Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer

The incidence of new primary cancers was evaluated in 3538 postmenopausal patients who had received surgical treatment for primary breast cancer. Of these patients, 1828 with a low risk of recurrence received no further treatment. High-risk patients were randomly assigned to one of two groups. The first group (n = 846) received postoperative radiotherapy, while the second group (n = 864) received radiotherapy plus tamoxifen at a dose of 30 mg given daily for 48 weeks. The median observation time was 7.9 years. In comparison with the number of new cancers in the general population, the number of new cancers in the three groups was elevated mostly due to a high number of cancers of the contralateral breast and of colorectal cancers in the high-risk groups. The cumulative risk of nonlymphatic leukemia was increased among patients who received postoperative radiotherapy (P = .04). Cancer incidence in the high-risk tamoxifen-treated group relative to that in the high-risk group not treated with tamoxifen was not significant (1.3). No protective effect of tamoxifen on the opposite breast was seen (rate ratio for breast cancer = 1.1), but a tendency to an elevated risk of endometrial cancer was observed (rate ratio = 3.3; 95% confidence interval = 0.6-32.4). Continued and careful follow-up of women treated with tamoxifen is necessary to clarify the potential cancer-suppressive or cancer-promoting effects of this drug.     

Treatment of metastatic breast cancer with aminoglutethimide after progression on chemotherapy and/or hormonal therapy with tamoxifen

Sixty patients suffering from metastatic breast cancer, whose disease progressed on chemotherapy and/or hormonal therapy with tamoxifen, were treated with aminoglutethimide. The overall objective response rate was 33%, including 3% complete responses. The median duration of response was 8 months. Even patients who failed to respond to prior treatment modalities responded objectively to aminoglutethimide. Objective response was observed in all metastatic sites, except for lung. Subjective improvement was achieved in 70% of the patients. Although initial toxicity was high (67%), side effects of aminoglutethimide were transient, and therapy had to be discontinued in only 3 patients. The results of this study indicate that aminoglutethimide in combination with hydrocortisone is a very effective treatment for metastatic breast cancer, especially in patients with positive hormone receptors.     

Prognosis of uterine corpus cancer after tamoxifen treatment for breast cancer

Tamoxifen increases the risk of uterine corpus cancer. Since only few, mostly small, studies have examined prognosis of uterine corpus cancer following tamoxifen, we conducted a large retrospective cohort study to further investigate this. We examined histopathologic and immunohistochemical characteristics of 332 patients with uterine corpus cancer following breast cancer, according to tamoxifen use. Survival was examined in the same patients combined with 309 patients from a previous study with updated follow-up. Histological review of all cancers was performed. Long-term tamoxifen users showed a higher proportion of non-endometrioid tumors than non-users (32.7% vs. 17.4%, P = 0.004), especially serous adenocarcinomas and carcinosarcomas. An increased proportion of FIGO stage III and IV tumors was also observed (20.0% vs. 11.3%, P = 0.049). Within FIGO stage I, both short-term and long-term tamoxifen users showed a higher proportion of tumors limited to the endometrium than non-users (35.7% vs. 22.9%, P = 0.049 and 0.004 respectively). Uterine corpus cancers in long-term tamoxifen users were more often steroid receptor-negative (ERα, PRA and PRB, P < 0.05) and P53-positive (P = 0.015). Three-year uterine corpus cancer-specific survival was worse for long-term tamoxifen users than for non-users (82% vs. 93% P = 0.0001). The survival difference remained after adjustment for histopathologic and immunohistochemical characteristics (hazard ratio (HR) for ≥2 years tamoxifen = 2.4; 95% CI = 1.2–4.6). In conclusion, this large study clearly shows that tamoxifen-associated tumors have less favorable histological features and a worse survival. Our results can be applied when weighing risks and benefits of tamoxifen versus other hormonal agents used in the prevention and treatment of breast cancer. TAMARISK (Tamoxifen Associated Malignancies: Aspects of Risk)-group of the Comprehensive Cancer Centers (CCC): O. Visser (CCC Amsterdam), R. A. M. Damhuis (CCC Rotterdam), W. J. Louwman (CCC South Netherlands), J. A. A. M. van Dijck (CCC East Netherlands), Y. Westerman (CCC Middle Netherlands), M. J. M. Dirx (CCC Limburg), M. L. E. A. Jansen-Landheer (CCC West), L. de Munck (CCC Northern Netherlands), S. Siesling (CCC Stedendriehoek Twente).     

Risk of malignant mixed mullerian tumors after tamoxifen therapy for breast cancer

Recent studies have indicated that the tamoxifen-related risk of uterine corpus cancer may be especially high for some uncommon cell types, although the magnitude of risk has not been quantified. We evaluated data from 39 451 breast cancer patients diagnosed from 1980 through 2000 who were initially treated with tamoxifen and found that the overall risk of subsequent uterine corpus cancer was increased more than twofold (observed-to-expected ratio [O/E] = 2.17, 95% confidence interval [CI] = 1.95 to 2.41) relative to the general SEER population. The relative risk was substantially higher for malignant mixed mullerian tumors (MMMTs) (O/E = 4.62, O = 34, 95% CI = 3.20 to 6.46) than for endometrial adenocarcinomas (O/E = 2.07, O = 306, 95% CI = 1.85 to 2.32), although the excess absolute risk was smaller-an additional 1.4 versus 8.4 cancers per 10 000 women per year, respectively. Among those who survived for 5 years or longer, there was an eightfold relative risk for MMMTs and a 2.3-fold risk for endometrial adenocarcinomas, with patients developing MMMTs having a worse prognosis. These findings indicate that tamoxifen may have delayed effects, such as the increased risk of MMMTs, rare but aggressive tumors of unclear pathogenesis.     

Changes in serum hydroxyvitamin D levels of breast cancer patients during tamoxifen treatment or chemotherapy in premenopausal breast cancer patients

BackgroundWe investigated the effect of breast cancer adjuvant treatment on vitamin D status, as measured by serum hydroxyvitamin D (25OHD).MethodsPremenopausal patients (n = 483) diagnosed with non-metastatic breast cancer in 2009 at Asan Medical Center had serum 25OHD levels prospectively analysed at diagnosis and 6 and 12 months after surgery. We excluded patients who took vitamin D supplements or received neoadjuvant chemotherapy. Vitamin D sufficiency was defined as a serum level of ⩾30 ng/ml, insufficiency as 20–29 ng/ml and deficiency as <20 ng/ml.ResultsCompared with baseline serum 25OHD, patients who received chemotherapy had decreased serum 25OHD levels at 6 months (–5.52 ng/ml, p = 0.003) and 12 months (–1.24 ng/ml, p = 0.517) and patients who received anti-hormone therapy had significantly increased serum 25OHD levels at 6 months (+3.00 ng/ml, p = 0.681) and 12 months (+6.47 ng/ml, p = 0.002, respectively). Among patients who received chemotherapy, 49.5% were vitamin D sufficient at diagnosis but only 26.9% were sufficient 6 months after finishing chemotherapy and this percentage increased to 45.2% at 12 months.ConclusionsVitamin D levels decrease during chemotherapy but recover after treatment ends. Anti-hormone therapy with tamoxifen causes serum vitamin D levels to increase. Whether the increased serum vitamin D affects the antitumour effect of the tamoxifen has yet to be determined.     

Carcinogenic effects of adjuvant tamoxifen treatment and radiotherapy for early breast cancer.

The occurrence of new primary tumours among postmenopausal patients with primary breast cancer subsequent to adjuvant treatment in Denmark was assessed by linkage to the cancer registry. Following primary surgery, patients in low risk of recurrence (n = 1,828) received no further treatment while patients in high risk randomly received either adjuvant radiotherapy alone (n = 846) or radiotherapy + tamoxifen 30 mg daily for 48 weeks (n = 864). With a median follow-up of 8 years, the incidence of tumours in the contralateral breast was similar among tamoxifen-treated, and non-treated high-risk patients even after adjusting for tumours arising within the first year. The standardized incidence ratio for endometrial cancer was 1.9 (95% confidence interval 0.8-3.9) among tamoxifen treated, the cumulative incidence 1% compared to 0.3% among non-treated patients (p = 0.11). The cumulative risk of non-lymphocytic leukaemia was 0.9% and 0.1% among irradiated and non-irradiated patients respectively (p = 0.4). Prolonged follow-up of tamoxifen-treated patients with regard to new tumours is recommended.     

Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole

The use of adjuvant endocrine therapy in the treatment of hormone receptor-positive, early breast cancer has become important in both pre- and postmenopausal women. Tamoxifen has been the principal adjuvant hormonal therapy in pre- and postmenopausal women with hormone receptor-positive breast cancer for nearly 20 years. Recent data in premenopausal women suggest benefit from ovarian ablation with or without tamoxifen. Early results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial have demonstrated that the third-generation, selective aromatase inhibitor (AI) anastrozole ('Arimidex') is a suitable alternative adjuvant therapy for postmenopausal women with hormone receptor-positive disease. After recurrence or relapse on adjuvant endocrine therapy, responses to the sequential use of additional endocrine agents are common. The increase in the number of options now available for adjuvant therapy will have important implications for the selection of the optimal sequence of endocrine agents in the treatment of recurrent breast cancer. Menopausal status is an important factor in determining the endocrine therapy that a patient receives. For premenopausal women, tamoxifen and/or a luteinizing hormone-releasing hormone agonist such as goserelin ('Zoladex') are both options for adjuvant endocrine treatment. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women who have undergone ovarian ablation, the use of third-line therapy with an AI becomes possible. For postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant anastrozole. In addition, data suggest that fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist that downregulates the ER protein and has no known agonist effects, is a promising therapeutic option that has shown efficacy in the treatment of postmenopausal women with advanced breast cancer. Other agents that may be used in the sequence include the steroidal AI exemestane and the progestin megestrol acetate. The widening range of adjuvant endocrine options therefore represents an opportunity to prolong patient benefits in the treatment of hormone receptor-positive breast cancer, and will require the further refinement of the optimal sequence of endocrine agents for the treatment of recurrent breast cancer.     

早期乳腺癌保乳术后放化疗的最佳顺序

目的 探讨早期乳腺癌保乳治疗后放化疗最佳顺序，使保乳治疗的局部控制、远处转移和保乳效果达到最佳。方法 2000年1月～2002年11月，对38例符合保乳治疗条件的早期乳腺癌实施了保乳治疗。手术方式为局部广泛切除术和腋窝淋巴结清扫，术后2周开始化疗，化疗2周期后再开始放疗，全乳剂量50Gy，瘤床补充照射10～18Gy。放疗结束后根据使用化疗方案选择立即化疗或休息1周后再开始化疗，化疗共6周期。治疗结束后每3个月复查1次，放疗后6个月行乳房钼靶摄影。此后1年1次乳房照片检查。结果 38例保乳治疗的患者均定期复查，中位随访24个月(5～35个月)。未发现局部复发和远处转移。放疗后1年或以上的28例患者乳房外观良好。结论 早期乳腺癌保乳治疗中“三明治”式放化疗能满足保乳治疗的目的。     

Primary chemotherapy for early breast cancer

The use of primary chemotheraphy represents a novel approach being used with increasing frequency in the management of early breast cancer. Many studies now testify to the usefulness of this modality in increasing the frequency of breast conservation. The acceptance of high-risk breast cancer as a systemic, and therefore predominantly medical rather than a surgical, disease suggests, however, that its role is likely to be far more reaching. While some trials have so far suggested the possibility of a survival benefit for this approach, definitive conclusions are not yet possible and await the final mature results from several large randomized studies. Even if such studies do not show a large extra benefit for primary chemotheraphy over existing adjuvant treatment, the use of the primary tumour as an in vivo model of individual chemosensitivity and the identification of molecular markers as early predictors of response, suggest that this approach will become an integral part of the modern multidisciplinary management of early breast cancer.     

Conservation treatment intensified with tamoxifen and CAF chemotherapy without axillary dissection for early breast cancer patients with clinically-negative axillary nodes.

Axillary node dissection has been a routine part of breast cancer treatment for more than 100 years. As so few patients have been shown to have positive nodes, more consideration should be given to eliminating axillary node dissection for duct carcinoma in situ (DCIS) and T1a lesions. And for patients with a T1/2N0M0 cancer of the breast, lumpectomy alone without axillary dissection followed by radiation therapy to the intact breast and regional lymph nodes should be a reasonable treatment method that avoids arm morbidity. Between September 1989 and December 1998, we treated 79 breast cancer patients with this method intensified with tamoxifen and CAF chemotherapy. Before the start of the therapy, we performed a thorough evaluation using helical CT and doppler ultrasonography to exclude patients with significant swelling of axillary lymph nodes (more than 5 mm in short diameter). Through the end of December 1998, the mean follow-up period was 52.6 months. Up to this date, only one patient of the 79 showed local recurrence within 5 years after the start of the treatment. This patient received a second lumpectomy. She then experienced lung metastases 6 months later. She is currently receiving combined chemotherapy with docetaxel and cisplatin. The cause-specific survival rate of these 79 patients maintained 100% at 6 years, and no axillary failure has been experienced so far. The cosmetic results in 50 (65.8%) of the 76 patients who were alive at the end of December 1998 were rated as excellent, 26 (34.2%) as good, and none as fair or poor. Therefore, we have concluded that this method of treatment for early breast cancer could eliminate surgical damage and allow good cosmetic results, and that survival rates with this treatment are excellent.     

Serum lipid levels during and after adjuvant toremifene or tamoxifen therapy for breast cancer

Tamoxifen decreases serum cholesterol (S-cholesterol) level about 10% and low-density lipoprotein cholesterol (S-LDL) 15–20%, but in most studies it has increased serum triglyceride levels and had little effect on serum high-density cholesterol (S-HDL). The effect of another antiestrogen, toremifene, on the serum lipid profile has not been completely studied. We monitored serum lipid levels longitudinally in 141 axillary node-positive postmenopausal breast cancer patients who received randomly either 40mg toremifene or 20mg tamoxifen as adjuvant therapy for 36 months, and in 34 postmenopausal women who received no adjuvant systemic therapy after surgery for axillary node-negative breast cancer. No significant differences were found between the drugs in their effects on S-cholesterol, LDL, HDL, or triglyceride levels, or on the cholesterol-to-HDL or LDL-to-HDL ratios. For both drugs the S-cholesterol and S-LDL absolute lowering effect was the greater the higher the pretreatment level. For a patient with a median pretreatment value, toremifene decreased S-cholesterol 6% and tamoxifen 13%, and S-LDL decreased by 13% and 23%, respectively, at 6 months of therapy. Six months after stopping three-year antiestrogen therapy S- cholesterol and S-LDL levels had returned to the pretreatment levels. In conclusion, we found no major differences between 40mg toremifene and 20mg of tamoxifen in their effect on the serum lipid levels, which return to the pretreatment levels within 6 months after cessation of therapy.     

Optimum anthracycline-based chemotherapy for early breast cancer

Adjuvant chemotherapy improves the overall survival of women treated after surgery for early breast cancer. Several trials have suggested that anthracycline-containing regimens are more effective than those that do not contain anthracyclines. A modest overall benefit has also been confirmed by the Early Breast Cancer Trialists' Collaborative Group overview. Newer agents, such as the taxanes, are now being tested in the adjuvant setting in randomised trials. The control group of such studies should receive the optimum standard treatment. There are several anthracycline-based regimens in common use, varying in terms of the type of anthracycline used, the dose, and drug scheduling. We review the available evidence and consider whether the optimum anthracycline-containing chemotherapy schedule has now been identified.     

Lumpectomy plus tamoxifen or anastrozole with or without whole breast irradiation in women with favorable early breast cancer

PURPOSE: In women with favorable early breast cancer treated by lumpectomy plus tamoxifen or anastrazole, it remains unclear whether whole breast radiotherapy is beneficial. METHODS AND MATERIAL: Between January 1996 and June 2004, the Austrian Breast and Colorectal Cancer Study Group (ABCSG) randomly assigned 869 women to receive breast radiotherapy +/- boost (n = 414) or not (n = 417) after breast-conserving surgery (ABCSG Study 8A). Favorable early breast cancer was specified as tumor size <3 cm, Grading 1 or 2, negative lymph nodes, positive estrogen and/or progesterone receptor status, and manageable by breast-conserving surgery. Breast radiotherapy was performed after lumpectomy with 2 tangential opposed breast fields with mean 50 Gy, plus boost in 71% of patients with mean 10 Gy, in a median of 6 weeks. The primary endpoint was local relapse-free survival; further endpoints were contralateral breast cancer, distant metastases, and disease-free and overall survival. The median follow-up was 53.8 months. RESULTS: The mean age was 66 years. Overall, there were 21 local relapses, with 2 relapses in the radiotherapy group (5-y rate 0.4%) vs. 19 in the no-radiotherapy group (5.1%), respectively (p = 0.0001, hazard ratio 10.2). Overall relapses occurred in 30 patients, with 7 events in the radiotherapy group (5-y rate 2.1%) vs. 23 events in the no-radiotherapy group (6.1%) (p = 0.002, hazard ratio 3.5). No significant differences were found for distant metastases and overall survival. CONCLUSION: Breast radiotherapy +/- boost in women with favorable early breast cancer after lumpectomy combined with tamoxifen/anastrazole leads to a significant reduction in local and overall relapse.     

Risk of second primary cancer after breast cancer treatment

Technological advances in both diagnosis and treatment of breast cancer lead to early detection and better treatment management. Consequently, the population of long‐term survivors is on the rise. The risk of developing second cancers among breast cancer survivors was shown to be higher than that for the general population. The aim of this work was to review the literature on the risk of second primary cancer (SPC) after breast irradiation. Pubmed search of population‐based studies on SPC after breast irradiation was conducted and the findings (in terms of Standardised Incidence Ratio) were collated and discussed. Several studies confirmed the link between breast tumour irradiation and risk of SPC, showing a small, but valid risk. There are, however, confounding factors that can either underestimate or overestimate risks: misclassification of tumour status, genetic inheritance, smoking, environmental factors, and the lack of accurate data in cancer registries. While isolating these potential triggers might be difficult, this approach would allow better discernability between radiotherapy‐related risks and those generated by other factors. It is also important to evaluate the current status of treatment‐related late effects and to lower such risks by minimising the dose delivered to normal tissues.     

Pyomyositis after chemotherapy for breast cancer

Pyomyositis is a rare complication of chemotherapy. A 47-year-old woman with metastatic breast cancer, in whom pyomyositis developed after chemotherapy, is described. It was difficult to differentiate between pyomyositis and deep venous thrombosis early in her admission. Pyomyositis should be considered part of the differential diagnosis of deep venous thrombosis. This infection, after chemotherapy, usually is considered to be caused by neutropenia or immunodeficiency secondary to the cancer, or both. It is postulated that subclinical myopathy, secondary to the malignancy or drugs used in treating the malignancy, or both, may also predispose to pyomyositis.