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Concept: Trastuzumab

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HER2 is an oncogene, expression of which leads to poor prognosis in 30% of breast cancer patients. Although trastuzumab is apparently an effective therapy against HER2-positive tumors, its systemic toxicity and resistance in the majority of patients restricts its applicability. In this study we evaluated the effects of phenethyl isothiocyanate (PEITC) in HER2-positive breast cancer cells.

Concepts: Cancer, Breast cancer, Metastasis, Oncology, Chemotherapy, Trastuzumab, HER2/neu, Oncogene

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Background The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment. Methods In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan-Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients' outcomes during the period from 5 to 20 years. Results Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1-3), and 34% with four to nine nodes involved (T1N4-9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1-3, and 41% with T2N4-9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively. Conclusions After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.).

Concepts: Cancer, Breast cancer, Metastasis, Cancer staging, Epidermal growth factor receptor, Epidermal growth factor, Trastuzumab, HER2/neu

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Analysis of human epidermal growth factor receptor 2 (HER-2) status has become standard of care in breast cancer patients due to its important prognostic and therapeutic implications. Immunohistochemistry (IHC) is the most commonly used primary method for detection of HER-2 overexpression. Controversy exists on the interpretation of samples that are equivocal for HER 2 status (IHC 2+). Recent guidelines state that samples equivocal for HER 2 status require validation with fluorescent in situ hybridisation (FISH). The use of FISH, however, despite higher accuracy comes at a higher cost that is not affordable to all patients.

Concepts: Cancer, Breast cancer, Carcinoma in situ, Epidermal growth factor receptor, Epidermal growth factor, Growth factor, Trastuzumab, HER2/neu

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Trastuzumab improves survival in HER2+ breast cancer patients, with some evidence of adverse cardiac side effects. Current recommendations are to give adjuvant trastuzumab for one year or until recurrence, although trastuzumab treatment for only 9 or 10 weeks has shown similar survival rates to 12-month treatment. We present here a multi-arm joint analysis examining the relative cost-effectiveness of different durations of adjuvant trastuzumab.

Concepts: Health economics, Cancer, Breast cancer, Metastasis, Chemotherapy, Trastuzumab, HER2/neu, Pharmacoeconomics

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Easy and accurate HER2 testing is essential when considering the prognostic and predictive significance of HER2 in breast cancer. The use of a fully automated, quantitative FISH assay would be helpful to detect HER2 amplification in breast cancer tissue specimens with reduced inter-laboratory variability. We compared the concordance of HER2 status as assessed by an automated FISH staining system to manual FISH testing. Using 60 formalin-fixed paraffin-embedded breast carcinoma specimens, we assessed HER2 immunoexpression with two antibodies (DAKO HercepTest and CB11). In addition, HER2 status was evaluated with automated FISH using the Leica FISH System for BOND and a manual FISH using the Abbott PathVysion DNA Probe Kit. All but one specimen were successfully stained using both FISH methods. When the data were divided into two groups according to HER2/CEP17 ratio, positive and negative, the results from both the automated and manual FISH techniques were identical for all 59 evaluable specimens. The HER2 and CEP17 copy numbers and HER2/CEP17 ratio showed great agreement between both FISH methods. The automated FISH technique was interpretable with signal intensity similar to those of the manual FISH technique. In contrast with manual FISH, the automated FISH technique showed well-preserved architecture due to low membrane digestion. HER2 immunohistochemistry and FISH results showed substantial significant agreement (κ = 1.0, p < 0.001). HER2 status can be reliably determined using a fully automated HER2 FISH system with high concordance to the well-established manual FISH method. Because of stable signal intensity and high staining quality, the automated FISH technique may be more appropriate than manual FISH for routine applications.

Concepts: Cancer, Breast cancer, Anatomical pathology, Fluorescent in situ hybridization, In situ hybridization, Trastuzumab, Immunohistochemistry, Tamoxifen

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In the current genomic era, increasing evidence demonstrates that approximately 2% of HER2-negative breast cancers, by current standard testings, harbor activating mutations of ERBB2. However, whether patients with HER2-negative breast cancer with activating mutations of ERBB2 also experience response to anti-HER2 therapies remains unclear. This case report describes a patient with HER2-nonamplified heavily pretreated breast cancer who experienced prolonged response to trastuzumab in combination with pertuzumab and fulvestrant. Further molecular analysis demonstrated that her tumors had an elevated HER2 dimerization that corresponded to ERBB2 S310F mutation. Located in the extracellular domain of the HER2 protein, this mutation was reported to promote noncovalent dimerization that results in the activation of the downstream signaling pathways. This case highlights the fact that HER2-targeted therapy may be valuable in patients harboring an ERBB2 S310F mutation.

Concepts: Cancer, Breast cancer, Trastuzumab, HER2/neu, Tamoxifen

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A biosimilar product needs to demonstrate biosimilarity to the originator reference product, and the quality profile of the latter should be monitored throughout the period of the biosimilar’s development to match the quality attributes of the two products that relate to efficacy and safety. For the development of a biosimilar version of trastuzumab, the reference product, Herceptin®, was extensively characterized for the main physicochemical and biological properties by standard or state-of-the-art analytical methods, using multiple lots expiring between March 2015 and December 2019. For lots with expiry dates up to July 2018, a high degree of consistency was observed for all the tested properties. However, among the lots expiring in August 2018 or later, a downward drift was observed in %afucose (G0±G1±G2). Furthermore, the upward drift of %high mannose (M5+M6) was observed in the lots with expiry dates from June 2019 to December 2019. As a result, the combination of %afucose and %high mannose showed two marked drifts in the lots with expiry dates from August 2018 to December 2019, which was supported by the similar trend of biological data, such as FcγRIIIa binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity. Considering that ADCC is one of the clinically relevant mechanisms of action for trastuzumab, the levels of %afucose and %high mannose should be tightly monitored as critical quality attributes for biosimilar development of trastuzumab.

Concepts: Biology, Cytotoxicity, Trastuzumab, Antibody-dependent cell-mediated cytotoxicity, Multiplication, Years in the future, 2010s, Drift

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Trastuzumab is a key component of adjuvant therapy for stage I to III human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The rates and patterns of trastuzumab use have never been described in a population-based sample. The recent addition of HER2 information to the SEER-Medicare database offers an opportunity to examine patterns of trastuzumab use and to evaluate possible disparities in receipt of trastuzumab.

Concepts: Immune system, Breast cancer, Signal transduction, Epidermal growth factor receptor, Epidermal growth factor, Growth factor, Growth hormone, Trastuzumab

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ONT-380 (ARRY-380) is a potent and selective oral HER2 inhibitor. This Phase 1 study determined the maximum tolerated dose (MTD), pharmacokinetics (PK) and antitumor activity of ONT-380 in HER2 positive advanced solid tumors, with an expansion cohort of patients with HER2-positive MBC.

Concepts: Cancer, Breast cancer, Metastasis, Oncology, Chemotherapy, Tumor, Trastuzumab, Metastatic breast cancer

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Approximately, 25-30% of early-stage breast tumors are classified at the molecular level as HER2-positive, which is an aggressive subtype of breast cancer. Amplification of the HER2 gene in these tumors results in a substantial increase in HER2 mRNA levels, and consequently, HER2 protein levels. HER2, a transmembrane receptor tyrosine kinase (RTK), is targeted therapeutically by a monoclonal antibody, trastuzumab (Tz), which has dramatically improved the prognosis of HER2-driven breast cancers. However, ~30% of patients develop resistance to trastuzumab and recur; and nearly all patients with advanced disease develop resistance over time and succumb to the disease. Mechanisms of trastuzumab resistance (TzR) are not well understood, although some studies suggest that growth factor signaling through other receptors may be responsible. However, these studies were based on cell culture models of the disease, and thus, it is not known which pathways are driving the resistance in vivo. Using an integrative transcriptomic approach of RNA isolated from trastuzumab-sensitive and trastuzumab-resistant HER2+ tumors, and isogenic cell culture models, we identified a small set of mRNAs and lincRNAs that are associated with trastuzumab-resistance (TzR). Functional analysis of a top candidate gene, S100P, demonstrated that inhibition of S100P results in reversing TzR. Mechanistically, S100P activates the RAS/MEK/MAPK pathway to compensate for HER2 inhibition by trastuzumab. Finally, we demonstrated that the upregulation of S100P appears to be driven by epigenomic changes at the enhancer level. Our current findings should pave the path toward new therapies for breast cancer patients.

Concepts: Immune system, DNA, Protein, Cancer, Breast cancer, Signal transduction, Trastuzumab, HER2/neu