Treatment of breast cancer during pregnancy: an observational study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: BANSS Foundation, Biedenkopf, Germany and the Belgian Cancer Plan, Ministry of Health, Belgium.

The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: We assessed the efficacy of taxane chemotherapy in BRCA1- and BRCA2-associated patients compared with sporadic metastatic breast cancer patients. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Haptoglobin phenotype is not a predictor of recurrence free survival in high-risk primary breast cancer patients.

BACKGROUND: 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. METHODS: 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. RESULTS: In sample set I, the expression of a peak at mass-to-charge ratio 9198 (relative intensity 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. CONCLUSION: 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.

High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer.

BACKGROUND: The use of high-dose adjuvant chemotherapy for high-risk primary breast cancer is controversial. We studied its efficacy in patients with 4 to 9 or 10 or more tumor-positive axillary lymph nodes. METHODS: Patients younger than 56 years of age who had undergone surgery for breast cancer and who had no distant metastases were eligible if they had at least four tumor-positive axillary lymph nodes. Patients in the conventional-dose group received fluorouracil, epirubicin, and cyclophosphamide (FEC) every three weeks for five courses, followed by radiotherapy and tamoxifen. The high-dose treatment was identical, except that high-dose chemotherapy (6 g of cyclophosphamide per square meter of body-surface area, 480 mg of thiotepa per square meter, and 1600 mg of carboplatin per square meter) with autologous peripheral-blood hematopoietic progenitor-cell transplantation replaced the fifth course of FEC. RESULTS: Of the 885 patients, 442 were assigned to the high-dose group and 443 to the conventional-dose group. After a median follow-up of 57 months, the actuarial 5-year relapse-free survival rates were 59 percent in the conventional-dose group and 65 percent in the high-dose group (hazard ratio for relapse in the high-dose group, 0.83; 95 percent confidence interval, 0.66 to 1.03; P=0.09). In the group with 10 or more positive nodes, the relapse-free survival rates were 51 percent in the conventional-dose group and 61 percent in the high-dose group (P=0.05 by the log-rank test; hazard ratio for relapse, 0.71; 95 percent confidence interval, 0.50 to 1.00). CONCLUSIONS: High-dose alkylating therapy improves relapse-free survival among patients with stage II or III breast cancer and 10 or more positive axillary lymph nodes. This benefit may be confined to patients with HER-2/neu-negative tumors.

Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre.

PURPOSE: To compare the efficacy and safety of doxorubicin and docetaxel (AT) with fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line chemotherapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients (n = 216) were randomly assigned to either AT (doxorubicin 50 mg/m(2) and docetaxel 75 mg/m2) or FAC (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2); both regimens were administered on day 1, every 3 weeks. RESULTS: A median number of six cycles was delivered in both arms, with a median relative dose-intensity of more than 98%. Median time to progression (TTP) and median overall survival (OS) were significantly longer for patients on AT compared with FAC (TTP: 8.0 v 6.6 months, respectively; P = .004; and OS: 22.6 v 16.2 months, respectively; P = .019). The overall response rate (ORR) was significantly higher in patients on AT compared with FAC (58% v 37%, respectively; P = .003). The ORR on AT was also higher in patients with visceral disease compared with FAC patients with visceral disease (59% v 36%, respectively; P = .003). There were no differences in grade 3 to 4 neutropenia and infections (AT 89% v FAC 84% and AT 12% v FAC 9%, respectively). Neutropenic fever was more common in AT-treated patients than FAC-treated patients (33% v 9%, respectively; P < .001). Grade 3 to 4 nonhematologic toxicity was infrequent in both arms. Congestive heart failure was observed in 3% and 6% of patients on AT and FAC, respectively. CONCLUSION: In this phase II to III study, AT resulted in a significantly longer TTP and OS and a higher objective ORR than FAC. First-line AT is a valid treatment option for patients with MBC.

Randomized cross-over evaluation of body-surface area-based dosing versus flat-fixed dosing of paclitaxel.

PURPOSE: Despite dose calculation using body-surface area (BSA), pharmacokinetics of most anticancer drugs show wide interindividual variability. In this study, we evaluated the role of BSA in paclitaxel disposition. PATIENTS AND METHODS: Paclitaxel pharmacokinetics were prospectively studied in 12 patients that were treated in a randomized cross-over design with paclitaxel (3-hour infusion at a 3-week interval) at 175 mg/m2 in cycle 1 (A) and a flat-fixed dose of 300 mg in cycle 2 (B), or vice versa. Blood samples were collected up to 24 hours after dosing and analyzed for total and unbound paclitaxel. RESULTS: The area under the curves (AUC) of unbound paclitaxel were similar in both dosing groups, with mean values +/- SD (A v B) of 1.34 +/- 0.158 versus 1.30 +/- 0.329 microM x h, indicating that BSA-based dosing reduced the coefficient of variation by 53.3%. Unbound and total paclitaxel clearance was also significantly related to various body-size measures, including BSA (R > or = 0.617; P < or =.033), weight (R >or = 0.621; P < or =.031), and lean-body mass (r > or = 0.630; P < or = .028). We hypothesize that this is caused by the association of paclitaxel in the circulation with Cremophor EL, the distribution of which is linked to total blood volume, and thus to BSA. CONCLUSION: This study indicates that paclitaxel disposition is significantly related to BSA. This provides a pharmacokinetic rationale for BSA-based dosing of this drug.

Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study.

PURPOSE: We 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. RESULTS: The 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.

Postoperative serum proteomic profiles may predict recurrence-free survival in high-risk primary breast cancer.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Randomized phase II study comparing efficacy and safety of combination-therapy trastuzumab and docetaxel vs. sequential therapy of trastuzumab followed by docetaxel alone at progression as first-line chemotherapy in patients with HER2+ metastatic breast cancer: HERTAX trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Multimodality treatment for anaplastic thyroid carcinoma--treatment outcome in 75 patients.

PURPOSE: To retrospectively analyze the outcome of patients with anaplastic thyroid carcinoma (ATC) treated in the Erasmus MC. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: Despite the ultimately dismal prognosis of ATC-patients, multimodality treatment significantly improved local control and improved the median survival.

Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: No end point could be demonstrated as a good surrogate for OS in these trials. Tumor response may be an acceptable surrogate for PFS.