Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†.

BACKGROUND: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, ß = 0.8) 379 events had to be observed in the bevacizumab arms. RESULTS: With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. CONCLUSIONS: Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. CLINICAL TRIAL NUMBER: NCT 00567554, www.clinicaltrials.gov.

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.

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.

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.

Over-expression of cellular oncogenes in cystadenocarcinomas of the ovary.

A complex analysis of oncogene over-expression in ovarian cystadenocarcinomas of 20 patients was performed. Radioactively labelled cDNAs were synthesized from total cellular RNA from tumor cells and hybridized to dot blot filters. On each filter more than 20 different plasmids containing cloned oncogene fragments were immobilized. In concordance with published data fms was found over-expressed in 40% of the tumors. Elevated expression levels of the EGF receptor was also frequently detected. 35% of the tumors showed elevated N-ras mRNA levels. All those tumors' showed a highly dedifferentiated phenotype and were classified as G3-tumors. More over, simultaneous over-expression of different oncogenes correlated surprisingly strongly with tumor grading.

Frequent gains and losses of specific chromosome segments in human ovarian carcinomas shown by comparative genomic hybridization.

Total genomic DNA obtained from 24 ovarian carcinomas was examined for genomic imbalances by comparative genomic hybridization (CGH). A varying number of gains and losses (1 up to 31) of specific chromosomal segments was detected per tumor. Chromosomal segments which were most often present in increased copy numbers were (in decreasing order): 1q21, 8q24, 8q23, 3q26, 12p12-p13, 20q, 7q31, and 7q33-qter. Loss of material was found most frequently at 16q12, 13q13-q14, Xq, 8p21-p22, 5q13-q14, and 5q21. All these chromosomal segments involved in gains and losses may carry gene loci playing a more or less causal role in the process of ovarian malignancies. Based on these findings CGH can be regarded as a valuable tool for rapid screening of genomic imbalances in human tumors.

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.

[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.

[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.

Complete absence of the muscular layer of the ampullary part of the Fallopian tubes.

An unusual uterine tube anomaly in a 33-year old Nigerian woman is described. The ampullae of both uterine tubes completely lacked the muscular layer. The peritoneum was in direct contact with the tubal mucosa.

Morphologic differential diagnosis of idiopathic cardiomyopathies.

Scanning electron microscopic examination of the myocardium in cardiomyopathies is a valuable complementary method beside light and transmissionelectron microscopy for the differential diagnosis of this rare disease. In two cases of congestive cardiomyopathy no marked alterations of the myocardial architecture could be found whereas in one case of nonobstructive hypertrophic cardiomyopathy myocardial cell alterations and structure disorders could be demonstrated in an almost stereologic view. The pathogenesis of heart failure in this disease was clearly shown. Similar changes were not observed in hearts without cardiomyopathy or in other forms of cardiac hypertrophy.

[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.

[Local recurrence in breast cancer. Course of the disease with reference to morphologic parameters]. / Das Lokalrezidiv beim Mammakarzinom. Krankheitsverlauf unter Berücksichtigung morphologischer Parameter.

In 124 patients suffering from a local recurrence after primary treatment of a breast cancer the course of disease was checked in a retrospective manner. This particular study points out the dependence of the clinical outcome on morphological indicators. The results show that local recurrence is mostly accompanied by a generalisation of the disease and on the whole by a poor prognosis. After five years only 29% of the patients with local recurrence are still alive. Of the morphological indicators the lymphatic carcinomatosis is the most important factor related with poor prognosis. Infiltration of the pectoralis muscle has no influence on the further course. Only in few cases breast tissue that has been left after the first surgical therapy can be regarded as the starting point of a local recurrence. To avoid a further local recurrence the excision with clear tumour margins is necessary. If an incomplete removal has been carried out or in cases of narrow resection margins one has to reckon with new local recurrencies in half of all cases despite adjunctive radiotherapy. The results suggest that in cases of local recurrence beside the local treatment systemic therapy with hormones or chemotherapy might be important.

[Long-term studies of patients with borderline tumors of the ovaries]. / Langzeitbeobachtungen von Patientinnen mit Borderline-Tumoren der Ovarien.

This retrospective investigation comprises a follow-up observation of 51 patients with borderline tumours of the ovaries, who had been treated at the Department of Gynaecology of the University of Erlangen between January 1st 1966 and December 31st 1986. The average age was approx. ten years younger that of patients with invasive carcinomas and 65% of the patients were in stage I. For women in stage Ia desiring children, unilateral adnexectomy is sufficient in the context of meticulous staging laparotomy. The remaining ovary should be further exposed by wedge excision. Once the family is complete, hysterectomy and adnexectomy should then be carried out retrospectively in view of the high risk of bilaterality. In ovarian tumours of borderline malignancy stages II and III, the surgical therapy should correspond to the procedure for invasive carcinomas, with the objective of postoperative freedom from tumour. Lymphonodectomy is not obligatory in view of the very rare involvement of lymph nodes. The question as to the necessity of adjuvant therapy is still open. Our observations indicate, that combination chemotherapy, containing cisplatinum is effective as adjuvant therapy in advanced stages as well as in recurrences, which cannot be completely resected surgically. 18% of our patients with borderline tumours suffered a recurrence or tumour progression, in consequence of which five died (10%). The recurrences were manifested clinically after 33 months at the earliest, and after 164 months at the latest, so that the follow-up in these patients should extend over a period of more than ten years.

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.

Histological features of "pagetoid reticulosis" (Woringer-Kolopp) in pre-mycosis fungoides.

The case of a 66-year-old female with chronic skin lesions is described, which clinically resembled parakeratosis variegata but histologically showed the pattern of "pagetoid reticulosis" (Woringer-Kolopp). The intraepidermal pagetoid cells were lymphoid cells which, by electron microscopy, could be identified as small Sézary cells. The intraepidermal presence of numerous atypical reticulum cells does not support the theory of "pagetoid reticulosis" as a separate nosological entity, but rather stresses the epidermotropic character of (pre-)mycosis fungoides just known from intraepidermal Pautrier microabscesses.

A contribution to the natural history of breast cancer. III. Changes in the basement membranes in breast cancers with stromal microinvasion.

Twenty-eight small breast cancers and 17 other breast cancer specimens from which appropriate semi-thin sections had been prepared were examined by electron microscopy and special staining techniques for alterations in the basement membranes and the basal lamina. In each case disruptions of the basement membranes were invariably observed at the point of initial invasion. Two types of invasion were noted: (1) bud-like protrusions of intraduct cancer with disruption of the basement membranes at the point of invasion; (2) extensive basement membrane defects with single cancer cell invasion. Our study confirms that invasive breast cancer originates in intraductal or lobular carcinoma in situ.