Alwynne Tidy

Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial

BACKGROUND Tamoxifen, a drug with antioestrogenic effects, is predicted to prevent the occurrence of breast cancer. We have undertaken a trial of tamoxifen in healthy women who are at increased risk of breast cancer because of family history. We report a planned interim analysis. METHODS Between October, 1986, and April, 1996, we accrued 2494 healthy women aged between 30 and 70 with a family history of breast cancer. They have been randomised (double blind) to receive tamoxifen 20 mg per day orally or placebo for up to 8 years. Follow-up included clinical assessment, annual mammography, and assessment of toxicity and compliance. The primary endpoint was the occurrence of breast cancer, which was analysed on an intention-to-treat basis with a survival curve. FINDINGS With a median follow-up of 70 months, 2471 women (tamoxifen 1238, placebo 1233) were suitable for analysis. The groups were evenly matched at baseline, and compliance was good. The overall frequency of breast cancer is the same for women on tamoxifen or placebo (tamoxifen 34, placebo 36, relative risk 1.06 [95% CI 0.7-1.7], p=0.8). Participants who were already on hormone-replacement therapy when they entered the study had an increased risk of breast cancer compared with non-users. Those participants who started such therapy while on trial had a significantly reduced risk. The safety profile of tamoxifen was as expected. INTERPRETATION We have been unable to show any effect of tamoxifen on breast-cancer incidence in healthy women, contrary to the report from the NSABP-P1 study showing a 45% reduction in healthy women given tamoxifen versus placebo. Differences in the study populations for the two trials may underlie these conflicting findings: eligibility in our trial was based predominantly on a strong family history of breast cancer whereas in the NSABP trial was mostly based on non-genetic risk factors. The importance of oestrogen promotion may vary between such populations.

Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women.

PURPOSE Tamoxifen is an effective treatment for metastatic and primary breast cancer and is now being evaluated as a chemoprevention agent in healthy women. Any long-term effects on estrogen-sensitive tissues such as bone may have important therapeutic implications. METHODS We measured bone mineral density (BMD) in the lumbar spine and hip using dual-energy x-ray absorptiometry (DXA) in premenopausal and postmenopausal healthy women who participated in our placebo-controlled tamoxifen chemoprevention of breast cancer trial. RESULTS BMD data are now available from 179 women for this analysis. In premenopausal women, BMD decreased progressively in the lumbar spine (P < .001) and in the hip (P < .05) for women on tamoxifen, but not those on placebo. The mean annual loss in lumbar BMD per year over the 3-year study period in tamoxifen-treated compliant women who remained premenopausal throughout the study period was 1.44% (1.88% calculated on an intent-to-treat basis) compared with a small gain of 0.24% per annum for women on placebo (P < .001). Tamoxifen had the opposite effect in postmenopausal women. The mean annual increase in BMD for women on tamoxifen was 1.17% in the spine (P < .005) and 1.71% in the hip (P < .001) compared with a noninsignificant loss for women on placebo. CONCLUSION These results indicate that tamoxifen treatment is associated with a significant loss of BMD in premenopausal women, whereas it prevents bone loss in postmenopausal women. These adverse and beneficial effects of tamoxifen should be considered in the assessment of the therapeutic benefits for both the adjuvant treatment and the chemoprevention of breast cancer.

Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer.

PURPOSE The development of bone metastases depends on tumor-induced osteoclastic resorption of bone, which may be inhibited by the antiosteolytic bisphosphonate clodronate. Given to patients with primary breast cancer, clodronate might reduce the subsequent incidence of bone metastases. PATIENTS AND METHODS This double-blind, multicenter trial accrued 1,069 assessable patients with operable breast cancer between 1989 and 1995. All patients received surgery, radiotherapy, chemotherapy, and tamoxifen as required. Patients were randomized to receive oral clodronate 1,600 mg/d or a placebo for 2 years starting within 6 months of primary treatment. The primary end point was relapse in bone, analyzed on an intent-to-treat basis, during the medication period and during the total follow-up period (median follow-up, 2,007 days). Secondary end points were relapse in other sites, mortality, and toxicity. RESULTS During the total follow-up period, there was a nonsignificant reduction in occurrence of bone metastases (clodronate, n = 63; placebo, n = 80; hazards ratio [HR], 0.77; 95% confidence interval [CI], 0.56 to 1.08; P =.127). During the medication period there was a significant reduction in the occurrence of bone metastases (clodronate, n = 12; placebo, n = 28; HR, 0.44; 95% CI, 0.22 to 0.86; P =.016). The occurrence of nonosseous metastases was similar (clodronate, n = 112; placebo, n = 128; P =.257), but there was a significant reduction in mortality (clodronate, n = 98; placebo, n = 129; P =.047) during the total follow-up period. CONCLUSION Clodronate, given to patients with primary operable breast cancer, may reduce the occurrence of bone metastases, although this reduction was only significant during this medication period. There was a significant reduction in mortality.

Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]

IntroductionExperimental and clinical data show that the oral bisphosphonate clodronate (Bonefos®) can inhibit tumor-induced osteoclastic bone resorption. This randomized, double-blind, placebo-controlled, multicenter trial was designed to determine if the addition of oral clodronate to standard treatment for primary operable breast cancer could reduce the subsequent occurrence of bone metastases and thereby improve overall survival.Methods1,069 patients with primary operable stage I-III breast cancer were randomized to receive oral clodronate (1,600 mg/day) or placebo for 2 years, in conjunction with standard treatment for primary breast cancer including surgery, radiotherapy, adjuvant chemotherapy, and/or tamoxifen. All patients were assessed for bone metastases at two and five years and additionally when clinically indicated. Survival status was determined as of the close of the study on 30 June 2000 with a median follow up of 5.6 years. The treatment arms were compared using the unstratified log-rank test. Hazard ratios (HRs) with 95% confidence intervals were calculated.ResultsOral clodronate significantly reduced the risk of bone metastases in all patients over the 5 year study period (51 patients versus 73 patients with placebo; HR = 0.692, P = 0.043); the difference was also statistically significant over the 2 year medication period (19 patients versus 35 patients with placebo; HR = 0.546, P = 0.031). These differences were most pronounced in patients with stage II/III disease (39 patients versus 64 patients with placebo, HR = 0.592, P = 0.009 over 5 years; 16 patients versus 32 patients with placebo, HR= 0.496, P = 0.020 over 2 years). Survival data also favoured the clodronate arm (HR for all patients = 0.768, P = 0.048; HR for stage II/III disease = 0.743, P = 0.041), although this was not significant due to multiple analyses. Oral clodronate was well tolerated, with mild-to-moderate diarrhoea being the most frequently reported adverse event.ConclusionThese results confirm that oral clodronate will significantly improve the 5 year bone relapse free survival when used as a supplementary adjuvant treatment for patients receiving standard treatment for primary operable breast cancer.

Adjuvant aminoglutethimide for postmenopausal patients with primary breast cancer: analysis at 8 years.

PURPOSE The study purpose was to evaluate aminoglutethimide (AG) as adjuvant therapy in patients with primary node-positive breast cancer in a randomized double-blind placebo-controlled trial. PATIENTS AND METHODS In a multicenter trial, 354 postmenopausal women with early breast cancer and histologically confirmed positive axillary lymph nodes were randomized after surgery to received aminoplac. Patients were prescribed either AG 250 mg four times per day and hydrocortisone 20 mg twice per day or placebos of identical appearance for 2 years. RESULTS After a median follow-up of 8.1 years, there has been no overall benefit for AG in terms of either event-free survival or overall survival (OS). However, the results are consistent with interim analyses with a significantly improved event-free survival for patients who received AG for up to 4 years, although this benefit subsequently disappears. Similarly, there is an improved OS for patients who received AG for up to 4 years, but this also subsequently disappears. There was a marginal advantage for estrogen receptor (ER)-positive patients who received AG (n = 74; P = .054). There was no difference in the sites of relapse. There was a significant increase in toxicity for patients who received AG. CONCLUSION The lack of survival benefit with long-term follow-up for AG may indicate that aromatase inhibitors have less of an impact on early breast cancer than tamoxifen and may imply different biologic mechanisms of action.

Correction: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]

It has been brought to our attention that there was a typographical error in our recent article [1] published in March 2006.

Immunohistochemical Phenotype after 20-Year Follow-Up of the Royal Marsden Tamoxifen Breast Cancer Prevention Trial (RMTBCPT).

Background: 20-yrs after starting the randomized, double-blind RMTBCPT (13-year median follow-up) 186 women developed invasive breast cancer, 82 on tamoxifen and 104 on placebo1. There was a significant reduction in the incidence of invasive ER+ but not ER- breast cancer that was significant after but not during the 8yr treatment period. The phenotype of ER+ breast cancer is highly variable. We have therefore assessed PgR, HER2, EGFR and Ki67 expression in as many as possible of these tumours.Methods: Tumour blocks were available on 154 participants, 65 on tamoxifen and 89 on placebo a similar distribution to the whole population. Staining was conducted using the following antibodies: ER, clone 6F11(Vector); PgR, clone 16 (Vector); HER2, HercepTest + K5207 (Dako), FISH PathVysion (Abbott) for IHC 2+ cases; EGFR, clone 31G7 (Invitrogen); Ki67 clone Mib1(Dako). ER and PgR were quantified as H-scores, HER2 and EGFR as + or –, and Ki67 as % cells staining.Results: There were 47 and 18 ER+ and ER- tumours in the tamoxifen arm vs 76 and 13 in the placebo arm, showing a 37% (95% CI 10- 57%, p=0.01) reduction of ER+ tumours which was essentially the same as that in the whole population1.There were 38 and 27 PgR+ and PgR- tumours in the tamoxifen arm vs 58 and 31 in the placebo arm, showing a 33% (95% CI 0-56%, p=0.05) reduction of PgR+ tumours. The distribution of ER/PgR tumours according to arm and time on trial at tumour diagnosis is shown in the table (there were no ER-PgR+ cases).The decrement in ER+ tumours was predominantly in ER+PgR+ cases after 8yrs but extended to ER+PgR- cases. It is important to note that the post 8yr tumour phenotype cannot be affected by continued exposure to tamoxifen. ER levels were significantly lower in the tamoxifen-treated group even among tumours presenting as ER+ (median H-score 123 vs 161, p=0.02). There were 9 and 6 HER2+ and 11 and 12 EGFR+ cases in the tamoxifen and placebo arms, respectively (p=NS for both). The mean (95%CI) levels of Ki67 were 8.4% (6.3-11.1) and 8.5% (6.8-10.6) in the 2 arms, respectively.Discussion: The decrement in ER+ tumours in the tamoxifen-treated women was restricted to the post-treatment period and was similar to that seen in the overall population1. Among the ER+ group there was a similar proportional reduction of PgR+ and PgR- tumours by tamoxifen.There was no evidence of enhanced HER2 or EGFR expression or increased proliferation in tumours developing in the tamoxifen arm but ER expression was reduced even among ER+ tumours.1Powles et al, JNCI, 2007;99:283-90.Supported by the Da Costa International Fund for Breast Cancer Prevention Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1046.