Joan Houghton

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses.

The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow‐up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early‐stage breast cancer, anastrozole was superior to tamoxifen in terms of disease‐free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow‐up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months).

Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial

BACKGROUND As a consequence of mammographic breast screening programmes, ductal carcinoma in situ is diagnosed with increasing frequency. Mastectomy for localised ductal carcinoma in situ is thought to be an over-treatment by many physicians, but there is much controversy as to whether complete local excision alone is sufficient. We aimed to assess the effectiveness of adjuvant radiotherapy and tamoxifen. METHODS We used a 2x2 factorial design in a randomised controlled trial. Between May, 1990, and August, 1998, 1701 patients recruited from screening programmes were randomised to both treatments in combination or singly, or to none, or to either one (eg, radiotherapy) with an elective decision to give or to withhold the other (ie, in this case tamoxifen). Patients had complete surgical excision of the lesion confirmed by specimen radiography and histology. Patients have been followed up at least once a year. Median follow-up was 52.6 (range 2.4-118.3) months. Our primary endpoint was the incidence of ipsilateral invasive disease. FINDINGS Ipsilateral invasive disease was not reduced by tamoxifen but recurrence of overall ductal carcinoma in situ was decreased (hazard ratio 0.68 [0.49-0.96]; p=0.03). Radiotherapy reduced the incidence of ipsilateral invasive disease (0.45 [0.24-0.85]; p=0.01) and ipsilateral ductal carcinoma in situ (0.36 [0.19-0.66]; p=0.0004), but there was no effect on the occurrence of contralateral disease. There was no evidence of interaction between radiotherapy and tamoxifen. INTERPRETATION Radiotherapy can be recommended for patients with ductal carcinoma in situ treated by complete local excision; however, there is little evidence for the use of tamoxifen in these women.

Relationship Between Quantitative Estrogen and Progesterone Receptor Expression and Human Epidermal Growth Factor Receptor 2 (HER-2) Status With Recurrence in the Arimidex, Tamoxifen, Alone or in Combination Trial

PURPOSE To determine the relationship between quantitative estrogen-receptor (ER) and progesterone-receptor (PgR) expression and human epidermal growth factor 2 (HER-2) status with time to recurrence (TTR) in postmenopausal women with hormone receptor-positive primary breast cancer treated with anastrozole or tamoxifen as adjuvant therapy. PATIENTS AND METHODS Formalin-fixed, paraffin-embedded tumor blocks were retrospectively collected from patients in the monotherapy arms of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial and centrally tested for ER, PgR and HER-2. ER and PgR were scored using continuous scales and HER-2 was scored as 0 to 3+ with 2+ cases being analyzed by fluorescence in situ hybridization. RESULTS Blocks were collected from 2,006 of 5,880 eligible patients. Tissue was assessable and ER and/or PgR positivity confirmed centrally in 1,782 cases. In these, TTR was longer for anastrozole than for tamoxifen by a similar extent to that in the overall trial. None of the three biomarkers identified a set of patients with differential benefit from anastrozole over tamoxifen. Patients with low ER, low PgR, and high HER-2 expression had a poorer prognosis with either drug. Only 2.6% of patients in the highest quartile of PgR experienced recurrence after 5 years, compared with 13.2% in the lowest quartile. CONCLUSION Quantitative expression of ER and PgR and HER-2 status did not identify patients with differential relative benefit from anastrozole over tamoxifen: TTR was longer for anastrozole than for tamoxifen in all molecular subgroups. Low ER or PgR or high HER-2 expression are associated with a high risk of recurrence with either anastrozole or tamoxifen.

Postoperative radiotherapy and late mortality: evidence from the Cancer Research Campaign trial for early breast cancer.

OBJECTIVE--To identify any excess mortality caused by adjuvant radiotherapy for early breast cancer. DESIGN--Prospective randomised clinical trial. Two thousand subjects needed for study to have a 90% chance of detecting a difference in survival rate of 7% with 95% significance. Patients were followed up until June 1988, giving follow up of 158-216 months. SETTING--A multicentre trial mainly drawing patients from centres in the United Kingdom. PATIENTS--2800 Women presenting with clinical stage I or II carcinoma of the breast from June 1970 to April 1975. INTERVENTIONS--One group of women (n = 1376) had simple mastectomy followed by immediate postoperative radiotherapy (1320 to 1510 rets). The remaining women (n = 1424) had simple mastectomy with subsequent careful observation of the axilla, radiotherapy being delayed until there was obvious progression or recurrence of disease locally. END POINT--Increased mortality in patients treated with radiotherapy from causes other than breast cancer. MEASUREMENTS AND MAIN RESULTS--Survival was measured from time of first treatment to death or last follow up. Deaths from any cause and from specified causes were counted as events. Comparison over the whole follow up showed a slight excess mortality in the group treated with radiotherapy (relative risk 1.04; 95% confidence interval 0.94 to 1.15). The relative risk of death from breast cancer was 0.97 (0.87 to 1.08) but that of death from other causes was 1.37 (1.09 to 1.72), the increase mainly being in women who had had tumours of the left breast (1.61 (1.17 to 2.24)) and had been treated with orthovoltage (1.85 (1.27 to 2.71)). Analysis of causes of death after five years showed a relative risk of 2.11 (1.25 to 3.59) for new malignancies and of 1.65 (1.05 to 2.58) for cardiac disease, the increase in cardiac mortality being most pronounced in patients who had had tumours of the left breast and whose treatment had included orthovoltage radiation (relative risk 2.67 (1.28 to 5.55)). CONCLUSIONS--Adjuvant radiotherapy after simple mastectomy for early breast cancer produces a small excess late mortality from other cancers and cardiac disease. The risk has to be balanced against the higher risk of local recurrence when immediate postoperative radiotherapy is not given. The balance has to be assessed for each patient, and for many patients radiotherapy will still be desirable in the initial treatment of their early breast cancer.

Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: A sub-protocol of the 'Arimidex (TM) and Tamoxifen Alone or in Combination' (ATAC) trial

The ATAC trial evaluates in a randomized, double-blind design, Arimidex™ (anastrozole) alone or in combination with tamoxifen, relative to tamoxifen alone as 5-year adjuvant treatment in postmenopausal women with early breast cancer. Patients included in the pharmacokinetic (PK) sub-protocol had been in ATAC for ≥3 months, taking their medication in the morning and were 100% compliant for the preceding 14 days. Blood samples were collected 24 ± 4 h after last dose. Trough (Cmin) plasma concentrations of anastrozole, tamoxifen and desmethyltamoxifen (DMT) were measured by validated methods. The PK results were based on a total of 347 patients (131 anastrozole (1 mg o.d.), 111 tamoxifen (20 mg o.d.), 105 anastrozole and tamoxifen (1 and 20 mg o.d. respectively)). The geometric mean steady-state trough plasma concentrations of tamoxifen and DMT were statistically equivalent in patients receiving tamoxifen alone or in combination with anastrozole: geometric mean tamoxifen = 94.8 ng ml–1and 95.3 ng ml–1in tamoxifen alone and combination groups, respectively; geometric mean DMT = 265.1 and 277.6 ng ml−1in the tamoxifen and anastrozole and tamoxifen groups, respectively. The geometric mean anastrozole levels were 27% lower (90% Cl 20–33%; P < 0.001) in the presence of tamoxifen than with anastrozole alone. Baseline plasma oestradiol levels were not obtained in the PK sub-protocol, however, such information was available from a similar ATAC sub-protocol, which evaluated bone mineral density. Mean oestradiol levels were 21.3, 19.3, and 21.6 pmol l−1prior to treatment and 3.7, 20.9 and 3.6 pmol l−1after 3 months in the anastrozole, tamoxifen, and combination groups, respectively (n = 167). On-treatment values were below the detection limit (3 pmol l−1) in 43.6 and 38.5% of the anastrozole alone and anastrozole in combination with tamoxifen groups, respectively. As a result of (a) the lack of effect of anastrozole on tamoxifen and DMT levels and (b) the observed fall in blood anastrozole levels having no significant effect on oestradiol suppression by anastrozole, we conclude that the observed reduction in anastrozole levels by tamoxifen is unlikely to be of clinical significance when anastrozole and tamoxifen are administered together.

Tolerability of hormone therapies for breast cancer: how informative are documented symptom profiles in medical notes for 'well-tolerated' treatments?

Hormonal therapies for cancer are often viewed as a gentler option than many other cancer treatments, but is low toxicity an accurate perception of patients’ experiences? Side effects tend to be described as minimal or well tolerated, yet published symptoms from hormonal therapy vary considerably in their descriptions and frequencies. Previous research has highlighted under-reporting of side effects by clinical staff so as part of a wider study examining tamoxifen and goserelin treatment as adjuvant therapy for breast cancer, treatment- related symptoms documented in medical notes were compared with those that patients reported during a research interview. There was a significant difference in the frequency of many side effects reported by the two methods in this study. Sixty four out of 72 (89%) women who had received adjuvant tamoxifen or goserelin had side effects recorded in their medical notes, compared with 74/75 (99%) reporting side effects at interview. We compared the published frequencies of commonly reported symptoms with those found ourselves. The discrepancies between patient-reported and clinician-recorded (usually from clinical trial data) symptom profiles were similar to those found in our study. Without accurate comprehensive side effect profiles for hormone therapies, prospective patients cannot make informed judgements on proposed treatments.

Is clinical breast examination an acceptable alternative to mammographic screening

Breast cancer screening and mammography have almost become synonymous in the public perception, yet this should not necessarily be the case. Ideally, a screening tool for breast cancer would reduce mortality from breast cancer while having a low false alarm rate and being relatively cheap. Screening should not be at the expense of the symptomatic services nor inappropriately divert scarce resources away from equally deserving areas of the NHS that are less politically sensitive.1 An ideal screening test would be simple, inexpensive, and effective. Of the three modalities of breast cancer screening—breast self examination, clinical breast examination, and mammography—breast self examination fulfils the first two criteria, but early results of two randomised trials conducted in Russia and China suggest that it would not be effective in reducing mortality from breast cancer. 2 3 Clinical breast examination is also relatively simple and inexpensive, but its effectiveness in reducing mortality from breast cancer has not been directly tested in a randomised trial. Mammography is complex, expensive, and only partially effective. We believe that there is sufficient circumstantial evidence to suggest that clinical breast examination is as effective as mammography in reducing mortality from breast cancer and that the time has come to compare these two screening methods directly in a randomised trial. #### Summary points The goal of breast screening is to prevent death and not simply to detect cancers by mammography Mammography does detect some cancers “early,” but many of these are not potentially lethal and their detection causes needless anxiety Clinical breast examination is more likely to detect cancers that are potentially lethal Results of the second Canadian national breast screening study suggest that mammographic detection of cancers that are not palpable does not affect mortality New GMC guidelines on informed consent state that women in the NHS breast screening programme should …

Patients’ preferences for adjuvant endocrine therapy in early breast cancer: what makes it worthwhile?

Adjuvant endocrine therapy improves recurrence and survival rates, but has side effects and is inconvenient. The aim of this study was to determine the preferences of premenopausal women who had adjuvant endocrine therapy in a randomised trial. In all, 85 (or eighty-five) women completed semistructured interviews 6–30 months after finishing adjuvant endocrine therapy. Hypothetical scenarios based on known potential survival times (5 or 15 years) and rates (60% or 80% at 5 years) without adjuvant endocrine therapy were used to determine the smallest gains women judged necessary to make their adjuvant endocrine therapy worthwhile. Although a third of the women considered gains of 1% in survival rates or 6 months in survival times sufficient to make their adjuvant endocrine therapy worthwhile, more than half the women required gains of at least 5% in survival rates or 3 years in survival time as necessary to make adjuvant endocrine therapy worthwhile. Larger benefits were required by women who had longer treatment, worse side effects, and by those who were treated with goserelin alone. The route of administration (tablet vs injection) did not affect preferences and some women judged small benefits sufficient to make their adjuvant endocrine therapy worthwhile, but many women required larger benefits than their counterparts in similar studies of preferences for adjuvant chemotherapy.

Social class and weight as prognostic factors in early breast cancer.

Data from the Cancer Research Campaign trial for early breast cancer have been used to study the effect of social class and weight on prognosis after primary treatment either by a simple mastectomy plus post-operative radiotherapy or by a simple mastectomy followed by a watch policy. There were 2455 patients for whom both social class could be determined and weight was recorded. These patients presented in clinical stages I and II and were recruited between June 1970 and April 1975. The cut-off date for the analysis was 31 December 1991. When the survival curves of patients in manual classes were compared with those in non-manual classes, there was a tendency for the latter to do better, but the difference was not statistically significant (P = 0.12). By contrast, there was a highly significant difference (P = 0.002) in survival favouring patients weighing less than or equal to 60 kg compared with those weighing greater than 60 kg. The difference was confined to post-menopausal patients and was still highly significant when included in a multivariate analysis with social class, age, tumour size, clinical stage and tumour grade. The effect of weight was to increase the mortality due to breast cancer rather than other causes.

Results of the Cancer Research Campaign Adjuvant Trial for Perioperative Cyclophosphamide and Long-Term Tamoxifen in Early Breast Cancer Reported at the Tenth Year of Follow-Up

Over 2,000 patients with early breast cancer were recruited into a trial between 1980 and 1985. This trial was of a factorial 2 x 2 design to investigate the benefits of a short course of perioperative cyclophosphamide or tamoxifen 20 mg daily for 2 years. At the tenth year of follow-up no significant benefit is noted for perioperative cyclophosphamide, however the main effect analysis for adjuvant tamoxifen demonstrates a significant improvement in disease-free survival which increases with time during the follow-up period. These results are in keeping with the World Overview of Trials of Adjuvant Tamoxifen. However, this study is unique, having a large number of node negative patients and over 500 premenopausal women in a comparison of tamoxifen and control. The relative risk reductions for the node negative patients for disease-free survival are greater than for the node positive patients. This might suggest that the absolute benefit for adjuvant tamoxifen is similar in both groups of patients, bearing in mind the increased risk of relapse with the node positive patients. No trend for interaction emerges according to age or menopausal status suggesting an identical benefit for premenopausal women. Of particular interest is the development of contralateral breast cancer. The initial overall effect which emerged at the third year of follow-up ceases to be apparent. However, subgroup analysis according to menopausal status suggests a trend for interaction with a reduction in the risk of contralateral breast cancer in the postmenopausal women and an increase in the risk of contralateral breast cancer in premenopausal women. Plausible mechanisms exist to explain this difference in outcome and these data need to be checked against other large trials of adjuvant tamoxifen at a time when we are considering the chemoprophylaxis of breast cancer in high risk premenopausal women.