Large Primary Breast Cancer Research Articles

Role for sentinel lymph node dissection in the management of large (> or = 5 cm) invasive breast cancer.

Sentinel lymph node dissection (SLND) for small, early-stage breast cancer is well accepted. However, the role of SLND for large primary breast cancer is controversial. We investigated the feasibility and clinical applicability of SLND in patients with large (> or = 5 cm) breast cancers and clinically negative axillae. A prospectively entered database was used to identify all patients who underwent surgical management of histopathologically confirmed primary breast carcinomas > or = 5 cm in diameter between September 1991 and August 2000. Patients who had clinically negative axillae and underwent SLND followed by completion axillary lymph node dissection (ALND) were selected for the study. The positivity rate, accuracy rate, and false-negative rate of SLND were determined. Of the 41 patients selected for the study, 24 had infiltrating ductal carcinoma and 17 had infiltrating lobular carcinoma. Mean tumor size was 7.12 cm (range, 5-23 cm). At least one sentinel lymph node (SLN) was identified in all cases. Thirty patients had tumor-positive SLNs. Axillary metastasis was also identified in one patient who did not have a positive SLN. Thus, SLN status accurately predicted regional nodal status in 98% (40 of 41) of cases. The false-negative rate of SLND was 3% (1 of 31). None of the three patients with SLN micrometastasis, defined as a tumor focus < or = 2 mm, had tumor deposits in nonsentinel axillary lymph nodes. Only SLN macrometastasis (> 2-mm tumor deposit) and primary tumor size > or = 7 cm predicted nonsentinel axillary metastasis with significance on multivariate analysis (P = .008 and P = .046, respectively). SLND is feasible and accurate in patients with large breast cancers and clinically negative axillae. Axillary lymph node dissection can be avoided in nearly one third of patients by focused examination of the SLN.

Plasma insulin-like growth factor binding protein-3 proteolysis is increased in primary breast cancer.

Fasting blood samples were obtained before definitive surgery or biopsy in 128 patients referred to the department of surgery with suspected or manifest breast cancer. Insulin-like growth factor (IGF)-I, IGF-II and free IGF-I were measured by radioimmunoassay/immunoradiometric assay, while IGFBP-3 proteolysis was evaluated by Western immunoblot. 12 patients had ductal carcinoma in situ benign conditions, while staging revealed metastatic disease in 15 of 16 patients with invasive cancers. IGFBP-3 proteolysis above the normal range was recorded in 19 patients with invasive cancers, but in none of the patients suffering from DCIS/benign conditions. Increased IGFBP-3 proteolysis was most frequently recorded in patients harbouring large tumours and metastatic disease (Stage I: 0/19, 0%; Stage II: 3/45, 7%, Stage III: 9/37, 24%, and Stage IV: 7/15, 47%). IGFBP-3 proteolysis was significantly higher in Stage III (P =0.01) and IV (P< 0.001) patients compared to the other stage groups (P = 0.001). IGF-I and IGF-II correlated negatively to IGFBP-3 proteolysis and age. Plasma levels of IGF-I and -II were significantly lower in patients with elevated IGFBP-3 proteolysis compared to those within the normal range. Our findings reveal alterations in the IGF-system among a substantial number of patients with large primary breast cancers. © 2001 Cancer Research Campaign http://www.bjcancer.com

The effect of tamoxifen on breast tumour vascularity.

As there is experimental evidence to suggest that tamoxifen may exert an anti-angiogenic effect, the present study was designed to investigate the effect of primary tamoxifen on breast tumour angiogenesis. Fifty seven patients with large operable primary breast cancers were treated with tamoxifen (20 mg daily) for between three and six months prior to definitive surgery. Clinical response to treatment was assessed by serial ultrasound measurements of tumour volume and a responding tumour was defined as one in which there was a greater than 25% reduction in volume at the end of treatment. Patients underwent a wedge biopsy at diagnosis and definitive surgery on completion of tamoxifen, thus providing tumour sections before and after treatment. Microvessel counts (mvc) were performed following staining with the endothelial cell marker, antibody to Factor VIII, and changes in mvc were correlated with response. Forty three of 57 patients had tumours that responded to tamoxifen. There was no difference in pre-treatment mvc between non-responding and responding tumours. Post-treatment mvc was significantly higher in non-responding than responding tumours. There was a significant reduction in mvc in responding tumours following treatment with tamoxifen, and a significant increase in mvc was detected in non-responding tumours. A significant correlation was demonstrated between percentage change in mvc and percentage reduction in tumour volume. This is the first study to demonstrate a reduction in breast cancer angiogenesis in tumours that have responded to primary tamoxifen in the clinical setting.

Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.

Both mammary adipose tissue and breast cancers have the ability to aromatize androgens into oestrogens. Such potential may maintain the growth of hormone-dependent tumours. It has therefore been important to determine the effects of new aromatase inhibitors such as formestane, exemestane, anastrozole and letrozole on oestrogen biosynthesis and concentrations of endogenous hormones within the breast. Studies based on in vitro incubations of breast cancer and cultures of mammary adipose tissue fibroblasts demonstrate that these drugs are highly effective inhibitors, with IC50 values ranging between 1 and 50 nM (although the relative efficacy varies between tissues and test systems). Despite this potential, in vitro incubations of breast tissues from patients treated with type II inhibitors such as aminoglutethimide and letrozole can display paradoxically high aromatase activity; this appears to be caused by the reversible nature of the inhibition, coupled with induction/stabilization of the aromatase enzyme. To assess in situ effects within the breast, postmenopausal women with large primary breast cancers have been treated neoadjuvantly with aromatase inhibitors using a protocol that included (i) breast biopsy before treatment, (ii) definitive surgery after 3 months of treatment and (iii) infusion of [3H]androstenedione and [14C]oestrone in the 18 h immediately before biopsy and surgery. With this study design, it has been shown that drugs such as letrozole profoundly inhibit in situ aromatase activity and reduce endogenous oestrogens within the breast.

Effects of letrozole as primary medical therapy on in situ oestrogen synthesis and endogenous oestrogen levels within the breast

Abstract In situ aromatase activity and endogenous levels of oestrone and oestradiol were measure in breast tumours from 11 postmenopausal women with large primary oestrogen receptor positive breast cancers before and after three months systemic therapy with letrozole (2.5 mg daily). Patients were infused before and after treatment with 3 'H androstenedione (20MBq) and 14 C oestrone (1MBq) for 18 hours immediately before surgery. Oestrogens were purified from excised tumours and peripheral plasma. In situ aromatase activity was assessed by determining the relative amounts of 3 H and 14 C in the purified fractions and endogenous oestrone and oestradiol measured by immunoassay. One tumour showed no evidence of in situ oestrogen synthesis both before and after treatment; of the remaining 10 tumours, nine displayed a marked decrease in activity with treatment, the effect being statistically significant ( P = 0.022 by sign test). Endogenous levels of oestrogen (oestradiol + oestrone) also fell with treatment in all 10 tumour pairs examined. These results indicate that systemic therapy with letrozole significantly inhibits in situ oestrogen synthesis and decreases endogenous levels of oestrogen within the breasts of postmenopausal women.

Breast-Concerving Surgery Following Preoperative Radiotherapy to the Primary Breast Cancer of 3 cm or Larger: Histological Analysis of Size Reduction of the Tumors by Radiotherapy.

Fifteen women with primary breast cancer of 3 cm or larger were treated by radiotherapy of 5000 or 5100 cGy preoperatively for breast conservation. Among them, three responded completely to radiotherapy clinically, 6 did partially, and 6 showed minor response. Breast-concerving surgery was performed in all cases. Histologically one patient did not have cancer cells at surgery, while eight showed good response but had residual tumor, and the rest responded moderately. The histological margins were positive in six cases, of those three were positive due to an invasive component. Calculation of the size reduction of the primary tumor by radiotherapy at a histological level revealed that the invasive area of the tumors was 79.5% on average. There was a tendency, among well responding patients, to show a large reduction in size. However, the tumor cells tended to remain in the peripheral areas of the originally invasive areas. In summary, preoperative radiotherapy made the size of the primary tumors smaller in the majority of the cases clinically but the actual histological size reduction was relatively small in general. We conclude that preoperative radiotherapy is effective to extend the indications of conservative treatment in patients with a large primary breast cancer. However, care is required when we treat patients with a very large primary breast cancer conservatively.

Mammography in the assessment of response to medical treatment of large primary breast cancer

The sequential mammograms of 48 patients (median age: 54 years, range: 24-84 years) undergoing primary medical treatment for large operable breast cancer at this institution were reviewed, and compared to the findings at clinical assessment. Twenty-six patients underwent endocrine therapy using tamoxifen, and 22 chemotherapy (CMF or MMM). All had more than two mammograms which were reviewed blindly by two independent radiologists. Response to treatment by both evaluation modalities was recorded using WHO definitions (NC, PR, CR, PD). Some 81% of patients achieved an objective clinical response to treatment, whilst 63% showed mammographic response. Overall comparison of clinical examination with mammography showed agreement in 38 patients (79%) and disagreement in 10 (21%). Agreement in type of response but not in its degree was found in 22 cases (46%). The results suggest that in the majority of cases mammography provides a useful adjunct to clinical examination in monitoring response to primary medical treatment for breast cancer. However, radiological factors such as unchanging microcalcification, and the continuing presence of mammographic density contribute to the discrepancy with clinical response in some tumours, and the search for alternative modalities of assessment should continue.

Primary medical (neo-adjuvant) chemotherapy for operable breast cancer

84 patients with large operable breast cancer have been treated with primary medical chemotherapy rather than mastectomy in three sequential studies. 86% had tumours greater than 4 cm in diameter; median diameter was 6 cm (range 1–12). Median age was 46 years (range 23–66). In the first two studies 64 patients were treated with either CMF [cyclophosphamide 100 mg orally days 1–14, methotrexate 50 mg intravenously (i.v.) days 1 and 8, and 5-fluorouracil 1 g i.v. days 1 and 8, repeating at 28-day intervals for six courses] or MMM (mitozantrone 8 mg/m 2 i.v. once every 3 weeks, methotrexate 50 mg i.v. once every 3 weeks, mytomycin C 8 mg/m 2 once every 6 weeks, for 8 courses). 69% achieved an overall response including 17% complete remissions. 27% have had local relapse but only 3% uncontrolled local relapse. Only 14% have required mastectomy. In the third study which is ongoing, 19 patients have been treated with infusional FEC (5-fluorouracil 200 mg/m 2 i.v. 24 hourly by continuous infusion via a Hickman line for 6 months, epirubicin 50 mg/m 2 i.v. bolus once every 3 weeks for 6 months, cisplatin 60 mg/m 2 i.v. once every 3 weeks for 6 months with appropriate intravenous hydration). Overall response rate so far is 84% with 58% complete remissions. There have been no local relapses and no patient has required mastectomy. This study demonstrates that primary medical chemotherapy can be used to avoid mastectomy in the great majority of patients presenting with large operable primary breast cancer. Infusional FEC may be more active than conventional chemotherapy in terms of overall response and complete remission rate, and infusional FEC chemotherapy now needs to be compared with conventional chemotherapy. The concept of primary medical therapy should also be compared with conventional mastectomy followed by adjuvant chemotherapy.

Response to endocrine manipulation and oestrogen receptor concentration in large operable primary breast cancer

Forty-three patients with large (greater than or equal to 4 cm) but operable carcinoma of the breast have been treated by endocrine manipulation before definitive local surgery. This has allowed the study of the relationship between response to therapy and pretreatment oestrogen receptor (ER) concentration, as measured by a dextran-coated charcoal adsorption method. Premenopausal patients (17) were treated by surgical (4) or medical (13) oophorectomy. Post-menopausal patients (26) received either tamoxifen (10) or an aromatase inhibitor (16). Response was assessed from statistical analysis of the changes in tumour size. On completion of 12 weeks of endocrine therapy, there was significant regression of tumour size in 18 of the 43 patients. All 18 patients had tumours with ER concentrations of greater than or equal to 20 fmol mg-1 cytosol protein. Conversely all patients except one progressing on treatment had tumours with ER concentrations of less than 20 fmol mg-1 cytosol protein. This relationship applied for both premenopausal and post-menopausal patients. The overall response rate of patients with tumours of ER concentration greater than or equal to 20 fmol mg-1 cytosol protein was 60%.