PARP Inhibitor for Neoadjuvant Therapy in HER2-Negative Breast Cancer: A Systematic Review and Meta-Analysis of Efficacy and Safety.

Poly-ADP ribose polymerase inhibitor (PARPi) is approved for HER2-negative advanced breast cancer with BRCA1/2 mutation. In recent years, many studies have explored the application of PARPi in neoadjuvant therapy, but failed to reach a unified conclusion. PubMed, Clinicaltrials.gov, Cochrane CENTRAL, Embase, and key oncological meetings for trials were searched for studies reporting neoadjuvant regimens with PARPi in HER2-negative breast cancer. Pathological complete response (pCR), residual cancer burden (RCB), breast-conservation surgery rate (BCSR), clinical response, and adverse events were extracted and pooled in a meta-analysis using the Mantel Haenszel random/fixed effects model. Subgroup analyses of pCR were conducted according to BRCA1/2 status, and hormone receptor (HR) status. Five studies (N = 1223) were included, the addition of PARPi to neoadjuvant regimens significantly increased pCR rates (HR 1.45, 95%CI 1.09-1.92, P = .01, I2 = 86%). In subgroup analysis, the addition of PARPi increased the pCR rate both in HR-positive (n = 383) and HR-negative (n = 431) subgroups, which showed a dominant effect of PARPi regardless of HR status (HR 2.07, 95%CI 1.33-3.23, P = .001, I2 = 0%; HR 1.85, 95%CI 1.39-2.26, P < .0001, I2 = 0%, respectively). However, when we performed a subgroup analysis based on the status of BRCA1/2, no further benefit for PARPi was found. Adverse reactions were generally tolerable. Other outcome indexes, including RCB, clinical response, BCSR, and PARPi did not show a clinical benefit. Regardless of BRCA1/2 status, PARPi in neoadjuvant therapy, can improve the pCR rate of HER2-negative breast cancer, especially in HR-positive patients. Thus, we should have performed larger randomized trials and provided a stronger evidence-based basis.

mTOR inhibitor introduce disitamab vedotin (RC48-ADC) rechallenge microtubule-chemotherapy resistance in HER2-low MBC patients with PI3K mutation.

This study aimed to explore the efficacy and potential mechanisms of rechallenge therapy with microtubule-targeting agents (MTAs) in patients with HER2-low metastatic breast cancer (MBC). We performed a systematic review to investigate the rechallenge treatment concept in the field of HER2-low MBC treatment and utilized a series of cases identified in the literature to illustrate the concept. Here we reported two clinical cases of HER2-low MBC patients whose disease progressed after prior treatment with MTAs such as docetaxel and vincristine. When rechallenged with disitamab vedotin ((RC48-antibody-drug conjugate (ADC), a monomethyl auristatin (MMAE) MTA)), both patients achieved a partial response and the final progression-free survival (PFS) was 13.5 and 9 months, respectively. Genomic profiling detected a PIK3CA H1047R mutation in the patients. The patients were treated with everolimus before being rechallenged with RC48, which may lead to a better response. This study further summarizes and analyzes the potential mechanism of the PI3K-AKT signaling pathway in MTA resistance and reveals that the PIK3CA H1047R mutation may be a potential molecular marker for the efficacy prediction of mTOR inhibitors, providing new insights and potential therapeutic strategies for the application of MTAs to MBC patients.

Axillary lymph node dissection in triple-negative or HER2-positive breast cancer patients with clinical N2 achieving pathological complete response after neoadjuvant therapy: Is it necessary?

AIM: This study aims to identify suitable candidates for axillary sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) among clinical N2 (cN2) triple-negative (TN) or HER2 positive (HER2+）breast cancer patients following neoadjuvant therapy（NAT）. BACKGROUND: Despite the substantial axillary burden in cN2 breast cancer patients, high pathological response rates can be achieved with NAT in TN or HER2+ subtypes, thus enabling potential downstaging of axillary surgery. METHODS: A retrospective analysis was conducted on data from the CSBrS-012 study, screening 709 patients with initial cN2, either HER2+ or TN subtype, from January 1, 2010 to December 31, 2020. The correlation between axillary pathologic complete response (pCR) (yPN0) and breast pCR was examined. RESULTS: Among the 177 cN2 patients who achieved breast pCR through NAT, 138 (78.0 %) also achieved axillary pCR. However, in the 532 initial clinical N2 patients who did not achieve breast pCR, residual axillary lymph node metastasis persisted in 77.4 % (412/532) of cases. The relative risk of residual axillary lymph node metastasis in patients who did not achieve breast pCR was 12.4 (8.1-19.1), compared to those who did achieve breast pCR, P < 0.001. CONCLUSION: For cN2 TN or HER2+ breast cancer patients who achieve breast pCR following NAT, consideration could be given to downstaging and performing an axillary SLNB or TAD.

Comprehensive review of solid tumor bone marrow metastasis.

Bone marrow metastasis (BMM) of solid tumors refers to a group of diseases that originate from non-hematopoietic malignant tumor cells invading the bone marrow (BM) through complex metastatic patterns. If BMM identification is delayed, the disease will rapidly develop into disseminated carcinogenesis of the BM, which manifests as a series of hematological disorders and microangiopathic hemolytic anemia, leading to serious life-threatening conditions. Although the study of solid tumor BMM is receiving increasing attention, study remains limited, and most descriptions are derived from case reports. Currently, clinicians have insufficient understanding of BMM, and BMM occurrence is often not recognized early or treated effectively, resulting in high mortality rates. In this article, we review the epidemiology, molecular mechanisms, clinical diagnosis, treatment, and prognosis of solid tumor BMM.

Nomogram for predicting axillary upstaging in clinical node-negative breast cancer patients receiving neoadjuvant chemotherapy.

PURPOSE: The prediction of axillary lymph node status after neoadjuvant chemotherapy (NAC) becoming critical because of the advocation of the de-escalation of axillary management. We investigate associated factors of axillary upstaging in clinical node-negative (cN0) breast cancer patients receiving NAC to develop and validate an accurate prediction nomogram. METHODS: We retrospectively analyzed 1892 breast cancer patients with stage of cT1-3N0 treated by NAC and subsequent surgery between 2010 and 2020 in twenty hospitals across China. Patients randomly divided into a training set and validation set (3:1). Univariate and multivariate logistic regression analysis were performed, after which a nomogram was constructed and validated. RESULTS: In total, pathologic node negativity (ypN0) achieved in 1406 (74.3%) patients and another 486 (25.7%) patients upstaged to pathologic node positive (ypN+). Breast pathologic complete response (bpCR) was achieved in 445 (23.5%) patients and non-bpCR in 1447 (76.5%) patients. A nomogram was established by ER, tumor histology, HER2 status, cycle of NAC treatment, and the bpCR, which were confirmed by multivariate logistic analysis as independent predictors of nodal upstaging in the training cohort (n = 1419). The area under the receiver operating characteristic curve (AUC) of the training cohort and validation cohort (n = 473) were 0.73 (95% CI 0.693-0.751) and 0.77 (95% CI 0.723-0.812) respectively. CONCLUSION: We present a nomogram with a nationwide large sample data which can effectively predict axillary upstaging after neoadjuvant chemotherapy to give better advice for individualized axillary lymph node management of breast cancer.

Efficacy analysis of neoadjuvant chemotherapy with or without anthracyclines in female patients with HER2-positive breast cancer in China: a nationwide, multicenter, 10-year retrospective study (CSBrS-012).

Background: In the era of targeted therapy, whether patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are exempted from anthracycline usage in the neoadjuvant setting is controversial. Objectives: Our objective was to retrospectively analyze the differences in pathological complete remission (pCR) rates between the anthracycline group and the nonanthracycline group. Design: The CSBrS-012 study (2010-2020) included female primary breast cancer patients with neoadjuvant chemotherapy (NAC) who underwent standard breast and axillary surgery post-NAC. Methods: A logistic proportional hazard model was applied to estimate the association of covariates with pCR. Propensity score matching (PSM) was performed to balance the differences in baseline characteristics, and subgroup analyses were performed using the Cochran-Mantel-Haenszel test. Results: A total of 2507 patients were enrolled: the anthracycline group (n = 1581, 63%) and the nonanthracycline group (n = 926, 37%). A pCR was recorded in 17.1% (271/1581) of patients in the anthracycline group and in 29.3% (271/926) in the nonanthracycline group, and the difference in the pCR rate between the two groups was statistically significant [odds ratio (OR) = 2.00, 95% confidence interval (CI) (1.65-2.43); p < 0.001). In the subsequent subgroup analysis, substantial differences in pCR rates between the anthracycline and nonanthracycline groups were detected in the nontargeted [OR = 1.91, 95% CI (1.13-3.23); p = 0.015] and dual-HER2-targeted populations [OR = 0.55, 95% CI (0.33-0.92); p = 0.021) before PSM, whereas differences vanished after PSM. The pCR rates between the anthracycline and nonanthracycline groups did not differ for the single target population, either before or after PSM. Conclusion: In the presence of trastuzumab and/or pertuzumab, the pCR rate of patients with HER2-positive breast cancer receiving anthracycline was not superior to that of patients receiving nonanthracycline. Thus, our study further provides clinical evidence for exempting anthracycline treatment in HER2-positive breast cancer in the era of targeted therapy.

The Notch Signaling Pathway Contributes to Angiogenesis and Tumor Immunity in Breast Cancer.

Breast cancer in women is the first leading tumor in terms of incidence worldwide. Some subtypes of BC lack distinct molecular targets and exhibit therapeutic resistance; these patients have a poor prognosis. Thus, the search for new molecular targets is an ongoing challenge for BC therapy. The Notch signaling pathway is found in both vertebrates and invertebrates, and it is a highly conserved in the evolution of the species, controlling cellular fates such as death, proliferation, and differentiation. Numerous studies have shown that improper activation of Notch signaling may lead to excessive cell proliferation and cancer, with tumor-promoting and tumor-suppressive effects in various carcinomas. Thus, inhibitors of Notch signaling are actively being investigated for the treatment of various tumors. The role of Notch signaling in BC has been widely studied in recent years. There is a growing body of evidence suggesting that Notch signaling has a pro-oncogenic role in BC, and the tumor-promoting effect is largely a result of the diverse nature of tumor immunity. Immunological abnormality is also a factor involved in the pathogenesis of BC, suggesting that Notch signaling could be a target for BC immunotherapies. Furthermore, angiogenesis is essential for BC growth and metastasis, and the Notch signaling pathway has been implicated in angiogenesis, so studying the role of Notch signaling in BC angiogenesis will provide new prospects for the treatment of BC. We summarize the potential roles of the current Notch signaling pathway and its inhibitors in BC angiogenesis and the immune response in this review and describe the pharmacological targets of Notch signaling in BC, which may serve as a theoretical foundation for future research into exploring this pathway for novel BC therapies.

A systematic review and meta-analysis of BRCA1/2 mutation for predicting the effect of platinum-based chemotherapy in triple-negative breast cancer.

INTRODUCTION: Platinum-based chemotherapy (PBC) remains the mainstay of treatments for triple-negative breast cancer (TNBC). TNBC is a heterogeneous group, the issue of whether BRCA1/2 mutation carriers have a particular sensitivity to platinum agents is inconclusive. We conducted a meta-analysis to explore the relationship between BRCA1/2 mutation and PBC susceptibility in individuals with TNBC, aiming to gain more information on the size of the benefit of PBC in BRCA1/2 mutation carriers. MATERIALS AND METHODS: All studies applying PBC with a subgroup of BRCA1/2 status were included. All endpoints, including pCR and RCB in the neoadjuvant phase, DFS in the adjuvant phase, ORR, PFS, and OS in the advanced phase, were assessed using HRs and 95% Cl. RESULTS: From the 22 studies included, there were 2158 patients with TNBC, with 392 (18%) bearing the BRCA1/2 gene mutation. Based on 13 studies applying neoadjuvant PBC, we discovered that BRCA1/2 mutation was substantially associated with a 17.6% increased pCR rate (HR 1.32, 95% CI 1.17-1.49, p < 0.00001; I2 = 51%). Same result was observed in RCB0/I index (HR 1.38, 95% CI 1.08-1.76, P = 0.009; I2 = 0%). The meta-analysis of 6 trials addressing advanced therapy revealed that ORR rates were significantly higher in patients with BRCA1/2 mutation (HR 1.91, 95% CI 1.48-2.47, p < 0.00001; I2 = 32%), as well as PFS(HR 1.13, 95% CI 0.81-1.57, P = 0.47; I2 = 0%) and OS (HR 1.89, 95% CI 1.22-2.92, P = 0.004; I2 = 0%). CONCLUSION: According to our meta-analysis of 22 trials in TNBC, BRCA1/2 mutation carriers were significantly more sensitive to PBC regimens, especially in neoadjuvant and advanced therapy.

Prognostic value of baseline genetic features and newly identified TP53 mutations in advanced breast cancer.

Approximately 30% of breast cancer (BC) patients suffer from disease relapse after definitive treatment. Monitoring BC at baseline and disease progression using comprehensive genomic profiling would facilitate the prediction of prognosis. We retrospectively studied 101 BC patients ultimately experiencing relapse and/or metastases. The baseline and circulating tumor DNA-monitoring cohorts included patients with baseline tumor tissue and serial plasma samples, respectively. Samples were analyzed with targeted next-generation sequencing of 425 cancer-relevant genes. Of 35 patients in the baseline cohort, patients with TP53 mutations (P < 0.01), or CTCF/GNAS mutations (P < 0.01) displayed inferior disease-free survival, and patients harboring TP53 (P = 0.06) or NOTCH1 (P = 0.06) mutations showed relatively poor overall survival (OS), compared to patients with wild-type counterparts. Of the 59 patients with serial plasma samples, 11 patients who were newly detected with TP53 mutations had worse OS than patients whose TP53 mutational status remained negative (P < 0.01). These results indicate that an inferior prognosis of advanced breast cancer was potentially associated with baseline TP53, CTCF, and NOTCH1 alterations. Newly identified TP53 mutations after relapse and/or metastasis was another potential prognostic biomarker of poor prognosis.

Salvia chinensis Benth Inhibits Triple-Negative Breast Cancer Progression by Inducing the DNA Damage Pathway.

Objective: Triple-negative breast cancer (TNBC) is distinguished by early recurrence and metastases, a high proclivity for treatment resistance, and a lack of targeted medicines, highlighting the importance of developing innovative therapeutic techniques. Salvia chinensis Benth (SCH) has been widely studied for its anticancer properties in a variety of cancers. However, its significance in TNBC treatment is rarely discussed. Our study investigated the anticancer effect of SCH on TNBC and the underlying mechanisms. Methods: First, we used clonogenic, cell viability, flow cytometry, and Transwell assays to assess the effect of SCH on TNBC. Bioinformatic studies, especially network pharmacology-based analysis and RNA sequencing analysis, were performed to investigate the constituents of SCH and its molecular mechanisms in the suppression of TNBC. High-performance liquid chromatography and thin-layer chromatography were used to identify two major components, quercetin and ß-sitosterol. Then, we discovered the synergistic cytotoxicity of quercetin and ß-sitosterol and assessed their synergistic prevention of cell migration and invasion. Breast cancer xenografts were also created using MDA-MB-231 cells to test the synergistic therapeutic impact of quercetin and ß-sitosterol on TNBC in vivo. The impact on the DNA damage and repair pathways was investigated using the comet assay and Western blot analysis. Results: Our findings showed that SCH decreased TNBC cell growth, migration, and invasion while also inducing cell death. We identified quercetin and ß-sitosterol as the core active components of SCH based on a network pharmacology study. According to RNA sequencing research, the p53 signaling pathway is also regarded as a critical biological mechanism of SCH treatment. The comet assay consistently showed that SCH significantly increased DNA damage in TNBC cells. Our in vivo and in vitro data revealed that the combination of quercetin and ß-sitosterol induced synergistic cytotoxicity and DNA damage in TNBC cells. In particular, SCH particularly blocked the inter-strand cross-link repair mechanism and the double-strand breach repair caused by the homologous recombination pathway, in addition to inducing DNA damage. Treatment with quercetin and ß-sitosterol produced similar outcomes. Conclusion: The current study provides novel insight into the previously unknown therapeutic potential of SCH as a DNA-damaging agent in TNBC.

TMEM158 Regulates the Canonical and Non-Canonical Pathways of TGF-ß to Mediate EMT in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer with high metastatic potential. To date, no directed treatment options have been developed for the treatment of metastatic or advanced TNBC. The oncogene TMEM158, also known as RIS1, is upregulated by Ras-induced cellular senescence. Although TMEM158 has been shown to be involved in tumor progression, little is known about the molecular function and expression of TMEM158 in breast cancer. The present study evaluated the expression and prognostic relevance of TMEM158 in breast cancer patients from several databases. Gene set enrichment analysis (GSEA) showed that TMEM158 was closely associated with epithelial-mesenchymal transition (EMT) and TGF-ß pathways. Gain- and loss-of-function assays indicated that overexpressed TMEM158 might participate in EMT by activating the TGF-ß pathway, which in turn promotes tumor migration, invasion, and metastasis. These findings suggest that TMEM158 has the potential to become a new therapeutic target for TNBC.

A novel treatment strategy of HER2-targeted therapy in combination with Everolimus for HR+/HER2- advanced breast cancer patients with HER2 mutations.

The incidence of HER2 somatic mutations in breast cancer is about 2-4%, mainly occurring in the HR+/HER2- subtype. Preclinical studies suggest that HER2 mutations can lead to constitutive HER2 activation, but effective treatment options for the clinical management of patients with HER2 mutations remain obscure. Our study analyzed HER2 mutation status by performing next-generation sequencing using tumor tissues and over 300 plasma samples from 72 metastatic breast cancer patients. We observed that two patients bearing HER2 mutations (Patient #1 bearing S310F and V777L mutations, Patient #2 bearing 778insGSP mutation) achieved a durable partial response to Trastuzumab combined with Everolimus. In vitro experiments showed that T47D and MCF7 cells overexpressing these HER2 mutants (S310F, V777L, 778insGSP and L755S) were sensitive to HER2-targeted therapies combined with the mTOR inhibitor Everolimus. These findings provide a treatment option for patients with HER2 mutations by combining HER2-targeted therapies with Everolimus.

A potential role for metastasis-associated in colon cancer 1 (MACC1) as a pan-cancer prognostic and immunological biomarker.

BACKGROUND: Metastasis-Associated in Colon Cancer 1(MACC1) is a validated biomarker for metastasis and is linked to survival. Although extensive experimental evidence indicates an association between MACC1 and diverse cancers, no pan-cancer analyses have yet been performed for this marker, and the role of MACC1 in immunology remains unknown. MATERIAL AND METHODS: In our study, we performed the analysis of MACC1 expression and its influence on prognosis using multiple databases, including TIMER2, GEPIA2, Kaplan-Meier plotter. MACC1 promoter methylation levels were evaluated using the UALCAN database. Based on the TCGA database, we explored the relationship between MACC1 and tumor mutational burden (TMB), microsatellite instability (MSI), immune checkpoints using the R programming language. We evaluated the association between MACC1 and immune infiltration via TIMER and UALCAN. RESULTS: Our results revealed that abnormal DNA methylation may be an important cause for the different expression of MACC1 across cancer types. Meanwhile, we explored the potential oncogenic roles of MACC1 and found significant prognostic value. MACC1 may be related to T-cell function and the polarization of tumor-associated macrophages, especially in STAD and LGG. Its expression was associated with immune infiltration and was found to be closely related to immune checkpoint-associated genes, especially CD274 and SIGLEC15, indicating that MACC1 may be a potential immune therapeutic target for several malignancies. Our paper reveals for the first time the relationship between MACC1 and cancer immunology. CONCLUSIONS: MACC1 might act as a predictor for the immune response in cancer patients, and could also represent a new potential immunotherapeutic target.

Identification of differentially expressed genes-related prognostic risk model for survival prediction in breast carcinoma patients.

Since the imbalance of gene expression has been demonstrated to tightly related to breast cancer (BRCA) genesis and growth, common genes expressed of BRCA were screened to explore the essence in-between. In current work, most common differentially expressed genes (DEGs) in various subtypes of BRCA were identified. Functional enrichment analysis illustrated the driving factor of deactivation of the cell cycle and the oocyte meiosis, which critically triggers the development of BRCA. Herein, we constructed a 12-gene prognostic risk model relative to differential gene expression. Subsequently, the K-M curves, analysis on time-ROC curve and Cox regression were performed to assess this risk model by determining the respective prognostic value, and the prediction performance were ascertained for both training and validation cohorts. In addition, multivariate Cox regression was analysed to reveal the independence between risk score and prognostic stage, and the accuracy and sensitivity of prognosis are particularly improved after clinical indicators are included into the analysis. In summary, this study offers novel insights into the imbalance of gene expression within BRCA, and highlights 12 selected genes associated with patient prognosis. The risk model can help individualize treatment for patients at different risks, and propose precise strategies and treatments for BRCA therapy.

Correction: Oct-4 and Nanog promote the epithelial-mesenchymal transition of breast cancer stem cells and are associated with poor prognosis in breast cancer patients.

[This corrects the article DOI: 10.18632/oncotarget.2506.].

Breast cancer organoids from malignant pleural effusion-derived tumor cells as an individualized medicine platform.

Malignant pleural effusion (MPE) presents a severe medical condition in patients with advanced breast cancer (BC). We applied organoid culture technology to culture preoperative puncture specimen and corresponding surgical specimen-derived tumor cells from early BC patients and pleural effusion-derived tumor cells from advanced BC patients with MPE to study whether in vitro models could predict therapies of clinical patients. We successfully expanded pleural effusion-derived tumor organoids from 1 advanced triple-negative breast cancer (TNBC) patient with MPE which had been continuously propagated for more than 3 months. The organoids matched the histological characteristics of primary BC and metastatic supraclavicular lymph nodes by H&E staining and retained negative expression of TNBC biomarkers: estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and positive expression of antigen Ki-67. Multiple mutations were detected from this advanced TNBC patient with MPE by high-throughput sequencing of metastatic supraclavicular lymph node and the plasma sample. We performed the 3D drug screening tests combined with the clinical medication situation of this patient. The pleural effusion-derived tumor organoids were sensitive to capecitabine (IC50 1.580 µmol) and everolimus (IC50 4.008 µmol) single-agent treatments. The sensitivity to capecitabine was consistent with the clinical treatment response of this patient for capecitabine and with the sequencing results that reported MTHFR gene polymorphism mutation and TYMS -6bp/-6bp polymorphism mutation indicating effectiveness to fluorouracil. Our results suggested that an effective platform for ex vivo pleural effusion-derived tumor organoids from advanced TNBC patients with MPE could be used to identify treatment options and explore the clinicopathological characteristics of these patients.

Clinical characteristics and clinicopathological correlations of bilateral breast cancer in China: A multicenter study from Chinese Society of Breast Surgery (CSBrS-006).

OBJECTIVE: To investigate the clinical characteristics and clinicopathological correlations of bilateral breast cancer (BBC) in China. METHODS: Data of 440 patients diagnosed with BBC in 2018 were collected from 33 centers of the Chinese Society of Breast Surgery. Demographic characteristics, bilateral tumor characteristics, and comprehensive treatment data were obtained. Correlations between the clinicopathological characteristics of bilateral tumors were analyzed. RESULTS: The proportion of BBC was 0.22%-3.08%. A total of 33 (7.5%) patients had a family history of malignant tumors, 304 (69.1%) patients had synchronous BBC. Only 1 (0.2%) patient was male. More than half of all patients received concurrent or asynchronous endocrine/chemotherapy, 32.5% of all human epidermal growth factor receptor 2 (HER2)-positive patients received HER2-targeted therapy, and approximately 21.6% of all patients received radiotherapy. The most common pathological cancer type was invasive ductal cancer (>60%). Approximately 70% of all patients had bilateral hormone receptor (HR)-positive tumors and presented with a single breast mass. Significant correlations were found with pathological type, histological grade, locations of tumor, molecular subtype, Ki-67 index, tumor site and size of bilateral tumors. Results of the subgroup analysis showed more clinicopathological characteristics when synchronous BBC was compared with metachronous BBC. CONCLUSIONS: In China, the clinicopathological characteristics of bilateral tumors showed significant correlations, and more significant clinicopathological correlations were observed when synchronous BBC was compared with metachronous BBC.