Expression of endothelin-A-receptor predicts unfavourable response to neoadjuvant chemotherapy in locally advanced breast cancer.

Endothelin-1 (ET-1) and its receptors (ETAR and ETBR), referred to as the endothelin (ET) axis, are overexpressed in breast carcinomas and appear to influence tumour growth and progression. The objective of this study was to determine the effect of expression of the ET axis in breast carcinomas on response to cytotoxic chemotherapy. The study included 44 patients with locally advanced breast cancer participating in a prospective phase III study evaluating high-dose neoadjuvant chemotherapy of epirubicin and cyclophosphamide. Expression of ET-1, ETAR and ETBR was determined by semiquantitative immunohistochemical analysis of breast cancer tissue from prechemotherapy tru-cut biopsies. Immunohistochemical staining was positive for ET-1 in 61.5%, for ETAR in 35% and for ETBR in 35.9% of breast carcinomas. Pathological response to chemotherapy was significantly decreased in ETAR-positive patients (P=0.002). In total, 50% of ETAR-positive patients as compared to 7.7% of ETAR-negative patients attained pathologically 'no change'. Logistic regression confirmed ETAR as an independent predictive marker for pathological response (P=0.009). These data indicate that increased expression of ETAR in breast carcinomas is associated with resistance to chemotherapy. Determination of ETAR status may serve as a predictive marker for identifying patients less likely to be responsive to conventional chemotherapy.

[Sentinel node biopsy in breast cancer]. / Wächterlymphknotenbiopsie beim Mammakarzinom.

The international consensus conference from St. Gallen concerning the treatment of early breast cancer concluded in 2003, that sentinel node biopsy was now accepted as method allowing axillary staging in breast cancer. This procedure may avoid complete lymph node dissection in appropriate cases. Since numerous questions associated with the technique are still not defined and the procedure itself is not yet standardized, the German Society of Senology defined the conditions for the routine clinical use of sentinel node biopsy in an interdisciplinary consensus meeting.

[Preoperative chemotherapy in primary operable breast cancer with a dose-dense combination of doxorubicin and docetaxel (ADoc) - Experience of the GEPARDO-GABG study group]. / Präoperative Chemotherapie operabler primärer Mammakarzinome mit einer dosisdichten Kombination von Adriamycin und Docetaxel (ADoc) - Die Erfahrungen der GEPARDO-GABG-Studiengruppe -

OBJECTIVE: The German Adjuvant Breast Cancer Study Group (GABG) conducts trials of preoperative chemotherapy in patients with primary breast cancer using a combination of doxorubicin and docetaxel (ADoc). - PATIENTS AND METHODS: We conducted a parallel-grouped phase IIa-study with 42 patients with a conventionally dosed and a dose-dense ADoc-schedule (4 cycles of Doxorubicin 50 mg/m(2), Docetaxel 75 mg/m(2) i. v. day 1, q day 15 or 22; G-CSF day 3-15 only for the dose-dense schedule) and a randomized phase IIb-study (GEPARDO-Study) with 250 patients with ADoc +/- Tamoxifen. Biological factors were determined immunohistochemically on 197 core biopsies before treatment. A comparison to a sequential AC-Doc regimen including 913 patients has been completed recently. - RESULTS: ADoc can be applicated on schedule in 93 % of all patients. The dose-dense regimen shows a tendency to more toxicity but also to more efficacy. The rate of complete pathological remissions (pCR) was 9.7 %. No difference was found between chemo- and chemoendocrine treatment. Clinically negative lymphnodes and a negative estrogen receptor status is predictive for a higher pCR-rate. To date no differences in toxicity could be found between ADoc and AC-Doc. - CONCLUSIONS: The dose-dense ADoc regimen is well tolerated and highly effective as preoperative therapy of breast cancer.

Dose-dense doxorubicin, docetaxel, and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized, controlled, open phase IIb study.

PURPOSE: To investigate the effect of adding tamoxifen to a preoperative dose-dense doxorubicin and docetaxel regimen on the pathologic response of primary operable breast cancer. PATIENTS AND METHODS: Patients (tumor size > or = 3 cm, N0 to 2, M0) were prospectively randomized to receive every 14 days a total of four cycles of doxorubicin 50 mg/m2 and docetaxel 75 mg/m(2), either with (ADocT) or without (ADoc) simultaneous tamoxifen. Granulocyte colony-stimulating factor (G-CSF) was routinely given on days 5 to 10. Surgery followed 8 to 10 weeks after the start of treatment. RESULTS: Within 14 months, 250 patients were included in the study at 56 centers. Of 992 planned cycles, 97.9% were administered. Pathologically complete remission (pCR) with no detectable viable tumor cells was achieved in 9.7%. There was a nonsignificant difference of -1.2% in favor of ADoc, with a 95% confidence interval of -8.6% to 6.2%. A further 2.4% had only noninvasive tumor residues, and 13.8% had focal invasive residues. Complete and partial responses detected by palpation were observed in 28.9% and 52.4%, respectively. The response rates (complete and partial) by best appropriate imaging methods were 77.5% and 67.5% for ADocT and ADoc, respectively. Breast conservation was possible in 68.8% of the patients. A tendency toward more frequent toxic events was observed with ADocT treatment. Significant predictors of pCR to chemotherapy were negative lymph node and negative estrogen receptor status. CONCLUSION: A dose-dense regimen of ADoc with G-CSF offers high compliance, moderate toxicity, and rapid efficacy as a form of preoperative chemotherapy in operable breast cancer. Concurrent treatment with tamoxifen for 8 weeks could not improve the pathologic response rate.

Maximized reduction of primary breast tumor size using preoperative chemotherapy with doxorubicin and docetaxel.

PURPOSE: To assess the toxicity and efficacy of preoperative chemotherapy with doxorubicin and docetaxel in patients with primary operable breast cancer. PATIENTS AND METHODS: Forty-two patients with histologically confirmed primary breast cancer tumors of at least 2 cm in diameter received doxorubicin (50 mg/m(2) intravenously [IV] over 15 minutes) and docetaxel (75 mg/m(2) IV over 1 hour) every 14 (24 patients) or 21 (18 patients) days for four cycles. RESULTS: The median size of the primary tumor decreased significantly, from 4 cm (range, 2 to 10 cm) to 2 cm (range, 0 to 5 cm) on physical examination and from 3.4 cm (range, 1 to 8 cm) to 1. 8 cm (range, 0 to 4 cm) on sonography (P <.001). The overall response rate as assessed by physical examination was 93%, and complete remission of the primary tumor occurred in 33% of patients. The remission rate as assessed by sonographic measurement was 67%. Two patients (5%) had histologically confirmed complete responses. Sonography was more reliable than palpation in predicting histologically determined response. No grade 4 toxicity was noted, and grade 3 toxicity was reported with alopecia (95%), lethargy (17%), loss of appetite (10%), stomatitis (7%), leukopenia (5%), skin desquamation (5%), infection (5%), motor neuropathy (2%), and nausea (2%). The 3-week schedule was associated with less toxicity than the 2-week schedule. CONCLUSION: Preoperative combination chemotherapy with doxorubicin and docetaxel is highly effective and feasible in primary operable breast cancer.

[Preoperative chemotherapy of breast carcinoma]. / Präoperative Chemotherapie des Mammakarzinoms.

Preoperative chemotherapy represents the standard procedure in inflammatory breast cancer. However, only recently it could be demonstrated that preoperative chemotherapy is beneficial even for patients with operable primary breast cancer. The number of breast conserving surgeries could be increased significantly. Furthermore this in vivo chemosensitivity assay can provide important prognostic as well as predictivy informations. Preoperative chemotherapy is not associated with an increased risk for the patients as outcome is similar to patients with conventional adjuvant treatment. We investigated new regimens to improve this type of chemotherapy and reached a remission rate of 93% with a combination of adriamycin and docetaxel (ADoc). A randomized study (GEPARDO-study) comparing ADoc with ADoc + tamoxifen has recently been started in Germany by the German Adjuvant Breast Cancer Study Group (GABG).

[Indications, technique and results of ultrasound guided punch biopsy in breast diagnosis (n=307)]. / Indikationen, Technik und Ergebnisse der sonographisch gezielten Stanzbiopsie in der Mammadiagnostik (n = 307).

From May 1, 1992, to April 30, 1993, we performed 307 ultrasonic guided high-speed punch biopsies. In 119 of the 307 women, we dispensed with further surgical and histological procedures when the tentative diagnosis from complementary mammary diagnostic procedures revealed no pathological findings and concurred with the histological results of the punch biopsy. In 188 women, the biopsy was followed by surgical intervention and correlation of the histological findings. This group of patients showed a sensitivity of 98%, a specificity and positive prognostic value of 100%, and a negative prognostic value of 91%. If we combine the results of the complementary mammary diagnostic (including the punch biopsy), then the sensitivity, specificity, and positive and negative prognostic values for this surgically and histologically confirmed group of patients all reach 100%. In trained hands, the ultrasonic guided high-speed punch is a reliable means of determining the histological nature of lesions detected in ultrasonic scans. This technique has been perfected in our facility. Along with preoperative carcinoma detection, it permits us to avoid unnecessary operations when under defined conditions there are no pathological findings.

Prognostic value of S-phase fraction in head and neck squamous cell carcinomas and nodal negative breast carcinomas.

PURPOSE: The prognostic value of proliferative activity (percentage of S-phase cells = SPF) was determined in head and neck and nodal negative breast carcinomas and correlated with treatment outcome and analysis of recurrence. METHODS AND MATERIAL: SPF of 171 primary squamous cell carcinomas of the head and neck and 183 nodal negative breast carcinomas was determined by one-dimensional flow cytometry. RESULTS: For the whole population of head and neck carcinomas slowly proliferating tumors (SPF < median) had a better five-year survival rate (28%) than fast proliferating tumors (S-phase > median; 20% p < 0.05). Failure analysis revealed that the better survival of slowly proliferating tumors was due to the higher loco-regional control rate (62%) compared to fast proliferating tumors (43%; p < 0.05). Stepwise multivariate analysis revealed treatment modality (p = 0.107), SPF (p = 0.026) and UICC stage (p = 0.044) as independent prognostic factors for loco-regional recurrences and SPF (p = 0.0143) for three-year overall survival. In nodal negative breast cancer slowly proliferating tumors (SPF < median) had a better NED survival (92%) compared to fast proliferating tumors (SPF > median; NED survival 63%). The analysis of recurrence revealed a higher rate of distant metastases (15.7%) and of loco-regional recurrences (21%) for fast proliferating tumors as compared to slowly proliferating tumors (distant metastases: 1.1%; loco-regional recurrences 4.5%). Stepwise multivariate analysis showed that SPF (p = 0.001) was the only independent prognostic factor for NED survival; grading (p = 0.022), age (p = 0.003) and SPF (p = 0.007) for freedom from distant metastases; SPF (p = 0.0039), grading (p = 0.0956) and method of surgical treatment (p = 0.0715) for loco-regional recurrences. CONCLUSIONS: SPF has a relevant prognostic power for squamous cell head and neck cancer and nodal negative breast cancer.

[Breast cancer: breast saving therapy]. / Mammakarzinom: brusterhaltende Therapie.

Breast preservation has become an important option in the treatment of breast cancer patients. The selection of patients should be based upon history, actual clinical situation, mammographic and morphologic parameters. After careful evaluation of all those factors the surgical treatment and eventually an adjuvant postsurgical irradiation can be tailormade according to the associated individual risk-profile.

Results of surgical treatment of 1028 cervical cancers studied with volumetry.

BACKGROUND AND METHODS: The clinical staging system of cervical cancer according to the International Federation of Gynecology and Obstetrics (FIGO) entails a large measure of subjectivity. This study analyzed the results of 1028 patients with cervical cancer at three reference centers. All patients had radical surgery, and all surgical specimens were processed as histologic giant sections with precise volumetry of the tumor. RESULTS: The interpretation of the histologic findings of parametrial invasion, vascular involvement, and lymph node involvement was found to differ somewhat among the three centers. However, all these findings were associated with tumor size. Survival rates correlated more consistently with tumor volume than with clinical or histologic stage. Five-year survival rates ranged from 91% for patients with tumors smaller than 2.5 cm3 to 70% for those with tumors 10-50 cm3. The 5-year survival rate of 24 patients with tumors larger than 50 cm3 (71% of whom had lymph nodes with positive findings) was 48%. Survival rates were identical among the three centers for patients with tumors smaller than 10 cm3, despite different degrees of surgical radicality. In contrast, more radical surgery was associated with significantly better survival rates in patients with larger tumors. CONCLUSIONS: The results of this study indicate that volumetry of the tumor permits a more accurate assessment of therapeutic results in patients with cervical cancer than does the FIGO classification. Pretherapeutic assessment of tumor volume is possible with magnetic resonance imaging. It seems that maximum parametrial resection is not necessary for patients with smaller tumors (smaller than 10 cm3), but truly radical surgery in patients with bulky tumors achieves better results than those usually expected in Stage IIb cervical cancer and at least comparable to those of radiation therapy.

Prevention of chemotherapy-induced nausea and emesis in patients responding poorly to previous antiemetic therapy. Comparing tropisetron with optimised standard antiemetic therapy.

In a multicentre trial, 78 patients with a variety of malignancies, who had experienced insufficient control of emesis (greater than or equal to 3 episodes within 24 hours) while receiving standard antiemetics during previous chemotherapy, were randomly assigned to receive tropisetron 5mg once daily for 5 days or conventional antiemetic drugs. No attempt was made to standardise the conventional antiemetic treatment, which was given according to the usual practice of the participating institutions. Emesis was evaluated by counting emetic episodes and nausea by asking the patients to record on a diary chart the duration and severity of the nausea. Emesis was much better controlled with tropisetron than with standard drugs, complete control during the first 24 hours being achieved in 42% and 8% of patients, respectively, (p less than 0.001). Nausea was of significantly shorter duration (6.9 vs 10.3 hours; p less than 0.01) and was less severe (p less than 0.005) in the tropisetron group. The patients' overall assessment of treatment outcome was markedly better for tropisetron than for the standard antiemetic therapy. The superior efficacy of tropisetron was especially marked during the first 24 hours. For delayed nausea, no significant difference between treatments was seen. No serious adverse effects were observed.

[Diagnostic problems in local recurrence after breast saving therapy of breast cancer]. / Das diagnostische Problem des Lokalrezidivs nach brusterhaltender Therapie des Mammakarzinoms.

From 1970 to 1987, 331 breast cancer patients of the Department of Gynaecology of the University of Erlangen were treated by conservative breast surgery. Adjuvant radiotherapy of the remaining breast was applied to only one-third of the patients. 30 patients (9.8%) had a local recurrence. This study analyses the 21 patients with local recurrence after breast conserving therapy, treated afterwards again in our hospital. 60% of the recurrences occurred within 2 years after the primary treatment. In 18 cases, the recurrences were located in the vicinity of the segmental resection area, in 3 cases the recurrences were diagnosed as new second primaries in the ipsilateral breast. 19 of the 21 recurrences were diagnosed by palpation, 2 cases were detected by mammography examination only. The palpable recurrences could only be shown in the mammography in 14 cases. We conclude, that for patients with breast conserving therapy, a mammographic examination need not be increased in frequency, but a quarterly examination by palpation should be extended over more than 2 years.

[Thermolabile characteristics of steroid hormone receptors in breast cancer]. / Thermolabilität der Steroidhormonrezeptoren beim Mammakarzinom.

The thermolability of steroid hormone receptors was examined in a prospective study at the Gynaecology and Obstetrics Division, University of Erlangen, to clarify the cause of false negative hormone receptor findings. The loss of steroid hormone receptor content was measured in relation to the duration of operation, the time and duration of preservation. The investigations show a high thermolability of the steroid receptors. This is of considerable significance in conventional operations. Compared to the determination of hormone receptors at the time of biopsy for histological verification of the putative diagnosis of breast cancer, analysis at the end of the modified radical mastectomy and segment resection or excision of recurrences only detected 43% of the content of oestrogen receptors and 50% of the content of progesterone receptors. After storage of the surgical preparation for one hour at room temperature, the yield of oestrogen receptors fell to 35% and that of progesterone receptors fell to 31% of the original receptor content. A fresh determination of hormone receptors after cryopreservation for one to two weeks at -40 degrees C postoperatively showed only a minor loss of receptors amounting to 5.3% of the oestrogen receptors and 6.6% of progesterone receptors. On the other hand, cryopreservation at the same low minus temperature for five to six months, reduces the yield of oestrogen receptors by 34.6% and that of progesterone receptors by 33.9% compared to the intraoperative analysis.

Expression of oncogenes in human breast cancer specimens.

More than 60 breast cancer specimens were screened for their expression status of 25 different proto-oncogenes. The screening method is based on in vitro synthesis of a radioactive cDNA copied from the total cellular RNA of tumor tissue. This cDNA is hybridized to cloned oncogene probes which are immobilized to a GeneScreen membrane. Frequently multiple oncogenes were found expressed although expression levels were rather moderate. 25-30% of the analyzed tumors showed significant expression of either erbB, src, raf1, lck or H-ras. Although neu expression--an oncogene believed to be particular relevant as prognostic parameter for mamma carcinoma--was screened for most of the tumors with a heterologous gene probe, expression signals could be detected in about 20% cases. The only notable correlation with classical clinical parameters such as tumor size and proliferation stage, hormone receptor status and different DNA indices was the observation that tumors lacking the progesterone receptor frequently express multiple oncogenes. Advantages and limitations of the cDNA/dot-blot screening for oncogene expression are discussed.