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JOURNAL ARTICLE
Elena Guerini-Rocco, Federica Bellerba, Alberto Concardi, Sergio Vincenzo Taormina, Giulio Cammarata, Caterina Fumagalli, Aliana Guerrieri-Gonzaga, Debora Macis, Eliza Del Fiol Manna, Emanuela Balladore, Maria Cannone, Paolo Veronesi, Nicola Fusco, Bernardo Bonanni, Giuseppe Viale, Massimo Barberis, Sara Gandini, Matteo Lazzeroni
BACKGROUND AND AIM: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer with highly variable clinical behavior, but risk stratification is still challenging. We sought to identify immune-related gene expression signatures of pure DCIS associated with different risks of breast cancer recurrence. METHODS: A retrospective nested case-control study of 143 pure DCIS was performed including 70 women with subsequent ipsilateral breast event (IBE, in situ or invasive; cases) and 73 DCIS women with no IBE and matched for age, tumor size, treatment, hormone receptors/HER2 status, and follow-up time (controls)...
April 12, 2024: European Journal of Cancer
#2
JOURNAL ARTICLE
Veronica Calvo, Wei Zheng, Anna Adam-Artigues, Kirk A Staschke, Xin Huang, Julie F Cheung, Ana Rita Nobre, Sho Fujisawa, David Liu, Maria Fumagalli, David Surguladze, Michael E Stokes, Ari Nowacek, Mark Mulvihill, Eduardo F Farias, Julio A Aguirre-Ghiso
PURPOSE: The integrated stress response (ISR) kinase PERK serves as a survival factor for both proliferative and dormant cancer cells. We aim to validate PERK inhibition as a new strategy to specifically eliminate solitary disseminated cancer cells (DCC) in secondary sites that eventually reawake and originate metastasis. EXPERIMENTAL DESIGN: A novel clinical-grade PERK inhibitor (HC4) was tested in mouse syngeneic and PDX models that present quiescent/dormant DCCs or growth-arrested cancer cells in micro-metastatic lesions that upregulate ISR...
December 15, 2023: Clinical Cancer Research
#3
JOURNAL ARTICLE
Serena Negri, Elena De Ponti, Federica Paola Sina, Elena Sala, Cristina Dell'Oro, Gaia Roversi, Sara Lazzarin, Martina Delle Marchette, Alesssandra Inzoli, Claudia Toso, Simona Fumagalli, Maria Campanella, Joanne Kotsopoulos, Robert Fruscio
BACKGROUND: BRCA1 and BRCA2 gene mutations are responsible for 5% of breast cancer (BC) and 10-15% of ovarian cancer (EOC). The presence of a germline mutation and therefore the identification of subjects at high risk of developing cancer should ideally precede the onset of the disease, so that appropriate surveillance and risk-reducing treatments can be proposed. In this study, we revisited the family history (FH) of women who tested positive for BRCA mutations after being diagnosed with BC or EOC...
October 28, 2022: Molecular Genetics & Genomic Medicine
#4
JOURNAL ARTICLE
Ersilia Varone, Alexander Chernorudskiy, Alessandro Cherubini, Angela Cattaneo, Angela Bachi, Stefano Fumagalli, Gizem Erol, Marco Gobbi, Michael J Lenardo, Nica Borgese, Ester Zito
N-glycosylation and disulfide bond formation are two essential steps in protein folding that occur in the endoplasmic reticulum (ER) and reciprocally influence each other. Here, to analyze crosstalk between N-glycosylation and oxidation, we investigated how the protein disulfide oxidase ERO1-alpha affects glycosylation of the angiogenic VEGF121 , a key regulator of vascular homeostasis. ERO1 deficiency, while retarding disulfide bond formation in VEGF121 , increased utilization of its single N-glycosylation sequon, which lies close to an intra-polypeptide disulfide bridge, and concomitantly slowed its secretion...
October 2022: Redox Biology
#5
JOURNAL ARTICLE
E Razis, M J Escudero, C Palmieri, V Mueller, R Bartsch, G Rossi, S P Gampenrieder, H C Kolberg, N Zdenkowski, M Pavic, R M Connolly, L Rosset, J Arcuri, H Tesch, C Vallejos, J Retamales, A Musolino, L Del Mastro, C Christodoulou, S Aebi, S Paluch-Shimon, S Gupta, S Ohno, I Macpherson, M Ekholm, K Zaman, M Vidal, C Chakiba, D Fumagalli, A Thulin, I Witzel, N Kotecki, M Gil-Gil, B Linderholm
BACKGROUND: Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally. PATIENTS AND METHODS: A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site. RESULTS: A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24...
June 2022: ESMO Open
#6
RANDOMIZED CONTROLLED TRIAL
Matteo Lambertini, Shona Fielding, Sibylle Loibl, Wolfgang Janni, Emma Clark, Maria Alice Franzoi, Debora Fumagalli, Carmela Caballero, Luca Arecco, Sharon Salomoni, Noam F Ponde, Francesca Poggio, Hee Jeong Kim, Cynthia Villarreal-Garza, Olivia Pagani, Shani Paluch-Shimon, Alberto Ballestrero, Lucia Del Mastro, Martine Piccart, Jose Bines, Ann H Partridge, Evandro de Azambuja
BACKGROUND: Young age at breast cancer (BC) diagnosis has historically been a rationale for overtreatment. Limited data with short follow-up exist on the prognostic value of age at diagnosis in HER2-positive BC and the benefit of anti-HER2 therapy in young patients. METHODS: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in HER2-positive early BC patients investigating the addition of pertuzumab to adjuvant chemotherapy plus trastuzumab...
August 8, 2022: Journal of the National Cancer Institute
#7
JOURNAL ARTICLE
Richard D Gelber, Xin V Wang, Bernard F Cole, David Cameron, Fatima Cardoso, Vivianne Tjan-Heijnen, Ian Krop, Sherene Loi, Roberto Salgado, Astrid Kiermaier, Elizabeth Frank, Debora Fumagalli, Carmela Caballero, Evandro de Azambuja, Marion Procter, Emma Clark, Eleonora Restuccia, Sarah Heeson, Jose Bines, Sibylle Loibl, Martine Piccart-Gebhart
AIM: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations. METHODS: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest...
March 18, 2022: European Journal of Cancer
#8
JOURNAL ARTICLE
Zheqi Li, Yang Wu, Megan E Yates, Nilgun Tasdemir, Amir Bahreini, Jian Chen, Kevin M Levine, Nolan M Priedigkeit, Azadeh Nasrazadani, Simak Ali, Laki Buluwela, Spencer Arnesen, Jason Gertz, Jennifer K Richer, Benjamin Troness, Dorraya El-Ashry, Qiang Zhang, Lorenzo Gerratana, Youbin Zhang, Massimo Cristofanilli, Maritza A Montanez, Prithu Sundd, Callen T Wallace, Simon C Watkins, Caterina Fumagalli, Elena Guerini-Rocco, Li Zhu, George C Tseng, Nikhil Wagle, Jason S Carroll, Paul Jank, Carsten Denkert, Maria M Karsten, Jens-Uwe Blohmer, Ben Ho Park, Peter C Lucas, Jennifer M Atkinson, Adrian V Lee, Steffi Oesterreich
Constitutively active estrogen receptor-α (ER/ESR1) mutations have been identified in approximately one third of ER+ metastatic breast cancers. Although these mutations are known mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1 mutant tumors, genome-edited ESR1 Y537S and D538G mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell-cell contacts while decreasing cell-extracellular matrix (ECM) adhesion...
January 25, 2022: Cancer Research
#9
REVIEW
Caterina Fumagalli, Massimo Barberis
Breast tumor heterogeneity is a major challenge in the clinical management of breast cancer patients. Both inter-tumor and intra-tumor heterogeneity imply that each breast cancer (BC) could have different prognosis and would benefit from specific therapy. Breast cancer is a dynamic entity, changing during tumor progression and metastatization and this poses fundamental issues to the feasibility of a personalized medicine approach. The most effective therapeutic strategy for patients with recurrent disease should be assessed evaluating biopsies obtained from metastatic sites...
August 27, 2021: Diagnostics
#10
JOURNAL ARTICLE
Sara Pizzamiglio, Chiara Maura Ciniselli, Tiziana Triulzi, Chiara Gargiuli, Loris De Cecco, Evandro de Azambuja, Debora Fumagalli, Christos Sotiriou, Nadia Harbeck, Miguel Izquierdo, Paolo Nuciforo, Jens Huober, Vera Cappelletti, Saverio Cinieri, Martine Piccart, Maria Grazia Daidone, Giancarlo Pruneri, Mario Paolo Colombo, Elda Tagliabue, Paolo Verderio, Serena Di Cosimo
PURPOSE: Little is known about the efficacy of HER2-targeted therapy in patients with breast cancer showing different HER2-pathway dependence and immune phenotypes. Herein, we report a NeoALTTO exploratory analysis evaluating the clinical value of 22 types of tumor-infiltrating immune cells by CIBERSORT and 5 immune-related metagenes in the overall patient population, and in subgroups defined by the TRAR classifier as HER2-addicted (TRAR-low) or not (TRAR-high). PATIENTS AND METHODS: Association of baseline TRAR, immune-related metagenes, and CIBERSORT data with pathologic complete response (pCR) and event-free survival (EFS) were assessed using logistic and Cox regression models...
December 1, 2021: Clinical Cancer Research
#11
COMMENT
David Venet, Mattia Rediti, Marion Maetens, Debora Fumagalli, David N Brown, Samira Majjaj, Roberto Salgado, Lajos Pusztai, Nadia Harbeck, Sarra El-Abed, Yingbo Wang, Cristina Saura, Henry Gomez, Vladimir Fedorovich Semiglazov, Evandro de Azambuja, Jens Huober, Paolo Nuciforo, Serena Di Cosimo, Martine Piccart, Sherene Loi, Françoise Rothé, Christos Sotiriou
PURPOSE: The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNA) in predicting pathologic complete response (pCR) and survival outcomes in the NeoALTTO trial. EXPERIMENTAL DESIGN: The neoadjuvant phase III NeoALTTO trial enrolled 455 patients with HER2-positive early-stage breast cancer...
October 15, 2021: Clinical Cancer Research
#12
REVIEW
Carmen Criscitiello, Elena Guerini-Rocco, Giulia Viale, Caterina Fumagalli, Elham Sajjadi, Konstantinos Venetis, Roberto Piciotti, Marco Invernizzi, Umberto Malapelle, Nicola Fusco
Immune Checkpoint Inhibitors (ICIs) have remarkably modified the way solid tumors are managed, including breast cancer. Unfortunately, only a relatively small number of breast cancer patients significantly respond to these treatments. To maximize the immunotherapy benefit in breast cancer, several efforts are currently being put forward for the identification of i) the best therapeutic strategy (i.e. ICI monotherapy or in association with chemotherapy, radiotherapy, or other drugs); ii) optimal timing for administration (e...
2022: Anti-cancer Agents in Medicinal Chemistry
#13
JOURNAL ARTICLE
Fabio Conforti, Laura Pala, Eleonora Pagan, Elena Guerini Rocco, Vincenzo Bagnardi, Emilia Montagna, Giulia Peruzzotti, Tommaso De Pas, Caterina Fumagalli, Silvana Pileggi, Chiara Pesenti, Sergio Marchini, Giovanni Corso, Caterina Marchio', Anna Sapino, Rossella Graffeo, Laetitia Collet, Philippe Aftimos, Christos Sotiriou, Martine Piccart, Richard D Gelber, Giuseppe Viale, Marco Colleoni, Aron Goldhirsch
BACKGROUND: We report here for the first time, a comprehensive characterization of biological and clinical features of early-stage triple negative Invasive Lobular Carcinomas(TN-ILCs) METHODS: We analyzed all consecutive patients with early-stage TN-ILC operated at two reference cancer-centers between 1994 and 2012. Primary objective was to assess the invasive disease-free survival(iDFS). Co-primary objective was to assess biological features of TN-ILCs, including molecular intrinsic subtypes based on PAM-50 assay, expression of androgen receptor (AR) and mutational status of ERBB2-gene...
October 2021: Breast: Official Journal of the European Society of Mastology
#14
JOURNAL ARTICLE
Philippe Aftimos, Mafalda Oliveira, Alexandre Irrthum, Debora Fumagalli, Christos Sotiriou, Einav Nili Gal-Yam, Mark E Robson, Justin Ndozeng, Angelo Di Leo, Eva M Ciruelos, Evandro de Azambuja, Giuseppe Viale, Elsemieke D Scheepers, Giuseppe Curigliano, Judith M Bliss, Jorge S Reis-Filho, Marco Colleoni, Marija Balic, Fatima Cardoso, Joan Albanell, Caroline Duhem, Sandrine Marreaud, Dario Romagnoli, Beatriz Rojas, Andrea Gombos, Hans Wildiers, Angel Guerrero-Zotano, Peter Hall, Andrea Bonetti, Karolina Fs Larsson, Martina Degiorgis, Silvia Khodaverdi, Richard Greil, Ásgerdur Sverrisdóttir, Marta Paoli, Ethel Seyll, Sibylle Loibl, Barbro Linderholm, Gabriele Zoppoli, Nancy E Davidson, Oskar Th Johannsson, Philippe L Bedard, Sherene Loi, Susan Knox, David A Cameron, Nadia Harbeck, Maite Lasa Montoya, Mariana Brandão, Andrea Vingiani, Carmela Caballero, Florentine S Hilbers, Lucy R Yates, Matteo Benelli, David Venet, Martine J Piccart
AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA , and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1 ...
November 2021: Cancer Discovery
#15
RANDOMIZED CONTROLLED TRIAL
Andrew N J Tutt, Judy E Garber, Bella Kaufman, Giuseppe Viale, Debora Fumagalli, Priya Rastogi, Richard D Gelber, Evandro de Azambuja, Anitra Fielding, Judith Balmaña, Susan M Domchek, Karen A Gelmon, Simon J Hollingsworth, Larissa A Korde, Barbro Linderholm, Hanna Bandos, Elżbieta Senkus, Jennifer M Suga, Zhimin Shao, Andrew W Pippas, Zbigniew Nowecki, Tomasz Huzarski, Patricia A Ganz, Peter C Lucas, Nigel Baker, Sibylle Loibl, Robin McConnell, Martine Piccart, Rita Schmutzler, Guenther G Steger, Joseph P Costantino, Amal Arahmani, Norman Wolmark, Eleanor McFadden, Vassiliki Karantza, Sunil R Lakhani, Greg Yothers, Christine Campbell, Charles E Geyer
BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy...
June 24, 2021: New England Journal of Medicine
#16
JOURNAL ARTICLE
Cinzia Solinas, Debora Fumagalli, Maria Vittoria Dieci
The present commentary synthesizes the current evidence on the role of the immune response in HER2-positive breast cancer. It points out the strengths and weaknesses of the findings observed so far, particularly in the early setting, including the clinical significance of scoring tumor-infiltrating lymphocytes. A figure proposing research hypotheses for the implementation of immune checkpoint blockade use for patient candidates to neoadjuvant treatment is presented.
April 1, 2021: Cancers
#17
JOURNAL ARTICLE
José Bines, Emma Clark, Claire Barton, Eleonora Restuccia, Marion Procter, Amir Sonnenblick, Debora Fumagalli, Damien Parlier, Amal Arahmani, José Baselga, Giuseppe Viale, Linda L Reaby, Elizabeth Frank, Richard D Gelber, Martine Piccart, Christian Jackisch, Jennifer A Petersen
BACKGROUND: We assessed health-related quality of life (symptoms of therapy/patient functioning/global health status), in APHINITY (pertuzumab/placebo, trastuzumab, and chemotherapy as adjuvant HER2-positive early breast cancer therapy). METHODS: Patients received 1 year/18 cycles of pertuzumab/placebo with trastuzumab and chemotherapy and completed EORTC QLQ-C30 and BR23 questionnaires until 36 months post-randomisation/disease recurrence. Changes ≥10 points from baseline were considered clinically meaningful...
April 7, 2021: British Journal of Cancer
#18
JOURNAL ARTICLE
Nuria Chic, Stephen J Luen, Paolo Nuciforo, Roberto Salgado, Debora Fumagalli, Florentine Hilbers, Yingbo Wang, Evandro de Azambuja, István Làng, Serena Di Cosimo, Cristina Saura, Jens Huober, Aleix Prat, Sherene Loi
In early-stage HER2-positive breast cancer, biomarkers that guide de-escalation and/or escalation of systemic therapy are needed. CelTIL score is a novel, combined biomarker based on stromal tumor-infiltrating lymphocytes and tumor cellularity and determined in tumor biopsies at week 2 of anti-HER2 therapy only. We evaluated the prognostic value of CelTIL in 196 patients with early-stage HER2-positive disease treated with standard trastuzumab-based chemotherapy in the NeoALTTO phase III trial. Using a pre-specified CelTIL cutoff, a better 5-year event-free survival and overall survival was observed between CelTIL-high and CelTIL-low score with a 76...
March 31, 2021: Journal of the National Cancer Institute
#19
JOURNAL ARTICLE
Alvaro Moreno-Aspitia, Eileen M Holmes, Christian Jackisch, Evandro de Azambuja, Frances Boyle, David W Hillman, Larissa Korde, Debora Fumagalli, Miguel A Izquierdo, Ann E McCullough, Antonio C Wolff, Kathleen I Pritchard, Michael Untch, Sébastien Guillaume, Michael S Ewer, Zhimin Shao, Sung Hoon Sim, Zeba Aziz, Georgia Demetriou, Ajay O Mehta, Michael Andersson, Masakazu Toi, Istvan Lang, Binghe Xu, Ian E Smith, Carlos H Barrios, Jose Baselga, Richard D Gelber, Martine Piccart-Gebhart
AIM: To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial. PATIENTS AND METHODS: 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac)...
March 22, 2021: European Journal of Cancer
#20
RANDOMIZED CONTROLLED TRIAL
Martine Piccart, Laura J van 't Veer, Coralie Poncet, Josephine M N Lopes Cardozo, Suzette Delaloge, Jean-Yves Pierga, Peter Vuylsteke, Etienne Brain, Suzan Vrijaldenhoven, Peter A Neijenhuis, Sylvian Causeret, Tineke J Smilde, Giuseppe Viale, Annuska M Glas, Mauro Delorenzi, Christos Sotiriou, Isabel T Rubio, Sherko Kümmel, Gabriele Zoppoli, Alastair M Thompson, Erika Matos, Khalil Zaman, Florentine Hilbers, Debora Fumagalli, Peter Ravdin, Susan Knox, Konstantinos Tryfonidis, Aleksandra Peric, Bart Meulemans, Jan Bogaerts, Fatima Cardoso, Emiel J T Rutgers
BACKGROUND: The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age. METHODS: MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined...
April 2021: Lancet Oncology
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