Monitoramento do horizonte tecnológico: Medicamentos em desenvolvimento para tratamento do câncer de mama triplo negativo localmente avançado irressecável ou metastático / Monitoring the technological horizon: Drugs in development for the treatment of unresectable or metastatic locally advanced triple negative breast cancer

A DOENÇA: O câncer de mama triplo negativo (CMTN) é definido pela ausência da expressão dos receptores de estrogênio (RE), receptores de progesterona (RP) e receptores do fator de crescimento epidermal humano (HER2 ­ human epidermal growth factor receptor 2), que são marcadores presentes na maioria dos tipos de câncer de mama e utilizados para a definição do tratamento. Em média, entre os casos de câncer de mama, 15 a 20% são definidos como CMTN e mais de 30% desses casos progridem para doença metastática. Diferente dos outros tipos de câncer de mama, sua frequência é maior entre mulheres jovens abaixo de 50 anos, com maior prevalência entre aquelas com 35 anos. Os pacientes com CMTN apresentam geralmente tumores em graus mais avançados e desfechos clínicos ruins em termos de sobrevida global e sobrevida livre de doença. As curvas de sobrevida no CMTN, diferentes de outros subtipos de câncer de mama, são caracterizadas por um aumento na recidiva e uma diminuição na sobrevida durante os primeiros três a cinco anos após o diagnóstico. Apesar de avanços substanciais nos resultados clínicos de novos tratamentos para o câncer de mama nos últimos anos, o subtipo de CMTN permanece uma área com necessidade clínica ainda não atendida. Como não apresentam expressão de RE, RP e HER2, os tratamentos com hormonioterapia e terapia anti-HER2 não estão indicados para esses pacientes, sendo adotada a estratégia de quimioterapia, além da cirurgia e radioterapia, conforme preconizado nas Diretrizes Diagnósticas e Terapêuticas do Carcinoma de Mama. TRATAMENTO DISPONÍVEL: As Diretrizes Diagnósticas e Terapêuticas do Carcinoma de Mama de 2019 não fazem recomendação específica para o tratamento dos pacientes com CMTN. Entretanto, entre os medicamentos utilizados para o tratamento dos tipos de câncer de mama é relatado que a associação do bevacizumabe ao paclitaxel nos pacientes com CMTN proporciona um aumento na taxa de resposta e na sobrevida livre de progressão de doença sem alterar a sobrevida mediana global. De acordo com as Diretrizes de Tratamentos Oncológicos recomendados pela Sociedade Brasileira de Oncologia Clínica (SBOC) de 2021 para o câncer de mama metastático, os pacientes com CMTN devem ser tratados com quimioterapia. O regime deve ser individualizado com base no tamanho, localização e características do tumor; e sintomas e preferências do paciente. Além disso, devem ser considerados a resposta e o intervalo sem progressão com os tratamentos anteriores. Os taxanos e antracíclicos são os medicamentos do tratamento padrão tanto em (neo) adjuvância como na primeira linha de doença metastática. A doxorrubicina e a epirrubicina são os antracíclicos mais comumente usados no tratamento do câncer de mama. A escolha entre os taxanos é determinada pelo tratamento prévio, podendo-se escolher entre o paclitaxel e o docetaxel, de acordo com o perfil de toxicidade e preferência do paciente. No caso de pacientes refratários a antracíclicos e taxanos, existe uma série de opções de tratamentos quimioterápicos, que podem ser utilizados em monoterapia e associados. Os principais medicamentos utilizados em monoterapia são: capecitabina, eribulina, vinorelbine e gemcitabina. As terapias com medicamentos associados mais comumente utilizados são paclitaxel com gencitabina, docetaxel com capecitabina e combinações com platinas6 . Além desses, a adição de bevacizumabe à quimioterapia, em primeira ou segunda linha, resultou em aumento modesto de resposta objetiva e sobrevida livre de progressão, sem aumento de sobrevida global. ESTRATÉGIA DE BUSCA: Os medicamentos em fase de pesquisa clínica para câncer de mama triplo negativo foram identificados, inicialmente, na base de pesquisa clínica Clinicatrials.gov em 19 de abril de 2021, com filtros para estudo de intervenção, em fase 3 de ensaio clínico e em andamento. Foram excluídos da análise os estudos cuja situação estava desatualizada a mais de um ano na base e os estudos cujo objetivo da tecnologia era atuar como adjuvante ou neoadjuvante. Além disso, foram consultados as bases eletrônicas MEDLINE (via PubMed) e EMBASE (via Periódicos Capes) em 19 de abril de 2021; e Cortellis15, da Clarivate Analytics, em 28 de abril de 2021, utilizando o termo "advanced triple negative breast cancer" e seus sinônimos, com filtro para tecnologias em desenvolvimento na fase 3 de ensaio clínico. TECNOLOGIAS EM DESENVOLVIMENTO: Foram identificados 55 ensaios clínicos de fase 3, com 10 tecnologias em desenvolvimento para a indicação estudada e que foram elegíveis para compor este informe20: sacituzumabe govitecan, olaparibe, carelizumabe, pembrolizumabe, toripalimabe, TQB2450, alpelisibe, capivasertibe, ipatasertibe, e bicalutamida. O quadro 1 apresenta essas tecnologias consideradas com informações sobre sua classe terapêutica e situação regulatória nas agências sanitárias FDA, EMA, Health Canada e Anvisa. Algumas tecnologias estão em estágios iniciais do ensaio clínico de fase 3 sem resultados parciais publicados, entretanto, suas características serão descritas nesta seção. São eles: carelizumabe, toripalimabe, TQB2450, alpelisibe, capivasertibe e bicalutamida. CONSIDERAÇÕES FINAIS: O câncer de mama triplo negativo localmente avançado irressecável ou metastático é uma doença heterogênea com um prognóstico ruim e atualmente com poucas opções de tratamento em uso. A aprovação do medicamento atezolizumabe no Brasil, para uso em combinação com nab-paclitaxel trouxe um avanço para o tratamento alvo-direcionado para essa população. Este informe apresentou o panorama das tecnologias mais promissoras em fase de desenvolvimento clínico para a doença. Algumas em vias de administração com maior comodidade posológica, como a via oral (olaparibe, alpelisibe, capivasertibe, ipatasertibe e bicalutamida). A identificação dessas tecnologias neste informe projeta uma expectativa sobre diferentes vias moleculares de combate a doença que podem impactar no prognóstico dos pacientes com câncer de mama triplo negativo localmente avançado irressecável ou metastático. Algumas dessas tecnologias estão em fases finais de pesquisa clínica com resultados publicados e já são autorizadas ou iniciaram seus pedidos nas agências sanitárias internacionais. Entre elas destacam-se o sacituzumabe govitecan e o pembrolizumabe, ambas com autorização de comercialização recente pela agência sanitária dos EUA para a indicação de CMTN. Mesmo sendo essa autorização em um contexto de aprovação acelerada, que necessita de acompanhamento dos resultados dos estudos em andamento, existe um avanço para o tratamento da doença que hoje ainda é considerada com uma necessidade não atendida. O sacituzumabe govitecan obteve bons resultados para os desfechos de sobrevida livre de progressão, sobrevida global e taxa de resposta objetiva. Os resultados com pembrolizumabe, apesar de não indicarem uma diferença grande em relação ao comparador nos desfechos de sobrevida livre de progressão, se mostraram consistentes ao longo do tempo e foram maiores conforme o aumento da expressão de PD-1, indicando que pode existir uma relação direta com esse marcador. As tecnologias em desenvolvimento identificadas estão direcionadas a alvos moleculares específicos do desenvolvimento da doença, de modo que a definição dos subtipos moleculares é essencial para o planejamento das estratégias de tratamento, que cada vez mais serão baseadas em medicina personalizada, como por exemplo, a quantificação da expressão do PD-1 como biomarcador preditivo de benefício para a escolha dos pacientes que devem fazer imunoterapia. Espera-se que a conclusão dos estudos em andamento possa trazer resultados clínicos robustos que possam aumentar as opções terapêuticas do tratamento e assim representar um melhor prognóstico da doença.

Weekly Paclitaxel given concurrently with Durvalumab has a favorable safety profile in triple-negative metastatic breast cancer.

Therapeutic anti-PD-L1 antibodies are safe as a monotherapy, albeit with minimal efficacy in triple-negative breast cancer (TNBC). This trial aimed to test the safety and efficacy of Durvalumab and Paclitaxel in metastatic TNBC. In this open-label, one-arm trial, five cycles of weekly paclitaxel were delivered intravenously (IV) concurrent with Durvalumab that was given IV every 2 weeks. The combination was preceded by one cycle of paclitaxel alone, for immunological priming, followed by Durvalumab solo until disease progression or unacceptable toxicity. Between 2017 and 2019, 14 patients received at least one cycle of the combination therapy. The therapy was safe with no-dose limiting toxicity, except one case of skin lesions. Adverse events (AEs) were reported in 71% of patients, and there was no death due to the combination therapy. Regardless of grade, the most common AEs were headache and peripheral neuropathy, as each happened in four patients (29%), followed by fatigue and skin rash in three patients (21%) each. Grade 3/4 AEs were experienced by three patients (21%), with the most common being headache and anemia, which happened in two patients (14%). The confirmed objective response rate (ORR) was observed in five patients with a median duration of 10.0 months. Median Progression-free survival (PFS) and overall survival (OS) were 5 and 20.7 months, respectively. The combination of Durvalumab and Paclitaxel is safe, leaving room for additional agents. This is the first report on the combination of Durvalumab and Paclitaxel in the treatment of TNBC (NCT02628132).

Efficacy and Safety of Platinum-Based Chemotherapy as First-Line Therapy for Metastatic Triple-Negative Breast Cancer: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Triple-negative breast cancer constitutes approximately 12%-17% of all breast cancer cases, and >33% of patients develop distant metastases. Systemic cytotoxic chemotherapy is the primary treatment for patients with metastatic triple-negative breast cancer; however, the role of first-line platinum-based chemotherapy in these patients remains controversial. This meta-analysis evaluated the efficacy and safety of platinum-based first-line chemotherapy for patients with metastatic triple-negative breast cancer. METHODS: We systematically searched the PubMed, Embase, Cochrane, and Clinical Trials registry databases up to June 1, 2020 to identify randomized controlled trials that investigated platinum-based vs. first-line platinum-free chemotherapy in patients with metastatic triple-negative breast cancer. We used fixed and random effects models to calculate pooled hazard ratios and odds ratios with 95% confidence intervals for progression-free and overall survival, objective response rates, and grade 3 and 4 adverse events. RESULTS: Four randomized controlled trials (N = 590 patients) were included. Platinum-based chemotherapy significantly increased the objective response rates from 43.1% to 62.7% (odds ratio 2.34, 95% confidence interval 1.66-3.28, P < 0.001). Three randomized controlled trials (N = 414 patients) reported survival outcomes. Patients administered platinum-based regimens showed significantly longer progression-free survival (hazard ratio 0.55, 95% confidence interval 0.37-0.82, P = 0.004) and a nonsignificant trend toward improved overall survival (hazard ratio 0.76, 95% confidence interval 0.57-1.00, P = 0.05). Only 2 studies reported the rates of grade 3 and 4 adverse events; grade 3-4 thrombocytopenia was more commonly associated with platinum-based chemotherapy (odds ratio 7.54, 95% confidence interval 1.37-41.60, P = 0.02) and grade 3-4 fatigue with platinum-free chemotherapy (odds ratio 0.23, 95% confidence interval 0.08-0.68, P = 0.008). CONCLUSIONS: First-line platinum-based chemotherapy was associated with significantly increased objective response rates, longer progression-free survival, and a nonsignificant trend toward improved overall survival in patients with metastatic triple-negative breast cancer at the high risk of grade 3-4 thrombocytopenia.

Surface Expression of Kynurenine 3-Monooxygenase Promotes Proliferation and Metastasis in Triple-Negative Breast Cancers.

Kynurenine 3-monooxygenase (KMO) is the pivotal enzyme in the kynurenine pathway and is located on the mitochondrial outer membrane. The dysregulation of KMO leads to various neurodegenerative diseases; however, it is rarely mentioned in cancer progression. Our previous study showed that KMO overexpression in canine mammary gland tumors (cMGT) is associated with poor prognosis in cMGT patients. Surprisingly, it was also found that KMO can be located on the cell membranes of cMGT cells, unlike its location in normal cells, where KMO is expressed only within the cytosol. Since cMGT and human breast cancer share similar morphologies and pathogenesis, this study investigated the possibility of detecting surface KMO in human breast cancers and the role of surface KMO in tumorigenesis. Using immunohistochemistry (IHC), flow cytometry (FC), immunofluorescence assay (IFA), and transmission electron microscopy (TEM), we demonstrated that KMO can be aberrantly and highly expressed on the cell membranes of breast cancer tissues and in an array of cell lines. Masking surface KMO with anti-KMO antibody reduced the cell viability and inhibited the migration and invasion of the triple-negative breast cancer cell line, MDA-MB-231. These results indicated that aberrant surface expression of KMO may be a potential therapeutic target for human breast cancers.

Systemic therapy, survival and end-of-life costs for metastatic triple-negative breast cancer: retrospective SEER-Medicare study of women age ≥65 years.

Aim: To analyze therapy for metastatic triple-negative breast cancer (mTNBC), factors contributing to survival and costs. Patients & methods: Using 2010-2016 SEER-Medicare data, we identified women (≥65 years) with mTNBC. Results: Of 302 eligible patients, 152 (50%) received systemic therapy. In multivariable regression analyses, only age <75 years was associated with therapy receipt (odds ratio: 2.91; 95% CI: 1.79-4.74); and only systemic therapy significantly reduced risk of death (hazard ratio: 0.34; 95% CI: 0.26-0.44). Median overall survival was 13.4 (95% CI: 11.3-15.1) vs 3.3 months (95% CI: 2.7-3.9) in therapy vs no-therapy cohorts. Mean per-patient-per-month costs <30 days before end-of-life/follow-up were $14,100 and $15,600 (2019 USD), respectively. Conclusion: Poor outcomes and high costs indicate need for more effective mTNBC therapy.

Metastatic TNBC is closely associated with a fused mitochondrial morphology and a glycolytic and lipogenic metabolism.

Mitochondria modify their function and morphology to satisfy the bioenergetic demand of the cells. Cancer cells take advantage of these features to sustain their metabolic, proliferative, metastatic, and survival necessities. Understanding the morphological changes to mitochondria in the different grades of triple-negative breast cancer (TNBC) could help to design new treatments. Consequently, this research explored mitochondrial morphology and the gene expression of some proteins related to mitochondrial dynamics, as well as proteins associated with oxidative and non-oxidative metabolism in metastatic and non-metastatic TNBC. We found that mitochondrial morphology and metabolism are different in metastatic and non-metastatic TNBC. In metastatic TNBC, there is overexpression of genes related to mitochondrial dynamics, fatty-acid metabolism, and glycolysis. These features are accompanied by a fused mitochondrial morphology. By comparison, in non-metastatic TNBC, there is a stress-associated mitochondrial morphology with hyperfragmented mitochondria, accompanied by the upregulated expression of genes associated with the biogenesis of mitochondria; both of which are characteristics related to the higher production of reactive oxygen species observed in this cell line. These differences between metastatic and non-metastatic TNBC should provide a better understanding of metastasis and contribute to the development of improved specific and personalized therapies for TNBC.

Real-world effectiveness outcomes in patients diagnosed with metastatic triple-negative breast cancer.

Aim: This study examined treatment patterns and effectiveness outcomes of patients with metastatic triple-negative breast cancer (mTNBC) from US community oncology centers. Materials & methods: Eligible patients were females, aged ≥18 years, diagnosed with mTNBC between 1 January 2010 and 31 January 2016. Kaplan-Meier and Cox regression methods were used. Results: Sample comprised 608 patients with average age of 57.5 years and 505/608 patients (83.1%) received systemic treatment. Overall survival (OS) from first-line treatment found that African-American patients had shorter OS than White (9.3 vs 13.7 months; hazard ratio: 1.35; p = 0.006). Conclusion: More than 15% of women with mTNBC were not treated, indicating a high unmet need. Overall prognosis remains poor, which highlights the opportunity for newer therapies to improve progression-free survival and OS.

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial.

BACKGROUND: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer. METHODS: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine-carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Eligibility criteria included age at least 18 years, centrally confirmed triple-negative breast cancer; at least one measurable lesion; provision of a newly obtained tumour sample for determination of triple-negative breast cancer status and PD-L1 status by immunohistochemistry at a central laboratory; an Eastern Cooperative Oncology Group performance status score 0 or 1; and adequate organ function. The sponsor, investigators, other study site staff (except for the unmasked pharmacist), and patients were masked to pembrolizumab versus saline placebo administration. In addition, the sponsor, the investigators, other study site staff, and patients were masked to patient-level tumour PD-L1 biomarker results. Dual primary efficacy endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS of 10 or more, CPS of 1 or more, and intention-to-treat populations. The definitive assessment of progression-free survival was done at this interim analysis; follow-up to assess overall survival is continuing. For progression-free survival, a hierarchical testing strategy was used, such that testing was done first in patients with CPS of 10 or more (prespecified statistical criterion was α=0·00411 at this interim analysis), then in patients with CPS of 1 or more (α=0·00111 at this interim analysis, with partial alpha from progression-free survival in patients with CPS of 10 or more passed over), and finally in the intention-to-treat population (α=0·00111 at this interim analysis). This study is registered with ClinicalTrials.gov, NCT02819518, and is ongoing. FINDINGS: Between Jan 9, 2017, and June 12, 2018, of 1372 patients screened, 847 were randomly assigned to treatment, with 566 patients in the pembrolizumab-chemotherapy group and 281 patients in the placebo-chemotherapy group. At the second interim analysis (data cutoff, Dec 11, 2019), median follow-up was 25·9 months (IQR 22·8-29·9) in the pembrolizumab-chemotherapy group and 26·3 months (22·7-29·7) in the placebo-chemotherapy group. Among patients with CPS of 10 or more, median progression-free survival was 9·7 months with pembrolizumab-chemotherapy and 5·6 months with placebo-chemotherapy (hazard ratio [HR] for progression or death, 0·65, 95% CI 0·49-0·86; one-sided p=0·0012 [primary objective met]). Median progression-free survival was 7·6 and 5·6 months (HR, 0·74, 0·61-0·90; one-sided p=0·0014 [not significant]) among patients with CPS of 1 or more and 7·5 and 5·6 months (HR, 0·82, 0·69-0·97 [not tested]) among the intention-to-treat population. The pembrolizumab treatment effect increased with PD-L1 enrichment. Grade 3-5 treatment-related adverse event rates were 68% in the pembrolizumab-chemotherapy group and 67% in the placebo-chemotherapy group, including death in <1% in the pembrolizumab-chemotherapy group and 0% in the placebo-chemotherapy group. INTERPRETATION: Pembrolizumab-chemotherapy showed a significant and clinically meaningful improvement in progression-free survival versus placebo-chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

Cytokine profiling in serum-derived exosomes isolated by different methods.

Exosomes in blood play an important role in cell-to-cell signaling and are a novel source of biomarkers for the diagnosis and prognosis of diseases. Recently, evidence has accumulated that cytokines are released from encapsulated exosomes and are capable of eliciting biological effects upon contact with sensitive cells. However, there is currently limited information on exosome isolation methods for cytokine research. In this study, we evaluated three exosome isolation methods for their usability, yield, purity, and effectiveness in subsequent cytokine profiling. We found that ultracentrifugation (UC) and Exoquick (EQ), but not exoEasy, yielded appropriate exosome sizes, and EQ had higher exosome extraction efficiency than the other two methods. Although UC generated markedly fewer particles than EQ, it yielded a relatively high purity. Next, we performed a multiplex assay with the ProcartaPlex Immune Monitoring 65-Plex Panel to determine the feasibility of these methods for cytokine profiling. The results indicated significant differences among isolation methods when analyzing exosomal cytokine profiles. We further investigated the changes of exosomal cytokines according to breast cancer progression in triple-negative breast cancer. We found significantly decreased concentrations of MIP-3 alpha, IL-23, M-CSF, Eotaxin-3, BLC, SDF-1 alpha, IL-2R, MDC, FGF-2, IL-22, and IL-31 in exosomes from metastatic breast cancer (MBC) patients.

Pegylated liposomal doxorubicin in patients with metastatic triple-negative breast cancer: 8-year experience of a single center.

BACKGROUND: The known efficacy of doxorubicin in metastatic breast cancer is countered by its dose-limiting myelosuppression and cardiotoxicity. Pegylated liposomal doxorubicin (PLD) was discovered to overcome these problems. But the data regarding its use in metastatic TNBC (triple-negative breast cancer) is still insufficient. Our study aimed to assess the factors affecting the outcome of the patients with metastatic TNBC who received PLD. RESULTS: During a period of 8 years (January 2011-December 2018), we analyzed 39 eligible patients. The disease control rate (DCR) was 51.3%. Among all the analyzed factors, two of them significantly affected DCR. The first factor was the chemosensitivity to prior anthracycline. As patients with chemosensitive disease had higher DCR than those with the chemoresistant disease (P = .001). The second factor was the number of prior lines of chemotherapy. As the patients who received two prior lines had a higher DCR than those who received three lines or more (P = .023). Chemosensitivity was the only significant independent factor for DCR (odds ratio = .095, P = .008). For the studied patients, the median progression-free survival (PFS) was 7 months. The anthracycline-chemosensitivity was the only significant independent prognostic factor for PFS (P = .002). The median overall survival (OS) was 12 months. There was a marginally significant effect of anthracycline-chemosensitivity on OS (P = .052). CONCLUSION: The anthracycline-chemosensitivity is an independent predictive and prognostic factor for the patients with metastatic TNBC receiving PLD. In developing countries, PLD should be reserved for the patients whose tumors are anthracycline-chemosensitive.

Complete Response of Chemo-Refractory Metastatic Metaplastic Breast Cancer to Paclitaxel-Immunotherapy Combination.

BACKGROUND Metaplastic breast cancer (MPBC) is a rare subtype of breast cancer that is difficult to manage and is resistant to therapy. Immunotherapy is becoming a promising option for care of several types of cancers including triple negative breast cancer. CASE REPORT We present a case of a patient with chemo-refractory metastatic metaplastic-type of breast cancer with failures to 3 active lines of chemotherapy. The patient achieved a complete and sustained response to chemo-immunotherapy combination with acceptable tolerability and minimal adverse events. The treatment was a combination of anti-PD-L1 antibody (durvalumab) immunotherapy in combination with the chemotherapeutic agent, paclitaxel. CONCLUSIONS This is the first case reporting the successful use of durvalumab and paclitaxel combination for treatment of triple negative breast cancer in general, and in metastatic MPBC in specific.

MiR-140-5p inhibits cell proliferation and metastasis by regulating MUC1 via BCL2A1/MAPK pathway in triple negative breast cancer.

Noncoding RNAs play important roles in the progression of malignant tumors, including triple negative breast cancer (TNBC). Accumulating evidence supported the involvement of the oncogenic MUC1 in tumor metastasis. Our study aimed to explore the roles of miR-140-5p and MUC1 in TNBC and identify the potential underlying mechanisms. In the present study, we found that miR-140-5p expression was significantly decreased in TNBC tissues and associated with advanced clinical features and poor prognosis. MiR-140-5p overexpression suppressed TNBC cells proliferation, invasion ability in vitro and reduced tumor growth in vivo. Subsequently, MUC1 was verified to be a direct target of miR-140-5p in TNBC. Furthermore, we revealed that MUC1 could regulate MAPK pathway through regulating BCL2A1 expression in TNBC. Thus, our study indicated that miR-140-5p might regulate MUC1 to suppress TNBC cells proliferation and metastasis by regulating BCL2A1/MAPK pathway, suggesting miR-140-5p could serve as a potential therapeutic target for TNBC.

Epigenetic Regulation of NAMPT by NAMPT-AS Drives Metastatic Progression in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS. NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway in vitro and in vivo. In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer-specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC. SIGNIFICANCE: Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC.

A platinum(iv) prodrug to defeat breast cancer through disrupting vasculature and inhibiting metastasis.

A PtIV prodrug (PDMA) exhibits great potential for the therapy of metastatic triple-negative breast cancer (TNBC) through a synergistic action of antiangiogensis and antimetastasis.

SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program.

The capacity for tumor cells to metastasize efficiently is directly linked to their ability to colonize secondary sites. Here we identify Six2, a developmental transcription factor, as a critical regulator of a breast cancer stem cell program that enables metastatic colonization. In several triple-negative breast cancer (TNBC) models, Six2 enhanced the expression of genes associated with embryonic stem cell programs. Six2 directly bound the Sox2 Srr2 enhancer, promoting Sox2 expression and downstream expression of Nanog, which are both key pluripotency factors. Regulation of Sox2 by Six2 enhanced cancer stem cell properties and increased metastatic colonization. Six2 and Sox2 expression correlated highly in breast cancers including TNBC, where a Six2 expression signature was predictive of metastatic burden and poor clinical outcome. Our findings demonstrate that a SIX2/SOX2 axis is required for efficient metastatic colonization, underscoring a key role for stemness factors in outgrowth at secondary sites. SIGNIFICANCE: These findings provide novel mechanistic insight into stemness and the metastatic outgrowth of triple-negative breast cancer cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/4/720/F1.large.jpg.

SOX10, GATA3, GCDFP15, Androgen Receptor, and Mammaglobin for the Differential Diagnosis Between Triple-negative Breast Cancer and TTF1-negative Lung Adenocarcinoma.

Triple-negative breast cancer (TNBC) patients have an increased risk of developing visceral metastases and other primary nonbreast cancers, particularly lung cancer. The differential diagnosis of TNBC metastases and primary cancers from other organs can be difficult due to lack of a TNBC standard immunoprofile. We analyzed the diagnostic value of estrogen receptor, progesterone receptor, human epidermal growth factor receptor, thyroid transcription factor-1 (TTF1), Napsin A, mammaglobin, gross cystic disease fluid protein 15 (GCDFP15), Sry-related HMg-Box gene 10 (SOX10), GATA-binding protein 3 (GATA3), and androgen receptor in a series of 207 TNBC and 152 primary lung adenocarcinomas (LA). All tested TNBCs were TTF1 and Napsin A-negative. When comparing TNBC and TTF1-positive or negative LA, SOX10 had the best sensitivity (62.3%) and specificity (100%) as a marker in favor of TNBC compared with LA, irrespective of TTF1 status (P<0.0001). GATA3 had moderate sensitivity (30.4%) and excellent specificity (98.7%) and misclassified only 2/152 LA (1.3%). GCDFP15 had a moderate sensitivity (20.8%) and excellent specificity (98%) and misclassified only 3/152 (2%) LA. Mammaglobin and androgen receptor had moderate sensitivities (38.2% and 30%), good specificities (81.6% and 86%), and misclassified 28/152 and 21/152 LAs, respectively. In multivariate analysis, the best markers, enabling the distinction between SOX10-negative TNBC and TTF1 and Napsin A-negative LA were GATA3 (odds ratio=33.5; 95% confidence interval, 7.3-153.5; P<0.0001) and GCDFP15 (odds ratio=31.7; 95% confidence interval, 6.9-145.6; P<0.0001). Only 13/207 (6.3%) TNBC cases did not express any aforementioned marker. On the basis of our results, the best sequential immunohistochemical analysis to differentiate TNBC from TTF1-negative LA is first SOX10 followed by GATA3, and finally GCDFP15. This order is important in the diagnostic workup of small biopsies from lung nodules in women with a previous history of TNBC.

Targeted imaging and inhibition of triple-negative breast cancer metastases by a PDGFRß aptamer.

While the overall mortality for breast cancer has recently declined, management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and the lack of targeted therapies. Genomic profiling studies highlighted the high level of heterogeneity of this cancer, which comprises different subtypes with unique phenotypes and response to treatment. Platelet-derived growth factor receptor ß (PDGFRß) is an established mesenchymal/stem cell-specific marker in human glioblastoma and, as recently suggested, it may uniquely mark breast cancer cells with stem-like characteristics and/or that have undergone epithelial-mesenchymal transition. Methods: Immunohistochemical analysis for PDGFRß expression was performed on a human TNBC tissue microarray. Functional assays were conducted on mesenchymal-like TNBC cells to investigate the effect of a previously validated PDGFRß aptamer on invasive cell growth in three-dimensional culture conditions, migration, invasion and tube formation. The aptamer was labeled with a near-infrared (NIR) dye and its binding specificity to PDGFRß was assessed both in vitro (confocal microscopy and flow cytometry analyses) and in vivo (fluorescence molecular tomography in mice bearing TNBC xenografts). A mouse model of TNBC lung metastases formation was established and NIR-labeled PDGFRß aptamer was used to detect lung metastases in mice untreated or intravenously injected with unlabeled aptamer. Results: Here, we present novel data showing that tumor cell expression of PDGFRß identifies a subgroup of mesenchymal tumors with invasive and stem-like phenotype, and propose a previously unappreciated role for PDGFRß in driving TNBC cell invasiveness and metastases formation. We show that the PDGFRß aptamer blocked invasive growth and migration/invasion of mesenchymal TNBC cell lines and prevented TNBC lung metastases formation. Further, upon NIR-labeling, the aptamer specifically bound to TNBC xenografts and detected lung metastases. Conclusions: We propose PDGFRß as a reliable biomarker of a subgroup of mesenchymal TNBCs with invasive and stem-like phenotype as well as the use of the PDGFRß aptamer as a high efficacious tool for imaging and suppression of TNBC lung metastases. This study will allow for the significant expansion of the current repertoire of strategies for managing patients with more aggressive TNBC.

Effectiveness of Platinum-Based Treatment for Triple Negative Metastatic Breast Cancer: a Meta-Analysis

Background: Triple-negative breast cancer (TNBC) is a sub-group of breast cancers with a particularly poor prognosis. The results of studies investigating the role of platinum-based chemotherapy (PBC) in metastatic TNBC (mTNBC) have been conflicting. In this meta-analysis, our aim was to assess the effectiveness of PBCs for mTNBCs. Methods: The PubMed, Cochrane Controlled Trials Register Databases, and EBSCOhost databases were accessed. The English language was used as the search language and only human studies were included. The Newcastle­Ottawa Quality Assessment Scale and the Jadad scoring system were used to evaluate the quality of the included randomized controlled studies. Results: Seven studies and 1,571 patients were included in this meta-analysis. The pooled hazard ratio (HR) for overall survival (OS), evaluated on the basis of six studies, showed the use of PBC regimes to be related to OS in mTNBCs (HR 0.620; 95% CI 0.513-0.749; p:<0.001). Four studies containing HR and abstract statistics used for HR calculation were included in the meta-analysis for progression-free survival (PFS). The pooled HR again indicated a significant relation (HR, 0.628; 95% CI, 0.501-0.786; p:<0.001). Conclusions: In this meta-analysis, we confirmed that PBC regimes provide OS and PFS advantages compared to non-PBC regimes. The use of PBC regimes could be a good choice in mTNBC patients for better quality of life and survival.