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.

Planning for return to work during the first year after breast cancer metastasis: A Swedish cohort study.

BACKGROUND: Planning for return to work (RTW) is relevant among sub-groups of metastatic breast cancer (mBC) survivors. RTW and protective factors for RTW in patients with mBC were determined. METHODS: Patients with mBC, ages 18-63 years, were identified in Swedish registers, and data were collected starting 1 year before their mBC diagnosis. The prevalence of working net days (WNDs) (>90 and >180) during the year after mBC diagnosis (y1) was determined. Factors associated with RTW were assessed using regression analysis. The impact of contemporary oncological treatment of mBC on RTW and 5-year mBC-specific survival was compared between those diagnosed in 1997-2002 and 2003-2011. RESULTS: Of 490 patients, 239 (48.8%) and 189 (36.8%) had >90 and >180 WNDs, respectively, during y1. Adjusted odds ratios (AORs) of WNDs >90 or >180 during y1 were significantly higher for patients with age ≤50 years (AOR180  = 1.54), synchronous metastasis (AOR90  = 1.68, AOR180  = 1.67), metastasis within 24 months (AOR180  = 1.51), soft tissue, visceral, brain as first metastatic site (AOR90  = 1.47) and sickness absence <90 net days in the year before mBC diagnosis, suggesting limited comorbidities (AOR90  = 1.28, AOR180  = 2.00), respectively. Mean (standard deviation) WNDs were 134.9 (140.1) and 161.3 (152.4) for patients diagnosed with mBC in 1997-2002 and 2003-2011, respectively (p = 0.046). Median (standard error) mBC-specific survivals were 41.0 (2.5) and 62.0 (9.6) months for patients diagnosed with mBC in 1997-2002 and 2003-2011, respectively (p < 0.001). CONCLUSIONS: RTW of more than 180 WNDs was associated with younger age, early development of metastases and limited comorbidities during the year before the diagnosis of mBC. Patients diagnosed with mBC in 2003 or later had more WNDs and better survival than those diagnosed earlier.

Use of sickness benefits by patients with metastatic breast cancer-A Swedish cohort study.

OBJECTIVE: The objective of this study is to determine the prevalence and predictors of sickness absence (SA) and disability pension (DP) in women with metastatic breast cancer (mBC). METHODS: Data were obtained from Swedish registers concerning 1,240 adult women diagnosed 1997-2011 with mBC, from 1 year before (y-1) to 2 (y1) and 2 (y2) years after diagnosis. SA and DP prevalence was calculated. Odds ratios (AOR) were determined for factors associated with using long-term (SA > 180 days or DP > 0 days) sickness benefits. RESULTS: Prevalence of SA and DP was 56.0% and 24.8% during y-1, 69.9% and 28.9% during y1, and 64.0% and 34.7% during y2, respectively. Odds of using long-term sickness benefits were higher y1 and y2 in patients using long-term sickness benefits the year before diagnosis (AOR = 3.82, 95% CI 2.91-5.02; AOR = 4.31, 95% CI 2.96-6.29, respectively) and y2 in patients with mBC diagnosis 1997-2000 (AOR = 1.84, 95% CI 1.10-3.08) and using long-term sickness benefits the year after diagnosis (AOR = 22.10, 95% CI 14.33-34.22). CONCLUSIONS: The prevalence of sickness benefit utilisation was high and increased after mBC diagnosis, particularly for patients using long-term sickness benefits prior to diagnosis. Additional study is needed to determine factors that might reduce the need for sickness benefits and enhance work ability in these patients.

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.

Sickness absence and disability pension among swedish women prior to breast cancer relapse with a special focus on the roles of treatment and comorbidity.

OBJECTIVE: We aimed to determine the longitudinal prevalence and the predictors of sickness absence (SA) and disability pension (DP) in breast cancer (BC) women who eventually developed relapse. METHODS: A total of 1293 BC women, who were ages 20-63 years, diagnosed between 1996 and 2011 and by 2016 had all developed relapse, were identified in Swedish registers and were followed from two years before to five years after their primary diagnosis, while they were relapse-free. Annual prevalence of SA and DP was calculated. Logistic regression was used to estimate adjusted odds ratios (AOR) for long-term SA (>30 days) at one (y1) and three (y3) years post-diagnosis. RESULTS: Prevalence of long-term SA was 68.1% in y1 and 16.3% in y5. Prevalence of DP progressively increased from 16.3% in y1 to 29.0% in y5. Predictors of long-term SA included age <50 years (y1:AOR = 1.79 [1.39-2.29]), TNM stage III (y1:AOR = 1.54 [1.03-2.31]; y3:AOR = 2.21 [1.32-3.72]), metastasis (y1:AOR = 1.64 [1.26-2.12]; y3:AOR = 1.51 [1.05-2.18]), comorbidity (y1:AOR = 2.41 [1.55-3.76]; y3 AOR = 4.62 [2.49-8.57]) and any combination of radiotherapy, chemotherapy and hormonal therapy (y1:AOR = 2.05-5.71). CONCLUSION: Among BC women who later developed relapse, those who had higher stages of BC, had comorbidity and received neoadjuvant and/or adjuvant therapy were at significantly higher risk of needing long-term SA after their diagnosis.

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.

The positioning of economic principles under the changing conditions of the novel drug developmental process in cancer.

Cancer is a major burden to the health care system, presently mainly in developed countries, but is rapidly becoming a problem of similar magnitude in developing countries. Cancer ranks number two or three measured in loss of "good years of life" in Europe. The direct cost of cancer are estimated to be around 50% of total health care costs and of these costs a major part is linked to cancer drugs. With the ongoing revolution in the understanding of cancer and the development of an increasing number of new, but often very costly drugs, the health care systems in all parts of the world need to have a systematic way of evaluating new cancer drugs. Health technology assessment (HTA) now plays a major role in many parts of Europe. HTA has its focus on determining the value of new innovations in order to balance allocation of health care resources in a fair and equal way. This paper reviews the HTA process in general and for cancer drugs specifically. The key findings are that cancer drugs must be evaluated in a similar way as other health care technologies. One must however take into account that cancer drugs are often approved with a high level of uncertainty. Thus, it is of key importance that not only clinical efficacy, i.e., effect in pivotal clinical trials, is taken into account, but that there is a great need for follow-up studies so that post regulatory approval is able to properly measure population based effects [clinical effectiveness (CLE)].

Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression.

PURPOSE To investigate whether hormonal receptors and human epidermal growth factor receptor 2 (HER2) change throughout tumor progression, because this may alter patient management. PATIENTS AND METHODS The study cohort included female patients with breast cancer in the Stockholm health care region who relapsed from January 1, 1997, to December 31, 2007. Either biochemical or immunohistochemical (IHC)/immunocytochemical (ICC) methods were used to determine estrogen receptor (ER), progesterone receptor (PR), and HER2 status, which was then confirmed by fluorescent in situ hybridization for IHC/ICC 2+ and 3+ status. Results ER (459 patients), PR (430 patients), and HER2 (104 patients) from both primary tumor and relapse were assessed, revealing a change in 32.4% (McNemar's test P < .001), 40.7% (P < .001), and 14.5% (P = .44) of patients, respectively. Assessment of ER (119 patients), PR (116 patients), and HER2 (32 patients) with multiple (from two to six) consecutive relapses showed an alteration in 33.6%, 32.0%, and 15.7% of patients, respectively. A statistically significant differential overall survival related to intraindividual ER and PR status in primary tumor and relapse (log-rank P < .001) was noted. In addition, women with ER-positive primary tumors that changed to ER-negative tumors had a significant 48% increased risk of death (hazard ratio, 1.48; 95% CI, 1.08 to 2.05) compared with women with stable ER-positive tumors. CONCLUSION Patients with breast cancer experience altered hormone receptor and HER2 status throughout tumor progression, possibly influenced by adjuvant therapies, which significantly influences survival. Hence, marker investigations at relapse may potentially improve patient management and survival.

HER2 status in a population-derived breast cancer cohort: discordances during tumor progression.

This retrospective study investigates the correlation of intra-individual HER2 status between primary breast cancers and corresponding recurrences in a population derived cohort. The REMARK criteria were used as reference. In 151 breast cancer patients, primary tumors were analyzed for HER2 status on histopathology sections using immunohistochemistry (IHC) confirmed by fluorescence in situ hybridization (FISH) for IHC 2+ and 3+. Recurrences (loco regional and distant) were investigated by aspiration cytology, using HER2 immunocytochemistry (ICC) or FISH (ICC in 84 patients and FISH in 102 patients). In the 151 patients, sites of recurrence were bone/bone marrow 30%, liver 16%, local recurrence 18%, lung/pleura 10%, axillary lymph nodes 9%, skin (non-local) 7%, supra clavicular lymph nodes 5%, and other sites 7%. In 15 patients (10%) HER2 status changed, 7 of 108 patients (6%) from HER2 negative to HER2 positive and 8 of 43 (19%) from HER2 positive to HER2 negative. Intra-patient agreement in HER2 status was 76% (95% CI 64-87%), and the disagreement was 10% (95% CI 5-15%). The multivariable Cox analysis showed a significantly increased risk of dying in the patient group with changed HER2 status compared to patients with concordant positive HER2 status. Overall survival HR is 5.47 (95% CI 2.01-14.91) and survival from relapse HR is 3.22 (95% CI 1.18-8.77). The unstable status for HER2 in breast cancer is clinically significant and should motivate more frequent testing of recurrences.

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

BACKGROUND: Approximately 14% of Early Breast Cancers, EBCs, and 25% of Metastatic BCs, MBCs, are HER2 positive. There is an effective treatment (trastuzumab) for both EBC (9% increased absolute disease free survival at five years) and MBC (five to nine months' prolonged overall survival). Patients with BC are treated within each of the six different Health Care Regions (HCRs) in Sweden. This aim of this project was to study the introduction and usage of trastuzumab in BC in the six HCRs in Sweden. MATERIALS AND METHODS: We used official sales data and cancer statistics in the model, and HER2 positive proportions of 25% (prevalent population in year 2000; first year of trastuzumab sales) and 14% and treatment times of 38 weeks and 52 weeks for MBC and EBC, respectively, based on clinical trial data. We used years 2000-2004 for the MBC analyses. In year 2005 data on trastuzumab in EBC were presented, and approval came in year 2006. We studied years 2006-2008 for the use in both EBC and MBC. RESULTS: The percentage trastuzumab treated MBC patients for the entire period in the different HCRs (quarter 4 2000 to end 2004) was: North 57%, Stockholm 48%, South East 40%, South 17%, Uppsala 52%, West 34%. The Sweden average was 40%. The percentage treated patients (MBC and EBC), years 2006-2008 in the different HCRs was: North 68%, Stockholm 75%, South East 43%, South 44%, Uppsala 74%, West 43%. The Sweden average was 59%. CONCLUSION: The differences in usage of trastuzumab may be explained by variable interpretations of the clinical data and applications in clinical practice, budget issues and differences in coordination, experience and training.