T-DM1 Efficacy in Patients With HER2-positive Metastatic Breast Cancer Progressing After a Taxane Plus Pertuzumab and Trastuzumab: An Italian Multicenter Observational Study

Conte, Benedetta; Fabi, Alessandra; Poggio, F.; Blondeaux, Eva; Dellepiane, Chiara; D'Alonzo, A.; Buono, Giuseppe; Arpino, Grazia; Magri, Valentina; Naso, Giuseppe; Presti, Daniele; Mura, Silvia; Fontana, A.; Cognetti, Francesco; Molinelli, Chiara; Pastorino, S.; Bighin, Claudia; Miglietta, Loredana; Boccardo, Francesco; Lambertini, Matteo; Mastro, Lucia Del

doi:10.1016/j.clbc.2019.09.001

Cited by 39 publications

(35 citation statements)

References 18 publications

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“…HER2 and the activated pathways are targeted by treatments that include humanized, monoclonal antibodies trastuzumab and pertuzumab in combination with a taxane-based chemotherapy [ 111 ]. Once tumors progress on these first-line therapies, second line therapies are given in the form of HER tyrosine kinase inhibitors, lapatinib [ 11 ] or neratinib [ 12 ], or antibody conjugates, including T-DM1 (ado-trastuzumab emtansine) [ 112 ].…”

Section: Notch-mediated Resistance To Breast Cancer Treatmentmentioning

confidence: 99%

Notch Signaling in Breast Cancer: A Role in Drug Resistance

BeLow

Osipo

2020

Cells

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Breast cancer is a heterogeneous disease that can be subdivided into unique molecular subtypes based on protein expression of the Estrogen Receptor, Progesterone Receptor, and/or the Human Epidermal Growth Factor Receptor 2. Therapeutic approaches are designed to inhibit these overexpressed receptors either by endocrine therapy, targeted therapies, or combinations with cytotoxic chemotherapy. However, a significant percentage of breast cancers are inherently resistant or acquire resistance to therapies, and mechanisms that promote resistance remain poorly understood. Notch signaling is an evolutionarily conserved signaling pathway that regulates cell fate, including survival and self-renewal of stem cells, proliferation, or differentiation. Deregulation of Notch signaling promotes resistance to targeted or cytotoxic therapies by enriching of a small population of resistant cells, referred to as breast cancer stem cells, within the bulk tumor; enhancing stem-like features during the process of de-differentiation of tumor cells; or promoting epithelial to mesenchymal transition. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance through reduction or elimination of breast cancer stem cells. However, Notch inhibitors have yet to be clinically approved for the treatment of breast cancer, mainly due to dose-limiting gastrointestinal toxicity. In this review, we discuss potential mechanisms of Notch-mediated resistance in breast cancer cells and breast cancer stem cells, and various methods of targeting Notch through γ-secretase inhibitors, Notch signaling biologics, or transcriptional inhibitors. We also discuss future plans for identification of novel Notch-targeted therapies, in order to reduce toxicity and improve outcomes for women with resistant breast cancer.

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Section: Notch-mediated Resistance To Breast Cancer Treatmentmentioning

confidence: 99%

Notch Signaling in Breast Cancer: A Role in Drug Resistance

BeLow

Osipo

2020

Cells

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“…In addition, real-world data from the currently ongoing registries in the advanced setting should also be considered an important source of data to explore this unmet medical need. [26][27][28][29] With the current availability of several effective targeted agents as (neo)adjuvant and post-neoadjuvant treatment for patients with HER2-positive breast cancer, [30][31][32][33][34] defining the optimal performance of first-line anti-HER2 therapies in those relapsing after prior exposure in the early setting is becoming a clinically relevant research area. The present analysis has some limitations that should be acknowledged.…”

Section: Discussionmentioning

confidence: 99%

Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: analysis from the ALTTO (BIG 2-06) trial

et al. 2020

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BackgroundIn HER2-positive breast cancer, time elapsed between completion of (neo)adjuvant trastuzumab and diagnosis of metastatic disease (‘trastuzumab-free interval’, TFI) is crucial to choose the optimal first-line treatment. Nevertheless, there is no clear evidence to support its possible prognostic role.MethodsIn the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, patients with HER2-positive early breast cancer were randomised to 1 year of either trastuzumab alone, lapatinib alone, their sequence or their combination. This exploratory analysis included only patients in the trastuzumab alone or trastuzumab plus lapatinib arms who developed a distant disease-free survival (DDFS) event. Overall survival (OS) was defined as time between date of DDFS event and death; age at diagnosis, tumour size and hormone receptor status were the variables included in the multivariate models.ResultsOut of 8381 patients included in ALTTO, 404 patients in the trastuzumab alone and trastuzumab plus lapatinib arms developed a DDFS event, of which 201 occurred <12 months (group A) and 203 >12 months (group B) after completion of adjuvant trastuzumab. No significant difference in location of first DDFS event was observed (p=0.073); a numerically higher number of patients in group A than in group B developed brain metastasis (26% vs 15%). Choice of first-line therapy differed between the two groups (p=0.022): in group A, more patients received lapatinib (25% vs 11%) and less pertuzumab (8% vs 17%). Median OS was 29.3 and 18.4 months in groups B and A, respectively (adjusted HR 0.69; 95% CI 0.54–0.89; p=0.004). The longer OS for patients in group B was observed across the analysed subgroups without interaction according to hormone receptor status (p=0.814) nor type of administered adjuvant anti-HER2 treatment (p=0.233).ConclusionsTFI has prognostic value in patients with HER2-positive early breast cancer treated with adjuvant trastuzumab-based therapy. TFI is a valid tool to better individualise clinical recommendations and to design future first-line treatment trials for metastatic patients.

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“…Since the approval of pertuzumab and T-DM1, several studies have investigated T-DM1’s efficacy after prior treatment with pertuzumab, trastuzumab, and taxane-based chemotherapy. The median PFS of second-line T-DM1 was 6.3 months for 77 patients in the Gruppo Italiano Mammella (GIM) 14/BIOMETA study (a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer) and 10.5 months for 135 patients in a real-life setting [20, 21].…”

Section: Second-line Treatment: Trastuzumab Emtansinementioning

confidence: 99%

Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Current Treatment Standards and Future Perspectives

Dormann¹

2020

Breast Care

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Background: The basis of improved systemic therapy for inoperable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer is formed by HER2-targeting monoclonal antibodies. Dual HER2 blockade with pertuzumab and trastuzumab in combination with docetaxel in previously untreated patients, and trastuzumab emtansine (T-DM1, an antibody-drug conjugate [ADC] consisting of trastuzumab, a linker and a cytotoxic payload) after prior trastuzumab therapy have demonstrated progression-free survival (PFS) and overall survival (OS) superior to what was achieved with the previous treatment routine. Therefore, pertuzumab and trastuzumab with chemotherapy (preferably with a taxane) and T-DM1 are considered the current standard of care in the first- and second-line settings, respectively. For later lines of therapy, no uniformly recognized standard of care has been defined. Accepted options include treatment with trastuzumab beyond progression, in combination with a broad variety of single-agent chemotherapies used sequentially, or lapatinib (an HER2-targeting tyrosine kinase inhibitor [TKI]) in combination with either trastuzumab or capecitabine. However, most of these options have not been formally tested in patients receiving the current standard of care therapy for metastatic disease. Summary: In patients previously treated with today’s standard of care, including a significant subgroup with untreated or progressing brain metastases, the combination of tucatinib, a novel HER2-targeting TKI, with trastuzumab and capecitabine, demonstrates a clinically meaningful improvement in PFS and OS when compared to placebo with trastuzumab and capecitabine. Neratinib, another HER2 TKI, in combination with capecitabine, compared to lapatinib and capecitabine, as well as margetuximab, an HER2-directed monoclonal antibody with a fragment c (Fc) domain engineered to enhance immune activation, compared to trastuzumab, both combined with the investigator’s choice of chemotherapy, showed a statistically significantly longer PFS. However, not all patients in the respective trials had received pertuzumab and T-DM1 prior to enrollment and, so far, no improvement in OS has been demonstrated. After a median of 6 prior lines of therapy, trastuzumab deruxtecan (T-DXd), a novel ADC, showed a meaningful overall response and PFS. Although the safety profile was generally manageable, treatment-related interstitial lung disease (ILD) might pose a challenge in routine practice. Pyrotinib, another HER2 TKI, was evaluated in combination with capecitabine in patients after prior exposure to trastuzumab when pertuzumab and T-DM1 were not available. In this setting, PFS was better than with lapatinib and capecitabine. Key Messages: In 2020, pertuzumab and trastuzumab with taxane-based chemotherapy in the first line, and T-DM1 in the second line, remain the standard of care. Tucatinib, neratinib, margetuximab, and T-DXd expand the armamentarium for treatment beyond the second line. Pyrotinib might be another option, especially for patients, who do not have access to pertuzumab and T-DM1.

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T-DM1 Efficacy in Patients With HER2-positive Metastatic Breast Cancer Progressing After a Taxane Plus Pertuzumab and Trastuzumab: An Italian Multicenter Observational Study

Cited by 39 publications

References 18 publications

Notch Signaling in Breast Cancer: A Role in Drug Resistance

Notch Signaling in Breast Cancer: A Role in Drug Resistance

Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: analysis from the ALTTO (BIG 2-06) trial

Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Current Treatment Standards and Future Perspectives

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