Ulla Wilking

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% (McNemars 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

Abstract 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.

Health Related Quality of Life (HRQoL) in Swedish Relapse Free Breast Cancer Patients. A Study of EQ5D and TTO in a Patient Advocacy Population.

Health Related Quality of life (HRQoL) factors are central in all cancer therapy. We have examined two HRQoL instruments, EQ5D and TTO in women treated for breast cancer and free of relapse.The participants were all members Swedish breast cancer advocacy group BRO. The aim of this study was to evaluate HRQoL in relation to age, time of diagnosis and compare this with healthy Swedish females (HF) of the same age (Burstrom K et al 2006). Methods EQ-5D is a generic health-related quality of life (HRQoL) instrument/questionnaire that is used for economic evaluations of health interventions. The EQ-5D measures HRQoL in five dimensions and three levels of response, and correlate with disease specific quality of life instruments like EORTC QLQ-C30. Using population derived weights, EQ5D responses are translated to a global index between 0 (death) and 1 (full health).Time-Trade-Off (TTO) is used in health economics to determine the quality of life by trading improved quality of life for reductions in survival time. The respondent can choose to live 10 or 20 years in current health state or choose to give up some life years to live for a shorter period in full health. The number of years she/he is willing to give up to gain full health is translated into an index between 0 (willing to give up all remaining life time) and 1 (not willing to give up any remaining life time). Results We sent out these quality of life instruments to members of BRO. A total of 4900 (52%) responded out of which 4027 were free of relapse. Respondents had a mean age of 62.1 years. Tumor and treatment characteristics reflect the prevalent Swedish breast cancer population. Conclusions: The results of this study indicate that older (>60y) women with BC have better health status (measured by EQ5D and TTO), than healthy females (HF). Younger women ( Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5047.

HER-2/neu expression/amplification is not stable during tumor progression. A single institution study with intrapatient comparisons years 1999 through to 2007.

Abstract #6033 Background: HER-2/neu (HER2) expression/amplification has been considered to be intrapatient stable in primary breast cancer vs corresponding metastatic lesions. Treatment decisions, in many institutions, only rely on status in primary tumors. Few studies have been published on this subject. Single small studies reveal a high rate of concordance, while others reveal change in HER2 status (one study had 9 of 24 patients with no HER-2 amplification in the primary tumor changed genotype in circulating tumor cells, Meng et al PNAS 2004). At Radiumhemmet, Karolinska in Stockholm we have, whenever possible, morphologically verified all new metastases since 1999 using ultrasound-, CT- or X-ray guided or manually guided cytological aspirates. In addition to morphology, we aim to analyze receptors, HER-2 and proliferation MIB-1 on aspirates.
 Materials and methods: Retrospective analysis of intra patient HER-2 over expression/amplification on routinely analyzed primary cancers and corresponding metastatic lesions during the time period 1999 to 2007. Data from the Pathology laboratory at the Karolinska University Hospital and the population based registry at the Regional Cancer Registry in Stockholm were used for patient identification. Most immunihistochical/immunocytochemical (IHC) with 2+ or 3+ samples (using several antibodies with cell line controls) were fluorescent in situ hybridization (FISH) verified. IHC 3+ and/or FISH amplification (av. >2 copies per cell) was considered HER2 positive.
 Results: A total of 1067 breast cancers recurrences from the Stockholm hospitals were reported to the Regional Cancer Registry, 401 patients had a fine needle aspirate including a HER-2 analysis of recurrence/metastasis. 141 patients had HER-2 analyzed in both primary tumor (133 IHC, 8 FISH, 81 combined analyses) and the corresponding metastatic lesion (73 IHC, 67 FISH and 33 combined analyses). We identified 44 (31%) HER2 positive primary tumors and 44 (31%) HER2 positive metastases, respectively, in the 141 double tested tumors. 16 patients (11%) had a change in HER2 expression. 10 changed from negative to positive, and 6 changed from positive to negative (6/44 and 10/97, respectively altered their HER2 status). The metastatic sites of these patients were: loco-regional 3, liver 6, skeletal/ bone-marrow 2, lung 1, skin 4.
 Discussion: Our study shows that there are discrepancies between primary tumor and corresponding metastasis in HER-2 expression/amplification, within the same patient. If this is related to the heterogeneity of both the primary tumor and the metastasis, or if it is a true change in tumor cells is not yet clear. We also need to establish eventual inter metastatic heterogeneity in HER-2 expression. Our findings may, to some extent, explain why some patients with “HER2 negative” cancers respond, and vice versa. Cytological confirmation of radiological lesions adds diagnostic precision and is in our hands a very safe procedure which has important impact on patient management, in this case the use of trastuzumab. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6033.

Abstract P1-09-05: Re-Testing of HER2 Status in Recurring Metastatic Breast Cancer Is a Clinically Relevant and Cost-Effective Strategy

Introduction Previously HER2 status has been shown to change in 6 to 30% of recurring metastatic breast cancer (RMBC) patients (pts). Still most clinicians base trastuzumab (TZ) re-treatment decisions on prior HER2 testing of the primary tumor. This study investigates cost-effectiveness of re-testing of HER2 status (REHER) of metastasis in RMBC pts before TZ treatment in a Swedish setting. Materials and methods A Markov state transition model is used to simulate six different strategies for REHER and treatment of RMBC. The analysis is performed for two cohorts with different patient management and resource use, based on: I Treatment guidelines and published data on the patient group (guideline cohort, GC); II Clinical practice with real life data from a Swedish breast cancer database (real life cohort, RLC). Quality adjusted life year (QALY) weights and risks of progression and breast cancer death are taken from literature. Outcomes are measured as QALYs gained and costs, including both direct and indirect costs. Analyses are performed with life time perspective and both costs and outcomes are discounted at 3%. Costs have been converted to USD with an exchange rate of 7.367 SEK/USD. Testing and treatment strategies. Results Chemotherapy alone for all pts (strategy 0) is least costly and results in 1.309 QALYs gained. IHC testing all pts and treat FISH confirmed IHC 2+ 3+ pts with TZ (strategy 4) has lowest incremental cost-effectiveness ratio (ICER),

Abstract S3-5: Discordance in Hormone Receptor and HER2 Status in Breast Cancer during Tumor Progression

63,200 and

Discordance in hormone receptor status in breast cancer during tumor progression.

61,100 for GC and RLC respectively. FISH testing all pts and treating FISH+ with TZ (strategy 5) is the most efficient strategy resulting in 1.543 QALYs gained with an ICER at

HER2 gene amplification (HER2) and hormone receptor expression (ER/PR) in early (EBC) and metastatic breast cancer (MBC) in the same patients

75,500 and

Access to cancer drugs in Europe years 2005-2014.

73,300 respectively. Strategies 1 and 3 are dominated by simple dominance (less expensive alternative with better outcome). Strategy 2 is dominated by extended dominance (alternative with better effectiveness and lower ICER). Results for guideline and real life cohorts. Conclusion The cost of patient management calculated based on guidelines is similar to the one based on observed clinical practice. RLC is less costly but both cohorts give the same ranking of strategies. A Swedish study estimated willingness to pay (wtp) in Sweden to 88,900