Clodronate treatment influences MMP-2 associated outcome in node positive breast cancer

Purpose. Serum postoperative matrix metalloproteinase 2 (MMP-2) level is a predictor of outcome in node positive breast cancer and can be used to stratify patients into low and high risk groups. Our aim was to determine how clodronate treatment influences MMP-2 associated clinical outcome.Patients and methods. Women with primary node-positive breast cancer were randomized to control group or to receive oral clodronate for 3 years. Adjuvant chemo- or endocrine therapy was given to all patients. The follow-up time for all patients was 5 years. MMP-2 and MMP-9 levels were quantitatively measured from the serum of 252 patients before and after 1 year clodronate treatment using enzyme-linked immunoassays.Results. In clodronate-treated patients, postoperative MMP-2 levels did not predict 5-year disease-free survival or overall survival (DFS, in low MMP-2 group (<5.32 ng/ml, median) 53% versus in high MMP-2 group (>median) 63%, p=NS; OS, 68% versus 63%, p=NS). When the patients were grouped according to serum MMP-2 levels, survival rates among patients with low MMP-levels were better in control than clodronate treated patients (DFS, 82% versus 53%, p = 0.003; OS, 91% versus 68%, p=0.014). Among patients with high serum MMP-2 levels, no significant difference in DFS or OS was found between control and clodronate groups. In multivariate analysis of low risk patients, independent predictors for DFS were treatment, age, nodal and PgR status, and those for OS treatment together with nodal and ER status. During 12 months follow-up, MMP-2 levels increased significantly more in clodonate receiving patients than in controls (p = 0.002). In comparison, when the patients were grouped according to MMP-9 levels, clodronate also impaired DFS among patients with low MMP-9 levels (82% versus 53%, p = 0.02), but no influence on OS was observed (83% versus 70%, p = 0.09).Conclusions. Clodronate interferes with the prognostic value of serum MMP-2. Clodronate has a negative impact on outcome among patients with low serum MMP-2 and MMP-9 levels, while no such influence is observed among patients with high MMP-2 and MMP-9 levels.     

Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial.

PURPOSE: Bisphosphonates have effectively reduced the development and progression of bone metastases in advanced breast cancer. The aim of this study was to determine whether bone metastases could be prevented by adjuvant clodronate treatment in patients with primary breast cancer. PATIENTS AND METHODS: Between 1990 and 1993, 299 women with primary node-positive breast cancer were randomized to clodronate (n = 149) or control groups (n = 150). Clodronate 1,600 mg daily was given orally for 3 years. All patients received adjuvant therapy: premenopausal six cycles of CMF chemotherapy and postmenopausal antiestrogens (randomized to tamoxifen 20 mg or toremifene 60 mg/d for 3 years). Seventeen patients were excluded from the analyses because of major protocol violations. The final population was 282 patients. Intent-to-treat analyses were also performed for all major end points. The follow-up time was 5 years for all patients. RESULTS: Bone metastases were detected equally often in the clodronate and control groups: 29 patients (21%) versus 24 patients (17%) (P: = .27). The development of nonskeletal recurrence was significantly higher in the clodronate group compared with controls: 60 patients (43%) versus 36 patients (25%) (P: = .0007). The overall survival (OS) and disease-free survival (DFS) rates were also significantly lower in the clodronate group than in the controls (OS, 70% v 83%, P: = .009; DFS, 56% v 71%, P: = .007, respectively). In multivariate analyses, clodronate remained significantly associated with DFS (P: = .009). CONCLUSION: Adjuvant clodronate treatment does not prevent the development of bone metastases in node-positive breast cancer patients. However, clodronate seems to have a negative effect on DFS by increasing the development of nonskeletal metastases.     

The association between the preoperative serum levels of lipocalin-2 and matrix metalloproteinase-9 (MMP-9) and prognosis of breast cancer

ABSTRACT: BACKGROUND: Although a number of experimental studies have suggested the role of lipocalin-2 (LCN2) and matrix metalloproteinase-9 (MMP-9) in breast cancer progression, limited numbers of epidemiological studies have examined the relationship between the lipocalin-2 and MMP-9 levels and breast cancer survival. METHODS: Preoperative serum levels of lipocalin-2 and MMP-9 were measured in 303 breast cancer patients and 74 healthy controls recruited between 2004 and 2007. We examined the association between lipocalin-2 and MMP-9 levels and disease-free survival (DFS) using Cox proportional hazard regression model. RESULTS: The serum levels of lipocalin-2 and MMP-9 were not significantly different between patients and controls (P > 0.05). Elevated lipocalin-2 and MMP-9 levels were associated with reduced DFS of breast cancer (Ptrend = 0.029 and Ptrend = 0.063, respectively). When lipocalin-2 and MMP-9 levels were categorized based on the combined risk score, patients with higher levels of both lipocalin-2 and MMP-9 exhibited poor DFS compared to patients with lower levels (Ptrend = 0.004). Furthermore, these effects were profound in patients with BMI less than 25kg/m2 (adjusted hazard ratio (aHR), 3.17; 95% confidence intervals (CI), 1.66-6.06, Ptrend < 0.001) or lymph-node negative breast cancer (aHR, 5.36; 95% CI, 2.18-13.2, Ptrend < 0.001). CONCLUSIONS: Our study suggests that the elevated levels of lipocalin-2 and MMP-9 are associated with reduced breast cancer survival, particularly in patients with lower BMI and lymph-node negative breast cancers.     

人表皮生长因子受体2表达对腋淋巴结阳性和阴性乳腺癌患者预后的不同影响

目的 探讨人表皮生长因子受体2(Her-2)表达在腋淋巴结阳性和阴性乳腺癌患者预后中的意义.方法 采用抗Her-2单克隆抗体CB11进行免疫组化,检测981例原发性乳腺癌肿瘤组织Her-2蛋白的表达,分析其与乳腺癌预后的关系.结果 981例原发性乳腺癌Her-2蛋白的阳性表达率为19.7%(193/981),Her-2表达水平与乳腺癌患者的发病年龄、雌激素受体(ER)和孕激素受体(PR)表达状态明显相关(P<0.05).单因素分析显示,在腋淋巴结阳性的乳腺癌患者中,Her-2表达与预后显著相关,Her-2阳性者的5年无病生存(DFS)率和5年总生存(OS)率分别为48.8%和55.2%,Her-2阴性者分别为66.9%和76.4%,差异均有统计学意义(P<0.01).而在腋淋巴结阴性的患者中,Her-2表达与患者的5年DFS率和5年OS率均无显著相关性(P>0.05).多因素分析显示,在腋淋巴结阳性的乳腺癌患者中,Her-2表达水平是影响乳腺癌OS的独立因素,但不是影响乳腺癌DF5的独立因素.结论 在腋淋巴结阳性乳腺癌患者中,Her-2表达水平是重要的预后因素.     

Prognostic value of Helix pomatia in breast cancer. International (Ludwig) Breast Cancer Study Group.

Six hundred and eighty-four primary breast cancers from the International (Ludwig) Breast Cancer Study Group (IBCSG) were studied for Helix pomatia lectin (HPA) binding. There was a weak correlation between lymph node-positive and HPA positive (P = 0.04). In our series there was a large advantage in disease-free survival (DFS) and overall survival (OS) for node-negative patients (P < 0.0001 DFS and OS). However, there was no such advantage for HPA-negative patients (P = 0.23 DFS and P = 0.32 OS). We conclude that in this randomised patient group HPA is of no clinical predictive value.     

High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma.

PURPOSE: Matrix metalloproteinases (MMP) are proteolytic enzymes that play an important role in various aspects of cancer progression. In the present work, we have studied the prognostic significance of serum levels of gelatinase B (MMP-9), collagenase-1 (MMP-1), and collagenase-3 (MMP-13) in patients with advanced melanoma. EXPERIMENTAL DESIGN: Total pretreatment serum levels of MMP-9 in 71 patients and MMP-1 and MMP-13 in 48 patients were determined by an assay system based on ELISA. Total MMP levels were also assessed in eight healthy controls. The active and latent forms of MMPs were defined by using Western blot analysis and gelatin zymography. RESULTS: Patients with high serum levels of MMP-9 (> or = 376.6 ng/mL; n = 19) had significantly poorer overall survival (OS) than patients with lower serum MMP-9 levels (n = 52; median OS, 29.1 versus 45.2 months; P = 0.033). High MMP-9 levels were also associated with visceral or bone metastasis (P = 0.027), elevated serum alkaline phosphatase level (P = 0.0009), and presence of liver metastases (P = 0.032). Serum levels of MMP-1 and MMP-13 did not correlate with OS. MMP-1 and MMP-9 were found mainly in latent forms in serum, whereas the majority of MMP-13 in serum was active (48 kDa) form. MMP-13 was found more often in active form in patients (mean, 99% of the total MMP-13 level) than in controls (mean, 84% of the total MMP-13 level; P < 0.0001). After initiating the therapy, patients with elevated levels of MMP-1 (> or = 29.8 ng/mL, n = 10) progressed more rapidly than patients with lower levels (median, 1.9 versus 3.5 months; P = 0.023). Serum levels of MMP-9 and MMP-13 did not correlate with the time to progression (TTP). In multivariate analysis with age and gender, MMP-9 or MMP-1 turned out to be independent prognostic factors for OS [P = 0.039; hazard ratio (HR), 1.8; 95% confidence interval (95% CI), 1.03-3.3] or TTP (P = 0.023; HR, 2.7; 95% CI, 1.15-6.4), respectively. CONCLUSIONS: Our findings provide evidence that MMP-1, MMP-9, and MMP-13 play important roles at different phases of metastatic melanoma spread and that serum MMP-9, in particular, could have clinical value in identifying patients at high risk for melanoma progression.     

Prognostic impact of proteolytic factors (urokinase-type plasminogen activator, plasminogen activator inhibitor 1, and cathepsins B, D, and L) in primary breast cancer reflects effects of adjuvant systemic therapy.

PURPOSE: Prognostic and predictive impact of five proteolytic factors associated with tumor invasion and metastasis in primary breast cancer were evaluated after long-term follow-up. EXPERIMENTAL DESIGN: Antigen levels of urokinase-type plasminogen activator, plasminogen activator inhibitor-1 (PAI-1), Cathepsins B, D, and L were determined using immunochemical assays in primary tumor tissue of 276 patients. RESULTS: During follow-up (median 109 months), 119 (43%) patients relapsed, and 117 (42%) died. In the whole collective, lymph node status (P < 0.001; RR 3.8), Cathepsin L (P < 0.001; RR 2.6), and PAI-1 (P = 0.027; RR 1.7) were the only independent significant factors in multivariate analysis for disease-free survival (DFS). For overall survival (OS), lymph node status (P < 0.001; RR 2.9), Cathepsin L (P = 0.017; RR 1.9), PAI-1 (P = 0.01; RR 1.9), and grading (P = 0.026; RR 1.7) were significant. In the node-negative subgroup, PAI-1 was the only significant factor for DFS (P = 0.004; RR 3.7) and the strongest factor (P = 0.004; RR 3.7) for OS next to grading (P = 0.017; RR 3.1). In node-positive patients, Cathepsin L was the only significant factor for both DFS (P < 0.001; RR 3.2) and OS (P = 0.003; RR 2.5). For all proteolytic factors but Cathepsin L, the univariate prognostic impact on DFS was substantial in patients without adjuvant systemic therapy but was diminished if adjuvant therapy had been administered. Cathepsin L maintained its strong prognostic impact on DFS even in patients with adjuvant endocrine therapy (P = 0.01; RR 2.8). CONCLUSIONS: The observed effect of adjuvant systemic therapy on their prognostic strength suggests that the assessed proteolytic factors supply predictive information on therapy response.     

Clinical Significance of Occult Micrometastases in Axillary Lymph Nodes in "Node-negative" Breast Cancer Patients

The most important subgroup of breast cancer patients for whom reliable prognostic indicators are needed is women without axillary lymph node metastases. We evaluated the clinical significance of occult micrometastases in axillary lymph nodes in 148 consecutive "node-negative" breast cancer patients. The median age of the patients at surgery was 52 years and the median follow-up period after surgery was 98.5 months. Occult micrometastases were detected in 21 of 148 patients (14.2%) by means of immunohistochemical analysis using AE1/3 antibody and a single unstained section after routine histopathological examination. Log-rank tests indicated that the 7–year disease-free survival (DFS) and overall survival (OS) rates by Kaplan-Meier methods were significantly better in patients without occult micrometastases than in patients with occult micrometastases [DFS, 93% versus 71% ( P =0.0009); OS, 96% versus 76% ( P =0.0001)]. According to Cox's multivariate analysis, the presence of occult micrometastases had the most significant effect on DFS ( P =0.0053) and OS ( P =0.0035). These findings suggest that the presence of occult micrometastases is an independent and significant predictor of clinical outcome, and that their immunohistochemical detection after routine histopathological examination is useful for selecting the "node-negative" breast cancer patient subgroup at high risk for relapse and death.     

激素受体和人表皮生长因子受体2的表达与改良根治术后淋巴结阳性乳腺癌患者预后的关系

目的 探讨雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(Her-2)的表达情况与行改良根治术后腋窝淋巴结阳性乳腺癌患者预后的关系.方法 收集835例行改良根治术后腋窝淋巴结阳性乳腺癌患者的临床和随访资料.根据ER、PR和Her-2的免疫组化检查结果,将患者分为Rec-/Her-2-(三阴性)组、Rec-/Her-2+组、Rec+/Her-2+组和Rec+/Her-2-组,比较其局部区域复发率、远处转移率、无瘤生存率和总生存率.结果 835例患者中,三阴性组141例,Rec-/Her-2+组99例,Rec+/Her-2+组157例,Rec+/Her-2-组438例.Rec+/Her-2-患者的5年局部区域复发率为6.2%,低于其他患者(12.9%,P=0.004).与受体阳性组(Rec+/Her-2+和Rec+/Her-2-)比较,受体阴性组(Rec-/Her-2-和Rec-/Her-2+)有较高的5年远处转移率(26.4%和19.7%,P=0.0008)、较低的5年无瘤生存率(66.7%和75.6%,P=0.0001)和较低的5年总生存率(71.4%和84.2%.P=0.0000).多因素Cox回归分析结果显示,激素受体和Her-2的表达状态是乳腺癌患者局部区域复发、远处转移、无瘤生存和总生存的独立影响因素(均P<0.05),Rec+/Her-2-患者的局部区域复发风险低,受体阴性患者发生远处转移和死亡的风险高.结论 ER、PR和Her-2是改良根治术后腋窝淋巴结阳性乳腺癌患者的独立预后因素.     

Clinical significance of occult micrometastases in axillary lymph nodes in "node-negative" breast cancer patients.

The most important subgroup of breast cancer patients for whom reliable prognostic indicators are needed is women without axillary lymph node metastases. We evaluated the clinical significance of occult micrometastases in axillary lymph nodes in 148 consecutive "node-negative" breast cancer patients. The median age of the patients at surgery was 52 years and the median follow-up period after surgery was 98.5 months. Occult micrometastases were detected in 21 of 148 patients (14.2%) by means of immunohistochemical analysis using AE1 / 3 antibody and a single unstained section after routine histopathological examination. Log-rank tests indicated that the 7-year disease-free survival (DFS) and overall survival (OS) rates by Kaplan-Meier methods were significantly better in patients without occult micrometastases than in patients with occult micrometastases [DFS, 93% versus 71% (P = 0.0009); OS, 96% versus 76% (P = 0.0001)]. According to Cox's multivariate analysis, the presence of occult micrometastases had the most significant effect on DFS (P = 0.0053) and OS (P = 0.0035). These findings suggest that the presence of occult micrometastases is an independent and significant predictor of clinical outcome, and that their immunohistochemical detection after routine histopathological examination is useful for selecting the "node-negative" breast cancer patient subgroup at high risk for relapse and death.     

Intramammary lymph node metastases are an independent predictor of poor outcome in patients with breast carcinoma

BACKGROUND: Breast carcinoma with intramammary lymph node (intraMLN) metastases is considered to be Stage II disease, even in the absence of axillary lymph node involvement. Nonetheless, little is known regarding the clinical significance of intraMLN metastases. The goals of the current retrospective analysis were to elucidate the clinical relevance of intraMLN metastases and to assess the relation between such metastases and outcome in patients with breast carcinoma. METHODS: One hundred ninety-six intraMLN specimens obtained between 1983 and 2003 were identified in the pathology database at The University of Texas M. D. Anderson Cancer Center (Houston, TX); 130 of these specimens were obtained in association with a primary breast malignancy. Data on the clinical and pathologic features of these specimens were collected and evaluated on univariate and multivariate analysis for potential correlations with 5-year rates of disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). The median follow-up duration was 36 months (range, 12-180 months). RESULTS: The median age of the 130 patients in the current study was 53 years (range, 27-84 years). Twenty-four patients (18%) had intraMLNs that were identified preoperatively by either mammographic or sonographic methods; in the remaining 106 cases, intraMLNs were detected on pathologic examination of surgical breast specimens. IntraMLN metastases were found in 28% of all cases (n = 36). Most patients who had intraMLN metastases (81%) also had axillary metastases; however, isolated intraMLN metastases were documented in 6 patients (5%). Univariate analysis revealed that patients with intraMLN metastases (compared with all other patients) had poorer 5-year rates of DFS (54% vs. 89%; P = 0.001), DSS (66% vs. 90%; P = 0.001), and OS (64% vs. 88%; P = 0.004). Furthermore, multivariate analysis indicated that intraMLN involvement was an independent predictor of reduced DFS (hazard ratio, 2.33; P = 0.03), DSS (hazard ratio, 5.32; P = 0.002), and OS (hazard ratio, 3.22; P = 0.006). CONCLUSIONS: The current retrospective analysis demonstrated that the presence of intraMLN metastases is an independent predictor of poor outcome in patients with breast carcinoma. Identification of an intraMLN on preoperative imaging should prompt further histopathologic assessment. Identification of malignant intraMLNs by lymphatic mapping may help to identify high-risk patients for whom further evaluation of the axillary lymph nodes is warranted despite otherwise clinically negative findings in the axilla.     

Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow—a long-term follow-up

Background: Adding oral clodronate to postoperative adjuvant breast cancer therapy significantly improves disease-free survival (DFS) and overall survival (OS). Long-term follow-up data from the prospective, randomized, controlled study are reported.Patients and methods: Patients with primary breast cancer received clodronate 1600 mg/day for 2 years or no treatment along with standard adjuvant breast cancer treatment.Results: Analysis of 290 of 302 patients demonstrated that a significant improvement in OS was maintained in the clodronate group at a median follow-up of 103 ± 12 months; 20.4% of patients in the clodronate group versus 40.7% of control group patients (P = 0.04) died during the 8.5 years following primary surgical therapy. Significant reductions in the incidence of bony and visceral metastases and improvement in duration of DFS at 36- and 55-month follow-up periods were no longer seen with clodronate.Conclusion: These long-term survival data extend the survival advantage reported in previous studies with oral clodronate in breast cancer.     

BRCA2 mutations and androgen receptor expression as independent predictors of outcome of male breast cancer patients.

PURPOSE: Germline mutations of the BRCA2 gene are involved in the development of a considerable number of male breast cancer cases. Although phenotypic differences have been observed between sporadic and BRCA-related breast carcinomas, conflicting data exist on the differences in prognosis of women with hereditary and sporadic breast cancer. The purpose of the study was to investigate the prognostic value of BRCA2 status in male breast carcinoma (MBC). EXPERIMENTAL DESIGN: We studied 43 male breast cancer patients, including 12 with BRCA2 mutations. Tumor samples were characterized immunohistochemically using antibodies to estrogen receptor, progesterone receptor, and androgen receptor (AR). RESULTS: BRCA2-related tumors presented at the earlier age compared with sporadic tumors (P = 0.005). Patients positive and negative for BRCA2 mutations did not differ with respect to tumor size, lymph node involvement, histological grade, and sex hormone receptor status. Five-year disease-free survival (DFS) and overall survival (OS) were significantly decreased in BRCA2-positive patients (67% versus 28% for BRCA2-negative versus positive patients, respectively, P = 0.017 for DFS; 86% versus 25%, P = 0.006 for OS). Shorter survival was also correlated with expression of AR in tumor tissue (74% versus 33% for patients with tumors staining negatively and positively for AR, P = 0.029 for DFS; 71% versus 57%, P = 0.05 for OS). CONCLUSIONS: The BRCA2 mutations and AR expression in tumor tissue are independent adverse factors for MBC prognosis. BRCA2-related MBC presents at the earlier age compared with non-BRCA2-related cancer, but do not differ with respect to other clinicopathological features.     

Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy

The predictive role of the degree of endocrine responsiveness to preoperative chemotherapy (PCT) is unclear. We reviewed pretreatment biopsies of 553 patients with locally advanced breast cancer who were treated with PCT. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to the degree of estrogen (ER) and progesterone receptor (PgR) expression (ER and PgR absent, vs. ER or PgR 0–49%, vs. ER and PgR ≥50% of the cells positive). A statistically significant higher pCR rate was observed at the multivariate analysis for patients with ER and PgR absent tumors (17.7%) versus patients with tumors expressing high ER and PgR (0%) (OR 14.4 P < 0.001). Despite the higher incidence of pCR, a statistically significant worse disease-free survival (DFS), and overall survival (OS) was observed for patients with ER and PgR absent tumors versus patients with tumors expressing high ER and PgR (HR 6.4, 95% CI 3.5–11.6, for DFS; HR 3.6 95% CI 2.4–5.6 for OS). Response and outcome after PCT are correlated with the degree of expression of steroid hormone receptors. Studies on tailored preoperative therapies are needed.     

c-erbB-2 oncoprotein overexpression identifies a subgroup of estrogen receptor positive (ER+) breast cancer patients with poor prognosis

Purpose:To investigate the predictive value of c-erbB-2 oncoprotein expression as compared with established histopathological and cytometric indicators of disease evolution in breast carcinoma. Patients and methods:A short-term retrospective study was conducted on a series of 306 breast cancer patients. Classic prognostic factors included tumour size, nodal involvement, histological grading, and hormone receptor status. Flow cytometric DNA ploidy and S-phase fraction (SPF) were also assessed. A Cox proportional hazards regression model was used for multivariate statistical analysis. Results:c-erbB-2 overexpression was present in 43 out of 295 (14.6%) tumours, and showed a statistically significant correlation with high histological grade, DNA aneuploidy, high SPF and lack of estrogen receptors (ER). Univariate analysis revealed its association with worse disease-free survival (DFS) and overall survival (OS). The combined evaluation of c-erbB-2 with ploidy and SPF defines a variable (P + S + c) that showed a significant correlation with disease outcome. By multivariate analysis, only nodal status (P < 0.001) and P + S + c subgrouping (group 2: P = 0.002; group 3: P = 0.001) in relation to DFS, and nodal status (P = 0.001) and DNA ploidy (P = 0.006) in relation to OS, retained independent prognostic significance. Subset analyses showed that cytometric parameters, P + S + c subgrouping and hormone receptors were significantly correlated with disease outcome in node-positive patients, whereas in node-negative subgroup no prognostic indicators were found. c-erbB-2 overexpression exhibited a trend in node-positive breast cancer (DFS: P = 0.068; OS: P = 0.086), and significant correlation with poor clinical evolution in ER positive patients (DFS: P = 0.015; OS: P = 0.004), mostly receiving tamoxifen. Conclusions:c-erbB-2 is an independent prognostic indicator of DFS when evaluated in conjunction with ploidy and SPF. It also seems to predict response to tamoxifen therapy, by identifying a subgroup of ER positive (ER+) breast cancer patients with poor prognosis.     

Prognostic effect of amenorrhoea and elevated serum gonadotropin levels induced by adjuvant chemotherapy in premenopausal node-positive breast cancer patients

The purpose of the study was to determine the correlation between prognosis and chemotherapy induced amenorrhoea or elevated gonadotropin levels in node-positive breast cancer patients. Since we have previously found a better prognosis in patients with more profound leucopenia induced by adjuvant chemotherapy, we examined whether this effect was mediated through more efficient induction of amenorrhoea. The study population consisted of 126 premenopausal, primarily operable, node-positive breast cancer patients treated with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) adjuvant chemotherapy at the Department of Oncology, Helsinki University Central Hospital between 1990 and 1993. 12 months after the beginning of adjuvant chemotherapy, the patients were divided into groups with respect to their menstrual function (regular menstruation, irregular menstruation or amenorrhoea). Information about menstruation status and serum concentration of follicle stimulating hormone (FSH) and oestradiol were recorded at 12 and 24 months from the beginning of adjuvant chemotherapy. Median follow-up time was 72 months. Women who experienced amenorrhoea or had irregular menstruation after chemotherapy had a significantly better 5-year disease-free survival (DFS) in univariate analysis than women who continued to menstruate (P = 0.02). Amenorrhoea and irregular menstruation were associated with a better DFS among patients with oestrogen receptor (ER) positive primary tumours (P = 0.007), whereas no such association was found in ER negative cases (P = 0.86). 5-year overall survival (OS) in univariate analysis was also better in patients who experienced amenorrhoea (81%) or who had irregular menstruation (90%) after chemotherapy as compared with patients with regular menstruation (68%; 81 versus 68%, P = 0.05). The serum FSH level did not correlate significantly with outcome irrespective of the cut-off point chosen. Nodal status, tumour size and menstruation status after chemotherapy were also significantly associated with DFS in a multivariate analysis. The menstruation status after chemotherapy lost its significance for OS in a multivariate analysis whilst the number of affected lymph nodes, tumour size and oestrogen/progesterone receptor status retained their impact. There was no association between the degree of leucopenia and induction of amenorrhoea by CMF. Chemotherapy-induced ovarian function suppression (amenorrhoea/irregular menstruation) after chemotherapy had a favourable effect on DFS in premenopausal breast cancer patients. The post-chemotherapy menstruation status is a clinically usable marker for sufficient endocrine effect of chemotherapy in ER/PR-positive patients in all premenopausal age groups. FSH level seemed to be a less reliable indicator of the castration effect of adjuvant chemotherapy in this study.     

Survival analyses from the ZEBRA study. goserelin (Zoladex) versus CMF in premenopausal women with node-positive breast cancer

The Zoladex Early Breast Cancer Research Association (ZEBRA) trial compared the efficacy and tolerability of goserelin (Zoladex) with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy in pre-/perimenopausal women with node-positive early breast cancer. The results of disease-free survival (DFS) analyses have already been published. Here we present an update including data on overall survival (OS) from the ZEBRA trial at a median follow-up of 7.3 years. In patients with oestrogen receptor (ER)-positive tumours, non-inferiority of goserelin versus CMF for OS was shown; goserelin was again shown to be equivalent to CMF for DFS. This updated analysis has demonstrated that the two treatments are also equivalent for distant disease-free survival (DDFS). In patients with ER-negative disease, goserelin was inferior to CMF for DFS, DDFS and OS. This follow-up analysis confirms the previously reported outcomes from the ZEBRA trial and demonstrates that goserelin offers an effective alternative to CMF chemotherapy for adjuvant therapy of premenopausal patients with ER-positive, node-positive early breast cancer.     

Outcome of non-metastatic male breast cancer: 118 patients

Studies concerning adjuvant systemic therapy and prognosis in male breast carcinoma (MBC) are limited. We aimed to evaluate outcome of the changing practices of adjuvant systemic treatment and survival in operable MBC patients over the last two decades. The medical records of 148 MBC patients followed between the years 1986 and 2009 at 7 cancer center were evaluated retrospectively. One hundred and eighteen operable non-metastatic patients had sufficient data were included the study. One hundred and eighteen operable MBC were found to be eligible. Median age was 60 (range 29-83) years. Thirty-two percent of the patients had T3-4 tumors. Half of the patients had axillary lymph node-positive disease. The proportion of positivity of estrogen receptor(ER), progesterone receptor (PgR), and HER2 status were 82.9, 75.8, and 23.4%, respectively. Only, 7 patients had triple negative (TN). Adjuvant hormonotherapy was advised for 76.8% whereas adjuvant chemotherapy for 73.7% of the patients. Median follow-up was 40.9 months (range 3.8-186 months). Locoregional and/or distant recurrence developed in thirty-eight patients (32.2%). Twenty-three patients died during the follow-up period. Five-year disease-free survival (DFS) was found to be 60%, whereas overall survival (OS) was 82%. Larger tumor size and lymph node positivity were statistically significant poor prognostic factors for OS. Although statistical insignificant, patients with HER2-positive tumors have worse DFS (52 vs. 120 months, log rank P = .73) and OS (85 vs. 144 months, log rank P = .30) than HER2-negative ones. Although the frequency of the use of adjuvant systemic therapy in MBC has been increasing and survival rates improving for the last decades, lymph node status and tumor size are still the most important determining factors for prognosis. There is a need for further prognostic information in men with HER2-positive or TN breast cancer.     

Good clinical response of breast cancers to neoadjuvant chemoendocrine therapy is associated with improved overall survival.

BACKGROUND: We present extended follow-up from a prospective randomised trial evaluating the role of neoadjuvant chemoendocrine therapy in the treatment of operable breast cancer. PATIENTS AND METHODS: 309 women were randomised to primary surgery followed by eight cycles of adjuvant mitoxantrone, methotrexate with tamoxifen (2MT) or 2MT with mitomycin-C (3MT) versus the same regimen for four cycles before followed by four cycles after surgery. For this analysis the median follow-up of patients was 112 months. RESULTS: After 10 years follow-up there is still no statistically significant difference in disease-free survival (DFS) (71% versus 71%) or overall survival (OS) (63% versus 70%) when comparing adjuvant versus neoadjuvant treatment, respectively. Of 144 evaluable patients in the neoadjuvant arm, 74 achieved a good clinical response and 70 patients achieved a poor clinical response. Good responders had a superior DFS (80% versus 64%, P=0.01) and OS (77% versus 63%, P=0.03) compared to poor responders. CONCLUSIONS: At 10 years, neoadjuvant and adjuvant treatment continue to have equivalent OS and DFS. Good clinical response to neoadjuvant chemotherapy is associated with superior DFS and OS. This supports the use of clinical response of primary breast cancer to neoadjuvant therapy as a surrogate marker of survival benefit.     

Operable Breast Cancer of the Inner Hemisphere Is Associated with Poor Survival

Purpose

This study investigated the clinicopathological features of operable breast cancer lesions located in different hemispheres of the breast and determined related survival outcomes.

Methods

Data from 5,330 patients with invasive ductal carcinoma were retrospectively analyzed based on tumor location.

Results

The median follow-up time was 68 months (range, 18-176 months). Patients with breast cancer located in the outer hemisphere of the breast had lesions with more advanced nodal stages and more frequently received adjuvant chemotherapy than patients with breast cancer in the inner hemisphere. The 5-year disease-free survival (DFS) rates of patients with tumors located in outer versus inner hemispheres were 81.5% and 77.0%, respectively (p=0.004); the overall survival (OS) rates were 90.7% and 88.8%, respectively (p<0.001). The association between tumor location and the 5-year DFS rate was most apparent in node-positive patients (73.1% vs. 65.8% for outer vs. inner hemisphere lesions, p<0.001) and in patients with primary tumors greater than 2 cm in diameter (78.2% vs. 72.3%, p=0.002). Multivariate analysis showed that tumor location was an independent predictor of DFS (hazard ratio [HR], 1.23; p=0.002) and OS (HR, 1.28; p=0.006). There were no significant differences in 5-year DFS or OS rates between patients with outer versus inner hemisphere tumors when internal mammary node irradiation was performed.

Conclusion

This study demonstrated that tumor location was an independent prognostic factor for operable breast cancer. Internal mammary node irradiation is recommended for patients with breast cancer of the inner hemisphere and positive axillary lymph nodes or large primary tumors.