Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer—Immun-HER trial (GOIRC-01-2016)
Background It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab.Methods In this multicenter randomized phase II trial, all enrolled patients (pts) with T2–T4d HER2-positive BC received 3 cycles of neoadjuvant treatment...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/11/e007667.full |
| _version_ | 1826805057418428416 |
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| author | Benedetta Pellegrino Luisa Carbognin Emilio Bria Alberto Zambelli Filippo Montemurro Elena Fiorio Claudio Zamagni Nicoletta Campanini Michele Tognetto Gabriele Missale Antonino Musolino Stefania Gori Giuseppe Maglietta Chiara Tommasi Olga Serra Elisabetta Cretella Massimo Ambroggi Antonio Frassoldati Giancarlo Bisagni Chiara Casarini Antonella Mura Lorenzo Gianni Renata Todeschini Enrico Maria Silini |
| author_facet | Benedetta Pellegrino Luisa Carbognin Emilio Bria Alberto Zambelli Filippo Montemurro Elena Fiorio Claudio Zamagni Nicoletta Campanini Michele Tognetto Gabriele Missale Antonino Musolino Stefania Gori Giuseppe Maglietta Chiara Tommasi Olga Serra Elisabetta Cretella Massimo Ambroggi Antonio Frassoldati Giancarlo Bisagni Chiara Casarini Antonella Mura Lorenzo Gianni Renata Todeschini Enrico Maria Silini |
| author_sort | Benedetta Pellegrino |
| collection | DOAJ |
| description | Background It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab.Methods In this multicenter randomized phase II trial, all enrolled patients (pts) with T2–T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD).Results Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: −0.73). Grade≥3 AE incidence rates were similar between the two arms.Conclusions SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response.Trial registration number NCT03144947, and EudraCT number: 2016-000435-41. |
| first_indexed | 2024-03-09T08:31:21Z |
| format | Article |
| id | doaj.art-cb245d7c7a6b4364ba2d9bf6da750467 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2025-03-17T02:04:24Z |
| publishDate | 2023-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-cb245d7c7a6b4364ba2d9bf6da7504672025-02-14T01:30:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-11-01111110.1136/jitc-2023-007667Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer—Immun-HER trial (GOIRC-01-2016)Benedetta Pellegrino0Luisa Carbognin1Emilio Bria2Alberto Zambelli3Filippo Montemurro4Elena Fiorio5Claudio Zamagni6Nicoletta Campanini7Michele Tognetto8Gabriele Missale9Antonino Musolino10Stefania Gori11Giuseppe Maglietta12Chiara Tommasi13Olga Serra14Elisabetta Cretella15Massimo Ambroggi16Antonio Frassoldati17Giancarlo Bisagni18Chiara Casarini19Antonella Mura20Lorenzo Gianni21Renata Todeschini22Enrico Maria Silini23Medical Oncology and Breast Unit, University Hospital of Parma, Parma, ItalyComprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Roma, ItalyUniversità Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, ItalyOncology Unit, ASST Papa Giovanni XXIII, Bergamo, Lombardia, ItalyDepartment of Oncology and Hematology, Candiolo Cancer Institute, Candiolo, ItalyMedical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy27 IRCCS Azienda Ospedaliero-universitaria di Bologna, Bologna, ItalyDepartment of Medicine and Surgery, University of Parma, Parma, ItalyGruppo Oncologico di Ricerca Clinica (GOIRC), Parma, ItalyDepartment of Medicine and Surgery, University of Parma, Parma, ItalyDepartment of Medicine and Surgery, University of Parma, Parma, ItalyMedical Oncology Unit, Ospedale Sacro Cuore—Don Calabria—Negrar (VR), negrar, ItalyResearch Unit, University Hospital of Parma, Parma, ItalyDepartment of Medicine and Surgery, University of Parma, Parma, ItalyMedical Oncology and Breast Unit, University Hospital of Parma, Parma, ItalyMedical Oncology Unit, Ospedale di Bolzano, Bolzano, ItalyMedical Oncology, Hospital of Piacenza, Piacenza, Emilia-Romagna, ItalySpecialist Medical Department, University Hospital Arcispedale Sant`Anna of Ferrara, Cona, Emilia-Romagna, ItalyMedical Oncology Unit, Azienda Unità Sanitaria Locale—IRCCS Tecnologie Avanzate e Modelli Assistenziali in Oncologia di Reggio Emilia, Reggio Emilia, Emilia-Romagna, ItalyMedical Oncology Unit, Ospedale di Sassuolo, Sassuolo, Modena, ItalyDepartment of Medical Oncology, Azienda USL Bologna, Bologna, ItalyOncology Department, Infermi Hospital, AUSL della Romagna, Rimini, ItalyGruppo Oncologico di Ricerca Clinica (GOIRC), Parma, ItalyDepartment of Medicine and Surgery, University of Parma, Parma, ItalyBackground It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab.Methods In this multicenter randomized phase II trial, all enrolled patients (pts) with T2–T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD).Results Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: −0.73). Grade≥3 AE incidence rates were similar between the two arms.Conclusions SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response.Trial registration number NCT03144947, and EudraCT number: 2016-000435-41.https://jitc.bmj.com/content/11/11/e007667.full |
| spellingShingle | Benedetta Pellegrino Luisa Carbognin Emilio Bria Alberto Zambelli Filippo Montemurro Elena Fiorio Claudio Zamagni Nicoletta Campanini Michele Tognetto Gabriele Missale Antonino Musolino Stefania Gori Giuseppe Maglietta Chiara Tommasi Olga Serra Elisabetta Cretella Massimo Ambroggi Antonio Frassoldati Giancarlo Bisagni Chiara Casarini Antonella Mura Lorenzo Gianni Renata Todeschini Enrico Maria Silini Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer—Immun-HER trial (GOIRC-01-2016) Journal for ImmunoTherapy of Cancer |
| title | Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer—Immun-HER trial (GOIRC-01-2016) |
| title_full | Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer—Immun-HER trial (GOIRC-01-2016) |
| title_fullStr | Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer—Immun-HER trial (GOIRC-01-2016) |
| title_full_unstemmed | Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer—Immun-HER trial (GOIRC-01-2016) |
| title_short | Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer—Immun-HER trial (GOIRC-01-2016) |
| title_sort | randomized open label phase ii biomarker study of immune mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced inflammatory or early her2 positive breast cancer immun her trial goirc 01 2016 |
| url | https://jitc.bmj.com/content/11/11/e007667.full |
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