Biological Roles and Clinical Applications of Exosomes in Breast Cancer: A Brief Review.

Breast cancer (BC) is a global health risk for women and has a high prevalence rate. The drug resistance, recurrence, and metastasis of BC affect patient prognosis, thus posing a challenge to scientists. Exosomes are extracellular vesicles (EVs) that originate from various cells; they have a double-layered lipid membrane structure and contain rich biological information. They mediate intercellular communication and have pivotal roles in tumor development, progression, and metastasis and drug resistance. Exosomes are important cell communication mediators in the tumor microenvironment (TME). Exosomes are utilized as diagnostic and prognostic biomarkers for estimating the treatment efficacy of BC and have the potential to function as tools to enable the targeted delivery of antitumor drugs. This review introduces recent progress in research on how exosomes influence tumor development and the TME. We also present the research progress on the application of exosomes as prognostic and diagnostic biomarkers and drug delivery tools.

Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial.

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.

Feasibility of a mobile health app-based self-management program for Chinese patients with breast cancer receiving chemotherapy: A randomized controlled pilot study.

Objective: There are currently an increasing number of mobile health (mHealth) programs offered to patients with breast cancer undergoing chemotherapy, but their rate of adherence to app usage has remained low. This study aimed to examine the feasibility of an mHealth app-based program such as the adherence rate of app usage and determine the preliminary effects on self-efficacy, quality of life, symptom burden and healthcare utilization in these patients. Methods: We conducted a randomized controlled pilot trial. Ninety-six participants were randomly allocated into either an intervention group or a control group (routine care plus a placebo app). The intervention group engaged in a 6-week self-regulation activity and received nurse-led social support via the app. The intention-to-treat principle was adopted. The generalized estimating equation was utilized to analyze the between-group, within-group and interaction effectiveness of this program. Results: Totally 96 participants were enrolled from 16 May to 23 August 2022. The average rate of adherence to app usage increased from 4.8% at week 3 to 51.2% at week 6. There was a statistically significant reduction in the physiological efficacy scores of the intervention (p < .001) and control groups (p < .001) at week 6, compared with the baseline. At week 6, the intervention group reported a significantly lower symptom burden (p = .042) and significantly better physical well-being than the control group (p = .024). Conclusions: It is feasible to perform an mHealth app-based self-management program for patients with breast cancer receiving chemotherapy. Nurses can utilize this program to facilitate patient self-management of symptoms during chemotherapy. Registration: Clinicaltrials.gov, https://clinicaltrials.gov, (NCT05192525).

Anti-HER2 therapy response assessment for guiding treatment (de-)escalation in early HER2-positive breast cancer using a novel deep learning radiomics model.

OBJECTIVES: Anti-HER2 targeted therapy significantly reduces risk of relapse in HER2 + breast cancer. New measures are needed for a precise risk stratification to guide (de-)escalation of anti-HER2 strategy. METHODS: A total of 726 HER2 + cases who received no/single/dual anti-HER2 targeted therapies were split into three respective cohorts. A deep learning model (DeepTEPP) based on preoperative breast magnetic resonance (MR) was developed. Patients were scored and categorized into low-, moderate-, and high-risk groups. Recurrence-free survival (RFS) was compared in patients with different risk groups according to the anti-HER2 treatment they received, to validate the value of DeepTEPP in predicting treatment efficacy and guiding anti-HER2 strategy. RESULTS: DeepTEPP was capable of risk stratification and guiding anti-HER2 treatment strategy: DeepTEPP-Low patients (60.5%) did not derive significant RFS benefit from trastuzumab (p = 0.144), proposing an anti-HER2 de-escalation. DeepTEPP-Moderate patients (19.8%) significantly benefited from trastuzumab (p = 0.048), but did not obtain additional improvements from pertuzumab (p = 0.125). DeepTEPP-High patients (19.7%) significantly benefited from dual HER2 blockade (p = 0.045), suggesting an anti-HER2 escalation. CONCLUSIONS: DeepTEPP represents a pioneering MR-based deep learning model that enables the non-invasive prediction of adjuvant anti-HER2 effectiveness, thereby providing valuable guidance for anti-HER2 (de-)escalation strategies. DeepTEPP provides an important reference for choosing the appropriate individualized treatment in HER2 + breast cancer patients, warranting prospective validation. CLINICAL RELEVANCE STATEMENT: We built an MR-based deep learning model DeepTEPP, which enables the non-invasive prediction of adjuvant anti-HER2 effectiveness, thus guiding anti-HER2 (de-)escalation strategies in early HER2-positive breast cancer patients. KEY POINTS: • DeepTEPP is able to predict anti-HER2 effectiveness and to guide treatment (de-)escalation. • DeepTEPP demonstrated an impressive prognostic efficacy for recurrence-free survival and overall survival. • To our knowledge, this is one of the very few, also the largest study to test the efficacy of a deep learning model extracted from breast MR images on HER2-positive breast cancer survival and anti-HER2 therapy effectiveness prediction.

An exosome-based specific transcriptomic signature for profiling regulation patterns and modifying tumor immune microenvironment infiltration in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor that lacks effective treatment and has a poor prognosis. Exosomes carry abundant genomic information and have a significant role in tumorigenesis, metastasis, and drug resistance. However, further exploration is needed to investigate the relationship between exosome-related genes and the heterogeneity and tumor immune microenvironment of TNBC. Based on the exosome-related gene sets, multiple machine learning algorithms, such as Cox boost, were used to screen the risk score model with the highest C-index. A 9-gene risk score model was constructed, and the TNBC population was divided into high- and low-risk groups. The effectiveness of this model was verified in multiple datasets. Compared with the low-risk group, the high-risk group exhibited a poorer prognosis, which may be related to lower levels of immune infiltration and immune response rates. The gene mutation profiles and drug sensitivity of the two groups were also compared. By screening for genes with the most prognostic value, the hub gene, CLDN7, was identified, and thus, its potential role in predicting prognosis, as well as providing ideas for the clinical diagnosis, treatment, and risk assessment of TNBC, was also discussed. This study demonstrates that exosome-related genes can be used for risk stratification in TNBC, identifying patients with a worse prognosis. The high-risk group exhibited a poorer prognosis and required more aggressive treatment strategies. Analysis of the genomic information in patient exosomes may help to develop personalized treatment decisions and improve their prognosis. CLDN7 has potential value in prognostic prediction in the TNBC population.

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study.

p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations (P = 0.037) and poor overall survival (OS) (P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

Safety analysis of immediate breast reconstruction with a deep inferior epigastric perforator (DIEP) flap in the post-COVID-19 era: a comparison between pre- and post-pandemic cohorts.

Background: The demand for immediate breast reconstruction with a deep inferior epigastric perforator (DIEP) flap is recovering as coronavirus disease 2019 (COVID-19) transitions from a pandemic to an endemic. This study sought to evaluate the safety of resuming DIEP flap reconstruction in the post-COVID-19 era. Methods: Consecutive breast cancer patients who underwent immediate breast reconstruction with a DIEP flap at the Comprehensive Breast Health Center, Ruijin Hospital were retrospectively included in the study. The patients were divided into a post-pandemic group (Group A) and a pre-pandemic group (Group B). The clinicopathological factors, surgical procedures, and rates of post-operative complications were compared between the two groups using the Mann-Whitney U test and Chi-squared test. Results: A total of 167 patients were included in the study, of whom 119 (71.3%) were in Group A and 48 (28.7%) were in Group B. The two groups had similar clinicopathological features, including age (P=0.988), body mass index (P=0.504), and tumor, node, metastasis (TNM) stage (P=0.932). The Group A patients were more likely to receive single perforator DIEP flap transplantation than the Group B patients (n=28, 22.8% vs. n=3, 5.8%, P=0.007). There was a numerical decrease in the mean operating time of Group A patients compared to Group B patients (9.82 vs. 10.12 hours, P=0.172). The mean length of stay after the surgery was significantly shorter after the pandemic than before the pandemic (11.2 vs. 14.3 days, P<0.001). The complication rates between the two groups were similar. Conclusions: This study provides evidence that resuming DIEP reconstruction is safe in the post-COVID-19 era.

Tumor size is associated with adjuvant chemotherapy benefit in T1N0M0 triple-negative breast cancer: a multicenter and propensity score matched analysis.

Background: Triple-negative breast cancer (TNBC) is characterized by aggressive phonotypes and relatively poor outcomes. There are controversies on the effect of adjuvant chemotherapy in small (T1N0M0) TNBCs, especially among T1a-b patients. This study evaluated the survival benefit of adjuvant chemotherapy and influential factors in T1N0M0 TNBC patients. Methods: All T1N0M0 TNBC patients were identified from the Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB) between January 2009 and December 2021. Propensity score matched (PSM) was applied to create a matched cohort. We used Kaplan-Meier analysis and Cox regression models to evaluate the associations of adjuvant chemotherapy with breast cancer-free interval (BCFI) and overall survival (OS). Stratified analysis according to different influential factors was also performed. Results: In total, 1,113 T1N0M0 TNBC patients (297 T1a, T1b and 816 T1c) were enrolled, including 928 patients with adjuvant chemotherapy and 185 patients without adjuvant chemotherapy. After matching 441 patients by using PSM analysis, 294 patients with chemotherapy and 147 patients without chemotherapy were identified. Patients with or without chemotherapy had similar BCFI (P=0.241) and OS (P=0.509). However, regarding patients with different tumor sizes, adjuvant chemotherapy could significantly improve BCFI in T1c patients (5-year BCFI: 92.1% vs. 79.5%, P=0.035) but not in T1a-b patients (5-year BCFI: 93.6% vs. 94.6%, P=0.546). No significant difference in OS was observed among patients with different tumor sizes. Subgroup analysis found that only tumor size was significantly associated with adjuvant chemotherapy benefit in terms of BCFI (Pinteraction=0.021) and OS (Pinteraction=0.040). Conclusions: The survival benefit of adjuvant chemotherapy was significantly associated with tumor size in T1N0M0 TNBC. Benefit of adjuvant chemotherapy was found in T1c, but not in T1a-b patients. Our findings do not support the routine use of chemotherapy in patients with T1a-bN0 TNBC.

Two-carbon tethered artemisinin-isatin hybrids: design, synthesis, anti-breast cancer potential, and in silico study.

Eleven two-carbon tethered artemisinin-isatin hybrids (4a-k) were designed, synthesized, and evaluated for their antiproliferative activity against MCF-7, MDA-MB-231, and MDA-MB-231/ADR breast cancer cell lines, as well as cytotoxicity toward MCF-10A cells in this paper. Among them, the representative hybrid 4a (IC50: 2.49-12.6 µM) was superior to artemisinin (IC50: 72.4->100 µM), dihydroartemisinin (IC50: 69.6-89.8 µM), and Adriamycin (IC50: 4.46->100 µM) against the three tested breast cancer cell lines. The structure-activity relationship revealed that the length of the alkyl linker between artemisinin and isatin was critical for the activity, so further structural modification could focus on evaluation of the linker. The in silico studies were used to investigate the mechanism of the most promising hybrid 4a. Target prediction, bioinformatics, molecular docking, and molecular dynamics revealed that the most promising hybrid 4a may exert anti-breast cancer activity by acting on multiple targets such as EGFR, PIK3CA, and MAPK8 and thus participating in multiple tumor-related signaling pathways.

Targeting cancer-associated adipocyte-derived CXCL8 inhibits triple-negative breast cancer progression and enhances the efficacy of anti-PD-1 immunotherapy.

Cancer-associated adipocytes (CAAs), one of the primary stromal components, exhibit intimate crosstalk and release multiple cell factors mediating local and systemic biological effects. However, the role of CAAs in the regulation of systemic immune responses and their potential value in the clinical treatment of triple-negative breast cancer (TNBC) are not well described. Transcriptome sequencing was performed on CAA and normal adipocyte (NA) tissues isolated from surgically resected samples from TNBC patients and healthy controls. Cytokines, including C-X-C motif chemokine ligand 8 (CXCL8, also known as IL-8), secreted from NAs and CAAs were compared by transcriptome sequencing and enzyme-linked immunosorbent assay (ELISA). Proliferation, migration and invasion assays were employed to analyze the role of CAAs and CAA-derived CXCL8 (macrophage inflammatory protein-2 (MIP2) as a functional surrogate in mice). TNBC syngraft models were established to evaluate the curative effect of targeting CXCL8 in combination with anti-PD-1 therapies. Real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), polymerase chain reaction (PCR) array, flow cytometry, immunohistochemistry (IHC), and immunofluorescence (IF) were applied to analyze immune cell infiltration and epithelial-mesenchymal transition (EMT) markers. Specifically, we demonstrated that CAAs and CAA-derived CXCL8 played important roles in tumor growth, EMT, metastasis and tumor immunity suppression. CAA-derived CXCL8 remodeled the tumor immune microenvironment not only by suppressing CD4+ T and CD8+ T immune cell infiltration but also by upregulating CD274 expression in TNBC. The combination of targeting the CXCL8 pathway and blocking the PD-1 pathway synergistically increased the tumor immune response and inhibited tumor progression. Thus, our results highlight the molecular mechanisms and translational significance of CAAs in tumor progression and immune ecosystem regulatory effects and provide a better understanding of the potential clinical benefit of targeting CAA-derived CXCL8 in antitumor immunity and as a new therapeutic moiety in TNBC.

Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC. Methods: In this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification. Results: We found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression. Conclusions: Hence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC.

Pathological complete response, category change, and prognostic significance of HER2-low breast cancer receiving neoadjuvant treatment: a multicenter analysis of 2489 cases.

BACKGROUND: HER2-low breast cancers (BC) show a good response to novel anti-HER2 antibody-drug conjugates (ADCs) in advanced setting. Nevertheless, little is known about the response, category change, and prognosis of HER2-low BC receiving neoadjuvant treatment (NAT). METHODS: Consecutive invasive BC patients who underwent ≥ 4 cycles of NAT and surgery from January 2009 to December 2020 were retrospectively reviewed. HER2-low was defined as IHC 1+ or 2+ and FISH negative. Concordance rates of HER2 and other biomarkers were analyzed by Kappa test. Kaplan-Meier analysis and Cox regression were used to assess the recurrence-free interval (RFI) and overall survival (OS). RESULTS: A total of 2489 patients were included, of whom 1023 (41.1%) had HER2-low tumors. HER2-low patients had a higher ER positivity rate than HER2-0 patients (78.5% vs. 63.6%, P < 0.001), and a similar breast pathological complete response (pCR) rate (20.6% vs. 21.8%, P = 0.617). Among non-pCR cases, 39.5% of HER2-0 tumors changed to HER2-low, and 14.3% of HER2-low tumors changed to HER2-0 after NAT. Low concordance rates of HER2-low status were found in both ER-positive (Kappa = 0.368) and ER-negative (Kappa = 0.444) patients. Primary HER2-low patients had a significantly better RFI than HER2-0 patients (P = 0.014), especially among ER-positive subset (P = 0.016). Moreover, HER2-low category change was associated with RFI in ER-positive subset (adjusted P = 0.043). CONCLUSIONS: Compared with HER2-0 patients, HER2-low patients had a high proportion of ER-positive tumor and a similar pCR rate, which were related with better prognosis, especially in residual cases after NAT. A remarkable instability of HER2-low status was found between the primary and residual tumor, indicating re-testing HER2 status after NAT in the new era of anti-HER2 ADCs therapy.

The anti-breast cancer potential of indole/isatin hybrids.

Breast cancer (BC) is one of the most prevalent malignancies and the major contributor to cancer mortality in women globally, with a high degree of heterogeneity and a dismal prognosis. As drug resistance is responsible for most BC fatalities and advanced BC is currently considered incurable, finding innovative anti-BC chemotherapeutics is urgently required. Indole and its analog isatin (indole-1H-2,3-dione) are prominent pharmacophores in the development of novel medications, and their derivatives exhibit strong anticancer activities, also against BC. In particular, indole/isatin hybrids exhibit significant potency against BC including multidrug-resistant forms and excellent selectivity by influencing a variety of biological targets associated with the disease, supplying helpful building blocks for the identification of potential new BC treatment options. This review includes articles from 2020 to the present and provides insights into the in vitro and in vivo anti-BC potential, molecular mechanisms, and structure-activity relationships (SARs) of indole/isatin hybrids that may be helpful in the development of innovative anti-BC chemotherapeutics.

Association between insulin resistance and cardiac remodeling in HER2-positive breast cancer patients: a real-world study.

BACKGROUND: Insulin resistance is an overlapping risk factor for both heart and breast cancer, while its interaction with cardiotoxicity in breast cancer (BC) patients is not clear. This study investigated the impact of insulin resistance on cardiac remodeling in patients with human epidermal growth factor receptor 2 (HER2)-positive BC during and after trastuzumab therapy in real-world clinical practice. METHODS: HER2-positive BC patients who received trastuzumab treatment between December 2012 and December 2017 were reviewed and 441 patients with baseline metabolic indices and serial echocardiographic measurements (baseline, 6, 12, and 18 months) after trastuzumab therapy initiation were included. Repeated measurement analysis of variance was used to evaluate temporal trends in multiparameter echocardiography. Linear mixed model was applied to further evaluate the role of insulin resistance in forementioned changes. Correlation of homeostasis model assessment-estimated insulin resistance (HOMA-IR) and triglyceride-glucose index (TyG) levels to changes in echocardiography parameters was explored. RESULTS: Of 441 patients (mean age 54 ± 10 [SD] years), 61.8% received anthracycline-based chemotherapy, 33.5% received left-sided radiotherapy, 46% received endocrine therapy. No symptomatic cardiac dysfunction was observed over the therapy course. A total of 19 (4.3%) participants experienced asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), and the peak onset time was 12 months after the initiation of trastuzumab. Albeit relatively low CTRCD incidence, cardiac geometry remodeling, especially left atrial (LA) dilation over therapy was notable and was more severe in high HOMA-IR and TyG level groups (P < 0.01). Noteworthy, a partial reversibility of cardiac remodeling was observed with treatment cessation. Additionally, HOMA-IR level positively correlated to changes in LA diameter from baseline to 12 months (r = 0.178, P = 0.003). No significant association (all P > 0.10) was detected between HOMA-IR or TyG level and dynamic left ventricular parameter evaluation. Multivariate linear regression analysis demonstrated that higher HOMA-IR level was an independent determinant for LA enlargement in BC patients during anti-HER2 targeted therapy course after adjusting for confounding risk factors (P = 0.006). CONCLUSION: Insulin resistance was associated with left atrial adverse remodeling (LAAR) in HER2-positive BC patients that received standard trastuzumab therapy, indicating that insulin resistance could be a supplementation to baseline cardiovascular risk stratification proforma for HER2-targeted antitumor therapies.

Time interval between breast cancer diagnosis and surgery is associated with disease outcome.

Time interval between breast cancer (BC) diagnosis and surgery is of concern to patients and clinicians, but its impact on survival remains unclear. We identified 5130 BC patients receiving surgery between 2009 and 2017 from the Shanghai Jiaotong University Breast Cancer Database (SJTU-BCDB), and divided as Ruijin cohort and SJTU cohort. All participants were divided into three groups according to the interval between diagnosis and surgery: ≤ 1 week, 1-2 weeks, and > 2 weeks. Among 3144 patients of Ruijin cohort, the estimated 5-year breast cancer-free interval (BCFI) rates for the ≤ 1 week, 1-2 weeks and > 2 weeks groups were 91.8%, 87.5%, and 84.0% (P = 0.088), and the estimated 5-year overall survival (OS) rates were 95.6%, 89.6%, and 91.5% (P = 0.002). Multivariate analysis showed that patients with a TTS > 2 weeks had significantly lower BCFI (HR = 1.80, 95%CI 1.05-3.11, P = 0.034) and OS (HR = 2.07, 95% CI 1.04-4.13, P = 0.038) rates than patients with a TTS ≤ 1 week. Among 5130 patients when combining Ruijin cohort with SJTU cohort, the estimated 5-year BCFI rates for the ≤ 1 week, 1-2 weeks, and > 2 weeks groups were 91.0%, 87.9%, and 78.9%, and the estimated 5-year OS rates for the ≤ 1 week, 1-2 weeks, and > 2 weeks groups were 95.8%, 90.6%, and 91.5%, both with a significantly p value < 0.001. Our findings demonstrated the prolonged time to surgery (more than 2 weeks) after BC diagnosis was associated with poor disease outcomes, suggesting that efforts to early initiate treatment after diagnosis need to be pursued where possible to improve survival.

Clinical characteristics, tumor-infiltrating lymphocytes, and prognosis in HER2-low breast cancer: A comparison study with HER2-zero and HER2-positive disease.

INTRODUCTION: HER2-low breast cancer is a gradually recognized and unexplored group of diseases. We aimed to investigate the clinical and prognosis features and to identify the role of stromal tumor-infiltrating lymphocytes (sTILs) in this population. METHODS: Consecutive primary breast cancer patients treated between January 2009 to June 2013 were retrospectively reviewed. HER2-low was defined as immunohistochemistry (IHC) 1+, or 2+ and fluorescence in situ hybridization (FISH) negative. sTILs were scored following the international guidelines. Clinicopathologic features and survival were compared according to HER2 and sTILs category. RESULTS: A total of 973 breast cancer patients were enrolled, including 615 (63.2%) HER2-low patients. HER2-low patients shared more similarity with HER2-0 cases in clinicopathological features. sTILs in HER2-Low patients was comparable to HER2-0 patients (p = 0.064), both significantly lower than HER2-positive ones (p < 0.001). Meanwhile, tumors with sTILs ≥50% accounted for the least proportion of HER2-low cases (p < 0.001). HER2 status had no significant influence on recurrence-free survival (RFS, p = 0.901) in the whole population. However, in the estrogen receptor (ER)-negative subgroup, HER2-low was related to worse RFS (p = 0.009) and OS (p = 0.001) compared with HER2-positive ones. sTILs increment was an independent favorable prognostic factor in the whole (OS, p = 0.003; RFS, p = 0.005) and HER2-low population (OS, p = 0.007; RFS, p = 0.009) after adjusted to clinicopathological parameters. CONCLUSIONS: HER2-low patients shared similar clinicopathological features with HER2-0 rather than HER2-positive cases and had relatively low sTILs. ER-negative/HER2-low patients had significantly inferior survival. sTILs increment was independently associated with favorable survival in the HER2-low group, suggesting a potential benefit from a novel treatment strategy.

Single-cell atlas reveals a distinct immune profile fostered by T cell-B cell crosstalk in triple negative breast cancer.

BACKGROUND: Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy. However, the unique features of the immune microenvironment of triple negative breast cancer (TNBC) compared with other subtypes of breast cancer remain elusive. Therefore, we aimed to depict and compare the immune landscape among TNBC, human epidermal growth factor receptor 2-positive (HER2+ ) breast cancer, and luminal-like breast cancer. METHODS: Single-cell RNA sequencing (scRNA-seq) was performed on CD45+ immune cells isolated from human normal breast tissues and primary breast tumors of various subtypes. By analyzing the scRNA-seq data, immune cell clusters were identified and their proportions as well as transcriptome features were compared among TNBC, human HER2+ breast cancer, and luminal-like breast cancer. Pseudotime and cell-cell communication analyses were also conducted to characterize the immune microenvironment. RESULTS: ScRNA-seq data of 117,958 immune cells were obtained and 31 immune clusters were identified. A unique immunosuppressive microenvironment in TNBC was decoded as compared to that in HER2+ or luminal-like breast cancer, which was characterized by higher proportions of regulatory T cells (Tregs) and exhausted CD8+ T cells and accompanied by more abundant plasma cells. Tregs and exhausted CD8+ T cells in TNBC exhibited increased immunosuppression signature and dysfunctional scores. Pseudotime analyses showed that B cells tended to differentiate to plasma cells in TNBC. Cell-cell communication analyses indicated that these unique features are fostered by the diversified T cell-B cell crosstalk in TNBC. Based on the T cell-B cell crosstalk, a prognostic signature was established that could effectively predict the prognosis status for patients with TNBC. Additionally, it was found that TNBC had a higher proportion of cytotoxic natural killer (NK) cells, whereas HER2+ or luminal-like breast cancer lost this feature, suggesting that HER2+ or luminal-like breast cancer, but not TNBC, may benefit from NK-based immunotherapy. CONCLUSIONS: This study identified a distinct immune feature fostered by T cell-B cell crosstalk in TNBC, which provides better prognostic information and effective therapeutic targets for breast cancer.

Association of serum lipid levels and clinical outcomes in early breast cancer patients.

Background: The association between dyslipidaemia and breast cancer remains controversial, especially regarding the dynamic changes in lipid levels. Objectives: This study aimed to elucidate the role of serum lipid levels and the changes in disease outcomes in patients with breast cancer. Methods: The lipid profiles of patients with breast cancer who underwent surgery between 2013 and 2017 were retrospectively reviewed. The lipid profiles comprised triglyceride (TG), total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein. Serum lipid levels were categorized into three groups based on the tertiles. The Wilcoxon test was used to compare changes in serum lipid levels during follow-up. Hazard ratios (HRs) for survival outcomes were estimated using a multivariate Cox regression analysis. Results: A total of 3499 women diagnosed with nonmetastatic invasive breast cancer were included in this study, with a median follow-up of 60.4 months. We confirmed that each 1-tertile increased TG at baseline [HR = 1.19, 95% confidence interval (CI) 1.02-1.39] and 1-year follow-up (HR = 1.46, 95% CI 1.07-1.98) led to worse relapse-free survival (RFS). A lower risk of disease relapse was observed with each 1-tertile upregulation in HDL at 1-year follow-up (HR = 0.72, 95% CI 0.56-0.92). Receiving systemic therapies tends to induce an elevation in plasma lipid levels 1 year after surgery, especially in terms of TG. Regarding the prognostic value of dynamic changes in lipid levels, patients with sustained high levels of TG had poorer RFS (HR = 1.90, 95% CI 1.16-3.11), whereas maintaining high levels of HDL led to better survival (HR = 0.60, 95% CI 0.37-0.97). Conclusion: High TG at baseline and during follow-up was associated with worse disease outcome in early breast cancer patients. Systemic treatment would lead to an elevation of serum lipid levels. Patients with sustained high HDL level at 1-year follow-up after surgery had a superior prognosis, warranting further clinical evaluation.

A senescence-associated signature refines the classification of different modification patterns and characterization of tumor immune microenvironment infiltration in triple-negative breast cancer.

Background: Recent studies have found that senescence-associated genes play a significant role in cancer biological processes. We aimed to analyze the characteristics and role of senescence-associated genes in triple-negative breast cancer (TNBC). Methods: We systematically screened senescence-associated secretory phenotype (SASP) genes based on the gene expression information in the TCGA database. According to the expression levels of senescence-associated genes, TNBC was classified into two subtypes, namely, TNBCSASP1 and TNBCSASP2, using an unsupervised cluster algorithm. We then performed gene expression, enrichment pathway, immune infiltration, mutational profile characterization, drug sensitivity and prognostic value analyses for the two subtypes. The reliability and prognostic predictive utility of this classification model were validated. The most prognostically relevant gene, FAM3B, was comprehensively identified and validated by tissue microarray in TNBC. Results: TNBC was classified into two senescence-associated subtypes, TNBCSASP1 and TNBCSASP2, based on the set of senescence-associated secretory phenotype genes, among which the TNBCSASP1 subtype had a poor prognosis. The TNBCSASP1 subtype was immunosuppressed, with suppressed immune-related signaling pathways and low immune cell infiltration. The effect of the mutation on the TP53 and TGF-ß pathways could be related to the poor prognosis of the TNBCSASP1 subtype. Drug sensitivity analysis showed that AMG.706, CCT007093, and CHIR.99021 were potential targeted drugs for the TNBCSASP1 subtype. Finally, FAM3B was a key biomarker affecting the prognosis of patients with triple-negative breast cancer. Compared to normal breast tissue, the expression of FAM3B was reduced in triple-negative breast cancer. Survival analysis showed that overall survival was significantly shorter in triple-negative breast cancer patients with high FAM3B expression. Conclusion: A senescence-associated signature with different modification patterns has critical potential for providing a better understanding of TNBC biological processes, and FAM3B might serve as an applicable target for TNBC therapy.