Prognostic role of inflammatory biomarkers in metastatic breast cancer.

PURPOSE: The effects of inflammation on the prognosis, life expectancy and several parameters such as response to treatment of breast cancer have been previously studied. The purpose of this study was to investigate the effect of inflammatory markers on prognosis in patients with metastatic breast cancer. METHODS: This study was conducted on 81 patients with metastatic breast cancer who have been followed up at the Department of Medical Oncology, Hacettepe University Institute of Oncology, between December, 2009 and March, 2014. For all studied parameters Kaplan-Meier survival estimates and p values computed by log-rank test were calculated. A p value < 0.05 was considered statistically significant. RESULTS: Median follow-up time was 26 months. There were 38 deaths due to disease progression during the follow up. The levels of serum albumin, and erythrocyte sedimentation rate (ESR) were not associated with a significant effect on overall survival (OS). Among patients with a higher serum C-reactive protein (CRP), the estimated mean survival was 84±36 months, compared to 278±113 months among patients with a normal serum CRP (p=0.032). When patients with higher and normal lactate dehydrogenase (LDH) levels were compared, their 2-year OS survival rates were 68.2 and 87.7%, respectively (p=0.034). Among patients with higher serum ferritin levels, the estimated mean survival was 29±10 months, compared to 212±113 months for normal serum ferritin (p=0.01). Among patients with higher serum beta-2 microglobulin (ß2-M), the estimated mean OS survival was 28±8 months, compared to 84±57 months for those with normal levels (p<0.01). CONCLUSION: Serum CRP, ferritin and ß2-M can be useful prognostic factors for OS in patients with metastatic breast cancer.

Risk factors and histopathological features of breast cancer among women with different menopausal status and age at diagnosis.

PURPOSE: Although there are studies that investigate different risk factors and clinicopathological features of breast cancer in women at different age groups and menopausal status, there is a need for studies with larger study populations due to controversial findings. We conducted this study to identify demographic parameters in breast cancer patients and histopathological features of the tumors for different age groups and compare them to demonstrate significant differences, if any. METHODS: 3325 women diagnosed with breast cancer in Hacettepe University Oncology Hospital Outpatient Clinic between January 1994 and March 2014 were included in this study. RESULTS: Postmenopausal women who were older than 65 were found to have higher number of children, higher rates of oral contraceptive use, greater age at menarche, and have higher rates of first full-time pregnancy before the age of 30. On the other hand, higher rates of grade 3 tumors, advanced lymph node stage, lymphovascular invasion, and triple negative breast cancers were more frequently seen in premenopausal women below the age of 35. Since earlier age at the time of diagnosis is associated with bad prognosis, early diagnosis of breast cancer gains importance in younger women. CONCLUSION: Implementing targeted screening programs of breast cancer for younger women may become a need in the future. Meanwhile, well-education on risks of breast cancer and regular self-examination for early diagnosis need to be emphasized for the prevention of breast cancer and related diseases in young ages.

Obesity is an independent prognostic factor of decreased pathological complete response to neoadjuvant chemotherapy in breast cancer patients.

PURPOSE: The relation between higher body mass index (BMI) and pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer (BC) is a controversial issue according to the data of Western and Asian patients. The aim of this study is to evaluate BMI and pCR to NAC and discuss the importance of pCR outcomes in Turkish BC patients as a bridging country between Europe and Asia. PATIENTS AND METHODS: Of the 4423 BC patients diagnosed between the years 1994 and 2015 in Hacettepe University Cancer Institute, 295 female patients with stage II and III BC were enrolled in the study. Three different group divisions were done according to patients' BMI as normal or underweight (N/U) patients (BMI <25 kg/m2), overweight (OW) patients (BMI = 25-29.9 kg/m2) and obese (OB) patients (BMI ≥30 kg/m2). BC subtypes were defined as luminal-like (ER/PR-positive and HER2-negative), HER2/luminal (ER/PR-positive and HER2-positive), HER2-type (ER/PR-negative and HER2-positive), and triple-negative (TNBC; ER/PR- and HER2-negative). The analysis of overall survival (OS) and recurrence-free survival (RFS) was performed according to Kaplan-Meier method. The Log-rank test was used to compare the subgroup analysis and logistic regression analysis to determine the independent prognostic factors. RESULTS: In this study, a total number of 93 (31.5%) patients were N/U, 107 (36.3%) patients were OW and 95 (32.2%) patients were OB. Among groups, except for the age, no baseline clinicopathological differences were found. In 70 (23.7%) patients, pCR was achieved. pCR rates in N/U, OW and OB were 31.2%, 22.4%, and 17.9% respectively, showing a considerable trend towards significance (P = 0.09 in chi-square test). In the multivariate logistic regression analysis, obesity was an independent adverse prognostic feature on pCR to NAC compared to N/U patients (OR, 0.34; 95% CI, 0.13 to 0.85, P = 0.02). The recurrence rates were slightly increased with the increase of BMI (N/U = 24.7%, OW = 29.0% and OB = 40%; P = 0.06 respectively). Median RFS was significantly higher in N/U group compared to OB patients (150 vs. 76 months respectively, P = 0.03) and was also higher in pCR group compared to non-pCR patients (151 vs. 77 months P = 0.004). Median OS was significantly higher in N/U patients compared to OB patients (N/U = not reached, OW = 211 and OB = 114 months; P = 0.01) and was also higher in pCR group compared to non-pCR patients (not reached vs. 211 months P = 0.04). In Cox regression analysis; pCR, histopathological grade and TNBC were found as independent prognostic factors on OS (HR, 0.29; 95% CI, 0.11 to 0.79, P = 0.015, HR, 2.09; 95% CI, 1.14 to 3.83, P = 0.017, HR, 1.95; 95% CI, 1.01 to 3.77, P = 0.046, respectively). CONCLUSION: It was observed that obesity was an important independent prognostic factor which has an adverse effect on pCR. Moreover it causes decreasing RFS and OS in BC patients who had received NAC. The probability of inefficient treatment in obese patients should be considered.

A case of vemurafenib-induced polyarhritis in a patient with melanoma: how to manage it?

Vemurafenib is an inhibitor of the BRAF V600E mutation which is associated with tumor responses in patients with metastatic melanoma. Although it is generally well tolerated, common side effects of vemurafenib have been reported. Arthralgia is one of the more common adverse event associated with vemurafenib. We herein report a 49-year-old woman diagnosed with metastatic melanoma harboring the BRAF V600E mutation with severe polyarthritis associated with vemurafenib after 7 days of treatment. Sonographic examination of affected joints revealed synovitis and the patient's articular symptoms were improved by analgesic and anti-inflammatory treatment, including corticosteroids. During therapy with selective BRAF inhibitors, arthritis represents a new adverse event that can require dose reduction. In case of this adverse event, treatment with anti-inflammatory drugs, such as ibuprofen and prednisone, should be initiated early to keep patients on treatment and to avoid drug discontinuation and tumor progression.

Trastuzumab 1-year vs 9-week in early-stage HER2-positive, lymph node negative breast cancer patients.

PURPOSE: Optimal duration of adjuvant trastuzumab therapy in early-stage HER2-positive, lymph node-negative breast cancer is unknown. To establish this, we compared 1-year and 9-week trastuzumab regimens in HER2-positive, lymph node-negative early-stage breast cancer patients. METHODS: We retrospectively analyzed 4374 breast cancer patients. There were 181 early-stage, lymph node-negative breast cancer patients who were treated with adjuvant trastuzumab for either 9-week or 1-year schedule. A total of 101 patients received trastuzumab for 9 weeks and the remaining 80 patients received this adjuvant therapy for 1 year. Disease free survival (DFS) and overall survival (OS) rates of both groups were calculated. RESULTS: There was no difference between groups according to OS. Five-year OS rates were 95.5% in the 9-week group and 93.3% in the 1-year group (p=0.78). DFS was affected by age, having tamoxifen therapy and disease stage. Nine-week trastuzumab group was superior to 1-year group and 5-year DFS rates were 91% in 9-week group and 81.2% in 1-year group (p=0.02). However, the 1-year group had more stage II patients than the 9-week group. We did not find any difference between groups regarding developing congestive heart failure. CONCLUSION: It appeared that 9-week trastuzumab treatment was not inferior to 1-year trastuzumab treatment in early-stage, lymph node-negative breast cancer patients.

Correlation of educational status and clinicopathological characteristics of breast cancer: a single center experience.

PURPOSE: Educational status may be an important parameter in assessing breast cancer risk and prognosis. The purpose of this study was to investigate the correlation between the level of education and clinicopathological characteristics of breast cancer, including tumor grade, HER-2 and estrogen receptor (ER) status, tumor size, axillary lymph node involvement and metastasis. METHODS: The study included 1800 women who were diagnosed with invasive breast cancer during 2005-2013 at Hacettepe University Cancer Institute. Patients were divided into three groups according to their educational status at the time of diagnosis as follows: low (illiterate and elementary school, 5 years or less of education), medium (secondary school and upper secondary school, 6-12 years of education) and high (university level, more than 12 years of education). The associations between educational status and clinicopathologic features of breast cancer at the time of diagnosis were evaluated. RESULTS: In all patient, a significant relationship was found between educational status and T stages (p<0.0001). Patients with higher educational levels were reported to have smaller tumor size regardless to their age and were less likely to have axillary lymph node involvement (p=0.001) or metastasis (p=0.001). A significant correlation was found between educational status and ER positivity in patients over 50 years of age (p=0.03). When the patients of all ages were evaluated, no statistically significant correlation was shown (p=0.27) between educational status and ER positivity. A significant relationship was found between educational status and HER-2 status (p=0.003), regardless of the patients' age. HER-2 positivity increased in patients with low educational status, however this significance was lost in patients over the age of 50 (p=0.1). CONCLUSION: The relationship between educational status and biological factors in breast cancer are not conclusive as yet, but this particular study revealed that educational status played a major influence in each of the five breast cancer prognostic factors: ER status, HER-2 status, tumor size, lymph node status and metastasis.

Left laterality is an independent prognostic factor for metastasis in N3 stage breast cancer.

PURPOSE: Development of metastasis in patients with breast cancer (BC) is the most important negative prognostic factor and this process mainly begins with lymphatic involvement. Therefore, axillary, subclavicular, internal mammary or supraclavicular nodal involvement is a crucial step before metastasis. Anatomical differences between the right and left lymphatic drainages of the breasts may significantly affect the rate, site and time to development of distant metastasis. The purpose of this study was to investigate if laterality is an independent prognostic factor for metastasis in N3 breast cancer patients. METHODS: From a total of 4215 BC patients diagnosed between 1994 and 2015 in our center, 305 non-metastatic women with pathological N3 (pN3) nodal status at presentation were enrolled in this study. Patients were divided into two groups: left and right BC. Analysis of overall survival (OS) and time to first metastasis (TTM) was performed according to Kaplan-Meier method with log-rank test. RESULTS: The median number of lymph node involvement and lymph node ratio (number of positive lymph nodes / total number of excised lymph nodes) between the two groups was equal (14 and 0,66 respectively). Recurrence was observed in 123 patients [53 (35%) right vs 70 (44%) left group]. Patients with left BC had significantly higher rate of axial bone metastases compared with the right BC group (55.7 vs 35.8%, p<0.02, respectively). TTM was significantly shorter in the left BC group [49.1 months (95% CI 36.5-61.8) vs 103.6 months (95% CI 47.0-160); p7equals;0.03, respectively]. Median OS did not differ between the groups, however, there was a trend towards lower OS in patients with left BC (p=0.68). CONCLUSION: Left laterality in patients with pN3 non-metastatic BC is an independent prognostic factor associated with shorter TTM, increased risk of distant metastases and axial bone involvement compared with right laterality.

Efficacy and safety of eribulin monotherapy in patients with heavily pretreated metastatic breast cancer.

PURPOSE: Eribulin is a non-taxane microtubule inhibitor, which can be used after anthracycline and taxane treatment in patients with metastatic breast cancer (MBC). The purpose of this study was to investigate the efficacy and safety of eribulin monotherapy in heavily pretreated MBC patients. METHODS: In this single-center trial, a total of 66 MBC patients who received eribulin monotherapy in Hacettepe University Cancer Institute between 2013 and 2015 were retrospectively analyzed. Kaplan-Meier survival analysis was carried out for progression free survival (PFS) and for overall survival (OS). Two-sided p values <0.05 were considered as statistically significant. RESULTS: Sixty-six patients who received at least one cycle of eribulin were registered. Most patients were heavily pretreated with a median of 4 (range 2-7) previous chemotherapy lines prior to eribulin. Median patient age was 50 years (range 28-67). Most patients were treated with eribulin at 4th or 5th line (33.3 and 27.3%, respectively). Brain metastases were present in 19 (28.8%) patients at the time of initial eribulin administration. Median PFS was 5 (95% CI 4.1-5.8) and median OS was 8 (95% CI 6-9.9) months. Fifteen patients (22.7%) responded to treatment with partial remission (PR) and 36 (54%) had stable disease (SD). No hypersensitivity reactions and no toxic deaths were observed. Three (5%) patients experienced grade 4 neurotoxicity. Fourteen (21.5%) patients developed grade 3-4 neutropenia. CONCLUSION: Eribulin monotherapy is an effective and safe regimen for MBC patients. Its low toxicity profile compared to other intravenous cytotoxic agents and the ease in its intravenous administration make this agent a preferable option for both physicians and patients.

Assessment of psychosocial factors and distress in women having adjuvant endocrine therapy for breast cancer: the relationship among emotional distress and patient and treatment-related factors.

PURPOSE: The aims of this study were to comprehensively describe the psychosocial and medical characteristics of women who initiated tamoxifen or aromatase inhibitors for breast cancer and to compare levels of emotional distress according to their medical (tumor demographics, treatment type, treatment duration) and psychosocial (self-esteem, perceived social support, sociodemographic) characteristics. METHODS: A total of 104 women currently receiving tamoxifen or aromatase inhibitors was recruited from outpatient clinics and they were asked to complete self-report questionnaires including the Rosenberg Self-Esteem Scale, the Multidimensional Scale of Perceived Social Support and the Hospital Anxiety and Depression Scale during their routine follow-up. Psychosocial and medical characteristics of the patients were first described and subsequently the score of emotional distress was compared with these. RESULTS: The patients' mean age was 52.49 ± 10.30 and they were being treated for an average of 24.3 months. Out of the patients' characteristics, educational and marital status, level of perceived social support and self-esteem were all significantly related with emotional distress. As for medical variables, the score of distress was relatively higher among patients in the first 2 years of their treatment than the patients who were in the second to fifth years of treatment, but this was not statistically significant. CONCLUSIONS: Given the results of this study, it appeared that patient variables, rather than the medical or treatment characteristics, were related with emotional distress in women undergoing endocrine treatment. For that reason it is critical that medical staff are aware of patient factors that relate to distress during a long period of adjuvant endocrine therapy.

Patients' understanding of treatment goals and disease course and their relationship with optimism, hope, and quality of life: a preliminary study among advanced breast cancer outpatients before receiving palliative treatment.

PURPOSE: The aims of this study were to explore advanced breast cancer patients' knowledge of treatment intent and expectation of illness course and to evaluate their relationship with optimism, hope, and quality of life (QoL). METHODS: Patients with advanced breast cancer (n = 55) who were treated in the ambulatory clinic of the University of Hacettepe were included in the study. They completed Life Orientation Scale, The Hope Scale, and the European Organization for Research and Treatment of Cancer Quality of Life questionnaires. The data regarding the knowledge of illness progression and the perceptions of therapy intent were assessed using self-administered open-ended questionnaires that were answered by the patients. RESULTS: The data revealed that 58.2 % of the patients had an inaccurate perception of treatment intent, believing the aim of treatment was cure, whereas only 38.2 % of the patients had a realistic expectation that their disease may remain stable or may progress over a year. In addition, the awareness of disease progression and perception of goals of treatment was significantly related to hope and optimism scores but not to QoL. CONCLUSIONS: A large proportion of patients diagnosed with advanced breast cancer believed that their treatment was "curative", and they would improve within a year. Findings of our study suggest that patients with inaccurate perception of treatment intent and unrealistic expectation of prognosis have higher hope and optimism scores than those who do not, but there were no significant differences in terms of global health status.

The effect of obesity on recurrence pattern in early breast cancer patients.

PURPOSE: Obesity is a well known risk factor for breast cancer recurrence and poor prognosis. We studied the effect of body mass index (BMI) on recurrence pattern in early breast cancer patients. METHODS: This retrospective cross-sectional study analyzed the data of 2731 early stage breast cancer patients. Patients who had metastatic disease at the time of diagnosis and with unknown BMI values were excluded from study (N=276). Patients were classified into three BMI categories: normal body weight, overweight, and obese. The recurrent/metastatic sites of patients were grouped in 8 categories: local, contralateral, lymph node, bone, lung, liver, brain and others. The association between first relapse site of early breast cancer patients and BMI categories were evaluated. RESULTS: The median patient age was 48 years (range 18-92). The median follow up time was 40 months (range 1-284). During follow-up, 469 (17.1%) patients developed recurrence and/or metastasis. Of 2455 total patients, 853 (34.6%) were classified as having normal weight, 898 (36.2%) were overweighted and 704 (29.2%) were obese. In the whole patient group no relation between metastatic sites and BMI groups was noticed. The first primary metastatic sites were also not associated with BMI groups in pre and postmenopausal subpopulations. In obese patients, disease free survival (DFS) was shorter compared to normal weighted patients, but the difference was not significant. There was no significant difference between site-specific DFS in relation to BMI categorization. Obese and overweighted patients had significantly shorter overall survival (OS) compared to the normal-weight group (p=0.003). CONCLUSION: Although obesity had no effect on recurrence pattern of early breast cancer patients, obese early breast cancer patients had shorter OS compared to their normal-weight counterparts.

The lymph node ratio as an independent prognostic factor for non-metastatic node-positive breast cancer recurrence and mortality.

PURPOSE: To examine the prognostic value of lymph node ratio (LNR) in pathological nodal (pN) stage breast cancer patients. Also, to analyse additional clinical and pathologic prognostic factors and the impact of LNR among molecular subtypes. METHODS: Among a total of 3088 patients, 1004 women with non-metastatic lymph node-positive breast cancer were analysed. The patients were classified into low (≤0.20), intermediate (0.20 to 0.65) and high-risk (>0.65) LNR groups. Univariate and multivariate Cox proportional hazards regression model for disease-free survival (DFS), and overall survival (OS) were performed to evaluate the prognostic value of LNR. RESULTS: The median LNR was 0.17 (range 0.02-1.00). Of the patients, 55.7% were in low, 32.1% in intermediate, and 12.3% in high risk group. When compared with low risk group, high risk group had more often large tumor size and high grade tumor with lymphovascular invasion. The median follow-up period was 46.8 months. The 5-year breast cancer-specific OS and DFS rates for patients with low, intermediate, and high were 88%-67%, 65%-48% and 53%-24%, respectively (both plog-rank<0.0001). On multivariate analysis, pN stage and LNR were both independent predictors of survival, however, an overlapping between N1 (250 months, 95% confidence interval [CI] 88.15-413.21) and N2 (176 months, 95% CI 129.51-222.93) curves in pN staging was determined. We also observed clear prognostic separation for triple negative breast cancer with LNR survival over pN staging. CONCLUSION: The LNR predicts survival more accurately than pN staging in node-positive breast cancer patients. The use of LNR may standardize the staging and guide decisions for adjuvant treatments.

Chemotherapy might not be beneficial in lymph node- negative, hormone-positive, and HER2-negative breast cancer patients: a long-term retrospective analysis.

INTRODUCTION: In lymph node-negative, hormone-positive, and Her2-negative breast cancer patients, the benefits of adding adjuvant chemotherapy to hormonal therapy continue to be debated, especially for low to intermediate grade and small tumors. METHODS: Excluding patients with T4 disease, we retrospectively reviewed the records of patients with long-term follow-up at our center between 2003 and 2014. Among node-negative, hormone-positive and HER2-negative breast cancer patients, we compared two groups of patients: those given both chemotherapy (doxorubicin+cyclophosphamide) and hormonotherapy, and those prescribed hormonotherapy alone. The primary endpoints were progression-free (PFS) and overall survival (OS). RESULTS: Overall, no difference was observed between these two treatment groups in either DFS or OS. However, for both outcomes, there was a trend towards improved DFS and OS favoring the hormone-only group. CONCLUSIONS: In selected subgroups of breast cancer patients, administering adjuvant hormonal therapy alone seems to be at least as good if not better than combining hormonotherapy and chemotherapy.

Efficacy of capecitabine monotherapy as the first-line treatment of metastatic HER2-negative breast cancer.

AIMS AND BACKGROUND: Capecitabine is a potent and safe agent that can be used after anthracycline and taxane treatment in patients with metastatic breast cancer (MBC). The purpose of this study was to investigate the efficacy and safety of capecitabine monotherapy as a first-line treatment in human epidermal receptor 2 (HER2)-negative patients with MBC. METHODS AND STUDY DESIGN: In this single-center trial, a total of 109 HER2-negative patients with MBC who received capecitabine monotherapy as first-line treatment between 2003 and 2014 were retrospectively analyzed. Kaplan-Meier survival analysis was carried out for progression-free survival (PFS) and for overall survival (OS). Two-sided p values of <0.05 were considered statistically significant. RESULTS: Median PFS was 7.0 ± 0.67 (confidence interval (CI) 5.6-8.3) months and median OS was 30 ± 4.1 (CI 21.8- 38.1) months. First-line capecitabine treatment for HER2-negative MBC was more effective in the estrogen receptor (ER)-positive patient population compared to the ER-negative group (median PFS 9 vs 4 months (p = 0.002), median OS 33 vs 21 months (p = 0.01)). Indeed, the overall response rate in the ER-negative group was 16%, while this was calculated as 38% for ER-positive cases. While most of our patient population was treated with a higher dose (1250 mg/m2), the observed grade 3-4 toxicities were lower compared to some previously reported phase II and phase III capecitabine studies. CONCLUSIONS: Capecitabine monotherapy is an effective and safe regimen for ER-positive, HER2-negative patients with MBC. Its low toxicity profile compared to other intravenous cytotoxic agents and the ease of its oral administration make this agent a preferable option for both physicians and patients.

The effect of renin-angiotensin-system inhibition on survival and recurrence of N3+ breast cancer patients.

PURPOSE: The purpose of this study was to evaluate the association between the rennin-angiotensin system (RAS) inhibition and the risk of breast cancer (BC) recurrence and progression in N3 positive patients. METHODS: The medical records of patients treated for N3 positive BC in Hacettepe Cancer Institute between 2005 and 2012 were evaluated. Angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB) users were defined as patients who took these medications for at least 6 months in no evidence of disease (NED) stage after the initial diagnosis. The primary and secondary outcome was disease-free survival (DFS) and overall survival (OS). Kaplan-Meier and Cox proportional hazard models were used. RESULTS: A total of 218 pathologic N3 BC patients were included. Follow up ranged from 12 to 212 months (median 49.58). Thirty one patients used ACE inhibitors/ARBs. Univariate analysis showed BC recurrence was lower and OS was higher among patients who used ACE inhibitors/ ARBs, however without reaching statistical significance (p=0.38 and p=0.24, respectively). RAS inhibition was associated with reduced risk of pathologic N3 BC recurrence. CONCLUSION: To the best of our knowledge this is the second study showing that the use of ACE inhibitors/ARBs may be effective in N3 BC. Because of the limited therapeutic options in BC, new drugs or new therapeutic modalities should be considered. In the future, studies with long-term follow-up may be helpful for their implication in clinical practice.