Nigel Sacks

High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer.

PURPOSE To investigate the efficacy of continuous infusion fluorouracil (5FU) with every-3-week epirubicin and cisplatin (ECF) as primary chemotherapy instead of immediate mastectomy for patients with large, potentially operable, breast cancer. PATIENTS AND METHODS Fifty patients with large operable breast cancer, median tumor diameter 6 cm (range, 3 to 12), were treated with 5FU 200 mg/m2/d via a Hickman line using an ambulatory pump for 6 months with epirubicin 50 mg/m2 intravenously (IV) and cisplatin 60 mg/m2 IV every 3 weeks for eight courses. Subsequent surgery and/or radiotherapy was determined by clinical response. RESULTS Forty-nine patients achieved an overall response (98%; 95% confidence interval [CI], 94% to 100%), including 33 complete clinical remissions (CRs) (66%; 95% CI, 53% to 79%). Only three patients (6%) still required mastectomy. Tumor cellularity was markedly reduced on repeat needle biopsy following 3 weeks of treatment in 81% of patients versus only 36% in similar patients after conventional chemotherapy (P < .002). Severe (World Health Organization [WHO] grade 3 to 4) toxicity was rare, with nausea/vomiting being the most common, occurring in 20% of patients. CONCLUSION Primary infusional ECF appears to be more active on clinical and histopathologic grounds than conventional chemotherapy for large operable breast cancer and is well tolerated. This approach now merits randomized comparison to determine if high CR rates may translate into improved survival.

Comparison of the Systemic and Intratumoral Effects of Tamoxifen and the Aromatase Inhibitor Vorozole in Postmenopausal Patients With Primary Breast Cancer

PURPOSE To determine biologic differences, if any, between presurgical endocrine treatment with an aromatase inhibitor (vorozole) and tamoxifen in patients with postmenopausal primary breast cancer. PATIENTS AND METHODS Randomization was to 12 weeks of 2.5 mg of vorozole per day or 20 mg of tamoxifen per day, both orally. Clinical response was assessed monthly together with serum sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogens (E1, E2, and E1S), lipids, insulin-like growth factor-1 (IGF-1), and bone metabolites (CrossLaps CTx). Tissue samples for Ki67, apoptotic index (AI), estrogen receptor, and progesterone receptor were collected at 0, 2, and 12 weeks. RESULTS Ki67 fell by 58% and 43% (means) at 2 weeks in the vorozole and tamoxifen patients, respectively (P =.13). In the vorozole group, the correlations of proportional changes in Ki67 at 2 weeks with tumor volume changes and clinical response at 12 weeks were not significant (P =.09) and marginally significant (P =.04), respectively. Serum lipids did not differ between groups. Serum levels of EI, E2, and E1S were suppressed markedly by vorozole, whereas levels of SHBG increased and LH and FSH fell significantly with tamoxifen. IGF-1 levels fell significantly with tamoxifen (P =.001) compared with the nonsignificant rise with vorozole. Twelve-week CTx values fell by 19% with tamoxifen (P =.006) and rose by 11% with vorozole (P =.15). CONCLUSION The correlation with vorozole of Ki67 with volume and clinical response supports this as an intermediate marker. The nonsignificant effects on bone and lipid metabolism by the aromatase inhibitor may be important to consider for adjuvant and potential prevention strategies.

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/m2 i.v. once every 3 weeks, methotrexate 50 mg i.v. once every 3 weeks, mitomycin C 8 mg/m2 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/m2 i.v. 24 hourly by continuous infusion via a Hickman line for 6 months, epirubicin 50 mg/m2 i.v. bolus once every 3 weeks for 6 months, cisplatin 60 mg/m2 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.

Modulation of Bcl-2 and Ki-67 expression in oestrogen receptor-positive human breast cancer by tamoxifen

The expression of the bcl-2 proto-oncogene, which is associated with prolonged cell survival and prevention of programmed cell death, was investigated in human primary breast carcinomas prior to and following endocrine therapy with the anti-oestrogen, tamoxifen. Using the BCL-2-100 antibody, a 26-kD protein was detected by western immunoblot in the cytosols of oestrogen receptor (ER)+ve human breast cancers. In a cross-sectional study, the immunohistochemical expression of Bcl-2 was observed in 32% of invasive breast cancers, but in 65% of tumours treated with tamoxifen (P = 0.009). There was a significant association of Bcl-2 with ER status, with 64% of untreated and 88% of tamoxifen-treated Bcl-2-positive tumours being ER+ve. A significantly lower Ki-67 score was found in tamoxifen-treated tumours which were Bcl-2-positive compared with Bcl-2-negative (9.3 versus 24.6%, P = 0.01). In a separate series of sequential Trucut biopsies from 18 patients, the frequency of Bcl-2 expression was increased in ER+ve tumours from 3/12 to 8/11 following tamoxifen (P = 0.04). This was also associated with a significant reduction in mean Ki-67 score from 32 to 12% (P = 0.0004). The observations from this study clearly indicate that Bcl-2 in human breast cancer is associated with ER status, and that expression is enhanced in ER+ve tumours following tamoxifen, in association with reduced cell proliferation.

Cathepsin D levels in primary breast cancers: Relationship with epidermal growth factor receptor, oestrogen receptor and axillary nodal status

Cathepsin D and the epidermal growth factor receptor (EGFr) have both been proposed as poor prognostic markers in breast cancer. We have compared the tumour cytosolic cathepsin D level with EGFr and oestrogen receptor (ER) levels and the axillary node status of 131 patients with operable breast cancer, to see if EGFr and cathepsin D are co-regulated. Cathepsin D level was measured using a two-site immunoradiometric assay kit. No correlation was found between the level of cathepsin D and EGFr, ER or nodal status. Since the raised level of cytosolic cathepsin D was not related to EGFr, it may be that measuring the level of both of these markers in the same sample will give additional prognostic information.

Hormone replacement therapy in women with previous breast cancer.

As breast cancer is known to be a tumour sensitive to the effects of endogenous oestrogens, clinicians are reluctant to prescribe hormone replacement therapy (HRT) to women with a history of previous breast cancer for fear of stimulating disease recurrence, and it is currently contraindicated in this group of women. However, an increasing proportion of breast cancer patients are requesting the use of HRT to relieve the symptoms of oestrogen deficiency, which are also a common side-effect of adjuvant therapy for breast cancer. Observational data on the use of HRT in breast cancer survivors has not demonstrated an increase in disease recurrence, but uncertainty will continue in the absence of data from prospective, randomized trials. This review aims to demonstrate why it is ethical and scientifically important to undertake such studies.

How Much of the Effect of Chemotherapy Is Due to Hormonal Manipulation

Despite the widely held belief that there is a lack of progress in the management of patients with breast cancer, remarkable advances in fact have been made. It has now been conclusively shown that a treatment intervention given after surgery for operable or early breast cancer can improve long-term survival as well as perturb the natural history of breast cancer. Administering adjuvant systemic therapy to patients presenting with seemingly localized early breast cancer (currently comprising approximately 70% of cases) was initiated by the realization that subclinical metastatic disease is usually present at the time of first diagnosis.

The Role of Hormone Replacement Therapy and Alternative Treatments

Hormone replacement therapy (HRT), whether this consists of unopposed estrogen or estrogen combined with a progestogen, is a very effective intervention for the management of estrogen deficiency symptoms. However, combined regimens are associated with a small increase in the risk of developing postmenopausal breast cancer if used long-term (i.e. >5 years). As most breast cancers are estrogen dependent, concern exists that prescription of HRT in breast cancer survivors for symptom control will stimulate the growth of occult metastatic disease and, adversely affect prognosis. Therefore, HRT is contraindicated in this patient population. However, the management of estrogen deficiency symptoms has become an important aspect of the overall care of women after breast cancer as such symptoms are one of the most common adverse effects of endocrine breast cancer therapy. Whereas many alternatives, both prescription-based and complementary therapies, are used instead of HRT, the evidence base for the majority is poor with many lacking evaluation of efficacy in placebo-controlled trials. Furthermore, some of these alternatives exhibit hormonal activity and it is unknown whether antagonism with concurrently prescribed endocrine therapy may occur, their indiscriminate use cannot be recommended.In the absence of effective or evaluated alternatives for symptom control, HRT has been prescribed to breast cancer patients increasingly on an individual basis. The rationale for this is based on the fact that short-term use does not appear to be associated with an excess breast cancer risk and that exposure prior to breast cancer diagnosis is not associated with a poorer survival. Several observational studies have failed to show that HRT increases recurrence or breast cancer death when prescribed after diagnosis. However, continued ad hoc use will not add to the existing evidence base. Preliminary analysis of two large randomized trials of HRT use in this patient group have yielded contradictory results, the number of breast cancer events being too small to determine whether patient, tumor, or treatment characteristics account for this discrepancy. Whilst the question of safety of HRT remains uncertain, it is equally important that alternatives be evaluated with similar rigor if women are to be adequately informed of their potential risks and benefits.

Hormone replacement therapy and benign breast disease

The exact incidence of new breast symptoms with hormone replacement therapy (HRT) and its trophic effects on benign breast disorders is not well quantified and remains relatively understudied. This is a rapidly growing clinical issue as the rate of HRT use is increasing. Significant mastalgia with breast tenderness, mammographic changes and benign and premalignant breast proliferative epithelial diseases with and without atypia are common with HRT. Mammographic sensitivity and specificity are decreased by the increased focal and diffuse mammographic density caused by oestrogen and/or progestogen. There is a widely perceived but incorrect belief that progestogens are beneficial for the breast in terms of symptoms and breast cancer risk; however, the opposite now appears to be the case. The small but significant risk of the diagnosis of invasive breast cancer with HRT has diverted attention in the medical literature away from the actual increase in the incidence of benign breast disease. This is well and truly counter-balanced by the many proven important health benefits of therapy in postmenopausal women including prevention of osteoporosis and improved quality of life.

Primary medical (neoadjuvant) chemotherapy with continuous infusional 5-FU (F), epirubicin (E) and cisplatin (P) for large operable breast cancer: A very active new regimen

mens, from 1988 to 1990 and relate them to the surgery adopted. 150 (66%) were premenopausal at diagnosis and 77 (34%) were postmenopausal; median age was 49 years. In 20 1 cases (9 1%) quadrantectomy + axillary dissection + radiotherapy was carried out. In 26 cases (9%) tumour size did not decrease or increased, and mastectomy was performed. In 8 cases (3.5%) no tumour was found on microscopic examination, while in 158 (70%) the macroscopic size of the tumour had reduced to 12.5 cm. Axillary lymphnodes were free of metastases in 90 patients (38.8%). It is concluded that primary chemotherapy can expand the indication for breast conservation to tumours of 3 cm or more in diameter. Careful attention should be paid however, to a number of aspects of surgical technique: the tumour should be precisely located with tattoo marks on the skin prior to chemotherapy; the extent of tumour regression must be carefully evaluated: the presence of microcalcifications must always be taken into account and the incision must respect radicality and aesthetic criteria. The specimen must be evaluated microscopically and the margins determined. Finally, adequate attention must be paid to breast re-modelling.