Immunohistochemical HER2 Status Evaluation in Breast Cancer Pathology Samples: A Multicenter, Parallel-Design Concordance Study.

OBJECTIVE: As patients with increased human epidermal growth factor receptor (HER2) overexpression are more likely to benefit from trastuzumab treatment, the accuracy of HER2 receptor status in breast cancer patients is significant for appropriate disease management. However, this assessment is not harmonized and results may be highly variable between centers. The aim of this study was to investigate the degree of interlaboratory variability in the results of HER2 expression reported by 5 participating centers and to assess the concordance between these centers and a reference laboratory.Materials and Methods: A total of 30 breast cancer samples were tested and scored for HER2 expression using immunohistochemical method in 5 centers from Turkey and in a reference laboratory from Netherlands (Academic Medical Center, Amsterdam). All the participating centers had an experience of more than 10 years regarding the HER2 testing. The results were compared both among the centers and with the reference laboratory. RESULTS: When the concordance of participating centers and the reference laboratory was evaluated regarding negative (0-1+), equivocal 2(+) and positive 3(+) classification of HER2 immunostaining, the highest concordance was found in Center-A, and the lowest in Center-C (Kendall's tau-b concordance coefficient 0.911 and 0.724, respectively). The concordance of the centers with reference laboratory was 80.0% both in equivocal and positive samples, while it increased up to 91.8% in negative samples. CONCLUSIONS: This study showed that in general there is sufficiently good agreement between the reference laboratory and the participating centers for immunohistochemical HER2 assessment.

Diagnostic serum vitamin D level is not a reliable prognostic factor for resectable breast cancer.

AIM: There are inconsistent results about the effects of vitamin D level on breast cancer prognosis. We aimed to investigate the effect of vitamin D levels on the prognosis of resectable breast cancer in a patient group with highly different clothing styles. PATIENTS & METHODS: A total of 186 breast cancer patients were enrolled in the study. RESULTS: Vitamin D level was sufficient, insufficient and deficient in 17.2, 52.2 and 30.6% of patients, respectively. There was a significant relationship between clothing style and serum 25 (OH) D levels. We could not establish any relation between vitamin D level and tumor characteristics or survival. CONCLUSION: Vitamin D supplementation can be more important than diagnostic serum vitamin D level on prognosis of breast cancer.

Breast cancer survivors suffer from persistent postmastectomy pain syndrome and posttraumatic stress disorder (ORTHUS study): a study of the palliative care working committee of the Turkish Oncology Group (TOG).

PURPOSE: Persistent postmastectomy pain syndrome (PMPS) is one of the most important disturbing symptoms. Posttraumatic stress disorder (PTSD) is an anxiety disorder which is characterized by reactions to reminders of the trauma that has been experienced. The purpose of this study is to evaluate the predictors of PMPS and PTSD in Turkish breast cancer survivors and the correlation between PMPS and PTSD. METHOD: The study is designed as a multicenter survey study. Breast cancer patients in remission were evaluated. Patients were evaluated with structured questionnaires to assess the PMPS and clinical parameters associated with it. The Turkish version of the posttraumatic stress disorder checklist-civilian version (PCL-C) was used. RESULTS: Between February 2015 and October 2015, 614 breast cancer survivors in outpatient clinics were evaluated. The incidence of PMPS documented is 45.1 %. In the multivariate analysis low income, presence of PTSD and <46 months after surgery were associated with increased risk of PMPS. PTSD was documented in 75 %, and the mean PCL-C score was 32.4 ± 11.1. PMPS and being married at the time of the evaluation were linked with PTSD. CONCLUSIONS: It is the first data about the association between PMPS and PTSD. The clinicians should be aware of PMPS and PTSD in breast cancer survivors.

Nine weeks versus 1 year adjuvant trastuzumab in patients with early breast cancer: an observational study by the Turkish Oncology Group (TOG).

BACKGROUND: Optimal duration of adjuvant trastuzumab in early breast cancer is an unresolved issue. In this observational study, we compared the outcome of 9 weeks and 1 year adjuvant trastuzumab in early breast cancer patients in Turkey. METHODS: Records of 680 patients with HER2-positive early breast cancer who received adjuvant trastuzumab plus chemotherapy were obtained and patients were followed up to compare the disease-free survival (DFS) outcome of 9 weeks versus 1 year trastuzumab. RESULTS: Nine weeks and 1 year trastuzumab was given to 202 (29.7 %) and 478 (70.3 %) patients, respectively. There was a significantly lower rate of patients with negative lymph nodes in the 9-week trastuzumab group. At median 3 years of follow-up from the date of starting trastuzumab, the DFS rates were 88.6 and 85.6 %, respectively (p = 0.670). When adjusted for all the prognostic factors that were significant on univariate analysis, again there was no significant difference in DFS between the groups (HR 0.675; 95 % CI 0.370-1.231; p = 0.200). Cardiac toxicity defined as a ≥15 % decrease in LVEF was significantly higher in the 1-year trastuzumab group (1.88 % versus none for 1-year and 9-week trastuzumab groups, respectively; p = 0.050). CONCLUSION: The results of this observational study suggest that DFS outcome of 9 weeks of adjuvant trastuzumab may be comparable to 1 year adjuvant trastuzumab: this needs confirmation by randomized trials.

The Outcome of Patients with Triple Negative Breast Cancer: The Turkish Oncology Group Experience.

OBJECTIVE: Triple negative breast cancer (TNBC) is generally considered as a poorer prognostic subgroup, with propensity for earlier relapse and visceral involvement. The aim of this study is to evaluate the outcome of non-metastatic TNBC patients from different centers in Turkey and identify clinical and pathologic variables that may effect survival. MATERIALS AND METHODS: Between 1993-2007, from five different centers in Turkey, 316 nonmetastatic triple negative breast cancer patients were identified with follow-up of at least 12 months. The data was collected retrospectively from patient charts. The prognostic impact of several clinical variables were evaluated by the Kaplan-Meier and Cox multivariate anayses. RESULTS: Mean age at diagnosis was 49 years (range: 24-82). The majority of the patient group had invasive ductal carcinoma (n: 260, 82.3%) and stage II disease (n: 164; 51.9%). Majority of the patients (87.7%) received adjuvant chemotherapy. 5 year overall survival (OS) and disease-free survival (DFS) rates were 84.6% and 71.6%, respectively. Univariate analysis revealed locally advanced disease (p: 0.001), advanced pathological stage (p: 0.021), larger tumor size (T1&T2 vs T3&T4) (p<0.001), nodal positivity (p: 0.006), and extensive nodal involvement (p<0.001) as significant factors for DFS; whereas, advanced pathological stage (p: 0.017), extensive nodal involvement (p<0.001) and larger tumor size (p: 0,001) and presence of breast cancer-affected member in the family (p=0.05) were identified as prognostic factors with an impact on OS. Multivariate analysis revealed larger tumor size (T3&T4 vs T1&T2) and presence of lymph node metastases (node-positive vs node-negative) as significant independent prognostic factors for DFS (Hazard ratio (HR): 3.03, 95% CI: 1.71-5.35, p<0.001 and HR: 1.77, 95% CI: 1.05-3.0, p=0.03, respectively). Higher tumor stage was the only independent factor affecting overall survival (HR: 2.81; 95% CI, 1.27-6.22, p=0.01). CONCLUSION: The outcome of patients with TNBC in this cohort is comparable to other studies including TNBC patients. Tumor size and presence of lymph node metastasis are the major independent factors that have effect on DFS, however higher tumor stage was the only negative prognostic factor for OS.

Is obesity always a risk factor for all breast cancer patients? c-erbB2 expression is significantly lower in obese patients with early stage breast cancer.

OBJECTIVES: The purpose of this study was to evaluate the relationship between body mass index and lipid profiles with breast cancer prognosis together with the relationship of these parametres with known breast cancer prognostic indices including c-erbB2 expression. PATIENTS AND METHODS: Four hundred and thirty-three patients diagnosed with breast cancer at Ankara University, Faculty of Medicine, Department of Medical Oncology made up the study population. The primary endpoints were relapse and death. Body mass index at the time of diagnosis, lipid levels at the time of diagnosis, estrogen receptor status, progesterone receptor status, c-erbB2 expression, tumor grade, patient age, axillary lymph node involvement level, tumor stage, menopausal status and surgery details were taken into account. RESULTS: The mean body mass indices were similar in the remission, relapse and mortality groups. Patients with body mass indices higher than 30 kg/m² had a lower incidence of c-erbB2 expression when compared to patients with body mass indices < 18.5 kg/m(2) (19 vs. 50 %, p = 0.009). Survival analysis revealed that patients with body mass indices < 18.5 kg/m(2) had significantly shorter disease free survivals when compared to patients with body mass indices between 25 and 29.9 kg/m(2). Mean serum lipid levels were similar in the remission, relapse and mortality groups. A trend toward relapse was shown in patients with total cholesterol > 240 mg/dl, but this was statistically insignificant. Survival analysis revealed that patients with triglyceride levels lower than 150 mg/dl had a statistically significant longer disease-free survival when compared to the other groups. Again a trend towards shorter overall survival was seen in patients with total cholesterol > 240 mg/dl, but this relationship was also statistically insignificant. CONCLUSION: Most large previous studies reported adverse breast cancer outcome with obesity. However in our study, patients with lower body weight had a shorter disease-free survival. This could be explained by the low number of patients in this study, genetic profile of the patient population, possible weight changes after treatment and the inverse relationship between body mass index and c-erbB2 expression.

ABO and Rh blood groups and risk of colorectal adenocarcinoma.

BACKGROUND: Previous studies have observed an association between ABO blood group and risk for certain gastrointestinal malignancies, including pancreatic and gastric cancer. However, it is unclear whether there is such an association with colorectal cancer (CRC). In this study, possible relationships between ABO blood groups and Rh factor and KRAS status in patients with CRC were investigated. MATERIALS AND METHODS: In 1,620 patients with CRC, blood group and Rh factor were examined and compared with the control group of 3,022,883 healthy volunteer blood donors of the Turkish Red Crescent between 2004 and 2011. The relationship of blood groups with wild type K-ras status was also evaluated. RESULTS: Overall distributions of ABO blood groups as well as Rh factor were comparable between patients (45% A, 7.2% AB, 16.4% B, 31.4% O, and 87.2% Rh+) and controls (42.2% A, 7.6% AB, 16.3% B, 33.9% O, and 87.7% Rh+) (p=0.099). However, there were statistically significant difference between patients and controls with respect to O vs. non O blood group (p=0.033) and marginally significant difference for A vs. non-A blood group (p=0.052). Among patients, the median age was 62 (range 17-97), 58.1% were male. There were no statistically significant differences respect to sex and K-ras status. CONCLUSION: In present study, the ABO/Rh blood groups were statistically significantly associated with the risk of CRC. There were no relationship between K-ras status and ABO blood group and Rh factor. However further studies with larger numbers of patients are needed to establish the role of blood groups and to define the mechanisms by which ABO blood type affect CRC.

Adjuvant oral etoposide plus cisplatin (EoP) following sequential doxorubicin/cyclophosphamide (AC) and docetaxel (T) in early breast cancer patients with 4 or more positive lymph nodes (10 years follow-up).

BACKGROUND AND OBJECTIVES: Previous reports suggest that including cisplatin plus etoposide in the adjuvant treatment may improve the outcomes in patients with early breast cancer. PATIENTS AND METHODS: Forty-one patients with early breast cancer and 4 or more positive lymph nodes were treated with 3 cycles of EoP (oral etoposide plus cisplatin) in addition to 3 cycles of AC (doxorubicin plus cyclophosphamide) and 3 cycles of T (docetaxel) (Group 1). Toxicity and survival results were compared to those with similar disease characteristics who were treated with 4 cycles of AC plus 4 cycles of T (Group 2) during the same period. RESULTS: There were no long-term side effects related to EoP. While median disease-free and overall survivals were not reached in Group 1, they were 107 ± 13 (p = 0.387) months and 123 ± 5 months (p = 0.618) in Group 2. Likewise 10-year disease-free survivals (DFS) were 59.3% and 44.7% respectively. CONCLUSIONS: The trend towards improvement in survival with adjuvant AC + T + EoP when compared to AC + T needs to be studied in randomized trial.

Long-term outcome of mesna, ifosfamide, mitoxantrone, etoposide (MINE) regimen as a consolidation in patients with aggressive non-Hodgkin lymphoma responding to CHOP.

In aggressive non-Hodgkin lymphoma (NHL), CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) regimen has been standard for decades, and rituximab has increased response rates and survival in CD20 positive patients, recently. The aim of this prospective trial was to evaluate the long-term efficacy and toxicity of MINE as a consolidation treatment in aggressive NHL patients who had achieved CR or unproven CR after six cycles of CHOP in the first line setting. The primary end-point was disease-free-survival (DFS). Thirty-eight patients were enrolled between February 1992 and May 2000. All of the patients received two cycles of MINE (mesna 1.3 g/m(2), ifosfamide 1.3 g/m(2), etoposide 65 mg/m(2) on days 1-3, and mitoxantrone 12 mg/m(2) on day 1, every 3 weeks) following response to CHOP. Initial bulky disease sites were also applied radiotherapy. Male/female ratio was 1.53(23/15). Median age was 49(30-73). Most of the patients had advanced stage (84.2% for stage >3) and high IPI score (79% for IPI score >2). Sixty percent had diffuse large cell histology. Median follow-up time was 118 months (9-195). Actual mean dose intensity was 88%. There were seven febrile neutropenia episodes. Two patients had grade two neuropathy, one had grade three mucositis and another one had non-neutropenic pneumonia. There was no early toxic death. No serious late toxicity was observed during long-term follow-up. Five- and 10-year DFS rates were both 65.3%. DFS rate in the patients with more than two poor prognostic factors according to IPI score is remarkably high (88%). Five- and 10-year OS was 62.5 and 59%, respectively. MINE regimen seems to be effective as a consolidation regimen, especially, in intermediate/high risk patients and has low early and late toxicities, and it warrants to be evaluated in phase III randomised trials with rituximab in CD20 positive aggressive NHL patients.

Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer.

BACKGROUND: In this non-randomized study we aimed to assess the efficacy of the addition of low molecular weight heparin (LMWH) to gemcitabine (GEM) plus cisplatinum (CDDP) combination chemotherapy on survival by prevention of thromboembolic complications in patients with advanced pancreatic cancer (APC). PATIENTS AND METHODS: Between November 1999 and February 2004, 69 consecutive patients with APC were treated with GEM (800 mg/m2, day 1, day 8) plus CDDP (35 mg/m2, day 1, day 8) every 21 days +/-LMWH (nadroparine calcium, 2,850 IU/day until disease progression). Ten out of 35 patients in LMWH group and 10 out of 34 patients in chemotherapy alone group had primary inoperable locally advanced disease and the rest of the patients had metastatic disease. RESULTS: Total response rate was 58.8% (11.7% CR) for the patients treated with LMWH and 12.1% for those treated without LMWH (P = 0.0001). LMWH group had a better median time to progression (TTP) and survival when compared to control group (7.3 vs. 4.0 months, P = 0.0001; 13.0 vs. 5.5 months, P = 0.0001). The toxicity was similar and acceptable in both groups. CONCLUSION: Addition of LMWH to GEM plus CDDP combination significantly improved the response and survival in patients with APC and the current schedule deserves to be tested in phase III trials.

Divided dose of cisplatin combined with gemcitabine in malignant mesothelioma.

Malignant mesothelioma is a rare but notoriously chemoresistant tumor. An impressive activity of gemcitabine and cisplatin combination in malignant mesothelioma has been shown. However, the hematological toxicity and nephrotoxicity related to this regimen affect the patient's life negatively. The aim of this study is to investigate the efficacy and toxicity of divided dose of cisplatin combined with gemcitabine in chemo-naïve patients with malignant mesothelioma. Twenty-six eligible patients with malignant mesothelioma were enrolled onto the study. Cisplatin 35 mg/m(2) and gemcitabine 800 mg/m(2) were administered on days 1 and 8 as intravenous infusion in a 3-week cycle, up to maximum 6 cycles. Response and toxicity evaluations were performed in 26 patients. Male-female ratio was 11/15 with a mean age of 50.5 years (37-70). Locations of tumor were pleura in 16 patients, and peritoneum in 10 patients. All patients had epitheloid subtype of malignant mesothelioma. The partial response and stable disease were observed in 6 patients (23.1%) and in 13 patients (50%), respectively, with an overall tumor control rate of 73.1%. Seven patients (26.9%) had progressive disease. Median time to disease progression and survival were 4 and 19.5 months, respectively. Grade 3 nausea and vomiting were observed in one patient (3.8%), grade 4 neutropenia developed in one patient (3.8%) and grades 3-4 thrombocytopenia and nephrotoxicity did not develop. There was no treatment related death. Divided dose of cisplatin combined with gemcitabine, at the current dosage and schedule, appears to be an active regimen in chemotherapy-naïve patients with malignant mesothelioma, and well-tolerated.

Expression of p53 protein and DNA flow cytometry in gastric adenocarcinoma: implications in patients treated with adjuvant etoposide, adriamycin and cisplatin.

AIMS AND BACKGROUND: We evaluated the prognostic value of p53 protein, DNA content and S-phase fraction in patients with adenocarcinoma of the stomach or the gastroesophageal junction treated with adjuvant etoposide, doxorubicin and cisplatin. METHODS AND STUDY DESIGN: Thirty-five consecutive patients with stage II or III gastric or gastroesophageal junction adenocarcinoma treated with at least two cycles of adjuvant etoposide, doxorubicin and cisplatin after curative gastric resection were included. The expression of p53 protein was determined by immunohistochemistry and DNA content by flow cytometry. The presence of p53 expression and DNA content was compared with clinicopathological features. RESULTS: Median age was 54 years (range, 31-71). P53 expression was detected in 42.9% (15 of 35) of gastric cancer tissues of the patients. Aneuploidy was observed in 31.4% of patients, and S-phase fraction was more than 10% in 22.9%. P53 immunoreactivity (33.3% vs 47.8%) was more common in advanced disease. There was no association among p53 immunoreactivity, DNA content and S-phase fraction. We also found no significant relationship between p53 immunoreactivity, DNA content, S-phase fraction or other clinicopathological parameters. In univariate analysis, the involvement of lymph nodes was a significant predictor of a poor outcome (P = 0.001). Also, p53-positive patients had a poor survival close to the level of significance (P = 0.051). Likewise, p53 immunoreactivity (P = 0.0071), in addition to lymph node involvement (P = 0.0016), were the independent prognostic factors in multivariate analysis. CONCLUSIONS: This trial supports the results of previous reports that p53 immunoreactivity is a prognostic factor for patients with adenocarcinoma of stomach or gastroesophageal junction treated with adjuvant chemotherapy.

Activity of irinotecan, cisplatin and dacarbazine (CPD) combination in previously treated patients with advanced colorectal carcinoma.

AIM: Irinotecan is an active drug after fluorouracil (FU) failure in patients with colorectal cancer (CRC). Also a modest activity of cisplatin and dacarbazine combination in FU resistant patients have been reported. We aimed to assess the efficacy of irinotecan, cisplatin and dacarbazine combination in previously treated patients with measurable advanced CRC. METHODS: Treatment schedule was irinotecan 150 mg/m2, iv, d1; cisplatin 20 mg/m2 and dacarbazine 200 mg/m2 iv, d1-d3; every 21 days. 48 patients with a median age of 51 were entered the study. RESULTS: Objective response rate was 33.3%. The overall disease stabilization rate was 75.6%. The median survival was 14 months, and the median progression-free survival was 7 months. Main toxicities were grade 2-3 vomiting (39.2%) and grade 3-4 neutropenia (17.4%). CONCLUSION: CPD combination seems to be very active, with acceptable safety profile, in patients with advanced CRC resistant to FUFA.