Christian Rudlowski

Matched-pair analysis of patients with female and male breast cancer: a comparative analysis

BackgroundMale breast cancer (MBC) is a rare disease accounting for approximately 1% of all breast carcinomas. Presently treatment recommendations are derived from the standards for female breast cancer. However, those approaches might be inadequate because of distinct gender specific differences in tumor biology of breast cancer. This study was planned in order to contrast potential differences between female and male breast cancer in both tumor biological behavior and clinical management.MethodsMBC diagnosed between 1995-2007 (region Chemnitz/Zwickau, Saxony, Germany) was retrospectively analyzed. Tumor characteristics, treatment and follow-up of the patients were documented. In order to highlight potential differences each MBC was matched with a female counterpart (FBC) that showed accordance in at least eight tumor characteristics (year of diagnosis, age, tumor stage, nodal status, grade, estrogen- and progesterone receptors, HER2 status).Results108 male/female matched-pairs were available for survival analyses. In our study men and women with breast cancer had similar disease-free (DFS) and overall (OS) survival. The 5-years DFS was 53.4% (95% CI, range 54.1-66.3) in men respectively 62.6% (95% CI, 63.5-75.3) in women (p > 0.05). The 5-years OS was 71.4% (95% CI, 62.1-72.7%) and 70.3% (95% CI, 32.6-49.6) in women (p > 0.05). In males DFS analyses revealed progesterone receptor expression as the only prognostic relevant factor (p = 0.006). In multivariate analyses for OS both advanced tumor size (p = 0.01) and a lack of progesterone receptor expression were correlated (p = 0.01) with poor patients outcome in MBC.ConclusionOur comparative study revealed no survival differences between male and female breast cancer patients and gives evidence that gender is no predictor for survival in breast cancer. This was shown despite of significant gender specific differences in terms of frequency and intensity of systemic therapy in favor to female breast cancer.

HIPEC ROC I: A phase i study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum‐based chemotherapy in patients with platinum‐sensitive recurrent epithelial ovarian cancer

This phase I study tested the safety, feasibility, pharmacokinetics and pharmacodynamics of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion (HIPEC) in patients with platinum‐sensitive recurrent epithelial ovarian cancer (EOC) undergoing secondary cytoreductive surgery followed by postoperative platinum‐based intravenous chemotherapy. Twelve patients with operable, recurrent platinum‐sensitive EOC (recurrence ≥6 months after first‐line therapy) were included according to the classical 3+3 dose‐escalation design at three dose levels—60, 80 and 100 mg/m2. After surgical cytoreduction, a single dose of cisplatin was administered via HIPEC for 90 min at 41–43°C. Postoperatively, all patients were treated with standard intravenous platinum‐based combination chemotherapy. One of six patients experienced a dose‐limiting toxicity (grade 3 renal toxicity) at a dose of 100 mg/m2. The remaining five patients treated with 100 mg/m2 tolerated their treatment well. The recommended phase II dose was established at 100 mg/m2. The mean peritoneal‐to‐plasma AUC ratio was 19·5 at the highest dose level. Cisplatin‐induced DNA adducts were confirmed in tumor samples. Common postoperative grade 1–3 toxicities included fatigue, postoperative pain, nausea, and surgical site infection. The ability to administer standard intravenous platinum‐based chemotherapy after HIPEC was uncompromised. Cisplatin administered as HIPEC at a dose of 100 mg/m2 has an acceptable safety profile in selected patients undergoing secondary cytoreductive surgery for platinum‐sensitive recurrent EOC. Favorable pharmacokinetic and pharmacodynamic properties of HIPEC with cisplatin were confirmed at all dose levels, especially at 100 mg/m2. The results are encouraging to determine the efficacy of HIPEC as a complementary treatment in patients with EOC.

Male Breast Cancer

Breast cancer is a rare disease in men representing nearly 1% of the total breast cancer cases worldwide. Due to the low incidence, there are no randomized clinical studies giving information on the optimal diagnostics and therapy for male breast cancer patients. Therefore, treatment recommendations are derived from established guidelines for breast cancer in women. However, the lack of awareness of this disease leads to its detection at a later stage in men associated with a worse prognostic outcome. The gender-specific differences in breast cancer are among others related to the differing genetic and hormonal environment and the anatomic constitution in men. For example, males have a much higher percentage of hormone receptor-positive tumors but a significantly lower fraction of carcinomas overexpressing HER2. This review focuses on epidemiology, pathogenesis, and clinical findings of male breast cancer, and discusses current findings available to treat this disease. To optimize disease outcome and tolerability of treatment, these data should be considered to improve the therapeutic index of male breast cancer patients.

Tamoxifen induces resistance to activated protein C

INTRODUCTION The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet. MATERIALS AND METHODS Blood samples were collected prospectively from women with breast cancer before (n=25) and monthly after start of adjuvant TAM treatment (n=75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally. RESULTS APC sensitivity decreased by 41% (p=0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p=0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed. CONCLUSIONS This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors.

Therapeutic strategies in male breast cancer: Clinical implications of chromosome 17 gene alterations and molecular subtypes

Male breast cancer (MBC) is a rare disease. To date, therapy is mainly based on studies and clinical experiences with breast cancer in women. Only little is known about molecular typing of MBC, particularly with regard to potential biological predictors for adjuvant therapy. In female breast cancer tumors with chromosome 17 centromere (CEP17) duplication, HER2 and/or Topoisomerase II alpha (Topo II-α) gene alterations have been suggested to be associated with poor prognosis and increased sensitivity to anthracycline-containing regimens. In a well characterized cohort of 96 primary invasive MBC, we studied CEP17, HER2 and Topo II-α alterations by fluorescence in-situ hybridization (FISH), and expression of hormone receptors (HR), HER2 and Ki67 by immunohistochemistry to define molecular subtypes. Tumor characteristics and follow-up data were available and correlated with molecular findings. HER2 amplification and Topo II-α amplification/deletion were exceptionally rare in MBC (6.3% and 3.1%, respectively). CEP17 polysomy were found in 9.4% of tumors. HER2, Topo II-α and CEP17 gene alterations were not correlated to patients outcome. 96.9% of our cases were HR positive. Triple negative tumors were found in only 3.1% of the cases. In nodal negative tumors luminal A subtypes were significantly associated with better overall survival. Our results provide evidence for a predominant male breast cancer phenotype, characterized by HR expression and a lack of HER2/Topo II-α alterations and CEP17 duplicates. Therefore, the impact of anthracycline sensitivity linked to HER2/Topo II-α alterations as found in female breast cancer has low clinical significance for this specific male breast cancer phenotype.

Impact of hormone-associated resistance to activated protein C on the thrombotic potential of oral contraceptives: a prospective observational study.

Introduction The increased thrombotic risk of oral contraceptives (OC) has been attributed to various alterations of the hemostatic system, including acquired resistance to activated protein C (APC). To evaluate to what extent OC-associated APC resistance induces a prothrombotic state we monitored plasma levels of thrombin and molecular markers specific for thrombin formation in women starting OC use. Elevated plasma levels of thrombin have been reported to characterize situations of high thrombotic risk such as trauma-induced hypercoagulability, but have not yet been studied during OC use. Patients and Methods Blood samples were collected prospectively from healthy women (n = 21) before and during three menstruation cycles after start of OC. APC resistance was evaluated using a thrombin generation-based assay. Plasma levels of thrombin and APC were directly measured using highly sensitive oligonucleotide-based enzyme capture assay (OECA) technology. Thrombin generation markers and other hemostasis parameters were measured additionally. Results All women developed APC resistance as indicated by an increased APC sensitivity ratio compared with baseline after start of OC (p = 0.0003). Simultaneously, plasma levels of thrombin, prothrombin fragment 1+2, and of thrombin-antithrombin complexes did not change, ruling out increased thrombin formation. APC plasma levels were also not influenced by OC use, giving further evidence that increased thrombin formation did not occur. Conclusions In the majority of OC users no enhanced thrombin formation occurs despite the development of APC resistance. It cannot be ruled out, however, that thrombin formation might occur to a greater extent in the presence of additional risk factors. If this were the case, endogenous thrombin levels might be a potential biomarker candidate to identify women at high thrombotic risk during OC treatment. Large-scale studies are required to assess the value of plasma levels of thrombin as predictors of OC-associated thrombotic risk.

A Rare Complication Following Breast Implant Surgery: Capsular Contracture with a Cutaneous Silicone Fistula after Breast Reconstruction with Silicone Gel Implants.

Background: We report the case of a 74-year-old female patient who presented at the Breast Care Centre with watery discharge from a fistula in the inframammary fold of the left breast. Case Report: The patient initially presented with watery discharge coming from the fistula, which later took on a more viscous consistency. She reported mild discomfort as well as mild erythema. Clinical examination and diagnostic approaches including magnetic resonance imaging (MRI) revealed a cutaneous silicone fistula as a rare complication following breast implant reconstruction. The condition was treated with excision of the fistula and bilateral implant removal. Conclusions: This case report documents a rare complication following breast reconstruction with implants, and is to our knowledge the first described MRI-detected cutaneous silicone fistula.

Prognostic Significance of Molecular Subtypes in Male Breast Cancer.

INTRODUCTION The relatively unfavorable outcome in male breast cancer has been attributed to more advanced local tumor stage and high incidence of lymph node invasion at the time of diagnosis. This study aimed to classify the molecular subtypes of male breast cancers based on the expression profile of immunomarkers and to evaluate their association with clinicopathological features and patients outcome. METHODS To define molecular subtypes a total of 174 cases of male breast carcinoma were examined retrospectively using immunostains for hormone receptors (HR) and cytokeratin 5/6 (CK5/6). Human epidermal growth factor receptor 2 (HER2) expression was evaluated by immunostaining and confirmed by fluorescent in situ hybridization. Tumor characteristics and overall survival (OS) data were available and correlated with protein expression and the molecular subtype. RESULTS The luminal A subtype (HR+/HER2-) was the most common subtype in male breast cancer (82.8%; n=144) with a median patients OS of 122 month. Luminal B tumors (HR-/HER+) were found in 6.2% (n=11), basal-like (HR-/HER2-/CK5/6+) in 9.6% (n=17) and HER2+/HR- carcinomas in 1.1% (n=2). Basal like male breast carcinoma showed a statistically significant reduced overall survival (median: 51 month; p CONCLUSIONS In our study group, luminal A was the predominant subtype of male breast carcinoma and showed an excellent patients outcome. However, like in females tumors with a basal like subtype which were known to show minor chemotherapy response had a worse prognostic outcome. Therefore, new therapeutic options have to be defined. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2110.

Matched-pair analysis of female and male breast cancer: a comprehensive cohort study.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #4129 Introduction: Male breast cancer (MBC) is a rare disease accounting for approximately 1% of all breast carcinomas. Due to the low incidence treatment guidelines based on prospective studies are lacking. Presently treatment recommendations are derived from the standards for female breast cancer. However, those approaches might be inadequate because of distinct gender specific differences in tumor biology of breast cancer. This study was planned in order to elucidate potential differences between female and male breast cancer in both tumor biological behavior and clinical practice. Patients and Methods: MBC diagnosed 1995-2007 (region Chemnitz/Zwickau, Saxony, Germany) was retrospectively analyzed. Tumor characteristics, treatment and follow-up of the patients were documented. In order to highlight potential differences matched-pairs of female and male breast cancer patients were created. Each MBC was matched with a female counterpart (FBC) that showed accordance in at least 5-7 tumor characteristics (age, TNM, grade, hormone receptors, HER2 stage). Results: FBC and MBC (n=113 patients each) were evaluable for this analysis. For MBC the following tumor characteristics were documented: >60% advanced stages (T2-4), only 6% well differentiated, 42.5% nodal-positive, 86% hormone-sensitive (ER-positive 79.2%, PR-positive 76.9%), 6.2% HER2 positive. 83.2% of MBC had a mastectomy/axillary dissection (FBC 49.0%), 55% adjuvant radiotherapy (FBC 66.7%), 64% adjuvant systemic therapy (FBC 80.6%), 32.7% chemotherapy (FBC 49.5%) and 47.8% endocrine treatment (FBC 60.1%). 31% of MBC had a relapse (FBC 25.9%), 68.1% overall survival (OS) (FBC 70.4%), 98 months (FBC 76 months) median survival time. In univariate analyses reduced OS of MBC was significant associated with advanced tumor stages (p<.005), poor histological grade (p<.05), receptor negative (p<.05) and nodal-positive tumors (p<.05). Furthermore adjuvant radiotherapy showed survival benefit. However, in multivariate analysis only tumor stage showed statistical significance (p<.01). Regarding these tumor characteristics no OS differences could be observed between FBC and MBC. However, MBC showed a trend to a shortened survival for receptor negative tumors in comparison to FBC (p=.055). Discussion: 1. Delayed diagnosis of MBC; 2. Our study showed more advanced and undifferentiated tumors with a high percentage of nodal positivity; 3. In our analysis these unfavorable tumor characteristics were not related to a poor OS; 4. We found no significant differences regarding disease outcome between FBC and MBC; despite of a more aggressive adjuvant treatment for FBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4129.

HER-2 and topoisomerase IIa gene alterations in male breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #4128 Background: In accordance to the guidelines for female breast cancer and due to more advanced tumor stages at diagnosis primary male breast cancer (MBC) is treated predominantly with anthracycline-based chemotherapeutic regimens. However, amplification of the HER2 and topoisomerase IIalpha (TOPO2A) genes has been linked to the effects of anthracyclines in female breast cancer. Presently no data are available reporting the percentage of TOPO2A amplification/deletion and its potential clinical impact on MBC. Here we present first data about HER2 and TOPO2A genomic alteration in MBC. Patients and Methods: We studied HER2 amplification and TOPO2A amplification/deletion (by fluorescence in situ hybridization) and HER2 protein expression (by immunohistochemical analysis) in 96 primary invasive MBCs using tissue microarrays. A gene copy number/chromosome 17 copy number ratio of 2.0 respectively 1.8 or higher indicated amplification of HER2 and TOPO2A. A TOPO2A/chromosome 17 ratio of less than 0.8 indicated gene deletion. In addition, HER2 protein expression was scored according to standard HercepTest guidelines (DAKO, Carpenteria, CA). Tumor characteristics and follow-up data were available and correlated with HER2/TOPO2A gene alterations and HER2 protein expression. Results: 91/96 cases were evaluable for TOPO2A/HER2 assessment. HER2 gene amplification were found in 6 cases (6,25%) of which 3 were classified as 3+, 2 as 2+ and 1 as 1+ positive for protein expression. TOPO2A amplification/deletion showed 3 patients (3.1%), 2 with amplification and one with a deletion. Only one patient had both HER2 and TOPO2A gene amplification. HER2/TOPO2A gene alterations were not related to the tumor characteristics, response to therapy or the patients survival. Conclusion: In female breast cancer recent studies have suggested that deletions or amplifications of the TOP2A gene are associated with poor prognosis and predictive of greater response to anthracycline-containing than to non-anthracycline-containing regimens. In this study group both HER2 and TOPO2A gene alterations were rare events. A simultaneous amplification was observed in only one case. Our data for MBC suggest that due to the low number of TOPO2A gene amplification/deletion the clinical significance of TOPO2A is of limited value. Based on these findings the role of anthracycline-containing regimens for MBC has necessarily to be defined. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4128.