Evolving landscape of human epidermal growth factor receptor 2-positive breast cancer treatment and the future of biosimilars

Jackisch, Christian; Lammers, Philip E.; Jacobs, Ira

doi:10.1016/j.breast.2017.01.010

Cited by 38 publications

(24 citation statements)

References 106 publications

(155 reference statements)

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“…Although ERBB2 expression is uncommon in melanomas (www.proteinatlas.org), it appears that high expression levels are caused by amplifications of the genomic locus. In breast and stomach cancers, high ERBB2 levels are associated with rapid tumor growth and metastatic spread and provide the rationale for targeting ERBB2 by treatment with trastuzumab and lapatinib . In a preclinical study of wild‐type BRAF/NRAS but ERBB2‐positive melanoma cell xenografts, it was demonstrated that ERBB2 dimerized with ERBB3, and tumor growth could be reduced significantly in vivo with the ERBB2‐specific antibody pertuzumab …”

Section: Resultsmentioning

confidence: 99%

“…In breast and stomach cancers, high ERBB2 levels are associated with rapid tumor growth and metastatic spread and provide the rationale for targeting ERBB2 by treatment with trastuzumab and lapatinib. 46,47 In a preclinical study of wild-type BRAF/ NRAS but ERBB2-positive melanoma cell xenografts, it was demonstrated that ERBB2 dimerized with ERBB3, and tumor growth could be reduced significantly in vivo with the ERBB2-specific antibody pertuzumab. 48 KIT can be targeted by small-molecule inhibitors, such as imatinib, which are approved for the treatment of gastrointestinal sarcomas with mutations in exon 11, encompassing the juxtamembrane region with amino acids 550 through 591.…”

Section: Resultsmentioning

confidence: 99%

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The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

Appenzeller

Gesierich

Thiem

et al. 2018

Cancer

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Background Increasing knowledge of cancer genomes has triggered the development of specific targeted inhibitors, thus providing a valuable therapeutic pool. Methods In this report, the authors analyze the presence of targetable alterations in 136 tumor samples from 92 patients with melanoma using a comprehensive approach based on targeted DNA sequencing and supported by RNA and protein analysis. Three topics of high clinical relevance are addressed: the identification of rare, activating alterations; the detection of patient‐specific, co‐occurring single nucleotide variants (SNVs) and copy number variations (CNVs) in parallel pathways; and the presence of cancer‐relevant germline mutations. Results The analysis of patient‐matched blood and tumor samples was done with a custom‐designed gene panel that was enriched for genes from clinically targetable pathways. To detect alterations with high therapeutic relevance for patients with unknown driver mutations, genes that are untypical for melanoma also were included. Among all patients, CNVs were identified in one‐third of samples and contained amplifications of druggable kinases, such as CDK4, ERBB2, and KIT. Considering SNVs and CNVs, 60% of patients with metastases exhibited co‐occurring activations of at least 2 pathways, thus providing a rationale for individualized combination therapies. Unexpectedly, 9% of patients carry potentially protumorigenic germline mutations frequently affecting receptor tyrosine kinases. Remarkably two‐thirds of BRAF/NRAS wild‐type melanomas harbor activating mutations or CNVs in receptor tyrosine kinases. Conclusions The results indicate that the integrated analysis of SNVs, CNVs, and germline mutations reveals new druggable targets for combination tumor therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

Appenzeller

Gesierich

Thiem

et al. 2018

Cancer

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“…TDBs with CD3 affinity in the nanomolar range had increased distribution to secondary lymphatic tissue which may lead to off-target toxicity (Figs. [2][3][4][5]. Previous studies with TDBs that have CD3 affinity in a similar range observed grade Ill-IV toxicity at selected doses within an hour of infusing a folate receptor/CD3-bispecific antibody in ovarian cancer patients, prompted by coating of peripheral T cells with the bispecific antibody and subsequent T-cell activation and cytokine release (27).…”

Section: Discussionmentioning

confidence: 99%

“…Breast cancer is the leading cause of death for women from 20 to 59 years of age diagnosed with any cancer, with approximately 705 new cases diagnosed daily (1). About 15% to 20% of breast cancer overexpress the HER2 and are more likely to invade axillary lymph nodes than other subtypes (2). Approved antibody therapeutics that target HER2 include the monoclonal antibodies trastuzumab and pertuzumab and the antibody-drug conjugate ado-trastuzumab emtansine.…”

Section: Introductionmentioning

confidence: 99%

Relative Target Affinities of T-Cell–Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model

Mandikian¹,

Takahashi

Lo³

et al. 2018

Molecular Cancer Therapeutics

111

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Anti-HER2/CD3, a T-cell-dependent bispecific antibody (TDB) construct, induces T-cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. Although therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen-binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy. To our knowledge, no distribution studies have been published using preclinical models wherein the T-cell-targeting arm of the TDB is actively bound to T cells. We used a combined approach involving radiochemistry, invasive biodistribution, and noninvasive single-photon emission tomographic (SPECT) imaging to measure TDB distribution and catabolism in transgenic mice with human CD3ε expression on T cells. Using CD3 affinity variants, we assessed the impact of CD3 affinity on short-term pharmacokinetics, tissue distribution, and cellular uptake. Our experimental approach determined the relative effects of (i) CD3 targeting to normal tissues, (ii) HER2 targeting to HER2-expressing tumors, and (iii) relative HER2/CD3 affinity, all as critical drivers for TDB distribution. We observed a strong correlation between CD3 affinity and distribution to T-cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T-cell-containing tissues. These observations have important implications for clinical translation of bispecific antibodies for cancer immunotherapy. .

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“…Currently, trastuzumab, pertuzumab, lapatinib, and trastuzumab emtansine (T-DM1) are approved for use in different clinical settings in patients with HER2-positive breast cancer. All of the above inhibit the HER2 pathway, albeit using different strategies [12,13]. Trastuzumab is a recombinant humanized monoclonal antibody that binds the extracellular subdomain IV with internalization and degradation of the HER2 receptor.…”

Section: Introductionmentioning

confidence: 99%

Late Administration of Trastuzumab Emtansine Might Lead to Loss of Chance for Better Outcome in Patients with HER2-Positive Metastatic Breast Cancer

et al. 2018

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The optimal sequence of anti-human epidermal growth factor receptor 2 (HER2) therapies in metastatic breast cancer (MBC) is still undetermined. Physicians must therefore make decisions based on clinical trials and their own experience for the best treatment sequence in these patients. The objective of this review is to summarize the efficacy and safety data for trastuzumab emtansine (T-DM1) in patients with MBC. Additionally, the concept of ‘loss of chance for a better outcome' is investigated. It applies to patients who are not receiving the best possible treatment for their disease. Physicians should strive to offer the best possible care, although getting optimal results in each individual patient is not guaranteed. Lastly, the number of patients with MBC lost per treatment line is evaluated. We conclude that both concepts reinforce the importance of giving the most active treatments as soon as possible in the course of disease to secure the longest possible survival for HER2-positive MBC patients.

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Evolving landscape of human epidermal growth factor receptor 2-positive breast cancer treatment and the future of biosimilars

Cited by 38 publications

References 106 publications

The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

Relative Target Affinities of T-Cell–Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model

Late Administration of Trastuzumab Emtansine Might Lead to Loss of Chance for Better Outcome in Patients with HER2-Positive Metastatic Breast Cancer

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