T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer

Fabi, Alessandra; Adami, Daniele; Valle, Elisabetta Della; Moscetti, Luca; Caputo, Roberta; Caruso, Michele; Carbognin, Luisa; Ciccarese, Mariangela; Verde, Nicla La; Arpino, Grazia; Cannita, Katia; Paris, Ida; Santini, Daniele; Montemurro, Filippo; Russillo, Michelangelo; Ferretti, Gianluigi; Filippelli, Gianfranco; Rossello, Rosalba; Fabbri, Agnese; Zambelli, Alberto; Leonardi, V.; D'Ottavio, A.M.; Nisticò, Cecilia; Stani, Simonetta Chiara; Giampaglia, Marianna; Scandurra, Giuseppa; Catania, Giovanna; Malaguti, Paola; Giannarelli, Diana; Cognetti, Francesco

doi:10.1016/j.breast.2018.07.004

Cited by 46 publications

(27 citation statements)

References 19 publications

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“…It is one of the frequently-used molecular targets for targeted therapy in the clinic, and~15-20% of GC cases have HER2 overexpression 6,7 . Although HER2-targeted monoclonal antibody drugs have been adopted widely as the targeted therapy for HER2-positive BC, this treatment strategy failed to show significantly therapeutic effect on HER2-positive GC 8 .…”

Section: Introductionmentioning

confidence: 99%

Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer

et al. 2021

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Trastuzumab emtansine (T-DM1), an antibody-drug conjugate consisted of the HER2-targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine, has shown potent therapeutic value in HER2-positive breast cancer (BC). However, a clinical trial indicated that T-DM1 exerts a limited effect on HER2-positive gastric cancer (GC), but the underlying mechanism is inconclusive. Our research attempted to reveal the probable mechanism and role of autophagy in T-DM1-treated HER2-positive GC. In this study, our results showed that T-DM1 induced apoptosis and exhibited potent therapeutic efficacy in HER2-positive GC cells. In addition, autophagosomes were observed by transmission electron microscopy. Autophagy was markedly activated and exhibited the three characterized gradations of autophagic flux, consisting of the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and the deterioration of autophagosomes in autolysosomes. More importantly, autophagic inhibition by the suppressors 3-methyladenine (3-MA) and LY294002 significantly potentiated cytotoxicity and apoptosis in HER2-positive GC cells in vitro, while the combined use of LY294002 and T-DM1 elicited potent anti-GC efficacy in vivo. In mechanistic experiments, immunoblot analysis indicated the downregulated levels of Akt, mTOR, and P70S6K and confocal microscopy analysis clearly showed that autophagic inhibition promoted the fusion of T-DM1 molecules with lysosomes in GC cells. In conclusion, our research demonstrated that T-DM1 induced apoptosis as well as cytoprotective autophagy, and autophagic inhibition could potentiate the antitumor effect of T-DM1 on HER2-positive GC. Furthermore, autophagic inhibition might increase the fusion of T-DM1 with lysosomes, which might accelerate the release of the cytotoxic molecule emtansine from the T-DM1 conjugate. These findings highlight a promising therapeutic strategy that combines T-DM1 with an autophagy inhibitor to treat HER-positive GC more efficiently.

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Section: Introductionmentioning

confidence: 99%

Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer

et al. 2021

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“…Согласно результатам многоцентрового ретроспективного исследования в Италии, которое включало сведения о 53 пациентах с HER2+ РМЖ с МГМ, получавших лечение T-DM1, у 2 (3,8 %) больных был достигнут полный ответ, у 11 (20,7 %) отмечался частичный ответ и у 16 (30,1 %) пациентов -стабилизация заболевания [44]. При медиане наблюдения 16 мес медиана ВБП достигала 7 мес, медиана ОВ -14 мес.…”

Section: системная терапияunclassified

Current approaches to the treatment of HER2‑positive breast cancer with brain metastases

Семиглазова

Sharashenidze

Керимова

et al. 2021

Opuholi ženskoj reproduktivnoj sistemy

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The article discusses modern approaches in the treatment of HER2-positive breast cancer (BC) with brain metastases (BM).The patients are subject to multidisciplinary, comprehensive and biologically – oriented treatment, with the involvement of a neurosurgeon and a radiation therapist to make a decision considering local treatment of BM, as well as a clinical oncologist to choose systemic drug therapy. Local treatment of HER2+ BC with BM patients includes surgical treatment and/or radiotherapy. Use of targeted anti-HER2 therapy changes “biology” of the disease from aggressive to indolent.In the prospective KAMILLA trial, clinically significant antitumor activity of trastuzumab emtansine was found for the first time both in patients with HER2+ BC with BM, who were previously treated with radiotherapy, and without radiotherapy in the anamnesis, which suggests the validity of further use of trastuzumab emtansine in this category of patients.The antitumor activity of trastuzumab emtansine in patients with HER2+ BC with BM was also confirmed in preclinical models. Despite the similar drug distribution in the tissues, trastuzumab emtansine, in contrast to trastuzumab, significantly slowed the growth of metastases, causing the induction of apoptosis in HER2+ BC models with BM in mice.

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“…In HER2 over-expressing breast cancer, anti-HER2 agents such as trastuzumab, drug–antibody conjugate (TDM-1), and TKIs (neratinib, lapatinib) have been shown to have activity in BMs. 92–94 , 120 ,121 In addition, the role of high-dose HER2 targeting monoclonal antibodies has shown promise using trastuzumab and pertuzumab in the PATRICIA study. 87 Lapatinib, a TKI-targeting HER2 and EGFR, shows CNS activity.…”

Section: Systemic Therapy For Bmsmentioning

confidence: 99%

Multidisciplinary patient-centered management of brain metastases and future directions

Palmer

Trifiletti

Gondi

et al. 2020

Neuro-Oncology Advances

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The incidence of brain metastasis is increasing as improvements in systemic therapy lead to increased survival. This provides new and challenging clinical decisions for patients who are trying to balance the risk of recurrence or progression with treatment-related side effects, and it requires appropriate management strategies from multidisciplinary teams. Improvements in prognostic assessment and systemic therapy with increasing activity in the brain allow for individualized care to better guide the use of local therapies and/or systemic therapy. Here, we review the current landscape of brain-directed therapy for the treatment of brain metastasis in the context of recent improved systemic treatment options. We also discuss emerging treatment strategies including targeted therapies for patients with actionable mutations, immunotherapy, modern whole-brain radiation therapy, radiosurgery, surgery, and clinical trials.

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T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer

Cited by 46 publications

References 19 publications

Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer

Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer

Current approaches to the treatment of HER2‑positive breast cancer with brain metastases

Multidisciplinary patient-centered management of brain metastases and future directions

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