Trastuzumab use in breast cancer patients in the six Health Care Regions in Sweden

Wilking, Ulla; Wilking, Nils; Bergh, Jonas

doi:10.3109/0284186x.2010.492790

Cited by 12 publications

(19 citation statements)

References 19 publications

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“…HER2 is amplified in approximately 14% of breast cancers in early stages and 25% of metastatic breast cancers. HER2 overexpression is associated with lymph node metastasis, short relapse time, poor survival and decreased response to endocrine and chemotherapy [1,2]. Trastuzumab is a humanized, monoclonal antibody that specifically blocks HER2 activation and cell signaling [3].…”

Section: Introductionmentioning

confidence: 99%

“…It is approved for use in patients who have HER2-positive disease, estrogen receptor/progesterone receptor-negative disease or a high-risk feature [4]. Patients that present breast cancer in early stage, when treated with trastuzumab had a 9% increase in absolute disease free survival at five years, while for patients with metastatic disease the period is extended only by five to nine months [2]. Nevertheless, 20% of breast cancer patients in early stages do not respond to trastuzumab therapy and 70% of the patients with metastatic disease who received trastuzumab as monotherapy become resistant to this antibody [5] by mechanisms which are still not completely understood.…”

Section: Introductionmentioning

confidence: 99%

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Heparan sulfate mediates trastuzumab effect in breast cancer cells

et al. 2013

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BackgroundTrastuzumab is an antibody widely used in the treatment of breast cancer cases that test positive for the human epidermal growth factor receptor 2 (HER2). Many patients, however, become resistant to this antibody, whose resistance has become a major focus in breast cancer research. But despite this interest, there are still no reliable markers that can be used to identify resistant patients. A possible role of several extracellular matrix (ECM) components—heparan sulfate (HS), Syn-1(Syndecan-1) and heparanase (HPSE1)—in light of the influence of ECM alterations on the action of several compounds on the cells and cancer development, was therefore investigated in breast cancer cell resistance to trastuzumab.MethodsThe cDNA of the enzyme responsible for cleaving HS chains from proteoglycans, HPSE1, was cloned in the pEGFP-N1 plasmid and transfected into a breast cancer cell lineage. We evaluated cell viability after trastuzumab treatment using different breast cancer cell lines. Trastuzumab and HS interaction was investigated by confocal microscopy and Fluorescence Resonance Energy Transfer (FRET). The profile of sulfated glycosaminoglycans was also investigated by [35S]-sulfate incorporation. Quantitative RT-PCR and immunofluorescence were used to evaluate HPSE1, HER2 and Syn-1 mRNA expression. HPSE1 enzymatic activity was performed using biotinylated heparan sulfate.ResultsBreast cancer cell lines responsive to trastuzumab present higher amounts of HER2, Syn-1 and HS on the cell surface, but lower levels of secreted HS. Trastuzumab and HS interaction was proven by FRET analysis. The addition of anti-HS to the cells or heparin to the culture medium induced resistance to trastuzumab in breast cancer cells previously sensitive to this monoclonal antibody. Breast cancer cells transfected with HPSE1 became resistant to trastuzumab, showing lower levels of HER2, Syn-1 and HS on the cell surface. In addition, HS shedding was increased significantly in these resistant cells.ConclusionTrastuzumab action is dependent on the availability of heparan sulfate on the surface of breast cancer cells. Furthermore, our data suggest that high levels of heparan sulfate shed to the medium are able to capture trastuzumab, blocking the antibody action mediated by HER2. In addition to HER2 levels, heparan sulfate synthesis and shedding determine breast cancer cell susceptibility to trastuzumab.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heparan sulfate mediates trastuzumab effect in breast cancer cells

et al. 2013

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“…[27] Unexplained regional variations create a situation where the area of residence seemingly arbitrarily determines the quality of healthcare. Even if the 'Robin Hood'-inspired reimbursement system is effective in reducing variability in income between regions in Sweden, there exists variability in the efforts of reducing/encouraging the uptake of innovative medicines for budgetary reasons.…”

Section: The Regional Levelmentioning

confidence: 99%

A New Reimbursement System for Innovative Pharmaceuticals Combining Value-Based and Free Market Pricing

Persson

Svensson

Pettersson

2012

Applied Health Economics and Health Policy

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Sweden has experienced a national value-based pricing (VBP) system for innovative outpatient drugs operated by the Pharmaceutical Benefits Board - LFN (now called the Dental and Pharmaceutical Benefits agency - TLV) since 2002. VBP has the character of a monopoly system, leading to reimbursement decisions where usage of new medicines is limited to subgroups and not the population for which the drug is approved. VBP relies on a broad societal perspective, encouraging innovations by signaling to firms that value-adding treatments are demanded. However, the VBP system is operated without a drug budget responsibility. The budget responsibility lies at the regional level, not operating VBP, thus an intrinsic conflict is built into the system. The aim of this article is to suggest a modification to the current reimbursement system in Sweden where payment for pharmaceuticals is split between the regional and national levels. The system is expected to make new innovative pharmaceuticals accessible to a larger number of patients and provide more consumer surplus without reducing the producer surplus. In short, the county councils pay the marginal cost of production while the state pays for the innovation.

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“…In Sweden, access to trastuzumab is also found to be dependent on the areas where patients live. Possible reasons are differences in the interpretation of clinical data by responsible physicians and different treatment protocols [57].…”

Section: Restrictions On Access and Geographic Variation In Usementioning

confidence: 99%