Studies of targeted therapy in breast cancer using trastuzumab : HER2 testing and trastuzumab treatment – clinical and economic evaluation

The incidence in breast cancer has more than tripled in Sweden since the 1960-ies. During the same time period the 5-year survival rate has increase from around 65% to almost 90%. The survival increase is mainly related to medical treatments (endocrine treatments, chemotherapy in different combinations), radiotherapy and breast cancer screening. Two thirds of costs for breast cancer are not related to these therapies, but to costs outside of the health care system (e.g. early retirement and premature death). Continued improvements in therapies would therefore be of great gain for the outcome and overall cost of breast cancer. One of these improvements has been the discovery of the Human Epidermal Growth Factor Receptor 2 (HER2) in the nineteen eighties and the development of the monoclonal antibody directed against HER2 (trastuzumab) in the nineteen nineties. Trastuzumab is registered for treatment of HER2 positive early and metastatic breast cancer. HER2 diagnosis and trastuzumab treatment are dependent on each other, as diagnosis is meaningless without the treatment and treatment is meaningless without diagnosis. This relationship is usually called co-dependent technologies. The aim of this thesis was to determine how a targeted patient population is optimally managed in terms of co-dependent technologies. The results demonstrate that HER2 testing is not optimally carried out in all situations. In 151 patients we found a 10% change in HER2 status between primary tumours and relapses (19% from HER2+ to HER2– and 6% from HER2– to HER2+). Patients with a change in HER2 status had a significant 5.47 (95% CI 2.01–14.91) increased risk of dying compared to patient with stable positive HER2 status (86% of these patients received trastuzumab treatment). In another study, there was a 32% change in 459 patients in Oestrogen Receptor (ER) status (ER+ to ER- 24.6% ER– to ER+ 7.8%). Also ER change is related to worse prognosis and patients with ER negative systemic relapses had a significant twofold (95% CI 1.39-2.87) increased risk of dying compared to patients with ER positive relapses. This shows that it is clinically relevant to re-test relapses for tumour marker status, and changes may offer additional treatment options. To be able to follow-up and monitor usage and outcome in clinical practice (clinical effectiveness as opposed to use in clinical trials: clinical efficacy) treatment with trastuzumab should be used according to guidelines, although we found large differences in usage between Health Care Regions (HCRs) in Sweden (years 2000-2004 300% difference between North HCR and South HCR, years 2006-2008 40% difference between Stockholm-Gotland and South-East and West HCRs). Another important aspect is that re-testing of HER2 status before trastuzumab treatment in the metastatic setting is cost-effective (USD 56,000 -USD 67,000 per Quality Adjusted Life Year and USD 39,000 – USD 46,000) and should therefore always be done. Diagnosis of HER2 status and treatment with trastuzumab is a challenge and this thesis points to the complexity of co-dependent technologies. The knowledge created could be used for the introduction of future co-dependent technologies in order to gain the most benefit, both to patients and to society

Drug utilization research in the area of cancer drugs

Increased biological understanding of cancer diseases has resulted in a paradigm shift in the medical treatment of cancer. Despite encouraging advances, most cancer types are still incurable and cancer is the second most common cause of death in developed countries.The high price of cancer drugs is a major challenge to equal access and puts heavy strains on public health care payers. After sharp increases in the 2000s, total expenditures on cancer drugs have levelled off due to patent expiration of many expensive and widely used drugs.Cancer drug utilization studies cover a great variety of topics. Four main research areas are patient adherence, physician adherence to guidelines, effectiveness and safety (outcomes research) and access (market uptake).Most cancer drugs are classified under Anatomical Therapeutic Chemical (ATC) group L. The use of defined daily dose (DDD) as a measurement unit is feasible for oral cancer drugs. As most cancer drugs are administered as infusions or injections at hospitals, usage is commonly measured in milligrams.Drug utilization research in the area of cancer is faced with a lack of data. Comparisons are challenging, as prices and population bases vary across regions. The linkage of registries and health care databases that include cancer drug usage will create improved opportunities in the future

The value of anticancer drugs:a regulatory view

The high prices of new anticancer drugs and the marginal added benefit perceived by some stakeholders have fuelled a debate on the value of anticancer drugs in the European Union, even though an agreed definition of what constitutes a drug's value does not exist. In this Perspective, we discuss the value of drugs from different viewpoints and objectives of decision makers: for regulators, assessment of the benefit-risk balance of a drug is a cornerstone for approval; payers rely on cost-effectiveness analyses carried out by health technology assessment agencies for reimbursement decisions; for patients, treatment choices are based on personal preferences and attitudes to risk; and clinicians can use several scales (such as the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS)) that have been developed as an attempt to measure value objectively. Although a unique definition that fully captures the concept of value is unlikely to emerge, herein we discuss the importance of understanding different perspectives, and how regulators can help to inform different decision makers

Societal cost of subcutaneous and intravenous trastuzumab for HER2-positive breast cancer – An observational study prospectively recording resource utilization in a Swedish healthcare setting

Introduction Trastuzumab is part of the standard treatment for HER2-positive breast cancer. The aim of this study was to estimate the societal value of trastuzumab administered through subcutaneous (SC) injection compared to intravenous (IV) infusion. Methods Female patients with HER2-positive breast cancer receiving SC or IV trastuzumab were consecutively enrolled from five Swedish oncology clinics from 2013 to 2015. Data on time and resource utilization was collected prospectively using patient and nurse questionnaires. Societal costs were calculated by multiplying the resource use by its corresponding unit price, including direct medical costs (pharmaceuticals, materials, nurse time, etc.), direct non-medical costs (transportation) and indirect costs (production loss, lost leisure time). Costs were reported separately for patients receiving trastuzumab for the first time and non-first time (“subsequent treatment”). Results In total, 101 IV and 94 SC patients were included in the study. The societal costs were lower with SC administration. For subsequent treatments the cost difference was €117 (IV €2099; SC €1983), partly explained by a higher time consumption both for nurses (14 min) and patients (23 min) with IV administration. Four IV and 16 SC patients received trastuzumab for the first time and were analysed separately, resulting in a difference in societal costs of €897 per treatment. A majority of patients preferred SC to IV administration. Conclusion SC administration resulted in both less direct medical costs and indirect costs, and was consequently less costly than IV administration from a societal perspective in a Swedish setting

Risk-adjusted benchmarking of long-term overall survival in patients with HER2-positive early-stage Breast cancer: A Swedish retrospective cohort study

Aim: The main objective of the current study was to explore the value of risk-adjustment when comparing (i.e. benchmarking) long-term overall survival (OS) in breast cancer (BC) between Swedish regions. We performed risk-adjusted benchmarking of 5- and 10-year OS after HER2-positive early BC diagnosis between Sweden's two largest healthcare regions, constituting approximately a third of the total population in Sweden. Methods: All patients diagnosed with HER2-positive early-stage BC between 01-01–2009 and 31-12-2016 in healthcare regions Stockholm-Gotland and Skane were included in the study. Cox proportional hazards model was used for risk-adjustment. Unadjusted (i.e. crude) and adjusted 5- and 10-year OS was benchmarked between the two regions. Results: The crude 5-year OS was 90.3% in the Stockholm-Gotland region and 87.8% in the Skane region. The crude 10-year OS was 81.7% in the Stockholm-Gotland region and 77.3% in the Skane region. However, when adjusted for age, menopausal status and tumour biology, there was no significant OS disparity between the regions, neither at the 5-year nor 10-year follow-up. Conclusion: This study showed that risk-adjustment is relevant when benchmarking OS in BC, even when comparing regions from the same country that share the same national treatment guidelines. This is, to our knowledge, the first published risk-adjusted benchmarking of OS in HER2-positive BC