The prognostic impact of obesity on molecular subtypes of breast cancer in premenopausal women.

PURPOSE: The increasing incidence of obesity throughout the world will result in expansion of the number of women at risk for developing breast cancer. Obesity is associated with adverse outcomes in postmenopausal women with breast cancer. In premenopausal women, the association is less clear. We investigated the impact of obesity on tumor features, hormonal status, recurrence and mortality in premenopausal breast cancer patients, classified according to molecular subtypes. METHODS: 818 premenopausal women with nonmetastatic breast cancer were analysed. Patients were classified into 3 groups according to body mass index (BMI): i) normal body weight (BMI: 18.5-24.9 kg/m(2)); ii) overweight (BMI: 25-29.9 kg/ m(2)); and iii) obese (BMI:>30 kg/ m(2)). Clinocopathologic characteristics and survival rates were analyzed for triple negative, HER-2 overexpressing and luminal subtypes. RESULTS: Obese patients compared with normal-weight women were older at diagnosis (p<0.001) and more often had high grade tumor (57.1 vs 42.3%; p=0.04) with lymphovascular invasion (79.5 vs 63.9%; p=0.03). The median follow-up period after diagnosis was 29 months. According to the molecular subtypes, overall survival (OS) and disease free survival (DFS) were significantly shorter in obese patients with triple negative breast cancer (TNBC) (p=0.001 and p=0.006, respectively). Obesity (HR 1.4; 95% CI 1.0-2.1; p=0.04) and lymphovascular invasion (HR 2.1; 95% CI 1.3- 3.3; p=0.02) were found to be independent prognostic factors for TNBC mortality. CONCLUSION: Obesity is associated with estrogen (ER) and progesterone receptor (PR) negative tumors and poor OS in premenopausal women with breast cancer.

Evaluation of changes in biologic markers ER, PR, HER 2 and Ki-67 index in breast cancer with administration of neoadjuvant dose dense doxorubicin, cyclophosphamide followed by paclitaxel chemotherapy.

PURPOSE: The aim of this study was to assess the changes in biologic markers of breast cancer ER, PR, HER 2 and Ki-67 in locally advanced breast cancer patients after neoadjuvant chemotherapy. METHODS: Data from 63 locally advanced breast cancer patients (stage II or III), whose histological diagnosis was made by core biopsies were retrospectively evaluated. The patients were given 4 cyles of 600 mg/m(2) cyclophosphamide, 60 mg/m(2) doxorubicin every 15 days followed by 4 cycles of paclitaxel 175 mg/m(2) every 15 days, and they underwent surgery within two weeks after the last chemotherapy cycle. Expressions in the preoperative and postoperative status of ER, PR, HER 2 and Ki-67 were compared. RESULTS: The patient mean age was 49.2 ±10.7 years and most (57.1%) were premenopausal. Clinical stages of patients ranged between T2N1 and T3N2. The pathological complete response (pCR) rate was 14.9 % (N=9). Two (5.7%) patients who were ER positive prior to treatment showed ER negativity after treatment. In 7 (21.17percnt;) patients PR became negative after neoadjuvant chemotherapy and in 3 (9.0%) patients PR became positive. Changes in ER and PR receptors were not statistically significant (ER p=0.500 and PR p=0.549, respectively), whereas in 2 (5. 8%) patients hormonal status changed significantly when compared to initial biopsies (p=0.003). In addition, median value for PR intensity decreased from 20 to 10% (p=0.003) and Ki-67 values decreased from 10 to 1% (p<0.001) following neoadjuvant therapy. Six (17%) patients exhibited some changes in HER 2 staining. HER 2 expression became 2+ in 3 patients who were HER 2 negative prior to treatment, and HER 2 expression became negative in two patients with HER 2 1+ and 2+ prior to treatment following neoadjuvant chemotherapy. CONCLUSION: The biological markers ER, PR, HER 2 and Ki- 67 index demonstrated differences after neoadjuvant treatment in breast cancer patients. These changes may affect the treatment decision.

Evaluation of changes of biologic markers ER, PR, HER 2 and Ki-67 in breast cancer with administration of neoadjuvant dose-dense doxorubicin, cyclophosphamide followed by paclitaxel.

PURPOSE: To assess the changes of biologic markers estrogen receptors (ER), progesterone receptors (PR), HER 2 and Ki-67 in locally advanced breast cancer patients after neoadjuvant chemotherapy. METHODS: Data from 63 locally advanced breast cancer patients (stage II or III), whose histological diagnosis was made by core biopsies were retrospectively evaluated. The patients were given 4 cycles of 600 mg/m(2) cyclophosphamide, 60 mg/m(2) doxorubicin every 15 days, followed by 4 cycles of paclitaxel 175 mg/m(2), followed by mastectomy within 2 weeks after the last chemotherapy cycle. The changes in ER, PR, HER 2 and Ki-67 status of the operated tumor tissue were compared with the material obtained by initial core biopsies. RESULTS: The patient mean age was 49.2±10.7 years. Most (57.1%) were premenopausal. Clinical disease stages ranged between T2N1 and T3N2. Pathological complete response (pCR) rate was 14.9 7 percent; (n=9). Two (5.7%) patients who were ER positive prior to treatment showed ER negativity after treatment. In 7 (21.1%) patients PR became negative and in 3 (9.0%) became positive after neoadjuvant chemotherapy. Changes in ER and PR receptors were not statistically significant (p=0.500 and PR p=0.549, respectively), whereas in 2 (5.8%) patients hormonal status changed significantly when compared to initial biopsies (p=0.003). In addition, the median value of PR intensity decreased from 20 to 10% (p=0.003) and Ki-67 decreased from 10 to 1% (p<0.001) following neoadjuvant therapy. Five (14.1%) patients exhibited some changes in HER 2 expression: HER 2 expression became 2+ in 3 patients previously being HER 2 negative, and in 2 patients HER 2 became negative whilst it was 1+ and 2+ prior to neoadjuvant chemotherapy. CONCLUSION: It was observed that the biologic markers ER, PR, HER 2 and Ki-67, from the same tumor material demonstrated differences after neoadjuvant treatment in breast cancer patients. These changes may affect the treatment decision.

Association between family history and clinicopathologic characteristics in 1987 breast cancer patients: single institution experience from Turkey.

PURPOSE: To evaluate the clinicopathologic characteristics and survival of patients with family history of breast/ ovarian cancer (FHBOC). METHODS: In this study with 1987 breast cancer patients, we analyzed their tumor characteristics and outcomes, as well as the total number, degree and age of affected relatives, and their type of cancer. Results were assessed using Pearson chi-square test, Kaplan-Meier method and Cox regression analysis. RESULTS: 24.1% (n=479) of the patients had FHBOC. Patients with FHBOC were younger (47.7 vs. 49.1 years; p=0.03) and tended to have node-negative breast cancer (45.4 vs. 39.8%; p=0.006). The median overall survival (OS) was shorter in patients with FHBOC with a borderline p-value (p=0.063), compared to patients with no family history. The median OS was shorter in patients who had ≥ 2 relatives with breast cancer (p=0.014), in those having first degree relatives with breast cancer, presenting with metastatic disease (p= 0.020). FHBOC patients with triple negative breast cancer had the highest risk of death (p<0.0001) and recurrence (p<0.0001). Patients who had at least one relative with breast cancer aged ≤ 50 years were also at increased risk of recurrence (p7equals;0.006). CONCLUSION: Our results suggest that patients with FH7horbar;BOC are younger, tend to have small tumor size, node-negative disease and their survival is shorter compared to patients without family history. This is the first study evaluating the clinicopathologic differences of patients with and without FHBOC in Turkish population.

Pure mucinous carcinoma of the breast: a single center experience.

PURPOSE: Mucinous breast carcinoma is rare subtype of breast cancer. Histopathologically, it is classified into two forms, pure and mixed type. It recurs late, metastasis to axillary lymph nodes is less common and is more hormone receptor positive. We herein present the data of our patients with pure mucinous breast cancer (PMBC) treated in our institution. METHODS: Among 1211 breast cancer patients with breast cancer diagnosed and treated in Hacettepe University Institute of Oncology, 20 patients (1.6%) with PMBC (defined as having mucinous component of more than 90%) were identified. Patient demographics, tumor characteristics and patient outcomes were assessed retrospectively. RESULTS: The median age at diagnosis was 52.5 years (range 27-80). The majority of the patients presented with stage II disease (n=15; 75%). One of 20 patients recurred with bone metastasis 50 months after diagnosis. Median follow-up was 39 months (range 3-137). Estrogen receptors (ER) were positive in 16 (80%) patients and HER-2 positive in one (5%). Twenty-five percent of the patients had positive axillary nodes. CONCLUSION: PMBC is a rare entity with favorable prognosis. Lymph node metastasis is rarely seen even in large -sized tumors.

Secondary hematological malignancies after treatment of non-metastatic breast cancer.

PURPOSE: To determine the frequency of secondary hematological malignancies in non-metastatic breast cancer (BC) patients who received adjuvant chemotherapy and radiotherapy. METHODS: Data of BC patients followed at Hacettepe University Institute of Oncology, Department of Medical Oncology between 2004 and 2010 were retrospectively analysed. RESULTS: There were 1,475 BC patients followed between 2004 and 2010 at our department; 1,319 (89.4%) of them had not metastatic disease. One thousand, one hundred eighty three (89.7%) early-stage BC patients received at least one treatment modality (radiotherapy and/or chemotherapy). The number of patients receiving only chemotherapy or only radiotherapy were 228 (17.3%) and 117 (8.9%), respectively. Eleven (1%) out of 1,066 BC patients receiving adjuvant/neoadjuvant chemotherapy were also treated with granulocyte colony stimulating factor (G-CSF). The frequency of secondary hematological malignancies among adjuvant or neoadjuvant chemotherapy BC patients was 0.56% (6/1,066); it was 0.59% (7/1,183) among radiotherapy and/or chemotherapy treated non-metastatic BC patients. Five patients developed acute myeloid leukemia (AML); 3 of them were AML-FAB M3 and 2 could not be subclassified. The 6th patient had multiple myeloma and the 7th had diffuse large B cell lymphoma (DLBCL). However, the latter did not receive cytotoxic chemotherapy for BC. CONCLUSION: Treatment-associated secondary hematological malignancies, especially myeloid leukemias, are a growing problem due to high prevalence of BC and the dismal outcome of secondary leukemias. Further studies are needed to determine the risk for other hematological malignancies, possible responsible agents, and mechanisms.

Differential alteration of drug-metabolizing enzyme activities after cyclophosphamide/adriamycin administration in breast cancer patients.

Cyclophosphamide (CPA) and adriamycin (ADR) are widely used drugs for cancer chemotherapy. It has been reported that CPA and ADR singly or in combination could alter activities of a variety of drug-metabolizing enzymes in animals via multiple mechanisms. However, the effects of CPA/ADR on drug metabolism are largely unknown in human beings. Losartan metabolism has been suggested as a marker for determination of CYP2C9 activity. Caffeine is a commonly used probe to assess the metabolic activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO). The present study was designed to analyze the effects of CPA/ADR on these drug-metabolizing enzymes by using losartan and caffeine as probe drugs. A single oral dose of 25 mg losartan and a cup of instant coffee was given to 15 breast cancer patients on three occasions (before, and 2-4 h and 3 weeks after the adjuvant CPA/ADR chemotherapy [600 mg CPA/m2/day, 60 mg ADR/m2/day]). Losartan, caffeine and their metabolites were analyzed by using high-pressure liquid chromatography. When compared with baseline, CYP1A2 activity was increased by 20% and CYP2C9 activity was decreased by 315% 3 weeks after the administration of CPA/ADR chemotherapy (p = 0.05). The chemotherapy did not change the activities of CYP2A6, NAT2 or XO. CPA/ADR treatment caused a differential effect on drug-metabolizing enzyme activities, and this may contribute to predicting the efficacy and toxicity of chemotherapeutics, as well as understanding the drug-drug interactions.

Myasthenic crisis following cisplatin chemotherapy in a patient with malignant thymoma.

Malignant thymomas are associated with numerous autoimmune disorders including myasthenia gravis. Myastenia gravis is characterized by antibodies against the acetylcholine receptors located on the neuromuscular junction of the skeletal muscle. We present a case with malignant thymoma who developed myasthenia crisis while he was treated with cisplatin chemotherapy.

Combination of docetaxel and doxorubicin as first-line chemotherapy in metastatic breast cancer.

Docetaxel (Taxotere) and doxorubicin have previously demonstrated a significant antitumor activity in patients with metastatic breast cancer. Furthermore, a lack of cross resistance and overlapping toxicities between the two agents have been reported. In a prospective study, docetaxel (80 mg/m2, 1-hr iv infusion) and doxorubicin (60 mg/m2, 1-hr iv infusion) were administered as first-line chemotherapy in metastatic breast cancer patients to evaluate the clinical efficacy and toxicity of the combination. Forty-three patients were enrolled in the study. The median age was 47 years (range, 30-69). The docetaxel-doxorubicin combination was applied with 3-week intervals until progression. Complete response was achieved in 9 (21.4%) of 42 assessable patients and partial response in 24 (57.2%) patients, for an overall response rate of 78.6%. Median response duration was 8 months (3-18 months). Nausea and vomiting (76%), alopecia (64%), neutropenia (35.7%) and mucositis (33%) were the major side effects of the combination. There was one case of cardiac toxicity. In conclusion, the docetaxel-doxorubicin protocol can be considered as an active regimen for the treatment of patients with metastatic breast cancer with acceptable toxicity and a fairly high response rate.

Primary low grade B-cell lymphoma of the dura in an immunocompetent patient.

Primary central nervous system lymphomas (PCNSL) represent only 1% of all non-Hodgkin's lymphomas (NHLs). A 66 year-old woman was hospitalized due to multiple episodes of syncope and seizures which occurred the week before admission to the hospital. A computerized tomography (CT) scan of the brain showed a right parietal lesion suggesting a subdural effusion. The patient was operated and a dural lesion extending to the epidural space and cerebral cortex was excised. Histologic findings suggested diagnosis of a low-grade lymphoma of the mucosa associated lymphoid tissue (MALT) type. The patient was treated with radiation therapy and has now completely recovered 12 months after surgery.

Primary breast lymphomas--a retrospective analysis of twelve cases.

This study was undertaken to define the natural history and treatment results of patients with primary breast non-Hodgkin's lymphoma (NHL). Twelve female patients who had been followed at Hacettepe University Hospital between 1973 and 1997 were retrospectively evaluated. All patients presented with breast masses (6 in the right breast and 6 in the left) that had recently enlarged. The most common histologic subtype was diffuse, small cleaved-cell lymphoma. Chemotherapy regimens were employed in 9 patients. Radiotherapy was delivered to the breast and its lymphatics in 8 patients. Lumpectomy, simple or modified radical mastectomy was performed in 5 cases. An objective response was attained with surgery, chemotherapy, or radiotherapy alone in 2, 1, and 1 cases, respectively. Combined modality treatment including either two or three modalities was successful in 7 cases. The median progression-free and overall survival times were 49 and 56 months, respectively. Although primary NHL of the breast is a rare disease compared to carcinoma, it should be considered in the differential diagnosis of breast masses.

Treatment of advanced soft tissue sarcomas with ifosfamide and doxorubicin combination chemotherapy.

Our objective was to assess the efficacy of a standard dose ifosfamide and doxorubicin containing regimen in the treatment of advanced soft tissue sarcomas. Forty consecutive patients with a median age of 35.5 years were treated. Ifosfamide was administered at a dose of 2.5 g/m(2)/day as 72-hour continuous infusion with mesna at the same dosage and schedule. Doxorubicin was given at the dose of 60 mg/m(2)/day as 2-hour infusion on day 1. Six patients had a complete response (15%), and 9 (22.5%) had a partial response, fourteen patients (35%) stable disease, and 11 (27.5%) did not respond to chemotherapy. The median duration of response was 13 and 5 months for the complete and partial responders, respectively. The median survival was 37 months. Febrile neutropenia was encountered in 9 cases (22.5%). The present ifosfamide and doxorubicin combination is a moderately effective and well-tolerable regimen in the treatment of advanced soft tissue sarcomas.

Serotonin receptor antagonists in prophylaxis of acute and delayed emesis induced by moderately emetogenic, single-day chemotherapy: a randomized study.

In this randomized study, the efficacy of a single dose of three serotonin antagonists were compared in prophylaxis of acute and delayed vomiting induced by moderately emetogenic, single-day chemotherapy in chemotherapy-naïve patients. A total of 54 patients were entered. Eighteen patients received ondansetron, 17 received tropisetron, and 19 received granisetron. Antiemetics were administered as 15-minute intravenous infusion before chemotherapy. Complete control of acute vomiting was achieved in 38.8% with ondansetron, 58.8% with tropisetron, and 73.7% with granisetron. Major response rates were 83.3%, 82.3%, and 89.5%, respectively. For the delayed control of emesis, complete control of delayed vomiting was achieved in 38.8% with ondansetron, 52.9% with tropisetron, and 73.7% with granisetron. The major response rates were 71.8%, 70.5%, and 100%, respectively. The adverse effects were rare and mild in all groups. The authors conclude that there may be clinically important differences among serotonin antagonists used for chemotherapy-induced emesis.

VB-CHEP chemotherapy regimen for aggressive non-Hodgkin's lymphomas.

Despite intensive search for the optimal combination chemotherapy for aggressive non-Hodgkin's lymphoma (NHL), the CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) regimen is still the standard therapy. We investigated the clinical efficacy of a new combination regimen consisting of vincristine, bleomycin-cyclophosphamide, adriamycin, etoposide and prednisolone (VB-CHEP) in patients with aggressive NHL. A total of 29 patients with aggressive NHL was enrolled into the protocol. Eight patients were consolidated with cisplatin and cytarabine and 5 patients received radiotherapy for bulky disease. Objective response was achieved in 82.8% of the patients. Complete remission (CR) and partial remission rates were 72.4%, and 10.3%, respectively. CR rate was significantly lower in patients with advanced stage, extranodal disease and bone marrow involvement. Median follow-up time is 34+ months; 17 patients are disease-free while 12 died and only 2 patients with CR have relapsed so far. Median response duration is 29+ months and the median survival is 48+ months. The survival rate is 69% in the first year and 66% in the second year. A total of 152 cycles were evaluated for toxicity. Major hematological toxicity was myelosuppression and neutropenia, detected in 50.65%, was mostly grades 1-2. Neutropenic fever occurred in only 11 cycles. The side effects of the consolidation therapy were also acceptable. We conclude that the VB-CHEP regimen with consolidation therapy for high-risk patients may be an effective treatment for advanced stage aggressive NHL.

Deletion 1p in a low-grade chondrosarcoma in a patient with Ollier disease.

Ollier disease is an uncommon, nonhereditary developmental disorder affecting enchondral ossification. Cytogenetic analysis of low-grade chondrosarcoma in a patient with Ollier disease (multiple enchondromatosis) revealed an interstitial deletion, del(1)(p11p31.2), as the only chromosome abnormality. This is the first cytogenetic study of a chondrosarcoma in a patient with Ollier disease. Such patients are at risk of developing chondrosarcoma and, because del(1p) is frequent in chondrosarcoma, it is suggested that this cytogenetic finding is associated with early chondrosarcomatous transformation.

Bolus and continuous infusion mitoxantrone in newly diagnosed adult acute lymphoblastic leukemia: results of two consecutive phase II clinical studies.

Two consecutive phase II clinical studies were designed to evaluate the efficacy and safety of bolus and continuous infusion (CI) mitoxantrone (MTZ) in 39 patients with newly diagnosed acute lymphocytic leukemia (ALL). MTZ was used as part of the classical ALL induction regimen. Twenty patients were treated with bolus MTZ (10 mg/m2 for 3 days) combined with vincristine and prednisone. The same regimen was given to a second set of 19 patients, except that MTZ was administered as a 24-hr CI. Both groups received bimonthly intensifications with vincristine and prednisone for 3 years, along with oral maintenance therapy. Patients in the CI-MTZ study arm received additional MTZ on the first day of intensification cycles. Seventeen patients (85%) in the bolus arm and 15 patients (79%) in the CI arm achieved complete remission (CR). Median disease-free survivals (DFS) in the bolus and CI groups were 11 and 15 months after median follow-ups of 16 (3.5-96) and 13 (2.3-32) months, respectively. At 2.5 years, DFS rates were 29.4% and 34.4% in the bolus and CI groups (p > 0.05). There were no significant differences between two groups in rates of early death, degree of organ toxicity, or duration of neutropenia and thrombocytopenia. Significant cardiac toxicity was not observed in either group. Bolus or CI administration of MTZ was equally effective and was well tolerated. Neither the mode of administration nor increasing the dose intensity of MTZ by incorporating intensification cycles reduced relapse rates. Development of new antileukemia agents and novel treatment approaches are still needed to improve the high relapse rates in adult ALL once a complete response is achieved.

Treatment of advanced refractory sarcomas with ifosfamide and etoposide combination chemotherapy.

Chemotherapy options for resistant advanced-stage sarcomas are limited and in most cases disappointing. In a phase II study, we treated 26 consecutive patients with refractory advanced sarcoma with ifosfamide and etoposide combination chemotherapy. All patients had received prior doxorubicin- and/or cyclophosphamide-based chemotherapies. Seventeen patients were male and 9 were female. The patients' median age was 35 years (range: 19-67 years). A total of 24 patients were eligible for evaluation of responses. Seven patients had a complete response (CR) (29.1%), 3 had a partial response (PR) (12.5%), 3 had stable disease (SD) (12.5%), and 11 had progressive disease (PD) (45.9%). An overall 41.6% objective response was achieved. Median time to treatment failure was 13.3 months. A total of 108 cycles of therapy were evaluable for evaluation of toxicity. Myelosuppression, observed in 55.5% of the treatment courses, was the major dose-limiting toxicity. Nausea and vomiting, seen in 64% of the courses, were the most important nonhematological side effects. Alopecia was almost universal. Hemorrhagic cystitis was observed in only 1 patient. We have concluded that the combination of ifosfamide, mesna, and etoposide is effective in advanced refractory sarcomas, and has acceptable toxicity.