Dual anti-HER2 blockade in late-line treatment of metastatic HER2-positive breast cancer
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In recent years, there has been a wide range of treatment options for patients with metastatic HER2-positive breast cancer, resulting in the highest life expectancy for these patients among all subtypes. The addition of pertuzumab to trastuzumab and docetaxel has been shown to increase overall survival and is therefore recognized as the standard first-line treatment. The most optimal second-line treatment option is trastuzumab emtansine. In addition, various combinations of cytostatics and anti HER2 targeting agents can be used. The choice of treatment options in heavily pretreated patients is of great interest. If they have not previously received pertuzumab, is it worth to use it and which combination is the best? One possible option is the combination of eribulin with the dual anti-HER2 blockade with trastuzumab and pertuzumab. Eribulin is an anti-microtubule agent that irreversibly blocks mitosis. In addition, it has non-mitotic effects – in vivo and in vitro experiments demonstrated its ability to restore normal tumor vascularization, reduce the area of hypoxia and, as a consequence, decrease tumor cells migration and invasion. This article represents a clinical case of the use of eribulin with double anti-HER2 blockade in the 6th line of treatment in a patient with metastatic HER2-positive breast cancer. Long-term control of the disease (within 2 years) with a satisfactory quality of life has been demonstrated.Keywords:
Pertuzumab
Eribulin
Trastuzumab emtansine
Lapatinib
HER2 overexpression occurs in about 15-20% of breast cancer cases and is associated with rapid tumor growth. The introduction in clinical practice of several drugs inhibiting the biological activity of HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and lapatinib, has clearly modified the prognosis for these patients. The combination of the two inhibitors of HER2, trastuzumab and pertuzumab, with a taxane (paclitaxel or docetaxel), is currently considered the first choice treatment for patients affected by HER2-positive metastatic breast cancer, whereas T-DM1 is considered the preferred treatment after the failure of first line therapy. We present the case of a 50-year-old woman affected by HER2-positive breast cancer with bone, hepatic, pulmonary and encephalic metastases, resistant both to trastuzumab-pertuzumab double-block treatment and to T-DM1, but sensitive to third line therapy to the combination lapatinib-capecitabine with a clinical response both for visceral and cerebral metastases (Oncology).
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The overexpression of the HER2 receptor and its gene amplification are observed in c. 20% of newly diagnosed cases of breast cancer and associated with a more aggressive clinical course and poorer prognosis. New HER2-targeted drugs, such as lapatinib, pertuzumab and trastuzumab emtansine, significantly improve patient outcomes. The article reviews the role of lapatinib in HER-targeted therapy and describes the treatment sequence of two women with HER2-positive advanced breast cancer.
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Abstract Objective: Gastric cancer has a poor prognosis. HER2 targeting therapy for gastric cancer would be considered important, because HER2 protein in gastric cancer is reported to be prognosis factor as well as breast cancer. Recently, trastuzumab has provided benefits for patients with HER2-positive gastric cancer in the ToGA trial (a phase III study of trastuzumab in HER2-positive advanced gastric cancer). On the other hand, pertuzumab, a new anti-HER2 antibody, can bind a different HER2 domain from trastuzumab and inhibits tumors by preventing the dimerization of HER2 and other HER family proteins. In this study, we investigated the efficacy of pertuzumab in combination with trastuzumab to consider a new approach to HER2-positive gastric cancers. Results: We examined the anti-tumor activity of pertuzumab in combination with trastuzumab in the mouse xenograft models of HER2-positive human gastric cancer, NCI-N87 and 4-1ST. Pertuzumab and trastuzumab were administered once a week i.p. for 3 weeks. The combination group showed a significant anti-tumor activity (tumor growth inhibition (TGI) % = 145 % and 105 % in NCI-N87 and 4-1ST, respectively) compared with the group treated only with pertuzumab (TGI % = 31 % and 29 %) or that treated only with trastuzumab (TGI % = 52 % and 55 %). In addition, the anti-tumor activity was higher than the maximum anti-tumor activities in either of those monotherapy groups. Furthermore this combination effect was also observed in vitro. Phosphorylation of HER2 was strongly blocked by exposure of these antimodies in combination. EGF-stimulated phosphorylation of EGFR was also down-regulated. As other mechanisms of the combination effect, we examined the ADCC activity of pertuzumab and trastuzumab by means of a real-time cell analyzer. Pertuzumab and trastuzumab had ADCC activity and that activity was enhanced when both of them were exposed. In addition we examined micro-vessel density (MVD) change after treatment in NCI-N87 tumor tissues with CD31-immunostaining. We observed MVD inhibition only in the tumor tissues treated with both pertuzumab and trastuzumab and not in the tissues treated with the drugs separately. VEGF levels in tumor tissues were reduced by pertuzumab or trastuzumab. The present results suggest that pertuzumab in combination with trastuzumab shows significant anti-tumor activity in HER2-positive human gastric cancers not only by directly inhibiting cell growth through down-regulation of HER2/EGFR signaling but also by enhancing ADCC activity and reducing MVD. Conclusion: The anti-tumor activity of pertuzumab and trastuzumab was higher than the maximum anti-tumor activity showed when pertuzumab or trastuzumab were used as single agent. The present study suggests that this combination therapy may provide greater benefits for patients with HER2-positive gastric cancers. Clinical evaluation is expected. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3477.
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HER2 is a prognostic factor in breast cancer. The combination of trastuzumab and chemotherapy has been established as a widely used standard treatment option for HER2-positive metastatic breast cancer. Despite the promising initial responses to trastuzumab therapy in a majority of patients, a subset of patients fails to benefit from treatment. Pertuzumab targets the human epidermal growth factor receptor 2 blocking HER2 with other HER family members. As a result, the formation of HER heterodimers is inhibited. Pertuzumab represents a new class of drugs called dimerization inhibitors. Owing their complimentary modes of action, there is strong rationale for the combination of pertuzumab with trastuzumab for the treatment of HER2 overexpressing the disease. In an effort to overcome trastuzumab resistance and further improve the outcome of patients with HER2-positive disease, dual blockade of the HER2 receptor with pertuzumab plus trastuzumab has been developed and stands for the standard treatment in this setting.
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The human epidermal growth factor receptor HER2/neu gene is amplified and overexpressed in 25 to 30% of breast cancers. In women with HER2-positive advanced or metastatic breast cancer, the anti-HER2 monoclonal antibody trastuzumab and the dual tyrosine kinase inhibitor lapatinib are both established options used in combination with cytotoxic chemotherapy. In patients who progress after first-line therapy with trastuzumab plus chemotherapy, continued trastuzumab or switching to lapatinib, both in combination with cytotoxic chemotherapy, offers clinical benefit. New agents in the metastatic disease setting include pertuzumab and trastuzumab emtansine. In the first-line setting, the addition of pertuzumab to trastuzumab/docetaxel yields longer median progression-free survival than placebo plus trastuzumab/docetaxel (18.5 vs. 12.4 months; p < 0.001). In the second-line setting, trastuzumab emtansine alone improves median progression-free survival compared with capecitabine plus lapatinib (9.6 vs. 6.4 months; p < 0.0001). The combination of trastuzumab emtansine plus pertuzumab has also shown encouraging preliminary activity. Other agents in clinical development include subcutaneous trastuzumab, afatinib, and neratinib. Numerous other treatments across a range of drug classes are currently in development for the treatment of HER2-positive metastatic breast cancer.
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Metastatic breast cancer (MBC) overexpressing human epidermal growth factor receptor-2 (HER2) once had an overall worse prognosis, but therapies targeting HER2 have altered the natural course of HER2-positive disease. The initial success of trastuzumab in improving survival rates led to the clinical development of lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1). HER2 protein overexpression and/or gene amplification remain the most important predictive factors for response to HER2-targeted therapies. The optimal duration of chemotherapy (CT) is at least 4–6 months (or longer) and/or to the time of maximal response, depending on toxicity and the absence of progression. HER2-targeted therapy continues until progression or unacceptable toxicity. For patients with estrogen receptor–positive/progesterone receptor–positive breast cancer who are not good candidates for CT or wish to avoid the toxicity of CT, initial hormone therapy in combination with HER2-targeted therapy is a reasonable option. For patients who relapse and were previously treated with adjuvant anti-HER2 therapy, the resumption of systemic treatment that includes HER2 blockade is recommended. As in the first-line setting, multiple choices are available for second- and third-line therapies. Successful targeting of HER2 has improved outcomes in HER2-positive breast cancer, but treatment resistance and brain metastases remain a problem. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in HER2-positive tumors.
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The majority of patients with metastatic breast cancer who are treated with the anti-HER2 monoclonal antibody, trastuzumab, generally develop resistance to the drug within a year after initiation of the treatment. Here we describe a new anti-HER2 humanized monoclonal antibody, 19H6-Hu, which binds to HER2 extracellular domain (ECD) with high affinity and inhibits proliferation of multiple HER2-overexpressing cancer cell lines as a single agent or in combination with trastuzumab. 19H6-Hu binds to the domain III in proximity to the domain IV of HER2 ECD, which differs from trastuzumab and pertuzumab. 19H6-Hu in combination with trastuzumab was more effective at blocking phosphorylation of ERK1/2, AKT(S473)and HER2 (Y1248) in HER2-positive cancer cells compared to trastuzumab alone or in combination with pertuzumab. Combination of three antibodies, 19H6-Hu, inetetamab (a trastuzumab analog) and pertuzumab exhibited much stronger inhibition of large NCI-N87 tumor xenografts (>400mm3) than the current standard of care, inetetamab (trastuzumab) plus Docetaxel (DTX), as well as the combination of 19H6-Hu, inetetamab and DTX. Our results highlight the functional variability of HER2 domains and provide a new insight into the design of HER2-targeting agents.
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Abstract Breast cancer (BC) is the second most common cancer and the second leading cause of mortality among women globally. Approximately 20 to 25% of BC patients have amplification of the human epidermal growth factor receptor 2 (HER2) genes, a marker of poor prognosis. However, the introduction of anti-HER2-therapies (trastuzumab, followed closely by lapatinib, pertuzumab, trastuzumab emtansine, and neratinib) has changed the natural history of HER2-positive BC and improved the outcome in HER2-positive BC patients. The preeminence of anti-HER2 combination therapy in achieving complete inhibition of the various HER receptor dimers has been demonstrated in clinical studies. However, despite these therapeutic advances, tumors expressing estrogen receptor have poorer responses to targeted therapy and are more likely to relapse. A better understanding of resistance to existing anti-HER2 agents, along with the role played by the microenvironment and of interconnected signaling pathways, can permit tailor-made therapeutic options for each patient. This review aimed to evaluate treatment approaches for BC patients with HER2-positive disease in the adjuvant and neoadjuvant settings, also exploring the possibilities of extended duration of anti-HER2 maintenance therapy.
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