Therapy In Breast Cancer Patients Research Articles

The cytosolic iron\u2013sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors

The relationship between ATR/Chk1 activity and replication stress, coupled with the development of potent and tolerable inhibitors of this pathway, has led to the clinical exploration of ATR and Chk1 inhibitors (ATRi/Chk1i) as anticancer therapies for single-agent or combinatorial application. The clinical efficacy of these therapies relies on the ability to ascertain which patient populations are most likely to benefit, so there is intense interest in identifying predictive biomarkers of response. To comprehensively evaluate the components that modulate cancer cell sensitivity to replication stress induced by Chk1i, we performed a synthetic-lethal drop-out screen in a cell line derived from a patient with triple-negative breast cancer (TNBC), using a pooled barcoded shRNA library targeting ~350 genes involved in DNA replication, DNA damage repair, and cycle progression. In addition, we sought to compare the relative requirement of these genes when DNA fidelity is challenged by clinically relevant anticancer breast cancer drugs, including cisplatin and PARP1/2 inhibitors, that have different mechanisms of action. This global comparison is critical for understanding not only which agents should be used together for combinatorial therapies in breast cancer patients, but also the genetic context in which these therapies will be most effective, and when a single-agent therapy will be sufficient to provide maximum therapeutic benefit to the patient. We identified unique potentiators of response to ATRi/Chk1i and describe a new role for components of the cytosolic iron–sulfur assembly (CIA) pathway, MMS19 and CIA2B-FAM96B, in replication stress tolerance of TNBC.

Diagnostic performance of digital breast tomosynthesis for predicting response to neoadjuvant systemic therapy in breast cancer patients: A comparison with magnetic resonance imaging, ultrasound, and full-field digital mammography.

BackgroundThe goals of neoadjuvant systemic therapy (NST) are to reduce tumor volume and to provide a prognostic indicator in assessing treatment response. Digital breast tomosynthesis (DBT) was developed and has increased interest in clinical settings due to its higher sensitivity for breast cancer detection compared to full-field digital mammography (FFDM).PurposeTo evaluate the accuracy of DBT in assessing response to NST compared to FFDM, ultrasound (US), and magnetic resonance imaging (MRI) in breast cancer patients.Material and MethodsIn this retrospective study, 95 stages II–III breast cancer patients undergoing NST and subsequent surgeries were enrolled. After NST, the longest diameter of residual tumor measured by DBT, FFDM, US, and MRI was compared with pathology. Agreements and correlations of tumor size were assessed, and the diagnostic performance for predicting pathologic complete response (pCR) was evaluated.ResultsMean residual tumor size after NST was 19.9 mm for DBT, 18.7 mm for FFDM, 16.0 mm for US, and 18.4 mm for MRI, compared with 17.9 mm on pathology. DBT and MRI correlated better with pathology than that of FFDM and US. The ICC values were 0.85, 0.87, 0.74, and 0.77, respectively. Twenty-five patients (26.3%) achieved pCR after NST. For predicting pCR, area under the receiver operating characteristic (ROC) curve for DBT, FFDM, US, and MRI were 0.79, 0.66, 0.68, and 0.77, respectively.ConclusionDBT has good correlation with histopathology for measuring residual tumor size after NST. DBT was comparable to MRI in assessing tumor response after completion of NST.

Multiparametric Circulating Tumor Cell Analysis to Select Targeted Therapies for Breast Cancer Patients.

Simple SummaryLiquid biopsies may act as a dynamic tool for identification of targets for precision therapy while circumventing limitations of tissue biopsies. In opposite to most liquid biopsy-related studies that analyze limited patient material for only one parameter, this study is based on a longitudinal and multiparametric analysis of circulating tumor cells (CTCs). A metastatic breast cancer patient was followed over a period of three years and analyses of the genome, RNA profiling, and in vitro drug testing on cultured CTCs were performed in a unique manner. We show that combining the strengths of multiple technologies for analysis yielded maximum information on the ongoing disease and, eventually, allowed choosing an effective therapy, which led to a massive reduction in CTC numbers. This approach provides a concept for future detailed longitudinal and multiparametric CTC analyses.Background: The analysis of liquid biopsies, e.g., circulating tumor cells (CTCs) is an appealing diagnostic concept for targeted therapy selection. In this proof-of-concept study, we aimed to perform multiparametric analyses of CTCs to select targeted therapies for metastatic breast cancer patients. Methods: First, CTCs of five metastatic breast cancer patients were analyzed by whole exome sequencing (WES). Based on the results, one patient was selected and monitored by longitudinal and multiparametric liquid biopsy analyses over more than three years, including WES, RNA profiling, and in vitro drug testing of CTCs. Results: Mutations addressable by targeted therapies were detected in all patients, including mutations that were not detected in biopsies of the primary tumor. For the index patient, the clonal evolution of the tumor cells was retraced and resistance mechanisms were identified. The AKT1 E17K mutation was uncovered as the driver of the metastatic process. Drug testing on the patient’s CTCs confirmed the efficacy of drugs targeting the AKT1 pathway. During a targeted therapy chosen based on the CTC characterization and including the mTOR inhibitor everolimus, CTC numbers dropped by 97.3% and the disease remained stable as determined by computer tomography/magnetic resonance imaging. Conclusion: These results illustrate the strength of a multiparametric CTC analysis to choose and validate targeted therapies to optimize cancer treatment in the future. Furthermore, from a scientific point of view, such studies promote the understanding of the biology of CTCs during different treatment regimens.

Effects of short-term existential group therapy for breast Cancer patients

ObjectivesCancer patients who suffer from existential difficulties, including fear of death, isolation, or loss of human relationships, try to accept these fears by exploring the meaning of their life. In particular, early psychological intervention for patients prevents them from psychosocial maladjustment afterwards. Therefore, we have developed the Short-term Existential Group Therapy Program (Short-term EGP) for cancer patients, focusing on relief of existential or spiritual suffering and/or pain. This study aims to statistically evaluate the effects of this program on breast cancer patients within the first year after cancer diagnosis.MethodsThirty-one patients completed our research program. A ninety-minute therapeutic group session was held once a week for 5 weeks. We performed the above assessments three times: just before and after the intervention, as well as a month after the end of intervention. Outcome assessment included measures of spiritual well-being (SELT-M), Mental Adjustment to Cancer (MAC) and Profile of Mood States (POMS).ResultsThe SELT-M “Overall QOL” scores were significantly increased after intervention, and these scores were maintained a month after intervention, particularly in those with high MAC “Hopelessness” scores. Subscales of the SELT-M scores were significantly increased after intervention, and these scores were maintained up to a month after intervention.ConclusionShort-term EGP intervention could be effective in helping patients relieve their existential distress. Some of the treatment effects were maintained a month after the end of the intervention. In addition, Short-term EGP could be particularly effective for those patients who feel hopelessness after cancer diagnosis.Trial registrationRetrospectively registered. University Hospital Medical Information Network (UMIN CTR) UMIN000040651. Registered June 4, 2020.

Value of 18F-FDG PET/CT for predicting axillary pathologic complete response following neoadjuvant systemic therapy in breast cancer patients: emphasis on breast cancer subtype

BackgroundNeoadjuvant systemic therapy (NST) is a widely accepted initial treatment modality that can lead to pathologic downstaging of the axillary disease burden in breast cancer patients. Axillary response as well as baseline 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography with computed tomography (PET/CT) differ between breast cancer subtypes. The value of baseline 18F-FDG PET/CT in predicting axillary response to NST is not yet established, possibly since breast cancer subtype was not taken into account. The purpose of this study was to investigate the value of baseline 18F-FDG PET/CT in predicting axillary response to NST with a specific emphasis on subtype.MethodsPET-parameters derived from the primary tumor as well as the most FDG-avid axillary lymph node were measured on baseline 18F-FDG PET/CT. Overall imaging findings were compared with the gold standard of histopathology of the axillary surgery specimen. Analyses for ER-positive/HER2-negative were performed separately from HER2-positive and TN patients. In addition, separate analyses for clinically node-positive patients were performed.ResultsSixty-six patients with 69 primary tumors were included in this study. Thirty-three axillae contained ER-positive/HER2-negative, 16 HER2-positive, and 20 TN breast cancer. No significant difference in PET-parameters between patients with axillary residual disease and axillary pathologic complete response were found for ER-positive/HER2-negative breast cancer. In the combined HER2-positive/TN subgroup, the SUVmax was significantly lower in patients without residual axillary disease in both the entire cohort and in patients with clinically node-positive disease. In this combined subgroup, a cut-off of 4.89 SUVmax measured on the most FDG-avid axillary lymph node could predict residual axillary disease with a sensitivity, specificity, PPV, and NPV of 90%, 69%, 53%, and 95%, respectively.ConclusionsPredicting axillary response following NST with baseline 18F-FDG PET/CT can be performed when focusing on breast cancer subtypes. The easily computed PET-parameter SUVmax can predict axillary response in HER2-positive and TN breast cancer. This study adds to the accumulating evidence that studies investigating the value of 18F-FDG PET/CT in breast cancer should always take subtypes into account.

Abstract 10797: Applying Cardiotoxicity Risk Prediction Scores in Women with Early-Stage Breast

Background: Cardiotoxicity is a common complication of anthracyclines and HER2-targeted therapies in breast cancer patients. Despite recognized risk factors, accurate prediction of cardiotoxicity risk remains a challenge. We applied 3 published risk prediction scores (Table) to a cohort of women with HER2+ breast cancer treated with anthracycline and trastuzumab and described their predictive accuracy. Methods: Women with stage I-III HER2+ breast cancer treated at the Princess Margaret Cancer Centre (Toronto) between 2006-2019 were identified retrospectively. Those with a pre-therapy MUGA scan or 2D echocardiography and ≥ 3 follow up scans using the same modality were included. CREC criteria were applied to define cardiotoxicity. Three risk prediction scores (Ezaz et al., Romond et al., and HFA-ICOS proformas) were used to classify patients into low/medium/high cardiotoxicity risk according to pretreatment characteristics. The proportion of patients who developed cardiotoxicity across risk categories were compared within each score using chi-square test. Results: Of 629 women (mean age 52.4 ± 10.9 years), 151 (24%) met CREC cardiotoxicity criteria. With the Ezaz et al. score , proportion of patients that developed cardiotoxicity was 24.4% (n = 141/577), 20% (n = 9/45) and 14.3% (n =1/7), in the low, medium, and high predicted risk groups, respectively (p = 0.665). With Romond et al. score , this was 17.9% (n = 40/223), 24.5% (n = 50/204) and 30.5% (n = 61/200), respectively (p = 0.01). HFA-ICOS was 15.5% (n = 30/193), 26.9% (n = 109/404), and 37.5% (n = 12/32), respectively (p = 0.002). Conclusion: In women with early stage HER2+ breast cancer receiving trastuzumab therapy, risk scores by Romond et al., and the HFA-ICOS proformas predict cardiotoxicity risk. However, for both these scores the incidence of cardiotoxicity in the “low” predicted risk group remains high (15.5%-17.9%). Therefore, there remains a need to develop more accurate risk prediction scores.

A pooled analysis of adding olanzapine to guideline-recommended antiemetic therapy for breast cancer patients treated with an anthracycline and cyclophosphamide in prospective and retrospective studies

A pooled analysis of adding olanzapine to guideline-recommended antiemetic therapy for breast cancer patients treated with an anthracycline and cyclophosphamide in prospective and retrospective studies

Heart Failure in Breast Cancer Survivors: Focus on Early Detection and Novel Biomarkers.

Breast cancer survival rate has greatly improved in the last two decades due to the emergence of next-generation anti-cancer agents. However, cardiotoxicity remains a significant adverse effect arising from traditional and emerging chemotherapies as well as targeted therapies for breast cancer patients. In this review, we will discuss cardiotoxicities of both traditional and emerging therapies for breast cancer. We will discuss current practices to detect cardiotoxicity of these therapies with the focus on new and emerging biomarkers. We will then focus on 'omics approaches, especially the use of epigenetics to discover novel biomarkers and therapeutics to mitigate cardiotoxicity. Significant cardiotoxicities of conventional chemotherapies remain and new and unpredictable new forms of cardiac and/or vascular toxicity emerge with the surge in novel and targeted therapies. Yet, there is no clear guidance on detection of cardiotoxicity, except for significant left ventricular systolic dysfunction, and even then, there is no uniform definition of what constitutes cardiotoxicity. The gold standard for detection of cardiotoxicity involves a serial echocardiography in conjunction with blood-based biomarkers to detect early subclinical cardiac dysfunction. However, the ability of these tests to detect early disease remains limited and not all forms of toxicity are detectable with these modalities. There is an unprecedented need to discover novel biomarkers that are sensitive and specific for early detection of subclinical cardiotoxicity. In that space, novel echocardiographic techniques, such as strain, are becoming more common-place and new biomarkers, discovered by epigenetic approaches, seem to become promising alternatives or adjuncts to conventional non-specific cardiac biomarkers.

Cost-effectiveness analysis of antiemetics therapy in breast cancer patients with moderate emetogenic chemotherapy in Prof. Dr. Margono Soekarjo Hospital, Indonesia

Chemotherapy-induced nausea and vomiting (CINV) significantly reduce the life quality of cancer patients. A 5-HT3 receptor antagonist, corticosteroid, and H2-blocker have been used to control moderate nausea and vomit in cancer patients. The exploration of the cost-effectiveness of several antiemetic combinations in breast cancer patients in Prof. Dr. Margono Soekardjo Hospital, Purwokerto, Indonesia was the aim of this research. Seventy-four Breast cancer patients who have prescribed moderate-emetogenic chemotherapy during the year 2017-1019 were included in this research. There were fifteen patients treated with the combination of ondansetron and dexamethasone (OD). Fourteen patients were treated with the combination of ondansetron and ranitidine (OR). Thirty-five patients were treated using ondansetron, dexamethasone, and ranitidine (ODR) combination. The effectiveness was represented by the absence of acute nausea and vomiting after receiving chemotherapy. The ODR combinations showed the highest effectivity on diminishing nausea and vomiting among breast cancer patients (0.400), followed by the OD combination (0.267) and the OR combination (0.214). However, the ODR combination generates the highest cost (4.6 million rupiahs) compared to other antiemetics combinations. Compared to the combination of ondansetron and dexamethasone, the combination of ODR provides higher ICER (ICER of 13 Million Rupiahs per case prevented) than the combination of OR (ICER of 8.5 million Rupiahs per case prevented). In conclusion, the combination of ondansetron, dexamethasone, and ranitidine generates the highest cost. It also provides the highest effectiveness in preventing nausea and vomiting.

Clinical Implications of Geometric and Dosimetric Uncertainties Due to Inter- and Intra-Fractional Movement During Volumetric Modulated Arc Therapy for Breast Cancer Patients

Compared to conventional radiotherapy (RT) techniques, modern RT with fewer fractions and smaller target volumes requires higher accuracy. This study evaluated the necessity of pre-treatment and intra-fractional cone-beam computed tomography (CBCT) by analyzing inter- and intra-fractional CBCT images of breast cancer patients receiving RT.From 57 patients, 1,206 pre-treatment CBCT and 1,067 intra-fractional CBCT images were collected. After positioning the patient according to the three skin markers drawn during simulation, pre-treatment CBCT images were acquired. During partial-arc volumetric modulated arc therapy, a simultaneous intra-fractional CBCT scan was taken as the gantry rotated around the patient. The change in position between simulation and the actual position of the patient before and during RT was assessed according to the differences in x-, y-, and z-axes. After the difference in each axis was measured, the absolute distance between two CT images was measured. Changes in dosimetric parameters were evaluated in selected patients with extreme intra-fractional movement.For right-sided breast cancer patients, left-sided breast cancer patients treated using deep-inspiration breath hold, and left-sided breast cancer patients treated using continuous positive airway pressure, median inter-fractional deviations were 0.53 (range 0.06-2.98) cm, 0.66 (range 0.08-4.41) cm, and 0.69 (range 0.04-3.80) cm and median intra-fractional deviations were 0.14 (range 0.00-0.62) cm, 0.23 (range 0.02-0.96) cm, and 0.24 (0.00-1.15) cm, respectively. Modified plans reflecting large changes in intra-fractional position in 10 selected cases revealed insufficient target coverage in seven cases and more than 20-fold increase in the volume of heart receiving more than 25 Gy of radiation in two cases.Even though the intra-fractional ROM was minimal in most cases, few cases showed huge variations that could significantly affect the goal of RT; therefore, intra-fractional verification might be necessary as well as inter-fractional verification.

Gene mutation can be treated in breast cancer by gene therapy

Breast cancer or carcinoma is mostly characterized by a series of genetic mutations or gene mutations and is therefore ideally place for gene therapy intervention. The aim of gene therapy is to deliver a nucleic acid based drug to either correct or destroy the cells harbouring the genetic aberration. More recently cancer gene therapy has evolved to also encompass delivery of RNA interference technologies, as well as cancer DNA vaccines. However the bottleneck in creating such nucleic acid pharmaceuticals lies in the delivery. Deliverability of DNA is limited as it is circulating nucleases, therefore numerous strategies have been employed to aid with biological transport. This review will discuss some of viral and non viral approaches to breast to breast cancer therapy an present the findings of clinical trials of these therapies in breast cancer patients. Also detailed are some of the most recent developments in non viral approaches to targeting in breast cancer gene therapy. This include transcriptional control, and the development of recombinant, multifunctional bio- inspired system.

"γδT Cell-IL17A-Neutrophil" Axis Drives Immunosuppression and Confers Breast Cancer Resistance to High-Dose Anti-VEGFR2 Therapy.

Angiogenesis is an essential physiological process and hallmark of cancer. Currently, antiangiogenic therapy, mostly targeting the vascular endothelial growth factor (VEGF)/VEGFR2 signaling axis, is commonly used in the clinic for solid tumors. However, antiangiogenic therapies for breast cancer patients have produced limited survival benefits since cancer cells rapidly resistant to anti-VEGFR2 therapy. We applied the low-dose and high-dose VEGFR2 mAb or VEGFR2-tyrosine kinase inhibitor (TKI) agents in multiple breast cancer mouse models and found that low-dose VEGFR2 mAb or VEGFR2-TKI achieved good effects in controlling cancer progression, while high-dose treatment was not effective. To further investigate the mechanism involved in regulating the drug resistance, we found that high-dose anti-VEGFR2 treatment elicited IL17A expression in γδ T cells via VEGFR1-PI3K-AKT pathway activation and then promoted N2-like neutrophil polarization, thus inducing CD8+ T cell exhaustion to shape an immunosuppressive microenvironment. Combining anti-VEGFR2 therapy with immunotherapy such as IL17A, PD-1 or Ly-6G mAb therapy, which targeting the immunomodulatory axis of “γδT17 cells-N2 neutrophils” in vivo, showed promising therapeutic effects in breast cancer treatment. This study illustrates the potential mechanism of antiangiogenic therapy resistance in breast cancer and provides synergy treatment for cancer.

Level of Combined Estrogen and Progesterone Receptor Expression Determines the Eligibility for Adjuvant Endocrine Therapy in Breast Cancer Patients.

Simple SummaryPatients whose breast cancers express low levels of hormone receptor (HR) could be eligible for adjuvant endocrine therapy; however, limited data are available to support this notion. Our retrospective study investigated the characteristics and survival of 6042 breast cancer patients according to four HR groups of combined estrogen and progesterone receptor expression. HR expression levels were prognostic for its recurrence and death of patients with breast cancer. Patients whose tumors expressed high levels of a single HR had the worst survival outcomes, and their risk of death continuously increased even after the 10-year follow-up. Endocrine therapy had a significant benefit for those whose tumors expressed high HR levels and a favorable tendency for patients with tumors expressing low HR levels. We established the value of HR expression level as a prognostic factor and the possible benefit of endocrine therapy for patients whose breast tumors expressed low HR levels.Hormone receptor (HR)-positive breast cancer has a heterogeneous pattern according to the level of receptor expression. Patients whose breast cancers express low levels of estrogen receptor (ER) or progesterone receptor (PgR) may be eligible for adjuvant endocrine therapy, but limited data are available to support this notion. We aimed to determine whether HR expression level is related to prognosis. Tumors from 6042 patients with breast cancer were retrospectively analyzed for combined HR levels of ER and PgR. Low expression was defined as ER 1–10% and PgR 1–20%. Four HR groups were identified by combining ER and PgR expression levels. Patients whose tumors expressed high levels of a single receptor showed the worst survival outcomes, and their risk continuously increased even after the 10-year follow-up. Endocrine therapy had a significant benefit for patients whose tumors expressed high HR levels and a favorable tendency for patients with tumors expressing low HR levels. We established the possible benefit of endocrine therapy for patients whose breast tumors expressed low HR levels. Thus, HR level was a prognostic factor and might be a determinant of extended therapy, especially for patients with high expression of a single receptor.

Influence of Hypofractionated Versus Conventional Fractionated Postmastectomy Radiation Therapy in Breast Cancer Patients With Reconstruction

We aimed to compare breast-related complications between hypofractionated adjuvant postmastectomy radiation therapy (PMRT) and conventional fractionated radiation therapy (RT) in patients with breast cancer undergoing reconstruction by reconstruction surgery type. Data from a total of 396 patients with breast cancer who underwent breast reconstruction after mastectomy between 2009 and 2018 were retrospectively reviewed. All patients received adjuvant PMRT according to either a conventional fractionation or hypofractionation schedule. We analyzed breast-related complications according to the timing of breast reconstruction (immediate or delayed). In cases of delayed reconstruction, only PMRT delivered before final delayed reconstruction was included. A major breast complication was defined as a breast-related toxicity that required reoperation or rehospitalization after the end of RT. The median follow-up time was 35.3 months (range, 8.8-122.7 months). Of all patients, 267 received immediate breast reconstruction and 129 received delayed breast reconstruction. In patients with immediate breast reconstruction, 91 were treated with conventional RT and 176 received hypofractionated RT. The occurrence of major breast-related complications did not differ significantly between the 2 fractionation regimens. Hypofractionated RT did not increase major wound problems (infection and dehiscence) compared with conventional RT. Furthermore, major contracture occurred significantly less frequently in hypofractionated RT. Of the patients who had delayed breast reconstruction, 48 received conventional RT and 81 received hypofractionated RT. There was no difference in the incidence of major breast complications between these 2 RT groups, and no difference in major breast complications were reported for either 1- or 2-stage delayed reconstruction. A time interval of >10 months between PMRT and final definitive reconstruction had a significantly lower incidence of major breast complications. Hypofractionated RT appears to be comparable with conventional fractionated RT in terms of breast-related complications in patients with breast cancer undergoing reconstruction, regardless of breast reconstruction type. An ongoing prospective randomized trial should confirm our findings.

THE POSSIBLE EFFECT OF FLAXSEED EXTRACT ON LETROZOLE-INDUCED POLYCYSTIC OVARY RAT MODEL: CORRELATIVE HISTOLOGICAL AND FUNCTIONAL STUDY

Background: Polycystic Ovary Syndrome (PCOS) is one of the most common metabolic disorders affecting women in the reproductive age leading to infertility/subfertility. It may occur as a complication of Letrozole (LTZ) therapy in breast cancer patients. Objective: This was a preliminary study to assess the possible protective and/or curative effect of flaxseed extract in a letrozole-induced PCO rat model. Material and Methods: Thirty-six adult female albino rats were divided into five main groups: Group I kept as the control group, Group II (Letrozole-induced PCO group), received letrozole solution (3 mg/kg) orally once daily by gastric tube for 21 days. Group III (combined flaxseed and letrozole group), received aqueous flaxseed extract (500 mg /kg/day) orally one hour before letrozole in the same dose and duration as group II, Group IV (recovery group), received letrozole in the same dose and duration as group II and then left without treatment for the next 4 weeks after PCO induction, Group V (flaxseed-treated group), treated with aqueous flaxseed extract orally once daily for the next 4 weeks after PCO induction. At the end of the experiment, final body weight, ovarian weight, blood glucose, serum antioxidants assay, and sex hormones levels were measured. Also, specimens of ovaries were processed for light and electron microscopic studies. Histomorphometric and statistical analyses were done. Results: letrozole-induced PCO resulted in a significant increase in final body weight, ovarian weight as well as abnormal blood glucose, sex steroids hormone levels, and antioxidant assays. Moreover, numerous ovarian cystic follicles, widespread cytoplasmic vacuolation in the granulosa lutein cells, congested blood capillaries, and increased fibrosis within the ovarian medulla were evident in the PCO group in concomitant with a significant increase in area percentage of collagen fibers. The ultrastructural assessment confirmed these distortions. The protective and curative potential of flaxseed is mostly comparable revealed improvement in the final body weight, biochemical markers and histological changes, with the protective effect was more pronounced than the curative one. Conclusion and Recommendation: Flaxseed succeeded in ameliorating letrozole-induced polycystic ovary owing to its phytochemicals, antioxidant and anti-inflammatory properties with folliculogenesis potentials. So, it is recommended to use flaxseed as a co-therapy with letrozole to reduce its hyperandrogenic effects.

Genetic mutation and biological pathway prediction based on whole slide images in breast carcinoma using deep learning

Breast carcinoma is the most common cancer among women worldwide that consists of a heterogeneous group of subtype diseases. The whole-slide images (WSIs) can capture the cell-level heterogeneity, and are routinely used for cancer diagnosis by pathologists. However, key driver genetic mutations related to targeted therapies are identified by genomic analysis like high-throughput molecular profiling. In this study, we develop a deep-learning model to predict the genetic mutations and biological pathway activities directly from WSIs. Our study offers unique insights into WSI visual interactions between mutation and its related pathway, enabling a head-to-head comparison to reinforce our major findings. Using the histopathology images from the Genomic Data Commons Database, our model can predict the point mutations of six important genes (AUC 0.68–0.85) and copy number alteration of another six genes (AUC 0.69–0.79). Additionally, the trained models can predict the activities of three out of ten canonical pathways (AUC 0.65–0.79). Next, we visualized the weight maps of tumor tiles in WSI to understand the decision-making process of deep-learning models via a self-attention mechanism. We further validated our models on liver and lung cancers that are related to metastatic breast cancer. Our results provide insights into the association between pathological image features, molecular outcomes, and targeted therapies for breast cancer patients.

139P HER2+/HR+ breast cancer patients at high risk of relapse derive benefit from extended adjuvant treatment with neratinib: An exploratory analysis from ExteNET study

Randomized clinical trials investigate general and representative patient populations, yet clinical decisions increasingly depend on the characteristics of individual patients. In this exploratory analysis of the ExteNET trial, we tested the efficacy of continuing with 1 year of neratinib after completing adjuvant trastuzumab therapy in breast cancer patients at high risk of relapse.

PO-1893 The dosimetric effect of varying seroma during proton and photon therapy in breast cancer patients

PO-1893 The dosimetric effect of varying seroma during proton and photon therapy in breast cancer patients

Role of epidermal growth factor receptor signaling in a Pt(II)-resistant human breast cancer cell line

Platinum complexes are currently used for breast cancer therapy, but, as with other drug classes, a series of intrinsic and acquired resistance mechanisms hinder their efficacy. To better understand the mechanisms underlying platinum complexes resistance in breast cancer, we generated a [Pt(O,O’-acac)(γ-acac)(DMS)]-resistant MCF-7, denoted as [Pt(acac)2]R. [Pt(O,O’-acac)(γ-acac)(DMS)] was chosen as previous works showed that it has distinct mechanisms of action from cisplatin, especially with regard to cellular targets. [Pt(acac)2]R cells are characterized by increased proliferation rates and aggressiveness with higher PKC-δ, BCL-2, MMP-9 and EGFR protein expressions and also by increased expression of various genes covering cell cycle regulation, invasion, survival, and hormone receptors. These [Pt(acac)2]R cells also displayed high levels of activated signaling kinases Src, AKT and ERK/2. [Pt(acac)2]R cells incubated with [Pt(O,O’-acac)(γ-acac)(DMS)], showed a relevant EGFR activation due to PKC-δ and Src phosphorylation that provoked proliferation and survival through MERK1/2/ERK1/2 and PI3K/Akt pathways. In addition, EGFR shuttled from the plasma membrane to the nucleus maybe acting as co-transcriptional factor. The data suggest that growth and survival of resistant cells rely upon a remarkable increase in EGFR level which, in collaboration with an enhanced role of PKC-δ and Src kinases support [Pt(acac)2]R cell. It could therefore be assumed that combination treatments targeting both EGFR and PKC-δ/Src can improve therapy for breast cancer patients.

Analysis of chest wall breathing motion, setup accuracy and dosimetric stability of VMAT technique radiation therapy in breast cancer patients

Analysis of chest wall breathing motion, setup accuracy and dosimetric stability of VMAT technique radiation therapy in breast cancer patients