Prognosis Of HER2-positive Breast Cancer Research Articles

Association between human epidermal growth factor receptor 2 status, namely low and zero expression, and prognosis in hormone receptor-positive breast cancer: a single-center retrospective study.

The recently developed anti-human epidermal growth factor receptor 2 (HER2) therapy has substantially improved the prognosis of HER2-positive breast cancer. The DESTINY-Breast04 trial results showed that trastuzumab deruxtecan (T-DXd) significantly prolonged the survival of patients with HER2-low breast cancer, thus presenting a paradigm shift in anti-HER2 therapy. This may facilitate a change in the treatment strategy for HER2-low breast cancer. However, the implication of HER2-low in hormone receptor (HR)-positive breast cancer is unclear. In this retrospective study, we aimed to reveal the association between HER2 status, namely HER2-low and HER2-zero, and prognosis in HR-positive breast cancer. We collected the data of 247 patients with estrogen receptor (ER)-positive/HER2-negative breast cancer (159 with HER2-low and 88 with HER2-zero breast cancer) who underwent surgery. Patients were divided into HER2-low and HER2-zero groups. Univariate analysis was performed to evaluate the baseline characteristics using the Wilcoxon rank sum test and Fisher's exact test. Survival analysis of the HER2-low and HER2-zero groups was performed using the Kaplan-Meier method. The median observation period was 2,706 days, and the median period until recurrence was 1,380 days; 25 patients (10%) had recurrences. Age (P=0.004) and menopausal status (P=0.04) were significant variables in the univariate analysis of baseline characteristics. In the subgroup analysis of luminal A- and B-like breast cancers, there was a significant difference in overall survival (OS) only in patients with luminal A-like breast cancer, but relapse-free survival (RFS) of the HER2-low luminal B-like cancer subgroups tended to be relatively short. We inferred that the HER2-low and HER2-zero statuses do not affect the RFS and OS of patients with ER-positive breast cancer. The prognostic significance of HER2-low or HER2-zero status in luminal A- and B-like breast cancers might differ, and a new treatment strategy is required for the HER2-low subgroup.

Ferroptosis biomarkers predict tumor mutation burden's impact on prognosis in HER2-positive breast cancer.

Ferroptosis has recently been associated with multiple degenerative diseases. Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases. However, the association of iron proliferation-related genes with prognosis in HER2+ breast cancer (BC) patients is unclear. To identify and evaluate fresh ferroptosis-related biomarkers for HER2+ BC. First, we obtained the mRNA expression profiles and clinical information of HER2+ BC patients from the TCGA and METABRIC public databases. A four-gene prediction model comprising PROM2, SLC7A11, FANCD2, and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort. Patients were stratified into high-risk and low-risk groups based on their median risk score, an independent predictor of overall survival (OS). Based on these findings, immune infiltration, mutations, and medication sensitivity were analyzed in various risk groupings. Additionally, we assessed patient prognosis by combining the tumor mutation burden (TMB) with risk score. Finally, we evaluated the expression of critical genes by analyzing single-cell RNA sequencing (scRNA-seq) data from malignant vs normal epithelial cells. We found that the higher the risk score was, the worse the prognosis was (P < 0.05). We also found that the immune cell infiltration, mutation, and drug sensitivity were different between the different risk groups. The high-risk subgroup was associated with lower immune scores and high TMB. Moreover, we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses. HRisk-HTMB patients had the worst prognosis, whereas LRisk-LTMB patients had the best prognosis (P < 0.0001). Analysis of the scRNA-seq data showed that PROM2, SLC7A11, and FANCD2 were significantly differentially expressed, whereas FH was not, suggesting that these genes are expressed mainly in cancer epithelial cells (P < 0.01). Our model helps guide the prognosis of HER2+ breast cancer patients, and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.

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

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. 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. 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. 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.

Abstract P2-11-07: Association of PIK3CA mutations with efficacy in HER2-positive first-line metastatic breast cancer: a meta-analysis

Abstract BACKGROUND: PIK3CA mutations have been shown to be associated with poor prognosis in HER2-positive breast cancer (BC). We combined data from three completed Phase III Roche-sponsored randomized trials of HER2-targeted therapy for the first-line treatment of HER2-positive metastatic BC (MBC); this allowed for exploration of the prognostic impact of PIK3CA mutations observed in the three individual trials across subgroups of interest. METHODS: Data from CLEOPATRA (pertuzumab + trastuzumab + docetaxel [PHD] vs. placebo [Pla] + HD; NCT00567190; N = 808), MARIANNE (HD vs. ado-trastuzumab emtansine [K] + Pla vs. K + P; NCT01120184; N = 1095), and PUFFIN (PHD vs. Pla + HD; NCT02896855; N = 243) were included. An individual patient data (IPD) meta-analysis was performed to test the association between PIK3CA mutation status in tumor tissue (mutated vs. wild type [WT]) and efficacy (progression-free and overall survival [PFS/OS]) in different biomarker and clinical subgroups. Confounder adjustment was conducted for age, Eastern Cooperative Oncology Group Performance Status, body mass index, treatment, disease type, and number of metastases (all at baseline). “Study” was included as a random effect in the IPD meta-analysis model to account for variability between studies. A landmark analysis was conducted on fast and non-fast progressors (cutoff of &amp;gt;137 days [i.e., after six chemotherapy cycles]) from CLEOPATRA and PUFFIN only, since they include the current standard-of-care regimens (PHD), by using Day 137 as the landmark time with separate Cox proportional hazards models. RESULTS: PIK3CA mutation data were available for 1905/2146 patients (89%; ~80% from primary tissue); mutation prevalence was 27% (n = 521). PIK3CA-mutated vs. WT in association with PFS in pooled treatment arms is shown in the table. OS data were consistent. CONCLUSIONS: PIK3CA mutations were associated with a worse prognosis across subgroups of interest, including in fast and non-fast progressors, in the two PHD-containing studies as compared with the overall ITT population. Table: PIK3CA-mutated vs. WT in association with PFS in pooled treatment arms Citation Format: Sandra Swain, Javier Cortés, Binghe Xu, Chiara Lambertini, Laurent Essioux, Adam Knott, Eleonora Restuccia, Katrin Madjar, Sanne Lysbet De Haas. Association of PIK3CA mutations with efficacy in HER2-positive first-line metastatic breast cancer: a meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-07.

Abstract P5-02-41: UBE2E3 promotes the progression of HER2-positive breast cancer and influences the efficacy of targeted therapy via EGFR stabilization

Abstract Background: In the past 20 years, the efficacy and prognosis of HER2-positive breast cancer have significantly improved. However, nearly 50% of patients still have residual invasive tumors after chemotherapy combined with dual-targeted neoadjuvant therapy, especially for those with disease progression during treatment. A lack of effective therapeutic regimens results from the failure of targeted therapy, whose heterogeneity is especially worthy of our attention. The aim of this study was to look for efficacy markers and investigate new drug-resistance mechanisms. Methods: Firstly, the high-throughput sequencing data from 81 patients who received neoadjuvant chemotherapy TCbH (paclitaxel + carboplatin + trastuzumab) was analyzed by the efficacy outcomes. They were divided into 8 patients with stable or progressive disease (SD/PD), 35 with partial response (PR), and 38 with pathological complete remission (pCR). Then, UBE2E3 was chosen from the different expression genes between SD/PD and pCR based on efficacy results and the weighted gene co-expression network (WGCNA). UBE2E3 clinical correlations were investigated using publicly available data from The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), and UBE2E3 was validated using immunohistochemistry (IHC) on 200 HER2-positive breast cancer tissue chips. Further, the UBE2E3 knockdown and overexpression stable transfer cell lines were constructed, and the effects of UBE2E3 on cell proliferation, clone formation, and drug sensitivity were verified by live cell imaging, the CCK8 assay, plate cloning, and IC50 assays, respectively. The tumor growth of UBE2E3 in vivo was investigated by an in situ transplantation tumor assay in nude mice. Meanwhile, the p-RB assay of mouse tissues by IHC was used to explore the effect of UBE2E3 on cell proliferation. RNA-seq was used to screen the downstream molecules of UBE2E3. Western blotting was used to verify the results of bioinformatics analysis and to explore the downstream key molecules. The protease inhibitor MG132 and actinomycin CHX were used to look at the effect on the stability of the target protein. Immunoprecipitation and silver staining assays were used to find interacting proteins with the UBE2E3. Results: Ten hub-genes which were efficacy-related were identified by WGCNA analysis, in which UBE2E3 was highly expressed in the SD/PD group (p &amp;lt; 0.05). In HER2-positive breast cancer, high expression of UBE2E3 was associated with poor prognosis and decreased disease-free survival both in public data and Fudan University Shanghai Cancer Center (FUSCC) data [HR 2. 36, (1.25–4.47), p &amp;lt; 0.05]. The experimental results demonstrated that UBE2E3 promoted the proliferation of HER2-positive breast cancer cells, enhanced clone formation, and resisted lapatinib’s treatment in cellular phenotype; and that UBE2E3 promoted tumor growth in vivo and upregulated the expression of p-RB. The differentially expressed genes’ sets of the RNA-seq between overexpressed cell lines and control showed that overexpressing UBE2E3 activated the EGFR pathway. Further, an immunoblot assay confirmed that UBE2E3 positively regulated EGFR levels and activated the downstream MAPK pathway. The proteasome inhibitor MG132 and CHX assays showed that UBE2E3 could stabilize EGFR proteins. The co-immunoprecipitation and silver staining assays showed that UBE2E3 stabilized EGFR proteins by interacting with c-Cbl. Conclusion: UBE2E3 could negatively affect the efficacy of HER2-positive breast cancer therapy and is significantly associated with poor prognosis. UBE2E3 may serve as a potential marker of efficacy and prognosis for HER2-positive breast cancer in the future. Therapeutic efficacy is affected by UBE2E3, which binds to c-Cbl and causes upregulation of EGFR expression in vivo, which in turn causes the MAPK pathway to be activated and tumor growth to be pushed up. Citation Format: Pei Li, Wei-Ru Chi, Bingqiu Xiu, Qi Zhang, Liyi Zhang, Ming Chen, Jingyan Xue, Xiaoyan Huang, Yayun Chi, Jiong Wu. UBE2E3 promotes the progression of HER2-positive breast cancer and influences the efficacy of targeted therapy via EGFR stabilization [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-41.

Abstract P5-02-53: P95HER2 Expression in HER2-Positive Breast Cancer

Abstract Background: -HER2-positive breast cancer subtype accounted for around 15-20% of all breast cancer. -The introduction of HER2-targeted therapy such as trastuzumab and pertuzumab has remarkably increased the patients’ prognosis of HER2-positive breast cancer. -However, resistance exists due to impaired drug binding to HER2 receptor and constitutive activation of HER2 downstream signaling pathways. -P95HER2 isoform is a truncated form of HER2 that retains the C terminal domain but lacks an N terminal trastuzumab binding site, leading to trastuzumab resistance in HER2-positive breast cancer. -A new P95HER2 antibody is developed to target the extracellular domain of p95HER2 in formalin-fixed paraffin-embedded (FFPE) HER2-positive breast cancer tissues by using hematoxylin and eosin (HE) staining method. Objectives: To evaluate the expression of P95HER2 and its clinicopathological characteristics in HER2-positive breast cancer. Methods: We assessed 68 HER2-positive patients (IHC 3+ or IHC 2+/in situ hybridization [ISH]+) from Fudan University Shanghai Cancer Center (FUSCC) who underwent breast cancer surgery and were treated with adjuvant chemotherapy (taxane or anthracycline or combination) plus trastuzumab from 2014 to 2016. P95HER2 HE antibody is provided by Simcere Pharma. In this study, we compared 27 patients with primary trastuzumab resistance with 41 non-relapse breast cancer patients. 14 patients have not received trastuzumab targeted therapy. P95HER2 staining of either 1+, 2+ or 3+ observed in any tumor area in HE slides was considered to be P95 HER2 positive. Chi-square test was used to determine the relationship between P95HER2 expression of patients’ characteristics. The main outcome measures were disease free-survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) by using log-rank test. Univariable and multivariable Cox regression analyses were used to identify independent factors related to prognosis. Results: From 2014 to 2016, we assessed the expression of P95HER2 expression in 68 HER2 positive breast cancer patients from FUSCC. Median follow-up was 45 months. In our study, 19 (27.9%) were P95HER2 positive. P95HER2 positive expression rate is higher in premenopausal patients than in postmenopausal patients (68.4% vs 38.8%, P= 0.028). Univariable analysis showed that higher T-stage (P= 0.018), higher N-stage (P= 0.001) and P95HER2 positive expression (P= 0.033) were associated with worse DDFS. Multivariable analysis showed that higher T-stage (hazard ratio, 6.019; 95% CI, 1.205-30.078; P= 0.029) and P95HER2 positive (hazard ratio, 2.349; 95%CI, 1.03-5.358; P= 0.042) independently predicted worse DDFS. P95HER2 positive was significantly associated with shorter 5-year DDFS (42.1% vs 67.6%, P= 0.028), but has no significant difference in DFS (36.8% vs 59.5%, P= 0.072) and OS (74.8% vs 81.2%, P= 0.685). Conclusions: P95HER2 positive was found more in premenopausal patients and was associated with a higher metastasis rate, indicating that P95HER2 expression tends to be a more aggressive isoform type of HER2-positive breast cancer. P95HER2 may serve as a therapeutic target for anti-HER2 therapy. Citation Format: Chih Wan Goh, Liyi Zhang, Wei-Ru Chi, Bingqiu Xiu, Jiajian Chen, Wenqing Yang, Chunxia Ao, Jianxing Tang, Jingyan Xue, Yayun Chi, Jiong Wu. P95HER2 Expression in HER2-Positive Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-53.

Tumor-Infiltrating Lymphocytes and Immune Response in HER2-Positive Breast Cancer.

Human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer accounts for 15 to 25% of breast cancer cases. Although therapies based on the use of monoclonal anti-HER2 antibodies present clinical benefit for a subtype of patients with HER2-positive breast cancer, more than 50% of them are unresponsive to targeted therapies or they eventually relapse. In recent years, reactivation of the adaptive immune system in patients with solid tumors has emerged as a therapeutic option with great potential for clinical benefit. Since the approval of the first treatment directed against HER2 as a therapeutic target, the range of clinical options has expanded greatly, and, in this sense, cellular immunotherapy with T cells relies on the cytotoxicity generated by these cells, which ultimately leads to antitumor activity. Lymphocytic infiltration of tumors encompasses a heterogeneous population of immune cells within the tumor microenvironment that exhibits distinct patterns of immune activation and exhaustion. The prevalence and prognostic value of tumor-infiltrating lymphocyte (TIL) counts are associated with a favorable prognosis in HER2-positive breast cancers. This review discusses emerging findings that contribute to a better understanding of the role of immune infiltrates in HER2-positive breast cancer. In addition, it summarizes the most recent results in HER2-positive breast cancer immunotherapy and anticipates which therapeutic strategies could be applied in the immediate future.

TP53-positive clones are responsible for drug-tolerant persister and recurrence of HER2-positive breast cancer

The prognosis of HER2-positive breast cancer has improved with the development of anti-HER2 therapies. In order to further improve the prognosis of HER2-positive breast cancer, it is essential to elucidate the cells that survive during the therapy (drug-tolerant persister DTP). Of the 2022 breast cancer patients operated at our institution during 2004-2018, 240 (12%) had HER2-positive breast cancer. Neo-adjuvant chemotherapy including trastuzumab (Tr-NAC) was administered to 94 of them. Forty-six of them were complete remission (CR), and 48 were non-CR. After 6.9 ± 3.7years of follow-up, all 46 CR cases showed no recurrence (Cohort A), and 48 non-CR cases were divided into 31 cases with no recurrence (Cohort B) and 17 cases with recurrence (Cohort C). In addition to clinical backgrounds, we compared genomic profiles for 27 patients (Cohort A; 15/48, B; 7/31, and C; 5/17) who consented to genomic analysis. Genomic abnormalities of TP53 and PIK3CA were frequently observed in biopsy samples pre Tr-NAC, but we found no differences between CR (Cohort A) and non-CR (Cohorts B + C). Then, we examined both of pre and post Tr-NAC samples of Cohort B (7) and C (5) to see the relationship between recurrence and genomic abnormalities. TP53 mutations were significantly more prevalent in Cohort C (5/5, 100%) than cohort B (3/7, 43%) in the surgical sample after treatment (p = 0.04). PyClone analysis of TP53 mutations showed that the cellular frequency of TP53 clones increased in 4 of 5 patients in Cohort C and none of B. On the other hand, we found no enhancement of PIK3CA mutant clones in Cohort C. The DTP after Tr-NAC associated with subsequent relapse had TP53 mutations, suggesting that overcoming DTP with TP53 mutations is the most important clinical challenge. Not applicable.

Risk Factors of Brain Metastasis and Prognosis in HER2-Positive Breast Cancer: A Single-Institution Retrospective Analysis from China.

BackgroundBrain metastasis (BM) frequently occurs in HER2-positive breast cancer (BC) patients, but the risk factors of BM in this type of patients are still unknown. Our study aims to assess the risk factors of BM and prognostic analysis in HER2-positive BC patients.MethodsUnivariate analysis used t-test, chi-square test, and Fisher’s exact test to find out the risk factors for BM, and multivariable analysis was done with stepwise logistic regression analysis. Prognostic data analysis was estimated by the Kaplan–Meier method.ResultsA total of 228 HER2-positive BC patients were included, of whom 214 patients were postoperative metastatic patients and 14 patients were de novo stage IV patients. Through comparing the stratified variables between 51 postoperative metastatic patients with BM and 163 postoperative metastatic patients without BM, the multivariate analysis showed that age ≤40 years (OR 2.321, 95% CI: 1.089 to 4.948) and first metastatic site with lung metastasis (OR 2.168, 95% CI: 1.099 to 4.274) were independent risk factors for BM in HER2-positive BC patients. Prognostic data of all 65 HER2-positive BC patients with BM showed that the time from the diagnosis of BC to the development of breast cancer brain metastasis (BCBM) was 36.3 months (95% CI: 30.0 to 42.1 months). The time from the diagnosis of first recurrence and metastasis stage to the diagnosis of BCBM was 11.35 months (95% CI: 7.1 to 18.4 months). The time from the diagnosis of BCBM to the time of follow-up was 24.1 months (95% CI: 13.9 to 37.5 months). Up until the time of follow-up data, a total of 38 patients had died, and the time from the diagnosis of BM of these 38 patients to death was 11.0 months (95% CI: 9.0 to 20.4 months).ConclusionThe prognosis of HER2-positive BC patients with BM was poor due to the lack of effective treatments for BM. Age ≤40 years and first metastatic site with lung metastasis were the independent risk factors for BM in HER2-positive BC patients. Future research about pre-emptive medical interventions may help to improve the prognosis of HER2-positive BC patients with high risk to develop BM.

Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer.

Anti-HER2 therapies have markedly improved prognosis of HER2-positive breast cancer. However, different mechanisms play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of trastuzumab resistance. AXL orchestrates epithelial-to-mesenchymal transition and heterodimerizes with HER2, leading to activation of PI3K/AKT and MAPK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models. Moreover, AXL expression in HER2-positive primary tumors was able to predict prognosis. Data from the PAMELA trial showed a change in AXL expression during neoadjuvant dual HER2 blockade, supporting its role in resistance. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs across HER2-amplified breast cancer patients with high AXL expression. Furthermore, it unveils the potential value of AXL as a druggable prognostic biomarker in HER2-positive breast cancer.

Impact of financial support on the prognosis of HER2-positive breast cancer from 2002 to 2020: a prospective cohort from western China.

Trastuzumab has significantly improved the outcomes of human epidermal growth factor receptor 2 (HER2)-positive breast cancer over 20 years, and remains a cornerstone of treatment for this subtype today. Higher mortality was reported in underinsured breast cancer, but the mechanism remains unclear. Financial support for trastuzumab has transitioned from no support, to the Breast Cancer Assistant Program (BCAP), and finally, health insurance. Exploring the association between survival outcomes and different financial supports is necessary to further improve the outcomes of HER2-positive breast cancer in resource-limited regions. A prospective cohort of primary early unilateral HER2-positive breast cancer patients registered between January 2002 and December 2020 was used. Patients were divided into the following 3 groups, based on when they were diagnosed with breast cancer: (I) before 2011 (no financial support); (II) 2011-2017 (BCAP support); and (III) 2018 onwards (health insurance support). Overall survival and invasive disease-free survival (iDFS) were the primary outcomes. The follow-up was performed according the standard procedure. Cox proportional hazards regression was used to explore the association between financial support and prognosis with adjustment of demographic and clinicopathological characteristics, and treatments. A total of 2,972 patients were finally identified. During the median follow-up period of 3.9 years, there were 153 breast cancer-related deaths. When fully adjusted potential covariates, patients supported by the BCAP had a 37% [hazard ratio (HR): 0.63, 95% CI: 0.41-0.96] decreased risk of overall mortality and that of patients covered by health insurance had a 64% decreased of overall mortality (HR: 0.36, 95% CI: 0.17-0.74) when compared with those who did not receive any financial support. Lower overall mortality was observed in patients covered by a higher reimbursement rate (HR: 0.68, 95% CI: 0.49-0.94) or the urban scheme (HR: 0.61, 95% CI: 0.43-0.86) than those covered by a lower reimbursement rate or the rural scheme. The same trends were also observed for iDFS and breast cancer-specific survival. Our findings revealed the independent role of financial support in improving the survival outcomes of the HER2-positive breast cancer in resource-limited regions and the underneath mechanism.

Clinical trial data and emerging strategies: HER2-positive breast cancer.

A deeper insight into tumor biology and HER2 signaling has led to the development of novel anti-HER2 drugs that have significantly improved the prognosis of patients with HER2-positive breast cancer. The breast cancer immune microenvironment has emerged as a potential prognostic factor. Moreover, the host immune system not only seems to play a critical role in the prognosis of HER2-positive breast cancer, but also seems to modulate treatment response to some HER2-targeted agents. Here, we review the latest evidence of the role of immunotherapy in HER2-positive breast cancer and present emerging strategies.

Durable Effect of Pyrotinib and Metronomic Vinorelbine in HER2-Positive Breast Cancer With Leptomeningeal Disease: A Case Report and Literature Review.

Leptomeningeal metastases (LM) are rare and catastrophic for metastatic breast cancer (MBC). The prognosis of HER2-positive breast cancer (BC) with LM is extremely poor. There is no high-quality evidence of treatment regimens in HER2-positive BC with LM yet. Here, we present a case of LM in a 50-year-old woman with HER2-positive BC. Immunohistochemistry revealed invasive ductal carcinoma, estrogen receptor negative, progesterone receptor negative, HER2 3+, P53 positive 80%, and Ki-67 positive 35%. Reported for the first time, the patient was given pyrotinib-targeted therapy (400 mg, oral, every day), metronomic vinorelbine (40 mg, oral, three times a week), and intrathecal methotrexate (10 mg, infrequent and irregular use due to poor compliance) synchronously. The patient received and benefited from the treatment regimen for 16 months. And the quality of life, as self-reported, improved significantly. We also comprehensively summarized all the case reports, observational studies, and clinical trials related to HER2-positive BC with LM in the PubMed database and ClinicalTrials.gov. Intrathecal chemotherapy (methotrexate, cytarabine, thiotepa), intrathecal trastuzumab, whole-brain radiotherapy, and systemic therapy are commonly used treatment options according to a review of the literature and research. Pembrolizumab and trastuzumab deruxtecan (DS-8201) as novel drugs are promising in LM. Furthermore, trastuzumab emtansine (T-DM1) and tyrosine kinase inhibitors (TKIs) such as tucatinib and neratinib have exhibited good efficacy in HER2-positive BC with central nervous system (CNS) metastases and deserve further exploration. In our report, combining pyrotinib-targeted therapy with metronomic chemotherapy is a potential regimen, which has presented satisfactory therapeutic efficacy and also warrants additional investigation in HER2-positive BC with LM.

Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis

PurposeRecent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab.MethodsWe collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009–2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting.ResultsOf the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004–3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3+ T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1+-immunosuppressive macrophage density in their primary tumours.ConclusionOur results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.

6-lncRNA Assessment Model for Monitoring and Prognosis of HER2-Positive Breast Cancer: Based on Transcriptome Data.

Background: In view of the high malignancy and poor prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, we analyzed the RNA expression profiles of HER2-positive breast cancer samples to identify the new prognostic biomarkers. Methods: The linear fitting method was used to identify the differentially expressed RNAs from the HER2-positive breast cancer RNA expression profiles in the Cancer Genome Atlas (TCGA). Then, a series of methods including univariate Cox, Kaplan-Meier, and random forests, were used to identify the core long non-coding RNAs (lncRNAs) with stable prognostic value for HER2-positive breast cancer. A clinical feature analysis was performed, and a competing endogenous RNA network was constructed to explore the role of these core lncRNAs in HER2-positive breast cancer. In addition, a functional analysis of differentially expressed messenger RNAs in HER-2 positive breast cancer also provided us with some enlightening insights. Results: The high expression of four core lncRNAs (AC010595.1, AC046168.1, AC069277.1, and AP000904.1) was associated with worse overall survival, while the low expression of LINC00528 and MIR762HG was associated with worse overall survival. The 6-lncRNA model has an especially good predictive power for overall survival (p < 0.0001) and 3-year survival (the area under the curve = 0.980) in HER2-positive breast cancer patients. Conclusion: This study provides a new efficient prognostic model and biomarkers of HER2-positive breast cancer. Meanwhile, it also provides a new perspective for elucidating the molecular mechanisms underlying HER2-positive breast cancer.

Human epidermal growth factor receptor 2 inhibits activating transcription factor 7 to promote breast cancer cell migration by activating histone lysine demethylase 1.

Receptor tyrosine-protein kinase erbB-2 (human epidermal growth factor receptor 2 [HER2])-based therapies can improve the prognosis of HER2-positive breast cancer (BRCA) patients; however, HER2-positive patients with distal metastasis do not gain significant clinical benefit from molecular targeted therapy. A database analysis, immunohistochemistry, and quantitative real-time polymerase chain reaction were used to evaluate the expression of activating transcription factor 7 (ATF7) and its clinical value. A transwell chamber assay was used to assess migration and cell signaling was assessed by immunoblotting. ATF7 was expressed at a low level in HER2-enriched BRCA specimens compared with normal or HER2-negative specimens, which was corroborated in HER2-positive tissue chips and cultured cells. ATF7 gradually decreased with increased tumor stage and low ATF7 was associated with poor prognosis in HER2-positive BRCA patients. ATF7-upregulation inhibited, whereas ATF7-knockdown promoted migration, activity of matrix metalloproteinase 9 (MMP9), MMP2, and uridylyl phosphate adenosine and plasminogen activator inhibitor-1 (PAI-1) expression in HER2-positive cells. HER2 overexpression markedly reduced ATF7 expression in MCF-10A mammary epithelial cells, along with decreased E-cadherin, and increased N-cadherin and migration, which were abrogated by exogenous ATF7 transfection. Mechanistically, HER2 upregulation mediated the decline of ATF7 and activated histone lysine demethylase 1 (LSD1), followed by elevation of histone H3K9 dimethylation (H3K9me2) and H3K4me2. However, the enhanced effects on LSD1 and H3K9me2, excluding H3K4me2, were abrogated by exogenous ATF7. ATF7 was negatively associated with KDM1A (encoding LSD1 protein) expression. ATF7 may be a useful diagnostic and prognostic marker for metastatic HER2-positive BRCA. The ATF7/LSD1/H3K9me2 axis may be responsible for metastasis in HER2-positive cells.

POU4F1 confers trastuzumab resistance in HER2-positive breast cancer through regulating ERK1/2 signaling pathway

Over-expression of the human epidermal growth factor receptor-2 (HER2) is related to aggressive tumors and poor prognosis in breast cancer. Trastuzumab (TRA) resistance leads to tumor recurrence and metastasis, resulting in poor prognosis in HER2-positive breast cancer. POU Class 4 Homeobox 1 (POU4F1) is a member of the POU domain family transcription factors, and has a key role in regulating cancers. However, its effects on TRA-resistant HER2-positive breast cancer are still vague. In the present study, we found that POU4F1 expression was dramatically increased in clinical breast cancer specimens with TRA resistance. Higher POU4F1 was also detected in HER2-positive breast cancer cells with TRA resistance than that of the parental ones. Poor prognosis was detected in breast cancer patients with high POU4F1 expression. Under TRA treatment, POU4F1 knockdown significantly reduced the proliferative capacity of HER2-positive breast cancer cells with TRA resistance. POU4F1 silence also sensitized resistant HER-positive breast cancer cells to TRA treatment in vivo using a xenograft mouse model, along with the markedly reduced tumor growth rate and tumor weight. Moreover, we found that POU4F1 deletion greatly decreased the activation of mitogen-activated or extracellular signal-regulated protein kinase kinases 1 and 2 (MEK1/2) and extracellular-regulated kinase 1/2 (ERK1/2) signaling pathways in breast cancer cells with TRA resistance. Migration and invasion were also effectively hindered by POU4F1 knockdown in TRA-resistant HER2-positive breast cancer cells. Notably, we found that POU4F1 deletion-improved chemosensitivity of HER2-positive breast cancer cells with drug-resistance to TRA treatment was closely associated with the blockage of ERK1/2 signaling. Collectively, our findings reported a critical role of POU4F1 in regulating TRA resistance, and demonstrated the underlying molecular mechanisms in HER2-positive breast cancer. Thus, POU4F1 may be a promising prognostic and therapeutic target to develop effective treatment for overcoming TRA resistance.

Approachment to the Brain Metastasis without Extracranial Metastasis of the HER2 Positive Metastatic Breast Cancer

Introduction: Breast cancer is one of the most common malignancy that metastases to brain with the risk of 10-16%. Brain metastasis has been reported to be more common among younger women with tumors larger diameter and higher grade, hormone negative and HER2 positive ones. We reviewed inhere treatment of patients with brain metastasis without extracranial metastasis of HER-2 positive breast cancer. Patients and Method: Totally 470 HER2 positive breast cancer patients were evacuated and treatment and clinicopathological factors of 20 patients with brain progression without extracranial metastasis were revised retrospectively. Overall survival (OS) and progression free survival (PFS)and related factors were analysed with univariate analysis. Results: Median survival could not to be reached but, 3 years survival rate was 77% and median PFS was 16.1 months. Brain metastasis were treated with surgery followed with radiotherapy among 9 patients (45%) and only with radiotherapy other 11 (55%) patients. While nearly half of the patients received trastuzumab based therapy after local treatment, lapatinib-capecitabine were given to 7 (35%) and TDM-1 to 4 (20%) patients. There is no significant relation with anti-HER2 therapy in respect to OS or PFS. Conclusion: Although anti-HER2 therapy has known to be improve prognosis of HER-2 positive breast cancer with brain metastasis, there is no consensus which therapy is better. Treatment option can be based adverse effect, patient performance or cost-effectiveness until in the future prospectively designed study related the anti-HER2 therapy after local brain therapy will be come up.

Roles of neutrophil/lymphocyte ratio in prognosis and in differentiation of potential beneficiaries in HER2-positive breast cancer with trastuzumab therapy

BackgroundThe relationship of neutrophil/lymphocyte ratio (NLR) to prognosis of HER2-positive breast cancer (BC) is not well studied. We aimed to assess the prognostic role of NLR in HER2-positive BC patients treated with or without trastuzumab.MethodsThe clinical data of 843 HER2-positive BC patients from July 2013 to July 2018 were collected. The difference among variables was calculated by chi-square test. The associations between clinicopathological factors, NLR and disease-free survival (DFS) were analyzed by univariate and multivariate analyses.ResultsPatients were divided into three groups. In group 1 containing 255 patients without trastuzumab treatment, pretreatment NLR showed no predictive value. Patients with trastuzumab treatment were divided into two groups on equal, according to pretreatment NLR values, low NLR (group 2) and high NLR (group 3). Patients in group 2 showed significantly higher 3-year DFS rate than patients in group 1 and group 3 (95.3% vs. 91.6% vs. 90.5%, respectively, P = 0.011); patients in the group 1 and group 3 had a similar 3-year DFS outcome. Multivariate analysis showed high pretreatment NLR was significantly associated with shorter DFS (HR = 2.917, 95% CI = 1.055–8.062, P = 0.039) in HER2-positive BC patients treated with trastuzumab.ConclusionsAmong HER2-positive trastuzumab-treated BC patients, low pretreatment NLR value was associated with better DFS, and it might help to differentiate potential beneficiaries of trastuzumab treatment.

Abstract P5-04-26: Expression of cytotoxic T lymphocyte antigen-4 (CTLA-4) is associated with tumor-infiltrating lymphocytes (TILs) levelin HER2-positive breast cancers

Abstract Though CTLA4 expression was reported in various tumor types, expression of CTLA4 is not well known in breast cancers, especially HER2-positive breast cancers. TILs level has significant role in treatment response and prognosis in HER2-positive breast cancers. Total 167 patients with HER2-positive breast cancers were included. All patients were pre-operatively chemotherapy and radiotherapy naïve. All received adjuvant standard treatment. Histologic TILs evaluation was performed with full face hematoxylin and eosin sections. Immunohistochemistry for CTLA4 was performed with tissue microarray sections. CTLA4 expression was evaluated separately for tumor cells and TILs. Cytoplasmic and/or membranous stains were assessed and human appendix was used as positive control. The intensity and percentage of positivity were evaluated collectively. Immunostaining score was calculated by multiplying percentage of positive cells by staining intensity. Total immunostaining score was obtained by adding tumor cells score and TILs score. Expression level was divided into two categories (low and high) according to mean value. Only 11 patients (6.6%), 47 patients (28.1), and 10 patients (6.0) showed total negative staining for CTLA4 on tumor cells, TILs and both on tumor cells and TILs, respectively. According to mean score on tumor cells, 97 (58.1%) patients showed low level of CTLA4 expression and 70 (41.9%) showed high level of CTLA4 expression. One hundred and two (61.1%) patients had low expression and 65 (38.9%) patients had high expression of CTLA4 on TILs based on the mean value of score of TILs. According to mean value of total score both on tumor cells and TILs, 70 patients (41.9%) were categorized as high expression and 97 patients (58.1%) were categorized as low CTLA4 expression. TILs level, CTLA4 immunostaining score on tumor cells, CTLA4 immunostaining score on TILs, and total CTLA4 immunostaining score on tumor cells and TILs were significantly correlated each other. High expression level of CTLA4 on tumor cells was significantly associated with negative expression of hormone receptor and high TILs level. Also, high CTLA4 expression on TILs significantly correlated with high histologic grade, negative expression of hormone receptor and high TILs level. High level of total CTLA4 expression both on tumor cells and TILs was significantly correlated with negative expression of hormone receptor and high TILs level. However, expression level of CTLA4 was not associated with overall survival and disease-free survival. In conclusions, CTLA4 expression was common in HER2-positive breast cancers and the level of CTLA4 expression was associated with hormone receptor negativity and TILs level in HER2-positive breast cancers. Table 1. Correlation of TILs level, CTLA4 immunostaining score on tumor cells, TILs, and total immunostaining scoreimmunostaining score on tumor cellsimmunostaining score on TILsTotal immunostaining score on tumor cells and TILsTILs level0.254 (&amp;lt;0.001)0.394 (&amp;lt;0.001)0.312 (&amp;lt;0.001)Immunostaining score of CTLA-4 in tumor cells0.565 (&amp;lt;0.001)0.815 (&amp;lt;0.001)Immunostaining score of CTLA-4 in TILs0.783 (&amp;lt;0.001) Table 2. Correlation between CTLA-4 expression and clinicopathologic factorsLowHighLowHighLowHighHistologic grade1.0000.0390.754Low (grade 1, 2)51 (52.6)36 (51.4)60 (58.8)27 (41.5)52 (53.6)35 (50.0)High (grade 3)46 (47.4)34 (48.6)42 (41.2)38 (58.5)45 (46.4)35 (50.0)Necrosis0.3251.0000.325Absent30 (30.9)27 (38.6)35 (34.3)22 (33.8)30 (30.9)27 (38.6)Present67 (69.1)43 (61.4)67 (65.7)43 (66.2)67 (69.1)43 (61.4)Lymphovascular invasion0.7540.2650.754Absent51 (52.6)39 (55.7)51 (50.0)39 (60.0)51 (52.6)39 (55.7)Present46 (47.4)31 (44.3)51 (50.0)26 (40.0)46 (47.4)31 (44.3)Hormone receptor expression0.0120.0400.005Negative37 (38.1)41 (58.6)41 (40.2)37 (56.9)36 (37.1)42 (60.0)Positive60 (61.9)29 (41.4)61 (59.8)28 (43.1)61 (62.9)28 (40.0)TILs level0.001&amp;lt;0.001&amp;lt;0.001≤10%42 (43.3)19 (27.1)50 (49.0)11 (16.9)44 (45.4)17 (24.3)20-60%45 (46.4)29 (41.4)43 (42.2)31 (47.7)43 (44.3)31 (44.3)&amp;gt;60%10 (10.3)22 (31.4)9 (8.8)23 (35.4)10 (10.3)22 (31.4) Citation Format: Ahrong Kim, Jee Yeon Kim, So Jeong Lee. Expression of cytotoxic T lymphocyte antigen-4 (CTLA-4) is associated with tumor-infiltrating lymphocytes (TILs) levelin HER2-positive breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-26.