60 results on '"Prat, P."'
Search Results
2. Analytical and clinical validation of PATHWAY Anti-HER-2/neu (4B5) antibody to assess HER2-low status for trastuzumab deruxtecan treatment in breast cancer
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Garrido, Charo, Manoogian, Melissa, Ghambire, Dhiraj, Lucas, Shawn, Karnoub, Maha, Olson, Matthew T., Hicks, David G., Tozbikian, Gary, Prat, Aleix, Ueno, Naoto T., Modi, Shanu, Feng, Wenqin, Pugh, Judith, Hsu, Ching, Tsurutani, Junji, Cameron, David, Harbeck, Nadia, Fang, Qijun, Khambata-Ford, Shirin, Liu, Xuemin, Inge, Landon J., and Vitazka, Patrik
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- 2024
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3. Neoadjuvant sunitinib plus exemestane in post-menopausal women with hormone receptor-positive/HER2-negative early-stage breast cancer (SUT_EXE-08): a phase I/II trial
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Bartomeu Fullana, Serafín Morales, Anna Petit, Ania Alay, Helena Verdaguer, Fina Climent, Valentí Navarro-Perez, Mónica Cejuela, Patricia Galvan, Anna Gumà, Antonio Llombart-Cussac, David Cordero, Oriol Casanovas, Aleix Prat, Miguel Gil-Gil, and Sonia Pernas
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Breast cancer ,Neoadjuvant endocrine therapy ,Antiangiogenic therapy ,Exemestane ,Sunitinib ,PAM50 ,Medicine ,Science - Abstract
Abstract Neoadjuvant endocrine therapy (NET) for hormone receptor-positive (HR+) breast cancer might be as effective as chemotherapy, with a better toxicity profile. Blocking a crucial process such as angiogenesis with sunitinib may have a synergistic effect with NET. We aimed to assess the efficacy and safety of neoadjuvant sunitinib plus exemestane in early-stage HR+/HER2-negative breast cancer. In this phase I/II study, postmenopausal women with HR+/HER2− stage II-III breast cancer received neoadjuvant exemestane at conventional dose of 25mg plus sunitinib in a 3 + 3 design at 25mg (3/1weeks scheme) or 37.5mg continuous dose, for 6 months. Coprimary endpoints were the recommended dose of sunitinib combined with exemestane and objective response. Secondary endpoints included safety and biomarkers of early response. For 15 months, 18 patients were enrolled, 15 at sunitinib 25mg and 3 at 37.5mg. Median age was 73, 77% of patients had T2 tumors and 67% node-positive disease. The most common grade 2 toxicity was asthenia (44%), as was hypertension (22%) for grade 3. No grade 4–5 were reported. Twelve patients (66%) achieved an objective response. VEGFR-2 levels significantly decreased after one month of treatment. Differential gene expression analysis showed downregulation of ESR1, PGR and NAT1 in post-treatment samples and upregulation of EGFR, MYC, SFRP1, and FOXC1. PAM50 analysis on 83% of patients showed a prevalence of luminal A subtype, both in pre-treatment (63.6%) and post-treatment tumors (54.5%). Sunitinib plus exemestane was associated with substantial yet reversible toxicities, providing safety, efficacy and biological impact insights of combining an antiangiogenic drug with hormone therapy in early-stage breast cancer. Trial registration: Registered with ClinicalTrials.gov, NCT00931450. 02/07/2009
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- 2024
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4. Neoadjuvant sunitinib plus exemestane in post-menopausal women with hormone receptor-positive/HER2-negative early-stage breast cancer (SUT_EXE-08): a phase I/II trial
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Fullana, Bartomeu, Morales, Serafín, Petit, Anna, Alay, Ania, Verdaguer, Helena, Climent, Fina, Navarro-Perez, Valentí, Cejuela, Mónica, Galvan, Patricia, Gumà, Anna, Llombart-Cussac, Antonio, Cordero, David, Casanovas, Oriol, Prat, Aleix, Gil-Gil, Miguel, and Pernas, Sonia
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- 2024
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5. Optimising of axillary therapy in breast cancer: lessons from the past to plan for a better future
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Kaidar-Person, Orit, Tramm, Trine, Kuehn, Thorsten, Gentilini, Oreste, Prat, Aleix, Montay-Gruel, Pierre, Meattini, Icro, and Poortmans, Philip
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- 2024
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6. 6th and 7th International consensus guidelines for the management of advanced breast cancer (ABC guidelines 6 and 7)
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Fatima Cardoso, Shani Paluch-Shimon, Eva Schumacher-Wulf, Leonor Matos, Karen Gelmon, Matti S. Aapro, Jyoti Bajpai, Carlos H. Barrios, Jonas Bergh, Elizabeth Bergsten-Nordström, Laura Biganzoli, Maria João Cardoso, Lisa A. Carey, Mariana Chavez-MacGregor, Runcie Chidebe, Javier Cortés, Giuseppe Curigliano, Rebecca A. Dent, Nagi S. El Saghir, Alexandru Eniu, Lesley Fallowfield, Prudence A. Francis, Sandra X. Franco Millan, Jenny Gilchrist, Joseph Gligorov, William J. Gradishar, Renate Haidinger, Nadia Harbeck, Xichun Hu, Ranjit Kaur, Belinda Kiely, Sung-Bae Kim, Smruti Koppikar, Marion J.J. Kuper-Hommel, Frédéric E. Lecouvet, Ginny Mason, Shirley A. Mertz, Volkmar Mueller, Claire Myerson, Silvia Neciosup, Birgitte V. Offersen, Shinji Ohno, Olivia Pagani, Ann H. Partridge, Frédérique Penault-Llorca, Aleix Prat, Hope S. Rugo, Elzbieta Senkus, George W. Sledge, Sandra M. Swain, Christoph Thomssen, Daniel A. Vorobiof, Peter Vuylsteke, Theresa Wiseman, Binghe Xu, Alberto Costa, Larry Norton, and Eric P. Winer
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ABC ,Advanced ,Metastatic ,Breast cancer ,Guidelines ,Consensus ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
This manuscript describes the Advanced Breast Cancer (ABC) international consensus guidelines updated at the last two ABC international consensus conferences (ABC 6 in 2021, virtual, and ABC 7 in 2023, in Lisbon, Portugal), organized by the ABC Global Alliance. It provides the main recommendations on how to best manage patients with advanced breast cancer (inoperable locally advanced or metastatic), of all breast cancer subtypes, as well as palliative and supportive care. These guidelines are based on available evidence or on expert opinion when a higher level of evidence is lacking. Each guideline is accompanied by the level of evidence (LoE), grade of recommendation (GoR) and percentage of consensus reached at the consensus conferences. Updated diagnostic and treatment algorithms are also provided. The guidelines represent the best management options for patients living with ABC globally, assuming accessibility to all available therapies. Their adaptation (i.e. resource-stratified guidelines) is often needed in settings where access to care is limited.
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- 2024
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7. 'Positioning of tucatinib in the new clinical scenario of HER2-positive metastatic breast cancer: An Italian and Spanish consensus paper'
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Pierfranco Conte, Eva Ciruelos, Giuseppe Curigliano, Michelino De Laurentiis, Lucia Del Mastro, Alessandra Gennari, Antonio Llombart, Miguel Martìn, Francesca Poggio, Aleix Prat, Fabio Puglisi, and Cristina Saura
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Breast cancer ,HER2 ,Tucatinib ,TKI ,Brain metastases ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: Advancements in monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates (ADCs) have notably enhanced outcomes for metastatic HER2-positive breast cancer patients. Despite the expanding treatment options and clinical complexities, determining the optimal sequence of HER2-targeted therapies remains partly uncertain, influenced by various factors. Methods: To refine HER2-positive metastatic breast cancer management, particularly regarding tucatinib's position, a Steering Committee of leading oncologists in breast cancer care devised a panel of statements via a Delphi approach, focusing on five key topics: general clinical management, therapeutic approaches for patients with HER2-positive breast cancer and brain metastases, treatment sequence, and tucatinib's safety and efficacy. Results: A total of 29 statements were deliberated, with strong consensus achieved for most. However, no consensus emerged regarding the management of brain progression alongside stable extracranial disease: 48 % advocated for switching to tucatinib, while 53 % favored a stereotactic brain radiotherapy (SBRT) approach if feasible. Conclusion: The unanimous consensus attained in this Delphi panel, particularly regarding tucatinib's efficacy and safety, underscores oncologists' recognition of its clinical significance based on existing trial data. These findings align closely with current literature, shedding light on areas necessitating further investigation, not thoroughly explored in prior studies. Moreover, the results underscore the scarcity of data on managing brain progression alongside stable extracranial disease, emphasizing the imperative for dedicated research to address these gaps and yield definitive insights.
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- 2024
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8. Tumor biomarkers and efficacy in patients treated with trastuzumab emtansine + pertuzumab versus standard of care in HER2-positive early breast cancer: an open-label, phase III study (KRISTINE)
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de Haas, Sanne L, Slamon, Dennis J, Martin, Miguel, Press, Michael F, Lewis, Gail D, Lambertini, Chiara, Prat, Aleix, Lopez-Valverde, Vanesa, Boulet, Thomas, and Hurvitz, Sara A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Clinical Research ,Clinical Trials and Supportive Activities ,Breast Cancer ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Female ,Humans ,Ado-Trastuzumab Emtansine ,Antineoplastic Combined Chemotherapy Protocols ,B7-H1 Antigen ,Biomarkers ,Tumor ,Breast Neoplasms ,Class I Phosphatidylinositol 3-Kinases ,Neoadjuvant Therapy ,Receptor ,ErbB-2 ,Standard of Care ,Trastuzumab ,Tumor Microenvironment ,Tumor biomarkers ,Trastuzumab emtansine ,Pertuzumab ,HER2-positive breast cancer ,KRISTINE ,Receptor ,erbB-2 ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundKRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus docetaxel + carboplatin + trastuzumab + pertuzumab (TCH + P) in patients with HER2-positive, stage II-III breast cancer. We investigated the association of biomarkers with clinical outcomes in KRISTINE.MethodsPatients were randomized to receive neoadjuvant T-DM1 + P or TCH + P and assessed for pathologic complete response (pCR; ypT0/is, ypN0). HER2 status (per central assessment), hormone receptor status, PIK3CA mutation status, HER2/HER3 mRNA levels, tumor-infiltrating lymphocyte levels, PD-L1 status, and NanoString data were analyzed. pCR rates by treatment arm were compared across biomarker subgroups. Analyses were descriptive.ResultsBiomarker analyses included data from all 444 patients (T-DM1 + P, n = 223; TCH + P, n = 221) enrolled in KRISTINE. Biomarker distribution was balanced across treatment arms. All subgroups with higher HER2 amplification/expression and immune marker levels showed numerically higher pCR rates in both arms. Mutated versus non-mutated PIK3CA tumors were associated with numerically lower pCR rates in the T-DM1 + P arm but not in the TCH + P arm. In a multivariate analysis, Prediction Analysis of Microarray with the 50-gene classifier (PAM50) HER2-enriched subtype, HER2 gene ratio ≥ 4, and PD-L1-positive status positively influenced the pCR rate. Biomarkers associated with lower pCR rates (e.g., low HER2 levels, positive hormone receptor status, mutated PIK3CA) were more likely to co-occur. Dynamic on-treatment biomarker changes were observed. Differences in the treatment effects for T-DM1 + P versus TCH + P were similar to those observed in the intent-to-treat population for the majority of the biomarker subgroups.ConclusionsAlthough our biomarker analysis did not identify a subgroup of patients that benefited from neoadjuvant T-DM1 + P versus TCH + P, the data revealed that patients with higher HER2 amplification/expression and immune marker levels had improved response irrespective of treatment arm. These analyses confirm the role of HER2 tumor biology and the immune microenvironment in influencing pCR in the neoadjuvant setting and reaffirm the molecular diversity of HER2-positive breast cancer.Trial registrationClinicalTrials.gov NCT02131064. Registered 06 May 2014.
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- 2023
9. A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB)
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Mayer, Ingrid A, Prat, Aleix, Egle, Daniel, Blau, Sibel, Fidalgo, J Alejandro Pérez, Gnant, Michael, Fasching, Peter A, Colleoni, Marco, Wolff, Antonio C, Winer, Eric P, Singer, Christian F, Hurvitz, Sara, Estévez, Laura García, van Dam, Peter A, Kümmel, Sherko, Mundhenke, Christoph, Holmes, Frankie, Babbar, Naveen, Charbonnier, Laure, Diaz-Padilla, Ivan, Vogl, Florian D, Sellami, Dalila, and Arteaga, Carlos L
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Breast Cancer ,Clinical Research ,Clinical Trials and Supportive Activities ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers ,Tumor ,Breast Neoplasms ,Cell Proliferation ,Class I Phosphatidylinositol 3-Kinases ,Female ,High-Throughput Nucleotide Sequencing ,Humans ,Letrozole ,Middle Aged ,Mutation ,Neoadjuvant Therapy ,Receptor ,ErbB-2 ,Receptors ,Estrogen ,Receptors ,Progesterone ,Signal Transduction ,Thiazoles ,Treatment Outcome ,Receptor ,erbB-2 ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PURPOSE:Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor-positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.Patients and Methods: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. RESULTS:In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. CONCLUSIONS:In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.
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- 2019
10. Biomarkers of immunotherapy response in breast cancer beyond PD-L1
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Chic, Nuria, Brasó-Maristany, Fara, and Prat, Aleix
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- 2022
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11. Gene expression profiles of breast cancer metastasis according to organ site
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Fara Brasó‐Maristany, Laia Paré, Nuria Chic, Olga Martínez‐Sáez, Tomás Pascual, Meritxell Mallafré‐Larrosa, Francesco Schettini, Blanca González‐Farré, Esther Sanfeliu, Débora Martínez, Patricia Galván, Esther Barnadas, Belinda Salinas, Pablo Tolosa, Eva Ciruelos, Esther Carcelero, Cecilia Guillén, Barbara Adamo, Reinaldo Moreno, Maria Vidal, Montserrat Muñoz, and Aleix Prat
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breast cancer ,gene expression profiling ,HER2‐low ,metastatic sites ,PAM50 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
In advanced breast cancer, biomarker identification and patient selection using a metastatic tumor biopsy is becoming more necessary. However, the biology of metastasis according to the organ site is largely unknown. Here, we evaluated the expression of 771 genes in 184 metastatic samples across 11 organs, including liver, lung, brain, and bone, and made the following observations. First, all PAM50 molecular intrinsic subtypes were represented across organs and within immunohistochemistry‐based groups. Second, HER2‐low disease was identified across all organ sites, including bone, and HER2 expression significantly correlated with ERBB2 expression. Third, the majority of expression variation was explained by intrinsic subtype and not organ of metastasis. Fourth, subtypes and individual subtype‐related genes/signatures were significantly associated with overall survival. Fifth, we identified 74 genes whose expression was organ‐specific and subtype‐independent. Finally, immune profiles were found more expressed in lung compared to brain or liver metastasis. Our results suggest that relevant tumor biology can be captured in metastatic tissues across a variety of organ sites; however, unique biological features according to organ site were also identified and future studies should explore their implications in diagnostic and therapeutic interventions.
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- 2022
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12. HER2DX genomic test in HER2-positive/hormone receptor-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab: A correlative analysis from the PerELISA trialResearch in context
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Valentina Guarneri, Fara Bras..-Maristany, Maria Vittoria Dieci, Gaia Griguolo, Laia Par.., Mercedes Mar.ín-Aguilera, Federica Miglietta, Michele Bottosso, Carlo Alberto Giorgi, Paula Blasco, Oleguer Castillo, Patricia Galv..n, Ana Vivancos, Patricia Villagrasa, Joel S. Parker, Charles M. Perou, PierFranco Conte, and Aleix Prat
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HER2-positive ,Breast cancer ,HER2DX ,Biomarker ,Gene expression ,Trastuzumab ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: HER2DX is a prognostic and predictive assay in early-stage HER2-positive breast cancer based on clinical features and the expression of 4 gene signatures (immune, proliferation, luminal differentiation and HER2 amplicon), including ERBB2 mRNA levels. Here, we evaluated the ability of HER2DX to predict efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HER2-positive/hormone receptor-positive breast cancer. Methods: HER2DX was evaluated on pre-treatment tumour samples from the PerELISA phase II study focused on postmenopausal patients with operable HER2-positive/hormone receptor-positive breast cancer. Patients received 2-weeks of letrozole, and then underwent a re-biopsy for Ki67 evaluation. Patients with endocrine therapy sensitive disease (ESD) (i.e., >20.0% Ki67 relative reduction at week 2) continued letrozole and 5 cycles of trastuzumab and pertuzumab. Primary aim was to test the ability of HER2DX risk-score, HER2DX pCR score and HER2DX ERBB2 mRNA score (as continuous variables and group categories) to predict pathological complete response (pCR) in patients with ESD. Logistic regression and receiver...operator curve (ROC) analysis assessed associations of HER2DX scores with pCR and ESD. Findings: HER2DX was evaluated in 55 patients (86.0%) enrolled in PerELISA and 40 patients (73.0%) had ESD. The pCR rate in patients with ESD was 22.5% (9/40). In this group, HER2DX pCR score and HER2DX ERBB2 mRNA score were significantly associated with pCR (p.ß=.ß0.008 and p.ß=.ß0.003, univariate logistic regression model; area under ROC [AUC].ß=.ß0.803 and 0.896). The pCR rate in low, medium, and high HER2DX pCR score groups was 7.7% (2/26), 46.2% (6/13) and 100.0% (1/1), respectively. The pCR rate in low, medium, and high HER2DX ERBB2 score groups was 0.0% (0/12), 7.7% (1/13) and 53.3% (8/15), respectively. HER2DX pCR score was also significantly associated with Ki-67 response following 2-weeks of letrozole (p.ß=.ß0.002, univariate logistic regression model; AUC.ß=.ß0.775). The rate of ESD in low, medium, and high HER2DX pCR score groups was 89.7% (26/29), 65.0% (13/20) and 16.7% (1/6), respectively. Interpretation: HER2DX predicts response following neoadjuvant letrozole in combination with dual HER2 blockade with trastuzumab and pertuzumab in early-stage HER2-positive/hormone receptor-positive breast cancer. Funding: This study received funding from Reveal Genomics.
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- 2022
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13. Dissecting the biological heterogeneity of HER2-positive breast cancer
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Francesco Schettini and Aleix Prat
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HER2 ,Breast cancer ,Intrinsic subtypes ,HER2-enriched ,PAM50 ,TILs ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease.
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- 2021
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14. Modelling hypersensitivity to trastuzumab defines biomarkers of response in HER2 positive breast cancer
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Laura Díaz-Gil, Fara Brasó-Maristany, Claudriana Locatelli, Ariana Centa, Balász Győrffy, Alberto Ocaña, Aleix Prat, and Atanasio Pandiella
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Breast cancer ,Trastuzumab ,Hypersensitive ,Response ,Biomarker ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Trastuzumab-based therapies are the therapeutic option for HER2 positive (HER2+) breast cancer. HER2 amplification is the only biomarker validated for trastuzumab-based therapies. However, a proportion of tumors become refractory during treatment course. For this reason, the finding of new biomarkers beyond HER2 overexpression to identify patients who would benefit most from trastuzumab regimens is of outstanding importance. Methods Models of trastuzumab-resistant or hypersensitive cells were generated by exposure to trastuzumab. Cell surface, total HER2, and analyses of proteins involved in cell cycle or apoptosis were analyzed by western blotting. Cell proliferation was analyzed by cell counting, cell cycle and apoptosis was evaluated by FACS. Transcriptomic characterization of the cellular models was performed using bioinformatic online tools, and clinico-genomic analyses were performed using the PAMELA clinical trial data. Results Besides differing in sensitivities to trastuzumab, the different cellular models also showed distinct response to other anti-HER2 drugs (lapatinib, neratinib, pertuzumab and T-DM1) used in the clinic. That differential effect was not due to changes in cell surface, total or activated HER2. Trastuzumab caused important induction of cell death in hypersensitive cells but not in parental or resistant cells. Transcriptomic analyses of these cellular models together with querying of online databases allowed the identification of individual genes and gene signatures that predicted prognosis and trastuzumab response in HER2+ breast cancer patients. Conclusion The identification of trastuzumab response biomarkers may be used to select patients particularly sensitive to facilitate the use of trastuzumab-based therapies and refine follow-up guidelines in patients with HER2+ tumors.
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- 2021
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15. RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer
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Adrián Sanz-Moreno, Sonia Palomeras, Kim Pedersen, Beatriz Morancho, Tomas Pascual, Patricia Galván, Sandra Benítez, Jorge Gomez-Miragaya, Marina Ciscar, Maria Jimenez, Sonia Pernas, Anna Petit, María Teresa Soler-Monsó, Gemma Viñas, Mansour Alsaleem, Emad A. Rakha, Andrew R. Green, Patricia G. Santamaria, Celine Mulder, Simone Lemeer, Joaquin Arribas, Aleix Prat, Teresa Puig, and Eva Gonzalez-Suarez
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Breast cancer ,HER2 ,Lapatinib ,NF-κB ,RANK ,RANKL ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Around 15–20% of primary breast cancers are characterized by HER2 protein overexpression and/or HER2 gene amplification. Despite the successful development of anti-HER2 drugs, intrinsic and acquired resistance represents a major hurdle. This study was performed to analyze the RANK pathway contribution in HER2-positive breast cancer and anti-HER2 therapy resistance. Methods RANK and RANKL protein expression was assessed in samples from HER2-positive breast cancer patients resistant to anti-HER2 therapy and treatment-naive patients. RANK and RANKL gene expression was analyzed in paired samples from patients treated with neoadjuvant dual HER2-blockade (lapatinib and trastuzumab) from the SOLTI-1114 PAMELA trial. Additionally, HER2-positive breast cancer cell lines were used to modulate RANK expression and analyze in vitro the contribution of RANK signaling to anti-HER2 resistance and downstream signaling. Results RANK and RANKL proteins are more frequently detected in HER2-positive tumors that have acquired resistance to anti-HER2 therapies than in treatment-naive ones. RANK (but not RANKL) gene expression increased after dual anti-HER2 neoadjuvant therapy in the cohort from the SOLTI-1114 PAMELA trial. Results in HER2-positive breast cancer cell lines recapitulate the clinical observations, with increased RANK expression observed after short-term treatment with the HER2 inhibitor lapatinib or dual anti-HER2 therapy and in lapatinib-resistant cells. After RANKL stimulation, lapatinib-resistant cells show increased NF-κB activation compared to their sensitive counterparts, confirming the enhanced functionality of the RANK pathway in anti-HER2-resistant breast cancer. Overactivation of the RANK signaling pathway enhances ERK and NF-κB signaling and increases lapatinib resistance in different HER2-positive breast cancer cell lines, whereas RANK loss sensitizes lapatinib-resistant cells to the drug. Our results indicate that ErbB signaling is required for RANK/RANKL-driven activation of ERK in several HER2-positive cell lines. In contrast, lapatinib is not able to counteract the NF-κB activation elicited after RANKL treatment in RANK-overexpressing cells. Finally, we show that RANK binds to HER2 in breast cancer cells and that enhanced RANK pathway activation alters HER2 phosphorylation status. Conclusions Our data support a physical and functional link between RANK and HER2 signaling in breast cancer and demonstrate that increased RANK signaling may contribute to the development of lapatinib resistance through NF-κB activation. Whether HER2-positive breast cancer patients with tumoral RANK expression might benefit from dual HER2 and RANK inhibition therapy remains to be elucidated.
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- 2021
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16. A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer
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Peter Schmid, Marie-Paule Sablin, Jonas Bergh, Seock-Ah Im, Yen-Shen Lu, Noelia Martínez, Patrick Neven, Keun Seok Lee, Serafín Morales, J. Alejandro Pérez-Fidalgo, Douglas Adamson, Anthony Gonçalves, Aleix Prat, Guy Jerusalem, Laura Schlieker, Rosa-Maria Espadero, Thomas Bogenrieder, Dennis Chin-Lun Huang, John Crown, and Javier Cortés
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Breast cancer ,HER2-negative ,Hormone receptor-positive ,Insulin-like growth factor ,Xentuzumab ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). Methods Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). Results MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3–not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7–9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57–1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05–0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). Conclusions Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). Trial registration ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.
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- 2021
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17. Frequency and spectrum of PIK3CA somatic mutations in breast cancer
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Olga Martínez-Sáez, Nuria Chic, Tomás Pascual, Barbara Adamo, Maria Vidal, Blanca González-Farré, Esther Sanfeliu, Francesco Schettini, Benedetta Conte, Fara Brasó-Maristany, Adela Rodríguez, Débora Martínez, Patricia Galván, Ana Belén Rodríguez, Antonio Martinez, Montserrat Muñoz, and Aleix Prat
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Breast cancer ,PIK3CA ,Mutations ,Alpelisib ,Companion diagnostic ,Hotspot mutations ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Purpose The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA-mutated (PIK3CAmut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. Methods Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/HER2−), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2− advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay. Results Patients with PIK3CAmut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CAmut BC. Among patients with double PIK3CAmut tumors (12% of all PIK3CAmut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CAmut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2− BC were not part of the therascreen panel. Conclusion PIK3CA mutations in BC are heterogenous and ~ 20% of patients with a known PIK3CA mutation, and 95% with a known double PIK3CAmut tumor, would not be captured by the therascreen panel. Finally, the clinical utility of PIK3CA mutations not present in the therascreen companion diagnostic assay or identified by other sequencing-based assays needs further investigation.
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- 2020
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18. Modelling hypersensitivity to trastuzumab defines biomarkers of response in HER2 positive breast cancer
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Díaz-Gil, Laura, Brasó-Maristany, Fara, Locatelli, Claudriana, Centa, Ariana, Győrffy, Balász, Ocaña, Alberto, Prat, Aleix, and Pandiella, Atanasio
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- 2021
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19. A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer
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Schmid, Peter, Sablin, Marie-Paule, Bergh, Jonas, Im, Seock-Ah, Lu, Yen-Shen, Martínez, Noelia, Neven, Patrick, Lee, Keun Seok, Morales, Serafín, Pérez-Fidalgo, J. Alejandro, Adamson, Douglas, Gonçalves, Anthony, Prat, Aleix, Jerusalem, Guy, Schlieker, Laura, Espadero, Rosa-Maria, Bogenrieder, Thomas, Huang, Dennis Chin-Lun, Crown, John, and Cortés, Javier
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- 2021
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20. RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer
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Sanz-Moreno, Adrián, Palomeras, Sonia, Pedersen, Kim, Morancho, Beatriz, Pascual, Tomas, Galván, Patricia, Benítez, Sandra, Gomez-Miragaya, Jorge, Ciscar, Marina, Jimenez, Maria, Pernas, Sonia, Petit, Anna, Soler-Monsó, María Teresa, Viñas, Gemma, Alsaleem, Mansour, Rakha, Emad A., Green, Andrew R., Santamaria, Patricia G., Mulder, Celine, Lemeer, Simone, Arribas, Joaquin, Prat, Aleix, Puig, Teresa, and Gonzalez-Suarez, Eva
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- 2021
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21. First Nationwide Molecular Screening Program in Spain for Patients With Advanced Breast Cancer: Results From the AGATA SOLTI-1301 Study
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Sonia Pernas, Patricia Villagrasa, Ana Vivancos, Maurizio Scaltriti, Jordi Rodón, Octavio Burgués, Paolo Nuciforo, Jordi Canes, Laia Paré, Marta Dueñas, Maria Vidal, Juan Miguel Cejalvo, Antonia Perelló, Antonio Llommbard-Cussac, Joan Dorca, Alvaro Montaño, Tomás Pascual, Mafalda Oliveira, Gloria Ribas, Inmaculada Rapado, Aleix Prat, and Eva Ciruelos
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breast cancer ,molecular genetic ,DNA sequence analyses ,PAM50 subtype ,molecular targeted therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundThe SOLTI-1301 AGATA study aimed to assess the feasibility of a multi-institutional molecular screening program to better characterize the genomic landscape of advanced breast cancer (ABC) and to facilitate patient access to matched-targeted therapies in Spain.MethodsDNA sequencing of 74 cancer-related genes was performed using FFPE tumor samples in three different laboratories with three different gene panels. A multidisciplinary advisory board prospectively recommended potential targeted treatments. The primary objective was to determine the success of matching somatic DNA alteration to an experimental drug/drug class.ResultsBetween September 2014 and July 2017, 305 patients with ABC from 10 institutions were enrolled. Tumor sequencing was successful in 260 (85.3%) patients. Median age was 54 (29-80); most tumors were hormone receptor-positive/HER2-negative (74%), followed by triple-negative (14.5%) and HER2-positive (11.5%). Ninety-seven (37%) tumor samples analyzed proceeded from metastatic sites. Somatic mutations were identified in 163 (62.7%) patients, mostly in PIK3CA (34%), TP53 (22%), AKT1 (5%), ESR1 (3%), and ERBB2 (3%) genes. Significant enrichment of AKT1 mutation was observed in metastatic versus primary samples (9% vs. 2%; p=0.01). Genome-driven cancer therapy was recommended in 45% (n=116) of successfully screened patients, 11% (n=13) of whom finally received it. Among these patients, 46.2% had a PFS of ≥6 months on matched therapy.ConclusionsAGATA is the first nationwide molecular screening program carried out in Spain and we proved that implementing molecular data in the management of ABC is feasible. Although these results are promising, only 11% of the patients with genome-driven cancer therapy received it.
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- 2021
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22. Case Report: A Case Study Documenting the Activity of Atezolizumab in a PD-L1-Negative Triple-Negative Breast Cancer
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Fara Brasó-Maristany, Miriam Sansó, Nuria Chic, Débora Martínez, Blanca González-Farré, Esther Sanfeliu, Lucio Ghiglione, Esther Carcelero, Javier Garcia-Corbacho, Marcelo Sánchez, Dolors Soy, Pedro Jares, Vicente Peg, Cristina Saura, Montserrat Muñoz, Aleix Prat, and Ana Vivancos
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immunotherapy ,breast cancer ,biomarkers ,ctDNA ,case report ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune checkpoint inhibitors in TNBC beyond PD-L1 expression and to better select patients that will benefit from immunotherapy.
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- 2021
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23. Oestrogen receptor activity in hormone-dependent breast cancer during chemotherapy
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Nuria Chic, Francesco Schettini, Fara Brasó-Maristany, Esther Sanfeliu, Barbara Adamo, Maria Vidal, Débora Martínez, Patricia Galván, Blanca González-Farré, Javier Cortés, Joaquín Gavilá, Cristina Saura, Mafalda Oliveira, Sònia Pernas, Olga Martínez-Sáez, Jesús Soberino, Eva Ciruelos, Lisa A. Carey, Montserrat Muñoz, Charles M. Perou, Tomás Pascual, Meritxell Bellet, and Aleix Prat
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Pre-menopause ,Progesterone receptor ,Hormone receptor positive ,Breast cancer ,Chemotherapy ,Oestrogens ,Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Chemotherapy efficacy in early-stage hormone receptor-positive (HR+) breast cancer (BC) according to menopausal status needs a biological explanation. Methods: We compared early-stage HR+ BC biological features before and after (neo)adjuvant chemotherapy or endocrine therapy (ET), and assessed oestrogen receptor (ER) pathway activity in both pre- and post-menopausal patients. The nCounter platform was used to detect gene expression levels. Findings: In 106 post-menopausal patients with HR+/HER2-negative BC randomized to neoadjuvant chemotherapy or ET (letrozole+ribociclib), a total of 19 oestrogen-regulated genes, including progesterone receptor (PGR), were found downregulated in the ET-based arm-only. We confirmed this finding in an independent dataset of 20 letrozole-treated post-menopausal patients and found, conversely, an up-regulation of the same signature in HR+/HER2-negative MCF7 cell line treated with estradiol. PGR was found down-regulated by 2 weeks of ET+anti-HER2 therapy in pre-/post-menopausal patients with HR+/HER2-positive (HER2+) BC, while anti-HER2 therapy alone increased PGR expression in HR-negative/HER2+ BC. In 88 pre- and post-menopausal patients with newly diagnosed HR+/HER2-negative BC treated with chemotherapy, the 19 oestrogen-regulated genes were found significantly downregulated only in pre-menopausal patients. In progesterone receptor (PR)+/HER2-negative BC treated with neoadjuvant chemotherapy (n=40), tumours became PR-negative in 69.2% of pre-menopausal patients and 14.8% of post-menopausal patients (p=0.001). Finally, a mean decrease in PGR levels was only observed in pre-menopausal patients undergoing anti-HER2-based multi-agent chemotherapy. Interpretation: Chemotherapy reduces the expression of ER-regulated genes in pre-menopausal women suffering from hormone-dependent BC by supressing ovarian function. Further studies should test the value of chemotherapy in this patient population when ovarian function is suppressed by other methods. Funding: Instituto de Salud Carlos III, Breast Cancer Now, the Breast Cancer Research Foundation, the American Association for Cancer Research, Fundació La Marató TV3, the European Union's Horizon 2020 Research and Innovation Programme, Pas a Pas, Save the Mama, Fundación Científica Asociación Española Contra el Cáncer, PhD4MDgrant of “Departament de Salut”, exp SLT008/18/00122, Fundación SEOM and ESMO. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s).
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- 2021
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24. Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial
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Barbara Adamo, Meritxell Bellet, Laia Paré, Tomás Pascual, Maria Vidal, José A. Pérez Fidalgo, Salvador Blanch, Noelia Martinez, Laura Murillo, Patricia Gómez-Pardo, Ana López-González, Kepa Amillano, Jordi Canes, Patricia Galván, Blanca González-Farré, Xavier González, Patricia Villagrasa, Eva Ciruelos, and Aleix Prat
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Breast cancer ,Metronomic ,Vinorelbine ,Letrozole ,Window of opportunity ,Gene expression ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed. Methods Postmenopausal women with untreated stage I–III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures. Results Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1–2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (− 73.2%) was superior to both monotherapy arms combined (− 49.9%; p = 0.001) and mVNB (− 19.1%; p
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- 2019
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25. Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer
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Gaia Griguolo, Tomás Pascual, Maria Vittoria Dieci, Valentina Guarneri, and Aleix Prat
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Breast cancer ,HER2 ,Targeted treatment ,Immunity ,Tumor infiltrating lymphocytes ,Immune checkpoints ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Growing evidence suggests a clear role of the host immune system in HER2+ breast cancer. In addition, HER2+ breast cancer is generally considered more immunogenic than hormone receptor-positive (HR+)/HER2-, and specific molecular HER2+ subgroups (e.g. HER2-enriched disease) are more immunogenic than others (e.g. Luminal A or B). From a clinical perspective, the immune system plays a relevant prognostic role in HER2+ breast cancer and contributes to the therapeutic effects of trastuzumab. However, as more HER2-targeted agents become available, a better understanding of the role played by the immune system in modulating therapy response to different agents will be needed. Furthermore, the recent introduction in oncology of immune checkpoint inhibitors capable of unleashing anti-tumor immune response opens new possibilities for therapeutic combinations in HER2+ breast cancer. Here, we review the current pre-clinical and clinical data on the interplay between the immune system and HER2+ breast cancer, focusing on different HER2-targeted treatments and the biological heterogeneity that exists within HER2+ disease. Finally, we discuss new therapeutic approaches exploiting the immune system to increase activity or revert resistance to HER2-targeted agents.
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- 2019
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26. Safety, activity, and molecular heterogeneity following neoadjuvant non-pegylated liposomal doxorubicin, paclitaxel, trastuzumab, and pertuzumab in HER2-positive breast cancer (Opti-HER HEART): an open-label, single-group, multicenter, phase 2 trial
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Joaquín Gavilá, Mafalda Oliveira, Tomás Pascual, Jose Perez-Garcia, Xavier Gonzàlez, Jordi Canes, Laia Paré, Isabel Calvo, Eva Ciruelos, Montserrat Muñoz, Juan A. Virizuela, Isabel Ruiz, Raquel Andrés, Antonia Perelló, Jerónimo Martínez, Serafín Morales, Mercedes Marín-Aguilera, Débora Martínez, Juan C. Quero, Antonio Llombart-Cussac, and Aleix Prat
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Breast cancer ,PAM50 ,HER2 ,intrinsic subtypes ,cardiac safety ,HER2-enriched ,Medicine - Abstract
Abstract Background The Opti-HER HEART trial aimed to optimize activity while minimizing cardiac risk by combining trastuzumab, pertuzumab, and paclitaxel with non-pegylated liposomal doxorubicin in the treatment of HER2-positive early breast cancer. Methods Patients with stage II–IIIB HER2-positive breast cancer received neoadjuvant trastuzumab, pertuzumab, paclitaxel, and a non-pegylated liposomal doxorubicin every three weeks for six cycles. The primary endpoint was cardiac safety during neoadjuvant therapy. Type A (symptomatic congestive heart failure) and B (asymptomatic reduction of left ventricular ejection fraction) cardiac events were evaluated. Secondary endpoints included the evaluation of the pathological complete response (pCR) rate and overall response rate, among others. As an ad-hoc exploratory analysis, the expression of 55 breast cancer-related genes, including the PAM50 genes, was measured in 58 baseline tumor samples and 60 surgical specimens. Results Eighty-three patients were recruited. The incidence of cardiac events during neoadjuvant treatment was 2.4%. No type A cardiac event was observed. The overall pCR rate was 56.6% (95% confidence interval (CI) 45.3–67.5%). The HER2-enriched subtype, which represented 52.0% of all baseline samples, was associated with a higher pCR rate compared to non-HER2-enriched tumors (83.3% vs. 46.3%; odds ratio 5.76, 95% CI 1.71–19.42). The association of subtype with pCR was independent of known clinicopathological variables, including hormone receptor status. Compared to baseline samples, surgical specimens showed a significant downregulation of proliferation-related genes (MKI67 and CCNB1) and ERBB2 levels, and a significant upregulation of luminal-related (ESR1 and PGR) and immune (CD8A) genes. Conclusions The combination of dual HER2 blockade with trastuzumab and pertuzumab with paclitaxel and non-pegylated liposomal doxorubicin is associated with a low rate of cardiac events. The HER2-enriched subtype is associated with a high rate of pCR. Trial registration clinicaltrials.gov, NCT01669239, Registered 20 August 2012.
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- 2019
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27. SOLTI-1805 TOT-HER3 Study Concept: A Window-of-Opportunity Trial of Patritumab Deruxtecan, a HER3 Directed Antibody Drug Conjugate, in Patients With Early Breast Cancer
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Tomás Pascual, Mafalda Oliveira, Eva Ciruelos, Meritxell Bellet Ezquerra, Cristina Saura, Joaquin Gavilá, Sonia Pernas, Montserrat Muñoz, Maria J. Vidal, Mireia Margelí Vila, Juan M. Cejalvo, Blanca González-Farré, Martin Espinosa-Bravo, Josefina Cruz, Francisco Javier Salvador-Bofill, Juan Antonio Guerra, Ana María Luna Barrera, Miriam Arumi de Dios, Stephen Esker, Pang-Dian Fan, Olga Martínez-Sáez, Guillermo Villacampa, Laia Paré, Juan M. Ferrero-Cafiero, Patricia Villagrasa, and Aleix Prat
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Breast Cancer ,ERBB3 ,HER3 ,U3-1402 ,patritumab deruxtecan ,HER3-DXd ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Preclinical data support a key role for the human epidermal growth factor receptor 3 (HER3) pathway in hormone receptor (HR)–positive breast cancer. Recently, new HER3 directed antibody drug conjugates have shown activity in breast cancer. Given the need to better understand the molecular biology, tumor microenvironment, and mechanisms of drug resistance in breast cancer, we designed this window-of-opportunity study with the HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402).Trial Design: Based on these data, a prospective, multicenter, single-arm, window-of-opportunity study was designed to evaluate the biological effect of patritumab deruxtecan in the treatment of naïve patients with HR-positive/HER2-negative early breast cancer whose primary tumors are ≥1 cm by ultrasound evaluation. Patients will be enrolled in four cohorts according to the mRNA-based ERBB3 expression by central assessment. The primary endpoint is a CelTIL score after one single dose. A translational research plan is also included to provide biological information and to evaluate secondary and exploratory objectives of the study.Trial Registration Number: EudraCT 2019-004964-23; NCT number: NCT04610528.
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- 2021
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28. Dissecting the effect of hormone receptor status in patients with HER2-positive early breast cancer: exploratory analysis from the ALTTO (BIG 2-06) randomized clinical trial
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Lambertini, Matteo, Campbell, Christine, Gelber, Richard D., Viale, Giuseppe, McCullough, Ann, Hilbers, Florentine, Korde, Larissa A., Werner, Olena, Chumsri, Saranya, Jackisch, Christian, Wolff, Antonio C., Vaz-Luis, Ines, Ferreira, Arlindo R., Prat, Aleix, Moreno-Aspitia, Alvaro, Piccart, Martine, Loi, Sherene, and de Azambuja, Evandro
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- 2019
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29. Different Pathological Complete Response Rates According to PAM50 Subtype in HER2+ Breast Cancer Patients Treated With Neoadjuvant Pertuzumab/Trastuzumab vs. Trastuzumab Plus Standard Chemotherapy: An Analysis of Real-World Data
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Tamara Díaz-Redondo, Rocio Lavado-Valenzuela, Begoña Jimenez, Tomas Pascual, Fernando Gálvez, Alejandro Falcón, Maria del Carmen Alamo, Cristina Morales, Marta Amerigo, Javier Pascual, Alfonso Sanchez-Muñoz, Macarena González-Guerrero, Luis Vicioso, Aurora Laborda, Maria Victoria Ortega, Lidia Perez, Aranzazu Fernandez-Martinez, Nuria Chic, Jose Manuel Jerez, Martina Alvarez, Aleix Prat, Nuria Ribelles, and Emilio Alba
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breast cancer ,real-world data ,neoadjuvant ,pertuzumab ,trastuzumab ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Double blockade with pertuzumab and trastuzumab combined with chemotherapy is the standard neoadjuvant treatment for HER2-positive early breast cancer. Data derived from clinical trials indicates that the response rates differ among intrinsic subtypes of breast cancer. The aim of this study is to determine if these results are valid in real-world patients.Methods: A total of 259 patients treated in eight Spanish hospitals were included and divided into two cohorts: Cohort A (132 patients) received trastuzumab plus standard neoadjuvant chemotherapy (NAC), and Cohort B received pertuzumab and trastuzumab plus NAC (122 patients). Pathological complete response (pCR) was defined as the complete disappearance of invasive tumor cells. Assignment of the intrinsic subtype was realized using the research-based PAM50 signature.Results: There were more HER2-enriched tumors in Cohort A (70 vs. 56%) and more basal-like tumors in Cohort B (12 vs. 2%), with similar luminal cases in both cohorts (luminal A 12 vs. 14%; luminal B 14 vs. 18%). The overall pCR rate was 39% in Cohort A and 61% in Cohort B. Better pCR rates with pertuzumab plus trastuzumab than with trastuzumab alone were also observed in all intrinsic subtypes (luminal PAM50 41 vs. 11.4% and HER2-enriched subtype 73.5 vs. 50%) but not in basal-like tumors (53.3 vs. 50%). In multivariate analysis the only significant variables related to pCR in both luminal PAM50 and HER2-enriched subtypes were treatment with pertuzumab plus trastuzumab (Cohort B) and histological grade 3.Conclusions: With data obtained from patients treated in clinical practice, it has been possible to verify that the addition of pertuzumab to trastuzumab and neoadjuvant chemotherapy substantially increases the rate of pCR, especially in the HER2-enriched subtype but also in luminal subtypes, with no apparent benefit in basal-like tumors.
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- 2019
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30. Frequency and spectrum of PIK3CA somatic mutations in breast cancer
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Martínez-Sáez, Olga, Chic, Nuria, Pascual, Tomás, Adamo, Barbara, Vidal, Maria, González-Farré, Blanca, Sanfeliu, Esther, Schettini, Francesco, Conte, Benedetta, Brasó-Maristany, Fara, Rodríguez, Adela, Martínez, Débora, Galván, Patricia, Rodríguez, Ana Belén, Martinez, Antonio, Muñoz, Montserrat, and Prat, Aleix
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- 2020
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31. Safety, activity, and molecular heterogeneity following neoadjuvant non-pegylated liposomal doxorubicin, paclitaxel, trastuzumab, and pertuzumab in HER2-positive breast cancer (Opti-HER HEART): an open-label, single-group, multicenter, phase 2 trial
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Gavilá, Joaquín, Oliveira, Mafalda, Pascual, Tomás, Perez-Garcia, Jose, Gonzàlez, Xavier, Canes, Jordi, Paré, Laia, Calvo, Isabel, Ciruelos, Eva, Muñoz, Montserrat, Virizuela, Juan A., Ruiz, Isabel, Andrés, Raquel, Perelló, Antonia, Martínez, Jerónimo, Morales, Serafín, Marín-Aguilera, Mercedes, Martínez, Débora, Quero, Juan C., Llombart-Cussac, Antonio, and Prat, Aleix
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- 2019
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32. Corrigendum: PAM50 Subtypes in Baseline and Residual Tumors Following Neoadjuvant Trastuzumab-Based Chemotherapy in HER2-Positive Breast Cancer: A Consecutive-Series From a Single Institution
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Sonia Pernas, Anna Petit, Fina Climent, Laia Paré, J. Perez-Martin, Luz Ventura, Milana Bergamino, Patricia Galván, Catalina Falo, Idoia Morilla, Adela Fernandez-Ortega, Agostina Stradella, Montse Rey, Amparo Garcia-Tejedor, Miguel Gil-Gil, and Aleix Prat
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breast cancer ,HER2 ,pathological complete response ,gene expression ,molecular intrinsic subtype ,residual disease ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2019
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33. PAM50 Subtypes in Baseline and Residual Tumors Following Neoadjuvant Trastuzumab-Based Chemotherapy in HER2-Positive Breast Cancer: A Consecutive-Series From a Single Institution
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Sonia Pernas, Anna Petit, Fina Climent, Laia Paré, J. Perez-Martin, Luz Ventura, Milana Bergamino, Patricia Galván, Catalina Falo, Idoia Morilla, Adela Fernandez-Ortega, Agostina Stradella, Montse Rey, Amparo Garcia-Tejedor, Miguel Gil-Gil, and Aleix Prat
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breast cancer ,HER2 ,pathological complete response ,gene expression ,molecular intrinsic subtype ,residual disease ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: HER2-enriched subtype has been associated with higher response to neoadjuvant anti-HER2-based therapy across various clinical trials. However, limited data exist in real-world practice and regarding residual disease. Here, we evaluate the association of HER2-enriched with pathological response (pCR) and gene expression changes in pre- and post-treatment paired samples in HER2-positive breast cancer patients treated outside of a clinical trial.Methods: We evaluated clinical-pathological data from a consecutive series of 150 patients with stage II-IIIC HER2-positive breast cancer treated from August 2004 to December 2012 with trastuzumab-based neoadjuvant chemotherapy. Expression of 105 breast cancer-related genes, including the PAM50 genes, was determined in available pre-and post-treatment formalin-fixed paraffin-embedded tumor samples using the nCounter platform. Intrinsic molecular subtypes were determined using the research-based PAM50 predictor. Association of genomic variables with total pCR was performed.Results: The pCR rate was 53.3%, with higher pCR among hormonal receptor (HR)-negative tumors (70 vs. 39%; P < 0.001). A total of 89 baseline and 28 residual tumors were profiled, including pre- and post-treatment paired samples from 26 patients not achieving a pCR. HER2-enriched was the predominant baseline subtype not only in the overall and HR-negative cohorts (64 and 75%, respectively), but also in the HR-positive cohort (55%). HER2-enriched was associated with higher pCR rates compared to non-HER2-enriched subtypes (65 vs. 31%; OR = 4.07, 95% CI 1.65–10.61, P < 0.002) and this association was independent of HR status. In pre- and post-treatment paired samples from patients not achieving a pCR, a lower proportion of HER2-enriched and twice the number of luminal tumors were observed at baseline, and luminal A was the most frequent subtype in residual tumors. Interestingly, most (81.8%) HER2-enriched tumors changed to non-HER2-enriched, whereas most luminal A samples maintained the same subtype in residual tumors.Conclusions: Outside of a clinical trial, PAM50 HER2-enriched subtype predicts pCR beyond HR status following trastuzumab-based chemotherapy in HER2-positive disease. The clinical value of intrinsic molecular subtype in residual disease warrants further investigation.
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- 2019
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34. A Pathology-Based Combined Model to Identify PAM50 Non-luminal Intrinsic Disease in Hormone Receptor-Positive HER2-Negative Breast Cancer
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Tomás Pascual, Miguel Martin, Aranzazu Fernández-Martínez, Laia Paré, Emilio Alba, Álvaro Rodríguez-Lescure, Giuseppe Perrone, Javier Cortés, Serafín Morales, Ana Lluch, Ander Urruticoechea, Blanca González-Farré, Patricia Galván, Pedro Jares, Adela Rodriguez, Nuria Chic, Daniela Righi, Juan Miguel Cejalvo, Giuseppe Tonini, Barbara Adamo, Maria Vidal, Patricia Villagrasa, Montserrat Muñoz, and Aleix Prat
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intrinsic subtype ,non-luminal ,PAM50 ,breast cancer ,gene expression ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: In hormone receptor-positive (HR+)/HER2-negative breast cancer, the HER2-enriched and Basal-like intrinsic subtypes are associated with poor outcome, low response to anti-estrogen therapy and high response to chemotherapy. To date, no validated biomarker exists to identify both molecular entities other than gene expression.Methods: PAM50 subtyping and immunohistochemical data were obtained from 8 independent studies of 1,416 HR+/HER2-negative early breast tumors. A non-luminal disease score (NOLUS) from 0 to 100, based on percentage of estrogen receptor (ER), progesterone receptor (PR) and Ki67 tumor cells, was derived in a combined cohort of 5 studies (training dataset) and tested in a combined cohort of 3 studies. The performance of NOLUS was estimated using Area Under the ROC Curve (AUC).Results: In the training dataset (n = 903) and compared to luminal disease, non-luminal disease had lower percentage of ER-positive cells (median 65.2 vs. 86.2%, p < 0.01) and PR-positive cells (33.2 vs. 56.4%, p < 0.01) and higher percentage of Ki67-positive cells (18.2 vs. 13.1%, p = 0.01). A NOLUS formula was derived: −0.45*ER −0.28*PR +0.27*Ki67 + 73.02. The proportion of non-luminal tumors in NOLUS-positive (≥51.38) and NOLUS-negative (
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- 2019
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35. Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial
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Adamo, Barbara, Bellet, Meritxell, Paré, Laia, Pascual, Tomás, Vidal, Maria, Pérez Fidalgo, José A., Blanch, Salvador, Martinez, Noelia, Murillo, Laura, Gómez-Pardo, Patricia, López-González, Ana, Amillano, Kepa, Canes, Jordi, Galván, Patricia, González-Farré, Blanca, González, Xavier, Villagrasa, Patricia, Ciruelos, Eva, and Prat, Aleix
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- 2019
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36. Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer
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Griguolo, Gaia, Pascual, Tomás, Dieci, Maria Vittoria, Guarneri, Valentina, and Prat, Aleix
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- 2019
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37. Prognostic ability of EndoPredict compared to research-based versions of the PAM50 risk of recurrence (ROR) scores in node-positive, estrogen receptor-positive, and HER2-negative breast cancer. A GEICAM/9906 sub-study
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Martin, Miguel, Brase, Jan C., Ruiz, Amparo, Prat, Aleix, Kronenwett, Ralf, Calvo, Lourdes, Petry, Christoph, Bernard, Philip S., Ruiz-Borrego, Manuel, Weber, Karsten E., Rodriguez, César A., Alvarez, Isabel M., Segui, Miguel A., Perou, Charles M., Casas, Maribel, Carrasco, Eva, Caballero, Rosalía, and Rodriguez-Lescure, Alvaro
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- 2016
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38. SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model
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Kim, G, Ouzounova, M, Quraishi, A A, Davis, A, Tawakkol, N, Clouthier, S G, Malik, F, Paulson, A K, D'Angelo, R C, Korkaya, S, Baker, T L, Esen, E S, Prat, A, Liu, S, Kleer, C G, Thomas, D G, Wicha, M S, and Korkaya, H
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- 2015
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39. TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases
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Anders, Carey, Deal, Allison M., Abramson, Vandana, Liu, Minetta C., Storniolo, Anna M., Carpenter, John T., Puhalla, Shannon, Nanda, Rita, Melhem-Bertrandt, Amal, Lin, Nancy U., Kelly Marcom, P., Van Poznak, Catherine, Stearns, Vered, Melisko, Michelle, Smith, J. Keith, Karginova, Olga, Parker, Joel, Berg, Jonathan, Winer, Eric P., Peterman, Amy, Prat, Aleix, Perou, Charles M., Wolff, Antonio C., and Carey, Lisa A.
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- 2014
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40. Molecular features of the basal-like breast cancer subtype based on BRCA1 mutation status
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Prat, Aleix, Cruz, Cristina, Hoadley, Katherine A., Díez, Orland, Perou, Charles M., and Balmaña, Judith
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- 2014
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41. Assignment of tumor subtype by genomic testing and pathologic-based approximations: implications on patient’s management and therapy selection
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Romero, A., Prat, A., García-Sáenz, J. Á., del Prado, N., Pelayo, A., Furió, V., Román, J. M., de la Hoya, M., Díaz-Rubio, E., Perou, C. M., Cladés, T., and Martín, M.
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- 2014
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42. PELO negatively regulates HER receptor signalling and metastasis
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Pedersen, K, Canals, F, Prat, A, Tabernero, J, and Arribas, J
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- 2014
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43. Endothelial-like properties of claudin-low breast cancer cells promote tumor vascular permeability and metastasis
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Harrell, J. Chuck, Pfefferle, Adam D., Zalles, Nicole, Prat, Aleix, Fan, Cheng, Khramtsov, Andrey, Olopade, Olufunmilayo I., Troester, Melissa A., Dudley, Andrew C., and Perou, Charles M.
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- 2014
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44. Characterization of cell lines derived from breast cancers and normal mammary tissues for the study of the intrinsic molecular subtypes
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Prat, Aleix, Karginova, Olga, Parker, Joel S., Fan, Cheng, He, Xiaping, Bixby, Lisa, Harrell, J. Chuck, Roman, Erick, Adamo, Barbara, Troester, Melissa, and Perou, Charles M.
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- 2013
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45. "Positioning of tucatinib in the new clinical scenario of HER2-positive metastatic breast cancer: An Italian and Spanish consensus paper".
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Conte, Pierfranco, Ciruelos, Eva, Curigliano, Giuseppe, De Laurentiis, Michelino, Del Mastro, Lucia, Gennari, Alessandra, Llombart, Antonio, Martìn, Miguel, Poggio, Francesca, Prat, Aleix, Puglisi, Fabio, and Saura, Cristina
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HER2 positive breast cancer ,METASTATIC breast cancer ,BREAST cancer ,PROTEIN-tyrosine kinase inhibitors ,THERAPEUTICS - Abstract
Advancements in monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates (ADCs) have notably enhanced outcomes for metastatic HER2-positive breast cancer patients. Despite the expanding treatment options and clinical complexities, determining the optimal sequence of HER2-targeted therapies remains partly uncertain, influenced by various factors. To refine HER2-positive metastatic breast cancer management, particularly regarding tucatinib's position, a Steering Committee of leading oncologists in breast cancer care devised a panel of statements via a Delphi approach, focusing on five key topics: general clinical management, therapeutic approaches for patients with HER2-positive breast cancer and brain metastases, treatment sequence, and tucatinib's safety and efficacy. A total of 29 statements were deliberated, with strong consensus achieved for most. However, no consensus emerged regarding the management of brain progression alongside stable extracranial disease: 48 % advocated for switching to tucatinib, while 53 % favored a stereotactic brain radiotherapy (SBRT) approach if feasible. The unanimous consensus attained in this Delphi panel, particularly regarding tucatinib's efficacy and safety, underscores oncologists' recognition of its clinical significance based on existing trial data. These findings align closely with current literature, shedding light on areas necessitating further investigation, not thoroughly explored in prior studies. Moreover, the results underscore the scarcity of data on managing brain progression alongside stable extracranial disease, emphasizing the imperative for dedicated research to address these gaps and yield definitive insights. [ABSTRACT FROM AUTHOR]
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- 2024
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46. PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer
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Martín, Miguel, Prat, Aleix, Rodríguez-Lescure, Álvaro, Caballero, Rosalía, Ebbert, Mark T. W., Munárriz, Blanca, Ruiz-Borrego, Manuel, Bastien, Roy R. L., Crespo, Carmen, Davis, Carole, Rodríguez, César A., López-Vega, José M., Furió, Vicente, García, Ana M., Casas, Maribel, Ellis, Matthew J., Berry, Donald A., Pitcher, Brandelyn N., Harris, Lyndsay, Ruiz, Amparo, Winer, Eric, Hudis, Clifford, Stijleman, Inge J., Tuck, David P., Carrasco, Eva, Perou, Charles M., and Bernard, Philip S.
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- 2013
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47. PAM50 assay and the three-gene model for identifying the major and clinically relevant molecular subtypes of breast cancer
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Prat, A., Parker, J. S., Fan, C., and Perou, C. M.
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- 2012
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48. Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse
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Harrell, J. Chuck, Prat, Aleix, Parker, Joel S., Fan, Cheng, He, Xiaping, Carey, Lisa, Anders, Carey, Ewend, Matthew, and Perou, Charles M.
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- 2012
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49. Erfahrungen aus dem Bayerischen Mammographie-Screening-Programm
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Nährig, J., Höfler, H., Heywang-Köbrunner, S. H., Prat, N., Hölzel, D., Wünsch, P. H., and Lebeau, A.
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- 2006
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50. The evolving landscape of metastatic HER2-positive, hormone receptor-positive Breast Cancer.
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Boscolo Bielo, Luca, Trapani, Dario, Nicolò, Eleonora, Valenza, Carmine, Guidi, Lorenzo, Belli, Carmen, Kotteas, Elias, Marra, Antonio, Prat, Aleix, Fusco, Nicola, Criscitiello, Carmen, Burstein, Harold J., and Curigliano, Giuseppe
- Abstract
• Triple-positive Breast Cancer (TPBC) display different biological features and gene expression profiles. • For some TPBC, endocrine therapy with anti-HER2 agents may avoid the use of chemotherapy. • CDK4/6 inhibitors may represent a valuable option, particularly in Luminal-subtype TPBC. • The expression of hormone receptors may represent the rationale for Antibody-drug conjugates combinations. Therapeutic agents targeting Human Epidermal Growth Factor Receptor 2 (HER2) demonstrated to positively impact the prognosis of HER2-positive breast cancer. HER2-positive breast cancer can present either as hormone receptor-negative or positive, defining Triple-positive breast cancer (TPBC). TPBC demonstrate unique gene expression profiles, showing reduced HER2-driven gene expression, as recapitulated by a higher proportion of Luminal-type intrinsic subtypes. The different molecular landscape of TPBC dictates distinctive clinical features, including reduced chemotherapy sensitivity, different patterns of recurrence, and better overall prognosis. Cross-talk between HER2 and hormone receptor signaling seems to be critical to determine resistance to HER2-directed agents. Accordingly, superior outcomes have been achieved with the use of endocrine therapy, representing the first subtype-specific pharmacological intervention unique to this subgroup. Additional targeted agents capable to tackle resistance mechanisms to anti-HER2, hormone agents, or both might further improve the efficacy of treatments, such as PI3K/AKT/mTOR inhibitors, particularly in a biomarker-enriched setting, and CDK4/6-inhibitors, with preliminary data suggesting a role of PAM50 subtyping to predict higher benefits in luminal tumors. Finally, the distinct biology of triple-positive tumors may yield the rationale for considering combinations within antibody-drug conjugate regimens. Accordingly, in this review, we summarized the current evidence and rationale for considering TPBC as a different entity, in which distinct therapeutical approaches leveraging on the different biological profile of TPBC may result in superior anticancer regimens and improved patient-centric outcomes. [ABSTRACT FROM AUTHOR]
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- 2024
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