Micrometastases in axillary lymph nodes in breast cancer, post-neoadjuvant systemic therapy.

INTRODUCTION: The significance of minimal residual axillary disease, specifically micrometastases, following neoadjuvant systemic therapy (NST) remains largely unexplored. Our study aimed to elucidate the prognostic implications of micrometastases in axillary and sentinel lymph nodes following NST. METHODS: This retrospective study analyzed primary breast cancer patients who underwent surgery after NST from September 2006 through February 2018. All patients received axillary lymph node dissection (ALND), either with or without sentinel lymph node biopsy. Recurrence-free survival (RFS)-associated variables were identified using a multivariate Cox proportional hazard model. RESULTS: Of the 978 patients examined, 438 (44.8%) exhibited no pathologic lymph node involvement (ypN0) after NST, while 89 (9.1%) had micrometastases (ypN1mi) and 451 (46.7%) had macrometastases (ypN+). Notably, 51.1% of the patients with sentinel lymph node micrometastases (SLNmi) had additional metastases, nearly triple that of SLN-negative patients (P < 0.001), and 29.8% of SLNmi patients were upstaged with the ALND. Although ypN1mi was not associated with RFS in patients post-NST (HR, 1.02; 95% CI, 0.42-2.49; P = 0.958), SLNmi patients experienced significantly worse RFS compared to SLN-negative patients (hazard ratio [HR], 2.23; 95% confidence intervals [CI], 1.12-4.46; P = 0.023). Additional metastases in SLNmi were more prevalent in patients with larger residual breast disease greater than 20 mm, HR-positive/HER2-negative subtype, and low Ki-67 LI (< 14%). CONCLUSIONS: SLNmi is a negative prognostic factor significantly associated with additional non-SLN metastases, while ypN1mi does not influence the prognosis compared to ypN0. Hence, additional ALND may be warranted to confirm axillary nodal status in patients with SLNmi.

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.

Exploring miRNA­target gene profiles associated with drug resistance in patients with breast cancer receiving neoadjuvant chemotherapy.

Exosomal microRNAs (miRNAs) are closely related to drug resistance in patients with breast cancer (BC); however, only a few roles of the exosomal miRNA-target gene networks have been clinically implicated in drug resistance in BC. Therefore, the present study aimed to identify the differential expression of exosomal miRNAs associated with drug resistance and their target mRNAs. In vitro microarray analysis was used to verify differentially expressed miRNAs (DEMs) in drug-resistant BC. Next, tumor-derived exosomes (TDEs) were isolated. Furthermore, it was determined whether the candidate drug-resistant miRNAs were also significant in TDEs, and then putative miRNAs in TDEs were validated in plasma samples from 35 patients with BC (20 patients with BC showing no response and 15 patients with BC showing a complete response). It was confirmed that the combination of five exosomal miRNAs, including miR-125b-5p, miR-146a-5p, miR-484, miR-1246-5p and miR-1260b, was effective for predicting therapeutic response to neoadjuvant chemotherapy, with an area under the curve value of 0.95, sensitivity of 75%, and specificity of 95%. Public datasets were analyzed to identify differentially expressed genes (DEGs) related to drug resistance and it was revealed that BAK1, NOVA1, PTGER4, RTKN2, AGO1, CAP1, and ETS1 were the target genes of exosomal miRNAs. Networks between DEMs and DEGs were highly correlated with mitosis, metabolism, drug transport, and immune responses. Consequently, these targets could be used as predictive markers and therapeutic targets for clinical applications to enhance treatment outcomes for patients with BC.

Early Implementation of Exercise to Facilitate Recovery After Breast Cancer Surgery: A Randomized Clinical Trial.

Importance: Recovery of shoulder function following breast cancer surgery is crucial for physical functioning and quality of life. While early implementation of shoulder rehabilitation exercises may enhance recovery, the optimal timing and exercise program remain unclear. Objective: To investigate whether an early exercise intervention, initiated 1 day postsurgery and continued for 1 month through subsequent visits, could improve shoulder range of motion (ROM) and strength in patients with breast cancer. Design, Setting, and Participants: A parallel-group, 2-arm randomized clinical trial was conducted between June 2020 and October 2021 at the Breast Cancer Center in Seoul, South Korea. Fifty-six patients (of 119 screened) with early-stage breast cancer who were scheduled for partial or total mastectomy were randomized into a tailored resistance exercise group (n = 28) or a usual care group (n = 28). Data were analyzed from November 2021 to June 2022. Interventions: The exercise intervention commenced 1 day postsurgery and consisted of 4 supervised exercise education sessions corresponding with surgeon visits and daily home-based exercises for the first postoperative month. Tailored programs, including stretching and strength exercises, were adjusted based on individual shoulder function recovery status. Main Outcomes and Measures: Primary end points were shoulder ROM and strength at 1 and 6 months postsurgery. Physical activity, body composition, and quality of life were assessed at 6 months. Results: Of 56 patients randomized (mean [SD] age, 50.3 [6.6] years), 54 completed the trial (96%), with 100% and 97% compliance to supervised and home-based exercise sessions, respectively. At 1 month postsurgery, 19 (67.9%) in the exercise group had fully recovered shoulder strength compared to 1 (3.6%) in the usual care group (P < .001). At 6 months, 22 (78.6%) in the exercise group had fully recovered shoulder ROM and 24 (85.7%) had fully recovered strength compared to 6 (21.4%) and 5 (17.9%), respectively, in the usual care group (P < .001). The exercise group exhibited less loss in muscle mass and improved physical activity and quality of life compared to the usual care group. Conclusion and Relevance: In this trial, 1-month tailored exercise program, initiated immediately after breast cancer surgery and supplemented with supervised sessions coinciding with surgeon visits, significantly improved shoulder function in patients with breast cancer. Trial Registration: WHO International Clinical Trials Registry identifier: KCT0006997.