Brain metastases in breast cancer: prognostic factors and management

Background The purpose of this retrospective study was to analyze the overall survival of patients with brain metastases due to breast cancer and to identify prognostic factors that affect clinical outcome. Methods Of the 7,872 breast cancer patients histologically diagnosed with breast cancer between January 1990 and July 2006 at the Asan Medical Center, 198 patients with solitary or multiple brain metastases were included in this retrospective study. Central nervous system (CNS) lesions were diagnosed by computed tomography (CT) or magnetic resonance imaging (MRI). Patients with leptomeningeal or dural metastases without co-existent parenchymal metastatic lesions were excluded in this study. We reviewed the medical records and pathologic data of these 198 patients to characterize the clinical features and outcomes. Results The median age of the patients at the diagnosis of brain metastases was 45 years (range 26–78 years). Fifty-five patients (28%) had a single brain metastasis, whereas 143 (72%) had more than two metastases. A total of 157 (79.2%) patients received whole-brain radiation therapy (WBRT). A total of 7 (3.6%) patients underwent resection of solitary brain metastases, 22 (11%) patients underwent gamma-knife surgery, three patients underwent intrathecal chemotherapy (1.5%) and 9 (4.6%) patients received no treatment. The overall median survival time was 5.6 months (95% confidence interval (CI), 4.7–6.5 months) and 23.1% of the patients survived for more than 1 year. The median overall survival time was 5.4 months for patients treated with WBRT, 14.9 months for patients treated with surgery or gamma-knife surgery only, and 2.1 months for patients who received no treatment (P < 0.001). Multivariate analysis demonstrated that Eastern Cooperative Oncology Group (ECOG) performance status (relative risk (RR) = 0.704, 95% CI 0.482–1.028, P = 0.069), number of brain metastases (RR = 0.682, 95% CI 0.459–1.014, P = 0.058), treatment modalities (RR = 1.686, 95% CI 1.022–2.781, P = 0.041), and systemic chemotherapy after brain metastases (RR = 1.871, 95% CI 1.353–2.586, P < 0.001) were independent factors associated with survival. Conclusion Although survival of breast cancer patients with brain metastases was generally short, the performance status, number of brain metastases, treatment modalities and systemic chemotherapy after brain metastases were significantly associated with survival. Patients with single-brain metastasis and good performance status deserve aggressive treatment. The characteristics of initial primary breast lesions did not affect survival after brain metastasis.     

Central nervous system metastases in a cohort of metastatic breast cancer patients treated with trastuzumab

Background  Several analyses suggest an increase of brain metastases in HER2 over-expressing breast cancers treated with trastuzumab as compared to historical series of unselected patients. Patients and methods  We analyzed the incidence of central nervous system (CNS) metastases in 78 patients with HER2 over-expressing breast cancer treated with trastuzumab between July 2000 and June 2006 at the Oncology Department of University Federico II in Naples. We also characterized and compared patients with and without CNS involvement. Results  The median follow-up was 35.3 months (95%CI 26.3–44); median overall survival was 56 months (95%CIs 46-nr); 5 patients showed CNS involvement before trastuzumab therapy while 31 developed CNS metastases during trastuzumab treatment. The median overall survival after CNS metastases was 25.4 months (95%CIs 15.2-nr); patients with CNS lesions showed worse overall survival than patients without CNS lesions (39.1 vs. 75 months, p = 0.005). Conclusion  CNS metastases are common events in patients with metastatic HER2 over-expressing breast cancer treated with trastuzumab; the impact on survival is detrimental even if survival after CNS metastases is longer than historical reports. Appropriate investigation of the role of CNS imaging screening and the prophylactic treatment strategies for CNS represents a priority research in this setting. E. Montagna and G. Cancello have contributed equally to this work.     

Clinicopathological features of breast cancers predict the development of leptomeningeal metastases: a case-control study

The incidence of leptomeningeal metastases (LM) in patients with breast cancer (BC) is increasing as a result of increased screening and improved patient survival. However, the median survival time after diagnosis of LM is between 5 weeks (without any treatment) and 5 months (for aggressively treated patients). In an attempt to identify clinicopathological risk factors for LM, we carried out a case-control study of 100 women with BC. Fifty patients with BC and LM were enrolled and an additional 50 patients with BC and no CNS metastases including leptomeningeal spread were selected as controls. Patients who had developed LM were selected between December 2006 and August 2008. The control group was matched for: age at diagnosis, year of diagnosis, and initiation of chemotherapy at BC diagnosis. The ILC type (P = 0.03), ER-negative (P = 0.01) and PR-negative status (P = 0.03), and initial M+ status at BC diagnosis (P = 0.008) tended to be more frequent in LM patients. These characteristics should lead to early appropriate assessments being performed in this targeted population when a neurological complaint appears, in order to detect LM as soon as possible.     

Surgical resection of brain metastases: the prognostic value of the graded prognostic assessment score

There is a need for better predictors for short survival in patients with brain metastases undergoing open surgery. The graded prognostic assessment (GPA) has recently been developed to predict survival in patients with brain metastases. We explored the prognostic capabilities of GPA in a consecutive neurosurgical population of brain metastases. Secondarily, we evaluated if GPA scores can provide information on safety of the operation and postoperative functional outcome. We retrospectively included all adult (≥18 years) patients undergoing open surgery for brain metastases from 2004 through 2009 (n = 141). The population was grouped into GPA 0–1 (n = 22, 16%), GPA 1.5–2.5 (n = 90, 64%), GPA 3 (n = 19, 14%), and GPA 3.5–4 (n = 10, 7%) according to the prognostic indices. Median survival times were 6.3 months (range 0.8–23.7) in GPA 0–1, 7.8 months in GPA 1.5–2.5 (range 0.2–75.0), 14.0 months in GPA 3 (range 0.0–77.4), and 18.4 months in GPA 3.5–4 (range 0.1–63.7). This represents a significant difference between groups (P = 0.010). There were no associations between GPA and 30-day mortality (P = 0.871), 3-month mortality (P = 0.750), complications (P = 0.330) or change in Karnofsky Performance status postoperatively (P = 0.558). GPA scores hold prognostic properties in patients operated for brain metastases. However, GPA did not predict short-term mortality, limiting the clinical usefulness in a neurosurgical population. The prognostic indices cannot be used alone to decide if surgery is warranted on an individual basis, or to evaluate risks and benefits of surgery.     

Central Nervous System Metastases in Thymic Epithelial Tumors: A Brief Report of Real-World Insight From RYTHMIC

Thymic epithelial tumors (TETs) are rare malignancies ranging from indolent thymoma A to aggressive thymic carcinomas (TCs). Brain metastases are extremely infrequent for TETs and have only been described in case reports or small single-center series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French nationwide network mandated to systematically review every TET case and prospectively includes all consecutive patients discussed by national or regional tumor boards. We analyzed patients with TETs and central nervous system (CNS) metastasis during their cancer history from this large French registry. In an 8-year period, 2909 patients were included in the database, including 248 TCs (8.5%). A total of 14 patients had CNS metastases, five (36%) at diagnosis and nine (64%) at relapse. Among them, 12 patients (86%) had a diagnosis of TC and two (14%) had thymoma A and B3. Surgical biopsies were performed, and the histologic subtype for non-TC tumors was centrally confirmed. Median overall survival was 22 months (95% confidence interval [CI]: 9.8–34.2), with longer, albeit not significant, overall survival when CNS metastases were present at diagnosis versus relapse (not reached versus 17 mo; p = 0.29); median progression-free survival was 13 versus 8 months (p = 0.06), respectively. A higher risk of death (hazard ratio = 5.34, 95% CI: 1.3–21.9, p = 0.02) and relapse (hazard ratio = 1.89, 95% CI: 0.9–3.7, p = 0.06) was observed for patients suffering from TC with brain metastases compared with those without CNS extension. CNS disease was extremely rare in our TET cohort (0.48%), reported at both diagnosis and progression, present primarily in TC, with prevalence rising to 4.9%.     

Fifteen-year median follow-up results after neoadjuvant doxorubicin, followed by mastectomy, followed by adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) followed by radiation for stage III breast cancer: a phase II trial (CALGB 8944)

Purpose To describe long-term results of a multimodality strategy for stage III breast cancer utilizing neoadjuvant doxorubicin followed by mastectomy, CMF, and radiotherapy. Patients and methods Women with biopsy-proven, clinical stage III breast cancer and adequate organ function were eligible. Neoadjuvant doxorubicin (30 mg/m² days 1–3, every 28 days for 4 cycles) was followed by mastectomy, in stable or responding patients. Sixteen weeks of postoperative CMF followed (continuous oral cyclophosphamide (2 mg/kg/day); methotrexate (0.7 mg/kg IV) and fluorouracil (12 mg/kg IV) weekly, weeks 1–8, and than biweekly, weeks 9–16). Radiation therapy followed adjuvant chemotherapy. Results Clinical response rate was 71% (79/111, 95% CI = 62–79%), with 19% complete clinical response. Pathologic complete response was 5% (95% CI = 2–11%). Median follow-up is 15.6 years. Half of the patients progressed by 2.2 years; half died by 5.4 years (range 6 months–15 years). The hazard of dying was greatest in the first 5 years after diagnosis and declined thereafter. Time to progression and overall survival were predicted by number of pathologically involved lymph nodes (TTP: HR [10 vs. 1 node] 2.40, 95% CI = 1.63–3.53, P < 0.0001; OS: HR 2.50, 95% CI = 1.74–3.58, P < 0.0001). Conclusions After multimodality treatment for locally advanced breast cancer, long-term survival was correlated with the number of pathologically positive lymph nodes, but not to clinical response. The hazard of death was highest during the first 5 years after diagnosis and declined thereafter, indicating a possible intermediate endpoint for future trials of neoadjuvant treatment. Memorial Sloan Kettering Cancer Center, New York, NY—L. Norton, supported by CA77651. University of California San Francisco, San Francisco, CA—I. C. Henderson, supported by CA60138.     

Pattern of metastatic spread in triple-negative breast cancer

Purpose The prognosis of women with triple-negative breast cancers (defined as cancers that are estrogen receptor-negative, progesterone receptor-negative and HER2/neu negative) is poor, compared to women with other subtypes of breast cancer. It is proposed that the underlying difference in recurrence rates may be explained in part by different routes of metastatic spread. Experimental design We studied a cohort of 1608 patients diagnosed with breast cancer, diagnosed between January 1987 and December 1997 at Women’s College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor-negative, progesterone receptor-negative and HER2/neu-negative. We compared the incidence rates of metastatic spread to bone and to other (non-bone) organs in women with triple-negative and other forms of breast cancer. Results Of the 1,608 patients, 180 (11.2%) had triple-negative breast cancer. The 1608 women were followed for a median of 9.0 years (range 0.1–19 years). Compared to other patients, those with triple-negative breast cancer had an increased likelihood of distant recurrence over the study period (adjusted hazard ratio (HR) 1.9; 95% CI: 1.5–2.5, P < 0.0001). The relatively poor prognosis was apparent in the five years after diagnosis (HR 2.9; 95% CI: 2.1–3.9; P = 0.0001) but not thereafter (HR 0.5; 95% CI: 0.2–1.1; P = 0.07). In particular, women with triple-negative breast cancer were four times more likely to experience a visceral metastasis within five years of diagnosis than those with other types of cancer (HR 4.0; 95% CI: 2.7–5.9; P < 0.0001). The rates of bone metastases were comparable for triple-negative and for other forms of cancer in this time period (HR 0.8; 95% CI: 0.4–1.6 P = 0.5). Conclusions The excess risk of distant recurrence in triple-negative breast cancers, versus other forms of cancer, is attributable in large part to an excess of visceral metastases in the first five years following diagnosis.     

Ventriculoperitoneal shunt for hydrocephalus caused by central nervous system metastasis

The development of better diagnostic tools and therapeutic modalities has increased the incidence of central nervous system (CNS) metastasis in malignant tumor patients. Hydrocephalus can result from CNS metastasis and frustrate cancer treatment. The authors sought to investigate the outcomes and the roles of ventriculoperitoneal shunts (VPS) in patients with CNS metastasis. The medical records of 50 consecutive patients who underwent VPS for hydrocephalus related to CNS metastasis were analyzed retrospectively. Data included features of primary malignancies, CNS involvement, clinical course and surgical outcome. Median patient age was 55.0 years (range 25–77), and 30 female and 20 male patients were included in the study. At the time of VPS, 10 patients had parenchymal metastases only and 40 patients had leptomeningeal seeding (LMS). Symptom improvement was observed postoperatively in 40 patients (80%), mean Karnofsky performance status (KPS) scale change was from 37.8 to 46.0, and median survival from VPS was 3.0 months (2 days to 54 months). A ventricular opening pressure of >30 cmH₂O (HR 6.44, 95% CI 1.26–32.9, P = 0.02) and further cancer treatment after VPS (HR 0.17, 95% CI 0.07–0.42, P < 0.0001) were found to be independent risk factors of poorer and better survival, respectively. Hydrocephalus in CNS metastasis requiring VPS is commonly associated with LMS. VPS is an effective palliative measure and an adequate cancer treatment after VPS may provide the best means of improving survival.     

Impact of comorbidity on mortality: a cohort study of 62,591 Danish women diagnosed with early breast cancer, 1990-2008

The incidence of breast cancer, as well as other chronic disease, increases with age, older breast cancer patients being more likely than younger to suffer from other diseases at time of diagnosis. Our objective was to assess the effect of comorbidity on mortality after early breast cancer. 62,591 women diagnosed with early breast cancer 1990–2008 were identified using the Danish Breast Cancer Cooperative Group Registry. Data were linked to the Danish National Patient Register and the Danish Register of Causes of Death. Main outcome measures were mortality from all causes, breast cancer, and non-breast cancer causes in relation to Charlson comorbidity index (CCI). Compared with patients without comorbidity (CCI 0), the presence of comorbidity increased the risk of dying from breast cancer as well as other causes with adjusted hazard ratios (HRs) for all-cause mortality of 1.45 (CI 95% 1.40–1.51) for CCI 1, 1.52 (95% CI 1.45–1.60) for CCI 2, and 2.21 (95% CI 2.08–2.35) for CCI 3+. Equivalent HRs for breast cancer-specific mortality were 1.30 (95% CI, 1.24–1.36) for CCI 1, 1.31 (95% CI 1.23–1.39) for CCI 2, and 1.79 (95% CI, 1.66–1.93) for CCI 3+ (all P values < 0.0001). For patients with CCI 0, 5-year overall survival increased over time from 72.5% (95% CI, 71.7–73.3%) in 1990–1994 to 81.6% (95% CI, 80.9–82.2) in 2000–2004, whereas the 5-year overall survival remained stable around 43% among the patients with CCI 3+. This population-based cohort study shows that compared with patients without comorbidity, the risk of dying from breast cancer as well as other causes increased significantly with increasing CCI score. While survival improved over time for patients without comorbidity, no improvement was seen among patients with severe comorbidity (CCI 3+).     

Age-specific trends of survival in metastatic breast cancer: 26 years longitudinal data from a population-based cancer registry in Stockholm,Sweden

Treatment of metastatic breast cancer (MBC) has evolved during the last decades but it is largely unknown whether this has led to improved survival in the general MBC population. Based on the regional, population-based breast cancer registry, we identified 5,463 patients diagnosed with MBC in Stockholm County during 1979–2004. Patients were divided into five cohorts based on the year of first MBC diagnosis and observed and relative survival were compared across the cohorts after adjustment for potential confounders. A significant trend of better survival over time was demonstrated for patients 60 years or younger (P < 0.001, by log-rank test for trend), but not for older patients (P = 0.12) or for the whole MBC population (P = 0.13). The adjusted observed survival of patients ≤60 years was significantly improved in the 2000–2004 cohort (P < 0.001, hazard ratio = 0.7, 95% confidence interval = 0.58–0.84), corresponding to a clinically significant increase of median survival with more than 3 months and absolute increase of 5-year survival with 8% or more compared to previous periods. Similarly, relative survival analysis indicated a 31% decreased mortality for the younger subpopulation in the 2000–2004 cohort (P < 0.001). Systemic adjuvant treatment was a negative prognostic factor after distant recurrence. Treatment advancements in MBC are not reflected by better survival for the whole MBC population. An improvement is only observed after the year 2000 and is restricted to younger patients.     

Prognostic value of chemotherapy-induced neutropenia in early-stage breast cancer

Neutropenia is one of the most important dose-limiting toxicities and often the reason for dose reduction. In this study we aimed to assess whether chemotherapy-induced neutropenia could be a marker of efficacy and associate with increased survival. Data from a retrospective survey for early breast cancer patients in our hospital were reviewed. Three hundred and thirty-five patients who had been treated with six cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF) were studied. The association between chemotherapy-induced neutropenia and overall survival (OS) was assessed. According to a multivariate Cox model with time-varying covariates, hazard ratios of death were 0.434 (95% confidence interval (CI), 0.298–0.634; P < 0.001) for patients with mild neutropenia, and 0.640 (95% CI, 0.42–0.975; P = 0.038) for those with severe neutropenia. Neutropenia occurring in early breast cancer patients is an independent predictor of increased survival. These findings suggest that neutropenia in patients who receive chemotherapy is strongly associated with a better prognosis.     

Stereotactic radiosurgery in the management of brain metastases from primary thyroid cancers

Patients with metastatic well-differentiated thyroid cancer have a generally favorable long-term outcome although multi-organ involvement is a known marker of poor prognosis. Brain metastases are rare, occurring in less than 1% of patients with thyroid cancer. Few patients have been managed with stereotactic radiosurgery (SRS). A retrospective database of 5,067 patients treated for brain metastases between 1985 and 2007 was generated from 11 institutions. Thyroid cancer patients were identified in this database and, when possible, additional information was obtained from further chart review. Patients were excluded if they had incomplete treatment or follow-up information. Two validated prognostic indices, Graded prognostic Assessment (GPA) and Recursive Partitioning Analysis (RPA), were calculated for each patient. The overall survival times were calculated by the Kaplan–Meier method. Twenty-three thyroid cancer patients were identified (51% male, 48% female). Median age was 63 years (range 20–81). Pathology of the primary thyroid disease was available for twelve patients; the majority were diagnosed with differentiated thyroid cancer (n = 9 papillary, n = 2 Hürthle cell; 92%) and one had medullary subtype (8%). Median time from diagnosis of primary disease to brain metastasis was 41.8 months (range 0–516). Fifteen (65%) patients underwent SRS as part of their initial treatment with a median number of lesions treated of 1.5 (range 1–9). The median follow-up time for living patients was 35.2 months. Overall median survival time was 20.8 months (40% alive at last follow-up) and 37.4 months for SRS-treated patients (P = NS). A poor Karnofsky performance status was predictive of worse outcome (P = 0.001). GPA and RPA did not provide additional prognostic information. In conclusion, patients treated with SRS for brain metastases from primary thyroid cancer have a favorable prognosis with an expected median survival greater than 3 years. It is unclear as to whether current prognostic indices are relevant to this patient population.     

Expression of Bmi-1 protein in tumor tissues is associated with favorable prognosis in breast cancer patients

Purpose Abnormal expression of the cell cycle regulatory protein Bmi-1 has been studied in breast cancer, but the clinical relevance has not been fully elucidated. We studied the expression of Bmi-1 protein in breast cancer patients to define its clinical significance in breast cancer. Experimental Design Tissue microarrays were performed to evaluate the expression of Bmi-1 by immunohistochemistry in tumor tissues from 960 patients with stage I–III breast cancer. We assessed the relationship between the expression of Bmi-1 and pathologic prognostic indices as well as clinical long-term follow up outcome. Results Bmi-1 was expressed in 53.2% of breast cancer patients by immunohistochemistry, and the expression of Bmi-1 was significantly correlated with favorable prognostic indices at diagnosis. In univariate analysis, patients with Bmi-1 expression showed favorable relapse-free survival (88.6 ± 2.7% vs. 72.3 ± 4.3%, P = 0.041) and favorable overall survival (93.5 ± 2.2% vs. 82.6 ± 3.5%, P < 0.001) than patients without Bmi-1 expression. According to multivariate analyses, Bmi-1 expression was identified as independent prognostic factor for overall survival with a statistical significance (hazard ratio of Bmi-1 (−) patients compared to Bmi-1 (+) patients, 1.744; 95% CI, 1.013–3.003; P = 0.045). This correlation of Bmi-1 expression with favorable overall survival was maintained in patients underwent uniform chemotherapy, regardless of undergoing adjuvant chemotherapy. In a subset analysis according to ER status, Bmi-1 expression associated with favorable overall survival only in ER-positive patients. Conclusions Bmi-1 expression assessed with Immunohistochemistry may be associated with favorable overall survival in breast cancer patients, especially in patients with ER-positive breast cancer. Young Jin Choi and Yoon La Choi contributed equally to this work as first authors. Presented in part at the 29th Annual San Antonio Breast Cancer Symposium December 14–17, 2006.     

Fifteen-year trends in metastatic breast cancer survival in Greece

In the metastatic setting, a detected time trend to improved prognosis could be attributed to the corresponding recent advances in the therapeutic approaches. The aim of the current study was to first assess, in a large cohort of well over a thousand patients, the time trends in survival in MBC for the last 15 years and second to explore its association to prognostic factors affecting outcome including therapeutic regimen. This meta-analysis uses individual patient data collected from all the trials on MBC (6 nonrandomized, 4 randomized) conducted by HeCOG from 1991 through 2006. Four 4-year time periods (1991–1994, 1995–1998, 1999–2002, and 2003–2006) were constructed for exploration of time trends in survival according to the patient’s date of metastatic diagnosis. Different first line regimens in the 10 trials include anthracycline monotherapy (epirubicin, in the early 1990s) and taxane-containing regimens either as monotherapy or in different combinations with anthracyclines or other drugs. In two phase II studies and in the last randomized study, trastuzumab was administered in all the patients with HER2 overexpressing tumors. In this study, information is based on a total of 1361 patients with a median follow up of 3.7 years and median survival of 1.9 years (median survival 1.28, 1.68, 2.20, and 2.57 years for 1991–1994, 1995–1998, 1999–2002, and 2003–2006, respectively). Survival improved significantly across diagnosis time periods, by 25, 44, and 51%, respectively, in each time period (1995–1998: HR = 0.75, P = 0.004; 1999–2002: HR = 0.56, P < 0.001; 2003–2006: HR = 0.49, P < 0.001) as compared to the first time period (1991–1994). The effect of metastatic diagnosis time period remains almost unchanged in the presence of the following significant prognostic factors: performance status, hormonal receptor status, previous adjuvant chemotherapy, previous adjuvant hormonal treatment, visceral metastasis at entry, and number of metastatic sites. When exploring the effect of new systemic treatment introduction, taking into account the same significant prognostic factors, the effect of diagnosis time period disappears, and the survival improvement is explained directly by the introduction of new agents (hormonal treatment for metastatic disease: yes vs. no: HR = 0.72, P < 0.001; taxanes at first line: yes vs. no: HR = 0.69, P = 0.002; trastuzumab at first line: yes vs. no: HR = 0.63, P < 0.001). The results of this study provide significant evidence of improvement in prognosis of MBC patients within the last 15 years, taking into account all the important significant prognostic factors, and this improvement can be attributed to the use of new systemic treatment agents in the management of the disease.     

Subdividing the M1 stage of liver metastasis for nasopharyngeal carcinoma to better predict metastatic survival

In nasopharyngeal carcinoma (NPC), the M1 stage of the TNM classification does not differentiate between the site of metastasis or the number of metastatic lesions. However, NPC patients with lung or bone metastases survive longer than do those with liver metastasis (LM). We subdivided the M1 stage of LM to better predict survival in these patients. From the records of 305 NPC patients with LM treated at Sun Yat-sen University Cancer Center between January 2000 and December 2007, we determined the effects of clinical characteristics and the subclassifications of the M1 stage for LM characteristics [the number, size, timing (synchronous vs. metachronous), and distribution of metastases and metastases to other organs] on survival since the diagnosis of LM. Metastatic survival rates were 62% at 1 year, 31% at 2 years, and 21% at 3 years. Having 1–3 metastatic lesions, having lesions less than 5 cm in diameter, and having unilobular LM were better univariate predictors of metastatic survival. Better survival was independently predicted by having one to three (vs. more than three) metastatic lesions (hazards ratio = 0.52; 95% CI = 0.33–0.82) and unilobular (vs. bilobular) lesions (hazards ratio = 0.35; 95% CI = 0.22–0.57). The current report constitutes large samples of LM from NPC from our single institution with correlation between LM characteristics and metastatic survival. Patients with NPC and one to three liver metastases or unilobular metastases survive longer than their counterparts, and aggressive treatment should be considered.     

The role of topoisomerase IIα in predicting sensitivity to anthracyclines in breast cancer patients: a meta-analysis of published literatures

Topoisomerase IIα is not only a proliferation marker of tumor cells, but is also a target for anthracycline-based chemotherapy. Both in vitro and in vivo studies have shown that there is a relationship between topo IIα and chemosensitivity to anthracyclines, but the predictive role of topo IIα in breast cancer patients is still controversial. A meta-analysis based on published studies was performed to obtain an accurate assessment of the association between topo IIα and sensitivity to anthracycline-based chemotherapy. A total of 13 eligible studies, including 2,633 cases and 2,118 controls were identified. Topo IIα was associated with sensitivity to anthracyclines in locally advanced breast cancer patients who received neoadjuvant chemotherapy [five studies, including three using fluorescence in situ hybridization (FISH) and two using immunohistochemistry (IHC): relative risk (RR) = 1.93, 95% confidence interval (95% CI): 1.27–2.94, P = 0.002; two using FISH and three using IHC: RR = 1.98, 95% CI: 1.37–2.86, P < 0.001]. This association existed among three studies using FISH (RR = 2.03, 95% CI: 1.14–3.61, P = 0.017), but did not exist among three studies using IHC (P > 0.05). In early-stage breast cancer patients who received anthracycline-based adjuvant chemotherapy compared with non-taxane-based polychemotherapy, amplification [hazard ratio (HR) = 0.64, 95% CI: 0.49–0.83, P = 0.001; HR = 0.59, 95% CI: 0.35–1.01, P = 0.056] or deletion (HR = 0.82, 95% CI: 0.67–1.00, P = 0.051; HR = 0.58, 95% CI: 0.35–0.97, P = 0.036) of topo IIα was significantly associated with better recurrence-free survival and overall survival. In summary, the present meta-analysis suggests that topo IIα is a predictive factor for breast cancer patients who receive anthracycline-based chemotherapy. Larger and well-designed prospective studies are required to further evaluate the predictive role of topo IIα in clinical practice.     

Folate intake and breast cancer mortality in a cohort of Swedish women

Folate may influence breast cancer development and progression through its role in one-carbon metabolism. However, epidemiologic data on the relation between folate and breast cancer survival are limited. We investigated whether dietary folate intake was associated with survival in 3,116 women diagnosed with breast cancer in the population-based Swedish Mammography Cohort. Participants completed a 67-item food frequency questionnaire in 1987. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for death from breast cancer and death from any cause. During 25,716 person-years of follow-up from 1987 to 2008, there were 852 deaths with 381 breast cancer deaths. Dietary folate intake was inversely associated with breast cancer and overall mortality. Women in the highest quartile of folate intake had a multivariable HR (95% CI) of death from breast cancer of 0.78 (0.58–1.03) compared to those in the lowest quartile (P _trend = 0.03). The corresponding HR (95% CI) for death from any cause was 0.79 (0.66–0.96; P _trend = 0.004). The protective association between dietary folate intake and breast cancer death was strongest among those with ER-negative tumors (HR = 0.42; 95% = CI 0.22–0.79; P _trend = 0.01) comparing the highest to lowest quartile. Our findings suggest that folate intake before breast cancer diagnosis may improve breast cancer and overall survival. While these findings need to be confirmed in future studies, they do offer assurance that dietary folate intake at the levels observed in our population does not unfavorably affect survival after breast cancer.     

Her-2 prognostic value in very early-stage breast cancer: a single-institution retrospective analysis

To evaluate overall survival, distant metastases-free survival and local relapse-free survival rates in a subgroup of patients affected by breast cancer expressing Her-2/neu. Data of 195 women affected by very early-stage breast cancer (pT1a-b pN0) who underwent whole breast radiotherapy after conservative surgery with or without chemotherapy and/or hormone therapy between January 2000 and December 2006 were evaluated. Chi-square test was used to compare the distribution of variables (age, tumour histology, oestrogens and progesterone receptors, tumour grading and adjuvant chemotherapy) between Her-2-positive and Her-2-negative patients. Survival rates were analysed with Kaplan–Meier curves; impact of variables on poor outcome was evaluated with Cox regression method. Median follow-up time was 63.5 months (range 13.8–113.6). Her-2/neu-positive patients (32/16.4%), compared to Her-2/neu-negative patients (163/83.6%), were younger (P = 0.0001), were affected by ductal infiltrating carcinoma (P = 0.039), had negative oestrogens receptors (P = 0.0001) and were not treated with chemotherapy (P = 0.001). Her-2-positive patients had lower overall survival (P = 0.00001) and lower distant metastases-free survival (P = 0.00001) compared to Her-2-negative patients, but no difference in local relapse-free survival was found between the two groups (P = 0.28). After multivariate analysis, Her-2-positive status was a prognostic factor for overall survival (P = 0.00001) and for distant metastases-free survival (P = 0.0001), but not for local relapse-free survival (P = 0.97). Her-2-positive patients have lower overall survival and distant metastases-free survival when compared to Her-2 negative patients but similar local relapse-free survival rates. These patients could be treated with conservative surgery, if feasible, but should receive more aggressive and tailored systemic adjuvant therapies.     

A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer

Blood relatives of patients with ataxia-telangiectasia (A-T) have an increased risk to develop breast cancer. Allelic heterogeneity has made it difficult to confirm the role of ATM, the gene mutated in A-T, for breast cancer susceptibility in the general population. We now report that a nonsense mutation, p.E1978X (c.5932G>T), is both a classical A-T mutation and a breast cancer susceptibility allele in Eastern European populations. In a case–control study from Belarus, the E1978X mutation was identified in 10/1,891 Byelorussian breast cancer cases (0.5%) compared with 1/1,019 population controls [odds ratio (OR): 5.4; 95% confidence interval (95% CI), 0.7–42.4, P = 0.1]. A second case–control study from Russia identified the E1978X mutation in two Russian and one Ukrainian cases out of 611 breast cancer patients but not in any Russian or Ukrainian controls (P = 0.1). In a third case–control study from Poland, E1978X was observed in 7/3,910 Polish breast cancer cases (0.2%) compared with 1/2,010 cancer-free population controls (OR: 3.6; 95% CI: 0.4–29.3, P = 0.4). In the combined analysis, E1978X was significantly associated with breast cancer (Mantel–Haenszel OR: 5.6, 95% CI: 1.3–21.4, P = 0.01). Taken together, this study provides first evidence for the association of a common A-T causing mutation with breast cancer in Eastern European founder populations.