 days of diagnosis). RESULTS: A total of 133,514 participants newly diagnosed between January 2010 and December 2017 were included in the study. The median waiting time for initial treatment in the total population increased from 8 days, in 2010, to 14 days, in 2017. In the Seoul-Seoul group, the waiting time increased from 10 days, in 2010, to 16 days, in 2017. Although the median waiting time was approximately 10 days in the Metro-Metro and Other-Other groups, it was 27 and 24 days, in the Metro-Seoul and Other-Seoul group, respectively, in 2017. The proportion of delayed upfront surgery by more than 30 days was higher in the Metro-Seoul (odds ratio [OR], 8.088; 95% confidence interval [CI], 7.357-8.893; p < 0.001) and Other-Seoul (OR, 6.210; 95% CI, 5.717-6.750; p < 0.001) groups than in the Metro-Metro (OR, 1.468; 95% CI, 1.352-1.594; p < 0.001) and Other-Other (reference) groups. Previous medical history and treatment at tertiary hospital were observed as factors related to delayed surgery. CONCLUSION: Waiting times for breast cancer surgery have increased across all regions of Korea, with those traveling to Seoul experiencing particularly long wait times.