Reproducibility of FDG PET based metabolic tumor volume measurements and of their FDG distribution within.

AIM: The aim of this study was to report on the reproducibility of F-18-fluorodeoxyglucose (FDG) PET MTV (metabolic tumor volume) 40% and MTV2.5, as well as on the intratumor reproducibility in patients, predominantly suffering from lung cancer and squamous cell carcinoma of the head and neck (SCCHN). METHODS: Nineteen patients (14 men) who underwent a baseline staging FDG PET-CT examination and a second radiotherapy treatment planning FDG PET-CT examination prior to treatment initiation within 17 days (range: 7-37 days) from each other were included. Bland-Altman analysis was performed on MTV40% and MTVSUV2.5 values obtained of the primary tumor. For voxelwise comparison of the FDG distribution within tumors the transformation matrices, defined on the CT images, were applied to the corresponding FDG images. Accordingly, the MTV40% of the primary tumor volume was defined and copied on the second FDG image. The coordinates and SUV values of each pixel in the corresponding volumes in both FDG images were used for paired comparison. RESULTS: The standard deviation of the percentage spread around the means of both measurements was respectively 32.5% for MTVSUV2.5 versus 18.8% for MTV40%. Using a cut-off value of 1.96 SD, differences exceeding 64% in MTVSUV2.5 and 37% in MTV40% may be considered to be clinically relevant. Correlation coefficients derived from the voxelwise paired comparison of SUV values within MTV40% volumes delineated on scan 1 and scan 2 ranged from 0.67 to 0.96 (mean: 0.83). Bland-Altman plots demonstrated a low reproducibility for low SUV values and a high(er) reproducibility for high SUV values (inverted triangular shape) in all tumor volumes under study. CONCLUSION: The reproducibility of MTV40% proved better than that of MTVSUV2.5 with a cut-off of 37% (increase or decrease) in MTV allowing to define clinically significant changes. Furthermore, intratumoral voxelwise FDG distribution did not change significantly in most of the patients during the time interval studied.

Symptomatic bilateral choroidal metastasis from breast cancer as first clinical sign of advanced metastatic tumor disease 31 years after diagnosis.

We report a 62-year-old caucasian woman with bilateral choroidal metastases as only clinical presenting sign of advanced metastatic tumour disease. She presented with decreased vision in the left eye since 5 days. She was treated for breast cancer 31 years before. Fundoscopy and ultrasound analysis showed a large choroidal metastasis in the left eye and one asymptomatic lesion in the right eye. Systemic screening revealed multiple lung and bone metastases. Health practitioners should be aware that choroidal metastasis from breast carcinoma can present throughout life. Small asymptomatic lesions may be detected that still can be treated effectively.

Third consensus on medical treatment of metastatic breast cancer.

BACKGROUND: Treatment options for patients with metastatic breast cancer (MBC) include a rapidly expanding repertoire of medical, surgical and supportive care measures. DESIGN: To provide timely and evidence-based recommendations for the diagnostic workup and treatment of patients with MBC, an international expert panel reviewed and discussed the evidence available from clinical trials regarding diagnostic, therapeutic and supportive measures with emphasis on their impact on the quality of life and overall survival of patients with MBC. RESULTS: Evidence-based recommendations for the diagnostic workup, endocrine therapy, chemotherapy, use of targeted therapies and bisphosphonates, surgical treatment and supportive care measures in the management of patients with MBC were formulated. CONCLUSIONS: The present consensus manuscript updates evidence-based recommendations for state-of-the-art treatment of MBC depending on disease-associated and biological variables.

Preceding sentinel node biopsy in early breast cancer: does it affect the number of axillary lymph nodes?

In the staging of early breast cancer a positive sentinel node biopsy is followed by axillary dissection in order to assess the number of metastasised lymph nodes. Immediate axillary dissection has been abandoned in our centre. If necessary, an axillary dissection takes place about two weeks later, but the post surgical inflammatory reaction might hinder dissection and decrease the number of removed lymph nodes. In a retrospective study, the total number of lymph nodes removed by sentinel node biopsy followed later by axillary dissection (n = 53) was compared with the total number of lymph nodes removed by axillary dissection without previous sentinel node biopsy in combination with breast conserving therapy (n = 113), or following breast conserving therapy (n = 15), or in combination with mastectomy (n = 65). A total number of 12 (median) lymph nodes were removed by sentinel node biopsy followed later by axillary dissection. Only in the mastectomy + axillary dissection group were less lymph nodes (median of 9) removed (P = 0.009). Multiple regression showed the total number of axillary lymph nodes to be correlated with age (R = -0.21; P = 0.002) and with the number of lymph nodes with metastasis (R = 0.31; P < 0.0001). Age distribution showed that the mastectomy + axillary dissection group had the oldest patient population. The number of removed axillary lymph nodes is not decreased by preceding sentinel node biopsy, but depends on other factors.

The role of oncoplastic surgery in breast cancer.

The authors discuss the objectives of oncoplastic surgery in breast cancer management. Indications and advantages are summarised. Some surgical techniques are described. The authors report their own experience with oncoplastic surgery (26 patients who had immediate breast reconstruction after tumorectomy, and 126 patients who had lumpectomy alone. Oncoplastic surgery was characterised by a wider excision, with negative margins in all cases. In isolated breast conservative tumorectomy, 20% of the margins were positive, requiring re-excision or radical mastectomy. Oncoplastic surgery is preferred especially in younger patients with smaller breasts, since it is less cosmetically mutulating and allows complete tumor resection with save margins.

Incorporating PARP-inhibitors into clinical routine: A tailored treatment strategy to tackle ovarian cancer.

DNA repair mechanisms play a key role in oncogenesis and cancer progression in women with BRCA mutation-positive (BRCAm) ovarian cancer (OC). The BRCA1/2 and poly(ADP-ribose) polymerase (PARP) proteins are considered the foremost mediators among the various components of double-strand and single-strand repair, respectively. A series of new therapeutic drugs that target PARP have been developed for BRCAm OC. This class of agents provokes tumour-specific cytotoxicity with minimal side effects by inducing synthetic lethality, of which they are the first clinical example. The European Medicines Agency granted accelerated licensing approval for the first-in-class-drug that inhibits PARP, olaparib (Lynparza™, AstraZeneca). Olaparib can be used as a monotherapeutic maintenance treatment in patients with platinum-sensitive relapsed (germline and/or somatic) BRCAm high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer responsive to platinum-based chemotherapy. Seen in light of these recent events, this review article will focus on (a) how PARP-inhibitors exploit cancer-specific defects in the homologous recombination repair apparatus and (b) how BRCA testing is implemented in routine clinical care.

Comparison of L-758,298, a prodrug for the selective neurokinin-1 antagonist, L-754,030, with ondansetron for the prevention of cisplatin-induced emesis.

Substance P is localised in brainstem regions associated with emesis. Based on studies in the ferret, it was postulated that a neurokinin-1 (NK1) receptor antagonist would have antiemetic activity as monotherapy in humans receiving chemotherapy. L-758,298 is a water-soluble, intravenous (i.v.) prodrug for L-754,030, a potent and selective NK1 receptor antagonist. This double-blind, randomised, active-agent (ondansetron)-controlled study enrolled 53 cisplatin-naïve patients and evaluated the prevention of both acute (0-24 h) and delayed (days 2-7) emesis after cisplatin treatment (50-100 mg/m(2)). All patients received i.v. L-758,298 (60 or 100 mg) (n=30) or ondansetron (32 mg) (n=23) before cisplatin and efficacy was evaluated up to day 7 post-cisplatin. Nausea was assessed by means of a four-point ordinal scale at intervals over the 7 day period. In the acute period, the proportion of patients without emesis in the L-758,298 and ondansetron groups was 37 and 52%, respectively (no significant difference between the groups). Comparing the distribution of average nausea scores over the entire first 24 h revealed no significant difference between the groups. In the delayed period, the proportion of patients without emesis in the L-758,298 and ondansetron treatment groups was 72 and 30%, respectively (P=0.005). The distribution of average nausea scores in the delayed period was lower in the L-758,298 group compared with the ondansetron group (P=0.15 for the entire delayed period and P=0.043 for day 2 only). No serious adverse events were attributed to L-758,298. A single dose of L-758,298 substantially suppressed the delayed nausea and vomiting characteristic of high dose cisplatin and also appeared to reduce acute emesis post-cisplatin. The data also support the proposition that the underlying mechanism(s) of acute and delayed emesis are different.

Iodine-labeled tamoxifen uptake in primary human breast carcinoma.

UNLABELLED: Assessing tumor uptake and retention of (123)I-labeled tamoxifen (TX) could increase our understanding of TX's action and the mechanisms involved in resistance to the drug. METHODS: Nine untreated primary breast carcinoma patients underwent whole-body planar and tomographic (SPECT) imaging 30 min and 4-5 h after injection of 185 MBq (123)I-TX. Tumor-to-normal tissue uptake ratios (T/N) derived from SPECT images were related to estrogen receptor (ER) and progesterone receptor (PR) status. RESULTS: In 4 of 9 patients, all of whom were ER+/PR+, (123)I-TX tumor uptake was clearly depicted. In 2 of them, involved axillary lymph nodes were also visualized. T/N consistently increased over time. All ER+/PR- and ER-/PR- tumors as well as 2 ER+/PR+ tumors were (123)I-TX-. CONCLUSION: These preliminary findings suggest that (123)I-TX is preferentially taken up in alpha-ER+/PR+ breast tumors known to be more likely to respond to endocrine treatment.

Pharmacokinetics of intravenous alendronate.

Alendronate is a potent bisphosphonate that has been studied for the treatment of osteoporosis and Paget's disease of the bone. To examine the pharmacokinetics of this drug, several groups of postmenopausal women were dosed intravenously in several studies. Twelve patients with metastatic bone disease were administered an intravenous dose of 10 mg of 14C-labeled alendronate (approximately 26 muCi), and plasma, feces, and urine samples were collected for 72 hours. Radioactivity was excreted almost exclusively in urine, and all of it was accounted for by alendronate. Overall recovery accounted for 47% of dose, with the remainder presumed to be retained in bone. Metabolism of alendronate was not observed. Renal clearance of alendronate was 71 mL/min. An additional 10 subjects were given repeated i.v. administrations of alendronate to demonstrate that previous exposure does not alter the pharmacokinetic behavior of the drug. Examination of the findings from these and other studies in which alendronate was administered intravenously revealed that disposition of single doses is linear in the range of 0.125 to 10 mg. With the possible exception of a somewhat greater skeletal retention of a systemically administered dose, the pharmacokinetics of i.v. alendronate were found to be similar to those of other bisphosphonates.

Different responses to preoperative chemotherapy for invasive lobular and invasive ductal breast carcinoma.

AIM: Preoperative chemotherapy (PCT) is used in primary breast cancer, to facilitate breast conservative surgery (BCS). Clinical and pathologic responses are important prognostic parameters. Biologic markers are needed to individualize treatment. PATIENTS AND METHODS: One hundred and thirty-five patients with breast carcinoma were treated with PCT, followed by surgery and adjuvant therapy. Clinical response and pathological complete response (pCR), biological markers and type of surgery were compared between invasive ductal (IDC) and invasive lobular carcinoma (ILC). RESULTS: Overall response (OR) for IDC was 75% compared to 50% for ILC (P=0.0151). Pathological CR was 15% for IDC and 0% for ILC (P=0.0066). Fifty-six percent of the responding patients had BCS, in contrast with 16% of the non-responders. BCS was performed in 50% of patients with IDC, in 38% of the patients with ILC. Salvage surgery was more necessary in ILC (19%) compared to IDC (4%) (P=0.0068). Patients with ILC were more frequently ER-positive and HER-2 negative than patients with IDC. CONCLUSIONS: Clinical and pathological responses are lower in ILC compared to IDC. After PCT, patients with large ILC should preferably be offered mastectomy with immediate breast reconstruction. However, PCT still remains valuable to evaluate tumor response and biologic factors in vivo.

Increasing serum levels of alpha-fetoprotein in a patient with relapsing gallbladder carcinoma.

Alpha-fetoprotein (AFP) is a useful serum tumor marker especially for hepatocellular carcinoma and yolk-sac tumor. Increased serum levels of AFP have also been found in adenocarcinoma of the stomach, the pancreas, the colon and the lung, and in some squamous cell carcinomas of the lung. We describe a patient with a recurrent gallbladder carcinoma, presenting with increasing serum levels of AFP as the tumor progresses. Remarkable are the histologic changes in the metastases of the tumor, which showed more dedifferentiation as the number of cells containing AFP increased.

Imaging requirements for personalized medicine: the oncologists point of view.

While conventional chemotherapy regimens aim to be cytotoxic against proliferating cells, molecular targeted therapies are directed at specific cancer-associated pathways. To optimize cancer care, an early evaluation of treatment response is warranted for any tumor type - and for any treatment - by using conventional imaging modalities such as ultrasound, CT and MR, FDG-PET or specific radiotracer. FDG-PET is one of the most extensively and successfully used imaging modalities to achieve an early response evaluation. A high SUV-value is a surrogate for malignancy in terms of cancer care and a decrease in FDG-uptake after therapy is associated with treatment response and a favorable clinical outcome. Anyhow, the potential of PET reaches further. By providing metabolic information PET (with or without CT) can help to select patients for targeted therapy and to adapt treatment protocols. PET with FDG and maybe other, more specific PET tracers, promises to direct in a better way personalized cancer care and thus promote translational research. An interesting aspect of molecular imaging is the ability to achieve knowledge on distribution and expression levels of a given receptor. Hereby, imaging could help in guiding systemic treatment given a broad spectrum of radiotracers, detecting specific mutations at molecular level in vivo. From an oncologists point of view the concept of 'personalized medicine' should evolve to include 'personalized imaging' as well as 'personalized treatment' in order to optimize cancer care, reduce side effects and improve quality of life for cancer patients.

CA 15.3 measurements for separating FDG PET/CT positive from negative findings in breast carcinoma recurrence. Factors influencing the area under the ROC curve.

UNLABELLED: In breast cancer CA 15.3 is considered the tumour marker of choice. CA 15.3 is directly related to the disease extent and to hormone status (estrogen receptor ER+/ ER-, progesterone receptor PR+/PR-). This study was designed to assess the impact of disease extent, hormone receptor and HER2-status, and circulating blood volume on the area-under the ROC-curve of CA 15.3 to separate FDG PET positive from negative findings. PATIENTS, METHODS: We retrospectively evaluated 379 FDG PET/CT examinations performed in 80 patients with breast cancer. Blood volumes were derived using the formulas by Nadler and multiplied by their corresponding CA 15.3 measurement. RESULTS: ROC-curve analysis revealed an AUC of 0.695 (p = 0.0001) for CA 15.3 to separate FDG PET positive from negative findings. AUC measurements to separate normal scan findings from loco-regional disease and metastatic disease were 0.527 (p = 0.587) and 0.732 (p = 0.0001), respectively. AUC measurements for CA 15.3 to separate positive from negative FDG PET findings, in ER+ and ER- patients, were respectively 0.772 (p = 0.0001) and 0.596 (p = 0.143). AUC measurements for CA 15.3 to separate positive from negative FDG PET findings, in PR+ and PR- patients, were respectively 0.675 (p = 0.0001) and 0.694 (p = 0.0001). In HER2-positive and -negative patients, the AUC measurements were respectively 0.594 (p = 0.178) and 0.701 (p = 0.0001) to separate positive from negative FDG PET findings. CONCLUSION: The AUC for CA 15.3 measurements to separate FDG PET positive from negative findings in breast cancer patients with suspected recurrence proved to be directly related to the extent of the recurrent disease and hormone receptor status and inversely related to HER2-status. Correcting CA 15.3 measurements for blood volumes did not impact the AUC.

PARP inhibitors in oncology: a new synthetic lethal approach to cancer therapy.

Damage to DNA has emerged as a major culprit in cancer. Mammalian cells are continuously exposed to DNA damage, caused by exogenous toxins as well as endogenous activities such as DNA replication and cellular free radical generation. It is therefore essential that cells have DNA repair mechanisms in place to preserve its genomic integrity. Interestingly, cancer cells frequently harbour defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis, but also provides a weakness in the tumour that can be exploited therapeutically. In this context, it has been shown that homologous recombination (HR)-deficient tumour cells--including those with defects in BRCA1/2--are highly sensitive to blockade of the base excision repair (BER) pathway via inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a novel 'synthetic lethal' approach to cancer therapy. Recent clinical trials have shown an enhancement of the cytotoxic effect of chemotherapy by adding a PARP inhibitor to the standard treatment. Still, clinical outcome may be even further improved if these drugs would be used as first-line therapy. In conclusion, it can be stated that an exciting new class of drugs has entered the arena of cancer therapy. However, additional clinical studies are needed before PARP inhibitors can definitely enter daily clinical practice.

Prognostic value of serial blood S100B determinations in stage IIB-III melanoma patients: a corollary study to EORTC trial 18952.

S100B is a prognostic factor for melanoma as elevated levels correlate with disease progression and poor outcome. We determined its prognostic value based on updated information using serial determinations in stage IIb/III melanoma patients. 211 Patients who participated in the EORTC 18952 trial, evaluating efficacy of adjuvant intermediate doses of interferon α2b (IFN) versus observation, entered a corollary study. Over a period of 36 months, 918 serum samples were collected. The Cox time-dependent model was used to assess prognostic value of the latest (most recent) S100B determination. At first measurement, 178 patients had S100B values <0.2 µg/l and 33 ≥ 0.2 µg/l. Within the first group, 61 patients had, later on, an increased value of S100B (≥ 0.2 µg/l). An initial increased value of S100B, or during follow-up, was associated with worse distant metastasis-free survival (DMFS); hazard ratio (HR) of S100B ≥ 0.2 versus S100B < 0.2 was 5.57 (95% confidence interval (CI) 3.81-8.16), P < 0.0001, after adjustment for stage, number of lymph nodes and sex. In stage IIb patients, the HR adjusted for sex was 2.14 (95% CI 0.71, 6.42), whereas in stage III, the HR adjusted for stage, number of lymph nodes and sex was 6.76 (95% CI 4.50-10.16). Similar results were observed regarding overall survival (OS). Serial determination of S100B in stage IIb-III melanoma is a strong independent prognostic marker, even stronger compared to stage and number of positive lymph nodes. The prognostic impact of S100B ≥ 0.2 µg/l is more pronounced in stage III disease compared with stage IIb.

A 41-year-old man with breast cancer and dyspnoea: an exceptional complication in an uncommon disease.

A case of advanced breast cancer in a young male, who developed progressive dyspnoea a few months after treatment with chemotherapy is described. The clinical and radiological picture, supported by lung function testing, finally revealed the tentative diagnosis of bronchiolitis obliterans, most probably due to cyclophosphamide, one of the drugs used in the cytotoxic therapy. Two distinct clinical patterns of pulmonary toxicity associated with cyclophosphamide are reviewed: the acute pneumonitis that occurs early in the course of treatment; and the chronic, progressive, fibrotic process, of which bronchiolitis obliterans is an uncommon presentation. Cyclophosphamide pulmonary toxicity is primarily a clinical diagnosis and the typical features are discussed. Early-onset pneumonitis due to cyclophosphamide is a reversible process with a good prognosis. On the other hand, late-onset pneumonitis or lung fibrosis is essentially irreversible and follows a chronically progressive course over months to years. It almost inevitably leads to terminal respiratory failure.

Cardiac toxicity of trastuzumab: experience at the Ghent Unversity Hospital, Belgium.

INTRODUCTION: Trastuzumab (TRAS) is a humanised monoclonal antibody that is targeted against the HER2 growth factor receptor. Over-expression of the receptor occurs in around 15-25% of women with early breast cancer (CA). Four major adjuvant trials compared trastuzumab treatment with observation after neoadjuvant or adjuvant chemotherapy in women with high risk HER2-positive breast cancer. Results of these trials showed that trastuzumab treatment given every 3 weeks for 1 year achieved a significant improvement of disease free survival and overall survival. However, cardiac toxicity occurred more in the trastuzumab arm than in the observation arm resulting in symptomatic congestive heart failure and a significant drop in left ventricular ejection function (LVEF). AIM OF THE STUDY: The purpose of this analysis is to evaluate cardiac toxicity of adjuvant trastuzumab treatment in 30 breast cancer patients. Study parameters were cardiac toxicity assessed by LV function, disease free survival and overall survival. MATERIALS AND METHODS: Based on the adjuvant trials and in expectation of the reimbursement of trastuzumab in the adjuvant setting, a convention was set up between the Belgian National Institute for Health and Disability Insurance and hospital centres specialized in the treatment of breast cancer. In this convention, trastuzumab was offered to patients diagnosed with invasive, non-metastatic breast cancer with an over-expression of HER2 proven by a positive FISH test. Metastatic lymph nodes or a tumour measuring more than 10 mm had to be present. At least 4 cycles of adjuvant or neoadjuvant chemotherapy had to be given to the patient. Radiotherapy could be administered. The time interval between chemotherapy or radiotherapy and treatment with trastuzumab could not be more than 6 months. LVEF determined by MUGA scan or by ultrasonography at the start of trastuzumab treatment had to be more than 55%. RESULTS: 30 breast cancer patients were treated with adjuvant trastuzumab in our hospital between June 2006 and July 2007. All patients met the inclusion criteria. Six patients stopped trastuzumab treatment because of cardiac toxicity. All these patients had received prior anthracycline neoadjuvant or adjuvant chemotherapy. Five of these patients were found to have a LVEF < 55%, one showing symptoms of congestive cardiomyopathy.The sixth patient was diagnosed with a newly developed tricuspid valve insufficiency grade 3. Follow-up data of 20 months since the start of trastuzumab treatment showed that 27 patients were disease-free. Two patients died because of progressive breast cancer disease. One patient was lost of follow-up. CONCLUSION: In this small group of breast cancer patients, treated with adjuvant trastuzumab, cardiac toxicity expressed as a decreased left ventricular function seems to have a higher incidence compared to the other adjuvant trials. Therefore, a close cardiac monitoring for several years should be recommended in patients treated with trastuzumab.

Trastuzumab treatment of early stage breast cancer is cost-effective from the perspective of the Belgian health care authorities.

Trastuzumab (Herceptin, Roche) is a recombinant, humanized monoclonal antibody directed against the neu-HER2 protein, since May 2002 reimbursed in Belgium for the treatment of metastatic HER2+ breast cancer and since June 2007 also in adjuvant therapy of HER2+ early stage breast cancer. The purpose of this study was to estimate the cost-effectiveness from the Belgian health care payer perspective of reimbursing trastuzumab in the Latter indication. A Markov state transition model was designed to adequately capture the natural history and course of disease for early stage breast cancer patients, and to simulate cost and disease progression over a life time perspective. The model estimates differences in outcomes for patients treated with adjuvant trastuzumab during 1 year compared to current therapy, and captures cost consequences and health benefits of trastuzumab treatment. Health benefits were expressed in terms of quality-adjusted life years gained, and future benefits were discounted at 1.5%. Costs were calculated from the perspective of the Belgian authorities' health care budget, and future costs were discounted at 3%. Where relevant, the costs per Markov state were obtained from the IMS Hospital Disease database. Additionally, an expert opinion analysis on resource use during the follow-up of treated early breast cancer patients provided the cost estimates for states with minor or without hospital costs. The incremental cost-effectiveness ratio based on a life time simulation was estimated at Euro 10,315 per quality-adjusted life year gained. It can be concluded that trastuzumab treatment of HER2+ early stage breast cancer patients is cost-effective from the perspective of the Belgian health care authorities.

Second consensus on medical treatment of metastatic breast cancer.

The present consensus manuscript defines evidence-based recommendations for state-of-the-art treatment of metastatic breast cancer depending on disease-associated and biologic variables.

An economic evaluation of Herceptin in adjuvant setting: the Breast Cancer International Research Group 006 trial.

BACKGROUND: Herceptin (trastuzumab) is a humanized monoclonal antibody that is being tested in the adjuvant setting. Cost implications of using trastuzumab, as administered in the Breast Cancer International Research Group 006 trial, are being calculated. This provides information on the treatment's value for money. METHODS: Standard breast cancer treatment models were set up for different subpopulations according to stage (I, II, III) and menopausal condition (<50 and >50 years). Costs were calculated from the hospital's point of view, using the micro-costing method. Life expectancy data were based on literature. Our comparator was the existing practice. In addition to a sensitivity analysis, a threshold analysis on the prices of trastuzumab and docetaxel was performed to target an acceptable incremental cost-effectiveness ratio. RESULTS: Treatment costs were euro 45,034 (doxorubicin and cyclophosphamide --> docetaxel and trastuzumab) or euro 47,765 (docetaxel, carboplatin and trastuzumab). This was largely (79% and 75%, respectively) attributed to trastuzumab. According to our threshold analysis, an acceptable incremental cost-effectiveness ratio can be reached if health improvements are large enough and/or price discounts are given. CONCLUSIONS: Trastuzumab is a promising but very expensive antibody. With the current pressure on health-care budgets, cost implications of using trastuzumab in adjuvant setting must be calculated before use of the product becomes wide-spread. This provides essential information for price-setting policies and for policy makers considering reimbursement.