Therapy In Breast Cancer Patients Research Articles

Casein kinase 1 controls the shuttling of epidermal growth factor receptor and estrogen receptor in endometrial carcinoma induced by breast cancer hormonal therapy: Relevance of GPER1/Src

Casein kinase 1 plays a crucial role in carcinogenesis. 4-Hydroxytamoxifen (4-OHT), which is widely used to treat breast cancer, often leads to the development of endometrial carcinoma with poor prognosis, particularly among women who receiving long-term treatment. This study was performed to elucidate whether specific inhibition of casein kinase 1 (CK1) controls 4-OHT-mediated Ishikawa cell carcinogenesis. 4-OHT significantly stimulated the activity of estrogen receptor alpha (ERα) and nuclear translocation and expression of epidermal growth factor receptor (EGFR) from the plasma membrane to perinuclear or nuclear regions, as well as the activities of G-protein-coupled estrogen receptor 1 (GPER1) and Src in Ishikawa cells. However, inhibition of EGFR by Gefitinib blocked all these events, and inhibition of GPER1 or Src produced a partial block. GPER1 and Src controlled Ishikawa cell carcinogenesis in different manners: GPER1 accelerated EGFR mobility without affecting ERα activity, while Src activated ERα and EGFR without any change in GPER1 expression. EGFR and GPER1 performed reciprocal regulation in endometrial cell carcinogenesis via direct interaction in 4-OHT-treated Ishikawa cells, implying a possible key role of GPER1 in these events. Inhibition of CK1 by CKI-7 and IC261, however, impeded all changes beginning with EGFR translocation and activity in 4-OHT-treated Ishikawa cells. These findings indicate that inhibition of CK1 could control 4-OHT-mediated activation and translocation of ER/EGFR and GPER1/Src expression, inhibiting 4-OHT-triggered endometrial carcinogenesis. Therefore, targeting of CK1 by CKI-7 and IC261 could be a prospective adjuvant therapy for breast cancer patients taking tamoxifen.

Relation Between Baseline CXCR1 Expression And Neoadjuvant Chemotherapy Response In Breast Cancer Patients.

To examine the C-X-C Motif Chemokine Receptor 1 expression in breast cancer tissues prior to neo-adjuvant chemotherapy, and its relationship to neo-adjuvant chemotherapy effectiveness and other prognostic variables. The prospective study was conducted at Kafrelsheikh University Hospital, Egypt, from November 2018 to March 2021, and comprised patients with recent histopathologically proven breast cancer cases eligible for chemotherapy. Paraffin blocks of tumourspecimens were stained by immunohistochemicalstain using concentrating rabbit anti-human C-X-C Motif Chemokine Receptor 1 polyclonal antibody kits. C-X-C Motif Chemokine Receptor 1 expression was classified into low and high categories. Patients were followed for 2 years for treatment response, disease recurrence and mortality. Data was analysed using SPSS 25. Of the 100 females with mean age 50.2±12.1 years, 52(52%) had their left side affected, while 48(48%) had their rightside affected. There were 52(52%) cases with mean age 49.2±12.9 years having high C-X-C Motif Chemokine Receptor 1 expresssion, while 48(48%) with mean age 51.4±11.2 years had low expression. There was a significant association between high expression and advanced tumour grade, advanced tumourstage, higher frequency of triple negative breast cancer and higher frequency of Ki-67-positive cancers (p<0.05). Patients with high C-X-C Motif Chemokine Receptor 1 expression had significantly lower frequency of complete pathological response when compared with patients with low expression (p<0.001). Patients with high expression had higher frequency of recurrence, shorter disease-free survival, higher mortality and shorter overall survival, but the difference was not significant (p>0.05). Multivariate logistic regression analysis identified triple negative hormonal status (p=0.031) and high baseline C-X-C Motif Chemokine Receptor 1 expression (p<0.001) as significant predictors of complete pathological response. There was found to be a link between baseline C-X-C Motif Chemokine Receptor 1 expression in breast cancer tissues and pathological response to neoadjuvant therapy in breast cancer patients.

Unveiling the Power of Anticancer Drug Screening: A Clinical Case Study Comparing the Effectiveness of Hollow Fiber Assay Microtube Array Membrane (MTAM-HFA) in Breast Cancer Patients.

Breast cancer is a severe public health problem, and early treatment with powerful anticancer drugs is critical for success. The researchers investigated the clinical results of a novel screening tool termed Microtube Array Membrane Hollow Fiber Assay (MTAM-HFA) in breast cancer patients in this clinical investigation. In all trial participants, the MTAM-HFA was utilized to identify active medicines for the treatment of breast cancer. The MTAM-HFA was shown to be extremely useful in predicting patient response to anticancer medication therapy in this study. Furthermore, the substantial association between the MTAM-HFA screening outcome and the clinical outcome of the respective patients emphasizes the promise of this unique screening technology in discovering effective anticancer medication combinations for the treatment of breast cancer. These findings indicate that the MTAM-HFA has clinical significance and might be a valuable tool in the development of tailored therapy for cancer care. This study provides helpful information for physicians and scientists working on breast cancer therapy research. The potential benefits of employing MTAM-HFA to find accurate therapies for breast cancer patients might lead to enhanced personalized medicine approaches to cancer care, resulting in better patient outcomes. Overall, the MTAM-HFA screening approach has the potential to revolutionize customized cancer therapy, providing hope to both patients and physicians.

Choosing a breast reconstruction method when planning radiotherapy in breast cancer patients

The list of indications to adjuvant radiation therapy for breast cancer patients was extended in recent years, regardless of the type of reconstruction. Surgeons and radiologists have to choose the most appropriate sequence of reconstruction and to reduce the risk of complications. Radiotherapy is one of the main factors causing complications in patients undergoing breast reconstruction, and vice versa, the implant might hinder radiotherapy, preventing proper delivery of the required radiation dose. Both oncologists and radiologists try to reduce the incidence of complications, which is an important interdisciplinary aim. This article investigates international experience of well-known cancer centers and experience of the Department of Oncology and Reconstructive Breast and Skin Surgery, P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Radiology Research Center, Ministry of Health of Russia. We analyzed the choice of the breast reconstruction method in patients undergoing radiotherapy after surgery and developed recommendations for choosing an optimal method of reconstructive surgery.

Topometric Preparation and Contouring in Radiotherapy Planning Patients after Breast Reconstruction with Syntetic Materials

Purpose: Set out and substantiate basing on contemporery data and personal experience the key features and nuances of topometric preparation and contouring of the irradiated volumes when planning external beam radiation therapy in breast cancer patients after immediate reconstruction with usage of synthetic materials.&#x0D; Materials and methods: In terms of this article are outlined the main provisions regarding topometric preparation, the need of expander deflation, the determination of irradiated volumes, and the effects of the metal port of the expander on the dose distribution.&#x0D; Results: Evidence-based recommendations on the implementation of such stages of the technological chain of external beam radiation therapy, as topometric preparation and contouring of irradiated volumes in patients with breast cancer after immediate reconstruction with synthetic materials, are briefly presented.

P128 Intraoperative Ultrasound Guided Tailored Axillary Surgery After Neoadjuvant Therapy in Breast Cancer Patients

P128 Intraoperative Ultrasound Guided Tailored Axillary Surgery After Neoadjuvant Therapy in Breast Cancer Patients

Acute myocarditis during adjuvant therapies for breast cancer: a case report

BackgroundWith the improvement of optimal perioperative drug therapy for breast cancer patients, physicians now have to treat the adverse effects and comorbidities associated with long-term treatments. We report a case who suffered cardiac arrest due to acute myocarditis developed after initiation of adjuvant treatment.Case presentationAfter completing preoperative chemotherapy and undergoing curative surgery for right breast cancer, a 46-year-old female patient started adjuvant tamoxifen and resumed trastuzumab. Two months later, she complained fever and dyspnea. Blood tests showed a marked increase in hepatic enzymes, and the patient was rushed to our emergency room on suspicion of drug-induced liver injury. In the emergency room, the patient went into cardiac arrest shortly after tachycardia with ST-segment elevation appeared on the monitored electrocardiogram. Resuscitation was started immediately and tracheal intubation, intra-aortic balloon pumping, and extracorporeal membrane oxygenation were started. Coronary angiography results were negative for ischemic heart disease. A diagnosis of fulminant myocarditis was made and steroid pulse therapy and immunoglobulin therapy were started. After the start of treatment, the symptoms of heart failure improved steadily and the patient was discharged on the 28th day. Histological findings of the myocardial biopsy revealed degeneration and necrosis of myocardial cells with marked lymphocytic infiltration, consistent with the histology of lymphocytic myocarditis. Serum cytomegalovirus, coxsackie B virus and adenovirus antibodies were all elevated and these findings were consistent with acute viral myocarditis.ConclusionsWe report a case with strong indications for therapy-induced liver damage, who was ultimately diagnosed with acute viral myocarditis and successfully treated with multidisciplinary therapy. We believe that our findings would be useful for other clinicians in managing similar patients.

Adherence to oral anticancer hormonal therapy in breast cancer patients and its relationship with treatment satisfaction: an important insight from a developing country

BackgroundHormone-positive breast cancer is the most common type and represents a burden in all countries. Treatment satisfaction might be a predictor for adherence, as higher satisfaction with medication encourages patients to adhere appropriately to the medication and, consequently, successfully achieve the treatment goals. The present study evaluated the adherence of women with hormone-positive breast cancer to oral hormonal drugs and correlated it with treatment satisfaction and other sociodemographic and clinical factors.MethodsA cross-sectional design was applied. This study included two cancer centers. Data were collected from patients through face-to-face interviews and medical record reviews. The Medication Adherence Scale was adapted to assess medication adherence, and the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4 was adopted to measure treatment satisfaction.ResultsThe final analysis included 106 patients, with a mean age ± SD of 51.9 ± 1.2. Approximately 35% were hospitalized in the past year. Current hormonal therapy among cancer patients included letrozole (38.7%), tamoxifen (31.1%), exemestane (17%), and anastrozole (13.2%). The median adherence score was 5.0 [4.8–6.0], and 62.3% adhered fully to their oral hormonal drugs in the past week. The median scores of effectiveness, side effects, convenience, and global satisfaction were 66.67 [61.11.0–72.22], 75.00 [48.44–100.00], 66.67 [66.67–72.22], and 71.43 [57.14–78.57], respectively. A significantly lower adherence score was identified in patients living in camps (p = 0.020). Patients with comorbidities and those who continued on the same hormonal therapy had higher adherence scores, although they were not statistically significant. Multiple linear regression analysis showed that two domains of treatment satisfaction, side effects (p = 0.013) and global satisfaction (p = 0.018), were predictors of adherence to oral hormonal drugs.ConclusionsThe current study revealed a significant association between treatment satisfaction and adherence to oral hormonal therapy. We recommend creating a specialized scale to measure adherence, considering the psychosocial factors that affect hormonal anticancer medication adherence.

Abstract P1-10-07: Role of postmastectomy radiation therapy in breast cancer patients according to pathologic nodal status after neoadjuvant chemotherapy

Abstract Purpose: The role of post-mastectomy radiation therapy (PMRT) in breast cancer patients after neoadjuvant chemotherapy (NAC) is highly controversial. This study aimed to evaluate the impact of PMRT according to pathologic nodal status. Methods and Materials: We retrospectively reviewed 682 patients with clinical stage II-III breast cancer who underwent NAC and mastectomy from 2013 to 2017. Of total, 596 (87.4%) received PMRT and 86 (12.6%) did not. We investigated the relationship amongst locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), overall survival (OS), and various prognostic factors. Subgroup analyses to identify the patients who may benefit from PMRT were also performed. Results: The median follow-up duration was 67 months. In ypN+ patients (n = 368, 51.2%), PMRT showed significant benefit for LRRFS, DFS, and OS (all p &amp;lt; 0.001). Based on multivariate analysis, histologic grade (HG) III (hazard ratio [HR] = 3.67, p = 0.002), lymphovascular invasion (LVI) (HR = 2.38, p = 0.045), and ypN2-3 (HR = 2.37, p = 0.02) were identified as significant risk factors for poor LRRFS. In ypN1 patients with more than two factors among (i) luminal subtype (ii) HG I-II and (iii) absence of LVI, PMRT showed no significant difference in LRRFS (p = 0.18). In ypN0 patients (n = 351, 48.8%), PMRT was not significantly associated with LRRFS, DFS, and OS. However, PMRT showed better LRRFS in triple-negative breast cancer (TNBC) subtype (p = 0.04). Conclusion: PMRT had a high impact on treatment outcomes in patients with residual lymph nodes following NAC and mastectomy. Among the ypN0 patients, PMRT may be beneficial only in the TNBC subtype. Citation Format: Dowook Kim, Jin Ho Kim, In Ah Kim, Ji Hyun Chang, Kyung Hwan Shin. Role of postmastectomy radiation therapy in breast cancer patients according to pathologic nodal status after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-07.

Abstract PD12-07: PD12-07 The effect of BMI on the pathological response after neoadjuvant systemic therapy in breast cancer patients: a nationwide retrospective study

Abstract Background: Neoadjuvant systemic therapy is increasingly applied in breast cancer patients to improve surgical and oncological outcomes. There is only limited data from clinical practice on the relevance of body mass index (BMI) on the pathologic complete response (pCR) rate following neoadjuvant systemic treatment (NST). We aimed to retrospectively analyze the impact of BMI on pCR after NST for Dutch breast cancer patients. Methods: Patients diagnosed with invasive breast cancer between 2019 and 2021 who were treated with NST followed by a surgical procedure, were selected from the Netherlands Cancer Registry (NCR). Patients were divided into three groups based on BMI: patients with underweight/normal weight (BMI&amp;lt; 25 kg/m2), patients with overweight (BMI 25-29.9 kg/m2) and patients with obesity (BMI&amp;gt;30 kg/m2). Patients with unknown BMI, ER/PR/HER2 or pCR status were excluded for analysis. The primary outcome was pCR after NST. The association between BMI and pCR was estimated using logistic regression models with the expression of odds ratios (ORs). Results: After applying in- and exclusion criteria, 4430 patients were included for analysis, statified into four molecular breast cancer subtypes; HR+/HER2- (n=2256), HR+/HER2- (n=722), HR-/HER2+ (n=405) and HR-/HER2- (n=1047). The predictors age, differentiation grade, histological type, clinical tumor (cT) and nodal (cN) stage and molecular breast cancer subtype were found siginificant for achieving pCR after NST. Multivariabele regression analysis identified differentiation grade, cT and cN stage and molecular subtype as independent predictors for pCR after NST. There was no association between pCR and (continuous or categorical) BMI. Above mentioned analyses performed by stratification according to molecular breast cancer subtype, also showed no statistically meaningful association between BMI and pCR. Conclusion: In this nationwide retrospective cohort study, evaluating 3340 patients with invasive breast cancer, we found no evidence of BMI being a predictive factor for achieving pCR following NST in neither the whole cohort, nor stratified according to molecular breast cancer subtype. Table 1. Multivariable regression analysis of the total cohort Citation Format: Britt Jansen, Anke Gielen, Mariette Agteroff, Marissa van Maaren, Sandra Beijer, Martine Moossdorff, Marjolein Smidt, Emily Postma. PD12-07 The effect of BMI on the pathological response after neoadjuvant systemic therapy in breast cancer patients: a nationwide retrospective study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD12-07.

Abstract P4-03-19: Expected real-world impact of escalation and de-escalation of Her2-directed therapy in breast cancer patients receiving neoadjvuant therapy

Abstract Background: For patients with palpable, early stage, Her2+ breast cancer, neoadjuvant therapy (NAT) is the preferred approach to curative treatment. While Trastuzumab (T) is standardly included in NAT protocols globally, there is variable ability to escalate or potentially de-escalate therapy due to perceived cost/benefit of additional Her2 targeting therapies, such as Pertuzumab (P) in the early stage setting. The impact of neoadjuvant Pertuzumab (NeoP) does have potentially significant impact on the need for therapeutic interventions in the setting of recurrence. It is challenging to estimate the real world impact financially on escalated therapy in the neoadjuvant setting and likewise the long-term effects of cost of recurrent therapy. We wanted to assess and estimate the impact of NeoP addition to T in British Columbian patients with Her2+ early breast cancer, and estimate incremental impact on short and long-term costs to our cancer system. Methods: Utilizing quality assurance database prospectively updated at BC Cancer Vancouver, we extracted cases of patients with Her2+ breast cancer who received NAT between 2012 – 2021 to provide real world estimations of prevalence of cases and estimated annual costs. Descriptive statistics were utilized to calculate rate of pCR in patients receiving neoadjuvant her2 directed therapy. Expected rates of improvement in pCR with the addition of NeoP were extracted from meta-analyses of Her2 directed therapy in the neoadjuvant setting. The publicly available national pCODR Ecomonic Guidance Reports were utilized to identify cost per cycle per patient of Pertuzumab, Trastuzumab, TDM-1 and chemotherapy in the Canadian healthcare system. The additional cost of NeoP per centre, per year, was compared to the current cost of non-Pertuzumab containing neoadjvuant regimen. Based on recurrence data collected from the database, the expected impact of NeoP on rate of recurrence and subsequent need for Her2 directed therapy in the metastatic setting was calculated. Results: 347 patients with HER2+ breast cancer received neoadjuvant T + chemotherapy at the BC Cancer Vancouver Centre between May 2012 and May 2022. 137 patients (39.5%) achieved pCR and 210 (60.5%) did not achieve pCR. Of those who did not achieve pCR, 12% recurred and 6% died, compared to only 5% and 1% respectively in the group that did achieve pCR. Based on a risk ratio of 1.57, we calculated the expected rate of pCR in our real world cohort would have increased from 39.5% to 62.3% with the availability of NeoP routinely. For each year of data in our cohort, an average of 40 patients with Her2 positive disease were treated with neoadjvant therapy. Using modeling based on our real world cohort we predicted an added cost of $669,920 to provide neoadjuvant pertuzuamb at one Canadian Cancer centre per year. Based on extraction of data from current state, where adjvuant TDM-1 is provided for 13 cycles in the setting of no PCR, the adjuvant TDM-1 costs were estimated to be $1, 729, 151 without NeoP and $1,067377 with NeoP. The cost difference for addition of NeoP in the treatment of early Her2+ breast cancer at one Canadian Centre per year was calculated as $8,146 increase in cost. In patients who had recurrence in our cohort we observed a shorter median survival than expected with most patients succumbing to their recurrence within a 2-3 year period. We expanded our modeling to assess the incremental impact on estimated cost of treatment for those who may recur. We estimated a cost saving of $85,054 per centre, per year, related to decrease in risk of recurrence of Her2+ breast cancer in those who receive NeoP. Conclusion: While the additional cost per centre of adding NeoP was $8146, the subsequent decrease in expected rate of recurrence resulted in a cost savings of $85,054. Citation Format: Andrew Mollenthiel, Aidan Morris, Corke Lauren, Christine Simmons. Expected real-world impact of escalation and de-escalation of Her2-directed therapy in breast cancer patients receiving neoadjvuant therapy. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-19.

Chromosomal radiosensitivity of human breast carcinoma cells and blood lymphocytes following photon and proton exposures

Breast carcinomas (BC) are among the most frequent cancers in women. Studies on radiosensitivity and ionizing radiation response of BC cells are scarce and mainly focused on intrinsic molecular mechanisms but do not include clinically relevant features as chromosomal rearrangements important for radiotherapy. The main purpose of this study was to compare the ionizing radiation response and efficiency of repair mechanisms of human breast carcinoma cells (Cal 51) and peripheral blood lymphocytes (PBL) for different doses and radiation qualities (60Co γ-rays, 150 MeV and spread-out Bragg peak (SOBP) proton beams). The radiation response functions obtained using the conventional metaphase assay and premature chromosome condensation (PCC) technique enabled us to determine the number of chromosomal breaks at different time after irradiation. Both cytogenetic assays used confirmed the higher biological radiosensitivity for proton beams in tumor cells compared to PBL, corresponding to higher values of the linear LQ parameter α. additionally, the ratio of the LQ parameters β/α describing efficiency of the repair mechanisms, obtained for chromosome aberrations, showed higher numbers for PBL than for Cal 51 for all exposures. Similar results were observed for the ratio of PCC breaks determined directly after irradiation to that obtained 12 h later. This parameter (t0/t12) showed faster decrease of the repair efficiency with increasing LET value for Cal 51 cells. This finding supports the use of the proton therapy for breast cancer patients.

Adherence to Adjuvant Endocrine Therapy in Breast Cancer Patients.

Adjuvant endocrine therapy (AET) reduces breast cancer recurrence and mortality of women with hormone-receptor-positive tumors, but poor adherence remains a significant problem. The aim of this study was to analyze AET side effects and their impact on adherence to treatment. A total of 373 breast cancer patients treated with AET filled out a specific questionnaire during their follow up visits at the Breast Unit of our Centre. Side effects were reported by 81% of patients, 84% of those taking tamoxifen and 80% of those taking aromatase inhibitors (AIs). The most common side effect in the tamoxifen group was hot flashes (55.6%), while in the AI group it was arthralgia (60.6%). The addition of GnRH agonists to both tamoxifen and AI significantly worsened all menopausal symptoms. Overall, 12% of patients definitively discontinued AET due to side effects, 6.4% during the first 5 years and 24% during extended therapy. Patients who had previously received chemotherapy or radiotherapy reported a significantly lower discontinuation rate. AET side effects represent a significant problem in breast cancer survivors leading to irregular assumption and discontinuation of therapy. Adherence to AET may be improved by trustful patient-physician communication and a good-quality care network.

Mammographic assessment of breast density as a tool for predicting the response to neoadjuvant therapy in breast cancer patients.

Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer-related death among women worldwide. For locally advanced diseases and high-risk tumors, neoadjuvant therapy (NAT) is the treatment of choice. Some studies show that mammographic density (MD) tumor margins and the presence of microcalcifications play a prognostic role in BC patients. Hence, the objective of this retrospective study was to assess if MD could predict the response to NAT among different molecular subtypes of BC patients undergoing NAT at The "Prof. Dr I. Chiricuta" Oncology Institute of Cluj-Napoca, Romania (IOCN). Furthermore, the association between MD, tumor margins and the presence of microcalcifications with clinico-pathological data was analyzed. Eighty-four breast cancer patients diagnosed and treated at IOCN were included in this study. The morphological characteristics of the tumors were framed according to the BIRADS lexicon. The presence or absence of microcalcifications was also assessed. First, the significance of associations between breast density, margins and microcalcifications and clinico-pathological parameters of the patients were tested with Fisher or Fisher-Freeman-Halton Exact Test. Next, using multinomial logistic regression, we modelled the associations between the pathological response measured by Miller Payne and Residual cancer burden (RCB) systems and the BI-RADS. Variables having significant univariate tests were selected as candidates for the multivariable analysis (adjusted model). Breast densities were significantly associated with the age of the patients (p=0.01), number of positive lymph nodes (p=0.037), margins (p=0.002) and combined categories of Miller-Payne (p=0.034) and RCB pathological response (p=0.021). Margins was significantly associated with ki67 proliferation index (p=0.029), estrogen receptor (ER) (p=0.007), progesterone receptor (PR) (p=0.019), molecular subtype (p<0.001) and the number of clinically observed positive lymph nodes at diagnosis (p=0.019). In our cohort, BC patients with lower MD had higher odds of achieving pCR following NAT, suggesting the role of MD as a clinical prognostic marker. Larger multicenter studies are warranted to validate the prognostic value of MD, which could aid in patients stratification based on their likelihood to respond to NAT.

Adjuvant Therapy in Breast Cancer Patients With Microscopic Residual Disease

IntroductionSurgical resection is the gold standard for early-stage breast cancer. Positive surgical margins are associated with poor outcome. Endocrine therapy (ET) is recommended as primary systemic treatment for hormone receptor positive (HR+) breast cancer after surgery. We hypothesized that chemoenocrine therapy (CET) would not be associated with improved survival relative to ET for patients with positive margins. Materials and methodsThe National Cancer Database was queried for pathologic stage I HR + HER2-breast cancer patients treated with partial mastectomy and adjuvant whole-breast irradiation between 2004 and 2017. The adjuvant treatment approaches to positive surgical margins were investigated and compared. Overall survival was compared between systemic treatment groups using multivariable cox proportional hazards regression. ResultsAmong 228,453 patients, a positive surgical margin (microscopic residual disease, R1) was identified in 3561 (1.6%) patients. Compared with complete resections, positive margin was associated with inferior overall survival (hazard ratio [HR] = 1.276, P = 0.003). Among the R1 patients, 78.7% received ET only, 11.7% received CET, 1.2% received chemotherapy only, and 8.5% received no systemic therapy. After controlling for patient, facility, and tumor characteristics, ET provided greatest survival benefit (relative to no therapy, HR = 0.378, P < 0.001) followed by CET (HR = 0.446, P = 0.020). Compared with ET alone, CET is not associated with additional overall survival benefit (HR = 1.179, P = 0.595). ConclusionsCET appeared not to be associated with an improved overall survival in early stage HR + HER2-breast cancer with microscopic residual disease relative to ET. Positive surgical margins therefore are probably not a relevant clinical factor for adjuvant chemotherapy decision-making.

Heterogeneity in hormone-dependent breast cancer and therapy: Steroid hormones, HER2, melanoma antigens, and cannabinoid receptors

Breast cancer is the most frequently diagnosed cancer and the leading cause of death by cancer among women worldwide. The prognosis of the disease and patients’ response to different types of therapies varies in different subgroups of this heterogeneous disease. The subgroups are based on histological and molecular characteristics of the tumor, especially the expression of estrogen (ER) and progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Hormone-dependent breast cancer, determined predominantly by the presence of ER, is the most common type of breast cancer. Patients with hormone-dependent breast cancer have an available targeted therapy, however, tumor cells can develop resistance to the therapy, which is a major obstacle limiting the success of treatment and enabling relapse to metastatic disease. The complicated crosstalk of both tumor-intrinsic and exogenous factors may contribute to endocrine resistance, although the underlying molecular details are still enigmatic. For example, the expression of the melanoma antigen genes (MAGE) correlates with a worse clinical prognosis and therapy resistance in many types of cancers, including breast cancer. Recent studies suggested that cancers co-opt MAGEs’ physiological functions to promote therapy resistance and potentially metastasis development. The response to the therapy can be also affected by the concurrent use of alternative therapy, e.g., cannabinoid use is popular among breast cancer patients. Cannabinoids interact with endogenous estrogen function, however, how they interfere with breast cancer therapy is still poorly understood. In this review, we summarize the role of ER, PR, and HER2 in hormone-dependent breast cancer; provide current knowledge of MAGEs and cannabinoid receptors in breast cancer; ultimately discuss the potential interlacement of their signaling paths which may underlay diverse responses to therapies in breast cancer patients simultaneously using cannabinoids. These interactions are poorly understood but critical for the advancement of conventional and complementary treatment options for patients, particularly the ones with metastatic disease.

Use of Aromatase Inhibitors in the Treatment of EstrogenDependent Breast Cancer and its Impact on Bone Health

With more than 1 in 10 new cancer diagnoses each year, breast cancer is the most common cancer in women and is responsible for being the second leading cause of cancer-related death among women worldwide. Among breast cancers, the majority diagnosed are estrogen-receptor-positive or estrogen-dependent breast cancers. Aromatase inhibitors are an effective form of targeted therapy for patients with estrogen-dependent breast cancer. The selective estrogen-receptor modulator tamoxifen is much less effective than the aromatase inhibitors anastrozole, letrozole, and exemestane in preventing recurrence in early breast cancer that is estrogen receptor positive. Selective estrogen-receptor modulators are expected to be replaced by aromatase inhibitors as the first-line adjunctive treatment for several patients. Third-generation aromatase inhibitors are quickly replacing tamoxifen as the endocrine medication of choice for post-menopausal women with breast cancer due to their superior efficacy in both adjuvant and metastatic settings. Aromatase inhibitor therapy for breast cancer patients undoubtedly provides benefits, particularly in terms of increased disease-free survival, but it may also have detrimental longterm effects on bone health. Lack of estrogen will invariably cause bone loss since any treatment that reduces estrogen could result in bone loss. The use of aromatase inhibitors is associated with an increased risk of fractures and accelerated rates of bone loss. The purpose of this research is to review the available information about the use of aromatase inhibitors in the treatment of estrogen-dependent breast cancer and their impact on bone health.

A service evaluation of joint working across sectors to promote self-administration of subcutaneous systemic anti-cancer therapy in breast cancer patients

Abstract Introduction Trastuzumab(T) is a humanized monoclonal antibody used in the treatment of HER2-positive breast cancer and is available as a subcutaneous(sc) formulation thereby allowing short and convenient administration. A lack of trained nurses to administer T at home and/or train patients at home to self-administer, together with challenges in maintaining cold-chain delivery have impeded uptake of home administration.1,2 In order to support patients’ ability to self-administer T at home, we have implemented an educational programme that includes nurse-led training, education material, support apps and follow-up telephone clinics. Home delivery of pre-filled syringes was enabled in collaboration with commercial providers for aseptics and logistic. Aim The aim of this service evaluation was to evaluate the utility of this programme from the patients’ perspective and to assess patient satisfaction and impact on quality of life (QOL). Methods A previously validated Self-Injection Assessment Questionnaire (SIAQ)3 was modified to assess patient satisfaction, perceptions and impact of the programme. Patients who had agreed to enrol on the ‘self-administration’ scheme, were asked to complete the questionnaire at baseline, at the third training session and at the second self-administered dose. Approval from a Research Ethics Committee is not required for this service evaluation. Results All 14 patients offered the questionnaire responded to all questions. The median age was 58 years old (age range 43-76), 11 patients were Caucasian, 2 were Asian and one was African/Caribbean. The average distance from their home address to hospital was 10.1 miles (range 4-19). Following completion of the one-to-one nurse training there was an improvement in patient confidence to self-administer sc. T. No differences in ‘feeling in control of their treatment’ or ‘satisfaction of attending hospital appointments’ were noted. Of the 11 patients who reached the self-administration stage, 10 reported that they felt ‘very confident’ and 8 reported that it was ‘very easy’ to give themselves the injection. All patients rated themselves ‘very satisfied’ with self-administration and reported that the nurse training programme helped them to be more confident. 10 patients reported that the App and written information was useful as well as the pre- and post- administration telephone clinics. All patients reported that the self-administration programme had a positive impact on their QOL by reducing the number of hospital visits. In the first 4 months of self-administration each patient reduced their hospital attendance by an average of 8 appointments (median=8) equating to 10 hours of time that would have been spent at hospital. Discussion/Conclusion The subcutaneous T self-administration programme was well received by patients. The nurse training sessions and supportive materials enabled patients to feel more confident about self-administration with no reported incidents or adverse events. This led to fewer hospital visits and improved QOL. This programme was critically dependent on the services of a commercial compounder and homecare provider, emphasizing the importance of joint working between the NHS and commercial sector. Evaluation of this programme will continue and will include other agents, including Phesgo® (sc trastuzumab and pertuzumab) which have more patients and will improve the reliability of the results.

EIF4A3-induced circBRWD3 promotes tumorigenesis of breast cancer through miR-142-3p_miR-142-5p/RAC1/PAK1 signaling

CircBRWD3 is a newly discovered circRNA, and its potential function has not been probed. Here, we aimed to molecularly dissect the role of circBRWD3 in the tumorigenesis and progression of breast cancer (BC). qRT-PCR analysis revealed that circBRWD3 expression was dramatically upregulated in BC tissues, a feature that was positively correlated with the poor prognosis of patients with BC. CircBRWD3 knockdown repressed cell proliferation and metastasis, while promoting cell apoptosis in vitro. Consistently, an in vivo circBRWD3 deficiency model exhibited suppressed tumor metastasis and oncogenesis. On the other hand, circBRWD3 overexpression promoted cancer cell activity and tumorigenesis. Further, mechanistic studies elucidated that circBRWD3 sponged both miR-142-3p and miR-142-5p to modulate RAC1 expression, which subsequently activated the RAC1/PAK1 signaling to facilitate the tumorigenesis and progression of BC. Moreover, we discovered that EIF4A3 facilitated circBRWD3 expression by targeting the upstream of BRWD3 pre-mRNA. In conclusion, our study reveals that circBRWD3 facilitates BC tumorigenesis by regulating the circBRWD3/miR-142-3p_miR-142-5p /RAC1/PAK1 axis. In addition, circBRWD3 expression is positively regulated by an RNA-binding protein, EIFA3. Our results provide valuable scientific data for early diagnosis and therapy for breast cancer patients.

Empagliflozin attenuates trastuzumab-induced cardiotoxicity through suppression of DNA damage and ferroptosis

Trastuzumab (TZM) is commonly used for target therapy in breast cancer patients with high HER2 although the cardiotoxicity restricts its clinical usage. DNA damage and ferroptosis are implicated in anti-tumor drug cardiotoxicity. Given the emerging use of SGLT2 inhibitors in clinical cardiology, this study evaluated the impact of SGLT2 inhibitor Empagliflozin on TZM-induced cardiotoxicity, and mechanism involved with a focus on DNA damage and ferroptosis. Adult C57BL/6 mice were challenged with TZM (10 mg/kg/week, i.p.) or saline for six weeks. A cohort of mice received Empagliflozin (10 mg/kg, i.p.) at the same time. Myocardial function, morphology, ultrastructure, mitochondrial integrity, oxidative stress, DNA damage and various cell death domains were evaluated in TZM-challenged mice with or without Empagliflozin treatment. Our data revealed that TZM challenge overtly increased levels of serum LDH and troponin I, promoted adverse myocardial remodeling (increased heart weight, chamber size, cardiomyocyte area and interstitial fibrosis), contractile dysfunction and intracellular Ca2+ mishandling, oxidative stress, lipid peroxidation, mitochondrial ultrastructural damage, DNA damage, apoptosis and ferroptosis, the effects of which were greatly attenuated or mitigated by Empagliflozin with little effects from Empagliflozin itself. In vitro study indicated that induction of DNA damage mimicked TZM-induced lipid peroxidation and cardiomyocyte contractile dysfunction while the ferroptosis inducer erastin mitigated Empagliflozin-offered protection against lipid peroxidation and cardiomyocyte dysfunction (but not DNA damage). Likewise, in vivo and in vitro inhibition of ferroptosis recapitulated Empagliflozin-offered cardioprotection against TZM exposure. Taken together, these data demonstrated that Empagliflozin may be possible candidate drug for TZM cardiotoxicity likely through a DNA damage-ferroptosis-mediated mechanism.