Search

The immunohistochemical determination of HER-2 to identify patients with advanced breast cancer candidates for Trastuzumab treatment proved neither accurate nor fully reliable, possibly because none of the current reagents detects the specific antigenic site target of Trastuzumab. To circumvent this problem, we conjugated the NH2 groups of Trastuzumab with biotin, and the compound obtained, designated BiotHER, was added directly to tissue sections. Biotin-labelling was revealed with horseradish peroxidase-conjugated streptavidin. Specificity and sensitivity of BiotHER immunostaining with respect to HER-2 amplification were tested on 164 breast carcinoma samples. BiotHER staining was detected on the tumour cell membrane of 12% of all specimens and in 49% specimens with gene amplification, while absent in nonamplified tumours. Predictivity of BiotHER status with respect to the clinical outcome was analysed in 54 patients with HER-2 amplified advanced breast cancer treated with Trastuzumab plus chemotherapy. BiotHER staining, detected in 50% of tumours with HER-2 amplification, was an independent predictor of clinical outcome. In fact, BiotHER positivity was independently associated with increased likelihood of tumour response and reduced risk of tumour progression and death. Biotinylated Trastuzumab can thus be used for immunohistochemical detection of HER-2 overexpression in breast cancer, and has the potential to identify patients likely to benefit from Trastuzumab treatment.

We investigated the activity and toxicity of a combination of vinorelbine (VNB), paclitaxel (PTX) and 5-fluorouracil (5-FU) continuous infusion administered as first-line chemotherapy in metastatic breast cancer patients pretreated with adjuvant anthracyclines. A total of 61 patients received a regimen consisting of VNB 25 mg m(-2) on days 1 and 15, PTX 60 mg m(-2) on days 1, 8 and 15 and continuous infusion of 5-FU at 200 mg m(-2) every day. Cycles were repeated every 28 days. Disease response was evaluated by both RECIST and World Health Organization (WHO) criteria. Objective responses were recorded in 39 of 61 patients (64.0%) assessed by WHO and in 36 of 50 patients (72.0%) assessable by RECIST criteria. Complete remission occurred in 15 (24.6%) and 14 patients (28.0%), respectively. The median time to progression and overall survival of entire population was 10.6 and 27.3 months, respectively, and median duration of complete response was 14.8 months. The dose-limiting toxicity was myelosuppression (leucopenia grade 3/4 in 52.5% of patients). Grade 3/4 nonhaematologic toxicities included mucositis/diarrhoea in 13.1%, skin in 3.3% and cardiac in 1.6% of patients. Grade 2/3 neurotoxicity was observed in five patients (7.2%). The VNB, PTX and 5-FU continuous infusion combination regimen was active and manageable. Complete responses were frequent and durable.

The knowledge of the status of axillary lymph nodes (LN) of patients with breast cancer is a fundamental prerequisite in the therapeutic decision. In the present work, we evaluated the impact of fine-needle aspiration cytology (FNAC) of ultrasonographically (US) selected axillary LN in the diagnosis of LN metastases and subsequently in the treatment of patients with breast cancer. Axillary US was performed in 298 patients with diagnosed breast cancer (267 invasive carcinomas and 31 ductal carcinoma in situ DCIS), and in 95 patients it was followed by FNAC of US suspicious LN. Smears were examined by routine cytological staining. Cases of uncertain diagnosis were stained in immunocytochemistry (ICC) with a combination of anticytokeratin and anti-HMFG2 antibodies. Eighty-five FNAC were informative (49 LN were positive for metastases, 36 were negative). In 49 of 267 patients with invasive breast carcinoma (18%), a preoperative diagnosis of metastatic LN in the axilla could be confirmed. These patients could proceed directly to axillary dissection. In addition, US-guided FNAC presurgically scored 49 out of 88 (55%) metastatic LN. Of all others, with nonsuspicious LN on US (203 cases including 31 DCIS), in which no FNAC examination was performed, 28 invasive carcinomas (16%) turned out to be LN positive on histological examination. Based on these data, US examination should be performed in all patients with breast cancer adding ICC-supported FNAC only on US-suspect LN. This presurgical protocol is reliable for screening patients with LN metastases that should proceed directly to axillary dissection or adjuvant chemotherapy, thus avoiding sentinel lymph node biopsy.

Several studies indicate that the short arm of chromosome 17 is one of the most frequently altered regions in sporadic breast carcinomas (45-60%). In the present report the 17p13.3-ter locus in tumour DNA of breast cancer patients, along with their matching normal lymphocyte DNA, have been mapped with four markers (D17S5, D17S379, ABR and D17S34), spanning nearly 3 cM of the telomer. Sixty-five of 143 heterozygous tumours had lost at least one of the markers at the minimum region of loss (45%). High levels of loss of these distal markers on 17p13.3 are independent of TP53 mutations and are associated with tumour cell proliferation. A follow-up period of over 7 years demonstrates that loss of these markers correlates both with disease-free (P = 0.004) and overall survival (P = 0.007). In addition we show that for disease-free survival the prognostic power of this genetic alteration is second only to axillary lymph node involvement (3.1 vs 6.3 relative risk), and is a better predictor than the mutational status of TP53 (1.6 relative risk). Our results are further evidence of the presence, within the region, of at least a second tumour suppressor gene distal to TP53, that might be targeted by deletions.

Fifty-one patients with advanced non-small cell lung carcinoma were treated with a combination of mitomycin C, vinblastine and cis-platin (MVP). Most cycles were given on an out-patient basis. Major side effects were leukopenia and peripheral neurotoxicity; one patient died of sepsis while leukopenic. In 44 evaluable patients the response rate was 50%, with one complete response. Overall median survival time was 280 days and median duration of responses was 232 days. A better performance status, disease limited to one hemithorax and no prior exposure to chemotherapy positively influenced the survival. MVP is an effective chemotherapy for non-small cell lung cancer and further experience with this combination is warranted.