IGF-1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER-positive breast cancer.

Preclinical studies indicate that activated IGF-1R can drive endocrine resistance in ER-positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of IGF-1R signaling on tamoxifen benefit in patients and we searched for approaches to overcome IGF-1R-mediated tamoxifen failure in cell lines. Primary tumor blocks from postmenopausal ER+ breast cancer patients randomized between adjuvant tamoxifen versus nil were recollected. Immunohistochemistry for IGF-1R, p-IGF-1R/InsR, p-ERα(Ser118), p-ERα(Ser167) and PI3K/MAPK pathway proteins was performed. Multivariate Cox models were employed to assess tamoxifen efficacy. The association between p-IGF-1R/InsR and PI3K/MAPK pathway activation in MCF-7 and T47D cells was analyzed with Western blots. Cell proliferation experiments were performed under various growth-stimulating and -inhibiting conditions. Patients with ER+, IGF-1R-positive breast cancer without p-IGF-1R/InsR staining (n = 242) had tamoxifen benefit (HR 0.41, p = 0.0038), while the results for p-IGF-1R/InsR-positive patients (n = 125) were not significant (HR 0.95, p = 0.3). High p-ERα(Ser118) or p-ERα(Ser167) expression was associated with less tamoxifen benefit. In MCF-7 cells, IGF-1R stimulation increased phosphorylation of PI3K/MAPK proteins and ERα(Ser167) regardless of IGF-1R overexpression. This could be abrogated by the dual IGF-1R/InsR inhibitor linsitinib, but not by the IGF-IR-selective antibody 1H7. In MCF-7 and T47D cells, stimulation of the IGF-1R/InsR pathway resulted in cell proliferation regardless of tamoxifen. Abrogation of cell growth was regained by addition of linsitinib. In conclusion, p-IGF-1R/InsR positivity in ER+ breast cancer is associated with reduced benefit from adjuvant tamoxifen in postmenopausal patients. In cell lines, stimulation rather than overexpression of IGF-1R is driving tamoxifen resistance to be abrogated by linsitinib.

Hierarchical clustering of activated proteins in the PI3K and MAPK pathways in ER-positive, HER2-negative breast cancer with potential therapeutic consequences.

BACKGROUND: The phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways are frequently activated in breast cancer which can result in antioestrogen resistance. Single protein markers failed to be introduced into clinical practice. We, therefore, aimed to find a better read-out of activation of the PI3K and MAPK pathways in ER+/HER2- breast cancer. Assessment of seven PI3K/MAPK proteins might better reflect pathway activation and distinguish patients without adjuvant tamoxifen benefit. METHODS: Tumour blocks were recollected from 293 primary postmenopausal ER+/HER2- breast cancer patients randomised between tamoxifen and no adjuvant therapy. PTEN, p-AKT(Thr308), p-AKT(Ser473), p-p70S6K, p-4EBP1, p-ERK1/2 and p-S6RP expression was assessed by immunohistochemistry followed by unsupervised hierarchical clustering. The primary endpoint was recurrence-free interval. Multivariate Cox models were used to assess tamoxifen benefit. A classification tool was developed based on protein expression profile. RESULTS: Subgroups were identified with preferentially activated (A) and preferentially not activated (N) proteins. Patients in group N derived significant benefit from tamoxifen (multivariate hazard ratio (HR) = 0.23, p = 0.000101), while patients from group A did not (multivariate HR = 1.37, p = 0.64), p for interaction 0.020. Our generated classification tool confirmed these results (p for interaction 0.024). CONCLUSIONS: Hierarchical clustering of seven PI3K/MAPK proteins reflects pathway activation and can guide treatment decisions in primary ER+/HER2- postmenopausal breast cancer patients.

Single-nucleotide polymorphisms in the genes of CES2, CDA and enzymatic activity of CDA for prediction of the efficacy of capecitabine-containing chemotherapy in patients with metastatic breast cancer.

We examined whether genetic polymorphisms (SNPs) in the capecitabine activation pathway and CDA enzymatic activity were associated with prognosis, benefit from capecitabine-containing treatment or capecitabine-related toxicities. The study population comprised 188 metastatic breast cancer patients of the ATX trial (EudraCT 2006-006058-83) randomized for first-line paclitaxel and bevacizumab with (ATX) or without capecitabine (AT). Cumulative capecitabine dose until grade ≥2 hand-foot syndrome or until first dose reduction were toxicity endpoints. We genotyped CDA c.-451C>T (rs532545), CDA c.-33delC (rs3215400) and CES2 c.-806C>G (rs11075646). CDA activity in baseline serum was measured with a spectrophotometric assay and values were analyzed using a median cut-off or as continuous variable. CDA c.-33delC was prognostic for overall survival (OS) independent of hormone receptor status. For the predictive analysis, progression-free survival benefit from ATX over AT was observed in patients with a CDA c.-33del/del or del/insC genotype, a CDA c.-451CC or CT genotype, and a CES2 c.-806CC genotype compared with their counterparts. There was a higher response rate for ATX over AT in patients with a CDA c.-451CT or TT genotype. Patients with high CDA enzymatic activity had more benefit from capecitabine, while this was marginally observed in the CDA low group. Toxicity endpoints were not associated with any candidate markers. In conclusion, CDA c.-33delC was associated with OS. Since particular SNPs in CDA and CES2 were associated with benefit from the addition of capecitabine to AT, their predictive value should be explored in a higher number of patients.

Evaluation of KDR rs34231037 as a predictor of sunitinib efficacy in patients with metastatic renal cell carcinoma.

The identification of biomarkers able to predict clinical benefit from vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors is urgently needed. Recently, Maitland and colleagues described an association between KDR-rs34231037 and soluble VEGFR2 levels as well as pazopanib pharmacodynamics. We investigated in a well-characterized series of metastatic clear cell renal cell carcinoma patients whether rs34231037 could influence sunitinib response. Clinical data and DNA were available from an international series of 276 patients. KDR-rs34231037 association with sunitinib response, clinical benefit, and progression-free survival was analyzed using logistic and Cox regression analyses. We found that G-allele carriers were over-represented among patients with clinical benefit during sunitinib treatment compared with those refractory to the treatment (odds ratio: 3.78; 95% confidence interval: 1.02-14.06; P=0.047, multivariable analysis). In conclusion, rs34231037 variant carriers seemed to have better sunitinib response than wild-type patients. Moreover, the association with tumor size reduction suggests that this single nucleotide polymorphism might also identify patients with successful tumor downsizing under anti-VEGFR therapy.

Genotypes of CYP2C8 and FGD4 and their association with peripheral neuropathy or early dose reduction in paclitaxel-treated breast cancer patients.

BACKGROUND: The purpose of this study was to evaluate single-nucleotide polymorphisms (SNPs) in genes encoding key metabolising enzymes or involved in pharmacodynamics for possible associations with paclitaxel-induced peripheral neuropathy. METHODS: The study population consists of 188 women from the multicenter, randomised, phase II ATX trial (BOOG2006-06; EudraCT number 2006-006058-83) that received paclitaxel and bevacizumab without or with capecitabine as first-line palliative therapy of HER2-negative metastatic breast cancer. Genotyping of CYP2C8*3 (c.416G>A), CYP3A4*22 (c.522-191C>T), TUBB2A (c.-101T>C), FGD4 (c.2044-236G>A) and EPHA5 (c.2895G>A) was performed by real-time PCR. Toxicity endpoints were cumulative dose (1) until first onset of grade ⩾1 peripheral neuropathy and (2) until first paclitaxel dose reduction from related toxicity (NCI-CTCAE version 3.0). SNPs were evaluated using the Kaplan-Meier method, the Gehan-Breslow-Wilcoxon test and the multivariate Cox regression analysis. RESULTS: The rate of grade ⩾1 peripheral neuropathy was 67% (n=126). The rate of dose reduction was 46% (n=87). Age ⩾65 years was a risk factor for peripheral neuropathy (HR=1.87, P<0.008), but not for dose reduction. When adjusted for age, body surface area and total cumulative paclitaxel dose, CYP2C8*3 carriers had an increased risk of peripheral neuropathy (HR=1.59, P=0.045). FGD4 c.2044-236 A-allele carriers had an increased risk of paclitaxel dose reduction (HR per A-allele=1.38, P=0.036) when adjusted for total cumulative paclitaxel dose. CONCLUSIONS: These findings may point towards clinically useful indicators of early toxicity, but warrant further investigation.

A functional bioassay to determine the activity of anti-VEGF antibody therapy in blood of patients with cancer.

BACKGROUND: Only a small proportion of patients respond to anti-VEGF therapy, pressing the need for a reliable biomarker that can identify patients who will benefit. We studied the biological activity of anti-VEGF antibodies in patients' blood during anti-VEGF therapy by using the Ba/F3-VEGFR2 cell line, which is dependent on VEGF for its growth. METHODS: Serum samples from 22 patients with cancer before and during treatment with bevacizumab were tested for their effect on proliferation of Ba/F3-VEGFR2 cells. Vascular endothelial growth factor as well as bevacizumab concentrations in serum samples from these patients were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: The hVEGF-driven cell proliferation was effectively blocked by bevacizumab (IC50 3.7 µg ml-1; 95% CI 1.7-8.3 µg ml-1). Cell proliferation was significantly reduced when patients' serum during treatment with bevacizumab was added (22-103% inhibition compared with pre-treatment). Although bevacizumab levels were not related, on-treatment serum VEGF levels were correlated with Ba/F3-VEGFR2 cell proliferation. CONCLUSIONS: We found that the neutralising effect of anti-VEGF antibody therapy on the biological activity of circulating VEGF can be accurately determined with a Ba/F3-VEGFR2 bioassay. The value of this bioassay to predict clinical benefit of anti-VEGF antibody therapy needs further clinical evaluation in a larger randomised cohort.

Association of single nucleotide polymorphisms in IL8 and IL13 with sunitinib-induced toxicity in patients with metastatic renal cell carcinoma.

PURPOSE: Earlier, the association of single nucleotide polymorphisms (SNPs) with toxicity and efficacy of sunitinib has been explored in patients with metastatic renal cell carcinoma (mRCC). Recently, additional SNPs have been suggested as potential biomarkers. We investigated these novel SNPs for association with sunitinib treatment outcome in mRCC patients. METHODS: In this exploratory study, we selected SNPs in genes CYP3A4, NR1I2, POR, IL8, IL13, IL4-R, HIF1A and MET that might possibly be associated with sunitinib treatment outcome. Each SNP was tested for association with progression-free survival (PFS) and overall survival (OS) by Cox-regression analysis and for clinical response and toxicity using logistic regression. RESULTS: We included 374 patients for toxicity analyses, of which 38 patients with non-clear cell renal cell cancer were excluded from efficacy analyses. The risk for hypertension was increased in the presence of the T allele in IL8 rs1126647 (OR = 1.69, 95 % CI = 1.07-2.67, P = 0.024). The T allele in IL13 rs1800925 was associated with an increase in the risk of leukopenia (OR = 6.76, 95 % CI = 1.35-33.9, P = 0.020) and increased prevalence of any toxicity > grade 2 (OR = 1.75, 95 % CI = 1.06-2.88, P = 0.028). No significant associations were found with PFS, OS or clinical response. CONCLUSIONS: We show that polymorphisms in IL8 rs1126647 and IL13 rs1800925 are associated with sunitinib-induced toxicities. Validation in an independent cohort is required.

Proteomics of genetically engineered mouse mammary tumors identifies fatty acid metabolism members as potential predictive markers for cisplatin resistance.

In contrast to various signatures that predict the prognosis of breast cancer patients, markers that predict chemotherapy response are still elusive. To detect such predictive biomarkers, we investigated early changes in protein expression using two mouse models for distinct breast cancer subtypes who have a differential knock-out status for the breast cancer 1, early onset (Brca1) gene. The proteome of cisplatin-sensitive BRCA1-deficient mammary tumors was compared with that of cisplatin-resistant mammary tumors resembling pleomorphic invasive lobular carcinoma. The analyses were performed 24 h after administration of the maximum tolerable dose of cisplatin. At this time point, drug-sensitive BRCA1-deficient tumors showed DNA damage, but cells were largely viable. By applying paired statistics and quantitative filtering, we identified highly discriminatory markers for the sensitive and resistant model. Proteins up-regulated in the sensitive model are involved in centrosome organization, chromosome condensation, homology-directed DNA repair, and nucleotide metabolism. Major discriminatory markers that were up-regulated in the resistant model were predominantly involved in fatty acid metabolism, such as fatty-acid synthase. Specific inhibition of fatty-acid synthase sensitized resistant cells to cisplatin. Our data suggest that exploring the functional link between the DNA damage response and cancer metabolism shortly after the initial treatment may be a useful strategy to predict the efficacy of cisplatin.

Adherence and patients' experiences with the use of oral anticancer agents.

A rapidly growing number of oral anticancer agents has become available in oncology and hematology. Though these introductions have several benefits, medication adherence is an issue of concern. Little is known about the factors influencing adherence to treatment with oral anticancer agents in daily practice. Material and methods. In this observational, multicenter study including 216 patients, carried out between October 2010 and March 2012, the use of oral anticancer drugs was assessed by means of a telephonic pill count, a questionnaire and a review of the patient's medical file and pharmacy medication records. Parameters collected were patients' demographics, treatment characteristics, beliefs and attitude towards disease and medicines, self-reported adherence, side effects, quality of life and satisfaction about information. Patients off treatment filled out a questionnaire about the reasons for discontinuation. Optimal adherence was defined as ≥ 95%-≤ 105%. Results. The mean adherence rate (AR) (n = 177) was 99.1% with 20.3% of patients having a sub-optimal AR (< 95%, > 105%) consisting both of under- and over-adherence. Multivariate analyses showed that being on a cyclic dosing regimen (rather than a continuous regimen), not living alone and being highly educated increased the chances of optimal adherence (ORs = 4.88, 4.59 and 2.53, respectively). In addition, optimal adherence was found to be less common in patients reporting treatment control (OR = 0.77). One third of 79 patients off treatment reported their experienced side effects as one of the reasons for discontinuation. Discussion. Although most patients are fully adherent to oral anticancer agents, there is a substantial number tending to non-adherence. Patients living alone and those on a continuous dosing regimen are most likely to adhere sub-optimally. Interventions to improve adherence should specifically address these patients and be tailored to the needs of the individual patient.

Proteomics of mouse BRCA1-deficient mammary tumors identifies DNA repair proteins with potential diagnostic and prognostic value in human breast cancer.

Breast cancer 1, early onset (BRCA1) hereditary breast cancer, a type of cancer with defects in the homology-directed DNA repair pathway, would benefit from the identification of proteins for diagnosis, which might also be of potential use as screening, prognostic, or predictive markers. Sporadic breast cancers with defects in the BRCA1 pathway might also be diagnosed. We employed proteomics based on one-dimensional gel electrophoresis in combination with nano-LC-MS/MS and spectral counting to compare the protein profiles of mammary tumor tissues of genetic mouse models either deficient or proficient in BRCA1. We identified a total of 3,545 proteins, of which 801 were significantly differentially regulated between the BRCA1-deficient and -proficient breast tumors. Pathway and protein complex analysis identified DNA repair and related functions as the major processes associated with the up-regulated proteins in the BRCA1-deficient tumors. In addition, by selecting highly connected nodes, we identified a BRCA1 deficiency signature of 45 proteins that enriches for homology-directed DNA repair deficiency in human gene expression breast cancer data sets. This signature also exhibits prognostic power across multiple data sets, with optimal performance in a data set enriched in tumors deficient in homology-directed DNA repair. In conclusion, by comparing mouse proteomes from BRCA1-proficient and -deficient mammary tumors, we were able to identify several markers associated with BRCA1 deficiency and a prognostic signature for human breast cancer deficient in homology-directed DNA repair.

Pertuzumab Plus Trastuzumab With or Without Chemotherapy Followed by Emtansine in ERBB2-Positive Metastatic Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: In ERBB2 (formerly HER2)-positive metastatic breast cancer (MBC), combining trastuzumab and pertuzumab with taxane-based chemotherapy is the first line of standard care. Given that trastuzumab plus pertuzumab was proven effective in ERBB2-positive MBC, even without chemotherapy, whether the optimal first-line strategy could be trastuzumab plus pertuzumab alone instead of with chemotherapy is unresolved. Objective: To assess overall survival (OS) at 2 years and progression-free survival (PFS) for patients randomly assigned to receive first-line pertuzumab plus trastuzumab alone or with chemotherapy followed by trastuzumab and emtansine at progression; PFS of second-line trastuzumab and emtansine treatment following trastuzumab plus pertuzumab; and OS and PFS in the ERBB2-enriched and ERBB2-nonenriched subtypes. Design, Setting, and Participants: This was a secondary analysis of a multicenter, open-label, phase 2 randomized clinical trial conducted at 27 sites in France, 20 sites in Switzerland, 9 sites in the Netherlands, and 1 site in Germany. Overall, 210 patients with centrally confirmed ERBB2-positive MBC were randomized between May 3, 2013, and January 4, 2016, with termination of the trial May 26, 2020. Data were analyzed from December 18, 2020, to May 10, 2022. Interventions: Patients randomly received pertuzumab (840 mg intravenously [IV], then 420 mg IV every 3 weeks) plus trastuzumab (8 mg/kg IV, then 6 mg/kg IV every 3 weeks) without chemotherapy (group A) or pertuzumab plus trastuzumab (same doses) with either paclitaxel (90 mg/m2 for days 1, 8, and 15, then every 4 weeks for ≥4 months) or vinorelbine tartrate (25 mg/m2 for first administration followed by 30 mg/m2 on days 1 and 8 and every 3 weeks for ≥4 months) followed by pertuzumab plus trastuzumab maintenance after chemotherapy discontinuation (group B). Main Outcomes and Measures: Overall survival at 24 months by treatment group, PFS for first-line treatment, PFS for second-line treatment, and patient-reported quality of life (QOL). Results: A total of 210 patients were included in the analysis, with a median age of 58 (range, 26-85) years. For group A, 24-month OS was 79.0% (90% CI, 71.4%-85.4%); for group B, 78.1% (90% CI, 70.4%-84.5%). Median PFS with first-line treatment was 8.4 (95% CI, 7.9-12.0) months in group A and 23.3 (95% CI, 18.9-33.1) months in group B. Unlike expectations, OS and PFS did not markedly differ between populations with ERBB2-enriched and ERBB2-nonenriched cancer. Adverse events were less common without chemotherapy, with small QOL improvements from baseline in group A and stable QOL in group B. Conclusions and Relevance: The findings of this secondary analysis of a randomized clinical trial suggest that the chemotherapy-free anti-ERBB2 strategy is feasible without being detrimental in terms of OS. The 50-gene prediction analysis of microarray signature could not help to identify the most appropriate patient population for this approach. Trial Registration: ClinicalTrials.gov Identifier: NCT01835236.

MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer.

Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K-AKT-mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies.

Sunitinib-induced changes in circulating endothelial cell-related proteins in patients with metastatic renal cell cancer.

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are effective agents in the treatment of metastatic renal cell cancer (mRCC). We here investigated whether inhibition of VEGFR signalin by sunitinib causes changes in plasma proteins associated with tumor endothelium. Forty-three patients with mRCC received sunitinib 50 mg/day in a 4-weeks on 2-weeks off schedule. Sequential plasma samples were obtained before treatment (C1D1), on C1D14, on C1D28, and on C2D1 before start of cycle 2. Plasma levels were assessed for VEGF, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), von Willebrand factor (vWF), circulating angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2). Total tumor burden was calculated at baseline and at first evaluation. Progression-free survival (PFS) and overall survival (OS) were determined. Tumor burden was positively associated with baseline circulating Ang-2 [Spearman's rho (ρ) = 0.378, p = 0.028] and vWF (ρ = 0.417, p = 0.008). During sunitinib treatment, circulating Ang-2 and sTie-2 significantly decreased (p < 0.001 for both), plasma levels of sVCAM-1 and VEGF significantly increased (p = 0.022 and p < 0.001), whereas those of sICAM-1 and vWF remained stable. These protein changes had recovered on C2D1. The reduction in circulating Ang-2 levels on C1D28 was positively correlated with the percentage decrease in tumor burden (ρ = 0.605; p = 0.002). Baseline protein levels and subsequent changes were not associated with PFS or OS. In conclusion, sunitinib-induced changes in Ang-2, sTie-2, sVCAM-1 and VEGF are related to the administration schedule, while reduction in Ang-2 is also associated with decrease in tumor burden.

Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging.

The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high-dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diffusion tensor imaging (DTI) with tract-based spatial statistics showed that chemotherapy was associated with focal changes in DTI values indicative for reduced white matter integrity. Single voxel proton MR spectroscopy (1H-MRS) in the left centrum semiovale (white matter) showed a reduction of N-acetylasparate/creatine indicative of axonal injury. Voxel-based morphometry demonstrated a reduction of gray matter volume that overlapped with fMRI hypoactivation (as reported in a previous publication) in posterior parietal areas and colocalized with DTI abnormalities. Also, DTI correlated with 1H-MRS only in the chemotherapy group. These results converge to suggest that high-dose adjuvant chemotherapy for breast cancer is associated with long-term injury to white matter, presumably reflecting a combination of axonal degeneration and demyelination, and damage to gray matter with associated functional deficits. Hormonal treatment with tamoxifen may also have contributed to the observed effects, although results from other studies indicate that it is unlikely that tamoxifen is solely or largely responsible. Using this multimodality approach we provide for the first time insight into the neural substrate underlying cognitive impairments following systemic administration of cytotoxic agents many years after treatment.

Use and costs of oral anticancer agents in the Netherlands in the period 2000-2008.

PURPOSE: In recent years, the number of oral anticancer agents has increased substantially. Although these agents have quickly been incorporated in the treatment of a variety of malignancies, data on their incidence, prevalence and costs are lacking. The objective of the present study was to obtain insight into the use and the costs of oral anticancer agents (with Anatomical Therapeutic Chemical classification system (World Health Organisation) code L01) in the Netherlands between 2000 and 2008. METHODS: Incidence and prevalence were determined using community pharmacy dispensing records obtained from the PHARMO Record Linkage System database. The data of costs were provided by the Genees- en hulpmiddelen Informatie Project of the Dutch Health Care Insurance Board (CVZ, Diemen, The Netherlands). RESULTS: In the years 2000-2008, the use of oral anticancer agents has more than doubled from 64 to 140 users per 100 000 inhabitants. The increase is mainly caused by the prescription of capecitabine for various indications. There was a 50-fold rise in costs on oral anticancer agents from €2 m in 2000 to approximately €100 m in 2008. The share in the costs of tyrosine kinase inhibitors (TKIs) in 2008 was 67% (€70 m) with the oldest TKI, imatinib, having a share of more than 50% within the group of TKIs. CONCLUSIONS: The increased use of oral anticancer agents is mainly due to the frequent prescription of capecitabine. The increased costs are caused by the registration of a variety of TKIs, in particular imatinib. The costs of new agents with an orphan drug status are very high as compared with those of capecitabine, a newer agent for which there are alternative treatment options.

SUBMIT: Systemic therapy with or without up front surgery of the primary tumor in breast cancer patients with distant metastases at initial presentation.

BACKGROUND: Five percent of all patients with breast cancer have distant metastatic disease at initial presentation. Because metastatic breast cancer is considered to be an incurable disease, it is generally treated with a palliative intent. Recent non-randomized studies have demonstrated that (complete) resection of the primary tumor is associated with a significant improvement of the survival of patients with primary metastatic breast cancer. However, other studies have suggested that the claimed survival benefit by surgery may be caused by selection bias. Therefore, a randomized controlled trial will be performed to assess whether breast surgery in patients with primary distant metastatic breast cancer will improve the prognosis. DESIGN: Randomization will take place after the diagnosis of primary distant metastatic breast cancer. Patients will either be randomized to up front surgery of the breast tumor followed by systemic therapy or to systemic therapy, followed by delayed local treatment of the breast tumor if clinically indicated.Patients with primary distant metastatic breast cancer, with no prior treatment of the breast cancer, who are 18 years or older and fit enough to undergo surgery and systemic therapy are eligible. Important exclusion criteria are: prior invasive breast cancer, surgical treatment or radiotherapy of this breast tumor before randomization, irresectable T4 tumor and synchronous bilateral breast cancer. The primary endpoint is 2-year survival. Quality of life and local tumor control are among the secondary endpoints.Based on the results of prior research it was calculated that 258 patients are needed in each treatment arm, assuming a power of 80%. Total accrual time is expected to take 60 months. An interim analysis will be performed to assess any clinically significant safety concerns and to determine whether there is evidence that up front surgery is clinically or statistically inferior to systemic therapy with respect to the primary endpoint. DISCUSSION: The SUBMIT study is a randomized controlled trial that will provide evidence on whether or not surgery of the primary tumor in breast cancer patients with metastatic disease at initial presentation results in an improved survival. TRIAL REGISTRATION: NCT01392586.

Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib.

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer.

Chemotherapy is associated with cognitive impairment in a subgroup of breast cancer survivors, but the neural circuitry underlying this side effect is largely unknown. Moreover, long-term impairment has not been studied well. In the present study, functional magnetic resonance imaging (fMRI) and neuropsychological testing were performed in breast cancer survivors almost 10 years after high-dose adjuvant chemotherapy (chemo group, n = 19) and in breast cancer survivors for whom chemotherapy had not been indicated (control group, n = 15). BOLD activation and performance were measured during an executive function task involving planning abilities (Tower of London) and a paired associates task for assessment of episodic memory. For the chemo group versus the control group, we found hyporesponsiveness of dorsolateral prefrontal cortex in the Tower of London, and of parahippocampal gyrus in the paired associates task. Also, the chemo group showed significantly impaired planning performance and borderline significantly impaired recognition memory as compared to findings in the control group. Whole-brain analyses demonstrated hyporesponsiveness of the chemo versus the control group in very similar regions of bilateral posterior parietal cortex during both the Tower of London and the paired associates task. Neuropsychological testing showed a relatively stable pattern of cognitive impairment in the chemo group over time. These results indicate that high-dose adjuvant chemotherapy is associated with long-term cognitive impairments. These impairments are underpinned by (a) task-specific hyporesponsiveness of dorsolateral prefrontal cortex and parahippocampal gyrus, and (b) a generalized hyporesponsiveness of lateral posterior parietal cortex encompassing attentional processing.

The use of erlotinib in daily practice: a study on adherence and patients' experiences.

BACKGROUND: Adherence to pharmacological therapy is a complex and multi-factorial issue that can substantially alter the outcome of treatment. It has been shown that cancer patients, especially when using long-term medication, have similar adherence rates to those of patients with other diseases. The consequences of poor adherence are poor health outcomes and increased health care costs. Only few studies have focused on the use of oral anticancer agents in daily practice. Information about the reasons for non-adherence is essential for the development of interventions that may increase adherence. This paper presents the CAPER-erlotinib protocol, which is designed to study the relationship between adherence to erlotinib and both the plasma concentration and side-effects in patients with NSCLC. Further, the relationships between patient characteristics, disease characteristics, side-effects, quality of life, patient beliefs and attitude towards disease and medication, dose adjustments, reasons for discontinuation and plasma concentration of erlotinib will be explored. METHODS/DESIGN: In this prospective observational cohort study 65 NSCLC patients of 18 years or older starting treatment with erlotinib will be followed for a period up to 16 weeks. The main study parameters are adherence, the plasma concentration of erlotinib and the number and grade of side-effects. At baseline and on erlotinib treatment in weeks 3-4, 8-9, 12 and 15-16, patients will be asked to fill out a questionnaire. In weeks 3-4, 8-9 and 15-16 blood samples are collected, which will be analysed for plasma concentration of erlotinib. Adherence will be measured using a medication event monitoring system. DISCUSSION: The present study aims to get more insight into patients' experiences with the use of erlotinib in daily practice and the various aspects that govern adherence. We hypothesize that side-effects play an important role in the way patients use erlotinib. We expect that the present study will provide valuable knowledge which will be useful for health care professionals to develop interventions to support patients. This approach will improve the adherence and persistence with the use of erlotinib in order to derive optimal benefit from the medication. TRIAL REGISTRATION: NTR1830.

Reduction in skin microvascular density and changes in vessel morphology in patients treated with sunitinib.

Hypertension is a common side effect in cancer patients treated with inhibitors of vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling and may represent a marker of clinical benefit. Functional rarefaction (a decrease in perfused microvessels) or structural rarefaction (a reduction in anatomic capillary density) may play an important role in the development of hypertension. We investigated whether sunitinib caused impairment of microvascular function and/or reduction of capillary density in patients with metastatic renal cell cancer (mRCC). Sixteen mRCC patients were treated with sunitinib (50 mg/day). Assessments of 24-h ambulatory blood pressure, microvascular endothelial function by laser Doppler fluxmetry, and capillary density by capillary microscopy were performed at baseline and days 14 and 28. Median blood pressure had increased on day 14 (systolic 10 mmHg, P<0.01 and diastolic blood pressure 8 mmHg, P<0.01). Capillary density had decreased from 69 to 61 capillaries/mm (P<0.01). This decrease was related to the increase in systolic and diastolic blood pressure (r=-0.57, P<0.05 and r=-0.68, P<0.01, respectively). A more pronounced decrease in capillary density was associated with increased visibility of the subpapillary plexus (P=0.041). Preliminary findings indicated that median progression-free survival was significantly prolonged in patients with a greater than 6 capillaries/mm decrease in density as compared with patients with a less pronounced decrease (P=0.044). In conclusion, reduction in skin capillary density is associated with a rise in blood pressure during sunitinib therapy and, by itself, might be useful as a predictive marker of clinical outcome.