Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases.

BACKGROUND: Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups. METHODS: We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44. RESULTS: Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin. CONCLUSIONS: The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. (Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov number, NCT02240472.).

Exploring the clinical outcomes and safety profile of inetetamab treatment in metastatic breast cancer patients: A multicenter assessment of a Chinese-origin recombinant Anti-HER2 monoclonal antibody.

BACKGROUND: Inetetamab is a novel recombinant humanized anti-HER2 monoclonal antibody. This study aimed to evaluate the efficacy and safety of inetetamab and predictive factors for response in HER2-positive metastatic breast cancer (MBC) patients. METHODS: A cohort of HER2-positive MBC patients who received inetetamab-based therapy between June 2020 and August 2021 was evaluated. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Adverse events (AEs) were graded according to the National Cancer Institute Common Toxicity Criteria. RESULTS: A total of 141 patients were included in the final analysis. The median PFS of the entire cohort was 7.1 months. The median number of treatment lines administered was three. The ORR was 36.9 %, and the DCR was 80.9 %. The most frequently employed treatment strategy was inetetamab + chemotherapy (49/141, 34.8 %), followed by inetetamab + HER2-tyrosine kinase inhibitors (HER2-TKIs) + chemotherapy, inetetamab + pertuzumab + chemotherapy, inetetamab + endocrine treatment and inetetamab + HER2-TKIs. Cox multivariate analysis revealed that PFS was associated with liver metastasis (hazard ratio [HR] 2.112, 95 % confidence interval [CI] 1.334-3.343, p = 0.001), previous HER2-TKI treatment (HR 2.019, 95 % CI 1.133-3.597, p = 0.017) and estrogen receptor positivity (HR 0.587, 95 % CI 0.370-0.934, p = 0.024). The toxicity was tolerable, with neutropenia being the most common treatment-related grade 3/4 AE (14.9 %). CONCLUSION: Inetetamab demonstrates effectiveness with a manageable safety profile, offering a promising therapeutic option for HER2-positive breast cancer patients who have shown resistance to prior anti-HER2 treatments.

Breast metastases from non-primary breast malignancies: What should we know?

BACKGROUND: Metastases from extramammary malignant neoplasms are very rare, accounting for less than 2% of all breast malignancies. OBJECTIVE: The aim of this study is to describe the clinicopathological features and prognosis of breast metastases from non-primary breast malignancies at our institution. METHODS: We performed a retrospective observational study, obtaining data from electronic medical records and pathology databases between January 1985 and December 2020 for patients diagnosed with breast metastasis from non-primary breast malignancies. Only patients diagnosed by biopsy were included. RESULTS: Fifteen patients diagnosed with breast metastases from non-primary breast malignancies were included, 13 women (86,67%) and 2 men (13,33%). The median age at time of initial diagnosis was 56 years (IQR 21-68). The most frequent primary malignancy was melanoma (9/15; 60%). The median time to diagnosis of breast metastases was 65 months (IQR 13-106). The most common diagnostic modality was CT-scan (10/15; 66,67%). The median follow-up was 96 months (IQR 29-136). Eight patients underwent surgery (53,3%), being the most common surgical intervention breast-conserving surgery (5/8; 62,5%). Mortality at the end of follow-up was 53,3% (8/15). On the survival analysis, we found no differences between patients undergoing surgery and those only receiving systemic treatment [41,5 months (IQR 17,5-57,5) versus 14 months (IQR 2-24), respectively; p = 0,161]. CONCLUSIONS: Breast metastases from non-primary breast malignancies are extremely rare and represent a diagnostic and therapeutic challenge, due to the poor prognosis of these patients. Thus, arriving at the correct diagnosis is crucial to avoid unnecessary treatment in this population.

Palliative care utilization and racial and ethnic disparities among women with de novo metastatic breast cancer in the United States.

PURPOSE: The potential disparities in palliative care delivery for underrepresented minorities with breast cancer are not well known. We sought to determine whether race and ethnicity impact the receipt of palliative care for patients with metastatic breast cancer (MBC). METHODS: We retrospectively reviewed the National Cancer Database for female patients diagnosed with stage IV breast cancer between 2010 and 2017 who received palliative care following diagnosis of MBC to assess the proportion of patients who received palliative care, including non-curative-intent local-regional or systemic therapy. Multivariable logistic regression analysis was performed to identify variables associated with receiving palliative care. RESULTS: 60,685 patients were diagnosed with de novo MBC. Of these, only 21.4% (n = 12,963) received a palliative care service. Overall, there was a positive trend in palliative care receipt from 18.2% in 2010 to 23.0% in 2017 (P < 0.001), which persisted when stratified by race and ethnicity. Relative to non-Hispanic White women, Asian/Pacific Islander women (aOR 0.80, 95% CI 0.71-0.90, P < 0.001), Hispanic women (adjusted odds ratio [aOR] 0.69, 95% CI 0.63-0.76, P < 0.001), and non-Hispanic Black women (aOR 0.94, 95% CI 0.88-0.99, P = 0.03) were less likely to receive palliative care. CONCLUSIONS: Fewer than 25% of women with MBC received palliative care between 2010 and 2017. While palliative care has significantly increased for all racial/ethnic groups, Hispanic White, Black, and Asian/Pacific Islander women with MBC still receive significantly less palliative care than non-Hispanic White women. Further research is needed to identify the socioeconomic and cultural barriers to palliative care utilization.

Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood–brain barrier and treatment strategies

Breast cancer (BC) is one of the most prevalent types of cancer in women. Despite advancement in early detection and efficient treatment, recurrence and metastasis continue to pose a significant risk to the life of BC patients. Brain metastasis (BM) reported in 17–20 percent of BC patients is considered as a major cause of mortality and morbidity in these patients. BM includes various steps from primary breast tumor to secondary tumor formation. Various steps involved are primary tumor formation, angiogenesis, invasion, extravasation, and brain colonization. Genes involved in different pathways have been reported to be associated with BC cells metastasizing to the brain. ADAM8 gene, EN1 transcription factor, WNT, and VEGF signaling pathway have been associated with primary breast tumor; MMP1, COX2, XCR4, PI3k/Akt, ERK and MAPK pathways in angiogenesis; Noth, CD44, Zo-1, CEMIP, S0X2 and OLIG2 are involved in invasion, extravasation and colonization, respectively. In addition, the blood–brain barrier is also a key factor in BM. Dysregulation of cell junctions, tumor microenvironment and loss of function of microglia leads to BBB disruption ultimately resulting in BM. Various therapeutic strategies are currently used to control the BM in BC. Oncolytic virus therapy, immune checkpoint inhibitors, mTOR-PI3k inhibitors and immunotherapy have been developed to target various genes involved in BM in BC. In addition, RNA interference (RNAi) and CRISPR/Cas9 are novel interventions in the field of BCBM where research to validate these and clinical trials are being carried out. Gaining a better knowledge of metastasis biology is critical for establishing better treatment methods and attaining long-term therapeutic efficacies against BC. The current review has been compiled with an aim to evaluate the role of various genes and signaling pathways involved in multiple steps of BM in BC(AU)

Integrative competing endogenous RNA network analyses identify novel lncRNA and genes implicated in metastatic breast cancer.

Competing endogenous RNAs (ceRNAs) have gained attention in cancer research owing to their involvement in microRNA-mediated gene regulation. Previous studies have identified ceRNA networks of individual cancers. Nevertheless, none of these studies has investigated different cancer stages. We identify stage-specific ceRNAs in breast cancer using the cancer genome atlas data. Moreover, we investigate the molecular functions and prognostic ability of ceRNAs involved in stage I-IV networks. We identified differentially expressed candidate ceRNAs using edgeR and limma R packages. A three-step analysis was used to identify statistically significant ceRNAs of each stage. Survival analysis and functional enrichment analysis were conducted to identify molecular functions and prognostic ability. We found five genes and one long non-coding RNA unique to the stage IV ceRNA network. These genes have been described in previous breast cancer studies. Genes acted as ceRNAs are enriched in cancer-associated pathways. Two, three, and three microRNAs from stages I, II, and III were prognostic from the Kaplan-Meier survival analysis. Our results reveal a set of unique ceRNAs in metastatic breast cancer. Further experimental work is required to evaluate their role in metastasis. Moreover, identifying stage-specific ceRNAs will improve the understanding of personalised therapeutics in breast cancer.

MR imaging phenotypes and features associated with pathogenic mutation to predict recurrence or metastasis in breast cancer.

OBJECTIVES: Distant metastasis remains the main cause of death in breast cancer. Breast cancer risk is strongly influenced by pathogenic mutation.This study was designed to develop a multiple-feature model using clinicopathological and imaging characteristics adding pathogenic mutations associated signs to predict recurrence or metastasis in breast cancers in high familial risk women. METHODS: Genetic testing for breast-related gene mutations was performed in 54 patients with breast cancers. Breast MRI findings were retrospectively evaluated in 64 tumors of the 54 patients. The relationship between pathogenic mutation, clinicopathological and radiologic features was examined. The disease recurrence or metastasis were estimated. Multiple logistic regression analyses were performed to identify independent factors of pathogenic mutation and disease recurrence or metastasis. Based on significant factors from the regression models, a multivariate logistic regression was adopted to establish two models for predicting disease recurrence or metastasis in breast cancer using R software. RESULTS: Of the 64 tumors in 54 patients, 17 tumors had pathogenic mutations and 47 tumors had no pathogenic mutations. The clinicopathogenic and imaging features associated with pathogenic mutation included six signs: biologic features (p = 0.000), nuclear grade (p = 0.045), breast density (p = 0.005), MRI lesion type (p = 0.000), internal enhancement pattern (p = 0.004), and spiculated margin (p = 0.049). Necrosis within the tumors was the only feature associated with increased disease recurrence or metastasis (p = 0.006). The developed modelIincluding clinico-pathologic and imaging factors showed good discrimination in predicting disease recurrence or metastasis. Comprehensive model II, which included parts of modelIand pathogenic mutations significantly associated signs, showed significantly more sensitivity and specificity for predicting disease recurrence or metastasis compared to Model I. CONCLUSIONS: The incorporation of pathogenic mutations associated imaging and clinicopathological parameters significantly improved the sensitivity and specificity in predicting disease recurrence or metastasis. The constructed multi-feature fusion model may guide the implementation of prophylactic treatment for breast cancers at high familial risk women.

HPV-positive cervical squamous cell carcinoma metastasis to the breast, mimicking primary tumor.

INTRODUCTION: Metastatic disease to the breast is a rare condition, with contralateral breast metastasis being the most common primary site. CASE PRESENTATION: We present the case of a patient who underwent treatment for an HPV positive squamous cell carcinoma (SCC) of the cervix who, during follow-up, complained of a nodule in her left breast. Anatomopathological results indicating squamous carcinoma, which was not able to be differentiated from breast metaplastic carcinoma. Resection of the lesion was carried out, confirming carcinoma with squamous cell differentiation with negativity for GCDFP-15, mammaglobin, p63 and SOX10, but with positivity for p16 and for high risk HPV, confirming a single metastatic lesion of cervical carcinoma. DISCUSSION/CONCLUSION: In the presence of SCC in the breast, the differential diagnosis may consider the presence of primary lesion, metaplastic carcinoma with squamous cell differentiation or metastatic disease. The use of markers such as p63, SOX10 and p16, may help for a definitive diagnosis.

ABL kinases regulate translation in HER2+ cells through Y-box-binding protein 1 to facilitate colonization of the brain.

Patients with human epidermal growth factor receptor 2-positive (HER2+/ERBB2) breast cancer often present with brain metastasis. HER2-targeted therapies have not been successful to treat brain metastases in part due to poor blood-brain barrier (BBB) penetrance and emergence of resistance. Here, we report that Abelson (ABL) kinase allosteric inhibitors improve overall survival and impair HER2+ brain metastatic outgrowth in vivo. Mechanistically, ABL kinases phosphorylate the RNA-binding protein Y-box-binding protein 1 (YB-1). ABL kinase inhibition disrupts binding of YB-1 to the ERBB2 mRNA and impairs translation, leading to a profound decrease in HER2 protein levels. ABL-dependent tyrosine phosphorylation of YB-1 promotes HER2 translation. Notably, loss of YB-1 inhibits brain metastatic outgrowth and impairs expression of a subset of ABL-dependent brain metastatic targets. These data support a role for ABL kinases in the translational regulation of brain metastatic targets through YB-1 and offer a therapeutic target for HER2+ brain metastasis patients.

Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.

BACKGROUND: Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers. METHODS: We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients. RESULTS: Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events. CONCLUSIONS: In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).

STAT3/HIF1A and EMT specific transcription factors regulated genes: Novel predictors of breast cancer metastasis.

Metastasis, the fatal hallmark of breast cancer (BC), is a serious hurdle for therapy. Current prognostic approaches are not sufficient to predict the metastasis risk for BC patients. Therefore, in the present study, we analyzed gene expression data from GSE139038 and TCGA database to develop predictive markers for BC metastasis. Initially, the data from GSE139038 which contained 65 samples consisting of 41 breast tumor tissues, 18 paired morphologically normal tissues and 6 from non-malignant breast tissues were analyzed for differentially expressed genes (DEGs). DEGs were obtained from three different comparisons: paired morphologically normal (MN) versus tumor samples (C), apparently normal (AN) versus tumor samples (C), and paired morphologically normal (MN) versus apparently normal samples (AN). Multiple bioinformatic methods were employed to evaluate metastasis, EMT and triple negative breast cancer (TNBC) specific genes. Further, regulation of gene expression, clinicopathological factors and DNA methylation patterns of DEGs in BC were validated with TCGA datasets. Our bioinformatic analysis showed that 40 genes were upregulated and 294 were found to be downregulated between AN vs C; 124 were upregulated and 760 genes were downregulated between MN vs C; 4 were upregulated and 13 were downregulated between MN vs AN. Analysis using TCGA dataset revealed 18 genes were significantly altered in nodal positive BC patients compared to nodal negative BC patients. Our study showed novel candidate genes as predictive markers for BC metastasis which can also be used for therapeutic targets for BC treatment.

Cystic hypersecretory carcinoma with invasion: Case series on a rare variant of carcinoma breast.

BACKGROUND: Cystic Hypersecretory Carcinoma (CHC) is a rare subset of breast carcinoma. It is part of a spectrum of cystic hypersecretory lesions which includes cystic hypersecretory hyperplasia (CHH), CHH with atypia, CHC in situ and CHC with invasion. Approximately 65 cases of cystic hypersecretory lesions have been reported; most of them were CHC in situ and only 19 cases of CHC with invasion have been reported so far. CASE PRESENTATION: We are reporting 2 cases of 47 and 62 year old women with a palpable breast mass for 6 and 1 month duration respectively. Trucut biopsy was carried out for both which showed high grade ductal carcinoma in situ with microinvasion in the first patient and the latter showed a tiny focus of invasive carcinoma. Simple mastectomy and modified radical mastectomy (MRM) were done for the respective cases; both showed dilated cystic spaces filled with eosinophilic secretions (thyroid colloid-like), lining neoplastic cells that showed variable degrees of proliferation, atypia and in situ carcinoma. There were foci of invasion in both cases and hence a morphological diagnosis of CHC with invasion was made. CONCLUSION: Owing to a smaller number of reported cases, little is known about the biological behavior, prognosis and molecular profile of cystic hypersecretory carcinoma.

Breast metastasis presenting as swelling with calcification - A case report and review of the literature.

Primary breast carcinomas often present as ill-defined, infiltrative lesions which may contain calcifications, whereas metastatic cancers from non-mammary sites are often more well-circumscribed, sharply demarcated from the adjacent breast tissue and are usually not associated with calcifications, although there are exceptions. We report an atypical case of a lady with lung adenocarcinoma with pleural involvement, who presented with diffuse breast swelling with calcifications on imaging from metastatic lung adenocarcinoma, the first of its kind in the literature. We postulate that the pathophysiology of this was due to lymphatic spread of the tumour from the pleura resulting in retrograde lymphovascular congestion of the breast, resulting in swelling and dystrophic calcification.

Pancreatic metastasis of invasive ductal breast carcinoma: A potential diagnostic pitfall.

The 42-year-old patient, diagnosed with Stage IIA breast cancer, completed the postoperative adjuvant chemotherapy and radiotherapy. At the 11th year of diagnosis, a 3 cm tumor was detected in the pancreas and pancreatectomy was performed. Although the diagnosis of primary pancreatic adenocarcinoma was made at first, then the pancreatic metastasis of breast cancer was discovered. Pancreatic metastasis of breast cancer is extremely rare, and a limited number of patients have been reported in the literature. Here, we report an additional case of this rare tumor and the problems correlating with its diagnosis.

Evaluation of breast cancer metastasis and mortality rates based on molecular subtype: A description study.

BACKGROUND: Breast cancer in Indonesia has continued to increase. One diagnostic modality is immunohistochemical examination to determine breast cancer subtypes. OBJECTIVE: To determine breast cancer metastasis and mortality rates based on molecular subtypes. METHODS: A descriptive study was conducted based on retrospective data from hospital medical records from January 2016 to December 2019. The data comprised age, clinical stage, histopathological grade, molecular subtype, location, metastasis, and breast cancer mortality. The data were processed and analyzed. RESULTS: This study involved 172 patients. The most prevalent breast cancer subtypes were luminal A (60, 34.8%), followed by HER2 (47, 27.4%), triple-negative (38, 22.4%), and luminal B (27, 15.4%). The metastasis rate was 37.21% (64/172), with bone the tissue most affected (32 cases, 50%), followed by lung (24 cases, 37.5%) and liver (8 cases, 12.5%). The highest rates of bone, lung, and liver metastases were subtypes luminal A (31%), HER2 (29%), and triple-negative (38%), respectively. The mortality rate was 21% (36/172), with most in the triple-negative group (28.9%), followed by luminal B (25.9%), HER2 (21.2%), and luminal A (13.3%). CONCLUSIONS: Determination of breast cancer molecular subtypes through immunohistochemistry can determine the level of metastasis and mortality in breast cancer.

Metastasis to Breast from Extramammary Solid Tumors and Lymphomas: A 20-Year Population-Based Study.

To discuss the clinicopathological features and prognosis of metastases to the breast from extramammary solid tumors and lymphomas, we reviewed Cancer Hospital of Chinese Academy of Medical Sciences database from 01/01/2000 to 12/31/2020. Fifty-nine patients were identified. The most common primary sites for breast metastases were lymph node and pulmonary, followed by nasal cavity, ovary, skin, etc. All the patients were treated with chemotherapy, 18 were operated, 14 accepted radiotherapy. Metastasis to breast should be considered in any patient with tumor history presenting a breast lump. Pathological with immunohistochemical examination should be performed to identify the original site.

Survival in metaplastic breast carcinoma: A case series.

BACKGROUND: Metaplastic breast carcinoma (MBC) is a rare type of breast cancer (0.20-1.00% of all cases). With a more aggressive clinical course, MBC frequently presents as a triple-negative subtype. OBJECTIVE: To describe a case series, analyzing patients survival in four MBC cases. METHODS: The cases were obtained from 532 medical records of breast cancer patients (0.7% of the total). RESULTS: All patients were female. Mean patient age was 49 years (range: 38-60 years). Mean tumor size was 8.9 cm (range: 3.0-15.5 cm). Mastectomy was performed in three cases. One patient had axillary nodal metastasis. All underwent chemotherapy and three received radiation therapy after surgery. CONCLUSIONS: With a mean follow-up of 36 months (range: 10-60 months), one case had a tumor recurrence (25%). Three patients (75%) died from metastatic disease and one (25%) is still alive and free of disease.