Ian Russell

Prognostic significance of tumor grade in clinical trials of adjuvant therapy for breast cancer with axillary lymph node metastasis

The prognostic significance of histologic tumor grade has been evaluated in 1537 women entered into the Ludwig Trials I‐IV of adjuvant therapy for node‐positive breast cancer. Tumor grade was determined on histologic review of primary tumor sections by two central review pathologists using a modification of the Bloom and Richardson grading system. The 5‐year overall survival rates (±SE) were: Grade 1, 86% ± 2; Grade 2, 70% ± 2; and Grade 3, 57% ± 2 (P <0.0001). This survival difference was seen in both premenopausal (P <0.0001) and postmenopausal (P <0.0001) women. Significant differences in disease‐free survival (DPS) by tumor grade were also observed (P <0.0001). The tumor grade determined by the 75 contributing local clinic pathologists was also highly significant for predicting DPS and overall survival. Tumor grade remained a statistically significant prognostic factor for DPS (P <0.0001) and overall survival (P <0.0001) in multivariate analyses controlling for nodal status, tumor size, estrogen receptor status, menopausal status, age, peritumoral vessel invasion, and treatment assigned. In postmenopausal patients for whom adjuvant treatment was compared with no adjuvant therapy, the prognostic significance of tumor grade was modified by the effect of treatment. The presence of vessel invasion by primary tumor cells was a stronger predictor of early recurrence than was increasing tumor grade in postmenopausal patients who received no adjuvant therapy. The higher failure rates for patients with high‐grade tumors was due to a larger number of failures in regional and visceral sites. Tumor grade can be determined by any pathologist and allows for selection of a subpopulation of breast cancer patients at high risk for early mortality.

Prognostic significance of peritumoral vessel invasion in clinical trials of adjuvant therapy for breast cancer with axillary lymph node metastasis

To assess the prognostic significance of peritumoral vessel invasion, data were examined for 1,510 women entered into the Ludwig Breast Cancer Group Trials I to IV evaluating adjuvant therapy for operable breast cancer with axillary nodal metastasis. Vessel invasion by tumor cells was identified by routine light microscopy in 59 per cent (889 of 1,510) of the patients and was equally distributed between premenopausal/perimenopausal (60 per cent, 468 of 778) and postmenopausal (58 per cent, 421 of 732) women. In logrank analyses stratified by nodal status (one to three or four or more positive nodes), the four-year disease-free survival (DFS) rate was significantly lower in patients with vessel invasion than in women without vessel invasion (50 per cent versus 65 per cent, P less than 0.0001). This DFS difference was seen for both premenopausal/perimenopausal (P = 0.0004) and postmenopausal (P = 0.0002) patients. The four-year overall survival rate was also lower in patients with vessel invasion (71 per cent versus 82 per cent, P = 0.0006), both for premenopausal/perimenopausal (P = 0.002) and postmenopausal (P = 0.04) women. The presence of vessel invasion was significantly associated with increasing numbers of positive axillary lymph nodes, rising tumor grade, nonstellate tumor border growth pattern, and higher steroid hormone receptor content of the primary tumor. The assessment of peritumoral vessel invasion continued to have prognostic significance for DFS (P less than 0.0001) and overall survival (P = 0.003) when evaluated in multivariate models controlling for treatment assigned, nodal status, tumor size, estrogen receptor status, menopausal status, and age. Depending on the subpopulation, patients with vessel invasion had a 41 per cent to 54 per cent greater risk of treatment failure than those without vessel invasion and a 29 per cent to 64 per cent greater risk of death. The percentage of treatment failures at distant sites was higher for women with than for those without vessel invasion (27 per cent versus 18 per cent, P = 0.003). In patients with axillary lymph node metastases, peritumoral vessel invasion may be a sign of increased systemic disease burden.

Analysis of cerbB2 expression using a panel of 6 commercially available antibodies

&NA; Results are presented of a study comparing cerbB2 (neu or Her2) expression as assessed immunohistochemically in breast neoplasia using a panel of 6 commercially available antibodies. The antibodies were examined utilizing conventional formalin fixed paraffin embedded tissue, and compared with molecular analysis of gene amplification. The aim was to determine the practical utility of each antibody, assessing ease of use, specific and non-specific staining characteristics, and expense, thus allowing a specific recommendation as to antibody of choice for immunohistochemical assessment of cerbB2 expression. Reassuringly, amongst the 38 breast lesions (36 carcinomas, 2 fibroadenomas) subjected to immunohistochemistry (IHC) with the panel of 6 antibodies (Ab), no gross discrepancy of staining pattern was seen. Of the 38 cases, 10 were positive (26%), where at least one Ab demonstrated clear cytoplasmic membrane staining. Of a total of 45 breast lesions (43 carcinomas, 2 fibroadenomas), including all those examined by IHC, the total number of cases showing cerbB2 amplification by DNA analysis was 14 (31%). Using the DNA amplification as a base line for comparison, one Ab (No. 4) was found to stain 6 of the 14 cases of breast carcinoma that were assessed as showing amplification at the DNA level. Four Abs (1,3,5,6) stained 5 of these cases. However, Abs 3,4 and 6 displayed artefactual cytoplasmic staining (in the absence of membrane staining) that precluded the practical use of these reagents. Therefore, based on additional considerations of cost and ease of use, Ab No. 1 was finally chosen for recommendation from the 6 Ab panel.

Multicycle High-Dose Chemotherapy and Filgrastim-Mobilized Peripheral-Blood Progenitor Cells in Women With High-Risk Stage II or III Breast Cancer: Five-Year Follow-Up

PURPOSE To determine the safety and efficacy of multiple cycles of dose-intensive, nonablative chemotherapy in women with poor-prognosis breast cancer. PATIENTS AND METHODS Women with stage II breast cancer and 10 or more involved nodes or four or more involved nodes and estrogen receptor-negative tumors and women with stage III disease received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2, with progenitor cell and filgrastim support every 28 days (n = 79) or 21 days (n = 20). Patients were reviewed at least twice yearly thereafter. Twenty-six patients had bone marrow and apheresis collections assessed for the presence of micrometastatic tumor cells. RESULTS Ninety-nine women (median age, 43 years; range, 24 to 60 years) were treated. Ninety-two completed all three cycles of chemotherapy. The major toxicity was severe, reversible myelosuppression that was more prolonged with successive cycles, and this did not differ between patients given treatment every 28 days and those treated every 21 days. Febrile neutropenia occurred in 176 (61%) of 287 cycles. Severe mucositis (grade 3 or 4) occurred in 23% of cycles but tended to be short-lived and was reversible. The cardiac ejection fraction fell by a median of 4% during treatment, and three patients developed evidence of cardiac failure after chemotherapy. Two patients (2%) died of acute toxicity. Three of 26 patients had evidence of circulating micrometastatic tumor cells. The actuarial distant disease-free and overall survival rates at 60-month follow-up were 64% (95% confidence interval [CI], 53% to 75%) and 67% (95% CI, 56% to 78%), respectively. CONCLUSION Multiple cycles of dose-intensive, nonablative chemotherapy is a feasible and safe approach. Disease control and survival are similar to those in other studies of myeloablative chemotherapy in poor-prognosis breast cancer. The regimen is being evaluated in a randomized trial of the International Breast Cancer Study Group.

In Situ and small invasive breast cancer register in Victoria, 1988 to 1992: Tumour characteristics and patient management

Background: All cases of in situ and invasive breast cancer are reported to the Victorian Cancer Registry. In 1988 a special subregister of all cases of carcinoma in situ and small invasive cancers up to 10 mm in size was established – the In situ and Small Invasive Breast Cancer Register (ISSIBCR). This was unique in being a population‐based register and only possible because in Victoria, as in some other Australian states, all cancers including in situ disease are reported to the Central Cancer Registry.

Comparison of mammary serum antigen (MSA) with β2-microglobulin (β2M) and carcinoembryonic antigen (CEA) assays in patients with breast cancer

Serum levels of mammary serum antigen (MSA), β2-microglobulin (β2M) and carcinoembryonic antigen (CEA) were evaluated in 186 subjects to assess their use in the diagnosis and monitoring of breast cancer, either singly or in combination. Raised MSA levels (>300 I.U.) were detected in 79% of patients with Stage I/II breast cancer, compared with 25% for β2M (>2000 μg/l) and 12% for CEA (>5 ng/ml) levels respectively. Of 53 patients with Stage III/IV breast cancer, 98% (MSA), 55% (β2M) and 64% (CEA) had raised levels. In 25 patients followed over 3–9 months, the changes in MSA levels correlated with the clinical course of the disease in 2325 (92%), compared with 725 (28%) using β2M, and 925 (36%) using CEA assays. The overall sensitivity, specificity and accuracy in detecting breast cancer were 88%, 95% and 99% for MSA; 39%, 90% and 96% for β2M; and 38%, 95% and 98% for CEA, respectively. MSA and β2M assays in combination enhanced the sensitivity in the detection of breast cancer (93%) especially early breast cancer, while maintaining specificity (90%). MSA seems to be superior to β2M or CEA as a tumour marker in breast cancer and its levels seem to correlate with tumour burden. While it appears that β2M or CEA measurements used alone are of little value in the current management of breast cancer, β2M may be a helpful adjunct to enhance the sensitivity of MSA assay especially in early breast cancer.

Delayed recovery of peripheral blood cell numbers after adjuvant cytotoxic chemotherapyfor stage II breast cancer

SummaryA study was made on the recovery of the bone marrow after adjuvant chemotherapy given to 30 post-mastectomy patients with stage II breast cancer treated with either melphalan or melphalan and methotrexate at 6-weekly intervals for 1 year. Counts of peripheral blood cells were made serially during treatment and then for a further 2 years after stopping chemotherapy. Mean counts for all cell types fell during chemotherapy and recovery was long-delayed. Thus 24 months after chemotherapy, mean counts for total leucocytes and platelets were significantly lower than mean pretreatment counts and counts for a normal female population, and the count for neutrophils was significantly lower than the count before treatment; after 24 months mean counts for lymphocytes were not significantly depressed. Melphalan was assumed to be the agent responsible. Slow haematological recovery after cessation of adjuvant chemotherapy therapy with one particular regimens points to the need for including long-term post-chemotherapy observation of the bone marrow in the assessment of adjuvant chemotherapy programmes.