ABSTRACT
BACKGROUND: Patients with early-stage hormone receptor positive, human epidermal growth factor receptor-2 (HER2) negative invasive breast cancer with 1-3 positive lymph nodes (N1) often undergo surgical excisions followed by adjuvant chemotherapy (ACT). Many patients have no benefit from ACT and receive unnecessary, costly treatment often associated with short- and long-term adverse events (AEs). Gene expression profiling (GEP) assays, such as the 21-gene assay (i.e. the Oncotype DX assay), can identify patients at higher risk for recurrence who may benefit from ACT. However, the budgetary consequence of using the Oncotype DX assay versus no GEP testing in the Netherlands is unknown. Our study therefore assessed it using a cost-consequence model. METHODS: A validated model was used to create the N1 model. The model compared the costs and consequences of using the Oncotype DX assay versus no GEP testing and MammaPrint, and subsequent ACT use with corresponding costs for chemotherapy, treatment of AEs, productivity losses, GEP testing, and treatment of recurrences, according to the Oncotype DX results. The model time horizon was 5 years. RESULTS: Costs for the total population amounted to 8.0 million (M), 16.2 M, and 9.5 M, and cost per patient amounted to 13,540, 27,455, and 16,154 for using the Oncotype DX assay, no GEP testing, and MammaPrint, respectively. Total cost savings of using the Oncotype DX assay amounted to 8.2 M versus no GEP testing and 1.5 M versus MammaPrint. Using the Oncotype DX assay would result in fewer patients receiving ACT and thus fewer AEs, sick days, and hospitalizations, leading to overall cost savings compared with no GEP testing and MammaPrint. CONCLUSIONS: Implementing Oncotype DX testing in this population can prevent unnecessary overtreatment, reducing clinical and economic burden on the patient and Dutch healthcare system.
Early-stage invasive breast cancer patients often undergo surgery followed by adjuvant chemotherapy. However, many of these patients have no benefit from adjuvant chemotherapy and thus receive unnecessary and costly treatment often associated with side-effects. Patients who may benefit from adjuvant chemotherapy can be identified by analyzing the genomic profile of the patients' tumors using a molecular diagnostic test called the 21-gene assay (also known as Oncotype DX assay). However, the budgetary consequences of using Oncotype DX for this purpose in the Netherlands are currently unknown and, therefore, assessed using a health-economic model. The model compared the costs and consequences of using the Oncotype DX assay versus no molecular diagnostic testing and an alternative molecular diagnostic test called MammaPrint. The three diagnostic testing strategies resulted in different costs in terms of several different costing categories and were compared with one another. The total costs were lowest for the diagnostic strategy using the Oncotype DX assay, as it would result in fewer patients receiving adjuvant chemotherapy compared with no molecular diagnostic testing and MammaPrint. Implementing the Oncotype DX assay as a molecular diagnostic test can identify the right patient who benefits from chemotherapy (prevent over- and undertreatment) and lead to cost-savings, reducing the clinical and economic burden on the patient and Dutch healthcare system.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Netherlands , Chemotherapy, Adjuvant , Gene Expression Profiling/methods , Neoplasm Recurrence, Local/drug therapyABSTRACT
Objectives: Patients with early-stage HR+/HER2- N0 breast cancer may receive adjuvant chemotherapy in combination with surgery. However, chemotherapy does not always lead to improved survival and incurs high healthcare costs and increased adverse events. To support decision-making regarding adjuvant chemotherapy, genomic profile testing performed with tests such as the Oncotype DX® test can help healthcare practitioners decide whether chemotherapy provides any benefit to these patients. As such, a cost-consequence model was developed with the aim to estimate the economic impact of using different gene expression tests or no testing, in patients with node-negative early-stage breast cancer. Methods: A cost-consequence model was developed to estimate the economic impact of three different scenarios in the Dutch setting: (1) Oncotype DX® test, (2) MammaPrint®, and (3) and no genomic profile testing. The model included chemotherapy costs, administration costs, short- and long-term adverse event costs, productivity loss, genomic profiling testing costs, cost of cancer recurrence, and hospitalization costs. Results: A treatment paradigm with Oncotype DX resulted in average savings per patient of 6,768 vs. a paradigm with MammaPrint and 13,125 vs. a paradigm with no genomic testing. Furthermore, due to less patients receiving adjuvant chemotherapy through better targeting by the Oncotype DX test, fewer adverse events, sick days, practice visits, and hospitalizations were required compared to MammaPrint and no genomic profiling. Conclusions: Testing with Oncotype DX test in Dutch clinical practice in patients with early-stage breast cancer proved to be cost-saving versus MammaPrint and no genomic profiling tests. Introducing the Oncotype DX test to the Dutch setting will likely reduce the economic resources that are required.
ABSTRACT
BACKGROUND: Low skeletal muscle index (SMI) in metastatic colorectal cancer (mCRC) patients is associated with poor outcomes. The prognostic impact of SMI changes during consecutive palliative systemic treatments is unknown. METHODS: This is a retrospective analysis of the phase 3 CAIRO3 study. The CAIRO3 study randomized 557 patients between maintenance capecitabine + bevacizumab (CAP-B) or observation, after six cycles capecitabine + oxaliplatin + bevacizumab (CAPOX-B). Upon first disease progression (PD1), CAPOX-B was reintroduced until second progression (PD2). SMI was assessed by computed tomography (CT) (total 1355 scans). SMI and body mass index (BMI) changes were analyzed for three time-periods; p1: during initial CAPOX-B, p2: randomization to PD1, and p3: PD1 to PD2. The association between absolute and change in SMI and BMI (both per 1 standard deviation) during p1-p3, with PD1, PD2, and survival was studied by Cox regression models. RESULTS: This analysis included 450 of the 557 patients randomized in the CAIRO3 study. Mean SMI decreased during p1: mean -0.6 SMI units [95% CI -1.07;-0.26] and p3: -2.2 units [-2.7;-1.8], whereas during p2, SMI increased + 1.2 units [0.8-1.6]. BMI changes did not reflect changes in SMI. SMI loss during p2 and p3 was significantly associated with shorter survival (HR 1.19 [1.09-1.35]; 1.54 [1.31-1.79], respectively). Sarcopenia at PD1 was significantly associated with early PD2 (HR 1.40 [1.10-1.70]). BMI loss independent of SMI loss was only associated with shorter overall survival during p3 (HR 1.35 [1.14-1.63]). CONCLUSIONS: In mCRC patients, SMI loss during palliative systemic treatment was related with early disease progression and reduced survival. BMI did not reflect changes in SMI and could not identify patients at risk of poor outcome during early treatment lines.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/drug therapy , Muscle, Skeletal/diagnostic imaging , Palliative Care/methods , Sarcopenia/epidemiology , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Body Mass Index , Clinical Trials, Phase III as Topic , Colorectal Neoplasms/complications , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Disease Progression , Female , Humans , Longitudinal Studies , Maintenance Chemotherapy/adverse effects , Maintenance Chemotherapy/methods , Male , Middle Aged , Prognosis , Progression-Free Survival , Randomized Controlled Trials as Topic , Retrospective Studies , Risk Factors , Sarcopenia/diagnosis , Sarcopenia/etiology , Time Factors , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: Increasing evidence suggests that severe skeletal muscle index (SMI) loss (sarcopenia) is associated with poor overall survival in metastatic colorectal cancer patients, but its mechanisms are unknown. We recently found, using data of the randomized phase 3 CAIRO3 study, that SMI loss was related with shorter time to disease progression and overall survival during first-line maintenance treatment with capecitabine + bevacizumab (CAP-B) or observation and during more intensive capecitabine + oxaliplatin + bevacizumab (CAPOX-B) reintroduction treatment. As a potential risk factor for reduced survival, we explored whether sarcopenia and SMI loss were associated with dose-limiting toxicities (DLTs) during CAP-B and CAPOX-B. METHODS: Sarcopenia status and SMI loss were assessed by using consecutive computed tomography scans. DLTs were defined as any dose delay/reduction/discontinuation of systemic treatment because of reported CTCAE (version 3.0) toxicities at the start or during treatment. Poisson regression models were used to study whether sarcopenia and body mass index (BMI) at the start of treatment and SMI and BMI loss during treatment were associated with DLTs. RESULTS: One hundred eighty-two patients (mean age 63.0 ± 8.8 years, 37% female) received CAP-B, and 232 patients (mean age 63.0 ± 9.0 years, 34% female) received CAPOX-B. At the start of CAP-B and CAPOX-B, 54% and 46% of patients were sarcopenic, respectively. Mean BMI was lower in sarcopenic patients, although patients were on average still overweight (sarcopenic vs. non-sarcopenic at the start of CAP-B 25.0 ± 3.9 vs. 26.7 ± 4.1 and CAPOX-B 25.8 ± 3.8 vs. 27.1 ± 3.8 kg/m2 ). Sarcopenia at the start of CAP-B was not associated with DLTs [relative risk 0.87 (95% confidence interval 0.64-1.19)], whereas patients with >2% SMI loss had a significantly higher risk of DLTs [1.29 (1.01-1.66)]. At the start of subsequent CAPOX-B, 25% of patients received a dose reduction, and the risk of dose reduction was significantly higher for patients with preceding SMI loss [1.78 (1.06-3.01)] or sarcopenia [1.75 (1.08-2.86)]. After the received dose reductions, sarcopenia or SMI loss was not significantly associated with a higher risk of DLTs during CAPOX-B [sarcopenia vs. non-sarcopenic: 0.86 (0.69-1.08) and SMI loss vs. stable/gain: 0.83 (0.65-1.07)]. In contrast, BMI (loss) at the start or during either treatment was not associated with an increased risk of DLTs. CONCLUSIONS: In this large longitudinal study in metastatic colorectal cancer patients during palliative systemic treatment, sarcopenia and/or muscle loss was associated with an increased risk of DLTs. BMI was not associated with DLTs and could not detect sarcopenia or SMI loss. Prospective (randomized) studies should reveal whether normalizing chemotherapeutic doses to muscle mass or muscle mass preservation (by exercise and nutritional interventions) increases chemotherapeutic tolerance and improves survival.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/toxicity , Colorectal Neoplasms/complications , Colorectal Neoplasms/drug therapy , Sarcopenia/etiology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/secondary , Dose-Response Relationship, Drug , Female , Humans , Longitudinal Studies , Male , Middle Aged , Neoplasm MetastasisABSTRACT
The androgen receptor (AR) has potential clinical relevance in metastatic breast cancer (mBC) since it might be a treatment target and has been associated with endocrine resistance. A minimal-invasive way to determine AR expression on metastatic tumor cells is by characterization of circulating tumor cells (CTCs). Here, we assessed AR mRNA expression in CTCs (CTC-AR) and in matched primary tumor samples from mBC patients representing different breast cancer subtypes. In addition, we explored CTC-AR-status in relation to outcome on endocrine therapy. AR, and 92 AR or estrogen receptor (ER) related genes, were measured in CellSearch-enriched CTCs from 124 mBC patients and in 52 matched FFPE primary tissues using quantitative reverse-transcriptase PCR. AR in CTCs was considered positive if the expression was 1 standard deviation higher than the expression measured in 11 healthy blood donors. A total of 31% of the mBC patients had AR-positive (AR+) CTCs. 58% of the matched CTC and primary tumor samples were discordant with respect to AR status, observing both switches from AR+ to AR-negative (AR-) and vice versa. There was no statistically significant difference in progression-free survival for patients treated with ER-targeting drugs and CTC-AR-status (13 AR+/ 37 AR- cases, p = 0.28). Thus, AR can be determined in RNA isolated from CTCs, with in our set 31% AR-positive samples. Given the discordance between AR status in CTC samples and corresponding primary tumors, determination of AR expression in CTCs might be a promising tool to select mBC patients for AR inhibiting agents.
Subject(s)
Breast Neoplasms/metabolism , Neoplasm Metastasis/pathology , Neoplastic Cells, Circulating/metabolism , Receptors, Androgen/metabolism , Adult , Aged , Aged, 80 and over , Androgens/metabolism , Biomarkers, Tumor/metabolism , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Neoplastic Cells, Circulating/pathology , Progression-Free Survival , Prospective Studies , Receptors, Estrogen/metabolismABSTRACT
The detection of mutated genes in cell-free DNA (cfDNA) in plasma has emerged as an important minimally invasive way to obtain detailed information regarding tumor biology. Reliable determination of circulating tumor-derived DNA, often present at a low quantity amidst an excess of normal DNA in plasma, would be of added value for screening and monitoring of cancer patients and for hypothesis-generating studies in valuable retrospective cohorts. Our aim was to establish a workflow to simultaneously assess four hotspot estrogen receptor mutations (mESR1) in cfDNA isolated from only 200 µL of plasma by means of uniplex or multiplex pre-amplification combined with digital PCR. This workflow was then applied in metastatic breast cancer (MBC) patients receiving systemic therapies for MBC. In accordance with previous studies, estrogen receptor mutations were more frequently detected in endocrine-treated MBC patients at progressive disease [34.1% (15/44)] than before the start of endocrine therapy [3.9% (2/51); P = 0.001]. For a subset of samples, results were compared with analysis of these mutations by Oncomine-targeted next-generation sequencing, which, although requiring a higher cfDNA input, yielded concordant results. The data establish development and validation of a digital PCR workflow for the simultaneous detection of several tumor-derived mutations in minute amounts of cfDNA and show the potential of this workflow for use on archived volume-limited blood samples.
Subject(s)
Breast Neoplasms/genetics , Cell-Free Nucleic Acids/genetics , DNA Mutational Analysis/methods , Estrogen Receptor alpha/genetics , Polymerase Chain Reaction/methods , Adult , Aged , Aged, 80 and over , Breast Neoplasms/blood , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Cell-Free Nucleic Acids/blood , Female , High-Throughput Nucleotide Sequencing/methods , Humans , Middle Aged , Mutation , Neoplastic Cells, Circulating/pathology , Sample Size , WorkflowABSTRACT
Mutations and splice variants in the estrogen receptor (ER) gene, ESR1, may yield endocrine resistance in metastatic breast cancer (MBC) patients. These putative endocrine resistance markers are likely to emerge during treatment, and therefore, its detection in liquid biopsies, such as circulating tumor cells (CTCs) and cell-free DNA (cfDNA), is of great interest. This research aimed to determine whether ESR1 mutations and splice variants occur more frequently in CTCs of MBC patients progressing on endocrine treatment. In addition, the presence of ESR1 mutations was evaluated in matched cfDNA and compared to CTCs. CellSearch-enriched CTC fractions (≥5/7.5 mL) of two MBC cohorts were evaluated, namely (a) patients starting first-line endocrine therapy (n = 43, baseline cohort) and (b) patients progressing on any line of endocrine therapy (n = 40, progressing cohort). ESR1 hotspot mutations (D538G and Y537S/N/C) were evaluated in CTC-enriched DNA using digital PCR and compared with matched cfDNA (n = 18 baseline cohort; n = 26 progressing cohort). Expression of ESR1 full-length and 4 of its splice variants (∆5, ∆7, 36 kDa, and 46 kDa) was evaluated in CTC-enriched mRNA. It was observed that in the CTCs, the ESR1 mutations were not enriched in the progressing cohort (8%), when compared with the baseline cohort (5%) (P = 0.66). In the cfDNA, however, ESR1 mutations were more prevalent in the progressing cohort (42%) than in the baseline cohort (11%) (P = 0.04). Three of the same mutations were observed in both CTCs and cfDNA, 1 mutation in CTCs only, and 11 in cfDNA only. Only the ∆5 ESR1 splice variant was CTC-specific expressed, but was not enriched in the progressing cohort. In conclusion, sensitivity for detecting ESR1 mutations in CTC-enriched fractions was lower than for cfDNA. ESR1 mutations detected in cfDNA, rarely present at the start of first-line endocrine therapy, were enriched at progression, strongly suggesting a role in conferring endocrine resistance in MBC.
Subject(s)
Breast Neoplasms/pathology , Estrogen Receptor alpha/genetics , Protein Isoforms/genetics , Aged , Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Cell-Free Nucleic Acids/blood , Cell-Free Nucleic Acids/genetics , Cohort Studies , Disease Progression , Estrogen Antagonists/therapeutic use , Estrogen Receptor alpha/blood , Female , Humans , Liquid Biopsy , Middle Aged , Mutation , Neoplasm Invasiveness , Neoplastic Cells, Circulating/pathology , Protein Isoforms/blood , Tamoxifen/therapeutic useABSTRACT
BACKGROUND: Preclinical and clinical studies have reported that human epidermal growth factor receptor 2 (HER2) overexpression yields resistance to endocrine therapies. Here the prevalence and prognostic impact of HER2-positive circulating tumor cells (CTCs) were investigated retrospectively in metastatic breast cancer (MBC) patients with a HER2-negative primary tumor receiving endocrine therapy. Additionally, the prevalence and prognostic significance of HER2-positive CTCs were explored in a chemotherapy cohort, as well as the prognostic impact of the estrogen receptor (ER) CTC status in both cohorts. METHODS: Included were MBC patients with a HER2-negative primary tumor, with ≥1 detectable CTC, starting a new line of treatment. CTCs were enumerated using the CellSearch system, characterized for HER2 with the CellSearch anti-HER2 phenotyping reagent, and characterized for ER mRNA expression. Primary end point was progression-free rate after 6 months (PFR6months) of endocrine treatment in HER2-positive versus HER2-negative CTC patients. RESULTS: HER2-positive CTCs were present in 29% of all patients. In the endocrine cohort (n=72), the PFR6months was 53% for HER2-positive versus 68% for HER2-negative CTC patients (P=.23). In the chemotherapy cohort (n=82), no prognostic value of HER2-positive CTCs on PFR6months was observed either. Discordances in ER status between the primary tumor and CTCs occurred in 25% of all patients but had no prognostic value in exploratory survival analyses. CONCLUSION: Discordances regarding HER2 status and ER status between CTCs and the primary tumor occurred frequently but had no prognostic impact in our MBC patient cohorts.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Neoplastic Cells, Circulating/metabolism , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Prognosis , Treatment OutcomeABSTRACT
Oncogenic osteomalacia (or tumour-induced osteomalacia) is a rare paraneoplastic syndrome caused by overproduction of fibroblastic growth factor 23 (FGF-23) by tumours. Excessive production of FGF-23 can lead to severe, symptomatic hypophosphataemia. The majority of cases have been associated with benign tumours of bone or soft tissue, such as haemangiopericytomas or other neoplasms of mesenchymal origin. We present a case of a 68-year-old woman with an FGF-23 producing B cell non-Hodgkin's lymphoma. Treatment with immunochemotherapy resulted in normalisation of serum FGF-23 and phosphate levels.
Subject(s)
Fibroblast Growth Factors/blood , Hypophosphatemia/etiology , Lymphoma, B-Cell/complications , Neoplasms, Connective Tissue/etiology , Paraneoplastic Syndromes/blood , Aged , B-Lymphocytes , Female , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/biosynthesis , Humans , Hypophosphatemia/blood , Lymphoma, B-Cell/blood , Lymphoma, Non-Hodgkin , Neoplasms, Connective Tissue/blood , Osteomalacia/blood , Osteomalacia/etiologyABSTRACT
BACKGROUND: Molecular characterization of circulating tumor cells (CTC) is promising for personalized medicine. We aimed to identify a CTC gene expression profile predicting outcome to first-line aromatase inhibitors in metastatic breast cancer (MBC) patients. METHODS: CTCs were isolated from 78 MBC patients before treatment start. mRNA expression levels of 96 genes were measured by quantitative reverse transcriptase polymerase chain reaction. After applying predefined exclusion criteria based on lack of sufficient RNA quality and/or quantity, the data from 45 patients were used to construct a gene expression profile to predict poor responding patients, defined as disease progression or death <9 months, by a leave-one-out cross validation. RESULTS: Of the 45 patients, 19 were clinically classified as poor responders. To identify them, the 75% most variable genes were used to select genes differentially expressed between good and poor responders. An 8-gene CTC predictor was significantly associated with outcome (Hazard Ratio [HR] 4.40, 95% Confidence Interval [CI]: 2.17-8.92, P < 0.001). This predictor identified poor responding patients with a sensitivity of 63% and a positive predictive value of 75%, while good responding patients were correctly predicted in 85% of the cases. In multivariate Cox regression analysis, including CTC count at baseline, the 8-gene CTC predictor was the only factor independently associated with outcome (HR 4.59 [95% CI: 2.11-9.56], P < 0.001). This 8-gene signature was not associated with outcome in a group of 71 MBC patients treated with systemic treatments other than AI. CONCLUSIONS: An 8-gene CTC predictor was identified which discriminates good and poor outcome to first-line aromatase inhibitors in MBC patients. Although results need to be validated, this study underscores the potential of molecular characterization of CTCs.
Subject(s)
Aromatase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Gene Expression Profiling/methods , Neoplastic Cells, Circulating , Oligonucleotide Array Sequence Analysis/methods , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Humans , Neoplasm Metastasis , Prognosis , Risk AssessmentABSTRACT
BACKGROUND: The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. METHODS: In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study's primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637. FINDINGS: Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36-57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56-0·81, p<0·0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 [23%] patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups. INTERPRETATION: Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life. FUNDING: Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Capecitabine , Colorectal Neoplasms/pathology , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/analogs & derivatives , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Oxaliplatin , Treatment OutcomeABSTRACT
Before using circulating tumor cells (CTCs) as liquid biopsy, insight into molecular discrepancies between CTCs and primary tumors is essential. We characterized CellSearch-enriched CTCs from 62 metastatic breast cancer (MBC) patients with ≥5 CTCs starting first-line systemic treatment. Expression levels of 35 tumor-associated, CTC-specific genes, including ESR1, coding for the estrogen receptor (ER), were measured by reverse transcription quantitative polymerase chain reaction and correlated to corresponding primary tumors. In 30 patients (48%), gene expression profiles of 35 genes were discrepant between CTCs and the primary tumor, but this had no prognostic consequences. In 15 patients (24%), the expression of ER was discrepant. Patients with ER-negative primary tumors and ER-positive CTCs had a longer median TTS compared to those with concordantly ER-negative CTCs (8.5 versus 2.1 months, P = 0.05). From seven patients, an axillary lymph node metastasis was available. In two patients, the CTC profiles better resembled the lymph node metastasis than the primary tumor. Our findings suggest that molecular discordances between CTCs and primary tumors frequently occur, but that this bears no prognostic consequences. Alterations in ER-status between primary tumors and CTCs might have prognostic implications.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , Neoplastic Cells, Circulating/metabolism , Breast Neoplasms/blood , Female , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Receptors, Estrogen/genetics , Retrospective Studies , TranscriptomeABSTRACT
The aim of this study was to investigate whether neutrophil-guided dose escalation of anthracycline-cyclophosphamide-containing chemotherapy (ACC) for breast cancer is feasible, in order to optimize outcome. Breast cancer patients planned for 3-weekly ACC were enrolled in this study. The first treatment cycle was administered in a standard BSA-adjusted dose. The absolute neutrophil count was measured at baseline and at day 8, 11 and 15 after administration of ACC. For patients with none or mild (CTC grade 0-2) neutropenia and no other dose-limiting toxicity, we performed a 10-25 % dose escalation of the second cycle with the opportunity to a further 10-25 % dose escalation of the third cycle. Thirty patients were treated in the adjuvant setting with either FE100C (n = 23) or AC (n = 4), or in the palliative setting with FAC (n = 3). Two out of 23 patients (9 %) treated with FEC did not develop grade 3-4 neutropenia after the first treatment cycle. Dose escalation was performed in these two patients (30 % in one and 15 % in the other patient). During dose escalation, there were no complications like febrile neutropenia. No patients treated with FAC or AC could be escalated, since all of them developed grade 3-4 neutropenia. We conclude that asymptomatic grade 3-4 neutropenia is likely to be achieved in the majority of patients with breast cancer treated with ACC according to presently advocated BSA-based dose levels. Escalation of currently advocated ACC doses without G-CSF, with a target of grade 3-4 neutropenia, is feasible, but only possible in a small proportion of patients. EudraCT 2010-020309-33.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Neutrophils/pathology , Adult , Aged , Anthracyclines/administration & dosage , Cyclophosphamide/administration & dosage , Dose-Response Relationship, Drug , Epirubicin/administration & dosage , Feasibility Studies , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Staging , Prognosis , Prospective StudiesABSTRACT
AIM: Anthracycline-induced cardiotoxicity is (partly) mediated by free radical overload. A randomized study was performed in breast cancer patients to investigate whether free radical scavenger super oxide dismutase (SOD) protects against anthracycline-induced cardiotoxicity as measured by changes in echo, electrocardiography and an array of biomarkers. METHOD AND RESULTS: Eighty female, chemotherapy-naïve breast cancer patients (median age 49, range 24-67 years) scheduled for four or five courses of adjuvant 3 weekly doxorubicin plus cyclophosphamide (AC) chemotherapy, were randomly assigned to receive 80 mg PC-SOD (human recombinant SOD bound to lecithin) or placebo, administered intravenously (i.v.) immediately prior to each AC course. The primary end point was protection against cardiac damage evaluated using echocardiography, QT assessments and a set of biochemical markers for myocardial function, oxidative stress and inflammation. Assessments were performed before and during each course of chemotherapy, and at 1, 4 and 9 months after completion of the chemotherapy regimen. In all patients cardiac effects such as increases in NT-proBNP concentration and prolongation of the QTc interval were noticed. There were no differences between the PC-SOD and placebo-treated patients in systolic or diastolic cardiac function or for any other of the biomarkers used to assess the cardiac effects of anthracyclines. CONCLUSION: PC-SOD at a dose of 80 mg i.v. is not cardioprotective in patients with breast carcinoma treated with anthracyclines.
Subject(s)
Anthracyclines/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Cardiotonic Agents/therapeutic use , Free Radical Scavengers/therapeutic use , Phosphatidylcholines/therapeutic use , Superoxide Dismutase/therapeutic use , Adult , Aged , Anthracyclines/administration & dosage , Anthracyclines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers/blood , Breast Neoplasms/pathology , Cardiotonic Agents/administration & dosage , Cardiotonic Agents/chemistry , Cardiotoxicity/diagnosis , Cardiotoxicity/prevention & control , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Cyclophosphamide/therapeutic use , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Doxorubicin/therapeutic use , Drug Administration Schedule , Echocardiography , Electrocardiography , Female , Free Radical Scavengers/administration & dosage , Free Radical Scavengers/chemistry , Humans , Injections, Intravenous , Middle Aged , Natriuretic Peptide, Brain/blood , Netherlands , Peptide Fragments/blood , Phosphatidylcholines/administration & dosage , Phosphatidylcholines/chemistry , Superoxide Dismutase/administration & dosage , Superoxide Dismutase/chemistry , Young AdultABSTRACT
BACKGROUND: Continuation of trastuzumab plus capecitabine (XH) showed a significantly improved overall response rate and time to progression compared with capecitabine (X) alone in women with HER2-positive breast cancer progressing during trastuzumab treatment. Here, we report the final analysis on overall survival. PATIENTS AND METHODS: Patients with HER2-positive, advanced breast cancer who progressed during treatment with trastuzumab with or without 1st-line metastatic chemotherapy were prospectively randomised to X (2500mg/m(2) on days 1-14, q3w) or XH (6 (8)mg/kg, q3w). Overall survival was a pre-specified secondary end-point. RESULTS: Median follow-up at June 2010 was 20.7months. Fifty nine of 74 and 60 of 77 patients died in the X and XH arm, respectively. Median overall survival was 20.6 and 24.9months with X and XH, respectively (HR=0.94 [0.65-1.35]; p=0.73). Performance status and metastatic site were independent prognosticators for overall survival. No difference between treatment arms was observed for patients who achieved clinical response or clinical benefit, respectively. Patients who continued/restarted anti-HER2 treatment (trastuzumab or lapatinib) after 2nd progression (N=52) had a post-progression survival of 18.8 compared with 13.3months for those who did not receive 3rd line treatment with anti-HER2 agents (N=88) (HR 0.63; p=0.02). CONCLUSIONS: Final overall survival analysis of the GBG-26 study did not demonstrate a significant survival benefit for treatment beyond progression with trastuzumab. However, in a post-hoc analysis, patients receiving anti-HER2 treatment as 3rd line therapy showed a better post-progression survival than those not receiving this targeted treatment.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Receptor, ErbB-2/antagonists & inhibitors , Antibodies, Monoclonal, Humanized/administration & dosage , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Capecitabine , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Europe , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Humans , Kaplan-Meier Estimate , Molecular Targeted Therapy , Proportional Hazards Models , Prospective Studies , Receptor, ErbB-2/metabolism , Risk Assessment , Risk Factors , Survival Rate , Time Factors , Trastuzumab , Treatment OutcomeABSTRACT
PURPOSE: Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. METHODS: In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. RESULTS: A strong and highly significant correlation (r = -0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. CONCLUSION: Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacokinetics , Breast Neoplasms/drug therapy , Cytochrome P-450 CYP2D6/genetics , Dextromethorphan , Tamoxifen/analogs & derivatives , Tamoxifen/pharmacokinetics , Adult , Aged , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Dextromethorphan/pharmacokinetics , Female , Genotype , Humans , Middle Aged , Polymorphism, Genetic , Prospective Studies , Tamoxifen/administration & dosage , Tamoxifen/adverse effects , Tamoxifen/metabolismABSTRACT
PURPOSE: Molecular characterization of circulating tumor cells (CTC) holds great promise. Unfortunately, routinely isolated CTC fractions currently still contain contaminating leukocytes, which makes CTC-specific molecular characterization extremely challenging. In this study, we determined mRNA and microRNA (miRNA) expression of potentially CTC-specific genes that are considered to be clinically relevant in breast cancer. EXPERIMENTAL DESIGN: CTCs were isolated with the epithelial cell adhesion molecule-based CellSearch Profile Kit. Selected genes were measured by real-time reverse transcriptase PCR in CTCs of 50 metastatic breast cancer patients collected before starting first-line systemic therapy in blood from 53 healthy blood donors (HBD) and in primary tumors of 8 of the patients. The molecular profiles were associated with CTC counts and clinical parameters and compared with the profiles generated from the corresponding primary tumors. RESULTS: We identified 55 mRNAs and 10 miRNAs more abundantly expressed in samples from 32 patients with at least 5 CTCs in 7.5 mL of blood compared with samples from 9 patients without detectable CTCs and HBDs. Clustering analysis resulted in 4 different patient clusters characterized by 5 distinct gene clusters. Twice the number of patients from cluster 2 to 4 had developed both visceral and nonvisceral metastases. Comparing transcript levels in CTCs with those measured in corresponding primary tumors showed clinically relevant discrepancies in estrogen receptor and HER2 levels. CONCLUSIONS: Our study shows that molecular profiling of low numbers of CTCs in a high background of leukocytes is feasible and shows promise for further studies on the clinical relevance of molecular characterization of CTCs.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , MicroRNAs/genetics , Neoplastic Cells, Circulating/pathology , RNA, Messenger/genetics , Biomarkers, Tumor/genetics , Cell Adhesion Molecules/genetics , Epithelial Cells/metabolism , Female , Gene Expression Profiling , Humans , Leukocytes , MicroRNAs/analysis , MicroRNAs/biosynthesis , Neoplasm Metastasis , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
PURPOSE: Statins have for long been considered to play a potential role in anticancer treatment based upon their ability to inhibit the mevalonate synthesis pathway. This randomised phase II trial compared the efficacy and safety of pravastatin added to epirubicin, cisplatin and capecitabine (ECC versus ECC+P) in patients with advanced gastric carcinoma. METHODS: Patients were randomised to receive up to six cycles of 3-weekly ECC with or without pravastatin (40 mg, once daily from day 1 of the first cycle until day 21 of the last cycle). Primary end-point was progression-free rate at 6 months (PFR(6 months)). Secondary end-points were response rate (RR), progression-free survival (PFS), overall survival (OS) and safety. For early termination in case of futility, a two-stage design was applied (P(0) = 50%; P(1) = 70%; α = 0.05; ß = 0.10). RESULTS: Thirty patients were enrolled. PFR(6 months) was 6/14 patients (42.8%) in the ECC+P arm, and 7/15 patients (46.7%) in the control arm, and therefore the study was terminated after the first stage. In the ECC and ECC+P arm, RR was 7/15 (46.7%) and 5/15 (33.3%), median PFS was 5 and 6 months and median OS was 6 and 8 months, respectively. Toxicity data showed no significant differences, although there was a trend towards more gastrointestinal side-effects such as diarrhoea and stomatitis in the ECC+P arm. CONCLUSION: In this randomised phase II trial the addition of pravastatin to ECC did not improve outcome in patients with advanced gastric cancer. Therefore, further testing of this combination in a randomised phase III trial cannot be recommended.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Adult , Aged , Capecitabine , Cisplatin/administration & dosage , Cisplatin/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Epirubicin/administration & dosage , Epirubicin/adverse effects , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/analogs & derivatives , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Pravastatin/administration & dosage , Pravastatin/adverse effectsABSTRACT
OBJECTIVE: To determine if the rational application of dose individualization of anticancer drugs leads to a reduction in costs. DESIGN: Data analysis. METHOD: At the Ikazia Hospital in Rotterdam, the Netherlands, over the first 19 weeks of 2006 the costs of the intravenous administration to patients of one or more anticancer drugs were determined. The costs of dosage based on body surface area (BSA) were calculated. Commercially available ampoule strengths were not taken into consideration. Using available pharmacokinetic data, it is reasonable to assume that a deviation of up to 10% based on an individualized dose calculated by body surface area, has a negligible effect on the outcome of treatment. For this reason drug costs by rounding off doses to whole ampoules were also investigated. A condition of this was that the rounded-off dose should not deviate by more than 10% from the dose calculated on body surface area. RESULTS: During the study period, 18 different anticancer drugs were administered a total of 939 times. If dosage had been based strictly on body surface area, drug costs would have been euro 509,664. Rounding off to whole ampoules with a dose margin of a maximum of 10% would have cost euro 465,619: a reduction in cost of 8.6%. CONCLUSION: The rational application of the dose individualization principle based on body surface area may result in a substantial reduction in expenditure on anticancer drugs.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/economics , Cancer Care Facilities/economics , Drug Costs , Patient Care/economics , Antineoplastic Agents/therapeutic use , Body Surface Area , Cost-Benefit Analysis , Costs and Cost Analysis , Dose-Response Relationship, Drug , Humans , Treatment OutcomeABSTRACT
PURPOSE: Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. METHODS: Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m(2) semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression. RESULTS: We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity. CONCLUSION: Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment.