A randomised trial comparing tamoxifen vs. surgery in patients over the age of 70 with operable breast cancer--final results after 28 years of follow-up.

A final review of a historical trial commenced in 1982 comprising 200 patients aged 70 or over with operable breast cancer randomised to surgery or tamoxifen with crossover on recurrence has shown that at 21-28 years follow-up,all have died from verified causes. 43 in the surgical arm and 40 in the Tamoxifen arm died of breast cancer (41.5% in total). 117 patients (58.5%) died of other verified causes unrelated to breast cancer. These patients in effect achieved a cure from breast cancer. The survival curves for both those treated by surgery or Tamoxifen are similar as are the associated curves comparing deaths from breast cancer and other causes. However although 50% of deaths from breast cancer occurred within the first five years of follow-up, further deaths from breast cancer occurred up to 25 years later. Thus at long term follow-up in a highly selected and favourable group of patients recurrence and death from breast cancer still occurred. This confirms the view that at no time in the post treatment period can one state that any patient is cured of breast cancer. However with favourable patient presentation and optimal current treatment there is a high probability that in a significant number of patients a personal cure will be achieved as described by Brinkley and Haybittle.

Long-term follow-up of a randomised trial designed to determine the need for irradiation following conservative surgery for the treatment of invasive breast cancer.

Four hundred consecutive patients aged under 70 years diagnosed with a clinical T1 or T2 breast cancer were randomised to receive post-operative radiotherapy (n = 208) or not (n = 192), and monitored to record all local recurrences, distant recurrences and deaths for up to 20 years (median 13.7 years). All patients were treated by wide local excision and adjuvant therapy [estrogen receptor (ER) positive: tamoxifen; ER negative: CMF chemotherapy]. Kaplan-Meier and log-rank test methods were used to estimate and compare survival and recurrence. The 20-year Kaplan-Meier rates for local breast recurrence were 28.6% [95% confidence interval (CI) 19.6% to 37.6%] for radiotherapy and 49.8% (95% CI 40.8% to 58.9%). There was no significant difference between the two groups with regard to disease-free or overall survival. The hazard ratio for death among women who received radiation, as compared with those that did not, was 0.91 (95% CI 0.64-1.28; P = 0.59). Therefore, post-operative radiotherapy produced a clear-cut reduction in locoregional recurrence 0.45 (0.31-0.64; P = 0.0001), but did not influence the incidence of distant metastases or time of death. However, of the 119 patients who had a local recurrence, 51 (42.8%) had a distant recurrence, whereas of the 281 without local recurrence only 59 (21%) ever had a distant recurrence. A Cox's regression analysis with local recurrence as a time-dependent variable showed a risk ratio of 5.28 (P < 0.0001). This strong relationship is dependent on the intensity of post-treatment follow-up and investigation.

Estrogen-receptor-directed neoadjuvant therapy for breast cancer: results of a randomised trial using formestane and methotrexate, mitozantrone and mitomycin C (MMM) chemotherapy.

BACKGROUND: We wanted to determine whether neoadjuvant systemic chemoendocrine therapy guided by the estrogen receptor (ER) status of the primary breast cancer, followed by conventional surgery and/or radiotherapy, reduces local and distant recurrence and improves survival compared with adjuvant treatment given conventionally postoperatively. PATIENTS AND METHODS: Two hundred ten patients with primary breast cancer (T1-T4, N0, N1-2) were randomised to receive treatment with neoadjuvant chemoendocrine therapy or conventional post-operative chemoendocrine therapy. Systemic therapy was based on the estrogen receptor (ER) status of the primary tumour obtained by trucut core biopsy. ER-negative patients received MMM chemotherapy (methotrexate (30 mg/m2), mitozantrone (7 mg/m2) and mitomycin (7 mg/m2) three-weekly for three months and ER-positive patients who were premenopausal received goserelin (3.75 mg monthly), and post menopausal women formestane (250 mg every two weeks) over three months. RESULTS: With a minimum of five years follow-up, there is no evidence of any survival benefit from the pretreatment neoadjuvant therapy regimen, with five year overall survival being 79% +/- 4.7% (neoadjuvant) and 87% +/- 3.4% (adjuvant). Similarly, there was no apparent benefit in terms of disease-free survival. There was, however, a significant reduction in the incidence of distant metastases in responders (4 of 51; 8%) compared with non-responders (17 of 49; 35%) (P < 0.01). There was a reduction in the need for surgery in responding patients with T1 and T2 tumours, since 10 of 74 (14%) had no detectable residual tumour, without any apparent increase in the risk of local or distant recurrence. CONCLUSION: In this study neoadjuvant treatment with endocrine or chemotherapy provided no obvious survival benefit to women with breast cancer. However, it does allow avoidance of surgery in some cases. Also, the patients whose tumours respond to neoadjuvant systemic therapy have a lower incidence of distant metastases after five year follow-up compared to those whose tumours fail to respond.

Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study.

BACKGROUND: Bone-marrow micrometastases have been found in patients with primary breast cancer. We report long-term follow-up of women with primary breast cancer, diagnosed between 1981 and 1986, who had multiple aspirates taken at the time of initial surgery. METHODS: 350 women with primary breast cancer were examined immunocytochemically with antibody to epithelial membrane antigen. We investigated associations with various prognostic factors as well as the effect of micrometastases on relapse-free survival and overall survival. FINDINGS: At median follow-up of 12.5 years, 151 patients had metastatic disease and 136 patients had died from breast cancer. 10-year relapse-free and overall survival were 43.9% (95% CI 33.4-54.7) and 44.9% (34.2-55.9) in patients with micrometastases, and 62.7% (56.5-68.6) and 65.7% (59.4-71.5) in patients without micrometastases at presentation (p<0.001). For relapse-free survival and overall survival, allowing for tumour size, lymph-node status, and vascular invasion, the effect of micrometastases decreased and was no longer significant, with a hazard ratio of 1.09 (0.74-1.61) for relapse-free survival and 1.21 (0.84-1.75) for overall survival. INTERPRETATION: The presence of bone-marrow micrometastases in patients with primary breast cancer is associated with a shorter relapse-free survival and overall survival, but is not an independent prognostic factor. This immunocytochemical technique may be of value in patients for whom pathological tumour size and lymph-node status are unavailable (ie, patients receiving primary medical treatment).

The detection of micrometastases in the peripheral blood and bone marrow of patients with breast cancer using immunohistochemistry and reverse transcriptase polymerase chain reaction for keratin 19.

The aim of this study was to determine whether reverse transcriptase polymerase chain reaction (RT-PCR) for keratin 19 (K19) provides additional information when combined with immunohistochemistry when used to detect micrometastases in blood and bone marrow in patients with primary breast cancer. We studied 78 patients with breast cancer who had no evidence of distant metastases. We collected blood and bone marrow, separated the mononuclear fraction and carried out RT-PCR and immunohistochemistry for K19. RT-PCR was done by two 40-cycle rounds using nested primers. In initial experiments, RT-PCR was shown to be capable of detecting one tumour cell in one million normal bone marrow cells, which was at least 10 times more sensitive than immunohistochemistry, while retaining specificity. Five per cent of the peripheral blood and 22% of the bone marrow samples contained K19 positive cells by immunohistochemistry staining. Using RT-PCR, these proportions increased to 25% and 35%, respectively. This represents a significantly greater detection frequency (P < 0.001 and P = 0.03, respectively). RT-PCR for K19 is a more sensitive method for detecting micrometastases in patients with primary breast cancer when compared with immunohistochemistry.

Assesssment of the effect of pretreatment with neoadjuvant therapy on primary breast cancer.

Patients with invasive cancer of the breast (T1-4, N0-2, M0) were assigned to pretreatment based on oestrogen receptor (ER) status; patients with ER-negative tumours received chemotherapy [mitozantrone, methotrexate and mitomycin C (MMM)] for 3 months, patients with ER-positive tumours underwent endocrine therapy [luteinising hormone releasing hormone (LHRH) agonist goserelin (leuprolide-premenopausal) or 4-hydroxyandrostenedione (formestane-post-menopausal)] for 3 months. Of the first 100 patients assessed at 3 months, 47 with ER-positive tumours had a 40.4% response (premenopausal 53.8%; post-menopausal 35%) and 53 with ER-negative tumours had a 60% response (premenopausal 57%; post-menopausal 63%). Patients with early breast cancer (T1/T2) had a complete clinical resolution in 41% (16/39) of cases after MMM and in 20% (7/35) of cases following endocrine therapy compared with 14% (2/14) advanced tumours (T3/T4) following MMM and (0/12) following endocrine therapy. However, in those patients achieving a complete clinical response, subsequent appropriate surgery showed that 16 of 19 patients (84%) had evidence of residual viable tumour on histological examination.

The importance of the resection margin in conservative surgery for breast cancer.

Eradication of breast cancer by wide local excision alone is not possible unless the clinical margins of excision exceeds 5 cm or a segmental mastectomy is performed, though recurrences may still occur after a segmental mastectomy. With inadequate excision radiotherapy to the breast is essential, but will not prevent local recurrence. In a prospective trial (1981 to 1990) to assess the value of radiotherapy to the breast when adjuvant therapy was administered, 418 patients treated by wide local excision and adjuvant chemotherapy (tamoxifen if oestrogen receptor-positive and CMF chemotherapy if oestrogen receptor-negative) were randomized to have loco-regional radiotherapy to the breast or not. At a minimum 5-year follow-up, the local recurrence rate in patients receiving radiotherapy was 13% compared to 35% in those not so treated. Local recurrence was strictly related to microscopic clearance in millimetres irrespective of clinical wide local excision, nodal, or menopausal status. Where, histologically, local excision was incomplete and patients received radiotherapy, the local recurrence rate was 17%. The criteria for wide local excision need to be strictly defined and histologically proven if post-operative radiotherapy is to achieve its effective function, that is the prevention of local recurrence. Radiotherapy cannot compensate for inadequate surgery.

Future prospects in limited surgery for early breast cancer.

There is a strong body of opinion that favours conservative surgery in early breast cancer, with certain provisos. If an operation that is less than a mastectomy is to be performed, it is essential that by histological assessment, the resection margins be > or = 10 mm clear, preferably 20 mm. Extensive DCIS is a serious stumbling block, as it suggests the possibility of multicentricity. It would seem that postoperative radiotherapy is always indicated on the grounds of an unacceptable local recurrence rate and thus an expression of a later higher risk of distant metastases. Because of the fact that recurrence both local and distant, are expressed by the nodal state, it is essential to assess the axillary lymph nodes. If they are positive, there are two choices, namely total axillary clearance or postoperative axillary radiotherapy; opinion is divided as to the best management. Because of the good prognosis in well treated pT1pN0 patients, it appears logical to offer these patients conservative surgery, postoperative radiotherapy and adjuvant therapy. The complications of this therapy are far outweighed by the advantage of a cure. In the node-positive patient, it is essential to offer the triumvirate of treatment, surgery, radiotherapy and adjuvant therapy (chemotherapy and tamoxifen) to try and reduce local and regional recurrence and distant metastases.

The importance of the non-palpable lesion in women under 50, detected by mammography on self-referral for screening, symptoms or follow up.

Between 1.1.88 and 31.12.91, 349 consecutive patients had an x-ray localization excision of a non-palpable breast lesion less than 10 mm in diameter detected by 2-view mammography performed as a result of self-referral for screening (133), breast symptoms (164), or follow-up for breast disease (52). All lesions greater than 11 mm were excluded. 250 had benign and 99 (28%) had malignant lesions. 37 of 99 (37%) patients with malignancy were aged 49 or under. 133 patients requested screening, 33 (25%) had carcinoma of whom 11 (33%) were aged 49 or less. 164 patients presented with breast symptoms; 47 (29%) had cancer and 15 (32%) of these were aged 49 or less. 52 patients requested follow up for breast diseases including previous cancers, 19 (37%) had carcinoma of which 11 were 49 years or less (58%). 223 had microcalcifications, of which 68 (31%) were positive for cancer, and 126 had no microcalcification, of which 31 (25%) patients had cancer. The specific spiculate radiological lesions yielded 16 carcinomas in 31 cases (52%). Microcalcification was seen in 110 patients under 49 with 27 (25%) carcinomas detected. Microcalcification was a significant diagnostic criterion in the patients aged 49 or less, accounting for 27/37 (73%) patients. Dutal carcinoma in situ accounted for 18/37 (49%) in patients aged 49 or less, and 19/62 (31%) in patients over 50 years. Mammography should not be withheld from patients who are seeking screening, have symptoms, or who wish to be followed up, irrespective of age.

Malignant myoepithelioma (myoepithelial carcinoma) of the breast: a detailed cytokeratin study.

AIMS: To study the expression of a range of cytokeratins by malignant myoepithelioma of the breast. METHODS: Immunophenotyping was carried out using a panel of antibodies on paraffin wax embedded and frozen material using immunohistochemistry and double-labelled immunofluorescence. Electron microscopy was also performed. RESULTS: The tumour cells were positive for CAM 5.2, actin, vimentin, and cytokeratin 14 and negative for cytokeratins 18 and 19. Electron microscopy showed well formed desmosomes and hemidesmosomes together with pinocytic vesicles, plentiful rough endoplasmic reticulum and 6 nM microfilaments with focal densities. CONCLUSIONS: The pattern of cytokeratin expression provides further evidence that tumours with a specific myoepithelial phenotype occur rarely in the breast.

Reversal of jejunoileal bypass in patients with morbid obesity.

Jejunoileal bypass for morbid obesity was performed on 182 patients between 1971 and 1982. At 19 years' follow-up 60 (33 per cent) have had to undergo reversal. The compelling reasons for reversal were life-threatening malnutrition, immune complex disease, renal oxalate stones, osteomalacia and severe electrolyte disturbance. All patients gained weight after reversal of the jejunoileal bypass; most gained all the weight they had lost. Thirty-one patients returned to grade III obesity and 14 to grade II. Twelve patients had an associated vertical gastroplasty: ten regained their previous weight and only two stayed within normal weight. Patients were generally free from bypass-associated symptoms and complications apart from arthralgia and arthritis. This report concludes a series of articles published by the authors on jejunoileal bypass over the past 20 years describing the rise and fall of this surgical procedure.

Prospective randomized trial of tamoxifen vs surgery in elderly patients with breast cancer.

Between 1982 and 1989, 200 patients aged 70 or over seen in one Breast Unit, who were considered to have a surgically resectable cancer of the breast were prospectively randomized to primary surgery or tamoxifen 20 mg per day. At a median follow-up of 6 years (range 3-11 years) and at the censoring date there were 61 first events in the tamoxifen group. Fifty three patients developed local relapse or progression of the cancer; three patients had simultaneous local progression or relapse and distant metastases. In addition a further five patients developed distant recurrence only. In the surgical arm there were 50 events. Thirty-six patients developed local recurrence only; eight had simultaneous local and distant recurrence. A further six patients developed distant metastases of which two subsequently developed local recurrence. There were 33 deaths in the tamoxifen group and 28 deaths in the surgical group of which 17 and 15, respectively were directly attributable to breast cancer. The disease-free interval did not differ between the two groups. Following treatment with tamoxifen, at the censoring date which was the date of last clinical examination or arbitrarily, the date of death, 39 patients had no evidence of relapse whereas in the surgical arm there were 50 patients who had no evidence of recurrence. Fifty-three patients in the tamoxifen arm had local relapse only and were available for crossover to surgery, 39 accepted surgery. Eight developed further local recurrence, 10 developed distant metastases and 21 remained free of disease. Thirty-six patients in the surgical group developed local relapse only and were available for crossover to tamoxifen. Thirty one accepted treatment with tamoxifen, 14 had progression of their local recurrence, seven developed distant metastases and 10 had no further recurrence. Thus in the tamoxifen group, 39 had no progression of their disease and a further 21 benefited from subsequent surgery: 60% in all. In the surgical group 50 had no recurrence of their disease and a further 10 benefited from subsequent tamoxifen therapy: 60% in all.

Gynaecological cytology and pelvic ultrasonography in patients with breast cancer taking tamoxifen compared with controls.

The objective of this study was to look at the effect of tamoxifen on the endometrium by comparing gynaecological cervical and endometrial cytology in breast cancer patients on tamoxifen for 3 years compared with controls. In addition, pelvic ultrasonography was employed to detect ovarian abnormalities and to measure endometrial thickness. Patients followed-up after primary surgical therapy for breast cancer were invited for gynaecological assessment consisting of clinical examination pelvic ultrasonography and a cervical smear and endometrial sampling. The patients taking tamoxifen (n = 49) has been on adjuvant hormone therapy for a minimum of 3 years. Control patients (n = 45) were also being followed-up for breast cancer. On examination the tamoxifen patients had very similar clinical findings to the control patients with regard to the cervix (normal in 84% of tamoxifen takers compared to 87% of controls). The uterus was clinically enlarged in eight patients on tamoxifen and in none of the control patients (P = 0.006) and only one ovarian cyst was clinically detectable in a patient taking tamoxifen. Pelvic ultrasonography between the two groups of patients was not statistically different (chi 2 test) and ovarian cysts were noted in nine patients from each group (tamoxifen patients 18% vs control patients 20%, n.s.). There was a highly significant difference in endometrial thickness in premenopausal patients (9.2 mm) compared with postmenopausal patients (6.4 mm, P = 0.001). There was also a suggestion that endometrial thickness was greater in tamoxifen treated patients (P = 0.08). In general, a greater proportion of patients taking tamoxifen had cervical and endometrial cells exhibiting hyperplastic nuclei, and in endocervical smears, this difference achieved statistical significance (Mann-Whitney test, P = 0.046). These findings show that a significantly increased proportion of patients taking tamoxifen had endocervical nuclear hyperplasia, and a trend towards increased endometrial thickness. These findings confirm that tamoxifen has mild oestrogenic activity. However, the lack of any difference in the incidence of dysplasia suggests that the carcinogenic potential of tamoxifen on the uterus is very low and the beneficial effects of tamoxifen as an adjuvant therapy for breast cancer outweighs its theoretical risks.

Effect of long-term tamoxifen therapy on cancellous bone remodeling and structure in women with breast cancer.

The effects of long-term tamoxifen therapy on bone remodeling were studied in 41 women with breast cancer, 22 treated with tamoxifen for a minimum of 15 months (mean 33) and 19 untreated. Transiliac crest bone biopsies were obtained and a comprehensive histomorphometric analysis performed using a semiautomatic image analysis system. There were no statistically significant differences between the two groups in bone area, osteoid perimeter and area, or osteoid width. Mineral appositional rate, adjusted appositional rate, and mineralization lag time were also similar in the two groups; however, tissue-based bone formation rate was significantly lower in the tamoxifen-treated women (p = 0.05) and the remodeling period significantly longer (p < 0.05). Mean and maximum resorption cavity depth and cavity area were significantly reduced in the tamoxifen-treated patients compared to the untreated patients (p < 0.01, p < 0.01, and p < 0.03, respectively). Calculated and directly measured indices of cancellous bone structure were similar in the two groups, although the data indicated a trend toward greater connectedness in the tamoxifen-treated group. These data indicate that tamoxifen does not exert an antiestrogenic effect on bone remodeling in the human and are consistent with a weak estrogenic effect.

Use of silicone implants after wide local excision of the breast.

The appearance of the breast after wide local excision for carcinoma may be unsatisfactory. In 59 patients undergoing wide local excision a silicone prosthesis was inserted into the cavity at the time of primary surgery. Assessment of the cosmetic result was performed after 12 months by questionnaire and clinical examination. Four prostheses were removed within 1 year because of infection (two patients), wound breakdown (one) and pain (one). Seven prostheses were subsequently removed because of severe capsular contraction. Capsular contraction was more common in patients who had received radiotherapy. Only 23 patients found the results of the implant acceptable or satisfactory. The immediate use of intramammary implants after wide local excision is currently associated with a poor cosmetic result, and the problem of the distorted breast after such excision requires continued attention.

Bilateral carcinoma of the breast.

In a retrospective review of 2820 patients with breast carcinoma seen at the Combined Breast Clinic of St George's Hospital over a 23-year period 101 cases were bilateral of which 52 (1.8%) presented synchronously and 49 (1.7%) metachronously. Twenty deaths occurred in the synchronous group after a mean follow-up of 56.2 months and 15 deaths in the metachronous group after a mean follow-up of 48.5 months following diagnosis of the second tumour. If timed from initial presentation patients with metachronous tumours fared better than those with unilateral disease (P < 0.01). There was no significant difference in survival between patients with metachronous (if timed from the second tumour), synchronous or unilateral breast carcinoma.