Ibrahim Petekkaya

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.

Association of breast cancer subtypes and body mass index.

AIMS AND BACKGROUND Breast cancer is a heterogeneous disease with various pathological and molecular subtypes. This study aims to determine the association between BMI and the distribution of breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2/neu) expression in pre- and postmenopausal breast cancers. METHODS AND STUDY DESIGN A total of 1847 female breast cancer patients were involved. After the exclusion of 457 patients due to missing subtype information (n = 400) or benign histology (n = 57), 1390 were included in the analyses. The histological type of the tumor, ER and PR expression, HER2/neu with immunohistochemistry and HER2/neu gene evaluation with interphase fluorescence in situ hybridization (if necessary), age, body weight, height and menopausal status at diagnosis were investigated retrospectively. The patients were stratified as having a normal body weight if BMI was ≤24.9 kg/m², as being overweight if BMI was between 25.0 and 29.9 kg/m², and as being obese if BMI was ≥30.0 kg/m². RESULTS Median BMI was 28.7 kg/m² (17.6-55.6) in the postmenopausal and 25.6 kg/m² (16.4-51.1) in the premenopausal group (P <0.001). BMI at diagnosis did not differ significantly between the molecular subtypes (P = 0.12). Distribution of BMI strata was similar between the molecular subtypes both in pre- and postmenopausal breast cancer (P = 0.24 and P = 0.99, respectively). Premenopausal women with a BMI of ≥25.0 kg/m² showed a tendency towards ER- tumors when compared to premenopausal women with a BMI of <25.0 kg/m² (P = 0.009). CONCLUSIONS The risk of specific breast cancer subtypes may not be associated with BMI in pre- and postmenopausal breast cancer. However, obesity might be related to an increased risk of premenopausal hormone receptor-negative breast cancer. Further studies are needed for clarification of the probable mechanisms in the pathogenesis of premenopausal hormone receptor-negative breast cancer.

Prognosis of breast cancer in patients with peritoneal metastasis

Number of Patients (n) 21 Age at Breast Cancer Diagnosis Mean (range) 48 (31–64) Median (range) 50 (31–64) Age at Peritoneal Metastasis Mean (range) 56 (38–71) Menopausal Status Post-menopausal 12 (57.1%) Pre-menopausal 6 (28.6%) Peri-menopausal 3 (14.3%) Patient Survival Number of dead patients 7 (33.3%) Number of living patients 13 (61.9%) Molecular Subtype Luminal A 8 (38.1%) Luminal B 5 (23.8%) Triple negative 2 (9.5%) Her-2 overexpressing 0 (0%) Unknown 6 (28.6%) Hormone Receptor Status ER status Positive 14 (66.7%) Negative 3 (14.3%) Unknown 4 (19.0%) PR status Positive 11 (52.4%) Negative 6 (28.6%) Unknown 4 (19.0%) Her2 status Positive 5 (23.8%) Negative 10 (47.6%) Histological Subtype IDC 7 (33.3) ILC 5 (23.8) Mixed 3 (14.3) Unknown 6 (28.6) To the Editor

Impact of adjuvant treatment modalities on survival outcomes in curatively resected pancreatic and periampullary adenocarcinoma.

BACKGROUND We examined the impact of adjuvant modalities on resected pancreatic and periampullary adenocarcinoma (PAC). METHODS A total of 563 patients who were curatively resected for PAC were retrospectively analyzed between 2003 and 2013. RESULTS Of 563 patients, 472 received adjuvant chemotherapy (CT) alone, chemoradiotherapy (CRT) alone, and chemoradiotherapy plus chemotherapy (CRT-CT) were analyzed. Of the 472 patients, 231 were given CRT-CT, 26 were given CRT, and 215 were given CT. The median recurrence-free survival (RFS) and overall survival (OS) were 12 and 19 months, respectively. When CT and CRT-CT groups were compared, there was no significant difference with respect to both RFS and OS, and also there was no difference in RFS and OS among CRT-CT, CT and CRT groups. To further investigate the impact of radiation on subgroups, patients were stratified according to lymph node status and resection margins. In node-positive patients, both RFS and OS were significantly longer in CRT-CT than CT. In contrast, there was no significant difference between groups when patients with node-negative disease or patients with or without positive surgical margins were considered. CONCLUSIONS Addition of radiation to CT has a survival benefit in patients with node-positive disease following pancreatic resection.

Serpentine Supravenous Hyperpigmentation Resulting from Vinorelbine Administration

tal and lobular epithelium and adjacent stroma (hormone and growth factor receptors and their ligands, cell cycle factors, vascular and angiogenic factors, and others), which are usually studied on biphasic breast tumors such as phyllodes tumors. Our hypothesis is that the stromal-epithelial interdependence has changed in some parts of presented TA, resulting in excessive fibrous proliferation and FA formation. Similar type of tumor phenotypic change is visible in phyllodes tumors that have progressed from FAs, what was demonstrated by clonal analysis.

Secondary malignancies mimicking primary pancreatic lymphoma

Malignancies localized to the pancreas at times can mimic many other types of cancer. In imaging studies, tumors localized to the pancreas can resemble lymphoma. Especially in elderly patients, these tumors which appear like pancreatic cancer are sometimes left untreated by physicians, without confirming with biopsy, because the expected survival is extremely short. In this case report we examine how these discrepancies could be resolved.

Behcet's Disease and Breast Cancer

To the Editor: Behcet’s disease (BD) is a systemic vasculitis, characterized by orogenital ulcers, uveitis, arthritis, and involvement of the gastrointestinal tract, central nervous system, and blood vessels which is frequently seen in Korea, China, Japan, and Turkey (1). In such rheumatic diseases, it has been theorized that the frequency of malignancies increase due to the disrupted immune system and use of immunosuppressive drugs; a conjecture which has been supported in a few studies (2). Even fewer studies have looked into the relationship between BD and malignancies (3). Here, we present four cases with a history of BD and briefly review literature pertinent to possible explanations regarding the connection between autoimmunity and malignancies. The first patient is a 49-year-old premenopausal patient with no predisposing risk factors of breast cancer. In 2007, she was diagnosed with BD and has been using colchicine ever since. Also, in 2007 she had a cyst excised from her left breast, which turned out to be benign in the pathologic examination. In March 2011, the patient presented with a mass in the upper outer quadrant of the left breast. A biopsy was performed which revealed signet ring cell carcinoma of the breast. A modified radical mastectomy was performed. The pathologic examination revealed a strong ER+, weak PR+, HER2+, T2N2M0 Grade 2 pure signet ring cell carcinoma of the breast. Adjuvant chemotherapy consisting of four cycles of adriamycin and cyclophosphamide (AC), concomitantly administered with 12 cycles of paclitaxel and a year of herceptin was initiated. Radiotherapy is also in the treatment plan. The second patient is a 45-year-old premenopausal female with a history of 36 months of oral contraceptive use. She was diagnosed with BD at the age of 37 and has been using colchicine ever since. She also has a history of 20 package years of smoking, and a cyst excision from the ovary, 12 years ago. The patient was being followed up for 3 years due to a mass in the breast via USG when a breast conserving excision was performed which revealed strong ER, PR+ and HER2 negative grade 2, T1N0M0 infiltrative ductal carcinoma in the upper outer quadrant of the right breast. Adjuvant chemotherapy consisting of six cycles of tamoxifen concomitantly administered two cycles of goserelin acetate and a single dose of leuprolide acetate and radiotherapy was commenced. The patient did not have any recurrences during follow-up. The third patient is a 56-year-old postmenopausal patient with no risk factors for breast cancer which has been diagnosed with BD for unknown duration of time. She presented with a mass in the lower outer quadrant of the breast, from which a biopsy was performed which revealed infiltrative lobular carcinoma (ILC). Following neo-adjuvant chemotherapy a modified radical mastectomy was performed which revealed a strongly ER+, weakly PR+, HER2 negative, grade 2, T2N1M0 ILC. Adjuvant chemotherapy was initiated accordingly; the patient is being followed up with no recurrence. The last patient that we will take into consideration is a 51-year-old premenopausal patient with no risk factors for breast cancer who has been diagnosed with BD 25 years ago. She has quit using colchicine only for the past 2 years. She presented with a mass in the lower inner quadrant of the left breast from which a biopsy was performed, which revealed a infiltrative ductal carcinoma. A modified radical mastectomy was performed. The pathologic examination identified a ER , PR+, HER2+ T2N0M0, Grade 3 infiltrative ductal carcinoma. Adjuvant chemotherapy consisting of four cycles of AC and five cycles of tamoxifen were initiated. The patient’s malignancy progressed despite a multitude of chemotherapy regimens that were administered, consistent with liver and brain metastasis. Currently the patient is stable and receiving paclitaxel and trastuzumab with signs of regression in the brain metastasis. A single center study conducted in Korea has identified three patients out of 1,769 who have concurrent breast cancer and BD (3). We have four patients of Address correspondence and reprint requests to: Emir Charles Roach, MD, Cleveland Clinic – Pathobiology, 9500 Euclid Avenue, Cleveland, OH 44106, USA, or e-mail: roache@ccf.org