Minimal impact of adjuvant exemestane or tamoxifen treatment on mammographic breast density in postmenopausal breast cancer patients: a Dutch TEAM trial analysis.

BACKGROUND: Mammographic breast density is one of the strongest independent risk factors for developing breast cancer. We examined the effect of exemestane and tamoxifen on breast density in Dutch postmenopausal early breast cancer patients participating in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. MATERIAL AND METHODS: Analogue mammograms of selected TEAM participants before start, and after one and two (and if available after three) years of adjuvant endocrine therapy were collected centrally and reviewed. Study endpoints were change in breast density over time, and correlations between breast density and locoregional recurrence (LRR), distance recurrence (DR), and contralateral breast cancer (CBC). RESULTS: Mammograms of 378 patients (181 tamoxifen, 197 exemestane) were included in the current per protocol analyses. Baseline breast density was low (breast density score<50% in 75% of patients) and not different between patients randomised to exemestane or tamoxifen (coefficient 0.16, standard error 0.17). Breast density did not change during treatment in exemestane (p=0.25) or tamoxifen users (p=0.59). No relation was observed between breast density and the occurrence of a LRR [hazards ratio (HR) 0.87, 95% CI 0.45-1.68, p=0.67], a DR (HR 1.02, 95% CI 0.77-1.35, p=0.90), or CBC (HR 1.31, 95% CI 0.63-2.72, p=0.48). CONCLUSION: The in general low breast density score in early postmenopausal breast cancer patients did not substantially change over time, and this pattern was not different between tamoxifen and exemestane users. Breast density was not a predictive marker for efficacy of adjuvant endocrine therapy.

Risk factors for non-sentinel lymph node metastases in patients with breast cancer. The outcome of a multi-institutional study.

BACKGROUND: In this multi-institutional prospective study, we evaluated whether we could identify risk factors predictive for non-sentinel lymph node (non-SN) metastases in breast cancer patients with a positive sentinel lymph node (SN). METHODS: In this multi-institutional study, 541 eligible breast cancer patients were included prospectively. RESULTS: The occurrence of non-SN metastases was related to the size of the SN metastasis (P = .02), primary tumor size (P = .001), and lymphovascular invasion (P = .07). The adjusted odds ratio was 3.1 for SN micro-metastasis compared with SN isolated tumor cells, 4.0 for SN macro-metastasis versus SN isolated tumor cells, 3.1 for tumor size (>3.0 cm compared with 3.0 cm, and with vessel invasion. CONCLUSION: We identified three predictive factors for non-SN metastases in breast cancer patients with a positive SN: size of the SN metastasis; primary tumor size; and vessel invasion. We were not able to identify a specific group of patients with a positive SN in whom the risk for non-SN metastases was less than 5%.

The prognostic value of proliferation in lymph-node-negative breast cancer patients is age dependent.

In lymph-node-negative invasive breast cancer patients<55 years, the proliferation marker mitotic activity index (MAI) has previously been shown to be the strongest prognosticator. In studies without age definition, MAI was not strongly prognostic. We investigated the age dependency of the prognostic value of proliferation for distant metastasis-free (MFS) and overall cancer-related survival (OS) in 1004 histologically diagnosed T1-3N0M0 invasive breast cancers (n=516, <55 years; n=322, 55-70 years; n=166, >70 years) without systemic adjuvant therapy and long follow-up (median: 108 months). The MAI decreases with age and the prognostic value of MAI varied by age group. For patients<55 years, hazard ratios (HR) for MAI>or=10 versus<10 for MFS and OS were 3.1 and 4.4, respectively (P<.0001 for both), but only 1.9 and 1.9 (P=.004 and .006) for patients aged 55-70 years, while over 70 years, MAI was not significant (P=.11). The prognostic value of proliferation was age-dependent. Prognostic breast cancer studies must clearly indicate the age group being studied.

Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer.

PURPOSE: We previously identified in a single-center study a 76-gene prognostic signature for lymph node-negative (LNN) breast cancer patients. The aim of this study was to validate this gene signature in an independent more diverse population of LNN patients from multiple institutions. PATIENTS AND METHODS: Using custom-designed DNA chips we analyzed the expression of the 76 genes in RNA of frozen tumor samples from 180 LNN patients who did not receive adjuvant systemic treatment. RESULTS: In this independent validation, the 76-gene signature was highly informative in identifying patients with distant metastasis within 5 years (hazard ratio, [HR], 7.41; 95% CI, 2.63 to 20.9), even when corrected for traditional prognostic factors in multivariate analysis (HR, 11.36; 95% CI, 2.67 to 48.4). The actuarial 5- and 10-year distant metastasis-free survival were 96% (95% CI, 89% to 99%) and 94% (95% CI, 83% to 98%), respectively, for the good profile group and 74% (95% CI, 64% to 81%) and 65% (53% to 74%), respectively for the poor profile group. The sensitivity for 5-yr distant metastasis-free survival was 90%, and the specificity was 50%. The positive and negative predictive values were 38% (95% CI, 29% to 47%) and 94% (95% CI, 86% to 97%), respectively. The 76-gene signature was confirmed as a strong prognostic factor in subgroups of estrogen receptor-positive patients, pre- and postmenopausal patients, and patients with tumor sizes 20 mm or smaller. The subgroup of patients with estrogen receptor-negative tumors was considered too small to perform a separate analysis. CONCLUSION: Our data provide a strong methodologic and clinical multicenter validation of the predefined prognostic 76-gene signature in LNN breast cancer patients.

Fatigue and relating factors in high-risk breast cancer patients treated with adjuvant standard or high-dose chemotherapy: a longitudinal study.

PURPOSE: Determine whether standard or high-dose chemotherapy leads to changes in fatigue, hemoglobin (Hb), mental health, muscle and joint pain, and menopausal status from pre- to post-treatment and to evaluate whether fatigue is associated with these factors in disease-free breast cancer patients. PATIENTS AND METHODS: Eight hundred eighty-five patients were randomly assigned between two chemotherapy regimens both followed by radiotherapy and tamoxifen. Fatigue was assessed using vitality scale (score < or = 46 defined as fatigue), poor mental health using mental health scale (score < or = 56 defined as poor mental health) both of Short-Form 36, muscle and joint pain with Rotterdam Symptom Checklist, and Hb levels were assessed before and 1, 2, and 3 years after chemotherapy. RESULTS: Fatigue was reported in 20% of 430 assessable patients (202 standard-dose, 228 high-dose) with at least a 3-year follow-up, without change over time or difference between treatment arms. Mean Hb levels were lower following high-dose chemotherapy. Only 5% of patients experienced fatigue and anemia. Mental health score was the strongest fatigue predictor at all assessment moments. Menopausal status had no effect on fatigue. Linear mixed effect models showed that the higher the Hb level (P = .0006) and mental health score (P < .0001), the less fatigue was experienced. Joint (P < .0001) and muscle pain (P = .0283) were associated with more fatigue. CONCLUSION: In 3 years after treatment, no significant differences in fatigue were found between standard and high-dose chemotherapy. Fatigue did not change over time. The strongest fatigue predictor was poor mental health.

Prospective multicenter validation of the independent prognostic value of the mitotic activity index in lymph node-negative breast cancer patients younger than 55 years.

PURPOSE: To validate the independent strong prognostic value of mitotic activity index (MAI) in lymph node (LN) -negative invasive breast cancer patients younger than 55 years in a nationwide multicenter prospective study. PATIENTS AND METHODS: Analysis of routinely assessed MAI and other prognosticators in 516 patients (median follow-up, 118 months; range, 8 to 185 months), without systemic adjuvant therapy or previous malignancies. RESULTS: Distant metastases occurred in 127 patients (24.6%); 90 (17.4%) died as a result of metastases. MAI (< 10, > or = 10) showed strong association with recurrence (hazard ratio [HR], 3.12; 95% CI, 2.17 to 4.50; P < or = .0001) and mortality (HR, 4.42; 95% CI, 2.79 to 7.01; P < .0001). The absolute difference in 10-year Kaplan-Meier estimates of time to distant recurrence as well as survival was 22% between MAI less than 10 versus > or = 10. This effect was independent of age, estrogen receptor (ER) status, and tumor diameter (which were significant prognosticators). In multivariate analysis with regard to patient age, tumor diameter, grade, ER status, and the St Gallen criterion, MAI proved to be an independent and the strongest prognosticator. Tubular formation (TF) and nuclear atypia (NA), as constituents of (expert revised) grade, had no (for TF) or limited (for NA, P = .048) additional prognostic value to the MAI. In the group with MAI less than 10, MAI less than 3 versus more than 3 had additional value but the classical threshold of 0 to 5 v 6 to 10 did not. With this additional subdivision of MAI as less than 3, 3 to 9, and more than 9, NA lost its additive prognostic value. CONCLUSION: The MAI is the strongest, most widely available, easily assessable, inexpensive, well-reproducible prognosticator and is well suited to routinely differentiate between high- and low-risk LN-negative breast cancer patients younger than 55 years.

Survivin is an independent prognostic marker for risk stratification of breast cancer patients.

BACKGROUND: Results in previous qualitative studies of the association of the apoptosis inhibitor survivin with prognosis of breast cancer patients have been contradictory. METHODS: Survivin mRNA was measured by quantitative TaqMan reverse transcription-PCR in 275 breast cancer tissues from patients with operable tumors and was correlated with established clinicopathologic factors, relapse-free survival [(RFS); 102 events], and overall survival [(OS); 81 events]. RESULTS: High survivin mRNA concentrations were found mainly in tissues from younger patients and in high-grade cancer tissues. High survivin concentrations were most strongly associated with estrogen receptor- or progesterone receptor-negative tumors. In univariate Cox regression analysis for RFS, survivin concentrations were significantly associated with poor prognosis with a hazard ratio (HR) of 1.99 (95% confidence interval, 1.31-3.02; P = 0.001) for every 10-fold increase in expression. For OS, a significant contribution of survivin to poor prognosis was found with a HR of 2.76 (1.67-4.55; P <0.001). Multivariate analyses were performed including established clinicopathologic factors. For RFS, age (P = 0.027), nodal category (P <0.001), and survivin [HR = 1.78 (1.18-2.68); P = 0.006] contributed significantly to the model. For OS, only nodal category (P <0.001) and survivin [HR = 3.05 (1.83-5.10); P <0.001] were significant. CONCLUSION: Survivin demonstrates a strong, independent, association with poor prognosis. Survivin might be used as a new marker to stratify breast cancer patients for more optimal treatment modalities, or it could be a promising new target for therapy.

Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition.

BACKGROUND: The value of regular surveillance for breast cancer in women with a genetic or familial predisposition to breast cancer is currently unproven. We compared the efficacy of magnetic resonance imaging (MRI) with that of mammography for screening in this group of high-risk women. METHODS: Women who had a cumulative lifetime risk of breast cancer of 15 percent or more were screened every six months with a clinical breast examination and once a year by mammography and MRI, with independent readings. The characteristics of the cancers that were detected were compared with the characteristics of those in two different age-matched control groups. RESULTS: We screened 1909 eligible women, including 358 carriers of germ-line mutations. Within a median follow-up period of 2.9 years, 51 tumors (44 invasive cancers, 6 ductal carcinomas in situ, and 1 lymphoma) and 1 lobular carcinoma in situ were detected. The sensitivity of clinical breast examination, mammography, and MRI for detecting invasive breast cancer was 17.9 percent, 33.3 percent, and 79.5 percent, respectively, and the specificity was 98.1 percent, 95.0 percent, and 89.8 percent, respectively. The overall discriminating capacity of MRI was significantly better than that of mammography (P<0.05). The proportion of invasive tumors that were 10 mm or less in diameter was significantly greater in our surveillance group (43.2 percent) than in either control group (14.0 percent [P<0.001] and 12.5 percent [P=0.04], respectively). The combined incidence of positive axillary nodes and micrometastases in invasive cancers in our study was 21.4 percent, as compared with 52.4 percent (P<0.001) and 56.4 percent (P=0.001) in the two control groups. CONCLUSIONS: MRI appears to be more sensitive than mammography in detecting tumors in women with an inherited susceptibility to breast cancer.

Complex of urokinase-type plasminogen activator with its type 1 inhibitor predicts poor outcome in 576 patients with lymph node-negative breast carcinoma.

BACKGROUND: The ability of a solid tumor to grow and metastasize has a significant dependence on protease systems, such as the plasminogen activation system. The plasminogen activation system includes the urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1), among other molecules. Both uPA and PAI-1 are established prognostic factors for patients with breast carcinoma. In the current study, the authors investigated whether the complex of uPA with PAI-1 is also associated with the natural course of this malignancy. METHODS: Cytosolic levels of uPA, PAI-1, and the uPA:PAI-1 complex were measured in tumor tissue from 576 patients with lymph node-negative invasive breast carcinoma using quantitative enzyme-linked immunosorbent assays. Patients did not receive adjuvant systemic therapy, and the median follow-up duration was 61 months (range, 2-187 months) after primary diagnosis. Correlations with well known clinicopathologic factors were assessed, and univariate and multivariate survival analyses were performed. RESULTS: uPA:PAI-1 complex levels were positively associated with adverse histologic grade and inversely correlated with estrogen and progesterone receptor status. On univariate analysis, increased levels of the uPA:PAI-1 complex were found to be associated with reduced recurrence-free survival (RFS) and overall survival (OS) rates. On multivariate analysis, uPA:PAI-1 complex levels were found to be an independent predictor of OS (P = 0.039), but not RFS (P = 0.240). When uPA and PAI-1 levels were not included in the multivariate analysis, uPA:PAI-1 complex levels became a significant predictor of both RFS and OS (P = 0.029 and P = 0.007, respectively). CONCLUSIONS: The results of the current study demonstrate that uPA:PAI-1 complex levels have prognostic value on univariate analysis. In addition, increased uPA:PAI-1 complex levels were significantly associated with poor OS on multivariate analysis. Increased uPA:PAI-1 complex levels were also significantly associated with reduced RFS rates after the exclusion of uPA and PAI-1 levels from the multivariate analysis model.

Predicting early failure after adjuvant chemotherapy in high-risk breast cancer patients with extensive lymph node involvement.

PURPOSE: There is limited knowledge of risk factors for breast cancer recurrence within 2 years. This study aimed to predict early failure and identify high-risk patients for prognostic and therapeutic purposes. EXPERIMENTAL DESIGN: We studied 739 patients from a randomized trial who were <56 years of age and had >/=4 or more positive lymph nodes, no distant metastases, and no previous other malignancies. After complete surgical treatment, patients received conventional-dose anthracycline-based chemotherapy or a high-dose scheme of anthracycline-based plus alkylating chemotherapy. We assessed clinical and (immuno)histological parameters to predict recurrence within 2 years. RESULTS: Early failure occurred in 19% (n = 137). Median survival after early failure was limited to 0.7 year. Estrogen and progesterone receptor negativity and visceral relapse predicted poor prognosis. Early failure was associated with young age, large tumors, high histological grade, angio-invasion, apical node metastasis, and >/=10 involved nodes. Estrogen receptor, progesterone receptor, and p27 negativity; HER2 overexpression; and p53 positivity also predicted early failure. The surgical or chemotherapy regimen and histological type did not. The same parameters except tumor size were associated with early death. Grade III, >/=10 involved nodes, and estrogen receptor negativity were independently associated with early failure and together identified a subset of patients (7%) with 3-fold increased early failure and 5-fold increased early death. CONCLUSIONS: Early failure is associated with poor survival. The combination of three commonly determined parameters constitutes a strong predictive model for early failure and death.

Tissue inhibitors of metalloproteinase expression in human breast cancer: TIMP-3 is associated with adjuvant endocrine therapy success.

Tissue inhibitors of matrix metalloproteinase (TIMPs) may be involved in tumour growth, apoptosis, angiogenesis, invasion, and the development of metastases. This study has evaluated the association of the expression levels of the TIMP forms 1, 2, 3, and 4, measured by quantitative real-time RT-PCR, with classical clinicopathological characteristics, ie age, menopausal status, tumour size, histological grade, number of involved lymph nodes, and steroid hormone receptor status, and with disease progression and treatment sensitivity in 273 breast cancer patients. The mRNA levels of TIMP-1 and TIMP-2 were not associated with any known clinicopathological tumour feature. TIMP-3 and TIMP-4 levels were significantly higher in steroid hormone receptor-positive samples, although the levels of TIMP-4 were much lower than those of the other TIMPs. Only TIMP-3 predicted relapse-free survival (RFS) time differently depending on post-surgical treatment as, in particular, the interaction of TIMP-3 with endocrine therapy (p = 0.008, HR = 0.24, 95% CI = 0.09-0.69) contributed significantly to RFS in multivariate Cox regression analysis. In subgroup analyses, the 107 patients treated with tamoxifen differed greatly in prognosis after dichotomization by the median TIMP-3 level (p = 0.0003). Thus, high tumour levels of the matrix metalloproteinases inhibitor and pro-apoptotic factor TIMP-3 are associated with successful tamoxifen treatment of patients with breast cancer.

The complex between urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-I) independently predicts response to first-line endocrine therapy in advanced breast cancer.

It has been shown that urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-I) have predictive value for therapy success in advanced breast cancer. Levels of the complex between uPA and PAI-I, formed when both molecules are in their active form, might have superior predictive power. Here, we investigate the association between levels of uPA:PAI-I complex and rate of response to first-line systemic therapy for advanced breast cancer. Tumor tissues of 170 patients with advanced breast cancer were analyzed for uPA:PAI-I complex concentrations using a quantitative enzyme-linked immunosorbent assay. The patients received either endocrine therapy (n=96) or chemotherapy (n=74) as first-line treatment after diagnosis of advanced disease. Of the endocrine treated patients, those with high levels of uPA:PAI-I complex showed a shorter progression-free survival (PFS) compared to patients with lower uPA:PAI-I complex levels (P=0.035). Furthermore, in the multivariate regression analysis a significant lower rate of response to first-line endocrine therapy was found in patients with high uPA:PAI-I complex levels compared to patients with low uPA:PAI-I complex levels (odds ratio (OR)=0.27, 95% CI, 0.09-0.59, P=0.018), in addition to the predictive impact of the steroid hormone receptor (ER/PgR) status (OR=2.68, 95% CI, 1.08-6.63, P=0.033). Complex levels did not predict efficacy of chemotherapy in patients with advanced breast cancer. The results show that the plasminogen activation system affects the response to endocrine therapy independent of steroid hormone receptor status and may be of help to further refine the indication for this treatment in individual patients. Further studies are warranted to explain this underlying resistance to endocrine therapy when uPA:PAI-I levels are high.

Mammaglobin is associated with low-grade, steroid receptor-positive breast tumors from postmenopausal patients, and has independent prognostic value for relapse-free survival time.

PURPOSE: The tumor mRNA expression levels of mammaglobin, a novel breast-specific and breast cancer-associated marker, were correlated with disease outcome in 280 patients with primary breast cancer. PATIENTS AND METHODS: Mammaglobin expression levels were assessed by quantitative reverse transcriptase polymerase chain reaction in frozen tumor tissue from breast cancer patients with a median age of 60 years (range, 30 to 88 years) and a median follow-up of 85 months (range, 2 to 169 months). RESULTS: High expression levels were associated with low-grade tumors (P =.018), with positive estrogen and progesterone receptor status (P <.001), and postmenopausal status (P =.010). In the analysis of all patients, low tumor mammaglobin expression levels predicted an early relapse both in Cox univariate (hazard ratio [HR], 0.52; 95% CI, 0.34 to 0.79; P =.002) and multivariate regression analyses corrected for the traditional prognostic factors (HR, 0.55; 95% CI, 0.35 to 0.88; P =.012). The association of mammaglobin expression with the rate of relapse was particularly favorable in patients who received adjuvant tamoxifen treatment (HR, 0.35; 95% CI, 0.17 to 0.71; P =.004). CONCLUSION: These results demonstrate that the assessment of the tumor mRNA expression level of the breast-specific protein mammaglobin could be useful to stratify patients for individual adjuvant treatment strategies.

Predictive impact of urokinase-type plasminogen activator: plasminogen activator inhibitor type-1 complex on the efficacy of adjuvant systemic therapy in primary breast cancer.

One of the most thoroughly studied systems in relation to its prognostic relevance in patients with breast cancer, is the plasminogen activation system. This system comprises of, among others, the urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-1). In this study we investigated whether the uPA:PAI-1 complex is associated with the responsiveness of patients with primary breast cancer to adjuvant systemic therapy. Quantitative enzyme-linked immunosorbent assays were used to assess the levels of uPA, PAI-1, and uPA:PAI-1 complex in 1119 tumors of patients with primary invasive breast cancer. These patients were followed for a median follow-up time of 59 months (range, 2-267 months) after the primary diagnosis. Correlations with well-known clinicopathological factors, and univariate and multivariate survival analyses were performed. High uPA:PAI-1 complex levels were correlated with an adverse histological grade, and inversely associated with negative estrogen and progesterone receptor status. High tumor levels of uPA:PAI-1 complex predicted an early relapse in the univariate relapse-free survival analysis (P < 0.001). The multivariate analysis showed that high uPA:PAI-1 complex levels were associated with a decreased relapse-free survival time (P = 0.033), independently of age, tumor size, number of lymph nodes affected, progesterone receptor status, uPA, adjuvant endocrine, and chemotherapy. More important, it was demonstrated that there is a larger benefit from adjuvant chemotherapy for patients with higher versus lower tumor levels of uPA:PAI-1 complex. The results of this study imply that the expression of uPA:PAI-1 complex independently predicts the efficacy of adjuvant chemotherapy in patients with primary breast cancer.

Vascular endothelial growth factor independently predicts the efficacy of postoperative radiotherapy in node-negative breast cancer patients.

PURPOSE: Vascular endothelial growth factor (VEGF) is a mediator of angiogenesis and is up-regulated under hypoxic conditions. Hypoxic tumors are known to exhibit resistance to radiotherapy. We investigated the association between VEGF levels in tumor tissue and the effect of radiotherapy for relapse-free survival (RFS) and overall survival (OS) in node-negative breast cancer. EXPERIMENTAL DESIGN: The study was performed on 489 patients; 221 patients received postoperative radiotherapy as part of the breast-conserving therapy (BCT), and 268 patients were treated by mastectomy only. VEGF levels were measured using a quantitative ELISA. None of the patients received adjuvant systemic therapy. The median follow-up was 64 months (range, 2-149) after BCT and 59 months (range, 2-117) after mastectomy. Correlations with well-known prognostic factors were studied, and univariate and multivariate survival analyses were performed. RESULTS: Only in the BCT group, high VEGF levels (equal or above the median level) predicted a reduced RFS and OS in univariate survival analysis (P = 0.004 and P = 0.028, respectively), implying that patients with high VEGF levels have less benefit from BCT. This was seen as a significant interaction between local treatment and VEGF for the total population for RFS (P = 0.012) and OS (P = 0.004). The interaction between local treatment and tumor size was also significant for both RFS (P = 0.046) and OS (P = 0.019) in the multivariate analysis. CONCLUSIONS: These results show that, in node-negative patients, both tumor size and VEGF content predict for a reduced efficacy of postoperative radiotherapy as part of BCT, indicating that the choice of local treatment of these patients can also be modified based on tumor VEGF content.

Vascular endothelial growth factor is associated with the efficacy of endocrine therapy in patients with advanced breast carcinoma.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a mediator of angiogenesis and is associated with a poor prognosis in patients with primary breast carcinoma. In the current study, the authors investigated whether there was an association between VEGF levels in tumor tissues and response rates to first-line, systemic therapy in patients with advanced breast carcinoma. METHODS: In 172 tumors from patients with primary breast carcinoma who developed distant metastases during follow-up, cytosolic levels of VEGF were measured using a quantitative enzyme-linked immunosorbent assay. Patients received either endocrine therapy (n = 96) or chemotherapy (n = 76) as first-line treatment after they were diagnosed with advanced disease. RESULTS: In univariate logistic regression analysis for response to endocrine therapy in 96 patients, an increasing level of VEGF, as a log-transformed, continuous variable, was correlated with a poor rate of response (P = 0.043). In multivariate analysis, a significantly lower rate of response to first-line endocrine therapy was found for patients who had high VEGF levels compared with patients who had low VEGF levels (P = 0.025). Similar results were found for the subgroup of 82 patients who received tamoxifen (P = 0.011). An association of VEGF with response to first-line endocrine therapy was found in addition to a predictive impact for estrogen receptor/progesterone receptor status (P = 0.027). VEGF levels did not predict the rate of response to first-line chemotherapy. CONCLUSIONS: The results demonstrated that the level of VEGF affects response to endocrine therapy independent of steroid hormone receptor status and may help to refine further the indication for this treatment in individual patients. Further studies are warranted to explain this underlying resistance to endocrine therapy.

Cyclin-E is a strong predictor of endocrine therapy failure in human breast cancer.

Recently, cyclin-E was reported to be the most prominent prognostic factor for breast cancer outcome described so far, even surpassing axillary nodal involvement. Earlier studies on the prognostic value of cyclin-E in breast cancer, however, yielded heterogeneous results. Therefore, we set out to confirm and extend these results by quantitative Taqman RT-PCR of cyclin-E levels in 277 resectable breast cancers. Cyclin-E levels were not associated with relapse-free survival (RFS) or overall survival (OS) in the total cohort of patients, or in the subset of patients without involved lymph nodes that were not treated with adjuvant systemic therapy. Besides several classical clinicopathological factors, the interaction between cyclin-E and adjuvant endocrine therapy (P=0.01, HR=3.04, 95% CI: 1.30-7.09) was found to contribute significantly in multivariate analyses. Cyclin-E levels were associated with poor RFS specifically in patients treated with adjuvant endocrine therapy (n=108, P=0.001, HR=4.01, 95% CI: 1.76-9.12), independent of estrogen receptor status. In conclusion, cyclin-E is not a pure prognostic factor in breast cancer, but rather a predictor of failure of endocrine therapy. Differences in literature on the presumed prognostic value of cyclin-E may be due to differences in treatment. Assessment of cyclin-E levels can aid in improving adjuvant treatment selection.

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.

Molecular beacon reverse transcription-PCR of human chorionic gonadotropin-beta-3, -5, and -8 mRNAs has prognostic value in breast cancer.

BACKGROUND: The beta-subunit of human chorionic gonadotropin (hCG) is encoded by four genes, of which expression of the hCGbeta-3, -5, and -8 genes could have prognostic value in breast cancer. METHODS: Applying a new, modified Molecular Beacon reverse transcription-PCR assay, we investigated the prognostic value of the hCGbeta-3, -5, and -8 gene transcripts in 129 sporadic unilateral breast cancer samples from patients with a median follow-up of 62.3 months. RESULTS: Expression of hCGbeta-3, -5, -8 was significantly (P = 0.020) associated with relapse-free survival (RFS). In multivariate survival analysis, hCGbeta-3, -5, and -8 maintained prognostic value for RFS, with high expression predicting shorter RFS (P = 0.015; hazard ratio, 2.25; 95% confidence interval, 1.17-4.34). Only 1 of 24 (4%) node-negative patients with low hCGbeta-3, -5, -8 expression relapsed, in contrast to 7 of 26 (27%) patients with high expression (P = 0.046). CONCLUSIONS: Expression of hCGbeta-3, -5, -8, which differ by only one nucleotide from other hCGbeta genes, can be assessed by our modified Molecular Beacon assay in breast cancer tissues. Expression of hCGbeta-3, -5, -8 has independent, prognostic value for RFS in breast cancer and may help identify node-negative patients with poor prognosis.