Zoledronic acid concurrent with either high- or reduced-dose palliative radiotherapy in the management of the breast cancer patients with bone metastases: a phase IV randomized clinical study.

INTRODUCTION: In this prospective study, the efficacy and safety of radiotherapy combined with zoledronic acid was evaluated. MATERIALS AND METHODS: Breast cancer patients with painful bone metastases were randomized to either high- or reduced-dose radiotherapy. All patients received zoledronic acid (4 mg) every 28 days from the beginning of radiotherapy. Analgesic and pain scores in addition to visual analog score (VAS) for treatment satisfaction and whole-body bone scintigraphy were evaluated. RESULTS AND CONCLUSION: No significant differences could be found in analgesic or pain scores and bone scintigraphy results between the groups. Our results suggest that reduced-dose radiotherapy produces similar response rates and response durations when used concomitantly with zoledronic acid.

Identification of patients who may benefit from the prophylactic cranial radiotherapy among breast cancer patients with brain metastasis.

BACKGROUND: To identify the candidates for prophylactic cranial radiotherapy (PCI) among the patients with early and advanced-stage breast cancer. METHODS: The demographic, pathologic and clinical features and survival results of 182 brain metastatic breast cancer patients treated with cranial radiotherapy were examined. RESULTS: Early stage patients who progressed with isolated brain metastasis had longer survival (13 months vs. 4 months P = 0.006). Lobular/mixed type histology (P = 0.033), high nuclear (P = 0.046) and high histological grade (P = 0.034) were the prognostic factors for isolated brain metastases. The most significant factor for the time to brain metastasis was the number of involved of lymph nodes (P = 0.004). In 60% of 148 patients with metastatic breast cancer, a progression with isolated brain metastasis was developed while the systemic disease was under control. Isolated brain metastasis progression was related to the presence of the hepatic metastasis at the first relapse (P = 0.001) and with ErbB-2 overexpression (P = 0.034). The time to the brain metastasis from the first extracerabral metastasis was associated with the high nuclear grade (P = 0.040) and with chemoresistance (P = 0.037). The median survival time after the brain metastases in chemosensitive patients was longer than in chemoresistant patients (8 months vs. 3 months P = 0.044). In chemoresistant patients (P = 0.0028) and/or in triple negative patients (P = 0.05) the development of the brain metastasis was early and the survival after brain metastasis was short. DISCUSSIONS: Since there is a tendency to early brain metastasis in early stage patients with high-grade, lobular/mixed type histology tumors and with a high number of involved lymph nodes, the value of PCI can be explored in these patients by a well designed prospective trial. Advanced stage chemosensitive patients with ErbB-2 over-expression and/or with hepatic metastasis at their first relapse may be candidates for PCI. There is no place for PCI in chemoresistant and triple-negative breast cancer patients.

True Local Recurrences after Breast Conserving Surgery have Poor Prognosis in Patients with Early Breast Cancer.

BACKGROUND: This study was aimed at investigating clinical and histopathologic features of ipsilateral breast tumor recurrences (IBTR) and their effects on survival after breast conservation therapy. METHODS: 1,400 patients who were treated between 1998 and 2007 and had breast-conserving surgery (BCS) for early breast cancer (cT1-2/N0-1/M0) were evaluated. Demographic and pathologic parameters, radiologic data, treatment, and follow-up related features of the patients were recorded. RESULTS: 53 patients (3.8%) had IBTR after BCS within a median follow-up of 70 months. The mean age was 45.7 years (range, 27-87 years), and 22 patients (41.5%) were younger than 40 years. 33 patients (62.3%) had true recurrence (TR) and 20 were classified as new primary (NP). The median time to recurrence was shorter in TR group than in NP group (37.0 (6-216) and 47.5 (11-192) months respectively; p = 0.338). Progesterone receptor positivity was significantly higher in the NP group (p = 0.005). The overall 5-year survival rate in the NP group (95.0%) was significantly higher than that of the TR group (74.7%, p < 0.033). Multivariate analysis showed that younger age (<40 years), large tumor size (>20 mm), high grade tumor and triple-negative molecular phenotype along with developing TR negatively affected overall survival (hazard ratios were 4.2 (CI 0.98-22.76), 4.6 (CI 1.07-13.03), 4.0 (CI 0.68-46.10), 6.5 (CI 0.03-0.68), and 6.5 (CI 0.02- 0.80) respectively, p < 0.05). CONCLUSIONS: Most of the local recurrences after BCS in our study were true recurrences, which resulted in a poorer outcome as compared to new primary tumors. Moreover, younger age (<40), large tumor size (>2 cm), high grade, triple negative phenotype, and having true recurrence were identified as independent prognostic factors with a negative impact on overall survival in this dataset of patients with recurrent breast cancer. In conjunction with a more intensive follow-up program, the role of adjuvant therapy strategies should be explored further in young patients with large and high-risk tumors to reduce the risk of TR.

Replacement of the tumor bed following oncoplastic breast-conserving surgery with immediate latissimus dorsi mini-flap.

The aim of the present study was to evaluate the geographic variability of the tumor bed following oncoplastic breast-conserving surgery (OP-BCS), and to assess its relevance for radiotherapy planning. In this prospective study, pre- and postoperative computerized tomography (CT) scans of 22 patients with early-stage breast cancer were fused. The preoperative gross tumor volume or excisional biopsy cavity were contoured under the guidance of preoperative radiological images. Postoperative lumpectomy cavities were contoured under the guidance of surgical clips. The conformity index (CI) was calculated and defined on a scale between 0 and 1, where 0 indicated no overlap and 1 indicated 100% concordance. Associations between CI and the number of clips, time interval between surgery and CT scans, pathological tumor size and age were assessed using independent sample testing. The median CI was 0.07 (in five cases, 1, and in eight cases, 0). The lumpectomy cavity shifted from the primary location in 36.4% of the cases. Median shifts between the isocenters of pre- and postoperative volumes were measured as 1.02 cm (range, 0.4-4.43 cm) in the x, 1.07 cm (range, 0.05-5.67 cm) in the y, and 1.12 cm (range, 0-3.75 cm) in the z directions. Only the clip number was determined to be significantly associated with CI (P=0.017). Pre- and postoperative tumor bed volumes were fully superposed in five of the 22 cases. The present study has shown that the tumor bed is markedly replaced following OP-BCS with latissimus dorsi mini-flap (LDMF) reconstruction. Special care should therefore be taken when defining the lumpectomy cavity following OP-BCS with LDMF reconstruction.

The Prognostic Impact of Molecular Subtypes and Very Young Age on Breast Conserving Surgery in Early Stage Breast Cancer.

BACKGROUND: Premenopausal breast cancer with a triple-negative phenotype (TNBC) has been associated with inferior locoregional recurrence free survival (LRFS) and overall survival (OS) after breast conserving surgery (BCS). The aim of this study is to analyze the association between age, subtype, and surgical treatment on survival in young women (≤40 years) with early breast cancer in a population with a high rate of breast cancer in young women. METHODS: Three hundred thirty-two patients ≤40 years old with stage I-II invasive breast cancer who underwent surgery at a single institution between 1998 and 2012 were identified retrospectively. Uni- and multivariate analysis evaluated predictors of LRFS, OS, and disease free survival (DFS). RESULTS: Most patients (64.2%) underwent BCS. Mean age and follow-up time were 35 (25 ± 3.61) years, and 72 months (range, 24-252), respectively. In multivariate analysis, multicentricity/multifocality and young age (<35 years) independently predicted for poorer DFS and OS. Those aged 35-40 years had higher LRFS and DFS than those <35 in the mastectomy group (p=0.007 and p=0.039, respectively). Patients with TNBC had lower OS compared with patients with luminal A subtype (p=0.042), and those who underwent BCS had higher OS than patients after mastectomy (p=0.015). CONCLUSION: Young age (< 35 years) is an independent predictor of poorer OS and DFS as compared with ages 35-40, even in countries with a lower average age of breast cancer presentation. In addition, TNBC in the young predicts for poorer OS. BCS can be performed in young patients with TNBC, despite their poorer overall survival.

Clinical and histopathological factors associated with Ki-67 expression in breast cancer patients.

The aim of the present study was to identify the optimal Ki-67 cut-off value in breast cancer (BC) patients, and investigate the association of Ki-67 expression levels with other prognostic factors. Firstly, a retrospective search was performed to identify patients with stage I-III BC (n=462). A range of Ki-67 index values were then assigned to five groups (<10, 10-14, 15-19, 20-24 and ≥25%). The correlation between the Ki-67 index and other prognostic factors [age, tumor type, histological and nuclear grade, tumor size, multifocality, an in situ component, lymphovascular invasion (LVI), estrogen and progesterone receptor (ER/PR) expression, human epidermal growth factor receptor (HER-2) status, axillary involvement and tumor stage] were investigated in each group. The median Ki-67 value was revealed to be 20% (range, 1-95%). A young age (≤40 years old), tumor type, size and grade, LVI, ER/PR negativity and HER-2 positivity were revealed to be associated with the Ki-67 level. Furthermore, Ki-67 was demonstrated to be negatively correlated with ER/PR expression (P<0.001), but positively correlated with tumor size (P<0.001). The multivariate analysis revealed that a Ki-67 value of ≥15% was associated with the largest number of poor prognostic factors (P=0.036). In addition, a Ki-67 value of ≥15% was identified to be statistically significant in association with certain luminal subtypes. The rate of disease-free survival was higher in patients with luminal A subtype BC (P=0.036). Following the correlation analysis for the Ki-67 index and the other prognostic factors, a Ki-67 value of ≥15% was revealed to be the optimal cut-off level for BC patients.

Vitamin D levels in patients with breast cancer: importance of dressing style.

BACKGROUND: Vitamin D deficiency is a potentially modifiable risk factor that may be targeted for breast cancer (BC) prevention. It may also be related to prognosis after diagnosis and treatment. The aim of our study was to determine the prevalence of vitamin D deficiency as measured by serum 25-hydroxy vitamin D (25-OHD) levels in patients with BC and to evaluate its correlations with life-style and treatments. MATERIALS AND METHODS: This study included 186 patients with stage 0-III BC treated in our breast center between 2010-2013. The correlation between serum baseline 25-OHD levels and supplement usage, age, menopausal status, diabetes mellitus, usage of bisphosphonates, body-mass index (BMI), season, dressing style, administration of systemic treatments and radiotherapy were investigated. The distribution of serum 25-OHD levels was categorized as deficient (<10ng/ ml), insufficient (10-24 ng/ml), and sufficient (25-80 ng/ml). RESULTS: The median age of the patients was 51 years (range: 27-79 years) and 70% of them had deficient/insufficient 25-OHD levels. On univariate analysis, vitamin D deficiency/insufficiency was more common in patients with none or low dose vitamin D supplementation at the baseline, high BMI (≥25), no bisphosphonate usage, and a conservative dressing style. On multivariate analysis, none or low dose vitamin D supplementation, and decreased sun-exposure due to a conservative dressing style were found as independent factors increasing risk of vitamin D deficiency/insufficiency 28.7 (p=0.002) and 13.4 (p=0.003) fold, respectively. CONCLUSIONS: The prevalence of serum 25-OHD deficiency/insufficiency is high in our BC survivors. Vitamin D status should be routinely evaluated for all women, especially those with a conservative dressing style, as part of regular preventive care, and they should take supplemental vitamin D.

Dosimetric comparison of field in field intensity-modulated radiotherapy technique with conformal radiotherapy techniques in breast cancer.

PURPOSE: The aim of this study was to be able to implement the field-in-field intensity-modulated radiotherapy (FiF) technique in our daily practice for breast radiotherapy. To do this, we performed a dosimetric comparison. MATERIALS AND METHODS: Treatment plans were produced for 20 consecutive patients. FiF plans and conformal radiotherapy (CRT) plans were compared for doses in the planning target volume (PTV), the dose homogeneity index (DHI), doses in irradiated soft tissue outside the target volume (SST), ipsilateral lung and heart doses for left breast irradiation, and the monitor unit counts (MU) required for treatment. Averaged values were compared using Student's t-test. RESULTS: With FiF, the DHI is improved 7.0% and 5.7%, respectively (P < 0.0001) over the bilateral and lateral wedge CRT techniques. When the targeted volumes received 105% and 110% of the prescribed dose in the PTV were compared, significant decreases are found with the FiF technique. With the 105% dose, the SST, heart, and ipsilateral lung doses and the MU counts were also significantly lower with the FiF technique. CONCLUSION: The FiF technique, compared to CRT, for breast radiotherapy enables significantly better dose distribution in the PTV. Significant differences are also found for soft tissue volume, the ipsilateral lung dose, and the heart dose. Considering the decreased MUs needed for treatment, the FiF technique is preferred over tangential CRT.

Clinical parameters and treatment results in recurrent granulosa cell tumor of the ovary.

OBJECTIVE: The objectives of this study were to evaluate the patients' characteristics and treatment results for 11 recurrent granulosa cell tumors (GCT) of the ovary. METHODS: Tumor registries were screened retrospectively for all patients treated between 1979 and 1999 for ovarian tumors at the University of Istanbul. All information about these patients was obtained from operation, pathology, and follow-up reports. Then the clinical data were extracted. The patients were classified in stages according to FIGO criteria. There were 952 ovarian carcinomas, of which 45 were GCT. Eleven of 45 patients (24%) developed recurrent disease on follow-up. RESULTS: All patients but one had advanced (III-IV) disease at diagnosis. The median progression-free interval (PFI) was 16 months (range, 5-39 months) with a marked difference in PFI between patients receiving (24 months) and not receiving (8 months) initial chemotherapy. Among patients received chemotherapy (six patients), two complete and two partial responses were observed, for an overall response rate of 67%. The median survival for all patients was 26 (4-73) months with a longer survival (38 versus 8 months) for patients retreated with a platinum-containing regimen. CONCLUSIONS: Despite the fact that small number of treated cases does not allow an adequate evaluation, retreatment with cis-platinum-containing regimens may be the treatment of choice for patients with recurrent disease.

Granulosa cell tumor of the ovary: retrospective analysis of 45 cases.

Adult granulosa cell tumors of the ovary are rare neoplasms, accounting for less than 5% of all ovarian malignancies. In addition to the tumor stage, residual disease, patient age, tumor size, extent of surgery, and also some histologic factors have been reported to be of prognostic importance. Tumor registries were screened for all patients treated between 1979 and 1998 for ovarian tumors at the University of Istanbul. There were 952 ovarian carcinomas, of which 47 were granulosa cell tumors. All charts were reviewed, and the clinical data were extracted. Prognostic factors and treatment results were evaluated retrospectively. The median follow-up was 84 (range: 6-141 months) months. According to univariate analysis, there were only two significant factors for overall survival (OS): stage and presence of residual disease. The OS of the 23 patients with early stage (mean, 122 months; median, unreached) was significantly (p = 0.0001) better than the OS of the 22 patients with advanced stage (mean, 34 months; median, 21 months). A significant difference (p = 0.0004) in OS was also observed between patients with residual (mean, 42 months; median, 21 months) and nonresidual (mean, 108 months; median, unreached) disease. In a multivariate analysis, only stage remained statistically significant (p = 0.0001). The overall 5-year survival rate was 55% and median survival after recurrence was 21 months. Despite the small number of patients, the study showed that stage and macroscopic residual disease are significant prognostic factors. The benefit of chemotherapy and radiotherapy remains controversial.

Inflammatory breast cancer: results of antracycline-based neoadjuvant chemotherapy.

Twenty-three patients with inflammatory breast cancer treated with a combined modality approach including anthracycline-based induction chemotherapy-surgery-chemotherapy-radiotherapy were reviewed. Twelve patients (52.2%) received FAC (5-fluorouracil, adriamycin, cyclophosphamide) and 11 patients (47.8%) were treated with FEC (5-fluorouracil, epirubicin, cyclophosphamide) induction chemotherapy for three cycles every 3 weeks. Surgery was followed by the initial chemotherapy or second-line chemotherapy for an additional six cycles to complete nine cycles and radiotherapy, respectively. The median overall survival (OS) time was 27 months and the median disease-free survival (DFS) was 13 months. Furthermore, patients treated with FAC induction chemotherapy have been found to have longer median OS and DFS periods compared to patients with FEC induction chemotherapy in both univariate and multivariate analysis. In conclusion, the superiority of doxorubicin-containing chemotherapy over epirubicin-containing chemotherapy should be established in larger randomized studies and more effective chemotherapeutic agents such as taxans are required for better survival rates in inflammatory breast cancer patients.