A Nomogram for Identifying HR+/Her2- Breast Cancer Patients with Positive Sentinel Lymph Nodes and Omitted Axillary Lymph Node Dissection Who Need Abemaciclib Therapy.

BACKGROUND The efficacy of abemaciclib in high-risk patients with early-stage HR+/Her2- breast cancer has been verified by MonarchE. However, accurately determining the number of axillary lymph node (ALN) metastases remains challenging. The Z0011 trial changed the axillary management strategy, eliminating the need for axillary lymph node dissection (ALND) in patients with 1-2 sentinel lymph node (SLN) metastases. Therefore, further exploration is needed to identify patients who could benefit from abemaciclib therapy. MATERIAL AND METHODS This retrospective study included cT1-2N0M0 HR+/Her2- patients with 1-2 positive SLNs who underwent ALND. Clinicopathological data were collected, and logistic regression analyses identified independent predictors for ≥4 positive ALNs. A predictive nomogram was developed, and discrimination and calibration were evaluated using the C-index and calibration curve. Clinical efficacy was assessed using decision curve analysis (DCA). RESULTS We enrolled 444 patients, with 77 (17.3%) having ≥4 positive ALNs. Independent predictors for ≥4 positive ALNs included abnormal ALN on ultrasound, mammographic calcifications, T stage, and the number of positive SLNs. The nomogram demonstrated an AUC of 0.777 (95% CI: 0.735-0.815, P<0.001), and internal validation showed good calibration and discrimination (C-index, 0.802; 95% CI: 0.779-0.824). DCA revealed a positive net benefit for risk levels ranging from 5% to 54%. CONCLUSIONS This nomogram is a convenient and reliable tool to predict the risk of ≥4 positive ALNs in HR+/Her2- patients. It aids in protocol selection by identifying SLN-positive patients who may benefit from abemaciclib therapy without ALND.

Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort, phase 2 trial.

BACKGROUND: Patients with HER2-positive metastatic breast cancer have a high risk of developing brain metastases. Efficacious treatment options are scarce. We investigated the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases. METHODS: We did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. Patients aged 18 years or older who had radiotherapy-naive HER2-positive brain metastases (cohort A) or progressive disease after radiotherapy (cohort B), with an Eastern Cooperative Oncology Group performance status of 0-2, received pyrotinib 400 mg orally once daily, and capecitabine 1000 mg/m2 orally twice daily for 14 days, followed by 7 days off every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was confirmed intracranial objective response rate by investigator assessment according to the Response Evaluation Criteria In Solid Tumours (version 1.1). Activity and safety were analysed in patients with at least one dose of study drug. The study is ongoing, but recruitment is complete. The study is registered with ClinicalTrials.gov, NCT03691051. FINDINGS: Between Jan 29, 2019, and July 10, 2020, we enrolled 78 women: 51 (86%) of 59 patients in cohort A and 18 (95%) of 19 patients in cohort B had previous exposure to trastuzumab. Median follow-up duration was 15·7 months (IQR 9·7-19·0). The intracranial objective response rate was 74·6% (95% CI 61·6-85·0; 44 of 59 patients) in cohort A and 42·1% (20·3-66·5; eight of 19 patients) in cohort B. The most common grade 3 or worse treatment-emergent adverse event was diarrhoea (14 [24%] in cohort A and four [21%] in cohort B). Two (3%) patients in cohort A and three (16%) in cohort B had treatment-related serious adverse events. No treatment-related deaths occurred. INTERPRETATION: To our knowledge, this is the first prospective study showing the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases, especially in radiotherapy-naive population. This combination deserves further validation in a randomised, controlled trial. FUNDING: National Cancer Centre Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

HN1L promotes migration and invasion of breast cancer by up-regulating the expression of HMGB1.

Recent reports showed that haematological and neurological expressed 1-like (HN1L) gene participated in tumorigenesis and tumour invasion. However, the expression and role of HN1L in breast cancer remain to be investigated. Here, bioinformatics, western blot and immunohistochemistry were used to detect the expression of HN1L in breast cancer. Wound healing, transwell assay, immunofluorescence assay and mass spectrum were used to explore the role and mechanism of HN1L on the migration and invasion of breast cancer, which was confirmed in vivo using a nude mice model. Results showed that HN1L was significantly over-expressed in breast cancer tissues, which was positively correlated with M metastasis of breast cancer patients. Silencing HN1L significantly inhibited the invasion and metastasis of breast cancer cells in vitro and lung metastasis in nude mice metastasis model of breast cancer. Mechanistically, HN1L interacted with HSPA9 and affected the expression of HMGB1, playing a key role in promoting the invasion and metastasis of breast cancer cell. These results suggested that HN1L was an appealing drug target for breast cancer.

ATF2 inhibits ani-tumor effects of BET inhibitor in a negative feedback manner by attenuating ferroptosis.

BET inhibitor (BETi) has potential therapeutic effects on human cancer especially in breast cancer. However, the detailed mechanisms remain unclear. Herein, we found that BETi JQ1 and I-BET-151 (I-BET) activated ATF2 through JNK1/2 pathway in breast cancer cells MDA-MB-231 (MB-231). In addition, overexpression of ATF2 blocked the reduction of cell viability induced by JQ1 or I-BET in breast cancer MB-231 and BT-549 cells, cervical cancer HeLa cells and lung cancer A549 cells. The induction of cell death by BETi was also attenuated by ATF2 in MB-231 and BT-549 cells. By contrast, depletion of ATF2 increased cancer cell sensitivity to BETi. In MB-231 cells xenograft model, ATF2 significantly inhibited the anti-tumor effects of JQ1. By detection of the oxidized form gluthione, malondialdehyde and lipid ROS, we showed that overexpression of ATF2 inhibited ferroptosis induced by BETi, whereas depletion of ATF2 promoted ferroptosis by BETi. Furthermore, the underlying mechanisms of ATF2-reduced ferroptosis were investigated. Overexpressed and depleted ATF2 were found to significantly upregulate and downregulate NRF2 protein and mRNA expression, respectively. The significantly positive correlations between NRF2 and ATF2 gene expression were found in breast, lung and cervical cancer tissues from TCGA database. In NRF2-depleted MB-231 cells, ATF2 failed to attenuate JQ1-stimulated ferroptosis. All these results suggested that ATF2 inhibited BETi-induced ferroptosis by increasing NRF2 expression. Altogether, our findings illustrated ATF2 suppressed ani-tumor effects of BETi in a negative feedback manner by attenuating ferroptosis. BETi combined with ATF2 or NRF2 inhibitor might be a novel strategy for treatment of human cancer.

NR5A2 synergizes with NCOA3 to induce breast cancer resistance to BET inhibitor by upregulating NRF2 to attenuate ferroptosis.

BET inhibitors (BETi) exert an excellent anti-cancer activity in breast cancer. However, the identification of new potential targets to enhance breast cancer sensitivity to BETi is still an enormous challenge. Both NR5A2 and NCOA3 are frequently involved in cancer cells resistance to chemotherapy, also associated with poor prognosis in breast cancer. However, the functions of NR5A2 and NCOA3 in BETi resistance remains unknown. In this study, we found that BETi JQ1 and I-BET151 exhibited anti-cancer effects in breast cancer by inducing ferroptosis. NCOA3 as a coactivator synergized with NR5A2 to prevent BETi-induced ferroptosis. Mechanistically, we identified NR5A2 synergized with NCOA3 to increase expression of NRF2, a transcription factor that controls the expression of many antioxidant genes. Moreover, inhibition of NR5A2 or NCOA3 using small molecule inhibitors enhanced anti-cancer effects of BETi against breast cancer in vivo and in vitro. Altogether, our findings illustrated NR5A2 synergized with NCOA3 to confer breast cancer cells resistance to BETi by induction of NRF2. Inhibition of NR5A2/NCOA3 combined with BETi might be a novel strategy for treatment of breast cancer.

Knockdown of LINC00665 inhibits proliferation and invasion of breast cancer via competitive binding of miR-3619-5p and inhibition of catenin beta 1.

BACKGROUND: Long intergenic non-protein coding RNA00665 (LINC00665) plays a crucial tumorigenic role in many cancers, such as gastric cancer and lung adenocarcinoma. However, its role and mechanism of action in the progression of breast cancer (BC) are unknown. METHODS: LINC00665 expression levels were determined using quantitative polymerase chain reaction analysis with BC tissues and cell lines. BC cell proliferation was tested by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, whereas BC cell migration and invasion capabilities were analyzed by performing transwell migration assays. Percentages of apoptotic cells were measured by flow cytometry. Interactions between LINC00665 and miR-3169-5p were examined by performing luciferase reporter assays, and the expression levels of proteins, such as ß-catenin, were examined by western blot analysis. RESULTS: LINC00665 was expressed at high levels in BC tissues and cells. Upregulated LINC00665 expression correlated with tumor size and tumor, node, and metastasis stages, but not with the age of patients. LINC00665 knockdown inhibited BC cell proliferation, migration, and invasion, whereas it promoted apoptosis. Moreover, bioinformatics analysis and the luciferase reporter assay revealed that LINC00665 bound the microRNA (miR) miR-3619-5p. miR-3619-5p expression correlated negatively with LINC00665 expression in BC tissues. miR-3619-5p overexpression inhibited BC cell proliferation, migration, and invasion, but promoted apoptosis. Simultaneous knockdown of LINC00665 and miR-3619-5p led to increased cell proliferation, migration, and invasion, and inhibited apoptosis. Additionally, catenin beta 1, which encodes the ß-catenin protein, was the target gene of miR-3619-5p. ß-catenin expression clearly decreased after LINC00665 knockdown and miR-3619-5p overexpression, but increased after simultaneous knockdown of LINC00665 and miR-3619-5p. CONCLUSION: LINC00665 knockdown inhibited BC cell proliferation and invasion by binding miR-3619-5p and inhibiting ß-catenin expression.

Restin suppressed epithelial-mesenchymal transition and tumor metastasis in breast cancer cells through upregulating mir-200a/b expression via association with p73.

BACKGROUND: Restin belongs to MAGE superfamily and is known as MAGE H1. Restin was firstly cloned from HL-60 cells treated with all-trans retinoic acid (ATRA). Previous studies showed a pro-apoptotic role of Restin in several cell lines. However, little information is available on its expression patterns and functions in vivo. Our study was performed to detect if Restin plays a role in breast cancer cells in vitro and in vivo. METHODS AND RESULTS: Real-time PCR and western blot were conducted to detect Restin expression in multiple breast cancer cell lines and Restin level was negatively related with cell motility. Restin overexpression and knockdown stable cell lines were established by transducing lentivirus into MCF-7 and MDA-MB-231 cells. Cell morphology, wound closure assay, transwell migration and invasion assays were performed to detect if Restin inhibited EMT. Our data showed that Restin overexpressed cells exhibited classical epithelial cell morphology, and Restin overexpression resulted in activation of epithelial markers and suppression of mesenchymal markers, and inhibition of cell migration and invasion. Tumor xenograft model was used to characterize the biological functions of Restin in vivo. We found that Restin overexpression led to reduced lung metastasis. Real-time PCR, western blot, luciferase assay and ChIP assay were performed to identify the potential targets of Restin and the underlying molecular mechanisms. Among several master regulators of EMT, only ZEB1/2 levels were dramatically inhibited by Restin. Unexpectedly, Restin indirectly regulated ZEB1/2 expression at post-transcriptional level. We further identified mir-200a/b, well-characterized mediators controlling ZEB1/2 expression, were transcriptionally activated by Restin and the regulation was dependent on the p53 binding site in mir-200b/a/429 promoter. Further mechanical studies demonstrated Restin interacted with p73, one of p53 family members, which contributed to Restin-mediated activation of mir-200a/b and suppression of ZEB1/2. CONCLUSIONS: Taken together, our results suggest that Restin inhibits EMT and tumor metastasis by controlling the expression of the tumor metastasis suppressor mir-200a/b via association with p73. Our findings not only establish a mechanistic link between Restin, EMT and tumor metastasis, but also provide strong evidence supporting the notion that MAGE Group II proteins may exert a tumor suppressive effect in vivo.

Clinical significance of topoisomerase 2A expression and gene change in operable invasive breast cancer.

This study aims to investigate clinical significance of topoisomerase 2A (TOP2A) expression and TOP2A gene change in operable invasive breast cancer. This is a retrospective analysis, which includes 256 patients diagnosed as operable invasive breast cancer. All postoperational waxed specimens were subjected to resectioning for staining. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), KI-67, TOP2A expression, and TOP2A gene changes were detected by immunohistochemistry (IHC) and fluorescent in situ hybridization technique (FISH), respectively. Correlation between TOP2A expression and clinicopathological characteristics was also investigated. Effects of TOP2A protein or gene changes on survival rate were detected. Results indicated that 165 were TOP2A positive (64.5 %), and 31 were gene amplification positive (12.1 %). Positive rate of TOP2A expression showed significant correlations with ER, KI-67, and HER-2. The difference of 5-year overall survival (OS) between TOP2A-positive and TOP2A-negative groups did not reach statistical significance (OS: P = 0.321, 85.9 vs. 79.6 %; disease-free survival [DFS]: P = 0.247, 83.3 vs. 75.3 %). Five-year OS in TOP2A amplification group was 68.8 %, which is lower than deficiency and control group (P > 0.05). Subgroup analysis showed no significant differences of OS and DFS either between TOP2A-positive and TOP2A-negative groups or between TOP2A amplification and control group in population of patients with HER-2 amplification, triple negative breast cancer, or hormone-positive breast cancer. In conclusion, positive rate of TOP2A expression correlates significantly with ER, KI-67, and HER-2. However, prognostic significance of either TOP2A expression or TOP2A gene changes in breast cancer and its various subtypes is limited.

[Analysis of predictive factors affecting sentinel lymph node status in early breast cancer patients].

OBJECTIVE: To investigate the predictive factors affecting sentinel lymph node status in early breast cancer patients. METHODS: Clinicopathological data of 1 038 patients with early breast cancer, who underwent sentinel lymph node biopsy in Henan Tumor Hospital between July 2010 and August 2013, were reviewed. Logistic regression analysis was performed to identify the relevance of clinicopathological features with sentinel lymph node metastases. RESULTS: This group was consisted of 1 038 female patients with an average of 48.6 years. Positive sentinel lymph nodes were found in 22.9% (238/1 038) of the patients. The average number of sentinel lymph nodes removed by surgery was 3.8. Tumor size, tumor location, histopathology, ER/PR status and Ki-67 level were significantly correlated with SLN metastasis(P < 0.05 for all). All the above factors but Ki-67 level were significant independent predictors for SLN metastasis(P < 0.01 for all). CONCLUSION: Negative hormone receptor status, invasive cancer of non-specific histopathological type, tumor size >2 cm, and tumor location in the outer upper quadrat are independent predictive factors of sentinel lymph node metastasis in patients with early breast cancer.

[Influencing factors of pathologic complete response after neoadjuvant chemotherapy in locally advanced breast cancer patients: results of a single-center 10-year retrospective study].

OBJECTIVE: To analyze the influencing factors of pathologic complete response (PCR) to neoadjuvant chemotherapy in locally advanced breast cancer patients. METHODS: A retrospective study was conducted to analyze the clinical data of 620 locally advanced breast cancer patients at Henan Cancer Hospital between April 2003 to February 2013. After neoadjuvant chemotherapy, 94 patients achieved PCR. The correlation between clinicopathological factors and PCR was analyzed. RESULTS: No significant correlations existed between PCR with patient age, menstrual status or pretherapeutic lymph node status. Increased chemotherapeutic cycles could improve the rate of PCR (14.1% or 19.5 %), but it had no statistical difference. The rate of PCR achieved by regimens of anthracycline plus taxane was higher (20.1%)than that by anthracycline-based regimens (12.7%). And the rate of PCR had significant difference between two regimens. In terms of biological indicators, PCR rate after neoadjuvant chemotherapy was associated with estrogen/progesterone receptor, but it had no correlation with Ki-67 index or the status of epidermal growth factor receptor. Logistic multifactorial analysis showed that tumor size ≤ 5 cm were significantly correlated with PCR. Trastuzumab could obviously increase the PCR rate (15.7% or 41.7 %) and there was statistical difference (P = 0.031). CONCLUSION: The regimens of anthracycline plus taxane can achieve a higher PCR rate. Patient age, menstrual status and pretherapeutic lymph node have no significant correlation with PCR. PCR rate is associated with the expression of ER/PR negative in breast cancer. Trastuzumab increase the PCR rate in the HER-2 positive patients. Tumor size ≤ 5 cm is a significant influencing factor of PCR rate.

NREP, transcriptionally upregulated by HIF-1α, aggravates breast cancer cell growth and metastasis by promoting glycolysis.

Breast cancer (BC) poses a great threat to women's health. Neuronal regeneration related protein (NREP) is a multifunctional protein that is involved in embryonic development, regeneration, and human disease. However, the biological function of NREP in tumors is rarely reported and its role in BC remains unknown. Bioinformatics analysis showed that NREP is highly expressed and closely correlated with poor survival in BC patients. Under hypoxic conditions, NREP was upregulated in BC cells, and this promotion was reversed by hypoxia-inducible factor HIF-1α suppression. Luciferase reporter system and chromatin immunoprecipitation assays confirmed that HIF-1α directly binds to the promoter of NREP to increase the transcriptional activity of NREP. NREP suppression inhibited cell proliferation, arrested the cell cycle at the G1/S phase, and promoted apoptosis and caspase-3 activity in BC cells. Suppression of NREP decreased the tube formation ability of HUVECs. In addition, NREP downregulation showed an inhibition effect on cell migration, invasion, and EMT of BC cells. In NREP overexpressed cells, all these changes were reversed. In vivo, animal experiments also confirmed that NREP promotes BC tumor growth and metastasis. In addition, NREP promoted cellular glycolysis and enhanced the levels of glucose consumption, ATP, lactate production, and glucose transporters expression in NREP-overexpressed BC cells. In summary, our results demonstrated that NREP could be transcriptional activated by HIF-1α, which may aggravate BC tumor growth and metastasis by promoting cellular glycolysis. This result suggested that NREP may play an essential part in BC progression.

The Impact of Sentinel Lymph Node Biopsy on Female Patients With T3-4c Breast Cancer and 1-2 Positive Lymph Nodes: A Population-Based Cohort Study.

PURPOSE: This study aimed to evaluate the efficacy of sentinel lymph node biopsy (SLNB) in patients diagnosed with cT3-4c breast cancer with no more than 2 positive sentinel lymph nodes. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) database, this retrospective study identified patients diagnosed with T3-4c breast cancer between 2010 and 2015. These patients were then categorized into 2 groups: the SLNB group, which underwent examination of 1-5 regional lymph nodes and the axillary lymph node dissection (ALND) group, which underwent examination of ≥10 regional lymph nodes. Propensity score matching analysis was used to assess the efficacy of SLNB in cT3-4c patients. RESULTS: A total of 1139 patients were included in the analysis, with 423 and 716 patients in the SLNB and ALND groups, respectively. The 10-year overall survival (OS) and breast cancer-specific survival (BCSS) rates in the SLNB group were 66.1% and 76.3%, respectively, compared with 66.0% and 73.8%, respectively. Statistical analysis revealed no significant differences between the 2 groups in terms of OS (HR = 1.00, 95% CI = 0.80-1.25, P = .997) and BCSS (HR = 1.08, 95% CI = 0.83-1.41, P = .551). Even after 1:1 propensity score matching, there were no significant differences in OS (HR = 0.87, 95% CI = 0.65-1.16, P = .341) and BCSS (HR = 0.82, 95% CI = 0.59-1.16, P = .266) between the 2 groups. CONCLUSION: This study demonstrates that SLNB does not adversely affect the survival of cT3-4c breast cancer patients with 1-2 sentinel lymph node metastases.

Trends and efficacy of omitting axillary lymph node dissection in early-stage male breast cancer with limited nodal involvement: A population-based cohort study.

BACKGROUND: The effectiveness of sentinel lymph node biopsy (SLNB) versus axillary lymph node dissection (ALND) in managing early-stage male breast cancer (MBC) patients with T1-2 tumors and limited lymph node metastasis, all receiving radiotherapy, remains uncertain. This study examines trends and survival outcomes for SLNB and ALND in the United States. METHODS: We conducted a retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER) data from 2010 to 2020 for MBC patients with T1-2 tumors and 1-2 positive lymph nodes undergoing radiotherapy. Patients were classified by nodes removed (SLNB ≤5, ALND ≥10), comparing overall survival (OS) and breast cancer-specific survival (BCSS) between the groups before and after propensity score matching. RESULTS: Of 299 MBC patients analyzed, SLNB usage increased from 18.8% in 2010 to 61.0% in 2020. Multivariable logistic regression highlighted significant associations of SLNB use with diagnosis year, race, surgery type, positive lymph node count, and metastasis size. No significant differences in 5-year OS (77.98% SLNB vs. 85.85% ALND, p = 0.337) or BCSS (91.54% SLNB vs. 94.97% ALND, p = 0.214) were observed. Propensity score matching (96 patients per group) confirmed similar 5-year OS (83.9% for SLNB vs. 82.0% for ALND, p = 0.925) and BCSS (90.1% for SLNB vs. 96.9% for ALND, p = 0.167). CONCLUSION: SLNB and ALND provide comparable survival outcomes in early-stage MBC patients with limited lymph node metastasis undergoing radiotherapy. The increased utilization of SLNB supports its consideration to reduce surgical morbidity in selected MBC patients despite limited direct evidence.

Assessment of the impact of residual tumors at different sites post-neoadjuvant chemotherapy on prognosis in breast cancer patients and development of a disease-free survival prediction model.

Background: Residual disease after neoadjuvant chemotherapy (NAC) in breast cancer patients predicts worse outcomes than pathological complete response. Differing prognostic impacts based on the anatomical site of residual tumors are not well studied. Objectives: The study aims to assess disease-free survival (DFS) in breast cancer patients with different residual tumor sites following NAC and to develop a nomogram for predicting 1- to 3-year DFS in these patients. Design: A retrospective cohort study. Methods: Retrospective analysis of 953 lymph node-positive breast cancer patients with residual disease post-NAC. Patients were categorized into three groups: residual disease in breast (RDB), residual disease in lymph nodes (RDN), and residual disease in both (RDBN). DFS compared among groups. Patients were divided into a training set and a validation set in a 7:3 ratio. Prognostic factors for DFS were analyzed to develop a nomogram prediction model. Results: RDB patients had superior 3-year DFS of 94.6% versus 85.2% for RDN and 81.8% for RDBN (p < 0.0001). Clinical T stage, N stage, molecular subtype, and postoperative pN stage were independently associated with DFS on both univariate and multivariate analyses. Nomogram integrating clinical tumor-node-metastasis (TNM) stage, molecular subtype, pathological response demonstrated good discrimination (C-index 0.748 training, 0.796 validation cohort), and calibration. Conclusion: The location of residual disease has prognostic implications, with nodal residuals predicting poorer DFS. The validated nomogram enables personalized DFS prediction to guide treatment decisions.

Understanding the impact of residual tumor location on prognosis after breast cancer treatment After receiving neoadjuvant chemotherapy, a treatment to shrink tumors before surgery, some breast cancer patients may still have residual tumor cells. Our study focuses on how the location of these remaining tumors ­ whether in the breast, lymph nodes, or both ­ affects the likelihood of the cancer not returning within the next 1 to 3 years. This likelihood is known as 'disease-free survival' (DFS). We analyzed data from 953 breast cancer patients who underwent neoadjuvant chemotherapy and still had residual tumors. By comparing DFS among patients with tumors remaining in different locations, we discovered that the specific location of the residual tumor significantly impacts the patient's long-term health and recovery. Additionally, we developed a predictive tool called a 'nomogram' to help doctors and patients assess the risk of cancer recurrence in the next 1 to 3 years. This tool considers various factors such as the size and type of the tumor, as well as the location and extent of the residual tumor after chemotherapy. Our research offers new insights into understanding the risk of recurrence after breast cancer treatment. This work not only enhances our comprehension of breast cancer management but also aids in devising more personalized and effective treatment strategies for patients in the future.

Targeted axillary dissection after neoadjuvant chemotherapy for highly selective patients with initial cN1 breast cancer: A single-center prospective trial.

BACKGROUND: Sentinel lymph node (SLN) biopsy is gradually accepted as the standard of care in breast cancer patients with down-staged axillary disease after neoadjuvant chemotherapy (NAC). However, it is still difficult to precisely define pre-NAC clinical node-positive (cN1) and post-NAC clinical node-negative (ycN0). This prospective single-center trial was designed to evaluate the feasibility and accuracy of standard targeted axillary dissection (TAD) after NAC in highly selective pre-NAC cN1 patients (not considering ultrasound-based axillary ycN staging). METHODS: This prospective trial included patients with initial pre-NAC cT1-3N1M0 invasive breast cancer but with a rigorous definition of cN1 from the Affiliated Cancer Hospital of Zhengzhou University. When NAC was effective (including complete and partial responses) and preoperative axillary palpation was negative, preoperative ultrasound-based axillary staging was not considered, and all patients underwent TAD followed by axillary lymph node (LN) dissection. The detection rate (DR) and false-negative rate (FNR) of TAD were calculated. RESULTS: A total of 82 patients were included, and 77 of them were eligible for data analysis. The DR for TAD was 94.8% (73/77). There were 26 patients with one abnormal LN at the time of diagnosis based on ultrasound, 45 patients with two, and 2 patients with three. One patient had one TAD LN, four patients had two TAD LNs, and 68 patients had three or more TAD LNs. Preoperative axillary palpation yielded negative results for all 73 patients who successfully underwent TAD. Preoperative ultrasound-based ycN0 and ycN+ conditions were detected for 52 and 21 cases, respectively. The FNR was 7.4% (2/27) for standard TAD (≥3 SLNs), which was lower than that of all successful TAD (≥1 SLN; 10.0%, 3/30). CONCLUSIONS: In rigorously defined pre-NAC cN1 breast cancer patients, standard TAD is feasible for those with negative axillary palpation after NAC, and FNR is also less than 10%. REGISTRATION: chictr.org.cn , ChiCTR2100049093.

Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases (PERMEATE trial): overall survival results from a multicenter, single-arm, two-cohort, phase 2 trial.

Background: The phase 2 PERMEATE study has shown the antitumor activity and safety of pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases. In this report, survival results were updated with extended follow-up. Methods: Between January 29, 2019 and July 10, 2020, adult patients with HER2-positive metastatic breast cancer who had radiotherapy-naïve brain metastases (cohort A, n = 59) or progressive disease after radiotherapy (cohort B, n = 19) were enrolled and received pyrotinib (400 mg once daily) and capecitabine (1000 mg/m2 twice daily on days 1-14 of each 21-day cycle) until disease progression or unacceptable toxicity. Secondary endpoints progression-free survival (PFS) and overall survival (OS) were updated, and post-hoc central nervous system (CNS)-PFS was analyzed. This study is registered with ClinicalTrials.gov (NCT03691051). Findings: As of February 2, 2023, the median follow-up duration was 30.9 months (interquartile range, 16.1-39.8). Median PFS was 10.9 months (95% confidence interval [CI], 7.6-14.6) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 35.9 months (95% CI, 24.4-not reached) in cohort A and 30.6 months (95% CI, 12.6-33.3) in cohort B. Median CNS-PFS was 13.6 months (95% CI, 9.0-15.8) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 34.1 months (95% CI, 21.7-not reached) for 14 patients with intracranial progression only in cohort A who restarted pyrotinib plus capecitabine after local radiotherapy. Interpretation: These data support further validation in a randomized controlled trial for the assessment of pyrotinib in combination with capecitabine as systemic therapy for patients with HER2-positive breast cancer and brain metastases. Funding: National Cancer Center Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.

Neoadjuvant camrelizumab plus nab-paclitaxel and epirubicin in early triple-negative breast cancer: a single-arm phase II trial.

Immunotherapy combined with chemotherapy has been demonstrated to be effective in early triple-negative breast cancer (TNBC). In this single-arm, phase II study with Simon's two-stage design, we investigated the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy in patients with early TNBC (NCT04213898). Eligible female patients aged 18 years or older with histologically confirmed treatment-naïve early TNBC were treated with camrelizumab (200 mg, on day 1), nab-paclitaxel (125 mg/m2, on days 1, 8, and 15), and epirubicin (75 mg/m2, on day 1) every three weeks for six cycles. The primary end point was the pathological complete response; secondary endpoints included safety, objective response rate, and long-term survival outcomes of event-free survival, disease-free survival, and distant disease-free survival. A total of 39 patients were enrolled between January 2020 and October 2021. Twenty-five patients achieved a pathological complete response (64.1%, 95%CI: 47.2, 78.8). The objective response rate was 89.7% (95%CI: 74.8, 96.7), including 35 patients with partial responses. Treatment-related adverse events of grade 3 or 4 occurred in 30 (76.9%) patients. In conclusion, the trial meets the prespecified endpoints showing promising efficacy and manageable safety of neoadjuvant camrelizumab plus nab-paclitaxel and epirubicin chemotherapy in female patients with early TNBC. Long-term survival outcomes are still pending.

Identification of a novel glycolysis-related prognosis risk signature in triple-negative breast cancer.

Introduction: Triple-negative breast cancer (TNBC) is a particularly aggressive cluster of breast cancer characterized by significant molecular heterogeneity. Glycolysis is a metabolic pathway that is significantly associated with cancer progression, metastasis, recurrence and chemoresistance. However, the potential roles of glycolysis-related genes in TNBC remain unclear. Methods: In the present study, we identified 108 glycolysis-related differentially expressed genes (DEGs) between breast cancer (BRCA) tumor tissues and normal tissues, and we divided patients into two different clusters with significantly distinct molecular characteristics, clinicopathological features, prognosis, immune cell infiltration and mutation burden. We then constructed a 10-gene signature that classified all TNBCs into low- and high-risk groups. Results: The high-risk group had significantly lower survival than the low-risk group, which implied that the risk score was an independent prognostic indicator for TNBC patients. Consequently, we constructed and validated a prognostic nomogram, which accurately predicted individual overall survival (OS) of TNBC. Moreover, the risk score predicted the drug sensitivity of chemotherapeutic agents and immunotherapy for TNBC patients. Discussion: The present comprehensive analysis of glycolysis-related DEGs in TNBC provides new methods for prognosis prediction and more effective treatment strategies.

A novel 12-gene prognostic signature in breast cancer based on the tumor microenvironment.

Background: The progression of breast cancer (BC) is highly dependent on the tumor microenvironment. Inflammation, stromal cells, and the immune landscape have been identified as significant drivers of BC in multiple preclinical studies. Therefore, this study aimed to clarify the predictive relevance of stromal and immune cell-associated genes in patients suffering from BC. Methods: We employed the estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm to calculate the stromal and immunological scores, which were then used to evaluate differentially expressed genes (DEGs) in BC samples using The Cancer Genome Atlas (TCGA) database. Univariate analyses were conducted to identify the DEGs linked to survival in BC patients. Next, the prognostic DEGs (with a log-rank P<0.05) were used to create a risk signature, and the least absolute shrinkage and selection operator (LASSO) regression method was used to analyze and optimize the risk signature. The following formula was used to compute the prognostic risk score values: Risk score = Gene 1 * ß1 + Gene 2 * ß2 +… Gene n * ßn. The median prognostic risk score values were used to divide BC patients into the low-risk (LR) and high-risk (HR) groups. The patient samples of the validation cohort were then assessed using this formula. We used principal component analysis (PCA) to determine the expression patterns of the different patient groups. Gene Set Enrichment Analysis (GSEA) was used to determine whether there were significant variations between the groups in the evaluated gene sets. Results: The present study revealed that DEGs linked with survival were closely associated with immunological responses. A prognostic signature was constructed that consisted of 12 genes (ASCL1, BHLHE22, C1S, CLEC9A, CST7, EEF1A2, FOLR2, KLRB1, MEOX1, PEX5L, PLA2G2D, and PPP1R16B). According to their survival, BC patients were separated into LR and HR groups using the identified 12-gene signature. The immunological status and immune cell infiltration were observed differently in the LR and HR groups. Conclusions: Our results provide novel insights into several microenvironment-linked genes that influence survival outcomes in patients with BC, which suggests that these genes could be candidate therapeutic targets.

Pathological response and predictive role of tumour-infiltrating lymphocytes in HER2-positive early breast cancer treated with neoadjuvant pyrotinib plus trastuzumab and chemotherapy (Panphila): a multicentre phase 2 trial.

PURPOSE: Panphila evaluated pyrotinib plus trastuzumab, docetaxel and carboplatin as neoadjuvant therapy for early breast cancer (BC), and investigated the predictive role of immune cell subpopulations. PATIENTS AND METHODS: In this multicentre phase 2 study, patients with human epidermal growth factor receptor 2-positive, stage T2-3N0-3M0 BC received pyrotinib 400 mg once daily plus docetaxel (75 mg/m2, day 1), carboplatin (6 mg/mL/min, day 1) and trastuzumab (8 mg/kg loading dose and 6 mg/kg maintenance dose, day 1) for 6 cycles of 21 days each. Simon's 2-stage design was adopted. The primary end-point was pathological complete response (pCR, ypT0/is ypN0) rate. Tumour-infiltrating lymphocytes (TILs) were assessed by haematoxylin and eosin staining and multiplex immunohistochemistry. RESULTS: In the modified intention-to-treat population (n = 69), 38 patients (55.1%) achieved pCR. In the safety population (n = 74), the most common grade ≥3 adverse events were diarrhoea (43.2%), anaemia (37.8%), vomiting (16.2%) and platelet count decrease (10.8%). No treatment-related deaths occurred. Analysis of single immune subpopulations revealed a significant association of pCR with higher baseline infiltration by stromal (s)-CD20+, s-CD8+ and s-CD4+ TILs. Unsupervised hierarchical clustering of stromal immune markers identified a group of patients characterised by high s-CD20+, s-CD8+, s-CD4+ and s-FOXP3+ immune cells infiltration, which was independently associated with pCR. CONCLUSION: Neoadjuvant pyrotinib plus trastuzumab-based chemotherapy exhibits promising efficacy and manageable toxicity in patients with human epidermal growth factor receptor 2-positive early BC, and thus phase 3 trials are warranted. Our findings also contribute to understanding the potential role of the immune microenvironment in response to neoadjuvant pyrotinib-based therapy.