M Bontenbal

Erasmus MC, Rotterdam, South Holland, Netherlands

Are you M Bontenbal?

Claim your profile

Publications (73)520.19 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSEWe aimed to determine the prognosis of patients with breast cancer diagnosed during pregnancy (BCP). PATIENTS AND METHODS In this cohort study, a multicentric registry of patients with BCP (from Cancer in Pregnancy, Leuven, Belgium, and GBG 29/BIG 02-03) compiled pro- and retrospectively between 2003 and 2011 was compared with patients who did not have associated pregnancies, using an age limit of 45 years. Patients with a diagnosis postpartum were excluded. The main analysis was performed using Cox proportional hazards regression of disease-free survival (DFS) and overall survival (OS) on exposure (pregnant or not), adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status, histology, type of chemotherapy, use of trastuzumab, radiotherapy, and hormone therapy.ResultsThe registry contained 447 women with BCP, mainly originating from Germany and Belgium, of whom 311 (69.6%) were eligible for analysis. The nonpregnant group consisted of 865 women. Median age was 33 years for the pregnant and 41 years for the nonpregnant patients. Median follow-up was 61 months. The hazard ratio of pregnancy was 1.34 (95% CI, 0.93 to 1.91; P = .14) for DFS and 1.19 (95% CI, 0.73 to 1.93; P = .51) for OS. Cox regression estimated that the 5-year DFS rate for pregnant patients would have increased from 65% to 71% if these patients had not been pregnant. Likewise, the 5-year OS rate would have increased from 78% to 81%. CONCLUSION The results show similar OS for patients diagnosed with BCP compared with nonpregnant patients. This information is important when patients are counseled and supports the option to start treatment with continuation of pregnancy.
    Journal of Clinical Oncology 04/2013; 31(20). DOI:10.1200/JCO.2012.45.6335 · 18.43 Impact Factor
  • Cancer Research 12/2012; 72(24 Supplement):P6-07-05-P6-07-05. DOI:10.1158/0008-5472.SABCS12-P6-07-05 · 9.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Little is known about the treatment of breast cancer during pregnancy. We aimed to determine whether treatment for breast cancer during pregnancy is safe for both mother and child. We recruited patients from seven European countries with a primary diagnosis of breast cancer during pregnancy; data were collected retrospectively if the patient was diagnosed before April, 2003 (when the registry began), or prospectively thereafter, irrespective of the outcome of pregnancy and the type and timing of treatment. The primary endpoint was fetal health for up to 4 weeks after delivery. The registry is ongoing. The study is registered with ClinicalTrials.gov, number NCT00196833. From April, 2003, to December, 2011, 447 patients were registered, 413 of whom had early breast cancer. Median age was 33 years (range 22-51). At the time of diagnosis, median gestational age was 24 weeks (range 5-40). 197 (48%) of 413 women received chemotherapy during pregnancy with a median of four cycles (range one to eight). 178 received an anthracycline, 15 received cyclophosphamide, methotrexate, and fluorouracil, and 14 received a taxane. Birthweight was affected by chemotherapy exposure after adjustment for gestational age (p=0·018), but not by number of chemotherapy cycles (p=0·71). No statistical difference between the two groups was observed for premature deliveries before the 37th week of gestation. 40 (10%) of 386 infants had side-effects, malformations, or new-born complications; these events were more common in infants born before the 37th week of gestation than they were in infants born in the 37th week or later (31 [16%] of 191 infants vs nine [5%] of 195 infants; p=0·0002). In infants for whom maternal treatment was known, adverse events were more common in those who received chemotherapy in utero compared with those who were not exposed (31 [15%] of 203 vs seven [4%] of 170 infants; p=0·00045). Two infants died; both were exposed to chemotherapy and delivered prematurely, but both deaths were thought not to be related to treatment. Median disease-free survival for women with early breast cancer was 70·6 months (95% CI 62·1-105·5) in women starting chemotherapy during pregnancy and 94·4 months (lower 95% CI 64·4; upper 95% CI not yet reached) in women starting chemotherapy after delivery (unadjusted hazard ratio 1·13 [95% CI 0·76-1·69]; p=0·539). Although our data show that infants exposed to chemotherapy in utero had a lower birthweight at gestational age than did those who were unexposed, and had more complications, these differences were not clinically significant and, since none of the infants was exposed to chemotherapy in the first trimester, were most likely related to premature delivery. Delay of cancer treatment did not significantly affect disease-free survival for mothers with early breast cancer. Because preterm birth was strongly associated with adverse events, a full-term delivery seems to be of paramount importance. BANSS Foundation, Biedenkopf, Germany and the Belgian Cancer Plan, Ministry of Health, Belgium.
    The Lancet Oncology 08/2012; 13(9):887-96. DOI:10.1016/S1470-2045(12)70261-9 · 24.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We assessed the efficacy of taxane chemotherapy in BRCA1- and BRCA2-associated patients compared with sporadic metastatic breast cancer patients. Response rates (RRs) to and progression-free survival (PFS) after taxane chemotherapy of 35 BRCA1-associated and 13 BRCA2-associated metastatic breast cancer patients were compared with those outcomes in 95 matched (1:2) sporadic patients. Matching was performed for age at and year of diagnosis of primary breast cancer, year of metastatic disease, and line of therapy (first vs second or third). Among BRCA1-associated patients, the RR was worse (objective response [OR], 23% vs 38%; progressive disease [PD], 60% vs 19%; P < 0.001); and the median PFS shorter (2.2 vs 4.9 months; P = 0.04) compared with sporadic patients. In the subgroup of hormone receptor (HRec)-negative patients, BRCA1-associated patients (n = 20) had a worse RR (OR, 20% vs 42%, respectively; PD, 70% vs 26%, respectively; P = 0.03) and a shorter PFS (1.8 vs 3.8 months; P = 0.004) compared with sporadic patients (n = 19). These outcomes in HRec-positive patients were similar in BRCA1-associated (n = 11) and sporadic (n = 61) patients (OR, 36% vs 38%; PD, 28% vs 20%; median PFS, both 5.7 months). In BRCA2-associated patients, who were mainly HRec-positive, the OR was higher than in sporadic patients (89% vs 38%, respectively; P = 0.02), whereas the median PFS was not significantly different (7.1 vs 5.7 months, respectively). BRCA1-associated, HRec-negative metastatic breast cancer patients were less sensitive to taxane chemotherapy than sporadic HRec-negative patients. HRec-positive BRCA1- and BRCA2-associated patients had a sensitivity to taxane chemotherapy similar to that of sporadic patients.
    Cancer 02/2012; 118(4):899-907. DOI:10.1002/cncr.26351 · 4.89 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Better breast cancer prognostication may improve selection of patients for adjuvant therapy. We conducted a retrospective longitudinal study in which we investigated sera of high-risk primary breast cancer patients, to search for proteins predictive of recurrence-free survival. Sera of 82 breast cancer patients obtained after surgery, but prior to the administration of adjuvant therapy, were fractionated using anion-exchange chromatography, to facilitate the detection of the low-abundant serum peptides. Selected fractions were subsequently analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS), and the resulting protein profiles were searched for prognostic markers by appropriate bioinformatics tools. Four peak clusters (i.e. m/z 3073, m/z 3274, m/z 4405 and m/z 7973) were found to bear significant prognostic value (P ≤ 0.01). The m/z 3274 candidate marker was structurally identified as inter-alpha-trypsin inhibitor heavy chain 4 fragment(658-688) in serum. Except for the m/z 7973 peak cluster, these peaks remained independently associated with recurrence-free survival upon multivariate Cox regression analysis, including clinical parameters of known prognostic value in this study population. Investigation of the postoperative serum proteome by, e.g., anion-exchange fractionation followed by SELDI-TOF MS analysis is promising for the detection of novel prognostic factors. However, regarding the rather limited study population, validation of these results by analysis of independent study populations is warranted to assess the true clinical applicability of discovered prognostic markers. In addition, structural identification of the other markers will aid in elucidation of their role in breast cancer prognosis, as well as enable development of absolute quantitative assays.
    Journal of Cancer Research and Clinical Oncology 09/2011; 137(12):1773-83. DOI:10.1007/s00432-011-1055-4 · 3.08 Impact Factor
  • Cancer Research 04/2011; 70(24 Supplement):S6-2-S6-2. DOI:10.1158/0008-5472.SABCS10-S6-2 · 9.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Because chemotherapy for metastatic breast cancer (MBC) is associated with relevant toxicity, sequential monotherapy trastuzumab followed by cytotoxic therapy at disease progression might be an attractive approach. In a multicenter phase II trial, 101 patients with overexpression of human epidermal growth factor receptor 2 (HER2(+)) MBC were randomized between combination-therapy trastuzumab (Herceptin) plus docetaxel (H+D) and sequential therapy of single-agent trastuzumab followed at disease progression by docetaxel alone (H→D) as first-line chemotherapy for metastatic disease. The primary endpoint was progression-free survival (PFS) after completed sequential or combination therapy. For the H+D group the median PFS was 9.4 vs. 9.9 months for the H→D group and 1-year PFS rates were 44% vs. 35%, respectively. However the overall response rates (ORRs) were 79% vs. 53%, respectively (P = .016), and overall survival was 30.5 vs. 19.7 months, respectively (P = .11). In the H→D group, response rates to monotherapy trastuzumab and subsequent docetaxel were 34% and 39%, respectively, with a median PFS during single-agent trastuzumab of 3.9 months. The incidence and severity of neuropathy were significantly higher in the H+D group. Retrospective analysis of trastuzumab treatment beyond progression (applied in 46% of patients in the H+D group and 37% in the H→D group) showed a correlation with longer overall survival in both treatment arms (36.0 vs. 18.0 months and 30.3 vs. 18.6 months, respectively). First-line treatment in patients with MBC with H→D resulted in a similar PFS compared with H+D, but the response rate was lower and the overall survival nonsignificantly shorter.
    Clinical Breast Cancer 04/2011; 11(2):103-13. DOI:10.1016/j.clbc.2011.03.003 · 2.11 Impact Factor
  • EJC Supplements 03/2010; 8(3):205-205. DOI:10.1016/S1359-6349(10)70520-6 · 9.39 Impact Factor
  • Cancer Research 02/2010; 69(24 Supplement):2098-2098. DOI:10.1158/0008-5472.SABCS-09-2098 · 9.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To retrospectively analyze the outcome of patients with anaplastic thyroid carcinoma (ATC) treated in the Erasmus MC. Seventy-five ATC-patients were treated between 1972 and 2003. Mean age was 68 years. Tumor stage was IVA in 9%, IVB in 51%, and IVC in 40%. Thirty-six patients underwent up-front surgery, with 53% resulting in R0/R1 resection. Before 1988 adjuvant treatment consisted of conventional radiotherapy (RT) and/or chemotherapy (CT). As of 1988, 30 eligible patients were enrolled in a newly designed protocol. This consists of locoregional RT in 46 fractions of 1.1 Gy, given twice daily, followed by prophylactic irradiation of the lungs (PLI) in 5 daily fractions of 1.5 Gy. During radiation, low-dose Doxorubicine (15 mg/m(2)) is administered weekly and is followed by adjuvant Doxorubicine (50 mg/m(2)) 3-weekly up to a cumulative dose of 550 mg/m(2). Twenty-five ineligible patients were treated conventionally. Overall median survival was 3 months, 1-year OS 9%. Locoregional control was significantly higher in patients who had undergone R0/R1 resection or chemoradiation, with best results for patients who underwent both (complete remission in 89%). However, the survival benefit of patients who reached CR remained borderline (median OS 7 months, 1-year OS 32%). Three patients survived for more than 5 years; all had undergone R0/R1 surgical resection and chemoradiation. Acute toxicity in the protocol group was significantly higher than in the nonprotocol group, with 46% versus 11% grade 3 pharyngeal and/or esophageal toxicity. Despite the ultimately dismal prognosis of ATC-patients, multimodality treatment significantly improved local control and improved the median survival.
    Radiotherapy and Oncology 04/2009; 92(1):100-4. DOI:10.1016/j.radonc.2009.02.016 · 4.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Better breast cancer prognostication may improve selection of patients for adjuvant therapy. We conducted a retrospective follow-up study in which we investigated sera of high-risk primary breast cancer patients, to search for proteins predictive of recurrence free survival. Two sample sets of high-risk primary breast cancer patients participating in a randomised national trial investigating the effectiveness of high-dose chemotherapy were analysed. Sera in set I (n = 63) were analysed by surface enhanced laser desorption ionisation time-of-flight mass spectrometry (SELDI-TOF MS) for biomarker finding. Initial results were validated by analysis of sample set II (n = 371), using one-dimensional gel-electrophoresis. In sample set I, the expression of a peak at mass-to-charge ratio 9198 (relative intensity <or= 20 or > 20), identified as haptoglobin (Hp) alpha-1 chain, was strongly associated with recurrence free survival (global Log-rank test; p = 0.0014). Haptoglobin is present in three distinct phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2), of which only individuals with phenotype Hp 1-1 or Hp 2-1 express the haptoglobin alpha-1 chain. As the expression of the haptoglobin alpha-1 chain, determined by SELDI-TOF MS, corresponds to the phenotype, initial results were validated by haptoglobin phenotyping of the independent sample set II by native one-dimensional gel-electrophoresis. With the Hp 1-1 phenotype as the reference category, the univariate hazard ratio for recurrence was 0.87 (95% CI: 0.56 - 1.34, p = 0.5221) and 1.03 (95% CI: 0.65 - 1.64, p = 0.8966) for the Hp 2-1 and Hp 2-2 phenotypes, respectively, in sample set II. In contrast to our initial results, the haptoglobin phenotype was not identified as a predictor of recurrence free survival in high-risk primary breast cancer in our validation set. Our initial observation in the discovery set was probably the result of a type I error (i.e. false positive). This study illustrates the importance of validation in obtaining the true clinical applicability of a potential biomarker.
    BMC Cancer 12/2008; 8(1):389. DOI:10.1186/1471-2407-8-389 · 3.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Dutch evidence-based guideline 'Treatment of breast cancer' has been revised, and integrated with the guideline 'Screening for and diagnosis of breast cancer'. The guideline can be found on www. oncoline.nl and on www.cbo.nl. The Internet programme 'Adjuvant!' (www.adjuvantonline.com) can be used to predict both the prognosis and the efficacy of systemic adjuvant therapy for each patient. The indications for adjuvant chemotherapy and endocrine therapy have been widened. The aim is to reduce the absolute probability of death by at least 4-5% within 10 years. The goal of neoadjuvant chemotherapy in operable breast cancer is to enable breast-conserving therapy for large tumours in relatively small breasts. One could consider transferring responsibility for follow-up after 5 years from the hospital to the screening organisation following mastectomy, to the family doctor following breast-conserving therapy, and to an outpatient clinic for hereditary tumours in carriers of gene mutation. Cessation of follow-up above the age of 75 could also be considered.
    Nederlands tijdschrift voor geneeskunde 12/2008; 152(46):2507-11.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neutropenia following high-dose chemotherapy leads to a high incidence of infectious complications, of which central venous catheter-related infections predominate. Catheter-related infections and associated risk factors in 392 patients participating in a randomized adjuvant breast cancer trial and assigned to receive high-dose chemotherapy and peripheral stem-cell reinfusion were evaluated. Median catheter dwell time was 25 days (range 1-141). Catheter-related infections were seen in 28.3% of patients (11 infections per 1000 catheter-days). Coagulase-negative staphylococci were found in 104 of 186 positive blood cultures (56%). No systemic fungal infections occurred. Cox regression analysis showed that duration of neutropenia >10 days (P=0.04), using the catheter for both stem-cell apheresis and high-dose chemotherapy (P= <0.01), and use of total parenteral nutrition (TPN, P=0.04) were predictive for catheter-related infections. In conclusion, a high incidence of catheter-related infections after high-dose chemotherapy was seen related to duration of neutropenia, use of the catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications.
    Bone Marrow Transplantation 07/2008; 42(7):475-81. DOI:10.1038/bmt.2008.195 · 3.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Overall survival (OS) can be observed only after prolonged follow-up, and any potential effect of first-line therapies on OS may be confounded by the effects of subsequent therapy. We investigated whether tumor response, disease control, progression-free survival (PFS), or time to progression (TTP) could be considered a valid surrogate for OS to assess the benefits of first-line therapies for patients with metastatic breast cancer. Individual patient data were collected on 3,953 patients in 11 randomized trials that compared an anthracycline (alone or in combination) with a taxane (alone or in combination with an anthracycline). Surrogacy was assessed through the correlation between the end points as well as through the correlation between the treatment effects on the end points. Tumor response (survival odds ratio [OR], 6.2; 95% CI, 5.3 to 7.0) and disease control (survival OR, 5.5; 95% CI, 4.8 to 6.3) were strongly associated with OS. PFS (rank correlation coefficient, 0.688; 95% CI, 0.686 to 0.690) and TTP (rank correlation coefficient, 0.682; 95% CI, 0.680 to 0.684) were moderately associated with OS. Response log ORs were strongly correlated with PFS log hazard ratios (linear coefficient [rho], 0.96; 95% CI, 0.73 to 1.19). Response and disease control log ORs and PFS and TTP log hazard ratios were poorly correlated with log hazard ratios for OS, but the confidence limits of rho were too wide to be informative. No end point could be demonstrated as a good surrogate for OS in these trials. Tumor response may be an acceptable surrogate for PFS.
    Journal of Clinical Oncology 05/2008; 26(12):1987-92. DOI:10.1200/JCO.2007.10.8407 · 18.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Taxanes (paclitaxel or docetaxel) have been sequenced or combined with anthracyclines (doxorubicin or epirubicin) for the first-line treatment of advanced breast cancer. This meta-analysis uses data from all relevant trials to detect any advantages of taxanes in terms of tumor response, progression-free survival (PFS), and survival. Individual patient data were collected on eight randomized combination trials comparing anthracyclines + taxanes (+ cyclophosphamide in one trial) with anthracyclines + cyclophosphamide (+ fluorouracil in four trials), and on three single-agent trials comparing taxanes with anthracyclines. Combination trials included 3,034 patients; single-agent trials included 919 patients. Median follow-up of living patients was 43 months, median survival was 19.3 months, and median PFS was 7.1 months. In single-agent trials, response rates were similar in the taxanes (38%) and in the anthracyclines (33%) arms (P = .08). The hazard ratios for taxanes compared with anthracyclines were 1.19 (95% CI, 1.04 to 1.36; P = .011) for PFS and 1.01 (95% CI, 0.88 to 1.16; P = .90) for survival. In combination trials, response rates were 57% (10% complete) in taxane-based combinations and 46% (6% complete) in control arms (P < .001). The hazard ratios for taxane-based combinations compared with control arms were 0.92 (95% CI, 0.85 to 0.99; P = .031) for PFS and 0.95 (95% CI, 0.88 to 1.03; P = .24) for survival. Taxanes were significantly worse than single-agent anthracyclines in terms of PFS, but not in terms of response rates or survival. Taxane-based combinations were significantly better than anthracycline-based combinations in terms of response rates and PFS, but not in terms of survival.
    Journal of Clinical Oncology 04/2008; 26(12):1980-6. DOI:10.1200/JCO.2007.10.8399 · 18.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: The traditional endpoint to assess the efficacy of chemotherapies for metastatic breast cancer is overall survival (OS), but this endpoint can only be observed after prolonged follow-up. Moreover, with the number of active compounds available in this disease, any potential effect of first-line therapies on OS may be confounded by the effects of second-line therapies. It is therefore of interest to investigate whether tumor response or progression-free survival (PFS) could replace OS as the primary endpoint in randomized trials for patients with metastatic breast cancer. Methods: Individual patient data were collected on 4,256 patients in 12 randomized trials comparing an anthracycline (alone or in combination) with a taxane (alone or in combination with an anthracycline). Tumor response was assessed using WHO criteria. Progression-free survival was calculated from date of randomization to progression or death from any cause. Overall survival was calculated from date of randomization to death from any cause. Surrogacy was assessed through the correlation between the endpoints as well as the correlation between the treatment effects on the endpoints. Correlation coefficients were estimated along with their 95% confidence interval (CI). Results: Median follow-up of alive patients was 41 months, median OS 20 months, median PFS 7 months. Tumor response was strongly associated with PFS (survival odds ratio=5.8, 95% CI=5.0-6.5) and with OS (survival odds ratio=3.0, 95% CI=2.6-3.3). The correlation coefficient between response log odds ratios and PFS log hazard ratios was 0.97 (95% CI=0.74-1.21). The correlation coefficient between response log odds ratios and OS log hazard ratios was 0.56 (95% CI=-0.33-1.44). The rank correlation between PFS and OS was 0.695 (95% CI=0.693-0.696). The correlation between the log hazard ratios for PFS and OS was 0.44 (95% CI=- 0.41 -1.30). Conclusions: Tumor response is predictive of longer PFS and longer OS. Treatment effects on response are strongly correlated with treatment effects on PFS but not on OS. PFS is poorly correlated with OS, and treatment effects on PFS are poorly correlated with treatment effects on OS. These results indicate that tumor response is an acceptable surrogate for PFS but no endpoint is a good surrogate for OS in these trials. Associations between treatment effects are not precisely estimated despite the relatively large sample sizes.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Taxanes (T, paclitaxel or docetaxel), in view of their partial lack of cross resistance with anthracyclines (A, doxorubicin or epirubicin), generated great enthusiasm in the 1990’s for the treatment of breast cancer. Taxanes were sequenced or combined with anthracyclines and compared with standard regimens for first-line treatment of advanced disease. Randomized trials, however, have shown inconsistent results, particularly in terms of survival, which was rarely improved. This prompted the current meta-analysis of individual data from all relevant trials, in order to reliably detect any advantages of taxanes in terms of tumor response, progression-free survival (PFS) and overall survival (OS) in first-line treatment of patients with metastaic breast cancer. Methods: Between December 2002 and May 2005, individual patient data were collected on 9 randomized combination trials comparing A + T (+ cyclophosphamide in 1 trial) with A + cyclophosphamide (+ 5-fluorouracil in 4 trials), and on 3 single agent trials comparing T (paclitaxel in 2 trials) with A. Combination trials included 3,337 patients, single agent trials 919 patients. Tumor response was assessed using WHO criteria. Progressionfree survival was calculated from date of randomization to progression or death from any cause. Results: Median follow-up of alive patients was 41 months, median OS 20 months, median PFS 7 months. In single agent trials, overall response rates were 33% (4% complete) in the T arms and 38% (6% complete) in the A arms (P=0.08). The hazard ratios for T compared with A were 1.19 (CI 1.04 – 1.36, P=0.01) for PFS and 1.01 (CI 0.88 – 1.16, P=0.90) for OS. In combination trials, response rates were 56% (10% complete) in T-based combinations and 45% (6% complete) in control arms (P<0.001). The hazard ratios for T-based combinations compared with control arms were 0.93 (CI 0.87 – 1.00, P=0.06) for PFS and 0.95 (CI 0.88 – 1.03, P=0.23) for OS. Conclusions: Single agent A was significantly better than single agent T in terms of PFS, marginally better in terms of response but not different in terms of OS. T-based combinations were significantly better than A-based combinations in terms of response rates, marginally better in terms of PFS but not different in terms of OS.
  • Annals of the New York Academy of Sciences 12/2006; 698(1):85 - 101. DOI:10.1111/j.1749-6632.1993.tb17193.x · 4.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Benefit from chemotherapy treatment in breast cancer patients is determined by the molecular make-up of the tumour. In a retrospective analysis, we determined the molecular subtypes of breast cancer originally defined by expression microarrays by immunohistochemistry in tumours of patients who took part in a randomised study of adjuvant high-dose chemotherapy in breast cancer. In addition, the topoisomerase II alpha (TOP2A) amplification status was determined by fluorescence in situ hybridisation and chromogenic in situ hybridisation. 411 of the 753 tumours (55%) were classified as luminal-like, 137 (18%) as basal-like and 205 (27%) as human epithelial receptor type 2 (HER2) amplified. The basal-like tumours were defined as having no expression of ER and HER2; 98 of them did express epidermal growth factor receptor and/or cytokeratin 5/6. The luminal-like tumours had a significantly better recurrence free and overall survival than the other two groups. From the 194 HER2-positive tumours, 47 (24%) were shown to harbour an amplification of TOP2A. Patients with an HER2-amplified tumour randomised to the high-dose therapy arm did worse than those in the conventional treatment arm, possibly caused by the lower cumulative anthracycline dose in the high-dose arm. The tumours with a TOP2A amplification contributed hardly to this difference, suggesting that TOP2A amplification is not the cause of the steep dose-response curve for anthracyclines in breast cancer. Possibly, the difference of the cumulative dose of only 25% between the treatment arms was insufficient to yield a survival difference.
    British Journal of Cancer 12/2006; 95(10). DOI:10.1038/sj.bjc.6603449 · 4.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: High-dose chemotherapy in the adjuvant treatment of breast cancer has been abandoned by many. 885 patients with stage III primary breast cancer and four or more axillary lymph node metastases were randomised to receive either five courses of FEC (fluorouracil, epirubicin and cyclophosphamide) followed by radiation therapy and tamoxifen, or the same treatment but with high-dose alkylating chemotherapy (cyclophosphamide, thiotepa and carboplatin) replacing the fifth course of FEC. Of these patients, 621 had HER2/neu-negative disease, as determined by immunohistochemistry and chromogenic in situ hybridisation. At a median follow-up of 84 months, a trend for a better relapse-free survival was observed in the high-dose arm: (hazard ratio (HR) 0.84, P = 0.076, two-sided). The 621 patients with HER2/neu-negative disease benefited from high-dose therapy, while patients with HER2/neu-positive disease did not (test for interaction, P = 0.006). There was a marked relapse-free survival benefit for patients with HER2/neu-negative disease (71.5% versus 59.1%, 5 years after randomisation; HR 0.68, P = 0.002) and also a survival benefit (78.2% versus 71.0% at 5 years; HR 0.72, P = 0.02). The findings from this subgroup analysis provide additional evidence that HER2/neu-positive breast cancer is relatively resistant to alkylating agents. For HER2/neu-negative tumours, however, high-dose chemotherapy should remain the subject of clinical studies.
    Annals of Oncology 05/2006; 17(4):588-96. DOI:10.1093/annonc/mdl001 · 7.04 Impact Factor

Publication Stats

3k Citations
520.19 Total Impact Points


  • 1987–2013
    • Erasmus MC
      • • Department of Medical Oncology
      • • Daniel den Hoed Centre
      • • Department of Immunology
      Rotterdam, South Holland, Netherlands
  • 1990–2011
    • Erasmus Universiteit Rotterdam
      • Department of Medical Oncology
      Rotterdam, South Holland, Netherlands
  • 2008
    • Hasselt University
      Hasselt, Flemish, Belgium
  • 1997–2008
    • Institut Jules Bordet
      Bruxelles, Brussels Capital, Belgium
  • 2000
    • Integraal Kankercentrum Nederland
      Amsterdamo, North Holland, Netherlands
  • 1996
    • Cross Cancer Institute
      Edmonton, Alberta, Canada
  • 1993–1995
    • Netherlands Cancer Institute
      • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
  • 1986
    • TNO
      Delft, South Holland, Netherlands