Phase II trial of humanized anti-Lewis Y monoclonal antibody for advanced hormone receptor-positive breast cancer that progressed following endocrine therapy

OBJECTIVES: The Lewis-Y antigen is expressed in 44%-90% of breast cancers (BCs). The expression of the antigen in carcinoma tissue differs from that in normal tissues. This study aimed to evaluate the clinical benefit of the humanized anti-Lewis Y monoclonal antibody, hu3S193, in advanced hormone receptor-positive and Lewis Y-positive BC after administration of endocrine therapy (ET). METHODS: A single-arm phase II study was conducted in seven centers. Patients with advanced hormone receptor-positive BC who failed first-line ET were included. The inclusion criterion was the observation of tumoral expression of the Lewis Y antigen during immunohistochemistry. The treatment comprised hu3S193 antibody administration at weekly intravenous doses of 20 mg/m2 for 8-week cycles. The primary endpoint was the clinical benefit rate. ClinicalTrials.gov NCT01370239. RESULTS: The study stopped accrual following an unplanned interim analysis as the hu3S193 antibody lacked sufficient activity to justify continuation of the study. Twenty-two patients were enrolled, of whom 21 were included in the efficacy analysis. The clinical benefit rate was 19%, with four patients presenting with stable disease after 24 weeks. One patient with prolonged stable disease received medication for over 2 years. No partial or complete responses were observed. The median time to progression and overall survival was 5.4 and 37.5 months, respectively. CONCLUSIONS: The humanized anti-Lewis Y monoclonal antibody, hu3S193, exhibited insufficient activity in this cohort. However, the possibility of activity in a more strictly selected subgroup of patients with higher levels of Lewis Y tumoral expression cannot be overlooked

Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60- month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸ 1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher’s exact tests and the OS by Kaplan–Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (≥60 years) (1.84) compared with younger (≤40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.Fil: de Almeida, Liz María. Instituto Nacional de Câncer; BrasilFil: Cortés, Sandra. Pontificia Universidad Católica de Chile; ChileFil: Vilensky, Marta. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Valenzuela, Olivia. Universidad de Sonora; MéxicoFil: Cortes Sanabria, Laura. Hospital de Especialidades Centro Medico Nacional Siglo XXI; MéxicoFil: de Souza, Mirian. Instituto Nacional de Câncer; BrasilFil: Barbeito, Rafael Alonso. Universidad de la República; UruguayFil: Abdelhay, Eliana. Instituto Nacional de Câncer; BrasilFil: Artagaveytia, Nora. Universidad de la Republica; UruguayFil: Daneri Navarro, Adrian. Universidad de Guadalajara; MéxicoFil: Llera, Andrea Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Müller, Bettina. Instituto Nacional del Cáncer; ChileFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Velazquez, Carlos. Universidad de Sonora; MéxicoFil: Alcoba, Elsa. Hospital Maria Curie; ArgentinaFil: Alonso, Isabel. Centro Hospitalario Pereira Rossell; UruguayFil: Bravo, Alicia I.. Hospital Higa Eva Perón; ArgentinaFil: Camejo, Natalia. Universidad de la República; UruguayFil: Carraro, Dirce Maria. A. C. Camargo Cancer Center; BrasilFil: Castro, Mónica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Cataldi, Sandra. Instituto Nacional del Cáncer; UruguayFil: Cayota, Alfonso. Instituto Pasteur de Montevideo; UruguayFil: Cerda, Mauricio. Universidad de Chile; ChileFil: Colombo, Alicia. Universidad de Chile; ChileFil: Crocamo, Susanne. Instituto Nacional de Câncer; BrasilFil: Silva-Garcia, Aida A.. Universidad de Guadalajara; MéxicoFil: Viña, Stella. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Zagame, Livia. Instituto Jalisciense de Cancerología; MéxicoFil: Jones, Beth. University of Yale; Estados UnidosFil: Szklo, Moysés. University Johns Hopkins; Estados Unido

The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients

Purposes: Most molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches. Patients and Methods: We collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes. Results: PAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors. Conclusions: This is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America. Clinical Trial Registration: ClinicalTrials.gov (Identifier: NCT02326857).Fil: Llera, Andrea Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Abdelhay, Eliana Saul Furquim Werneck. Instituto Nacional de Cancer; BrasilFil: Artagaveytia, Nora. Universidad de la Republica; UruguayFil: Daneri Navarro, Adrián. Universidad de Guadalajara; MéxicoFil: Müller, Bettina. Instituto Nacional del Cáncer; ChileFil: Velazquez, Carlos. Universidad de Sonora; MéxicoFil: Alcoba, Elsa B.. Hospital Maria Curie; ArgentinaFil: Alonso, Isabel. Centro Hospitalario Pereira Rossell; UruguayFil: Alves Da Quinta, Daniela Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad Argentina de la Empresa; ArgentinaFil: Binato, Renata. Instituto Nacional de Cancer; BrasilFil: Bravo, Alicia Inés. Hospital Regional de Agudos Eva Perón; ArgentinaFil: Camejo, Natalia. Universidad de la Republica; UruguayFil: Carraro, Dirce Maria. Centro Internacional de Pesquisa; BrasilFil: Castro, Mónica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Castro Cervantes, Juan M.. Umae Hospital de Especialidades Centro Medico Nacional Siglo XXI; MéxicoFil: Cataldi, Sandra. Instituto Nacional del Cáncer; UruguayFil: Cayota, Alfonso. Instituto Pasteur de Montevideo; UruguayFil: Cerda, Mauricio. Universidad de Chile; ChileFil: Colombo, Alicia. Universidad de Chile; ChileFil: Crocamo, Susanne. National Cancer Institute; Estados UnidosFil: Del Toro Arreola, Alicia. Universidad de Guadalajara; MéxicoFil: Delgadillo Cisterna, Raúl. Umae Hospital de Especialidades Centro Medico Nacional Siglo Xxi; MéxicoFil: Delgado, Lucía. Universidad de la Republica; UruguayFil: Fernandez, Elmer Andres. Area de Cs. Agrarias, Ingeniería, Cs. Biológicas y de la Salud de la Universidad Catollica de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Fejerman, Laura. University of California at Davis; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Trinchero, Alejandra. Hospital Regional de Agudos Eva Perón; ArgentinaFil: Valenzuela, Olivia. Universidad de Sonora; MéxicoFil: Vedham, Vidya. National Cancer Institute; Estados UnidosFil: Zagame, Livia. Instituto Jalisciense de Cancerología; MéxicoFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Translational Results of Zo-NAnTax: A Phase II Trial of Neoadjuvant Zoledronic Acid in HER2-Positive Breast Cancer

Breast cancer is a heterogeneous disease with distinct clinical and molecular characteristics. Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of new molecular drug targets. The breast cancer subtype with super expression and/or amplification of human growth factor receptor 2 (HER2) is clinically aggressive, but prognosis significantly shifted with the advent of anti-HER2 targeted therapy. Zoledronic-acid (ZOL) combined with a neoadjuvant Trastuzumab-containing chemotherapy regimen (Doxorubicin, Cyclophosphamide followed by Docetaxel, Trastuzumab) increased the pCR rate in a RH-positive/ HER2-positive subgroup, according to the phase II Zo-NAnTax trial. To verify genes that could be related to this response, a microarray assay was performed finding 164 differentially expressed genes. Silico analysis of these genes showed signaling pathways related to growth factors, apoptosis, invasion, and metabolism, as well as differentially expressed genes related to estrogen response. In addition, the RAC3 gene was found to interact with the MVD gene, a member of the mevalonate pathway. Taken together, these results indicate that RH-positive/ HER2-positive patients present gene alterations before treatment, and these could be related to the improvement of pCR

Targeting Senescence as a Therapeutic Opportunity for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is associated with an elevated risk of recurrence and poor prognosis. Historically, only chemotherapy was available as systemic treatment, but immunotherapy and targeted therapies currently offer prolonged benefits. TNBC is a group of diseases with heterogeneous treatment sensitivity, and resistance is inevitable and early for a large proportion of the intrinsic subtypes. Although senescence induction by anticancer therapy offers an immediate favorable clinical outcome once the rate of tumor progression reduces, these cells are commonly dysfunctional and metabolically active, culminating in treatment-resistant repopulation associated with worse prognosis. This heterogeneous response can also occur without therapeutic pressure in response to damage or oncogenic stress, playing a relevant role in the carcinogenesis. Remarkably, there is preclinical and exploratory clinical evidence to support a relevant role of senescence in treatment resistance. Therefore, targeting senescent cells has been a scientific effort in many malignant tumors using a variety of targets and strategies, including increasing proapoptotic and decreasing antiapoptotic stimuli. Despite promising results, there are some challenges to applying this technology, including the best schedule of combination, assessment of senescence, specific vulnerabilities, and the best clinical scenarios. This review provides an overview of senescence in TNBC with a focus on future-proofing senotherapy strategies

Twist1 Influences the Expression of Leading Members of the IL-17 Signaling Pathway in HER2-Positive Breast Cancer Cells

Breast cancer (BC) is a heterogeneous disease composed of multiple subtypes with different molecular characteristics and clinical outcomes. The metastatic process in BC depends on the transcription factors (TFs) related to epithelial-mesenchymal transition (EMT), including the master regulator Twist1. However, its role beyond EMT in BC subtypes remains unclear. Our study aimed to investigate the role of Twist1, beyond EMT, in the molecular subtypes of BC. In patients, we observed the overexpression of TWIST1 in the HER2+ group. The silencing of TWIST1 in HER2+ BC cells resulted in the upregulation of 138 genes and the downregulation of 174 genes compared to control cells in a microarray assay. In silico analysis revealed correlations between Twist1 and important biological processes such as the Th17-mediated immune response, suggesting that Twist1 could be relevant for IL-17 signaling in HER2+ BC. IL-17 signaling was then examined, and it was shown that TWIST1 knockdown caused the downregulation of leading members of IL-17 signaling pathway. Taken together, our findings suggest that Twist1 plays a role on IL-17 signaling in HER2+ BC

Neoadjuvant zoledronic acid for HER2-positive breast cancer: the Zo-NAnTax trial

Background: Preclinical evidence suggests that zoledronic acid (ZOL) works synergistically with chemotherapy by enhancing anti-tumor activity. ZOL blocks the mevalonate pathway and may indirectly interact with human epidermal growth factor receptor 2 (HER2) pathway activation. The clinical efficacy and biological rationale of chemotherapy plus anti-HER2 therapy and ZOL as a part of neoadjuvant therapy has not been previously tested. Patients and methods: We conducted a phase II clinical trial to evaluate the efficacy and safety of ZOL as part of a neoadjuvant treatment in patients with HER2-positive breast cancer (BC). The protocol consisted of four cycles of doxorubicin/cyclophosphamide with ZOL, followed by four cycles of docetaxel with trastuzumab and ZOL prior to surgery. The primary endpoint was the pathologic complete response (pCR) rate. Secondary endpoints were safety and the identification of clinicopathological characteristics associated with pCR. Results: A total of 71 patients with stage IIA to IIIB BC were included, with 60 eligible for the safety assessment and 58 for the efficacy analysis. Overall, the pCR rate was 42%, with higher rates in hormone receptor (HR)-positive tumors (40%), which contrasts with the results of pivotal trials. The most commonly observed grade 3 and 4 events were febrile neutropenia (grade 3, 20%; grade 4, 3%) and diarrhea (grade 3, 12%). Conclusions: The addition of ZOL as a repositioning drug in neoadjuvant treatment was an effective and well-tolerated therapy. This drug combination might overcome endocrine and anti-HER2 resistance. The higher pCR rates in the HR-positive subgroup deserve further translational investigation

Advanced Stage at Diagnosis and Worse Clinicopathologic Features in Young Women with Breast Cancer in Brazil: A Subanalysis of the AMAZONA III Study (GBECAM 0115)

PURPOSE: Breast cancer (BC) in young women is uncommon and tends to present with more aggressive characteristics. To better understand and characterize this scenario in Brazil through real-world data, we performed a subanalysis of AMAZONA III study (ClinicalTrials.gov identifier: NCT02663973). METHODS: The AMAZONA III study (GBECAM 0115) is a prospective registry that included 2,950 women newly diagnosed with invasive BC in Brazil from January 2016 until March 2018 at 22 sites. Valid data were obtained from 2,888 patients regarding age at diagnosis and complete baseline information. To compare epidemiologic and clinicopathological features at the time of diagnosis, patients with BC were divided into two groups according to age: ≤ 40 years and > 40 years. Quantitative variables were described as means, and categorical variables were described as frequencies and percentages and compared using the Pearson's χ2 test. RESULTS: Of 2,888 women diagnosed with BC, 486 (17%) were ≤ 40 years old. Young women had higher educational level, most were employed and a significant number were married (P < .001 for all associations). Younger patients were more symptomatic at BC diagnosis (P < .001), and they also presented more frequently with stage III, T3/T4, grade 3 tumors, HER-2-positive, luminal B, and triple-negative subtypes. CONCLUSION: Brazilian women younger than age 40 years have unfavorable clinicopathological features of BC at diagnosis, with more aggressive subtypes and advanced stage when compared with older women. These differences are not explained by socioeconomic or ethnic imbalances. The causes of a higher prevalence of BC among young women in Brazil deserve additional investigation.SCOPUS: ar.jinfo:eu-repo/semantics/publishe