ABSTRACT
BACKGROUND: Ehlers-Danlos syndrome (EDS) is a rare inherited connective tissue disease characterized by hyperextensibility of the skin and joints and tissue fragility of the skin and blood vessels, Vascular EDS is the most severe form of EDS, with abnormal arterial fragility. There have been no reports of breast cancer occurring in patients with vascular EDS. Here, we report here a very rare case of breast cancer in a patient with vascular EDS. CASE PRESENTATION: A 46-year-old woman with vascular EDS underwent partial left mastectomy and sentinel lymph node biopsy for left breast cancer (cStage 0) detected by medical examination. The final pathological diagnosis was invasive ductal carcinoma of the breast (pStage IA) [hormone receptor-positive, HER2 score 2 equivocal (FISH-positive), Ki-67LI 18%, luminal-HER2 type]. BluePrint was submitted as an aid in determining the postoperative treatment strategy, BluePrint Molecular Subtype HER2-type. However, the 10-year breast cancer mortality risk using Predict was low (5%). After consultation with the patient, the decision was made to administer postoperative radiation to the preserved breast along with hormone therapy only. There was no delay in postoperative wound healing, and the patient was free of metastatic recurrence for 9 months after surgery. CONCLUSION: We performed surgery, postoperative radiotherapy, and hormonal therapy in a breast cancer patient with vascular EDS without major complications.
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The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies. Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed. The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876-16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2- subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group. The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group.
ABSTRACT
Hyaluronan (HA), as a component of extracellular matrix, has pivotal roles in both physiological and pathological condition. In breast cancer, while high molecular weight HA is produced by hyaluronan synthase, it is degraded by hyaluronidases (hyaluronidase-1 (HYAL1) and hyaluronidase-2 (HYAL2)) into low molecular weight HA (LMW HA), which is considered to have pro-tumorigenic effects in human malignancies. However, HA and HYAL2, the rate-limiting enzyme of HA degradation, have not been comprehensively examined in breast cancer and clinicopathological significance of LMW HA remains to be elucidated in breast cancer. We therefore histochemically localized HA as well as HYAL2 in 116 breast cancer tissues. In addition, we examined size-dependent function of HA on breast cancer cell proliferation and migration using MCF-7 and MDA-MB-231 breast cancer cell lines. HA was localized in both the stroma and breast carcinoma cells, while HYAL2 was predominantly localized in breast carcinoma cells. HA was significantly correlated with cell proliferation and invasion ability as well as increased risk of recurrence especially in HYAL2 positive group. On the other hand, HYAL2 was correlated with breast cancer cell proliferation and increased risk of recurrence. In addition, in vitro analyses revealed that lower molecular weight HA increased sphere forming ability and migration in MCF-7 and MDA-MB-231, whereas higher molecular weight HA inhibited them. It was concluded that HA needs to be degraded by HYAL2 to exert pro-tumorigenic effects and comprehensive HA/HYAL2 status serves as a potent prognostic factor in breast cancer.
Subject(s)
Breast Neoplasms , Cell Movement , Cell Proliferation , Hyaluronic Acid , Hyaluronoglucosaminidase , Humans , Hyaluronoglucosaminidase/metabolism , Female , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/enzymology , Hyaluronic Acid/metabolism , Middle Aged , Adult , Aged , GPI-Linked Proteins/metabolism , GPI-Linked Proteins/analysis , Cell Line, Tumor , Cell Adhesion Molecules/metabolism , Neoplasm Recurrence, Local/pathologyABSTRACT
PURPOSE: This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial). METHODS: Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0-17, Intermediate: 18-30, High: 31-100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV). RESULTS: In total, 102 patients [Low: n = 44 (43.1%), Intermediate: n = 38 (37.5%), High: n = 20 (19.6%)] in Group A, and 45 in Group B, who had progression in Group A were analyzed. The median follow-up time was 23.8 months for Group A and 8.9 months for Group B. Multivariate analysis in Group A showed that low-risk [hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.04-0.53, P = 0.003] and intermediate-risk (HR 0.22, 95% CI 0.06-0.78) with de novo stage IV breast cancer were significantly associated with better prognosis compared to high-risk. However, no significant difference was observed among patients with recurrence. No prognostic significance was observed in Group B. CONCLUSION: We found a distinct prognostic value of the 21-Gene Breast Recurrence Score® assay by the types of ABCs and a poor prognostic value of the high RS for patients with de novo stage IV BC treated with fulvestrant monotherapy. Further validations of these findings are required.
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High-mobility group box 1 (HMGB1) functions as damage-associated molecular pattern (DAMPs), released into extracellular space during cellular stress. Extracellular HMGB1 act as signal molecules through Toll-like receptor (TLR) 2 or TLR4, exerting diverse functions in both normal cells and malignant cells including breast cancer. However, their comprehensive examination in breast cancer tissues is lacking. Thus, we immunolocalized them in 112 breast cancer tissues, correlating their immunoreactivity with clinicopathological parameters and clinical outcomes to clarify their significance in breast cancer. We demonstrated that nuclear HMGB1 immunoreactivity was correlated with tumor progression and longer disease-free survival. In contrast, TLR2 immunoreactivity was correlated with increased cell proliferation and shorter disease-free survival, dependent on cytoplasmic HMGB1 immunoreactivity. Additionally, TLR4 immunoreactivity correlated with chemoresistance, regardless of cytoplasmic HMGB1 immunoreactivity. It was therefore considered that TLR2 collaboratively contributed to breast cancer progression with HMGB1-DAMPs to become a worse prognostic factor. Meanwhile, TLR4 served as a worse prognostic factor associated with chemoresistance, irrespective of HMGB1.
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Homologous recombination (HR) repairs DNA damage including DNA double-stranded breaks and alterations in HR-related genes results in HR deficiency. Germline alteration of HR-related genes, such as BRCA1 and BRCA2, causes hereditary breast and ovarian cancer (HBOC). Cancer cells with HR deficiency are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents. Thus, accurately evaluating HR activity is useful for diagnosing HBOC and predicting the therapeutic effects of anti-cancer agents. Previously, we developed an assay for site-specific HR activity (ASHRA) that can quantitatively evaluate HR activity and detect moderate HR deficiency. HR activity in cells measured by ASHRA correlates with sensitivity to the PARP inhibitor, olaparib. In this study, we applied ASHRA to lymphoblastoid cells and xenograft tumor tissues, which simulate peripheral blood lymphocytes and tumor tissues, respectively, as clinically available samples. We showed that ASHRA could be used to detect HR deficiency in lymphoblastoid cells derived from a BRCA1 pathogenic variant carrier. Furthermore, ASHRA could quantitatively measure the HR activity in xenograft tumor tissues with HR activity that was gradually suppressed by inducible BRCA1 knockdown. The HR activity of xenograft tumor tissues quantitatively correlated with the effect of olaparib. Our data suggest that ASHRA could be a useful assay for diagnosing HBOC and predicting the efficacy of PARP inhibitors.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Ovarian Neoplasms , Piperazines , Humans , Female , Homologous Recombination , BRCA1 Protein/genetics , Phthalazines/pharmacology , Phthalazines/therapeutic use , Antineoplastic Agents/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Poly(ADP-ribose) Polymerases/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , DNA/therapeutic useABSTRACT
AIM: Patients with cancer experience various forms of psychological distress, including depressive symptoms, which can impact quality of life, elevate morbidity risk, and increase medical costs. Psychotherapy and pharmacotherapy are effective for reducing depressive symptoms among patients with cancer, but most patients prefer psychotherapy. This study aimed to develop an efficient and effective smartphone psychotherapy component to address depressive symptom. METHODS: This was a decentralized, parallel-group, multicenter, open, individually randomized, fully factorial trial. Patients aged ≥20 years with cancer were randomized by the presence/absence of three cognitive-behavioral therapy (CBT) skills (behavioral activation [BA], assertiveness training [AT], and problem-solving [PS]) on a smartphone app. All participants received psychoeducation (PE). The primary outcome was change in the patient health questionnaire-9 (PHQ-9) total score between baseline and week 8. Secondary outcomes included anxiety. RESULTS: In total, 359 participants were randomized. Primary outcome data at week 8 were obtained for 355 participants (99%). The week 8 PHQ-9 total score was significantly reduced from baseline for all participants by -1.41 points (95% confidence interval [CI] -1.89, -0.92), but between-group differences in change scores were not significant (BA: -0.04, 95% CI -0.75, 0.67; AT: -0.16, 95% CI -0.87, 0.55; PS: -0.19, 95% CI -0.90, 0.52). CONCLUSION: As the presence of any of the three intervention components did not contribute to a significant additive reduction of depressive symptoms, we cannot make evidence-based recommendations regarding the use of specific smartphone psychotherapy.
Subject(s)
Cognitive Behavioral Therapy , Depression , Neoplasms , Smartphone , Humans , Male , Female , Middle Aged , Depression/therapy , Neoplasms/complications , Neoplasms/therapy , Adult , Cognitive Behavioral Therapy/methods , Aged , Psychotherapy/methods , Outcome Assessment, Health Care , Mobile ApplicationsABSTRACT
INTRODUCTION: Triple-negative breast cancer (TNBC), recognized as the most heterogeneous type of breast cancer (BC), exhibits a worse prognosis than other subtypes. Mitochondria dynamics play a vital role as mediators in tumorigenesis by adjusting to the cell microenvironments. However, the relationship between mitochondrial dynamics and metabophenotype exhibits discrepancies and divergence across various research and BC models. Therefore, this study aims to explore the role of mitochondrial dynamics in TNBC drug resistance and tumorigenesis. METHODS: The Wst-8 test was conducted to assess doxorubicin sensitivity in HCC38, MDA-MB-231 (TNBC), and MCF-7 (luminal). Confocal microscopy and FACS were used to quantify the mitochondrial membrane potential (ΔφM), mitophagy, and reactive oxygen species (ROS) production. Agilent Seahorse XF Analyzer was utilized to measure metabolic characteristics. Dynamin-related protein-1 (DRP1), Parkin, and p62 immunohistochemistry staining were performed using samples from 107 primary patients with BC before and after neoadjuvant chemotherapy (NAC). RESULTS: MDA-MB-231, a TNBC cell line with reduced sensitivity to doxorubicin, reduced ΔφM, and enhanced mitophagy to maintain ROS production through oxidative phosphorylation (OXPHOS)-based metabolism. HCC38, a doxorubicin-sensitive cell line, exhibited no alterations in ΔφM or mitophagy. However, it demonstrated an increase in ROS production and glycolysis. Clinicopathological studies revealed that pretreatment (before NAC) expression of DRP1 was significant in TNBC, as was pretreatment expression of Parkin in the hormone receptor-negative group. Furthermore, low p62 levels seem to be a risk factor for recurrence-free survival. CONCLUSION: Our findings indicated that the interplay between mitophagy, linked to a worse clinical prognosis, and OXPHOS metabolism promoted chemotherapy resistance in TNBC. Mitochondrial fission is prevalent in TNBC. These findings suggest that targeting the unique mitochondrial metabolism and dynamics in TNBC may offer a novel therapeutic strategy for patients with TNBC.
Subject(s)
Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Mitochondrial Dynamics , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Ubiquitin-Protein Ligases/genetics , Carcinogenesis , Tumor MicroenvironmentABSTRACT
This is a prognostic report by the Japanese Breast Cancer Society on breast cancer extracted from the National Clinical Database-Breast Cancer Registry of Japan. Here, we present a summary of 457,878 breast cancer cases registered between 2004 and 2016. The median follow-up duration was 5.6 years. The median age at the start of treatment was 59 years (5-95%: 38-82 years) and increased from 57 years between 2004 and 2008 to 60 years between 2013 and 2016. The proportion of patients with Stage 0-II disease increased from 74.5% to 78.3%. The number of cases with estrogen and progesterone receptor positivity increased from 74.8% to 77.9% and 60.5% to 68.1%, respectively. Regarding (neo-)adjuvant chemotherapy, the taxane (T) or taxane-cyclophosphamide (C) regimen increased by 2.4% to 8.2%, but the (fluorouracil (F)) adriamycin (A)-C-T/(F) epirubicin (E)C-T and (F)AC/(F)EC regimens decreased by 18.6% to 15.2% and 13.5% to 5.0%, respectively. Regarding (neo-)adjuvant anti-human epidermal growth factor-2 (HER2)-targeted therapy, the use of trastuzumab increased from 4.6% to 10.5%. The rate of sentinel lymph node biopsy increased from 37.1% to 60.7%, while that of axillary dissection decreased from 54.5% to 22.6%. Improvements in disease-free and overall survival were observed in patients with HER2-positive breast cancer, but there was no apparent trend in patients with hormone receptor-positive, HER2-negative, or triple-negative breast cancers.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Humans , Middle Aged , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Japan/epidemiology , Receptor, ErbB-2 , Epirubicin , Cyclophosphamide , Trastuzumab/therapeutic use , Taxoids/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant , RegistriesABSTRACT
BACKGROUND: Invasive lobular carcinoma (ILC) is distinct from invasive ductal carcinoma (IDC) in terms of their hormonal microenvironments that may require different therapeutic strategies. We previously reported that selective estrogen receptor modulator (SERM) function requires F-box protein 22 (Fbxo22). Here, we investigated the role of Fbxo22 as a potential biomarker contributing to the resistance to endocrine therapy in ILC. METHODS: A total of 302 breast cancer (BC) patients including 150 ILC were recruited in the study. Fbxo22 expression and clinical information were analyzed to elucidate whether Fbxo22 negativity could be a prognostic factor or there were any correlations among clinical variables and SERM efficacy. RESULTS: Fbxo22 negativity was significantly higher in ILC compared with IDC (58.0% vs. 27.0%, P < 0.001) and higher in postmenopausal patients than premenopausal patients (64.1% vs. 48.2%, P = 0.041). In the ILC cohort, Fbxo22-negative patients had poorer overall survival (OS) than Fbxo22-positive patients, with 10-year OS rates of 77.4% vs. 93.6% (P = 0.055). All patients treated with SERMs, Fbxo22 negativity resulted in a poorer outcome, with 10-year OS rates of 81.3% vs. 92.3% (P = 0.032). In multivariate analysis regarding recurrence-free survival (RFS) in ILC patients, Fbxo22 status was independently predictive of survival as well as lymph node metastasis. CONCLUSION: Fbxo22 negativity significantly impacts on survival in BC patients with IDC and ILC, and the disadvantage was enhanced among ILC postmenopausal women or patients treated with SERMs. The findings suggest that different therapeutic strategies might be needed according to the different histopathological types when considering adjuvant endocrine therapy.
Subject(s)
Breast Neoplasms , Carcinoma, Ductal, Breast , Carcinoma, Lobular , Female , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Carcinoma, Lobular/pathology , Selective Estrogen Receptor Modulators/therapeutic use , Carcinoma, Ductal, Breast/pathology , Treatment Outcome , Tumor MicroenvironmentABSTRACT
The Japanese Breast Cancer Society initiated the breast cancer registry in 1975, which transitioned to the National Clinical Database-Breast Cancer Registry in 2012. This annual report presents data from 2020 and analyzes the ten-year mortality rates for those aged 65 and older. We analyzed data from 93,784 breast cancer (BC) cases registered in 2020 and assessed 10-year mortality rates for 36,279 elderly patients diagnosed between 2008 and 2012. In 2020, 99.4% of BC cases were females with a median age of 61. Most (65%) were diagnosed at early stages (Stage 0 or I). Breast-conserving surgery rates varied with stages: 58.5% at cStage I, 30.8% at cStage II, and 13.1% at cStage III. Sentinel lymph node biopsy was done in 73.6% of cases, followed by radiotherapy in 70% of those post-conserving surgery and chemotherapy in 21.1% post-surgery. Pathology showed that 63.4% had tumors under 2.0 cm, 11.7% had pTis tumors, and 77.3% had no axillary lymph node metastasis. ER positivity was seen in 75.1%, HER2 in 14.3%, and 30% had a Ki67 positivity rate above 30%. Across all stages and subtypes, there was a trend where the 10-year mortality rates increased for individuals older than 65 years. In Stage I, many deaths were not directly linked to BC and, for those with HER2-type and triple-negative BC, breast cancer-related deaths increased with age. Within Stage II, patients older than 70 years with luminal-type BC often experienced deaths not directly linked to BC, whereas patients below 80 years with HER2-type and triple-negative BC, likely had breast cancer-related deaths. In Stage III, breast cancer-related deaths were more common, particularly in HER2 and triple-negative BC. Our prognostic analysis underscores distinct mortality patterns by stage, subtype, and age in elderly BC patients. It highlights the importance of personalized treatment strategies, considering subtype-specific aggressiveness, age-related factors, and comorbidities.
Subject(s)
Breast Neoplasms, Male , Breast Neoplasms , Triple Negative Breast Neoplasms , Aged , Female , Humans , Male , Breast/pathology , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms, Male/mortality , Breast Neoplasms, Male/pathology , Japan/epidemiology , Receptor, ErbB-2 , Registries/statistics & numerical data , Retrospective Studies , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathologyABSTRACT
PURPOSE: To evaluate the effectiveness of the texture analysis of axillary high-resolution 3D T2-weighted imaging (T2WI) in distinguishing positive and negative lymph node (LN) metastasis in patients with clinically node-negative breast cancer. METHODS: Between December 2017 and May 2021, 242 consecutive patients underwent high-resolution 3D T2WI and were classified into the training (n = 160) and validation cohorts (n = 82). We performed manual 3D segmentation of all visible LNs in axillary level I to extract the texture features. As the additional parameters, the number of the LNs and the total volume of all LNs for each case were calculated. The least absolute shrinkage and selection operator algorithm and Random Forest were used to construct the models. We constructed the texture model using the features from the LN with the largest least axis length in the training cohort. Furthermore, we constructed the 3 models combining the selected texture features of the LN with the largest least axis length, the number of LNs, and the total volume of all LNs: texture-number model, texture-volume model, and texture-number-volume model. As a conventional method, we manually measured the largest cortical diameter. Moreover, we performed the receiver operating curve analysis in the validation cohort and compared area under the curves (AUCs) of the models. RESULTS: The AUCs of the texture model, texture-number model, texture-volume model, texture-number-volume model, and conventional method in the validation cohort were 0.7677, 0.7403, 0.8129, 0.7448, and 0.6851, respectively. The AUC of the texture-volume model was higher than those of other models and conventional method. The sensitivity, specificity, positive predictive value, and negative predictive value of the texture-volume model were 90%, 69%, 49%, and 96%, respectively. CONCLUSION: The texture-volume model of high-resolution 3D T2WI effectively distinguished positive and negative LN metastasis for patients with clinically node-negative breast cancer.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Lymphatic Metastasis/diagnostic imaging , Lymphatic Metastasis/pathology , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathology , Magnetic Resonance Imaging/methods , Predictive Value of Tests , Retrospective StudiesABSTRACT
This is an annual report by the Japanese Breast Cancer Society regarding the clinical data on breast cancer extracted from the National Clinical Database-Breast Cancer Registry (NCD-BCR) of Japan. Here, we present an updated summary of 98,300 breast cancer cases registered in 2019. The median age at cancer diagnosis was 61 years (interquartile range 49-72 years), and 30.6% of the breast cancer patients were premenopausal. Of the 93,840 patients without distant metastases, 14,118 (15.0%) and 42,047 (44.8%) were diagnosed with stage 0 and I disease, respectively. Breast-conserving surgery was performed in 42,080 (44.8%) patients. Regarding axillary procedures, 62,677 (66.8%) and 7371 (7.9%) patients underwent sentinel node biopsy and axillary node dissection after biopsy, respectively. Whole breast irradiation was administered to 29,795 (70.8%) of the 42,080 patients undergoing breast-conserving surgery. Chest wall irradiation was administered to 5524 (11.1%) of the 49,637 patients who underwent mastectomy. Of the 6912 clinically lymph node-negative patients who received preoperative therapy, 5250 (76.0%) and 427 (6.2%) underwent sentinel node biopsy and axillary node dissection after biopsy, respectively; however, 602 (8.7%) patients initially underwent axillary node dissection without biopsy.
Subject(s)
Breast Neoplasms , Humans , Middle Aged , Aged , Female , Breast Neoplasms/epidemiology , Breast Neoplasms/surgery , Japan/epidemiology , Mastectomy , Lymphatic Metastasis/pathology , Sentinel Lymph Node Biopsy/methods , Lymph Node Excision , Axilla/surgery , Registries , Lymph Nodes/surgery , Lymph Nodes/pathologyABSTRACT
The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer were updated to the 2022 edition through a process started in 2018. The updated guidelines consist of 12 background questions (BQs), 33 clinical questions (CQs), and 20 future research questions (FRQs). Multiple outcomes including efficacy and safety were selected in each CQ, and then quantitative and qualitative systematic reviews were conducted to determine the strength of evidence and strength of recommendation, which was finally determined through a voting process among designated committee members. Here, we describe eight selected CQs as important updates from the previous guidelines, including novel practice-changing updates, and recommendations based on evidence that has emerged specifically from Japanese clinical trials.
Subject(s)
Breast Neoplasms , Female , Humans , Breast Neoplasms/drug therapy , East Asian People , JapanABSTRACT
It is known that estrogen receptor (ER) has extranuclear signaling functions in addition to classical genomic pathway, and estrogenic actions have been reported in ER-negative breast carcinoma cells. However, significance of cytoplasmic-ER immunoreactivity has not been reported in ER-negative breast carcinoma tissues. We immunolocalized cytoplasmic ER in 155 ER-negative breast carcinoma tissues and evaluated its clinicopathological significance including the prognosis. As a comparative cohort set, we also used 142 ER-positive breast carcinomas. Cytoplasmic-ER immunoreactivity was detected in the carcinoma cells, but not in the non-neoplastic mammary epithelium. Cytoplasmic-ER immunoreactivity was positive in the 35 out of 155 (23%) ER-negative breast carcinoma cases, whereas it was detected only in 2 out of 142 (1.4%) ER-positive cases. Cytoplasmic ER status was positively associated with cytoplasmic-PR status, but inversely associated with Ki67 labeling index or distant free-relapse survival rate. Moreover, cytoplasmic-ER status turned out to be an independent good prognostic factor for both distant relapse-free survival and breast cancer specific survival. These findings suggested that cytoplasmic ER plays important roles in the ER-negative breast carcinoma, and cytoplasmic ER is a potent good prognostic factor. Among the ER-negative breast cancer patients, clinical benefit of chemotherapy may be limited in the cytoplasmic-ER positive cases.
ABSTRACT
The identification of risk factors helps radiologists assess the risk of breast cancer. Quantitative factors such as age and mammographic density are established risk factors for breast cancer. Asymmetric breast findings are frequently encountered during diagnostic mammography. The asymmetric area may indicate a developing mass in the early stage, causing a difference in mammographic density between the left and right sides. Therefore, this paper aims to propose a quantitative parameter named bilateral mammographic density difference (BMDD) for the quantification of breast asymmetry and to verify BMDD as a risk factor for breast cancer. To quantitatively evaluate breast asymmetry, we developed a semi-automatic method to estimate mammographic densities and calculate BMDD as the absolute difference between the left and right mammographic densities. And then, a retrospective case-control study, covering the period from July 2006 to October 2014, was conducted to analyse breast cancer risk in association with BMDD. The study included 364 women diagnosed with breast cancer and 364 matched control patients. As a result, a significant difference in BMDD was found between cases and controls (P < 0.001) and the case-control study demonstrated that women with BMDD > 10% had a 2.4-fold higher risk of breast cancer (odds ratio, 2.4; 95% confidence interval, 1.3-4.5) than women with BMDD ≤ 10%. In addition, we also demonstrated the positive association between BMDD and breast cancer risk among the subgroups with different ages and the Breast Imaging Reporting and Data System (BI-RADS) mammographic density categories. This study demonstrated that BMDD could be a potential risk factor for breast cancer.
ABSTRACT
Kallikrein-related peptides (KLKs) form an evolutionally conserved subgroup of secreted serine proteases that consists of 15 members (KLK1-15). Previous studies have shown that KLKs regulate diverse biological processes, but the clinical significance of KLKs remains largely unclear in human breast cancers. We examined the expression profile of 15 KLK genes in breast carcinomas using microarray data. Next, we immunolocalized KLK12 in 140 breast carcinomas and evaluated its clinical significance. Subsequently, we examined the effects of KLK12 on proliferation and migration in breast cancer cell lines. From microarray analyses, it turned out that KLK12 was the most strongly associated with low-grade malignancy in breast carcinomas among the 15 KLK members. Immunohistochemical KLK12 status was positively associated with ER and PR status, while it was inversely associated with stage, pathological T factor, lymph node metastasis, and distant metastasis. Prognostic analyses demonstrated that KLK12 was a favorable prognostic factor for both disease-free and breast cancer-specific survival of the patients. Furthermore, the knockdown of KLK12 significantly increased cell proliferation activity and cell migration of breast cancer cells. These results suggest that KLK12 has antitumorigenic effects associated with proliferation and migration and immunohistochemical KLK12 status as a potent favorable prognostic factor in breast carcinoma patients.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/genetics , Prognosis , Kallikreins/genetics , Kallikreins/metabolismABSTRACT
BACKGROUND: Triple-negative breast cancer (TNBC) is characterized as highly immunogenic and lacks specific targeted therapies. Interleukin 17A (IL-17A) is a controversial cytokine and is known to have anti-tumor and pro-tumor roles depending on the tumor microenvironment. In addition, IL-17A has been recently implicated in the recruitments of neutrophil into tumor tissues. Although IL-17A is considered tumor-promoting in breast cancer, its significance in the possible regulation of neutrophil infiltration in TNBC is not clearly defined. MATERIALS AND METHODS: We immunolocalized IL-17A, CD66b (neutrophil marker), and chemokine (C-X-C motif) ligand 1 (CXCL1, neutrophil chemoattractant) in 108 TNBC specimens and assessed their correlation among each other. The correlation between these markers and clinicopathological parameters was also assessed. We subsequently performed in vitro study to address the possible regulation of CXCL1 by IL-17A using TNBC cell lines, MDA-MB-231 and HCC-38. RESULTS: It was revealed that IL-17A correlated significantly with CXCL1 and CD66b, also CD66b with CXCL1. Furthermore, IL-17A was significantly associated with shorter disease-free and overall survival, especially in a high density CD66b group of patients. In vitro results revealed that IL-17A upregulated CXCL1 mRNA expression in a dose and time dependent manner, and this induction was significantly suppressed by an Akt inhibitor. CONCLUSION: IL-17A was considered to contribute to neutrophil infiltration by inducing CXCL1 in TNBC tissues and educating neutrophils to promote tumor progression. IL-17A might therefore serve as a potent prognostic factor in TNBC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/pathology , Interleukin-17/metabolism , Prognosis , Neutrophil Infiltration , Tumor MicroenvironmentABSTRACT
BACKGROUND: Endocrine-resistant HR+/HER2- breast cancer (BC) and triple-negative BC (TNBC) are of interest for molecularly informed treatment due to their aggressive natures and limited treatment profiles. Patients of African Ancestry (AA) experience higher rates of TNBC and mortality than European Ancestry (EA) patients, despite lower overall BC incidence. Here, we compare the molecular landscapes of AA and EA patients with HR+/HER2- BC and TNBC in a real-world cohort to promote equity in precision oncology by illuminating the heterogeneity of potentially druggable genomic and transcriptomic pathways. METHODS: De-identified records from patients with TNBC or HR+/HER2- BC in the Tempus Database were randomly selected (N = 5000), with most having stage IV disease. Mutations, gene expression, and transcriptional signatures were evaluated from next-generation sequencing data. Genetic ancestry was estimated from DNA-seq. Differences in mutational prevalence, gene expression, and transcriptional signatures between AA and EA were compared. EA patients were used as the reference population for log fold-changes (logFC) in expression. RESULTS: After applying inclusion criteria, 3433 samples were evaluated (n = 623 AA and n = 2810 EA). Observed patterns of dysregulated pathways demonstrated significant heterogeneity among the two groups. Notably, PIK3CA mutations were significantly lower in AA HR+/HER2- tumors (AA = 34% vs. EA = 42%, P < 0.05) and the overall cohort (AA = 28% vs. EA = 37%, P = 2.08e-05). Conversely, KMT2C mutation was significantly more frequent in AA than EA TNBC (23% vs. 12%, P < 0.05) and HR+/HER2- (24% vs. 15%, P = 3e-03) tumors. Across all subtypes and stages, over 8000 genes were differentially expressed between the two ancestral groups including RPL10 (logFC = 2.26, P = 1.70e-162), HSPA1A (logFC = - 2.73, P = 2.43e-49), ATRX (logFC = - 1.93, P = 5.89e-83), and NUTM2F (logFC = 2.28, P = 3.22e-196). Ten differentially expressed gene sets were identified among stage IV HR+/HER2- tumors, of which four were considered relevant to BC treatment and were significantly enriched in EA: ERBB2_UP.V1_UP (P = 3.95e-06), LTE2_UP.V1_UP (P = 2.90e-05), HALLMARK_FATTY_ACID_METABOLISM (P = 0.0073), and HALLMARK_ANDROGEN_RESPONSE (P = 0.0074). CONCLUSIONS: We observed significant differences in mutational spectra, gene expression, and relevant transcriptional signatures between patients with genetically determined African and European ancestries, particularly within the HR+/HER2- BC and TNBC subtypes. These findings could guide future development of treatment strategies by providing opportunities for biomarker-informed research and, ultimately, clinical decisions for precision oncology care in diverse populations.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Female , Humans , Black People/genetics , Breast Neoplasms/ethnology , Breast Neoplasms/pathology , Mutation , Precision Medicine , Triple Negative Breast Neoplasms/ethnology , Triple Negative Breast Neoplasms/pathology , White PeopleABSTRACT
Tumor-associated macrophages (TAMs) contribute to tumor progression and chemoresistance; it is therefore important to clarify the altered functions of macrophages following chemotherapy. While extracellular heat shock protein (HSP) 70 is associated with therapeutic resistance, the effects of HSP70 on TAMs remain largely unknown. Here, we conducted in vitro experiments and immunohistochemistry in 116 breast carcinoma specimens to determine whether the secretion of HSP70 from breast cancer cells following chemotherapy affects macrophage function. It was revealed that the interaction of epirubicin (EPI)-exposed breast cancer cells with macrophages enhanced tumor progression, and EPI promoted the secretion of extracellular HSP70 from breast cancer cells. The expression of pro-tumorigenic macrophage marker CD163 was decreased in macrophages treated with a conditioned medium (CM) from HSP70-silenced breast cancer cells. Breast cancer cells treated with CM from HSP70-silenced breast cancer cells showed decreased expression of transforming growth factor (TGF)-ß, and the pro-tumorigenic effects of macrophages were impaired when TGF-ß signaling was inhibited. Immunohistochemistry demonstrated that HSP70 served as a poor prognostic factor in conjunction with macrophage infiltration. It was therefore concluded that extracellular HSP70 levels increased following chemotherapy and enhanced the pro-tumorigenic effects of TAMs, either directly or indirectly, by regulating TGF-ß expression in breast cancer cells.