HER2-Low Status Was Associated With Better Breast Cancer-Specific Survival in Early-Stage Triple-Negative Breast Cancer.

BACKGROUND: Based on the association between the hormone receptor and the status of human epidermal growth factor receptor 2 (HER2)-low, we investigated the clinicopathological and prognostic characteristics of the HER2-low status in early-stage triple-negative breast cancer (TNBC). METHODS: We collected the data of patients with TNBC who received treatment at our hospital and compared the pathological complete response (pCR) rate, overall survival (OS), and breast cancer-specific survival (BCSS) between the HER2-0 and HER2-low subtypes. RESULTS: A total of 1445 patients were included in the study, of which 698 patients (48.3%) showed HER2-low status. A similar pCR rate was observed between HER2-0 and HER2-low patients (34.9% vs. 37.4%; P = .549). T staging, N staging, and HER2 status were associated with BCSS, whereas T staging and N staging were associated with OS. Patients with the HER2-low status showed better BCSS than those with the HER2-0 status (96.6% vs. 93.7%; log-rank P = .027). In patients with non-pCR, the BCSS of the HER2-low subgroup was better than that of the HER2-0 subgroup (log-rank P = .047); however, no similar result was observed in patients with pCR. In patients with stage III, the BCSS and OS of the HER2-low subgroup were better than those of the HER2-0 subgroup (BCSS, log-rank P = .010; OS, log-rank P = .047). No similar results were observed in patients with stages I and II. CONCLUSION: The HER2-low expression was associated with better BCSS in TNBC, especially in the high-risk groups, suggesting that HER2-low breast cancer is a potential independent biological subtype.

Prognostic Value of the Evolution of HER2-Low Expression after Neoadjuvant Chemotherapy.

PURPOSE: Patients with human epidermal growth factor receptor 2 (HER2)-low advanced breast cancer can benefit from trastuzumab deruxtecan. Given the unclear prognostic characteristics of HER2-low breast cancer, we investigated the prognostic characteristics of HER2-low expression from primary tumor to residual disease after neoadjuvant chemotherapy (NACT). MATERIALS AND METHODS: The data of HER2-negative patients receiving NACT at our center were collected. Pathological complete response (pCR) rate were compared between HER2-0 and HER2-low patients. The evolution of HER2 expression from primary tumor to residual disease and its impact on disease-free survival (DFS) were examined. RESULTS: Of the 690 patients, 494 patients had HER2-low status, of which 72.3% were hormone receptor (HR)-positive (p < 0.001). The pCR rates of HER2-low and HER2-0 patients (14.2% vs. 23.0%) showed no difference in multivariate analysis regardless of HR status. No association was observed between DFS and HER2 status. Of the 564 non-pCR patients, 57 (10.1%) changed to HER2-positive, and 64 of the 150 patients (42.7%) with HER2-0 tumors changed to HER2-low. HER2-low (p=0.004) and HR-positive (p=0.010) tumors before NACT were prone to HER2 gain. HER2 gain patients had a better DFS compared with HER2-negative maintained patients (87.9% vs. 79.5%, p=0.048), and the DFS of targeted therapy group was better than that of no targeted therapy group (92.4% vs. 66.7%, p=0.016). CONCLUSION: Although HER2-low did not affect the pCR rate and DFS, significant evolution of HER2-low expression after NACT creates opportunities for targeted therapy including trastuzumab.

Dyslipidemia is associated with a poor prognosis of breast cancer in patients receiving neoadjuvant chemotherapy.

BACKGROUND: Lipid metabolism disorders may be involved in the occurrence and development of breast cancer. This study aimed to investigate the serum lipid changes during neoadjuvant chemotherapy for breast cancer and the effect of dyslipidemia on the prognosis of breast cancer patients. METHODS: We collected the data from 312 breast cancer patients who underwent surgery after receiving standard neoadjuvant therapy. χ2 test and T-test were employed to analyze the effect of chemotherapy on the serum lipid metabolism of patients. The effects of dyslipidemia on the disease-free survival (DFS) of patients with breast cancer were analyzed by χ2 test and COX regression analysis. RESULTS: A total of 56 out of 312 patients (17.9%) suffered from relapse. The baseline serum lipid level of the patients was significantly correlated with their age and body mass index (BMI) (p < 0.05). Chemotherapy increased the levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol, but decreased the level of high-density lipoprotein cholesterol (p < 0.001). Preoperative dyslipidemia was significantly associated with the axillary pCR rate (p < 0.05). COX regression analysis revealed that the full-course serum lipid level (HR = 1.896 [95%CI 1.069-3.360]; p = 0.029), N stage (HR = 4.416 [95%CI 2.348-8.308]; p < 0.001) and the total pCR rate (HR = 4.319 [95%CI 1.029-18.135]; p = 0.046) acted as prognostic factors affecting DFS in breast cancer. The relapse rate in patients with a high level of total cholesterol was higher than that in patients with a high level of triglycerides (61.9% vs 30.0%; p < 0.05). CONCLUSIONS: Dyslipidemia deteriorated after chemotherapy. The full-course serum lipid level may thus serve as a blood marker for predicting breast cancer prognosis. Serum lipids should therefore be closely monitored in breast cancer patients throughout the treatment course, and patients with dyslipidemia should be treated in a timely manner.

Impact of residual disease biomarkers on the prognosis of HER2-positive breast cancer following neoadjuvant therapy.

BACKGROUND: The changes in prognostic factors and clinicopathological characteristics of residual disease following neoadjuvant therapy (NAT) for breast cancer are important references for postoperative adjuvant therapy. The analyses of the relationship between the clinicopathological characteristics of residual diseases and the prognosis were not comprehensive in most previous studies. This study aimed to determine how prognostic factors changed following NAT and the impact of clinicopathological characteristics of residual disease on the prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: The study comprised 350 consecutive patients with HER2-positive breast cancer who had residual disease after surgery following NAT. The independent risk factors affecting the prognosis of HER2-positive breast cancer were analyzed using univariate and multivariate Cox regression analyses. Chi-square test and binary logistic regression were used to analyze the influencing factors of HER2 loss following NAT. RESULTS: The expression of prognostic factors changed significantly following NAT. A total of 44 patients (12.6%) had HER2 loss. HER2 status (immunohistochemistry (IHC) 3+ vs. IHC 2+/FISH+, p < 0.001) at baseline was associated with HER2 loss. In this investigation, the HER2 loss did not affect the prognosis. In univariate analysis, the decrease in Ki-67 (p < 0.001) after NAT was associated with improved prognosis, but this influence was lost in the Cox proportional hazards model. The ypN stage (p < 0.001), postoperative ER status (p = 0.020), Miller-Payne grade (p = 0.007), and targeted therapy (p = 0.003) were all independent prognostic factors. CONCLUSIONS: ER, PR, HER2, and Ki-67 changed significantly after NAT, but no impact of these changes on DFS was observed in this study. Postoperative N stage, postoperative ER status, MP grade, and targeted therapy were independent prognostic factors in patients with HER2-positive breast cancer after NAT.

Exploration of prognostic factors and the value of adjuvant chemotherapy in T1a,bN0M0 triple-negative breast cancer: a prospective cohort study based on the SEER database.

Background: There are limited published studies on the prognostic predictors and the value of adjuvant chemotherapy (CT) in T1a,bN0M0 triple-negative breast cancer (TNBC) after local therapy. Therefore, the aim of the present study was to explore the prognostic predictors and the value of adjuvant CT in this population. Methods: We identified T1a,bN0M0 TNBC cases registered in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. We analyzed associations between patient characteristics and overall survival (OS) and breast cancer-specific mortality (BCSM), and differences in OS and BCSM in a CT and no chemotherapy (no CT) cohort before and after propensity score matching. Results: Of the 3,065 SEER patients, 1,534 (50.0%) received adjuvant CT. The median follow up was 57 months (interquartile range: 39-75 months). The 5-year OS and cumulative BCSM were 93.6% and 3.3%, respectively. Younger age was not associated with lower OS or higher BCSM in the total and no CT cohorts. Higher histologic grade was associated with lower OS in the no CT cohort, and T1b tumors were associated with higher BCSM in the total cohort. Multivariable analysis showed no association between adjuvant CT and OS or BCSM. Conclusions: Patients with T1a,bN0M0 TNBC had an excellent prognosis with or without adjuvant CT. For this population, higher histologic grade and larger tumor size were predictors of poor prognosis, although the effect of age was complex. Our data did not support using adjuvant CT in patients with T1a,bN0M0 TNBC.

Evaluation of whether adjuvant chemotherapy can be safely omitted for older female patients with ER-positive, HER2-negative N1 breast cancer: a study based on the SEER database.

BACKGROUND: This study evaluated the trends and practice patterns associated with adjuvant chemotherapy (CT) use for patients aged ≥70 years with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) N1 (1-3 positive lymph nodes) breast cancer (BC). Furthermore, the relationship between adjuvant CT and survival in this set of patients was determined. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 6,711 women with ER+, HER2- N1 BC who were aged ≥70 years between 2010 and 2015. Demographic, clinical, and pathological predictors of CT use were identified using logistic regression. Multivariable Cox regression was used to identify variables that correlated with overall survival (OS), before and after propensity score matching (PSM). RESULTS: Younger age at diagnosis, other histological types, higher tumor grade, larger tumor size, breast reconstruction surgery, progesterone receptor-negative (PR-), and increased nodal involvement were associated with an increased probability of receiving CT. CT use was associated with improved 5-year OS, both before and after PSM [hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.58-0.75 and HR: 0.81, 95% CI: 0.68-0.96, respectively]. The exploratory subgroup analysis showed that although the benefit of CT was significant in the grade III subgroup, it was not significant in the grades I-II subgroups. CONCLUSIONS: Adjuvant CT improved 5-year OS in patients with ER+, HER2- N1 BC who were aged ≥70 years; however, the benefit of CT was more significant in the grade III subgroup than in the grades I-II subgroups.

Impact of Ipsilateral Supraclavicular Lymph Node Dissection (ISLND) for Breast Cancer Patients and a Nomogram for Predicting Ipsilateral Supraclavicular Pathological Complete Response (ispCR).

BACKGROUND: The purpose of this study was to evaluate the impact of ipsilateral supraclavicular lymph node dissection (ISLND) on the outcomes of breast cancer patients with ipsilateral supraclavicular lymph node metastasis (ISLNM), and to evaluate the prognostic value of ipsilateral supraclavicular pathological complete response (ispCR). Meanwhile, a nomogram was constructed to predict ispCR. METHODS: We retrospectively reviewed the medical documents of 353 patients with ISLNM but no distant metastasis at presentation. Based on whether ISLND was performed, patients were divided into radiotherapy (RT) and ISLND + RT groups. The impact of ISLND was evaluated after propensity score matching, and the prognostic value of ispCR was also analyzed. A nomogram to predict the probability of ispCR was constructed based on clinicopathologic variables. RESULTS: After propensity score matching, we found that the use of ISLND was associated with a higher rate of ipsilateral supraclavicular relapse-free survival (ISRFS; p < 0.0001). Among 307 patients who underwent ISLND, ispCR was associated with a higher rate of ISRFS and disease-free survival (p = 0.018 and p = 0.00033, respectively). Furthermore, the nomogram constructed with number of axillary lymph node metastases, breast pCR, size of the ipsilateral supraclavicular lymph nodes after neoadjuvant chemotherapy (NAC), number of NAC cycles, and Ki67 level showed a good fit for predicting ispCR. CONCLUSION: For breast cancer patients with ISLNM but no distant metastasis, ISLND may be beneficial in some certain subtypes, and ispCR indicated a better prognosis. Our nomogram is well-fitted to predict the probability of achieving ispCR.

Nomogram for Predicting Overall Survival and Assessing the Survival Benefit of Adjuvant Treatment in pT1-2N0M0 Triple-Negative Breast Cancer: A Surveillance, Epidemiology, and End Results-Based Study.

Background: Accurate survival prediction of triple-negative breast cancer (TNBC) is essential in the decision-making of adjuvant treatment. The aim of this prospective study was to develop a nomogram that predicts overall survival and assists adjuvant treatment formulation. Methods: A total of 16,977 patients with pT1-2N0M0 TNBC between 2010 and 2015 from the SEER database were enrolled. Independent prognostic factors associated with overall survival (OS) were identified using univariate and multivariate Cox regression hazards method and utilized to compose the nomogram. The survival benefit of adjuvant treatment on OS were analyzed after stratification by nomogram sum-score. Results: Patients were randomized 7:3 into the training and validation cohorts. Multivariate analysis revealed that age at diagnosis, grade, tumor size, laterality, and mastectomy type were independent prognostic factors of OS and were integrated to develop a nomogram for predicting prognosis. Patients were stratified into 3 prognostic subgroups according to the sum-score of our nomogram. There were no significant differences found in OS between surgery alone and other adjuvant treatment strategies in low risk group. In moderate risk group, patients receiving chemotherapy or the combination of chemotherapy and radiotherapy showed better OS than those receiving surgery alone or radiotherapy alone. For patients in high risk group, the combination of chemotherapy and radiotherapy could maximally improve the overall survival rate of patients. Conclusion: A novel nomogram for OS prediction and risk stratification in patients with pT1-2N0M0 TNBC was developed. This cohort study reveals the prognostic roles of different adjuvant treatment strategies in subgroups, which may provide a reference for the decision-making of postoperative treatment, eventually improving prognosis for individual patients.

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.

Neoadjuvant docetaxel with or without carboplatin plus dual HER2 blockade for HER2-positive breast cancer: a retrospective multi-center Chinese study.

BACKGROUND: This study aimed to compare the real-world efficacy and safety of the TCbHP regimen (docetaxel, carboplatin, trastuzumab and pertuzumab) and the THP regimen (docetaxel, trastuzumab and pertuzumab) as neoadjuvant therapy for Chinese patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. METHODS: We compared efficacy and safety outcomes from 72 Chinese patients with HER2-positive breast cancer who underwent neoadjuvant dual HER2 blockade plus TCb or T chemotherapy and surgery between March 2019 and June 2020. RESULTS: All 72 patients were women (32-76 years old) and the overall pathological complete response (pCR) rate was 70.8% (51/72). The pCR rates were 76.1% (35/46) for the TCbHP regimen and 61.5% (16/26) for the THP regimen (P=0.28). Univariate analyses revealed that pCR was associated with clinical T classification (P=0.024), AJCC stage (P=0.042), estrogen receptor (ER) status (P=0.002), progesterone receptor (PR) status (P=0.035), Ki-67 index (P<0.001), and immunohistochemical HER2 status (P<0.001). Multivariate analyses revealed that pCR was independently predicted by ER status (OR: 0.227, 95% CI: 0.053-0.852; P=0.032) and immunohistochemical HER2 status (OR: 43.673, 95% CI: 6.801-875.86; P<0.001). The common adverse events for both regimens included neutropenia, anemia, thrombocytopenia, nausea, and diarrhea. Relative to the THP group, the TCbHP group had higher frequencies of grade 3-4 thrombocytopenia (17% vs. 0%, P=0.044) and grade 3-4 diarrhea (15% vs. 0%, P=0.044). Both regimens had very good cardiac safety. CONCLUSIONS: These results suggest that both TCbHP and THP regimens may be useful neoadjuvant treatments for high-risk early or locally advanced HER2-positive breast cancer. Both regimens had generally good safety outcomes, although clinicians should be aware of the risks of grade 3-4 thrombocytopenia and diarrhea during TCbHP treatment. Elderly patients who require neoadjuvant therapy may benefit from 6 cycles of THP treatment, based on its good efficacy and mild adverse events.

Long intergenic noncoding RNA 00641 inhibits breast cancer cell proliferation, migration, and invasion by sponging miR-194-5p.

Long noncoding RNAs have an essential role in the tumorigenesis of breast cancer (BC). Nonetheless, the consequences of long intergenic noncoding RNA 00641 (LINC00641) in BC remain unidentified. This study shows that LINC00641 expression level was decreased in BC tissues. LINC00641 expression level was negatively related to tumor size, lymph-node metastasis, as well as clinical stage. LINC00641 overexpression inhibited cell proliferation, migration, and invasion but stimulated apoptosis in BC cells. LINC00641 overexpression also remarkably reduced BC growth and metastasis in vivo. LINC00641 acts as a competitive endogenous RNA to sponge miR-194-5p. miR-194-5p level was higher in BC tissues and cells compared with normal-adjacent tissues and normal breast epithelial cell. miR-194-5p expression was negatively correlated with LINC00641 expression in BC tissues. miR-194-5p overexpression reversed the effects of LINC00641 on cell proliferation, cycle, apoptosis, migration, as well as invasion. In conclusion, LINC00641 inhibits BC cell proliferation, migration, as well as invasion by sponging miR-194-5p.

A dual-targeting liposome conjugated with transferrin and arginine-glycine-aspartic acid peptide for glioma-targeting therapy.

The treatment of a brain glioma remains one of the most difficult challenges in oncology. In the present study a delivery system was developed for targeted drug delivery across the blood-brain barrier (BBB) to the brain cancer cells. A cyclic arginine-glycine-aspartic acid (RGD) peptide and transferrin (TF) were utilized as targeting ligands. Cyclic RGD peptides are specific targeting ligands of cancer cells and TFs are ligands that specifically target the BBB and cancer cells. Liposome (LP) was used to conjugate the cyclic RGD and TFs to establish the brain glioma cascade delivery system (RGD/TF-LP). The LPs were prepared by the thin film hydration method and physicochemical characterization was conducted. In vitro cell uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could target endothelial and tumor cells, as well as penetrate the tumor cells to reach the core of the tumor spheroids. The results of the in vivo imaging further demonstrated that the RGD/TF-LP provided the highest brain distribution. As a result, the paclitaxel-loaded RGD/TF-LP presents the best antiproliferative activity against C6 cells and tumor spheroids. In conclusion, the RGD/TF-LP may precisely target brain glioma, which may be valuable for glioma imaging and therapy.

Predictive role of molecular subtypes in response to neoadjuvant chemotherapy in breast cancer patients in Northeast China.

INTRODUCTION: Breast cancer is increasingly regarded as a heterogeneous disease which can be classified into distinct molecular subtypes with prognostic significance. MATERIALS AND METHODS: ER, PR, HER2 and ki-67 were used to divided 102 breast cancers treated with neoadjuvant chemotherapy (NCT) into 4 subtypes: luminal A (ER+, PR+, HER2-, and ki-67≤14%), luminal B (ER+, PR+, HER2- and ki-67>14% ; ER+ and/or PR+, HER2+), HER2-overexpression (ER-, PR- and HER2+) and triple-negative (ER-, PR-, and HER2-). RESULTS: Among 102 patients, a pCR was seen in 16 (15.7%) patients. The pathologic complete remission (pC) rates according to different subtypes are as follows: luminal A, 0 of 20 (0.0%), luminal B, 2 of 23 (8.7%), HER2-overexpression 4 of 18 (22.2%), and triple-negative, 10 of 41 (24.4%) (p=0.041). In triple-negative subtype patients, the rates of pCR differed significantly among the 3 chemotherapy regimens with 5.6% (1/18) for CEF (cyclophosphamide, epirubicin and flurouracil), 20.0% (1/5) for TE (docetaxel and epirubicin) and 44.4% (8/18) for TCb (docetaxel and carboplatin) (p=0.024). In locally advanced breast cancer patients, the rates of pCR seem to differ among the 3 chemotherapy regimens with 6.7% (2/30) for CEF, 0.0% (0/8) for TE and 23.1% (6/26) for TCb, but this did not attain statistical significance (p>0.05). CONCLUSIONS: Molecular subtypes are good predictors for response to NCT in breast cancer patients in Northeast China. Compared with luminal A tumors, HER2-overexpression and triple-negative subtypes are more sensitive to NCT. For triple-negative breast cancer, we concluded that the TCb combination is a promising NCT regimen. Our results also indicated that the TCb combination is promising for the treatment of locally advanced breast cancer.