Trastuzumab-resistant Disease Research Articles

The role of education in adjusting to changes in clinical practice for gastric or gastroesophageal junction adenocarcinomas.

470 Background: Gastric or gastroesophageal junction (GEJ) adenocarcinomas are difficult to treat and associated with poor prognosis, specifically in advanced disease. Recently approved and investigational immune checkpoint inhibitors (ICIs) and HER2-directed antibody-drug conjugates (ADCs) are changing the treatment landscapes for gastric cancer and GEJ cancer, allowing clinicians to manage difficult-to-treat patients. However, these advances also create knowledge and practice gaps that pose many challenges warranting education to close these gaps and to assess current practices. Methods: PlatformQ Health’s proprietary workflow digital technology was utilized to launch a 4-part CME series online in December 2021 which remains on-demand through December 2022 at OMedLive.com. Each module focused on the following topics: 1) HER2 testing, 2) Current care for HER2+ gastric or GEJ cancer, 3) Treatment for unresectable disease and trastuzumab-resistant disease, and 4) adverse event management. This series was conducted in partnership with the American Gastroenterological Association and accredited by the Postgraduate Institute for Medicine. Clinicians engaging in this educational series were assessed at pre- and immediate post-activity. Practice pattern insights and education impact were assessed post-activity. Results: To date, 2,568 US-based clinicians have participated in the educational series. All 6 questions across the 4 modules in the series showed significant improvements in knowledge and competence related to HER2 testing, defining the standard of care, treatment beyond trastuzumab resistance, treatment for unresectable disease, and managing adverse events. Provider insights evaluated post-series revealed 41% of clinicians will consult with a pulmonologist upon development of interstitial lung disease; 51% identified trastuzumab deruxtecan as a novel HER2-targeted therapy having the greatest potential to improve patient outcomes; and 26% reported not repeating HER2 expression testing following progression on a trastuzumab-containing regimen. Evaluating the impact of the educational series, 88% of clinicians reported a positive impact on patient experience and 94% on clinical practice change following participation. The qualitative data depicting the reported impact will be shared. Conclusions: This serialized education was effective in improving knowledge and competence across four major themes of practice within gastric and GEJ cancer management. Provider insights revealed practice shifts following participation and practice impact assessments demonstrated the rapid application of real-time digital education.

The Clinical Efficacy and Safety of Neratinib in Combination with Capecitabine for the Treatment of Adult Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2) positive cancers account for 15–20% of all breast tumors. Several drugs have been approved in the metastatic setting, including monoclonal antibodies, tyrosine kinase inhibitors (TKI) and, more recently, antibody-drug conjugates. Neratinib is a pan-HER, irreversible TKI with potent preclinical activity against trastuzumab-resistant breast cancer models. Based on Phase I and II clinical trials, the combination of neratinib plus capecitabine was compared to lapatinib and capecitabine, an established regimen for trastuzumab-resistant disease, in the randomized, Phase III NALA trial. In this trial, neratinib yielded increased progression-free survival, response duration and a benefit in time to intervention for CNS progression. However, there was no overall survival benefit, no increase in overall response rate and no improvement in QoL. The most frequent adverse event in the neratinib arm was diarrhea, which was manageable with prophylactic treatment with loperamide. Conclusion: Neratinib is a valuable addition to the therapeutic armamentarium to treat metastatic, HER2-positive breast cancer. The current positioning of the combination of neratinib and capecitabine based on the results of the NALA trial needs to consider the rapidly evolving scenario due to the recent introduction of new drugs, like the pure-HER2 TKI tucatinib and the antibody drug-conjugate trastuzumab-deruxtecan.

Pyrotinib plus capecitabine for HER2-positive, trastuzumab-resistant metastatic breast cancer: A pooled analysis of three randomized controlled trials.

1048 Background: Trastuzumab is the most widely used anti-HER2 agent in patients (pts) with HER2-positive breast cancer, both in (neo)adjuvant and metastatic settings; however, drug resistance is inevitable. This pooled study aimed to investigate the efficacy of pyrotinib plus capecitabine in pts with HER2-positive, trastuzumab-resistant relapsed or metastatic breast cancer. Methods: Data were derived from three randomized controlled trials, including a phase II (NCT02422199) and the PHOEBE phase III (NCT03080805) study comparing pyrotinib plus capecitabine vs lapatinib plus capecitabine and the PHENIX phase III (NCT02973737) study comparing pyrotinib plus capecitabine vs placebo plus capecitabine. Pts with trastuzumab-resistant disease were included in the analyses, including 39 pts who had relapsed within six months after adjuvant trastuzumab and 57 pts who had progressed within three months of trastuzumab treatment for metastatic disease. The pooled tumor response data (per blinded independent central review) were reported herein. Results: In the pooled analysis of all three studies, 63 pts received pyrotinib plus capecitabine. Among them, 28 (44.4%) pts had disease progression or died. The median progression free survival (PFS) was 12.4 months (95% CI, 6.9 to not reached). In total, 40 pts (63.5% [95% CI, 50.4% to 75.3%]) achieved objective response, and the estimated median duration of response (DoR) was 11.1 months (95% CI, 6.9 to not reached). In the pooled analysis involving the phase II and PHOEBE phase III, 43 pts were treated with pyrotinib plus capecitabine and 33 pts with lapatinib plus capecitabine. In total, 18 (41.9%) pts with pyrotinib plus capecitabine and 17 (51.5%) pts with lapatinib plus capecitabine had disease progression or died. The PFS tended to be prolonged with pyrotinib plus capecitabine vs lapatinib plus capecitabine (median, 12.4 months [95% CI, 6.9 to not reached] vs 6.9 months [95% CI, 5.5 to not reached]; hazard ratio, 0.62 [95% CI, 0.31 to 1.24]; p=0.0864). The objective response rate was 67.4% (95% CI, 51.5% to 80.9%) with pyrotinib plus capecitabine compared with 54.5% (95% CI, 36.4% to 71.9%) with lapatinib plus capecitabine. The estimated median DoR was 11.1 months [95% CI, 6.9 to not reached] vs not reached [95% CI, 4.2 months to not reached], respectively. Conclusions: Pyrotinib plus capecitabine showed favorable efficacy in pts with HER2-positive, trastuzumab-resistant relapsed or metastatic breast cancer. This combination could be a treatment option for this population.

Reduction of Global H3K27me3 Enhances HER2/ErbB2 Targeted Therapy

Monoclonal antibodies (mAbs) targeting the oncogenic receptor tyrosine kinase ERBB2/HER2, such as Trastuzumab, are the standard of care therapy for breast cancers driven by ERBB2 overexpression and activation. However, a substantial proportion of patients exhibit de novo resistance. Here, by comparing matched Trastuzumab-naive and post-treatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me3, a repressive histone modification catalyzed by polycomb repressor complex 2 (PRC2). In ErbB2+ breast cancer models, PRC2 silences endogenous retroviruses (ERVs) to suppress anti-tumor type-I interferon (IFN) responses. In patients, elevated H3K27me3 intumor cells following Trastuzumab treatment correlates with suppression of interferon-driven viral defense gene expression signatures and poor response. Using an immunocompetent model, we provide evidence that EZH2 inhibitors promote interferon-driven immune responses that enhance the efficacy of anti-ErbB2 mAbs, suggesting the potential clinical benefit of epigenomic reprogramming by H3K27me3 depletion in Trastuzumab-resistant disease.

Abstract 2036: A phase Ib pharmacokinetic drug-drug interaction evaluation of oral buparlisib in combination with lapatinib in HER2+/PI3K-activated, trastuzumab-resistant locally advanced, recurrent and metastatic breast cancer (MBC)

Abstract Background: A novel combination of oral lapatinib (LPT), a selective dual ErbB1/ErbB2 targeted drug, + oral buparlisib (B) a pan-class I PI3K inhibitor, could provide a synergestic antitumor activity in trastuzumab resistant disease. LPT has been shown to be a potent CYP3A4 inhibitor which is also mainly involved in BKM120 metabolism. In this study we investigated the potential pharmacokinetic (PK) drug-drug interactions (DDI) related to the association of B and LPT. Methods: Trastuzumab-resistant HER2 + metastatic breast cancer (MBC) patients were treated with a continuous once daily dosing schedule of LPT + B. Dose levels [DL, LPT (mg)/B (mg)] ranged from 750/40 to 1,250/80. For PK analysis, 2 time point samples were collected on D1 and D8 and 10 time point samples were collected on D15 of cycle 1 for LPT and B assays. Plasma concentrations of B and LPT, were measured using UPLC coupled with tandem mass spectrometry validated methods. Population PK was modeled using a non linear mixed effect model program (Monolix version 4.3s) by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization). Results: 343 and 322 plasma concentrations were available for PK analysis of LPT and B respectively. A two-compartment open model adequately described B concentration versus time courses. The inter-individual variabilities (ISV) could be well estimated for all stuctural parameters (clearance: CL, volume of distribution: V, inter-compartmental clearance: Q) except for absorption constant: Ka. The population PK parameters obtained for the structural model were: Ka = 0.985 h−1, CL/F = 10.5L/h, V1/F = 54.8 L, Q/F = 46.3 L/h, V2/F = 582 L. Mean AUC0-24h(CV%) values for B were 10130 (34%), 15450 (29%), and 20560 (38%) ng*hr/mL for 40 mg, 60 mg and 80 mg dose level respectively. A one-compartment model adequately fitted the LPT plasma concentration-time data. The population PK parameters were CL/F = 25.7 L/h, V/F = 291 L and the absorption constant, Ka = 0.214 h−1. B has no significant effect on the PK of LPT and vice versa. Conclusions: B AUC increased proportionally with increasing dose. LPT PK parameters are consistent with those already published. There is no significant evidence for drug-drug PK interaction between LPT and B. Intra-occasion variabilities will be discussed. Citation Format: François Lokiec, Anthony Goncalves, Fanny Bret, Jihane Pakradouni, Magali Provansal, Renaud Sabatier, Jean-Marc Extra, Carole Tarpin, Nicolas Isambert, Mario Campone, Keyvan Rezai. A phase Ib pharmacokinetic drug-drug interaction evaluation of oral buparlisib in combination with lapatinib in HER2+/PI3K-activated, trastuzumab-resistant locally advanced, recurrent and metastatic breast cancer (MBC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2036.

Abstract P4-15-01: Integrin avb6 is a therapeutic target for high-risk breast cancer and enhances trastuzumab efficacy

Abstract The integrin avβ6 promotes migration, invasion and survival of cancer cells, but the biological relevance has yet to be ascertained in breast cancer. Our immunhistochemical analysis of over 2000 breast cancers has revealed that high expression of the protein for the integrin subunit beta6 (β6) is associated with very poor survival (HR = 1.99, P = 2.9×10-6) and increased metastases to distant sites (P = 0·02). This correlation was confirmed at the mRNA level via bioinformatic analysis of the 2000 women in the METABRIC cohort. Furthermore, co-expression of HER2 gave a significantly worse prognosis (HR = 3.43, P = 4×10-12), which we investigated further. We report from in vitro studies that HER2-driven invasion is mediated by αvβ6 in an Akt2-dependent manner. Using the well-tolerated αvβ6-blocking antibody 264RAD in vivo we show that antibody-blockade of this integrin suppressed growth of BT-474 and MCF-7/HER2-18 human breast cancer xenografts similarly to trastuzumab alone (P<0.001), the antibody used for treating HER2-positive cancers (both 10mg/kg, bi-weekly). Moreover, when 264RAD was co-administered it significantly enhanced the ability of trastuzumab to suppress BT-474 tumor growth with a reduction in mean tumor volume of 94.8%+/-1.18% compared to 70.8%+/-5.98% observed with trastuzumab alone (P<0.0001) after 2 weeks treatment. This trend was reproduced even in the MCF-7/HER2-18 trastuzumab-resistant breast cancer tumors where a 76.24%+/-10.15% reduction was observed with combination therapy (P<0.0001) compared with only 44.62%+/-10.43% (P = 0.0006) and 46.6%+/-14.71% (P = 0.0004) reductions in final volume with 264RAD and trastuzumab respectively. The combination therapy was so effective it almost eradicated 100mm3 BT-474 tumors and completely eliminated small (10-20mm3) MCF-7/HER2-18 tumors. 264RAD or trastuzumab prolonged survival to a similar degree (14.3% and 33.33% treated mice alive after 100d, respectively, no significant difference) but again, when both drugs were combined 85.7% of mice were alive after 100d, a highly significant response compared with PBS (P<0.0001) or monotherapies (264RAD: P<0.0001, trastuzumab: P<0.0001). Post-therapy biochemistry revealed residual tumors expressed significantly reduced αvβ6, HER2, HER3 and downstream signaling molecules including Akt2 and Smad2, essentially a much lower ‘grade’ tumour. Since 70% of women treated with trastuzumab either have, or develop resistance, we suggest combined targeting of αvβ6 and HER2 could provide an important novel therapy for thousands of women with breast cancer. In fact, over 39,000 American women annually (NIH statistics) will develop HER2+ breast cancers for which no specific therapies exist. Our data shows that in excess of 40% of these women with trastuzumab-resistant disease are also likely to express high levels of αvβ6. Our data also suggest that routine determination of the level of expression of αvβ6 on breast cancers would be a valuable clinical tool as it identifies novel high-risk groups of women that require enhanced therapeutic intervention. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-01.

Personalized medicine for metastatic breast cancer

With recent advances in DNA sequencing technology, recurrent genomic alterations can be identified in tumor samples from patients with metastatic breast cancer (MBC) to enrich clinical trials testing targeted therapies. This review provides an overview of clinically relevant genomic alterations in MBC and summarizes the recent clinical data from early phase trials of novel targeted treatments. The clinical development of personalized treatment includes targeted agents directed against PI3K/mTOR, fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2 (HER2), DNA repair, and cell cycle pathways. PI3K/mTOR pathway drugs are active in endocrine and trastuzumab-resistant disease. Drugs targeted at PI3K/mTOR, FGFR, and poly(ADP-ribose) polymerase show early signs of efficacy in MBC subpopulations enriched with relevant pathway aberrancies. Regimens combining targeted agents with either endocrine, anti-HER2, or chemotherapy treatments are also being studied in hormone receptor-defined and HER2-defined or pathway-enriched subgroups. A new approach to personalized medicine for MBC that involves molecular screening for clinically relevant genomic alterations and genotype-targeted treatments is emerging. Clinical trials are needed to determine whether rare subpopulations of MBC benefit from genotype-targeted treatments.

Trastuzumab: a novel standard option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer

The human epidermal receptor-2 (HER-2) is amplified in up to 25% of patients with gastroesophageal adenocarcinomas. Although the presence of this amplification does not appear to confer a poor prognosis, it provides a valuable novel therapeutic target for this group of patients. Trastuzumab is a fully humanized monoclonal antibody directed at HER-2 which binds the external domain of the receptor and exerts its action via a combination of antibody-dependent cytotoxicity, reduced shedding of the extracellular domain, inhibition of dimerization and possibly receptor downregulation. The ToGA trial was an international multicentre randomized phase III study which evaluated the addition of trastuzumab to a cisplatin plus fluoropyrimidine chemotherapy doublet in 594 patients with HER-2-positive advanced gastric or oesophagogastric junction adenocarcinoma. The combination of the antibody with chemotherapy significantly improved response rate, median progression-free survival and median overall survival without additional toxicity or adversely affecting quality of life. Accordingly, trastuzumab plus chemotherapy is now a standard first-line treatment option for patients with advanced HER-2-positive gastroesophageal cancer. Unfortunately, many patients with HER-2-positive cancer exhibit primary resistance to trastuzumab and the remainder will acquire resistance to the antibody; therefore, urgent investigation into novel agents which may circumvent resistance mechanisms is warranted. Small molecule inhibitors of HER-2, which commonly also target other members of the HER family of receptors, such as EGFR and HER-3, are currently undergoing evaluation in gastroesophageal cancer as first-line alternatives to trastuzumab and second-line salvage treatments for trastuzumab-resistant disease. Extrapolating the successful use of trastuzumab in the advanced disease setting, clinical trials are underway to assess the role of this antibody in the perioperative and adjuvant settings, where it is hoped that it will have a meaningful impact upon the currently poor survival rates.

Pertuzumab: a step forward in treating HER2-positive breast cancer

HER2-positive breast cancer represents an aggressive subtype of the disease occurring in approximately 20% of patients. While trastuzumab has revolutionized the treatment of HER2-positive breast cancer, a proportion of patients have de novo trastuzumab-resistant disease and even those who initially respond will eventually develop trastuzumab-resistance. The recent publication in the New England Journal of Medicine of the promising results of the CLEOPATRA trial for the combination of pertuzumab plus trastuzumab plus docetaxel in HER2-positive metastatic breast cancer (MBC) represented a significant advancement in the treatment of this illness (1).

Targeting HER2 in breast cancer: beyond trastuzumab

Trastuzumab has altered the natural history of HER2+ breast cancer. In the metastatic setting, it has improved progression-free and overall survival. In patients with operable breast cancer, adjuvant trastuzumab, when added to chemotherapy, has improved disease-free and overall survival. Unfortunately, virtually all patients with metastatic breast cancer develop disease that is at least partially resistant to trastuzumab. In these patients, there is still value in continuing trastuzumab in combination with other treatments, but trastuzumab alone is unable to fully suppress tumor growth. Multiple mechanisms of resistance to trastuzumab have been suggested including activation of other growth factor receptors, preferential finding of HER2 to HER3, loss of the extracellular domain of HER2, and activation of the PI3 kinase pathway as a result of PTEN loss or a PIK3CA mutation. It is unknown to what extent these mechanisms are relevant in individual patients, but it is probable that many different mechanisms of resistance are clinically important. Over the past decade, a number of treatments have been developed for patients with trastuzumab-resistant disease. At present, only lapatinib, a small-molecule inhibitor of HER1 and HER2, is commercially available. It is active when administered with either chemotherapy or trastuzumab. A variety of other therapies are under investigation in phase III clinical trials. Pertuzumab, a monoclonal antibody that inhibits HER2-HER3 heterodimers, appears to be effective when combined with trastuzumab ± chemotherapy. T-DM1, an antibody-drug conjugate, has also displayed remarkable activity in the setting of refractory disease and has limited toxicity. It is presently under investigation in multiple randomized trials. Neratinib is an oral irreversible tyrosine kinase inhibitor that targets HER1, HER2, and HER4. As a single agent, it appears to be more active than lapatinib, but is associated with more significant toxicity. It, too, is under evaluation in phase III trials in the adjuvant and metastatic settings. A variety of other agents are under active study including the mTOR inhibitors, the PI3kinase inhibitors, angiogenesis inhibitors, and IGFR antagonists. It is likely that a number of new agents will be available for the treatment of HER2+ breast cancer in the next several years, and outcomes for this group of patients will continue to improve.

Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence.

Background:We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer.Methods:We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo.Results:Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours.Conclusion:Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.

Targeted Therapies for HER2 Breast Cancer: A View of the Landscape

Trastuzumab was first described over 25 years ago and was approved for clinical use a decade ago. Since then, marked improvement in survival in patients with breast cancer has been achieved with use of trastuzumab. There is still room for improvement however, as approximately 40% of patients with HER2-amplified breast cancer do not derive significant benefit from trastuzumab. Furthermore, in patients with advanced disease, most patients who do respond end up developing resistance and progressive recurrent disease. Significant advances have been made in the understanding of acquired resistance to trastuzumab, and a large of number of newer HER2-directed therapies have been rationally developed targeting trastuzumab-resistant disease. Small molecules targeting multiple HER family tyrosine kinases such as lapatinib and neratinib have been the most promising.

Beyond Trastuzumab: Overcoming Resistance to Targeted HER-2 Therapy in Breast Cancer

Overexpression of the human epidermal growth factor receptor 2 (HER-2) represents a biological subclass of breast cancer with distinct molecular alterations, clinical behavior, and response to systemic therapy. Trastuzumab is a monoclonal antibody directed against HER-2 which has revolutionized the management of both early and advanced breast cancer. It may exert its anti-cancer effects through inhibition of intracellular signaling, upregulation of p27, impaired angiogenesis, induction of immune-mediated destruction, and blockade of cleavage of the extracellular domain of HER-2. In spite of its robust clinical activity, most women with metastatic HER-2 overexpressing breast cancer eventually progress on trastuzumab therapy. Possible mechanisms of resistance include: altered receptor antibody interaction, PTEN loss and enhanced Akt signaling, p27 loss, signaling through other receptors. Preclinical experiments, clinical experience with the use of trastuzumab beyond progression, and a recent phase III clinical trial with Lapatinib, a dual EGFR/HER-2 tyrosine kinase inhibitor, demonstrate that the HER-2 signaling axis remains an important therapeutic target even after progression on trastuzumab. A variety of novel strategies are currently in development to exploit this pathway following the onset of resistance, such as receptor antibodies, sheddase inhibitors, signal transduction inhibitors, heat shock protein inhibitors, proteasome inhibitors, anti-angiogenic agents, and immune-stimulatory therapies, either as single agents or in combination with trastuzumab. Rational clinical trial design, with attention to appropriate patient selection and prospective collection of biological material, is needed to ensure that the new generation of anti-HER-2 targeted therapies realizes its promise in the treatment of trastuzumab-resistant disease.

Targeting the Human Epidermal Growth Factor Receptor 2 (HER2) in the Treatment of Breast Cancer: Recent Advances and Future Directions

The HER2/neu (HER2) gene is a member of a family of genes which has been implicated in cancer. These four genes, HER1/EGFR, HER2, HER3 and HER4 encode for transmembrane proteins that are involved in the regulation of cell proliferation, differentiation and survival. Amplification of HER2 occurs in 20%-25% of breast cancers and is associated with an aggressive tumor phenotype and poor prognosis. Results from five randomized, phase III clinical trials have recently demonstrated that trastuzumab (Herceptin) significantly improves disease free survival and overall survival when used in conjunction with chemotherapy for early stage HER2-positive breast cancer. Despite adjuvant trastuzumab, approximately 15% of patients with early stage disease recur, and those with metastatic disease eventually become resistant to therapy. Novel treatment approaches are needed for patients who have either intrinsic or acquired resistance to trastuzumab. This article reviews the role of trastuzumab in managing early and advanced stage HER2-positive disease, the role of lapatinib (Tykerb) in trastuzumab resistant disease, and the novel agents in development targeting mechanisms of trastuzumab resistance.

HER-2-Positive Breast Cancer

Therapeutic antibodies have shown great promise as targeted agents in the treatment of patients with cancer. Trastuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor-2 (HER-2), is of special importance in breast cancers overexpressing HER-2. Such rationally designed substances bind to cancer cells expressing the targeted antigen and, by various mechanisms, lead to tumor cell degradation. Only one-third of patients, however, initially respond to trastuzumab monotherapy and the majority of initial responders demonstrate disease progression within 1 year of treatment initiation. Therefore, alternative compounds targeting the HER-2 receptor or downstream signaling pathways are of great importance. Lapatinib is a tyrosine kinase inhibitor, blocking tryosine kinase domains of both epidermal growth factor receptor and HER-2. This substance holds promise for the treatment of cancer after trastuzumab failure, and might be active in cerebral metastases. Other strategies in trastuzumab-resistant disease include bispecific antibodies (which bind to HER-2 and Fc receptors, thereby directing immune cells towards the tumor), the combination of antibodies, or targeting tumor vessel growth by blocking vascular endothelial growth factor (VEGF) or VEGF receptors. Heat shock protein 90, a chaperone protein that controls the folding of HER-2, also represents a potential target. Multi-targeted kinase inhibitors such as sunitinib or sortenib are already established in renal cell cancer. These compounds are currently being evaluated in breast cancer and might represent interesting options both in HER-2-positive and -negative disease. In conclusion, trastuzumab remains the gold standard in HER-2-positive breast cancer therapy. However, in trastuzumab-resistant disease, new strategies and compounds are currently under evaluation.