Overview of the research lines

Tailoring the treatment of early breast cancer

Breast cancers represent a heterogeneous spectrum of diseases and the use of the right treatment for the right patient, avoiding potential overtreatment in patients at good prognosis, remains a challenge. In early-stage breast cancer, an important question for researchers and clinicians is how to identify which patients would benefit from a more intensive treatment versus those who could spare it, in order to avoid over- and under-treatment.
In this context, the Clinical Oncology Section of DiSCOG has coordinated and conducted several escalation and de-escalation clinical trials for early breast cancer patients (e.g. PerElisa, CHERLOB, and ShortHER trials). Moreover, several translational research projects have been conducted and are being conducted with the aim of identifying patients potentially eligible for de-escalation/escalation strategies.

Publications

De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study. Guarneri V, Dieci MV, Bisagni G, Frassoldati A, Bianchi GV, De Salvo GL, Orvieto E, Urso L, Pascual T, Paré L, Galván P, Ambroggi M, Giorgi CA, Moretti G, Griguolo G, Vicini R, Prat A, Conte PF. Ann Oncol. 2019 Jun 1;30(6):921-926.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study. Conte P, Frassoldati A, Bisagni G, Brandes AA, Donadio M, Garrone O, Piacentini F, Cavanna L, Giotta F, Aieta M, Gebbia V, Molino A, Musolino A, Ferro A, Maltoni R, Danese S, Zamagni C, Rimanti A, Cagossi K, Russo A, Pronzato P, Giovanardi F, Moretti G, Lombardo L, Schirone A, Beano A, Amaducci L, Bajardi EA, Vicini R, Balduzzi S, D'Amico R, Guarneri V. Ann Oncol. 2018 Dec 1;29(12):2328-2333.

Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial. Dieci M V, Prat A, Tagliafico E, Paré L, Ficarra G, Bisagni G, Piacentini F, Generali D G, Conte P, Guarneri V. Annals Of Oncology, vol. 27, pp. 1867-1873, 2016

Trastuzumab-lapatinib as neoadjuvant therapy for HER2-positive early breast cancer: Survival analyses of the CHER-Lob trial. Guarneri V, Dieci MV, Griguolo G, Miglietta F, Girardi F, Bisagni G, Generali DG, Cagossi K, Sarti S, Frassoldati A, Gianni L, Cavanna L, Pinotti G, Musolino A, Piacentini F, Cinieri S, Prat A, Conte P; of the CHER-Lob study team. Eur J Cancer. 2021 Aug;153:133-141.

PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype. Guarneri V, Dieci MV, Bisagni G, Brandes AA, Frassoldati A, Cavanna L, Musolino A, Giotta F, Rimanti A, Garrone O, Bertone E, Cagossi K, Nanni O, Piacentini F, Orvieto E, Griguolo G, Curtarello M, Urso L, Paré L, Chic N, D'Amico R, Prat A, Conte P. Clin Cancer Res. 2020 Nov 15;26(22):5843-5851.

Loss of HER2 positivity and prognosis after neoadjuvant therapy in HER2-positive breast cancer patients. Guarneri V, Dieci MV, Barbieri E, Piacentini F, Omarini C, Ficarra G, Bettelli S, Conte P. Ann Onc, 2990-2994, 2013

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation. Prat A, Guarneri V, Paré L, Griguolo G, Pascual T, Dieci MV, Chic N, González-Farré B, Frassoldati A, Sanfeliu E, Cejalvo JM, Muñoz M, Bisagni G, Brasó-Maristany F, Urso L, Vidal M, Brandes AA, Adamo B, Musolino A, Miglietta F, Conte B, Oliveira M, Saura C, Pernas S, Alarcón J, Llombart-Cussac A, Cortés J, Manso L, López R, Ciruelos E, Schettini F, Villagrasa P, Carey LA, Perou CM, Piacentini F, D'Amico R, Tagliafico E, Parker JS, Conte P. Lancet Oncol. 2020 Nov;21(11):1455-1464.

First Prospective Multicenter Italian Study on the Impact of the 21-Gene Recurrence Score in Adjuvant Clinical Decisions for Patients with ER Positive/HER2 Negative Breast Cancer. Dieci MV, Guarneri V, Giarratano T, Mion M, Tortora, Giampaolo, De Rossi C, Gori, Stefania, Oliani C, Merlini L, Pasini F, Bonciarelli G, Griguolo G, Orvieto E, Michieletto S, Saibene T, Del Bianco P, De Salvo GL, Conte P. The Oncologist, vol. 23(3), pp. 297-305, 2017

PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. Loibl S, Majewski I, Guarneri V, Nekljudova V, Holmes E, Bria E, Denkert C, Schem C, Sotiriou C, Loi S, Untch M, Conte P, Bernards R, Piccart M, von Minckwitz G, Baselga J. Annals Of Oncology, vol. 27(8), pp. 1519-1525, 2016

Funding

Short-HER: multicentric randomised phase 3 trial of adjuvant chemotherapy plus 3 vs 12 months of trastuzumab in breast cancer patients with HER2 positive disease (AIFA FARM62MC97)
5x1000: Oncologia traslazionale - Progetto SHORT-HER
Ministero della Salute: Challenging the role of chemotherapy in HER2 positive early breast cancer (GR-2013-02356771)
PIK3CA mutations/PTEN loss and infiltrating tumor lymphocytes to personalize therapy in HER2+ early breast cancer (MFAG 2014 – 15938)

 
Immunotherapy and immune microenvironment in breast cancer

The last years have seen the rise of immunotherapy as a new efficient treatment strategy in several solid tumors. In the field of breast cancer, the addition of an immune checkpoint inhibitor to chemotherapy has recently shown efficacy in a selected population of metastatic breast cancer patients with triple-negative PD-L1 positive disease. Moreover, the addition of an immune checkpoint inhibitor to neoadjuvant chemotherapy has also been reported to increase pathologic complete response rates and survival in patients with early triple-negative breast cancer.
In this context, the Clinical Oncology Section of DiSCOG has coordinated and conducted two prospective trials exploring immunotherapy strategies for early breast cancer patients (the A-BRAVE trial and the GIADA trial). The A-BRAVE trial is a randomized phase III trial ongoing in more than 60 centers in Italy and UK, which has evaluated the efficacy of adjuvant immunotherapy with the anti-PD-L1 avelumab for one year for patients with high-risk triple negative breast cancer who completed the standard treatment with curative intent, including surgery and chemotherapy. The GIADA phase II study is a multicentric Italian trial which tested the efficacy of a preoperative sequence of chemotherapy followed by immunotherapy and endocrine treatment for patients with Luminal B HR+ breast cancer.
In addition, the Clinical Oncology Section of DiSCOG is currently involved in the design, coordination and conduction of the ATRiBRAVE trial, testing the use of ATR-inhibitors to restore sensitivity to immunotherapy in advanced triple-negative breast cancer pretreated with chemotherapy and immunotherapy in the early setting.

The Clinical Oncology Section of DiSCOG is also coordinating the upcoming research project “Immunometabolic profile to personalize immunotherapy for patients with early triple-negative breast cancer”, which aims to improve the selection of patients with triple-negative early breast cancer who may benefit from immunotherapy, through the combined assessment of immune- and metabolism-related parameters.
Moreover, several translational research projects have been conducted and are being conducted with the aim of identifying potential immune-related biomarkers for breast cancer patients.

Publications

Neoadjuvant chemotherapy and immunotherapy in Luminal B-like breast cancer: results of the phase II GIADA trial. Dieci MV, Guarneri V, Tosi A, Bisagni G, Musolino A, Spazzapan S, Moretti G, Vernaci GM, Griguolo G, Giarratano T, Urso L, Schiavi F, Pinato C, Magni G, Lo Mele M, De Salvo GL, Rosato A, Conte P. Clin Cancer Res. 2021 Oct 19

Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer. Dieci MV, Conte P, Bisagni G, Brandes AA, Frassoldati A, Cavanna L, Musolino A, Giotta F, Rimanti A, Garrone O, Bertone E, Cagossi K, Sarti S, Ferro A, Piacentini F, Maiorana A, Orvieto E, Sanders M, Miglietta F, Balduzzi S, D'Amico R, Guarneri V. Ann Oncol. 2019 Mar 1;30(3):418-423.

A comprehensive profiling of the immune microenvironment of breast cancer brain metastases. Griguolo G, Tosi A, Dieci MV, Fineberg S, Rossi V, Ventura A, Bottosso M, Bauchet L, Miglietta F, Jacob J, Rigau V, Fassan M, Jacot W, Conte P, Rosato A, Darlix A, Guarneri V. Neuro Oncol. 2022 May 24

Integration of tumour infiltrating lymphocytes, programmed cell-death ligand-1, CD8 and FOXP3 in prognostic models for triple-negative breast cancer: Analysis of 244 stage I-III patients treated with standard therapy. Dieci MV, Tsvetkova V, Griguolo G, Miglietta F, Tasca G, Giorgi CA, Cumerlato E, Massa D, Lo Mele M, Orvieto E, Guarneri V, Conte P. Eur J Cancer. 2020 Sep;136:7-15. doi: 10.1016/j.ejca.2020.05.014. Epub 2020 Jul 1. PMID: 32622323.

Immune characterization of breast cancer metastases: prognostic implications. Dieci MV, Tsvetkova V, Orvieto E, Piacentini F, Ficarra G, Griguolo G, Miglietta F, Giarratano T, Omarini C, Bonaguro S, Cappellesso R, Aliberti C, Vernaci G, Giorgi CA, Faggioni G, Tasca G, Conte P, Guarneri V. Breast Cancer Res. 2018 Jun 22;20(1):62.

Immune microenvironment and intrinsic subtyping in hormone receptor-positive/HER2-negative breast cancer. Griguolo G, Dieci MV, Paré L, Miglietta F, Generali DG, Frassoldati A, Cavanna L, Bisagni G, Piacentini F, Tagliafico E, Cagossi K, Ficarra G, Prat A, Conte P, Guarneri V. NPJ Breast Cancer. 2021 Feb 12;7(1):12.

Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, Ficarra G, Mathieu MC, Delaloge S, Curigliano G, Andre F. Ann Oncol, 25:611-618, 2014

Association of tumor-infiltrating lymphocytes with recurrence score in hormone receptor-positive/HER2-negative breast cancer: Analysis of four prospective studies. Miglietta F, Dieci MV, Giarratano T, Torri V, Giuliano M, Zustovich F, Mion M, Tondini CA, De Rossi C, Bria E, Franchi M, Merlini L, Giannatiempo R, Russo D, Fotia V, Poletti P, Caremoli ER, Arpino MG, De Salvo GL, Zambelli A, Guarneri V. Eur J Cancer. 2023 Dec;195:113399. doi: 10.1016/j.ejca.2023.113399. Epub 2023 Oct 26. PMID: 37950941.

A-BRAVE trial: A phase III randomized trial with avelumab in early triple-negative breast cancer with residual disease after neoadjuvant chemotherapy or at high risk after primary surgery and adjuvant chemotherapy. Pier Franco Conte, Maria Vittoria Dieci, Giancarlo Bisagni, Peter Schmid, Vittoria Fotia, Federico Piacentini, Michelino De Laurentiis, Adolfo G. Favaretto, Stefano Tamberi, Giulia Valeria Bianchi, Claudio Zamagni, Saverio Cinieri, Domenico C. Corsi, Lucia Del Mastro, Antonella Ferro, Alessandra Gennari, Marta Mion, Antonino Musolino, Gian Luca De Salvo, Valentina Guarneri. ASCO Congress 2024.

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer. Leon-Ferre RA, Jonas SF, Salgado R, Loi S, de Jong V, Carter JM, Nielsen TO, Leung S, Riaz N, Chia S, Jules-Clément G, Curigliano G, Criscitiello C, Cockenpot V, Lambertini M, Suman VJ, Linderholm B, Martens JWM, van Deurzen CHM, Timmermans AM, Shimoi T, Yazaki S, Yoshida M, Kim SB, Lee HJ, Dieci MV, Bataillon G, Vincent-Salomon A, André F, Kok M, Linn SC, Goetz MP, Michiels S; International Immuno-Oncology Biomarker Working Group. JAMA. 2024 Apr 2;331(13):1135-1144. doi: 10.1001/jama.2024.3056. PMID: 38563834; PMCID: PMC10988354.

Neoadjuvant nivolumab and chemotherapy in early estrogen receptor-positive breast cancer: a randomized phase 3 trial. Loi S, Salgado R, Curigliano G, Romero Díaz RI, Delaloge S, Rojas García CI, Kok M, Saura C, Harbeck N, Mittendorf EA, Yardley DA, Suárez Zaizar A, Caminos FR, Ungureanu A, Reinoso-Toledo JG, Guarneri V, Egle D, Ades F, Pacius M, Chhibber A, Chandra R, Nathani R, Spires T, Wu JQ, Pusztai L, McArthur H. Nat Med. 2025 Feb;31(2):433-441. doi: 10.1038/s41591-024-03414-8. Epub 2025 Jan 21. PMID: 39838118; PMCID: PMC11835735.

Immune and gene-expression profiling in estrogen receptor low and negative early breast cancer. Massa D, Vernieri C, Nicolè L, Criscitiello C, Boissière-Michot F, Guiu S, Bobrie A, Griguolo G, Miglietta F, Vingiani A, Lobefaro R, Taurelli Salimbeni B, Pinato C, Schiavi F, Brich S, Pescia C, Fusco N, Pruneri G, Fassan M, Curigliano G, Guarneri V, Jacot W, Dieci MV. J Natl Cancer Inst. 2024 Dec 1;116(12):1914-1927. doi: 10.1093/jnci/djae178. PMID: 39083015; PMCID: PMC11630536.

Tumor-Infiltrating Lymphocytes and Survival Outcomes in Early ERBB2-Positive Breast Cancer: 10-Year Analysis of the ShortHER Randomized Clinical Trial. Dieci MV, Bisagni G, Bartolini S, et al. JAMA Oncol. 2025;11(4):386–393. doi:10.1001/jamaoncol.2024.6872

Funding

Adjuvant treatment for high-risk triple negative breast cancer patients with the anti-PD-L1 antibody AVELUMAB: a phase III randomized trial (supported by Merck KGaA)
5x1000 IOV 2018 – Senior Grant: PEPITA
5x1000 IOV 2018 – Junior Grant: PRINCESS
5x1000 IOV – Senior Grant: MERLIN
Conquer Cancer Foundation of ASCO Young Investigator Award in Breast Cancer 2019: PRIMETIME
AIRC (Italian Association for Research against Cancer) 5 per Mille 2019 ID. 22759: Metastasis as a mechanodisease
AIRC IG - Immunometabolic profile to personalize immunotherapy for patients with early triple negative breast cancer

Molecular characterization and targeted therapeutic approaches for advanced breast cancer

Despite improvements in prevention, diagnosis and treatment, metastatic breast cancer still represents the leading cause of cancer deaths in women worldwide.
Breast cancer is an extremely heterogeneous disease and is currently classified into clinically relevant subgroups according to the expression of hormone receptors (HR, estrogen receptor and progesterone receptor) and HER2 (Human epidermal growth factor receptor type 2) by immunohistochemistry (IHC) and in situ hybridization (ISH). However, over the last few years several new clinically relevant biomarkers have emerged to guide use of targeted therapy in metastatic breast cancer. Some are already in use in clinical practice to select patient’s treatment, such as the presence of PIK3CA or germline BRCA 1/2 mutations or expression of PD-L1; however, the number of these new potential therapeutic biomarkers is constantly increasing. Moreover, the potential to assess these novel biomarkers through non-invasive techniques, as for example, liquid biopsies, represents a unique opportunity to improve the personalization of advanced breast cancer treatment.

Publications

Everolimus plus aromatase inhibitors as maintenance therapy after first-line chemotherapy: Final results of the phase III randomised MAIN-A (MAINtenance Afinitor) trial. Guarneri V, Giorgi CA, Cinieri S, Bengala C, Mariani G, Bisagni G, Frassoldati A, Zamagni C, De Rossi C, Amoroso V, Andreetta C, Ferro A, Zambelli A, Gori S, Garrone O, Dieci MV, Orlando L, Pastina I, Beninato T, Moretti G, Genovesi E, Cinefra M, Vicini R, Magni G, De Salvo GL, Conte P. Eur J Cancer. 2021 Sep;154:21-29.

Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). Johnston SRD, Harbeck N, Hegg R, Toi M, Martin M, Shao ZM, Zhang QY, Martinez Rodriguez JL, Campone M, Hamilton E, Sohn J, Guarneri V, Okada M, Boyle F, Neven P, Cortés J, Huober J, Wardley A, Tolaney SM, Cicin I, Smith IC, Frenzel M, Headley D, Wei R, San Antonio B, Hulstijn M, Cox J, O'Shaughnessy J, Rastogi P; monarchE Committee Members and Investigators. J Clin Oncol. 2020 Dec 1;38(34):3987-3998.

Evolution of HER2-low expression from primary to recurrent breast cancer. Miglietta F, Griguolo G, Bottosso M, Giarratano T, Lo Mele M, Fassan M, Cacciatore M, Genovesi E, De Bartolo D, Vernaci G, Amato O, Conte P, Guarneri V, Dieci MV. NPJ Breast Cancer. 2021 Oct 12;7(1):137.

ESR1 Gene Mutation in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Patients: Concordance Between Tumor Tissue and Circulating Tumor DNA Analysis. Urso L, Vernaci G, Carlet J, Lo Mele M, Fassan M, Zulato E, Faggioni G, Menichetti A, Di Liso E, Griguolo G, Falci C, Conte P, Indraccolo S, Guarneri V, Dieci MV. Front Oncol. 2021 Mar 11;11:625636.

Discordance in receptor status between primary and recurrent breast cancer has a prognostic impact: a single Institution analysis. Dieci MV, Barbieri E, Piacentini F, Ficarra G, Bettelli S, Dominici M, Conte P, Guarneri V. Ann Oncol, 24:101-108, 2013

Funding

Finalizzata Ministeriale 2016 GR-2016-02361279  - Tracking the dynamic evolution of ESR1 and PIK3CA mutations on circulating tumor DNA in metastatic breast cancer patients receiving endocrine maintenance treatment: a translational analysis of the prospective, multicenter, randomized MAIN-A study.
AIRC (Italian Association for Research against Cancer) 5 per Mille 2019 ID. 22759: Metastasis as a mechanodisease
University of Padova STARS Grant 2021: COBRA

University of Padova Grants Supporting TAlent in ReSearch@University (STARS) of Padua – Life Science – Starting Grants - Project: Tracking actionable biomarkers in relapsed/stage IV HER2-negative breast cancer patients (TRACK-ACTION-BC STUDY)

Real world studies on innovative anticancer drugs in breast cancer and the diagnostic-therapeutic pathway of breast cancer patients

Innovative drugs in oncology are approved and introduced in the clinical practice on the bases of pivotal clinical trials; as main limitations, clinical trials usually enroll highly selected patients and exclude some patient population which are often encounted in the clinical practice (e.g., elderly, poor performance status patients). Real world evidence may close the gap between the ideal scenario of the clinical trial and the daily clinical practice; this is the rational for designing these multicenter studies both at regional and national level, aiming at investigating effectiveness and cost-effectiveness of innovative anticancer drugs.
Moreover, beyond novel drugs, the optimization of the diagnostic-therapeutic pathway of cancer patients has also been identified as a key-point for potential improvement in the context of breast cancer treatment.

Publications

Epidemiology and clinical course of severe acute respiratory syndrome coronavirus 2 infection in cancer patients in the Veneto Oncology Network: The Rete Oncologica Veneta covID19 study. Guarneri V, Bassan F, Zagonel V, Milella M, Zaninelli M, Cattelan AM, Vianello A, Gori S, Aprile G, Azzarello G, Chiari R, Favaretto A, Oliani C, Scola A, Pastorelli D, Mandarà M, Zustovich F, Bernardi D, Chiarion-Sileni V, Morandi P, Toso S, Di Liso E, Ziampiri S, Caccese M, Zampiva I, Puccetti O, Celestino M, Dieci MV, Conte P; Veneto Oncology Network. Eur J Cancer. 2021 Apr;147:120-127.

Real-world effectiveness comparison of first-line palbociclib, ribociclib or abemaciclib plus endocrine therapy in advanced HR-positive/HER2-negative BC patients: results from the multicenter PALMARES-2 study. Provenzano L, Dieci MV, Curigliano G, Giuliano M, Botticelli A, Lambertini M, Rizzo G, Pedersini R, Sirico M, La Verde N, Gennari A, Zambelli A, Toss A, Piras M, Giordano M, Tagliaferri B, Generali D, Sartori D, Miliziano D, Menichetti A, Ligorio F, Zurlo C, Griguolo G, Berton Giachetti PP, Faso V, Corti C, Chiappe E, Scagnoli S, Pisegna S, Capasso C, De Angelis C, Arpino G, Criscitiello C, Guarneri V, Pruneri G, Mariani L, Vernieri C; PALMARES-2 Study Group. Ann Oncol. 2025 Apr 8:S0923-7534(25)00134-6. doi: 10.1016/j.annonc.2025.03.023. Epub ahead of print. PMID: 40204155.

Exceptional responses to systemic treatment in metastatic breast cancer: clinical features and long-term outcomes. Griguolo G, Bottosso M, Crema A, Giarratano T, Miglietta F, Bonomi G, Mioranza E, Napetti D, Massa D, Faggioni G, Dieci MV, Guarneri V. Eur J Cancer. 2025 Mar 26;219:115321. doi: 10.1016/j.ejca.2025.115321. Epub 2025 Feb 20. PMID: 39987798.

Funding

University of Padova BIRD 2021: Impact of MOlecular tumor board in the REal-life diagnostic-therapeutic pathway of cancer patients. The MORE study
Progetti Pubblico Privati CORIS 2019: RENEW
CaRiPaRo 2020: ROVID
Finalizzata Sanitaria Regionale 2017: RSF-2017-00000557

People involved:

Guarneri Valentina, Full Professor
Dieci Maria Vittoria, Associate Professor
Pasello Giulia, Associate Professor

Bonanno Laura, Assistant Professor
Griguolo Gaia, Assistant Professor
Miglietta Federica, Assistant Professor

Group members

Bottosso Michele, Di Liso Elisabetta, Faggioni Giovanni, Falci Cristina, Giarratano Tommaso, Giorgi Carlo Alberto, Girardi Fabio, Massa Davide, Menichetti Alice, Mioranza Eleonora, Tasca Giulia, Vernaci Grazia