Taner Babacan

Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer

Abstract Background: Trastuzumab emtansine (T-DM1), a novel drug developed for the treatment of HER2-positive breast cancer, is a human epidermal growth factor receptor (HER2) targeted antibody drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). It has been shown that, in preclinical studies, it has anti-tumor activity in trastuzumab refractory cancer cells. In this review, we aim to show the clinical data about trastuzumab-DM1 (T-DM1) therapy and to discuss the therapy advantages for the management of patients with HER2-positive breast cancer. Scope: T-DM1 showed positive results in clinical studies of HER2-positive metastatic breast cancer. PubMed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched up to September 2012 by using the terms ‘trastuzumab emtansine (T-DM1) and anti-HER2 treatment’; papers which were considered relevant for the aim of this review were selected by the authors. Findings: The phase III randomized trial EMILIA has shown that T-DM1 provided objective tumor responses and significantly improved progression free survival and overall survival compared to lapatinib and capacitabine combination in HER2-positive metastatic breast cancer patients treated with a prior taxane and trastuzumab regimen. It is believed that T-DM1 will play a role in the management of patients with advanced and early stage HER2-positive breast cancer, but this awaits further study. In particular, the ongoing phase III trials MARIANNE and TH3RESA will further give information about the place of T-DM1 in the treatment algorithms for HER2-positive disease. Conclusion: The trials of T-DM1 as a single agent and in combination with other chemotherapies have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. There are ongoing studies of T-DM1 showing an increasing tendency towards moving the study of these agents to earlier stages of HER2-positive breast cancer.

The Relationship between Urotensin II and its Receptor and the Clinicopathological Parameters of Breast Cancer

Background Urotensin II is a vasoactive polypeptide. It is known that some vasoactive polypeptides are produced and secreted by tumor cells, and act as a paracrine growth stimulant. The aim of this study was to examine the relationship between urotensin II and its receptor’s messenger RNA expression in breast cancer. Material/Methods Fifty-nine women with breast cancer were included in this study. The median age was 48 years. The relationships between urotensin II and urotensin II receptor mRNA expressions, which were derived from fresh breast cancer tissues and adjacent normal breast tissues, and clinical and pathological parameters, were assessed. Results We found expressions of urotensin II mRNA and its receptor in 55 of 59 breast cancer tissues and in 55 of 59 normal breast tissues. We found a positive significant correlation between urotensin II and its receptor (p=0.001, r=0.632), and found a negative, but insignificant, correlation between urotensin II and age (p=0.038, r=−0.281). Urotensin II levels were higher in the premenopausal group compared to the postmenopausal group (p<0.05). The mean urotensin II receptor expression was higher in the premenopausal group (p<0.05) compared to the postmenopausal group, and its expression was also higher in the group without extra-nodal invasion compared to that of the group with extra-nodal invasion (p=0.001). Urotensin II levels were higher in the group without lymphatic invasion compared to the group with lymphatic invasion (p=0.048). Conclusions This study is the first in the English medical literature to determine the urotensin II and its receptor mRNA expressions in breast cancer tissues. Consequently, urotensin II seems be associated with menopausal status, and extra-nodal and lymphatic invasion.

Metaplastic Breast Carcinoma: a Heterogeneous Disease

The aim of this study is to evaluate clinicopathologic characteristics and the multi-disciplinary treatment results of metaplastic breast cancer (MBC) patients treated in a single institute. Seventeen female patients with MBC treated in our department between June 2000 and January 2012 were identified and retrospectively evaluated. The median age at diagnosis was 46 years (range, 26-66 years). The median tumor size at diagnosis was 3.5 cm (range 1.5-12 cm). Six (35%) patients underwent breast conservation surgery and 11 (65%) mastectomy. Axillary lymph node metastasis was found in 6 (35%) patients. Twelve (71%) had triple negative tumors. Postoperative RT and systemic adjuvant treatment was given to all patients accordingly to stage and biological characteristics. Median follow-up time was 27 months (range, 12-151 months). At the time of this analysis, 14 (82%) patients were alive with no evidence of disease, and 1 (6%) was alive with disease. The 3-year OS was 91% and 5-year 80%, and DFS rates were 76% and 76%, respectively. Despite the young age of our patients with mostly high grade tumors, larger tumor size and higher rates of lymph node metastasis, the survival outcomes in our study are favorable in comparison with previously reported series.

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 patients 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.

Cetuximab-induced esophageal ulcer: the first report in literature.

Cetuximab, a monoclonal antibody to the extracellular domain of epidermal growth factor receptor (EGFR), is indicated for the treatment of metastatic colorectal cancers and head–neck cancers. Cetuximab is generally well tolerated but some side effects, such as skin rash, malaise, vomiting, diarrhea, hypomagnesemia, and hypersensitivity reactions, have been reported. Esophageal ulcer in patients receiving cetuximab treatment has not been described previously. We herein report a 59-year-old man diagnosed with metastatic rectal cancer with esophageal ulcers associated with cetuximab after five cycles of treatment. To the best of our knowledge, this is the first report that shows cetuximab may induce esophageal ulcers, which may be precursor lesions to a gastrointestinal tract perforation. (Published: 24 February 2014) Citation: Libyan J Med 2014, 9 : 23723 - http://dx.doi.org/10.3402/ljm.v9.23723

Safety of Tamoxifen During Pregnancy: 3 Case Reports and Review of the Literature

Dear Editors, Tamoxifen is one of the treatment options for estrogen receptor (ER)-positive breast cancers, and it is considered to be a teratogenic agent. Animal models have shown that tamoxifen can cause genitourinary developmental defects [1]. Although there is 1 case report showing that tamoxifen can cause genital defects in humans [2], other case studies report delivery of healthy babies by women using tamoxifen [3, 4]. Here we report on 3 breast cancer patients who became pregnant while undergoing tamoxifen therapy. The first case, a 32-year-old woman, presented with a left breast lump in 2007; incisional biopsy revealed infiltrative ductal carcinoma. The disease was staged as cT4cN2M1. The patient had bone metastasis at the time of diagnosis. Immunohistochemical analysis showed this tumor to be ER-positive (100%(+)), progesterone receptor (PR) 100% (+), and HER2-negative. The patient received adjuvant tamoxifen following adjuvant chemotherapy including paclitaxel, carboplatin and doxorubicin and radiotherapy. The patient became pregnant in 2009 while on a 6-month tamoxifen therapy. She discontinued tamoxifen when she discovered she was pregnant, so tamoxifen therapy lasted only 1.5 months. The patient delivered a healthy baby in 2010. After birth, positron emission tomography-computed tomography revealed regression of bone metastases. The second case, a 23-year-old woman, underwent right modified radical mastectomy for infiltrating ductal carcinoma in 2009. The disease was staged as T2N0M0. Immunohistochemical analysis showed this tumor to be ER 5% (+), PR 50% (+), and HER2-positive (3+). The patient received adjuvant chemotherapy including paclitaxel, carboplatin, doxorubicin and trastuzumab. Adjuvant tamoxifen and leuprolide were also recommended. No radiotherapy was administered. The patient received tamoxifen for 26 months and discontinued treatment of her own accord. 1 month after that she became pregnant and took no further therapy. She delivered a healthy baby in October 2012, and is herself in good health at present. The third case, a 35-year-old woman, underwent breast-conserving surgery and sentinel lymph node dissection for infiltrating ductal carcinoma in 2011. The disease was staged as T1N0M0. Immunohistochemical analysis showed this tumor to be ER 90% (+), PR 10% (+), and HER2-positive (2+), confirmed by fluorescent in situ hybridization. She did not receive any adjuvant chemotherapy except tamoxifen following radiotherapy. The patient became pregnant while taking tamoxifen for 6 months in 2011. She discontinued tamoxifen when 4 weeks pregnant and had a voluntary medical abortion at 6 weeks gestation. She subsequently continued tamoxifen treatment. Tamoxifen is a non-steroidal anti-estrogen agent used in the treatment of ER-positive breast cancers. It is contraindicated during pregnancy due to teratogenic effects, and recommended non-hormonal contraceptive methods may cause patients to get pregnant while on tamoxifen therapy. Von Schoultz et al. [5] have suggested that women taking tamoxifen who wish to become pregnant should stop tamoxifen at least 2 months prior to conception because of the drugs long half-life. Although there is insufficient knowledge regarding the use of tamoxifen and pregnancy outcomes in humans, there are some case reports indicating healthy deliveries [3, 4]. In contrast, there is 1 case report of a baby with ambiguous genitalia suggestive of a tamoxifen effect on the fetus [2]. Another case report showed a baby with congenital cranio-facial defects, who was exposed to cocaine, marijuana, and a bone scan along with tamoxifen during fetal development. The effects of tamoxifen during pregnancy were described in the study by Braems et al. [6], based on records provided by AstraZeneca. The AstraZeneca Safety Database registered 11 babies with congenital malformations out of 44 live births, which is 1 infant with malformations for every 4 live births. In fact, the actual number of malformations was even higher, because there were 6 terminations and 2 stillbirths with fetal defects, compared with 17 terminations and 1 stillbirth without fetal defects, which is a total rate of nearly 1 in 3 births [6]. We herein report 3 breast cancer cases in which the patients became pregnant while taking tamoxifen therapy. In the first case, the patient had a healthy baby who is now 2 years old and has no abnormalities. The second patient had an uncomplicated pregnancy and a normal healthy baby. The patient in the last case had an elective abortion after a discussion with her physician regarding the possible side effects of the chemotherapy. To conclude, due to the lack of long-term data on outcome and studies showing teratogenicity, use of tamoxifen during pregnancy is contraindicated despite reports of healthy babies after tamoxifen exposure. Premenopausal breast cancer patients who are taking tamoxifen should practice meticulous use of contraception, and they must be informed about the possible teratogenic effects of tamoxifen as well as the lack of long-term data on this subject.

Comparison of Three Different Induction Regimens for Nasopharyngeal Cancer

BACKGROUND The standard treatment of local advanced nasopharyngeal cancer is chemoradiotherapy. There is a lack of data concerning induction therapy. In this study we retrospectively examined patients treated with induction therapy and chemoradiotherapy. MATERIALS AND METHODS Locally advanced nasopharyngeal cancer patients treated between 1996 and 2013 in our clinic were included in the study. Three different induction regimens were administered to our patients in different time periods. The regimen dosages were: CF regimen, cisplatin 50mg/m2 1-2 days, fluorouracil 500mg/m2 1-5 days; DC, docetaxel 75mg/m2 1 day, cisplatin 75mg/m2 1 day; and DCF, docetaxel 75mg/m2 1 day, cisplatin 75mg/m2 1 day, 5-Fu 750mg/m2 1-5 days. Most of the patients were stage III (36.4%) and stage IV (51.7%). RESULTS Median follow-up time was 50 months (2-201 months). Three-year progression-free survival (PFS) was 79.3%, and 5-year PFS 72.4% in all patients. Three-year overall survival (OS) was 87.4% and 5-year OS 76% in all patients. In terms of induction therapies, 3-year OS was 96.5% in the DCF group, 86.6% in the DC group and 76.3% in the CF group (p=0.03). CONCLUSIONS There was no significant differences in response rate and PFS between the three regimens. OS in the DCF group was significantly higher than in the other groups. However, this study was retrospective and limited toxicity data were available; the findings therefore need to be interpreted with care.

Ascites as an initial presentation of spontaneously ruptured hydatid cyst

We describe the diagnosis of a 77-year-old woman admitted to our outpatient department with a 3-month history of abdominal bloating and distension. Abdominal computed tomography revealed a large cystic lesion in the posterior segment of the right hepatic lobe, with a separated germinal layer and widespread ascites with dense internal echoes and septal appearance. The result of a serum Echinococcus indirect haemagglutination test was positive and findings were indicative of the spontaneous rupture of a hydatid cyst into the peritoneal cavity without trauma. Ascites is rarely seen in the course of hydatid disease, but can result from cyst rupture into the peritoneal cavity. This should be considered in the differential diagnosis of ascites, especially in areas such as Turkey, where hydatid disease in endemic.

Abstract P1-12-16: Efficacy of adjuvant tamoxifen in hormone receptor-positive premenopausal breast cancer patients according to the body mass index

Introduction: Obesity is an independent risk factor for the development of breast cancer and has been associated with poor breast cancer outcomes. But, this association usually depend on hormone-receptor positivity and ovarian activity. Obesity was confirmed as an adverse prognostic factor in patients treated with aromatase inhibitors, but the adverse effects in patients treated with tamoxifen was not known exactly. Thus, we aimed to examine the efficacy of adjuvant tamoxifen in hormone receptor-positive premenopausal breast cancer patients according to the body mass index (BMI). Material-Methods: Newly diagnosed hormone receptor-positive breast cancer patients who were premenopausal and non-metastatic were enrolled to the study. Patients with BMI ranging between 18.5 and 24.9 kg/m2 as normal weight patients (Arm A, n = 408), and patients with a BMI ranging ≥ 25 kg/m2 were overweight and obese patients (Arm B, n = 418). Results: The median follow-up time for this analysis was 36 (6-327) months. The median age was 39.5 (22-57) and 43 (20-56) in Arm A and Arm B, respectively (P Conclusion: Our study showed that BMI have no worse effect on recurrence risk in patients treated with tamoxifen in hormone-receptor positive premenopausal breast cancer. Poor survival outcome was observed in overweight and obese patients can be due to dose limitations of chemotherapeutic agents and higher rate of comorbid diseases. Citation Format: Kadri Altundag, Mehmet AN Sendur, Sercan Aksoy, Taner Babacan, Yavuz Ozisik. Efficacy of adjuvant tamoxifen in hormone receptor-positive premenopausal breast cancer patients according to the body mass index [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-16.

Kalçanın çift taraflı geçici bölgesel osteoporozu: Olgu sunumu

Kalcanin gecici osteoporozu ani baslangicli kalca agrisi nedenlerinden biridir. Kalca agrisinin bir sure sonra ortadan kalkmasi ve femur basinda gec beliren osteoporoz gorunumu ile karakterize olan ve nadir rastlanan bir klinik durumdur. Hastalik travma olmaksizin baslar. Genellikle orta yas grubundaki erkeklerde ve ucuncu trimester gebelerde kalca agrisiyla seyreder. Istirahat ve analjezik tedavisine yanit verir. Bu makalede, kalca ve bacak agrisi nedeniyle basvuran, klinik muayene ve radyolojik incelemeler sonucunda gecici kalca osteoporozu tanisi alan 3. trimesterdeki bir gebe olgu sunuldu. Sonuc olarak ucuncu trimester gebelerde ani baslangicli kalca ve bacak agrisinda gecici kalca osteoporozu ayirici tanida akilda tutulmalidir.