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.

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.

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.

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.

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.

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.

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.

The usefulness of cytogenetic findings in differential-diagnosis of metastases of unknown origin.

Chromosomal abnormalities can be applied in the diagnosis and classification of some metastases of unknown origin. A selective search is most appropriate for treatable tumors, such as prostate, ovary, breast, small-cell lung cancer and germ cell tumors. Cytogenetic analysis may be particularly useful in these cases, since some of these tumors have been found to have specific chromosomal changes that are generally retained in the metastases. We discuss the usefulness of cytogenetic analysis in differentiating the origin of metastases and review the few cases reported in the literature.

Involvement of 10q22 in leiomyoma.

Cytogenetic investigation of uterine leiomyomas revealed a rearranged 10q22 present in nine tumors as a clonal change in most of the cells analyzed. These findings indicate that abnormalities involving chromosome 10 and, particularly 10q22, may characterize a cytogenetic subgroup of uterine leiomyomas.

Deletion 7q22 in uterine leiomyoma. A cytogenetic review.

The cytogenetic patterns of uterine leiomyomas have been extensively investigated, and cases characterized by specific clonal changes have been documented in detail. In these tumors one of the cytogenetic changes frequently observed has been a del(7), particularly del(7)(q22), usually as a sole anomaly. This is confirmed by our experience and by reports in the literature. The fact that del(7) is one of the most common abnormalities in leiomyoma raises the question of its role in tumor development. The main purpose of this review is to analyze the above aspect and to interpret its possible meaning. Our findings on cytogenetic abnormalities of chromosome 7 in leiomyoma, together with those reported in the literature, are reviewed and discussed. A listing of the genes located at 7q22 is also presented.

Inversion (X)(p22q13) in a uterine leiomyoma.

We report a case of uterine leiomyoma which showed a karyotype 46,X,inv(X)(p22q13) as the only clonal change in most of the cells. A few cells had an additional del(7), though del(7) has been found to be a primary change in leiomyomas. These findings indicate that the abnormality involving the X chromosome and particularly Xp22 can be considered as a primary chromosomal abnormality. We discuss the findings together with few reports of cases involving chromosome X in leiomyomas.

Translocation (6;10)(p21;q22) in uterine leiomyomas.

A translocation between chromosomes 6 and 10 was observed in two uterine leiomyomas. Translocation (6;10) may be important in the pathogenesis of a subgroup of uterine leiomyomas.

Trisomy 5 in long-term cultures from bone marrow of patients with solid tumors.

Long-term cultures of bone marrow from 15 cases diagnosed previously with primary solid tumors were analyzed cytogenetically. Of these cases, 10 had normal karyotypes and five had chromosomal abnormalities. Trisomy 5 was found in four cases, three with trisomy 5 as the only change and one with trisomy 5 and trisomy 12. These results suggest that trisomy 5 may be a nonrandom change associated with an in vitro or in vivo phenomenon.

Chromosome 7 biclonality in uterine leiomyoma.

Biclonal chromosome complements in uterine leiomyoma have been reported occasionally. These previous studies reported the presence of two unrelated clones containing mainly t(12;14) and del(7). We describe four cases of typical leiomyoma displaying two clones, both involving chromosome 7 but with a different deletion in each of the two clones. For two of the tumors, the biclonal origin is the only possible explanation; for the remaining two cases, the origin of the two deleted chromosomes 7 could also be explained by clonal evolution, since the more proximal deletion on chromosome 7 in one clone appears to be subsequent to the deletion of the other clone. Even in these cases, however, the biclonal origin cannot be excluded completely. Despite the mechanism of origin, deletion of chromosome 7 is the most common cytogenetic abnormality in leiomyoma, indicating that loss of genetic material from the long arm of this chromosome is critical for tumor development.

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.

Chromosome abnormalities in breast fibroadenomas.

Cytogenetic analysis of 25 breast fibroadenomas (FA) showed clonal chromosome alterations in three cases. Insertion (12;?) (q15;?) and deletion (2) (q14q31 or q32) were detected as a sole change in cases 1 and 3, respectively. Case 2 displayed the karyotype 45,XX,t(1;8;16)(q25;q23;q22-23), add (7)(p14), rea(15), -17. The present findings are discussed together with the reports on FA in the literature.

Cytogenetic findings in 21 malignant melanomas.

Cytogenetic analysis was performed on 21 tumor samples of malignant melanoma to identify the presence of consistent chromosome abnormalities. Four cases had a normal karyotype, and 17 were cytogenetically abnormal. Numerical chromosome alterations were observed in 15 tumors: 12 were hyperdiploid and three were hypodiploid. The most frequent losses consisted of chromosomes 5, 9, 17 and Y. The structural abnormalities were usually complex, consisting mainly of nonreciprocal translocations and deletions affecting 1p, 1q, 3p, and 9p. This study adds further data to previously reported melanoma cases, confirming that chromosomes 1, 3, 6, and 9 are nonrandomly affected.

Deletion of chromosome 13 in osteosarcoma secondary to irradiation.

The cytogenetic analysis of a radiation-induced osteosarcoma in a 31-year-old male is presented. Complex karyotypic changes with numerical and structural abnormalities, including a del(13)(q12.3q21.1), were observed. This deletion may indicate that loss of RB1 gene (locus in 13q14) may be involved in the development of radiation-induced osteosarcoma.