Fritz Jaenicke

Monitoring Primary Systemic Therapy of Large and Locally Advanced Breast Cancer by Using Sequential Positron Emission Tomography Imaging With [18F]Fluorodeoxyglucose

PURPOSE To evaluate positron emission tomography (PET) using [(18)F]fluorodeoxyglucose (FDG) for prediction of histopathologic response early during primary systemic therapy of large or locally advanced breast cancer. PATIENTS AND METHODS In a prospective multicenter trial, 272 FDG-PET scans were performed in 104 patients at baseline (n = 104) and after the first (n = 87) and second cycle (n = 81) of chemotherapy. The level and relative changes in standardized uptake value (SUV) of FDG uptake were assessed regarding their ability to predict histopathologic response. All patients underwent surgery after chemotherapy, and histopathologic response defined as minimal residual disease or gross residual disease served as the reference standard. RESULTS Seventeen (16%) of 104 patients were histopathologic responders and 87 were (84%) nonresponders. All patients for whom baseline SUV was less than 3.0 (n = 24) did not achieve a histopathologic response. SUV decreased by 51% +/- 18% after the first cycle of chemotherapy in histopathologic responders (n = 15), compared with 37% +/- 21% in nonresponders (n = 54; P = .01). A threshold of 45% decrease in SUV correctly identified 11 of 15 responders, and histopathologic nonresponders were identified with a negative predictive value of 90%. Similar results were found after the second cycle when using a threshold of 55% relative decrease in SUV. CONCLUSION FDG-PET allows for prediction of treatment response by the level of FDG uptake in terms of SUV at baseline and after each cycle of chemotherapy. Moreover, relative changes in SUV after the first and second cycle are a strong predictor of response. Thus, FDG-PET may be helpful for individual treatment stratification in breast cancer patients.

Clinical management of primary vulvar cancer

AIMS Vulvar cancer is a rare disease with increasing incidence over the last decades. Treatment includes surgical, radio- and chemotherapeutical options; however, due to the low incidence of the disease and the lack of randomised trials many questions regarding indication of different treatment approaches remain unanswered. This article discusses the current literature to elaborate recommendations for the management of primary vulvar cancer in clinical routine. METHODS We reviewed the available literature on treatment of invasive vulvar cancer with emphasis on therapeutic strategies such as surgery and radio/chemotherapy. RESULTS Surgery of the primary tumour and the groins remain the cornerstone of treatment in vulvar cancer with a strong trend towards a less radical approach in early stage disease. Complete vulvectomy was replaced by radical local excision with plastic reconstruction and the sentinel node technique was implemented to avoid the morbidity of complete groin dissection in node negative patients. In patients with advanced primary disease, treatment decisions are still a challenge. Criteria for the indication and performance of chemo/radiotherapy of the vulva/groins/pelvis are still not fully established and vary between different countries and institutions due to the low level of evidence. Often an individualised therapeutic approach aside from guidelines is necessary to treat these patients adequately. CONCLUSIONS To enable reasonable treatment decisions and avoid unnecessary morbidity, treatment in specialised centres should be intended at any time. Clinical studies performed by several study groups on an international level are urgently needed to further improve therapy.

Prognostic Role of Lymph Node Metastases in Vulvar Cancer and Implications for Adjuvant Treatment

Objective Lymph node metastases are the most important prognostic factor for recurrence and survival in vulvar cancer. However, information regarding the impact of the number of positive nodes in vulvar cancer is inconsistent, and so are recommendations when to apply adjuvant radiotherapy. Methods One hundred fifty-seven consecutive patients with primary squamous cell cancer of the vulva treated at our center were analyzed. All patients underwent primary surgery by triple incision resulting in complete tumor resection. Results Median age was 61 years; 49 patients (31%) had lymph node metastases; 21 patients had 1, 13 had 2, and 15 had more than 2 positive lymph nodes. Thirty-two percent of the patients received adjuvant radiotherapy. The risk of lymph node metastases increased with age, greater tumor size, deeper invasion, and higher tumor grade. Median follow-up was 36 months; 23 patients (14.6%) developed disease recurrence (61% vulva, 35% groins, and 4% both). Compared with node-negative patients, survival in all node-positive patients was significantly impaired (P < 0.001; disease-free patients after 2 years: 88% in node-negative patients; 60%, 43%, and 29% in patients with 1, 2, and >2 affected nodes, respectively), whereas no significant difference between the node-positive subgroups could be demonstrated regarding disease-free survival. In multivariate analysis, lymph node status remained the most important prognostic factor regarding disease-free survival, but the effect of positive nodes differed significantly dependent on adjuvant treatment (P = 0.001). In patients without adjuvant radiotherapy to the groins/pelvis, the number of metastatic nodes was highly relevant for prognosis (hazard ratio, 1.752; P < 0.001), whereas this effect disappeared in patients who were treated with adjuvant radiotherapy (hazard ratio, 0.972; P = 0.828). Conclusions The negative impact of lymph node metastases is already evident in patients with only 1 affected lymph node. In patients receiving adjuvant radiotherapy, the negative effect of additional lymph node metastases is reduced; adjuvant treatment might therefore be beneficial in patients with only 1 positive node.

Clinical management of borderline ovarian tumors

Borderline ovarian tumors (BOTs) are epithelial tumors of the ovaries characterized by cellular proliferation and nuclear atypia but without an infiltrative growth pattern. As they frequently affect younger patients the clinical management is complicated by considerations such as preserving fertility and reducing postoperative morbidity. Over the past several decades surgical therapy has shifted from a radical approach to more conservative treatment. There are various modes of surgery applied to the patients. All these developments have to be considered from an oncologic standpoint as BOTs represent a potentially malignant disease. Oncologic safety, as well as patients’ desires and expectations, have to be balanced to reach the most appropriate treatment for BOTs. For this reason current literature will be discussed in this review to give a thorough overview of this topic and to develop recommendations for the surgical management of these patients. Open questions will be identified to elaborate the need for future surveys and research.

Feasibility of Measuring the Prognostic Factors uPA and PAI-1 in Core Needle Biopsy Breast Cancer Specimens

References 1. Harris L , Fritsche H , Mennel R , et al . American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer . J Clin Oncol . 2007 ; 25 ( 33 ): 5287 – 5312 . 2. Harbeck N , Thomssen C , Berger U , et al . Invasion marker PAI-1 remains a strong prognostic factor after long-term follow-up both for primary breast cancer and following fi rst relapse . Breast Cancer Res Treat . 1999 ; 54 (2) : 147 – 157 . 3. Annecke K , Schmitt M , Euler U , et al . uPA and PAI-1 in breast cancer: review of their clinical utility and current validation in the prospective NNBC-3 trial . Adv Clin Chem. 2008 ; 45 : 31 – 45 . 4. Janicke F , Prechtl A , Thomssen C , et al . Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identifi ed by urokinase-type plasminogen activator and plasminogen activator Feasibility of Measuring the Prognostic Factors uPA and PAI-1 in Core Needle Biopsy Breast Cancer Specimens

Carbonic anhydrase IX in tumor tissue and sera of patients with primary cervical cancer

BackgroundCarbonic anhydrase IX (CAIX) is a membranous expressed metalloenzyme involved in pH homeostasis and cell adhesion. The protein is overexpressed in a variety of tumors and potentially associated with negative outcome. This study was designed to investigate the prognostic role of CAIX in serum and tumor tissue of patients with primary cervical cancer.MethodsTumor samples of 221 consecutive patients with primary cervical cancer who underwent surgery between 1993 and 2008 were analyzed for CAIX expression by immunohistochemistry. Additionally, preoperative serum CAIX concentrations were determined by ELISA in a subset of patients. Correlation with intratumoral CAIX expression as well as clinicopathological factors and outcome was analyzed.ResultsCAIX expression was observed in 81.9% of the tumor specimens; 62.0% showed a moderate or strong staining intensity. Moderate/strong expression was associated with squamous histology (p = 0.024), advanced tumor stage (p = 0.001), greater invasion depth (p = 0.025), undifferentiated tumor grade (p < 0.001) and high preoperative SCC-Ag values (p = 0.042). Furthermore patients with moderate/strong intratumoral CAIX expression had a higher number of metastatic lymph nodes compared to those with none/weak intratumoral expression levels (p = 0.047) and there was a non-significant association between high intratumoral CAIX expression and shorter survival (p = 0.118). Preoperative serum concentrations of CAIX ranged between 23 and 499 pg/mL and did not correlate with intratumoral expression or other clinicopathological variables.ConclusionCAIX is associated with advanced tumor stages and lymph node metastases in cervical cancer, potentially representing a new target in this disease. In contrast to other epithelial cancers we could not observe a correlation between serum CAIX and its intratumoral expression.

TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients

BackgroundAngiogenesis appears to play an important role in ovarian cancer. Vascular endothelial growth factor (VEGF) has recently been implicated as a therapeutic target in ovarian cancer. The tissue inhibitor of metalloproteinase 1 (TIMP-1) is involved in tissue invasion and angiogenesis. The application of serum TIMP-1 and VEGF to monitor primary therapy and predict clinical outcome of patients with ovarian cancer is unclear.MethodsPatients with epithelial ovarian cancer who presented for primary surgery were included in this study. A total of 148 serum samples from 37 patients were analyzed. Samples were prospectively collected at 4 predefined time points: 1. before radical debulking surgery, 2. after surgery and before platinum/taxane based chemotherapy, 3. during chemotherapy, 4. after chemotherapy. Serum VEGF-165 and TIMP-1 as well as CA-125 were quantified by ELISA or ECLIA and correlation with response and long-term clinical outcome was analyzed.ResultsSerum levels of all markers changed substantially during first-line therapy. High CA-125 (p = 0.002), TIMP-1 (p = 0.007) and VEGF-165 (p = 0.02) after chemotherapy were associated with reduced overall survival. In addition, elevated CA-125 (p < 0.001) and VEGF-165 (p = 0.006) at this time point predicted poor progression-free survival. TIMP-1 and VEGF-165 were closely correlated at all time-points during therapy.ConclusionsTIMP-1 and VEGF serum levels changed significantly during first-line therapy of ovarian cancer patients and predicted prognosis. These findings support the role of angiogenesis in ovarian cancer progression and the use of antiangiogenic therapy.

Management of patients with vulvar cancer: a perspective review according to tumour stage

Treatment of patients with vulvar cancer is challenging for gynaecologic oncologists. Owing to the localization in a sensitive area, surgical radicality and the indication for adjuvant treatment have to be balanced with psychosocial aspects to treat patients adequately. Clinical management is therefore highly dependent on the tumour stage. For patients with early-stage disease (FIGO I–II) therapy mainly concentrates on surgery with resection of the primary tumour and staging of the groin lymph nodes. In intermediate-stage vulvar cancer (FIGO III), advanced disease is expressed by affected inguinofemoral lymph nodes bringing radical lymphadenectomy and adjuvant therapy as well as radiation or chemoradiation into the focus of treatment. For locally advanced or metastatic vulvar cancer (FIGO IV) neoadjuvant or definitive chemoradiation has to be considered besides surgery. Owing to the low incidence of the disease, the level of evidence for different treatment modalities is poor. This review therefore puts different recommendations of clinical management in context and highlights the need for future trials.

Amplification of 8q21 in breast cancer is independent of MYC and associated with poor patient outcome

Copy number gains involving the long arm of chromosome 8, including high-level amplifications at 8q21 and 8q24, have been frequently reported in breast cancer. Although the role of the MYC gene as the driver of the 8q24 amplicon is well established, the significance of the 8q21 amplicon is less clear. The breast cancer cell line SK-BR-3 contains three separate 8q21 amplicons, the distal two of which correspond to putative target genes TPD52 and WWP1. To understand the effect of proximal 8q21 amplification on breast cancer phenotype and patient prognosis, we analyzed 8q21 copy number changes using fluorescence in situ hybridization (FISH) in a tissue microarray containing more than 2000 breast cancers. Amplification at 8q21 was found in 3% of tumors, and was associated with medullary type (P<0.03), high tumor grade (P<0.0001), high Ki67 labeling index (P<0.05), amplification of MYC (P<0.0001), HER2, MDM2, and CCND1 (P<0.05 each), as well as the total number of gene amplifications (P<0.0001). 8q21 copy number gains were significantly related to unfavorable patient outcome in univariate analysis. However, multivariate Cox regression analysis did not reveal an independent prognostic value of 8q21 amplification. The position of our FISH probe and data of a previously performed high-resolution CGH study in the breast cancer cell line SK-BR-3 involve TCEB1 and TMEM70 as new possible candidate oncogenes at 8q21 in breast cancer.

EGFR gene copy number increase in vulvar carcinomas is linked with poor clinical outcome

EGFR copy number increases have been frequently reported in cancer including vulvar carcinomas. Co-amplification of cancer genes plays an important role in the development of many tumour types. To better understand the effect of EGFR aberrations on vulvar cancer phenotype and patient prognosis, the authors analysed EGFR copy number changes using fluorescence in situ hybridisation and EGFR expression by immunohistochemistry in a tissue microarray containing 183 squamous cell carcinomas of vulva. Furthermore, the authors analysed the co-amplification frequency of EGFR with HER2, CCND1, MYC and PIK3CA, respectively. EGFR copy number increase was found in 39.3% of the tumours. Seventeen per cent of vulvar carcinomas showed EGFR high polysomy including 9% with amplification of the EGFR gene. Copy number gain of the EGFR locus was associated with non-basaloid phenotype (p=0.03), high-tumour stage (p<0.001), human papillomaviruse negativity of tumours (p=0.04) and the number of lymph node metastases (p=0.02). EGFR protein expression was statistically correlated to EGFR copy number increase (p<0.05). The observed co-amplification rate of EGFR with all four additionally examined oncogenes was much higher than statistically expected. There was a highly significant association between EGFR copy number increase and CCND1 amplifications (p<0.001) as well as the total number of gene amplifications (p=0.04). EGFR copy number gains were significantly related to unfavourable patient outcome in univariate analysis and multivariate Cox regression analysis. In conclusion, EGFR copy number increases are detectable in a substantial proportion of vulvar carcinomas with relationships to advanced tumour stages and the development of lymph node metastases. EGFR copy number aberrations are connected to other gene amplifications and probably define an human papillomaviruses-independent pathway in the development of vulvar carcinomas. These data support the potential utility of EGFR inhibitors as a therapeutic alternative in a subset of vulvar carcinomas.