Antibody-Drug Conjugates in Breast Cancer: A Comprehensive Review of How to Selectively Deliver Payloads.

Antibody-drug conjugates (ADCs) have surfaced as a promising group of anticancer agents employing the precise targeting capacity of monoclonal antibodies to transport highly effective cytotoxic payloads. Compared to conventional chemotherapy, they aim to selectively eradicate cancer cells while minimizing off-target toxicity on healthy tissues. An increasing body of evidence has provided support for the efficacy of ADCs in treating breast cancer across various contexts and tumor subtypes, resulting in significant changes in clinical practice. Nevertheless, unlocking the full potential of these therapeutic agents demands innovative molecular designs to address complex clinical challenges, including drug resistance, tumor heterogeneity, and treatment-related adverse events. This thorough review provides an in-depth analysis of the clinical data on ADCs, offering crucial insights from pivotal clinical trials that assess the efficacy of ADCs in diverse breast cancer settings. This aids in providing a comprehensive understanding of the current state of ADCs in breast cancer therapy, while also providing valuable perspectives for the future.

Circulating microRNAs as potential biomarkers in triple-negative breast cancer: a translational research study of the NACATRINE trial.

Liquid biopsy is increasingly vital in monitoring neoadjuvant breast cancer treatment. This study collected plasma samples at three time points from participants in the Neoadjuvant Carboplatin in Triple Negative Breast Cancer (NACATRINE), analyzing miRNA expression with NanoString's nCounter® Human v3 miRNA assay. In the carboplatin arm, four ct-miRNAs exhibited dynamic changes linked to pathologic complete response, with a combined area under the curve of 0.811. Similarly, the non-carboplatin arm featured four ct-miRNAs with an area under the curve of 0.843. These findings underscore the potential of ct-miRNAs as personalized tools in breast cancer treatment, assisting in predicting treatment response and assessing the risk of relapse. Integrating ct-miRNA analysis into clinical practice can optimize decisions and enhance patient outcomes.

Gene expression alterations predict the pathological complete response in triple-negative breast cancer exploratory analysis of the NACATRINE trial.

This exploratory analysis of the Neoadjuvant Carboplatin in Triple Negative Breast Cancer (NACATRINE) study aimed to identify the biomarkers of pathological complete response (pCR) in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC) within the context of a clinical trial. The NACATRINE trial is a phase II, single-center, randomized, open-label clinical trial that investigated the addition of carboplatin to sequential anthracycline- and taxane-based NAC for TNBC. We evaluated the gene expression in untreated samples to investigate its association with pCR, overall survival (OS), and disease-free survival (DFS). RNA was extracted from the tissue biopsy, and the nCounter Breast Cancer panel was used to analyze gene expression. Of the 66 patients included in the gene expression profiling analysis, 24 (36.4%) achieved pCR and 42 (63.6%) had residual disease. In unsupervised hierarchical clustering analyses, differentially expressed genes between patients with and without pCR were identified irrespective of the treatment (24 genes), carboplatin (37 genes), and non-carboplatin (27 genes) arms. In receiver operating characteristic (ROC) curve analysis, 10 genes in the carboplatin arm (area under the ROC curve [AUC], 0.936) and three genes in the non-carboplatin arm (AUC, 0.939) were considered to be potential pCR-associated biomarkers. We identified genes that were associated with improvements in OS and DFS in addition to being related to pCR. We successfully identified gene expression signatures associated with pCR in pretreatment samples of patients with TNBC treated with NAC. Further investigation of these biomarkers is warranted.

Neoadjuvant carboplatin in triple-negative breast cancer: results from NACATRINE, a randomized phase II clinical trial.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is the mainstay of treatment of stages II and III triple-negative breast cancer (TNBC). This study aims to evaluate if the addition of carboplatin to NACT is associated with an increase in the pathological complete response (pCR) rates in TNBC. METHODS: We conducted an open-label phase II randomized clinical trial in a single center in Brazil. Patients with stage II and III TNBC were randomized to receive standard NACT with or without carboplatin. All the patients received doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) both intravenously (i.v.) q21 days for four cycles. Patients were then randomized for additional treatment with weekly (wk) paclitaxel (80 mg/m2 i.v., for 12 cycles) plus wk carboplatin AUC 1.5 (experimental arm) or without wk carboplatin (control arm). Randomization was stratified according to gBRCA status, age, and AJCC 8th edition clinical stage (II vs. III). The primary endpoint was the pathologic complete response (pCR) rate. Secondary endpoints included recurrence-free survival and overall survival. RESULTS: Between 2017 and 2021, 146 patients were randomized, 73 on each arm. The median age was 45 years. Most patients (66.4%) had locally advanced stage III disease, 67.1% had T3/T4 tumors, and 56.2% had clinically positive axillary lymph nodes. Germline BRCA status was available for all patients, and 19.9% had pathogenic BRCA1/2 variants. The pCR rate (ypT0ypN0) was numerically increased by 13.7%, being 43.8% (31 of 73 patients) in the experimental and 30.1% (22 of 73 patients) in the control arm, not meeting the prespecified goal of increasing the pCR in 15% (p-value = 0.08). Survival outcomes are immature. CONCLUSION: The addition of carboplatin to standard NACT in stages II and III TNBC was associated with a non-statistically significant numerical increase in the pCR rate. Follow-up for survival outcomes and translational research initiatives are ongoing.

In silico evidence of Remdesivir action in blood coagulation cascade modulation in COVID-19 treatment.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has demonstrated several clinical manifestations which include not only respiratory system issues but also liver, kidney, and other organ injuries. One of these abnormalities is coagulopathies, including thrombosis and disseminated intravascular coagulation. Because of this, the administration of low molecular weight heparin is required for patients that need to be hospitalized. In addition, Remdesivir is an antiviral that was used against Middle East Acute Respiratory Syndrome, Ebola, Acute Respiratory Syndrome, and other diseases, showing satisfactory results on recovery. Besides, there is evidence suggesting that this medication can provide a better prognosis for patients with COVID-19. AIM: To investigate in silico the interaction between Remdesivir and clotting factors, pursuing a possibility of using it as medicine. METHODS: In this in silico study, the 3D structures of angiotensin-converting enzyme 2 (ACE2), Factor I (fibrinogen), Factor II (prothrombin), Factor III (thromboplastin), Factor V (proaccelerin), Factor VII (proconvertin), Factor VIII (antihemophilic factor A), Factor IX (antihemophilic factor B), Factor X (Stuart-Prower factor), and Factor XI (precursor of thromboplastin (these structures are technically called receptors) were selected from the Protein Data Bank. The structures of the antivirals Remdesivir and Osetalmivir (these structures are called ligands) were selected from the PubChem database, while the structure of Atazanavir was selected from the ZINC database. The software AutoDock Tools (ADT) was used to prepare the receptors for molecular docking. Ions, peptides, water molecules, and other ones were removed from each ligand, and then, hydrogen atoms were added to the structures. The grid box was delimited and calculated using the same software ADT. A physiological environment with pH 7.4 is needed to make the ligands interact with the receptors, and still the software Marvin sketch® (ChemAxon®) was used to forecast the protonation state. To perform molecular docking, ADT and Vina software was connected. Using PyMol® software and Discovery studio® software from BIOVIA, it was possible to analyze the amino acid residues from receptors that were involved in the interactions with the ligands. Ligand tortions, atoms that participated in the interactions, and the type, strength, and duration of the interactions were also analyzed using those software. RESULTS: Molecular docking analysis showed that Remdesivir and ACE2 had an affinity energy of -8.8 kcal/moL, forming a complex with eight hydrogen bonds involving seven atoms of Remdesivir and five amino acid residues of ACE2. Remdesivir and prothrombin had an interaction with six hydrogen bonds involving atoms of the drug and five amino acid residues of the clotting factor. Similar to that, Remdesivir and thromboplastin presented interactions via seven hydrogen bonds involving five atoms of the drug and four residues of the clotting factor. While Remdesivir and Factor V established a complex with seven hydrogen bonds between six antiviral atoms and six amino acid residues from the factor, and Factor VII connected with the drug by four hydrogen bonds, which involved three atoms of the drug and three residues of amino acids of the factor. The complex between Remdesivir and Factor IX formed an interaction via 11 hydrophilic bonds with seven atoms of the drug and seven residues of the clotting factor, plus one electrostatic bond and three hydrophobic interactions. Factor X and Remdesivir had an affinity energy of -9.6 kcal/moL, and the complex presented 10 hydrogen bonds and 14 different hydrophobic interactions which involved nine atoms of the drug and 16 amino acid residues of the clotting factor. The interaction between Remdesivir and Factor XI formed five hydrogen bonds involving five amino acid residues of the clotting factor and five of the antiviral atoms. CONCLUSION: Because of the in silico significant affinity, Remdesivir possibly could act in the severe acute respiratory syndrome coronavirus 2 infection blockade by interacting with ACE2 and concomitantly act in the modulation of the coagulation cascade preventing the hypercoagulable state.

Discrepancies in breast cancer's oncological outcomes between public and private institutions in the southeast region of Brazil: a retrospective cohort study.

Background: Brazil is a middle-income country with inequalities in its healthcare system. The disparities between public and private services affect the diagnosis and treatment of patients with breast cancer. The aim of this study is to assess whether disease-free survival (DFS) and overall survival (OS) are different in public and private specialized centers. Patient and methods: A retrospective cohort study with 1,545 breast cancer patients diagnosed from 2003 to 2011 at Barretos Cancer Hospital-BCH (public group, N = 1,408) and InORP Oncoclinicas (private group, N = 137) was conducted. A 1:1 propensity score matching (PSM) analysis was used to adjust the differences between the groups' characteristics (n = 137 in each group). Results: The median age at diagnosis was 54.4 years. Estimated DFS rates at 1, 5, and 10 years were 96.0%, 71.8%, and 59.6%, respectively, at BCH and 97.8%, 86.9%, and 78%, respectively, at InORP (HR: 2.09; 95% confidence interval [CI], 1.41-3.10; p < 0.0001). Estimated OS rates at 1, 5, and 10 years were 98.1%, 78.5%, and 65.4%, respectively, at BCH and 99.3%, 94.5%, and 91.9%, respectively, at InORP (HR: 3.84; 95% CI, 2.16-6.82; p < 0.0001). After adjustment by PSM, DFS and OS results in 1, 3, and 5 years remained worse in the public service compared to the private service. Conclusion: Patients treated in a public center have worse DFS and OS after a follow-up period of more than 5 years. These results were corroborated after carrying out the PSM.

Molecular Biology of Pediatric and Adult Ovarian Germ Cell Tumors: A Review.

Ovarian germ cell tumors (OGCTs) are rare in adults; indeed, they occur predominantly in children, adolescents, and young adults, and they account for approximately 11% of cancer diagnoses in these groups. Because OGCTs are rare tumors, our current understanding of them is sparse; this is because few studies have investigated the molecular basis of pediatric and adult cancers. Here, we review the etiopathogenesis of OGCTs in children and adults, and we address the molecular landscape of these tumors, including integrated genomic analysis, microRNAs, DNA methylation, the molecular implications of treatment resistance, and the development of in vitro and in vivo models. An elucidation of potential molecular alterations may provide a novel field for understanding the pathogenesis, tumorigenesis, diagnostic markers, and genetic peculiarity of the rarity and complexity of OGCTs.

Management of patients with recurrent/metastatic endometrial cancer: Consensus recommendations from an expert panel from Brazil.

Background: Endometrial cancer is of increasing concern in several countries, including Brazil, in part because of an ageing population, declines in fertility, and the increasing prevalence of obesity. Although endometrial tumors had lagged behind other cancer types in terms of treatment improvements, molecular characterization of these tumors is paving the way for novel therapies and an expansion of the therapeutic arsenal. We aimed to help medical oncologists who manage patients with recurrent or metastatic endometrial cancer in the Brazilian healthcare setting. Methods: The panel, composed of 20 medical oncologists, convened in November 2021 to address 50 multiple-choice questions on molecular testing and treatment choices. We classified the level of agreement among panelists as (1) consensus (≥75% choosing the same answer), (2) majority vote (50% to <75%), or (3) less than majority vote (<50%). Results: Consensus was present for 25 of the 50 questions, whereas majority vote was present for an additional 23 questions. Key recommendations include molecular testing for every patient with recurrent/metastatic endometrial cancer; choice of first-line treatment according to microsatellite instability and HER2, with the addition of programmed death ligand 1 (PD-L1) and hormone receptors (HRs) for second-line therapy; carboplatin and paclitaxel as the preferred option in first-line treatment of HER2-negative disease, with the addition of trastuzumab in HER2-positive disease; pembrolizumab plus lenvatinib as a key option in second line, regardless of HER2, PD-L1 or HRs; and various recommendations regarding treatment choice for patients with distinct comorbidities. Conclusion: Despite the existing gaps in the current literature, the vast majority of issues addressed by the panel provided a level of agreement sufficient to inform clinical practice in Brazil and in other countries with similar healthcare environments.

Evaluation of upper limb lymphoedema and diagnostic accuracy of bioimpedance spectroscopy. A comprehensive validation in a Brazilian population.

Lymphoedema is a complication of breast cancer treatment. Its early diagnosis is related to a good prognosis for lymphoedema treatment. The bioimpedance spectroscopy (BIS) evaluates changes in extracellular fluid. The objective of our study was to evaluate the validity, agreement and accuracy of BIS in the diagnosis of breast cancer-related lymphoedema in a Brazilian population. Methods: This is a prospective, cross-sectional study of a convenience sample of 462 women who underwent surgical treatment for breast cancer (mastectomy or breast-conserving treatment). The validity, agreement and accuracy were performed comparing BIS (lymphoedema index (L-DEX) ≥ 6.5 or 10) with volumetry by water displacement, which is the gold standard for evaluating lymphoedema. Receiver operating characteristic curve was performed. Additionally, other methods like perimetry and indirect volumetry of the upper limbs were compared with water displacement volumetry (direct volumetry), and the BIS were compared with subjective evaluation. Results: Considering L-DEX ≥ 10 the sensitivity of the BIS was 44.1%, specificity 95.4%, positive predictive value (PPV) was 70.7%, negative predictive value (NPV) was 87% and kappa was 0.459. The BIS with L-DEX ≥ 6.5, the sensitivity, specificity, PPV, NPV and kappa were 57%, 88.5%, 55.8%, 89% and 0.452, respectively. Area under curve was 0.724 and a possible cut-off point of L-DEX ≥ 7.35 with sensitivity of 57%, specificity of 90.7% and kappa value = 0.489. Conclusion: Although BIS was significantly associated with the subjective evaluation of lymphoedema, it showed low sensitivity and agreement and moderate correlation when used as a method for diagnosing the condition. Thus, it is not the most valid method for evaluating lymphoedema. In addition, it was not the most accurate method when compared with other objective evaluation tools. Public health resources are scarce and must be used consciously. The knowledge that BIS is not a more accurate method than other, lower-cost instruments allows for better targeting of these resources.

Effect of the association of amantadine and quetiapine in the treatment of rem sleep behavior disorder: case report / Efeito da associação de amantadina e quetiapina no tratamento do distúrbio do comportamento do sono rem: relato de caso / Efecto de la asociación de amantadina y quetiapina en el tratamiento del trastorno del comportamiento del sueño rem: reporte de un caso

The aim was to report the case of a patient with REM sleep behavior disorder, unresponsive to standard treatment and with complete control of the condition after association of amantadine. Female patient, 45 years old, with systemic arterial hypertension and hypothyroidism, referred to neurological care, reporting frequent episodes of nocturnal agitation in the first hours of sleep, with walking and vocalization, waking up easily if called. She complains of drowsiness and anxiety, secondary to the impact of the RBD on her personal life. She mentions previous attempts at drug treatment with benzodiazepines (Bromazepam and Clonazepam), Zolpidem and Trazodone, all without clinical improvement, with Quetiapine being introduced at a low dose (not yet tried) 25mg, with a therapeutic target of 50mg with partial improvement only with 25mg. When trying 50mg, presenting a worsening of the picture. In a new follow-up, therapy with Amantadine 50 mg/day associated with Quetiapine 25 mg/day was started. The patient returned reporting a significant improvement in the condition, less frequent episodes associated with reduced nocturnal movement. After adaptation of the combined therapy, with adjustments in the dose of Amantadine, an increase of 50mg every 14 days up to 200 mg/day, with the possibility of using quetiapine 50mg (balance between the drugs), the patient evolved stable, with a great improvement in the quality of life and absence of new episodes of the sleep disorder.

O objetivo foi relatar o caso de uma paciente com transtorno comportamental do sono REM, sem resposta ao tratamento padrão e com completo controle do quadro após associação de amantadina. Paciente do sexo feminino, 45 anos, com hipertensão arterial sistêmica e hipotireoidismo, encaminhada a atendimento neurológico relatando episódios frequentes de agitação noturna nas primeiras horas de sono, com deambulo e vocalização, despertava facilmente se chamada. Queixa-se de sonolência e ansiedade, secundárias ao impacto do TCSREM em sua vida pessoal. Menciona tentativas prévias de tratamento medicamentoso com benzodiazepínicos (Bromazepam e Clonazepam), Zolpidem e Trazodona, todos sem melhora clínica, sendo introduzido Quetiapina em dose baixa (ainda não tentado) 25mg, com alvo terapêutico de 50mg com melhora parcial apenas com 25mg. Ao tentar 50mg, apresentando piora do quadro. Em novo retorno, iniciou-se terapia com Amantadina 50 mg/dia associada a Quetiapina 25 mg/dia. A paciente retornou referindo melhora significativa do quadro, episódios em menor frequência associados a redução na movimentação noturna. Após adaptação da terapia combinada, com ajustes da dose de Amantadina, aumento de 50mg a cada 14 dias até 200 mg/dia, sendo possível o uso da quetiapina 50mg (equilíbrio entre os fármacos) a paciente evoluiu estável, com grande melhora da qualidade de vida e ausência de novos episódios do distúrbio de sono.

El objetivo fue reportar el caso de un paciente con trastorno de conducta del sueño REM, que no responde al tratamiento estándar y con un control completo de la condición después de la asociación de amantadina. Paciente femenina, de 45 años de edad, con hipertensión arterial sistémica e hipotiroidismo, referida a atención neurológica, reportando episodios frecuentes de agitación nocturna en las primeras horas de sueño, con marcha y vocalización, despertándose fácilmente si se le llama. Se queja de somnolencia y ansiedad, secundarias al impacto de la RBD en su vida personal. Menciona intentos previos de tratamiento farmacológico con benzodiazepinas (Bromazepam y Clonazepam), Zolpidem y Trazodona, todos sin mejoría clínica, con la introducción de quetiapina a una dosis baja (aún no probada) de 25mg, con un objetivo terapéutico de 50mg con mejoría parcial solo con 25mg. Al intentar 50mg, presentando un empeoramiento de la imagen. En un nuevo seguimiento se inició tratamiento con 50 mg/día de amantadina asociado a 25 mg/día de quetiapina. El paciente retornó reportando una mejoría significativa en la condición, episodios menos frecuentes asociados a reducción del movimiento nocturno. Después de la adaptación de la terapia combinada, con ajustes en la dosis de Amantadina, un aumento de 50mg cada 14 días hasta 200 mg/día, con la posibilidad de utilizar quetiapina 50mg (equilibrio entre los fármacos), el paciente evolucionó estable, con una gran mejoría en la calidad de vida y ausencia de nuevos episodios del trastorno del sueño.

Liquid Biopsy as a Tool for the Diagnosis, Treatment, and Monitoring of Breast Cancer.

Breast cancer (BC) is a highly heterogeneous disease. The treatment of BC is complicated owing to intratumoral complexity. Tissue biopsy and immunohistochemistry are the current gold standard techniques to guide breast cancer therapy; however, these techniques do not assess tumoral molecular heterogeneity. Personalized medicine aims to overcome these biological and clinical complexities. Advances in techniques and computational analyses have enabled increasingly sensitive, specific, and accurate application of liquid biopsy. Such progress has ushered in a new era in precision medicine, where the objective is personalized treatment of breast cancer, early screening, accurate diagnosis and prognosis, relapse detection, longitudinal monitoring, and drug selection. Liquid biopsy can be defined as the sampling of components of tumor cells that are released from a tumor and/or metastatic deposits into the blood, urine, feces, saliva, and other biological substances. Such components include circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) or circulating tumor RNA (ctRNA), platelets, and exosomes. This review aims to highlight the role of liquid biopsy in breast cancer and precision medicine.

COVID-19 liver and gastroenterology findings: An in silico analysis of SARS-CoV-2 interactions with liver molecules.

BACKGROUND: Coronavirus disease 19 (COVID-19) has not only been shown to affect the respiratory system, but has also demonstrated variable clinical presentations including gastrointestinal tract disorders. In addition, abnormalities in liver enzymes have been reported indicating hepatic injury. It is known that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) might infect cells via the viral receptor angiotensin-converting enzyme 2 (ACE2) which is expressed in several organs including the liver. The viral Spike glycoprotein binds to ACE2 and must be cleaved by Furin and Type 2 Serine Protease to enter the cells. After that, the Akt/mTOR signaling pathway is activated and several COVID-19 changes are triggered. AIM: To analyze liver and gastrointestinal symptoms and cell signaling pathways triggered by SARS-CoV-2 infection due to virus-liver interactions in silico. METHODS: In this in silico study, the three-dimensional structures of the Akt, mTORC1 and Furin (receptors) were selected from the Protein Data Bank (PDB) and the structures of inhibitors (ligands) MK-2206, CC-223 and Naphthofluorescein were selected from PubChem and ZINC databases. Ligand files were downloaded as 2D structures and converted to optimized 3D structures using ViewerLite 4.2 software. Marvin Sketch® software was used to calculate prediction of the protonated form of inhibitors in a physiological environment (pH 7.4). AutoDock Tools (ADT) software was used to calculate and delimit the Grid box used in the molecular docking of each structure selected in the PDB. In addition, protonated ligands were prepared for molecular docking using ADT software. Molecular docking was performed using ADT software tools connected to Vina software. Analysis of the amino acid residues involved in ligand interactions, as well as ligand twists, the atoms involved in interactions, bond type and strength of interactions were performed using PyMol® and Discovery Studio® (BIOVIA) software. RESULTS: Molecular docking analysis showed that the mTORC1/CC-223 complex had affinity energy between the receptor and ligand of -7.7 kcal/moL with interactions ranging from 2.7 to 4.99 Å. There were four significant chemical bonds which involved two of five polypeptide chains that formed the FKBP12-Rapamycin-Binding (FRB) domain. The strongest was a hydrogen bond, the only polar interaction, and Van der Waals interactions shown to be present in 12 residues of mTORC1's FRB domain. With regard to the Akt/MK-2206 complex there were three Van der Waals interactions and 12 chemical bonds in which seven residues of Akt were involved with all five rings of the MK-2206 structure. In this way, both ASP 388 and GLN 391 bind to the same MK-2206 ring, the smaller one. However, LYS 386 had four chemical bonds with the inhibitor, one with each structure ring, while LYS 387 binds two distinct rings. One of the MK-2206 inhibitor's rings which binds to LYS 387 also binds simultaneously to ILE 367 and LEU 385 residues, and the fifth ring of the structure was involved in a bond with the ALA 382 residue. The hydrogen bonds were the shortest bonds in the complex (2.61 and 3.08 Å) and all interactions had an affinity energy of -8.8 kcal/moL. The affinity energy in the Furin/Naphhofluorescein complex was -9.8 kcal/moL and involved six interactions ranging from 2.57 to 4.98 Å. Among them, two were polar and the others were non-polar, in addition to twelve more Van der Waals interactions. Two distinct hydrogen bonds were formed between Furin and its inhibitor involving GLN 388 and ALA 532 residues. ALA 532 also binds to two distinct rings of Naphthofluorescein, while TRP 531 residue has two simultaneous bonds with the inhibitor. CONCLUSION: Liver infection and signaling pathways altered by SARS-CoV-2 can be modulated by inhibitors that demonstrate significant interaction affinity with human proteins, which could prevent the development of infection and symptoms.

New insights into the discovery of drugs for triple-negative breast cancer metastasis.

INTRODUCTION: Triple-negative breast cancer (TNBC) is of great concern due to its aggressiveness and lack of targeted therapy. For these reasons, TNBC is one of the main causes of death in women, mainly due to metastases. Tumor dissemination has highlighted a set of possible targets, with extensive research into new single-target drugs, in addition to drug repurposing strategies, being undertaken to discover new classes of potential inhibitors of metastasis. AREAS COVERED: The authors here describe the main proposed targets and the bases of their pharmacological inhibition with different chemical compounds. The authors also discuss the state-of-the-art from the latest clinical trials and highlight other potential targets for metastatic TNBC. EXPERT OPINION: In the last decade, oncology research has changed its focus from primary tumors to moving tumor cells, their products, and to the secondary tumor and its surroundings, for the purpose of finding targets to treat metastasis. Consequently, our comprehension of the complexity of the metastatic process has increased drastically, with, furthermore, the discovery of new potential targets. Although promising, the wide range of strategies is still not effective to suppress TNBC metastasis in terms of increasing patient survival or decreasing the number of metastases. Treating or preventing metastasis continues to be a great challenge.

Molecular Biomarkers Predict Pathological Complete Response of Neoadjuvant Chemotherapy in Breast Cancer Patients: Review.

Neoadjuvant chemotherapy (NAC) is often used to treat locally advanced disease for tumor downstaging, thus improving the chances of breast-conserving surgery. From the NAC response, it is possible to obtain prognostic information as patients may reach a pathological complete response (pCR). Those who do might have significant advantages in terms of survival rates. Breast cancer (BC) is a heterogeneous disease that requires personalized treatment strategies. The development of targeted therapies depends on identifying biomarkers that can be used to assess treatment efficacy as well as the discovery of new and more accurate therapeutic agents. With the development of new "OMICS" technologies, i.e., genomics, transcriptomics, and proteomics, among others, the discovery of new biomarkers is increasingly being used in the context of clinical practice, bringing us closer to personalized management of BC treatment. The aim of this review is to compile the main biomarkers that predict pCR in BC after NAC.

Metformin for the treatment of breast cancer: protocol for a scoping review of randomised clinical trials.

INTRODUCTION: Innovation through the repurposing of generic drugs encloses several advantages when compared with the process of developing new drugs from scratch. Metformin is an established and inexpensive antidiabetic drug for which anticancer properties have been hypothesised. A systematic review of observational studies found promising results for metformin related to breast cancer in women with diabetes. Although the number of randomised clinical trials of metformin for the treatment of breast cancer increased over the last decades, the overall landscape of those studies in this heterogeneous field remains unclear. Hence, we designed the present scoping review protocol to map the literature on randomised clinical trials of metformin in the treatment of breast cancer to determine the value and scope of future systematic reviews on this subject and identify research gaps. METHODS: We will search MEDLINE (via PubMed), EMBASE, CENTRAL, LILACS, Web of Science and sources of grey literature. We will include any randomised clinical trial of metformin for the treatment of breast cancer in adult women, and will not impose restrictions regarding context, language or publication date. Two independent reviewers will screen and select studies, and chart the data. We will structure the presentation of our results based on the molecular types of breast cancer, their stages and treatment modalities. ETHICS AND DISSEMINATION: As a literature review, this study is exempt from ethics approval. Findings will be disseminated through presentations in conferences and a peer-reviewed publication. OPEN SCIENCE FRAMEWORK REGISTRATION: osf.io/yquba.

Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial.

BACKGROUND: Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). MATERIALS AND METHODS: NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. RESULTS: Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. CONCLUSION: These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC. IMPLICATIONS FOR PRACTICE: In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.

Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer.

The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole-exome sequencing (WES) was performed in the germline DNA of 52 non-BRCA1/BRCA2/TP53 mutation carrier women at high-risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using information from population and disease specific databases, in silico prediction tools and the American College of Medical Genetics and Genomics (ACMG) criteria. Loss of heterozygosity (LOH) of tumor samples and segregation analyses were performed whenever possible. The variants identified were investigated in a second, independent cohort of 17 BC cases. Pathogenic/Likely Pathogenic variants were identified in known cancer genes such as CHEK2, MUTYH, PMS2, and RAD51C. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer-related genes such as DROSHA and SLC34A2. Interestingly, the variant c.149T>G in the FAN1 gene was identified in two unrelated families, and exhibited LOH in the tumor tissue of one of them. In conclusion, this is the largest Brazilian WES study involving families at high-risk for HBOC which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer.

Using Co-segregation and Loss of Heterozygosity Analysis to Define the Pathogenicity of Unclassified Variants in Hereditary Breast Cancer Patients.

The use of gene panels introduces a new dilemma in the genetics field due to the high frequency of variants of uncertain significance (VUS). The objective of this study was to provide evidence that may help in the classification of these germline variants in terms of their clinical impact and association with the disease in question. A total of 52 unrelated women at-risk for HBOC and negative for BRCA1/BRCA2 pathogenic variants were evaluated through a gene panel comprising 14 breast and/or ovarian cancer susceptibility genes. Of the 453 germline variants identified, 15 variants (classes 3, 4, and 5) in the ATM, BRIP1, CHEK2, MRE11A, MUTHY, PALB2, RAD50, and RAD51C genes were evaluated via databases, co-segregation studies and loss of heterozygosity in the tumor. The co-segregation analysis allowed the establishment of an association with the presence of variants and the risk of cancer for variant c.316C>T in the BRIP1 gene. Four variants of uncertain significance showed loss of heterozygosity in the tumor (ATM c.4709T>C; CHEK2 c.1036C>T; PALB2 c.1001A>G, and RAD50 c.281T>C), which is an indication of pathogenicity. Thus, the present study provides novel evidence that favors the association of variants in moderate-risk genes with the development of hereditary breast cancer.

BR-BCSC Signature: The Cancer Stem Cell Profile Enriched in Brain Metastases that Predicts a Worse Prognosis in Lymph Node-Positive Breast Cancer.

Brain metastases remain an unmet clinical need in breast oncology, being frequently found in HER2-overexpressing and triple-negative carcinomas. These tumors were reported to be highly cancer stem-like cell-enriched, suggesting that brain metastases probably arise by the seeding of cancer cells with stem features. Accordingly, we found that brain-tropic breast cancer cells show increased stem cell activity and tumorigenic capacity in the chick embryo choriallantoic membrane when compared to the parental cell line. These observations were supported by a significant increase in their stem cell frequency and by the enrichment for the breast cancer stem cell (BCSC) phenotype CD44+CD24-/low. Based on this data, the expression of BCSC markers (CD44, CD49f, P-cadherin, EpCAM, and ALDH1) was determined and found to be significantly enriched in breast cancer brain metastases when compared to primary tumors. Therefore, a brain (BR)-BCSC signature was defined (3-5 BCSC markers), which showed to be associated with decreased brain metastases-free and overall survival. Interestingly, this signature significantly predicted a worse prognosis in lymph node-positive patients, acting as an independent prognostic factor. Thus, an enrichment of a BCSC signature was found in brain metastases, which can be used as a new prognostic factor in clinically challenging breast cancer patients.

Inflammatory Breast Cancer: Clinical Implications of Genomic Alterations and Mutational Profiling.

Inflammatory breast cancer (IBC) is a rare and aggressive type of breast cancer whose molecular basis is poorly understood. We performed a comprehensive molecular analysis of 24 IBC biopsies naïve of treatment, using a high-resolution microarray platform and targeted next-generation sequencing (105 cancer-related genes). The genes more frequently affected by gains were MYC (75%) and MDM4 (71%), while frequent losses encompassed TP53 (71%) and RB1 (58%). Increased MYC and MDM4 protein expression levels were detected in 18 cases. These genes have been related to IBC aggressiveness, and MDM4 is a potential therapeutic target in IBC. Functional enrichment analysis revealed genes associated with inflammatory regulation and immune response. High homologous recombination (HR) deficiency scores were detected in triple-negative and metastatic IBC cases. A high telomeric allelic imbalance score was found in patients having worse overall survival (OS). The mutational profiling was compared with non-IBC (TCGA, n = 250) and IBC (n = 118) from four datasets, validating our findings. Higher frequency of TP53 and BRCA2 variants were detected compared to non-IBC, while PIKC3A showed similar frequency. Variants in mismatch repair and HR genes were associated with worse OS. Our study provided a framework for improved diagnosis and therapeutic alternatives for this aggressive tumor type.