Clinical efficacy of tumor organoid-guided cancer therapy for locally advanced unresectable or metastatic breast cancer.

Patient-derived organoids (PDOs) may facilitate treatment selection. This retrospective cohort study evaluated the feasibility and clinical benefit of using PDOs to guide personalized treatment in metastatic breast cancer (MBC). Patients diagnosed with MBC were recruited between January 2019 and August 2022. PDOs were established and the efficacy of customized drug panels was determined by measuring cell mortality after drug exposure. Patients receiving organoid-guided treatment (OGT) were matched 1:2 by nearest neighbor propensity scores with patients receiving treatment of physician's choice (TPC). The primary outcome was progression-free survival. Secondary outcomes included objective response rate and disease control rate. Targeted gene sequencing and pathway enrichment analysis were performed. Forty-six PDOs (46 of 51, 90.2%) were generated from 45 MBC patients. PDO drug screening showed an accuracy of 78.4% (95% CI 64.9%-91.9%) in predicting clinical responses. Thirty-six OGT patients were matched to 69 TPC patients. OGT was associated with prolonged median progression-free survival (11.0 months vs. 5.0 months; hazard ratio 0.53 [95% CI 0.33-0.85]; p = .01) and improved disease control (88.9% vs. 63.8%; odd ratio 4.26 [1.44-18.62]) compared with TPC. The objective response rate of both groups was similar. Pathway enrichment analysis in hormone receptor-positive, human epidermal growth factor receptor 2-negative patients demonstrated differentially modulated pathways implicated in DNA repair and transcriptional regulation in those with reduced response to capecitabine/gemcitabine, and pathways associated with cell cycle regulation in those with reduced response to palbociclib. Our study shows that PDO-based functional precision medicine is a feasible and effective strategy for MBC treatment optimization and customization.

Neoadjuvant docetaxel plus carboplatin vs epirubicin plus cyclophosphamide followed by docetaxel in triple-negative, early-stage breast cancer (NeoCART): Results from a multicenter, randomized controlled, open-label phase II trial.

Previous studies have shown that the addition of carboplatin to neoadjuvant chemotherapy improved the pathologic complete response (pCR) rate in patients suffering from triple-negative breast cancer (TNBC) and patients who obtained a pCR could achieve prolonged event-free survival (EFS) and overall survival (OS). However, no studies have assessed the effects of the combination of docetaxel and carboplatin without anthracycline with taxane-based and anthracycline-based regimens. The NeoCART study was designed as a multicenter, randomized controlled, open-label, phase II trial to assess the efficacy and safety of docetaxel combined with carboplatin in untreated stage II-III TNBC. All eligible patients were randomly assigned, at a 1:1 ratio, to an experimental docetaxel plus carboplatin (DCb) for six cycles group (DCb group) or an epirubicin plus cyclophosphamide for four cycles followed by docetaxel for four cycles group (EC-D group). PCR (ypT0/is ypN0) was evaluated as the primary outcome. Between 1 September 2016 and 31 December 2019, 93 patients were randomly assigned and 88 patients were evaluated for the primary endpoint (44 patients in each group). In the primary endpoint analysis, 27 patients in the DCb group (61.4%, 95% CI 47.0-75.8) and 17 patients in the EC-D group achieved a pCR (38.6%, 95% CI 24.3-53.0; odds ratio 2.52, 95% CI 2.4-43.1; Pnoninferiority = .004). Noninferiority was met, and the DCb regimen was confirmed to be superior to the EC-D regimen (P = .044, superiority margin of 5%). At the end of the 37-month median follow-up period, OS and EFS rates were equivalent in both groups.

Ultrasound-assisted carbon nanoparticle suspension mapping versus dual tracer-guided sentinel lymph node biopsy in patients with early breast cancer (ultraCars): phase III randomized clinical trial.

BACKGROUND: Appropriate tracing methods for sentinel lymph node biopsy (SLNB) play a key role in accurate axillary staging. This prospective, non-inferiority, phase III RCT compared the feasibility and diagnostic performance of ultrasound-assisted carbon nanoparticle suspension (CNS) mapping with dual tracer-guided SLNB in patients with early breast cancer. METHODS: Eligible patients had primary breast cancer without nodal involvement (cN0), or had clinically positive lymph nodes (cN1) that were downstaged to cN0 after neoadjuvant chemotherapy. Patients were randomly assigned (1 : 1) to undergo either ultrasound-assisted CNS sentinel lymph node (SLN) mapping (UC group) or dual tracer-guided mapping with CNS plus indocyanine green (ICG) (GC group). The primary endpoint was the SLN identification rate. RESULTS: Between 1 December 2019 and 30 April 2021, 330 patients were assigned randomly to the UC (163 patients) or GC (167 patients) group. The SLN identification rate was 94.5 (95 per cent c.i. 90.9 to 98.0) per cent in the UC group and 95.8 (92.7 to 98.9) per cent in the GC group. The observed difference of -1.3 (-5.9 to 3.3) per cent was lower than the prespecified non-inferiority margin of 6 per cent (Pnon-inferiority = 0.024). No significant difference was observed in metastatic node rate (30.5 versus 24.4 per cent; P = 0.222), median number of SLNs harvested (3 (range 1-7) versus 3 (1-8); P = 0.181), or duration of surgery (mean(s.d.) 7.53(2.77) versus 7.63(3.27) min; P = 0.316) between the groups. Among the subgroup of patients who had undergone neoadjuvant treatment, the SLN identification rate was 91.7 (82.2 to 100) per cent in the UC group and 90.7 (81.7 to 99.7) per cent in the GC group. CONCLUSION: The diagnostic performance of ultrasound-assisted CNS mapping was non-inferior to that of dual tracer-guided SLN mapping with CNS plus ICG in patients with early breast cancer. REGISTRATION NUMBER: NCT04951245 (http://www.clinicaltrials.gov).

A nomogram to predict non-sentinel lymph node metastasis in patients with initial cN+ breast cancer that downstages to cN0 after neoadjuvant chemotherapy.

BACKGROUND AND OBJECTIVES: This study mainly explored the factors that influence non-sentinel lymph node (NSLN) metastasis in patients with breast cancer (BC) whose axillary lymph nodal status changed from clinically node positive (cN+) to clinically node negative (cN0) after neoadjuvant chemotherapy (NAC). METHODS: We retrospectively analyzed the clinicopathological factors affecting NSLN metastasis in a total of 179 patients with cN+ BC downstaged to cN0 (120 in the training set and 59 in the validation set) who underwent both sentinel lymph node (SLN) biopsy and axillary lymph node dissection following NAC. RESULTS: Among 179 patients enrolled, the overall NSLN metastatic rate was 24.0% (95% confidence interval [CI]: 17.7%-30.3%). In multivariate logistic regression analysis, the number of positive SLNs achieving a pathological complete remission of the breast and clinical node staging was independent predictors of NSLN metastasis. A nomogram was established based on these factors and displayed a good discriminatory capability, with an area under the curve of 0.919 (95% CI: 0.865-0.973) for the training set and 0.900 (95% CI: 0.812-0.988) for the validation set and its clinical utility was confirmed by the decision curve analysis. CONCLUSIONS: The nomogram established showed the ability to predict NSLN metastases in patients with initial cN+ BC that downstaged to cN0 after NAC.

Application of a carbon nanoparticle suspension for sentinel lymph node mapping in patients with early breast cancer: a retrospective cohort study.

BACKGROUND: To stage axillary lymph nodes in women with early-stage breast cancer, sentinel lymph node biopsy (SLNB), rather than axillary lymph node dissection (ALND), has been employed. Moreover, different tracer methods have various advantages and disadvantages. In recent years, carbon nanoparticle suspensions (CNSs) have been used as lymph node tracers during surgeries for thyroid cancer, gastric cancer, and colorectal cancer. The study retrospectively analyzed the feasibility and accuracy of CNS for sentinel lymph node (SLN) mapping in patients with early breast cancer. METHODS: This single-center, retrospective study included breast cancer patients who underwent SLNB from January 1, 2016, to December 31, 2017, in the Department of Breast Cancer, Guangdong General Hospital. All patients received standard SLNB surgery using a CNS tracer. RESULTS: A total of 332 cases were included in this study. The SLN identification rate was 99.1% (329/332), and the mean number of SLNs was 2.6 (range, 1-6). SLN metastasis was found in 62 (18.8%) cases, of which 90.3% were found to be macrometastases. The sensitivity of SLNB was 95.9% (47/49), with a specificity of 100% (42/42), a positive predictive value of 100% (47/47), a negative predictive value of 95.5% (42/44), and a false-negative rate of 4.1% (2/49). CONCLUSION: The identification and predictive values of a CNS tracer for SLNB were satisfactory.

Neoadjuvant Chemotherapy and Neoadjuvant Chemotherapy With Immunotherapy Result in Different Tumor Shrinkage Patterns in Triple-Negative Breast Cancer.

PURPOSE: This study aims to explore whether neoadjuvant chemotherapy with immunotherapy (NACI) leads to different tumor shrinkage patterns, based on magnetic resonance imaging (MRI), compared to neoadjuvant chemotherapy (NAC) alone in patients with triple-negative breast cancer (TNBC). Additionally, the study investigates the relationship between tumor shrinkage patterns and treatment efficacy was investigated. METHODS: This retrospective study included patients with TNBC patients receiving NAC or NACI from January 2019 until July 2021 at our center. Pre- and post-treatment MRI results were obtained for each patient, and tumor shrinkage patterns were classified into three categories as follows: 1) concentric shrinkage (CS); 2) diffuse decrease; and 3) no change. Tumor shrinkage patterns were compared between the NAC and NACI groups, and the relevance of the patterns to treatment efficacy was assessed. RESULTS: Of the 99 patients, 65 received NAC and 34 received NACI. The CS pattern was observed in 53% and 20% of patients in the NAC and NACI groups, respectively. Diffuse decrease pattern was observed in 36% and 68% of patients in the NAC and NACI groups. The association between the treatment regimens (NAC and NACI) and tumor shrinkage patterns was statistically significant (p = 0.004). The postoperative pathological complete response (pCR) rate was 45% and 82% in the NAC and NACI groups (p < 0.001), respectively. In the NACI group, 17% of patients with the CS pattern and 56% of those with the diffuse decrease pattern achieved pCR (p = 0.903). All tumor shrinkage patterns were associated with achieved a high pCR rate in the NACI group. CONCLUSION: Our study demonstrates that the diffuse decrease pattern of tumor shrinkage is more common following NACI than that following NAC. Furthermore, our findings suggest that all tumor shrinkage patterns are associated with a high pCR rate in patients with TNBC treated with NACI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04909554.

Multifactor artificial intelligence model assists axillary lymph node surgery in breast cancer after neoadjuvant chemotherapy: multicenter retrospective cohort study.

BACKGROUND: The high false negative rate (FNR) associated with sentinel lymph node biopsy often leads to unnecessary axillary lymph node dissection following neoadjuvant chemotherapy (NAC) in breast cancer. The authors aimed to develop a multifactor artificial intelligence (AI) model to aid in axillary lymph node surgery. MATERIALS AND METHODS: A total of 1038 patients were enrolled, comprising 234 patients in the primary cohort, 723 patients in three external validation cohorts, and 81 patients in the prospective cohort. For predicting axillary lymph node response to NAC, robust longitudinal radiomics features were extracted from pre-NAC and post-NAC magnetic resonance images. The U test, the least absolute shrinkage and selection operator, and the spearman analysis were used to select the most significant features. A machine learning stacking model was constructed to detect ALN metastasis after NAC. By integrating the significant predictors, we developed a multifactor AI-assisted surgery pipeline and compared its performance and false negative rate with that of sentinel lymph node biopsy alone. RESULTS: The machine learning stacking model achieved excellent performance in detecting ALN metastasis, with an area under the curve (AUC) of 0.958 in the primary cohort, 0.881 in the external validation cohorts, and 0.882 in the prospective cohort. Furthermore, the introduction of AI-assisted surgery reduced the FNRs from 14.88 (18/121) to 4.13% (5/121) in the primary cohort, from 16.55 (49/296) to 4.05% (12/296) in the external validation cohorts, and from 13.64 (3/22) to 4.55% (1/22) in the prospective cohort. Notably, when more than two SLNs were removed, the FNRs further decreased to 2.78% (2/72) in the primary cohort, 2.38% (4/168) in the external validation cohorts, and 0% (0/15) in the prospective cohort. CONCLUSION: Our study highlights the potential of AI-assisted surgery as a valuable tool for evaluating ALN response to NAC, leading to a reduction in unnecessary axillary lymph node dissection procedures.

Longitudinal MRI-based fusion novel model predicts pathological complete response in breast cancer treated with neoadjuvant chemotherapy: a multicenter, retrospective study.

Background: Accurate identification of pCR to neoadjuvant chemotherapy (NAC) is essential for determining appropriate surgery strategy and guiding resection extent in breast cancer. However, a non-invasive tool to predict pCR accurately is lacking. Our study aims to develop ensemble learning models using longitudinal multiparametric MRI to predict pCR in breast cancer. Methods: From July 2015 to December 2021, we collected pre-NAC and post-NAC multiparametric MRI sequences per patient. We then extracted 14,676 radiomics and 4096 deep learning features and calculated additional delta-value features. In the primary cohort (n = 409), the inter-class correlation coefficient test, U-test, Boruta and the least absolute shrinkage and selection operator regression were used to select the most significant features for each subtype of breast cancer. Five machine learning classifiers were then developed to predict pCR accurately for each subtype. The ensemble learning strategy was used to integrate the single-modality models. The diagnostic performances of models were evaluated in the three external cohorts (n = 343, 170 and 340, respectively). Findings: A total of 1262 patients with breast cancer from four centers were enrolled in this study, and pCR rates were 10.6% (52/491), 54.3% (323/595) and 37.5% (66/176) in HR+/HER2-, HER2+ and TNBC subtype, respectively. Finally, 20, 15 and 13 features were selected to construct the machine learning models in HR+/HER2-, HER2+ and TNBC subtypes, respectively. The multi-Layer Perception (MLP) yields the best diagnostic performances in all subtypes. For the three subtypes, the stacking model integrating pre-, post- and delta-models yielded the highest AUCs of 0.959, 0.974 and 0.958 in the primary cohort, and AUCs of 0.882-0.908, 0.896-0.929 and 0.837-0.901 in the external validation cohorts, respectively. The stacking model had accuracies of 85.0%-88.9%, sensitivities of 80.0%-86.3%, and specificities of 87.4%-91.5% in the external validation cohorts. Interpretation: Our study established a novel tool to predict the responses of breast cancer to NAC and achieve excellent performance. The models could help to determine post-NAC surgery strategy for breast cancer. Funding: This study is supported by grants from the National Natural Science Foundation of China (82171898, 82103093), the Deng Feng project of high-level hospital construction (DFJHBF202109), the Guangdong Basic and Applied Basic Research Foundation (grant number, 2020A1515010346, 2022A1515012277), the Science and Technology Planning Project of Guangzhou City (202002030236), the Beijing Medical Award Foundation (YXJL-2020-0941-0758), and the Beijing Science and Technology Innovation Medical Development Foundation (KC2022-ZZ-0091-5). Funding sources were not involved in the study design, data collection, analysis and interpretation, writing of the report, or decision to submit the article for publication.

Organic solvent-tolerant elastase efficiently hydrolyzes insoluble, cross-linked, protein fiber of eggshell membranes.

Eggshell membrane is a mechanically stable and insoluble cross-linked fibrous protein. Pseudomonas aeruginosa strain ME-4 synthesizes a metalloprotease that degrades the eggshell membrane. We cloned the encoding gene in Escherichia coli. The recombinant protease, over-expressed in E. coli, was inactive but addition of acetone to crude cell extracts restored the activity and removed many E. coli proteins. We purified the active, acetone-treated protease to homogeneity in a single chromatography step with 57% recovery. The recombinant protease partially hydrolyzed eggshell membrane and produced more soluble peptides and proteins than commercial elastase, α-chymotrypsin, and collagenase. The soluble peptides produced from hydrolyzed eggshell membrane inhibited angiotensin-I-converting enzyme activity. The degradation of eggshell membrane by the recombinant elastase could be applied to the production of soluble bioactive peptides.

Case report: solitary splenic metastasis occurring 19 months after primary treatment for occult breast cancer.

Occult breast cancer, commonly presenting with axillary lymphadenopathy, is an extremely rare entity of breast cancer. Metastasis to the spleen as a single site is rarely seen and has been little reported in literature. Herein we described a case of a 60-year-old patient who presented with an asymptomatic solitary splenic mass 19 months after axillary lymph node dissection, regional radiotherapy, and systemic therapy. Laparoscopic splenectomy was performed, and histopathological examination confirmed metastasis from occult breast cancer. Then, the patient was administered with oral vinorelbine and dual-targeted treatment. With over 10 months of follow-up, there is no evidence of recurrence or metastasis of malignancy. To our knowledge, this study reports the first case of solitary splenic metastasis from occult breast cancer and highlights the importance of considering splenic metastasis as the only site of recurrence during follow-up of primary cancer, regardless of its rarity. If possible, splenectomy may be a therapeutic strategy.

Homologous recombination deficiency predicts the response to platinum-based neoadjuvant chemotherapy in early-stage triple-negative breast cancer patients: a systematic review and meta-analysis.

Background: Recent studies have shown that homologous recombination deficiency (HRD) may be correlated with the pathological complete response (pCR) rate. This meta-analysis aimed to determine the predictive value of HRD for the pCR rate in patients with triple-negative breast cancer (TNBC) receiving platinum-based neoadjuvant chemotherapy (NCT). Methods: Published articles were searched in the PubMed, Embase, Medline, Web of Science, and Cochrane databases up to 1 June 2021, and studies reporting the pCR rate for HRD carriers on platinum-based NCT were selected. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined for the pCR rate, clinical response rate, and Grade 3 or higher adverse events (AEs) using the random-effects model. Bias risk was evaluated using the Cochrane Collaboration tool (PROSPERO, registration number CRD42021249874). Results: Seven studies were eligible. The results showed that HRD carriers had higher pCR rates than non-HRD carriers across all treatment arms (OR = 3.84, 95% CI = [1.93, 7.64], p = 0.0001). Among HRD carriers, the pCR rate was higher in patients on platinum-based NCT than in those without platinum exposure (OR = 1.95, 95% CI = [1.17, 3.23], p = 0.01). We did not observe marked pCR improvements in non-HRD carriers. Among HRD carriers, the pCR rates in the mutant and wild-type breast cancer susceptibility gene (BRCA) groups did not differ significantly (OR = 2.00, 95% CI = [0.77, 5.23], p = 0.16), but HRD carriers with wild-type BRCA had a significant advantage over non-HRD carriers on platinum-based NCT (OR = 3.64, 95% CI = [1.83, 7.21], p = 0.0002). Conclusion: HRD is an effective predictor of increased pCR rates in platinum-based NCT, especially in wild-type BRCA patients. Adding platinum to NCT for non-HRD carriers can increase the incidence of AEs but may not improve the therapeutic effect.

Prevention of taxane-associated acute pain syndrome with etoricoxib for patients with breast cancer: A phase II randomised trial.

BACKGROUND: For patients with breast cancer who receive docetaxel chemotherapy, taxane-associated acute pain syndrome (T-APS), considered a form of neural pathology, is a significant clinical problem. We evaluated the effect of prophylactic etoricoxib on T-APS in patients with breast cancer. MATERIALS AND METHODS: We conducted a phase II randomised trial including 144 patients with breast cancer receiving four cycles of docetaxel-based chemotherapy. Patients were randomised in the ratio 1:1 to receive prophylactic etoricoxib (60 mg, Day 1 to Day 8) or no prophylactic treatment. The primary end-point was the overall incidence of T-APS across all cycles. Secondary end-points included the incidence of severe pain (greater than 5 on a scale 0-10); severity and duration of T-APS; Functional Assessment of Cancer Therapy-Breast subscale; chronic sensory and motor neurotoxicity and adverse events. RESULTS: The overall incidence of T-APS across all cycles of chemotherapy in the etoricoxib group was 57.1%, while that in the control group was 91.5% (P < 0.001). The incidences of severe T-APS were 11.4% and 54.9% for the etoricoxib and control groups, respectively (P < 0.001). The mean Functional Assessment of Cancer Therapy-Breast subscale score of the etoricoxib group (103.79-107.24) was significantly higher than that of the control group (93.88-96.71) (P = 0.001 at cycle 1 and P < 0.001 at cycles 2-4). After four cycles of docetaxel chemotherapy, the etoricoxib group demonstrated a significantly higher mean Functional Assessment of Cancer Treatment Neurotoxicity subscale score than the control group (38.46, 95% CI: 37.63-39.29; 34.59, 95% CI: 33.73-35.45, respectively; P < 0.001). Electromyography showed that most peripheral sensory nerves in the etoricoxib group had significantly improved action potential amplitudes and conduction velocities compared with those in the control group. CONCLUSION: Prophylactic use of etoricoxib could significantly reduce the incidence and severity of docetaxel-induced acute pain syndrome and potentially decrease docetaxel-induced peripheral neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04565600.

Neoadjuvant therapy in triple-negative breast cancer: A systematic review and network meta-analysis.

BACKGROUND: Evidence for the preferred neoadjuvant therapy regimen in triple-negative breast cancer (TNBC) is not yet established. METHODS: Literature search was conducted from inception to February 12, 2022. Phase 2 and 3 randomized controlled trials (RCTs) investigating neoadjuvant therapy for TNBC were eligible. The primary outcome was pathologic complete response (pCR); the secondary outcomes were all-cause treatment discontinuation, disease-free survival or event-free survival (DFS/EFS), and overall survival. Odd ratios (OR) with 95% credible intervals (CrI) were used to estimate binary outcomes; hazard ratios (HR) with 95% CrI were used to estimate time-to-event outcomes. Bayesian network meta-analysis was implemented for each endpoint. Sensitivity analysis and network meta-regression were done. RESULTS: 41 RCTs (N = 7109 TNBC patients) were eligible. Compared with anthracycline- and taxane-based chemotherapy (ChT), PD-1 inhibitor plus platinum plus anthracycline- and taxane-based ChT was associated with a significant increased pCR rate (OR 3.95; 95% CrI 1.81-9.44) and a higher risk of premature treatment discontinuation (3.25; 1.26-8.29). Compared with dose-dense anthracycline- and taxane-based ChT, the combined treatment was not associated with significantly improved pCR (OR 2.57; 95% CrI 0.69-9.92). In terms of time-to-event outcomes, PD-1 inhibitor plus platinum plus anthracycline- and taxane-based ChT was associated with significantly improved DFS/EFS (HR 0.42; 95% CrI 0.19-0.81). CONCLUSIONS: PD-1 inhibitor plus platinum and anthracycline- and taxane-based ChT was currently the most efficacious regimen for pCR and DFS/EFS improvement in TNBC. The choice of chemotherapy backbone, optimization of patient selection with close follow-up and proactive symptomatic managements are essential to the antitumor activity of PD-1 inhibitor.

Low-dose apatinib combined with neoadjuvant chemotherapy in the treatment of early-stage triple-negative breast cancer (LANCET): a single-center, single-arm, phase II trial.

Background: Antiangiogenic therapy combined with chemotherapy could improve pathological complete response (pCR) for breast cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor 2. We assessed the efficacy and safety of apatinib combined with standard neoadjuvant chemotherapy in patients with triple-negative breast cancer (TNBC). Materials and methods: This single-arm, phase II study enrolled patients aged 18-70 years with previously untreated stage IIA-IIIB TNBC. Patients received oral apatinib at a dose of 250 mg once daily and intravenously docetaxel every 3 weeks for four cycles, followed by epirubicin plus cyclophosphamide every 3 weeks for four cycles. The primary endpoint was the pCR rate in the breast and lymph nodes. Secondary endpoints included objective response rate, event-free survival (EFS), overall survival (OS), and safety. Results: In all, 31 patients were enrolled, and the median follow-up time was 22.9 months (range: 10.1-41.6 months). The pCRs in both breast and lymph nodes were achieved in 17 [54.8%; 95% confidence interval (CI): 36.0-72.7] of 31 patients. Objective responses were achieved in 29 patients (93.5%; 95% CI: 78.6-99.2), and disease control was achieved in 31 patients (100%; 95% CI: 88.8-100.0). The 2-year EFS and 2-year OS were 90.9% and 94.4%, respectively. The five most common treatment-related adverse events were fatigue (51%), hypertension (41%), anorexia (39%), hand-foot syndrome (35%), and diarrhea (32%). Few grade 3 or more adverse events were observed. Conclusion: The combination of apatinib with docetaxel followed by epirubicin plus cyclophosphamide showed excellent efficacy and manageable toxicities; and further randomized controlled phase III trials are warranted. Trial registration: This trial was registered with ClinicalTrials.gov (NCT03243838) on 5 August 2017.

Visualization positioning-guided biopsy of suspicious breast microcalcifications: a retrospective cohort study.

BACKGROUND: At present, most histological evaluations of microcalcifications without a mass are performed using X-ray guided hook wire localization or vacuum-assisted stereotactic biopsy (VASB), but there are still several limitations to these techniques. Therefore, we designed a visualization positioning technique based on three directions of mammography to accurately locate suspected microcalcifications to guide the biopsy. METHODS: We retrospectively analyzed consecutive patients with suspicious microcalcifications who underwent visualization positioning-guided biopsy (VPB) from June 1, 2016, to June 1, 2021. The visualization positioning technique was performed using an electronic ruler to measure the vertical distance from the microcalcification core to the vertical lines on mammography. RESULTS: A total of 133 patients (median age 46 years; range, 22-87 years) who underwent VPB were included in our study. Among the 133 cases of microcalcifications based on pathological results, 104 were benign, 14 were high risk, and 15 were malignant. In 124 (93.2%) patients, microcalcification was confirmed during the first round of VPB specimen analysis. Only 6 (4.5%) and 3 (2.3%) patients underwent second and third extended resections, respectively, as the resected specimens did not contain microcalcifications. Four patients (3.0%) with malignant biopsy results underwent a subsequent operation. Two patients with DCIS underwent mastectomy and sentinel lymph node biopsy because of diffuse calcification. One patient had no residual cancer, and the other was upgraded to invasive ductal carcinoma (IDC). Two patients with IDC underwent breast-conserving surgery and mastectomy with sentinel lymph node biopsy. CONCLUSIONS: VPB can be used to evaluate breast microcalcifications when a mass is not present, making it an effective diagnostic technique.

Peritoneal Metastasis After Treated With Abemaciclib Plus Fulvestrant for Metastatic Invasive Lobular Breast Cancer: A Case Report and Review of the Literature.

Peritoneal metastases from invasive lobular carcinoma (ILC) of breast are uncommon and usually related to poor prognosis due to difficulty of detection in clinical practice and drug resistance. Therefore, recognizing the entities of peritoneal metastases of ILC and the potential mechanism of drug resistance is of great significance for early detection and providing accurate management. We herein report a case of a 60-year-old female who presented with nausea and vomiting as the first manifestation after treated with abemaciclib (a CDK4/6 inhibitor) plus fulvestrant for 23 months due to bone metastasis of ILC. Exploratory laparotomy found multiple nodules in the peritoneum and omentum, and immunohistochemistry confirmed that the peritoneal metastatic lesions were consistent with ILC. Palliative therapy was initiated, but the patient died two months later due to disease progression with malignant ascites. Whole exome sequencing (WES) was used to detect the tumor samples and showed the peritoneal metastatic lesions had acquired ESR1 and PI3KCA mutations, potentially explaining the mechanism of endocrine therapy resistance. We argue that early diagnosis of peritoneal metastasis from breast cancer is crucial for prompt and adequate treatment and WES might be an effective supplementary technique for detection of potential gene mutations and providing accurate treatment for metastatic breast cancer patients.

Tumor Microenvironment Characterization in Breast Cancer Identifies Prognostic and Neoadjuvant Chemotherapy Relevant Signatures.

Immune response which involves distinct immune cells is associated with prognosis of breast cancer. Nonetheless, less study have determined the associations of different types of immune cells with patient survival and treatment response. In this study, A total of 1,502 estrogen receptor(ER)-negative breast cancers from public databases were used to infer the proportions of 22 subsets of immune cells. Another 320 ER-negative breast cancer patients from Guangdong Provincial People's Hospital were also included and divided into the testing and validation cohorts. CD8+ T cells, CD4+ T cells, B cells, and M1 macrophages were associated with favourable outcome (all p <0.01), whereas Treg cells were strongly associated with poor outcome (p = 0.005). Using the LASSO model, we classified patients into the stromal immunotype A and B subgroups according to immunoscores. The 10 years OS and DFS rates were significantly higher in the immunotype A subgroup than immunotype B subgroup. Stromal immunotype was identified as an independent prognostic indicator in multivariate analysis in all cohorts and was also related to pathological complete response(pCR) after neoadjuvant chemotherapy. The nomogram that integrated the immunotype and clinicopathologic features showed good predictive accuracy for pCR and discriminatory power. The stromal immunotype A subgroup had higher expression levels of immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) and cytokines (IL-2, INF-γ, and TGF-ß). In addition, patients with immunotype A and B diseases had distinct mutation signatures. Therefore, The stromal immunotypes could predict survival and responses of ER-negative breast cancer patients to neoadjuvant chemotherapy.

Adjuvant CDK4/6 inhibitors combined with endocrine therapy in HR-positive, HER2-negative early breast cancer: A meta-analysis of randomized clinical trials.

BACKGROUND: The benefit of adjuvant cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) in hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) early breast cancer (EBC) is uncertain. Hence, we performed a meta-analysis to determine the efficacy and safety of adjuvant CDK4/6 inhibitors plus ET and to identify potential preferred subpopulations for this regimen. METHODS: A literature search was conducted in PubMed, Embase, Cochrane databases up to Jan 15, 2021. Hazard ratios (HRs) for invasive disease-free survival (IDFS) and risk ratios (RRs) for grade 3/4 adverse events (AEs) and treatment discontinuation were extracted. Analysis with predefined subgroup variables was done. Trial sequential analysis (TSA) was performed to assess the conclusiveness of survival outcomes. RESULTS: Three trials were eligible (N = 12647). Compared with ET, adjuvant CDK4/6 inhibitors with ET prolonged IDFS in patients with HR+/HER2- EBC (HR 0.87, 95% CI 0.76-0.98, p = 0.03, I2 = 19%), with positive therapeutic responses observed in patients with N2/N3 nodal status (HR 0.83, 95% CI 0.71-0.97, p = 0.02, I2 = 0%). None of the cumulative z-curves crossed the trial monitoring boundaries in TSA, and no reliable conclusion could be drawn. The combination treatment carried a higher risk of grade 3/4 AEs (RR 4.14, 95% CI 3.33-5.15, p < 0.00001) and an increase in treatment discontinuation due to AEs (RR 19.16, 95% CI 9.27-39.61, p < 0.00001). CONCLUSIONS: Adjuvant CDK4/6 inhibitors with ET might provide survival benefit in HR+/HER2- EBC. A statistically significantly improved IDFS was only observed in N2/N3 subgroup. However, overall evidence favoring the use of this combination regimen was inadequate.

Anthracycline-containing versus carboplatin-containing neoadjuvant chemotherapy in combination with trastuzumab for HER2-positive breast cancer: the neoCARH phase II randomized clinical trial.

BACKGROUND: Although dual blockade HER2-based neoadjuvant chemotherapy is associated with excellent outcomes for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, pertuzumab is not available to all patients due to cost. The optimal neoadjuvant chemotherapy for HER2-positive breast cancer in the presence of a single HER2 blockade is unknown. This study aimed to compare the efficacy and safety of epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (EC-TH) with docetaxel/carboplatin/trastuzumab (TCH) neoadjuvant setting for HER2-positive breast cancer under the single HER2 blockade. METHODS: Patients with stage II-IIIC HER2-positive breast cancer were randomly assigned to either eight cycles of EC-TH every 3 weeks during all chemotherapy cycles, or six cycles of TCH every 3 weeks. The primary endpoint was pathological complete response (pCR) (defined as the absence of invasive tumor cells in breast and axilla, ypT0/is ypN0). RESULTS: From May 2017 to November 2019, 140 patients were randomly assigned, and 135 patients were ultimately found evaluable for the primary endpoint. The pCR was recorded in 25 of 67 patients [37.3%; 95% confidence interval (CI), 25.8-50.0] in the EC-TH group and in 38 of 68 patients (55.9%, 95% CI, 43.3-67.9) in the TCH group (p = 0.032). The most common adverse events (AEs) were neutropenia in 24 of 67 (35.8%) patients in the EC-TH group versus 27 of 68 (39.7%) in the TCH group (p = 0.642), anemia in 33 of 67 (49.3%) patients in the EC-TH group versus 34 of 68 (50.0%) in the TCH group (p = 0.931), and thrombocytopenia in five of 67 (7.5%) patients in the EC-TH group versus 17 of 68 (25.0%) in the TCH group (p = 0.006). CONCLUSION: For patients receiving the single HER2 blockade trastuzumab for HER2-positive breast cancer, TCH regimen might be a preferred neoadjuvant therapy. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov identifier: NCT03140553) on 2 May 2017.

DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations.

BACKGROUND: Breast cancers can be divided into HER2-negative and HER2-positive subtypes according to different status of HER2 gene. Despite extensive studies connecting germline mutations with possible risk of HER2-negative breast cancer, the main category of breast cancer, it remains challenging to obtain accurate risk assessment and to understand the potential underlying mechanisms. METHODS: We developed a novel framework named Damage Assessment of Genomic Mutations (DAGM), which projects rare coding mutations and gene expressions into Activity Profiles of Signalling Pathways (APSPs). FINDINGS: We characterized and validated DAGM framework at multiple levels. Based on an input of germline rare coding mutations, we obtained the corresponding APSP spectrum to calculate the APSP risk score, which was capable of distinguish HER2-negative from HER2-positive cases. These findings were validated using breast cancer data from TCGA (AUC = 0.7). DAGM revealed that HER2 signalling pathway was up-regulated in germline of HER2-negative patients, and those with high APSP risk scores had exhibited immune suppression. These findings were validated using RNA sequencing, phosphoproteome analysis, and CyTOF. Moreover, using germline mutations, DAGM could evaluate the risk for HER2-negative breast cancer, not only in women carrying BRCA1/2 mutations, but also in those without known disease-associated mutations. INTERPRETATION: The DAGM can facilitate the screening of subjects at high risk of HER2-negative breast cancer for primary prevention. This study also provides new insights into the potential mechanisms of developing HER2-negative breast cancer. The DAGM has the potential to be applied in the prevention, diagnosis, and treatment of HER2-negative breast cancer. FUNDING: This work was supported by the National Key Research and Development Program of China (grant no. 2018YFC0910406 and 2018AAA0103302 to CZ); the National Natural Science Foundation of China (grant no. 81202076 and 82072939 to MY, 81871513 to KW); the Guangzhou Science and Technology Program key projects (grant no. 2014J2200007 to MY, 202002030236 to KW); the National Key R&D Program of China (grant no. 2017YFC1309100 to CL); Shenzhen Science and Technology Planning Project (grant no. JCYJ20170817095211560 574 to YN); and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313882 to KW and S2013010012048 to MY); Hefei National Laboratory for Physical Sciences at the Microscale (grant no. KF2020009 to GN); and RGC General Research Fund (grant no. 17114519 to YQS).