Neoadjuvant tamoxifen for hormone-sensitive non-metastatic breast carcinomas in early postmenopausal women.

BACKGROUND: From 1984 to 1996, 1581 postmenopausal women aged 50-70 years old were treated at Institut Bergonié for an infiltrative non-metastatic breast carcinoma with a positive estrogen and/or progesterone receptor determination. PATIENTS AND METHODS: Among them, 199 were treated with first line tamoxifen. Ninety-seven had operable disease (T2 >30 mm, T3, N0/1) and 102 had T4 tumours. RESULTS: After a mean treatment duration of 5.3 months, 89 T2 and T3 (92%) and 93 T4 (91%) were treated by surgery (conservative or not) with or without irradiation, or by irradiation alone. Conserving treatment levels were 53.6% and 44%, respectively. The other women were treated with either second-line chemotherapy or another hormonotherapy; the remaining patients continued regularly with tamoxifen. Overall survival is analysed with a 83 month median follow-up. CONCLUSIONS: A comparison between neoadjuvant endocrine therapy and surgery seems feasible to assess the concept of neoadjuvant hormonotherapy.     

Birth weight is associated with postmenopausal breast cancer risk in Swedish women

There is some evidence that birth weight is associated with breast cancer. Whether this association differs between premenopausal and postmenopausal ages is still unclear. The results from this study suggest that higher birth weight is a risk factor for postmenopausal breast cancer (OR 1.06, CI 1.00-1.12, per 100 g), independent of selected early-life and adult factors.     

第三代芳香化酶抑制剂在乳腺癌术后辅助治疗中的应用进展

近年来,第三代芳香化酶抑制剂应用于绝经后乳腺癌的辅助治疗,取得了令人鼓舞的结果,从而对他莫昔芬在乳腺癌辅助治疗中的地位提出了挑战。第三代芳香化酶抑制剂,特别是阿那曲唑有可能首先代替他莫昔芬成为绝经后妇女乳腺癌的新的标准辅助治疗药物。本文就近年来芳香化酶抑制剂的研究进展作一介绍和评述。     

Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis

One hundred fiftyone postmenopausal women with progressive metastatic breast cancer and no prior hormonal therapy were treated with either diethylstilbestrol (DES) or tamoxifen (TAM). One hundred fortythree eligible patients were followed until death or for a minimum of 14.1 years on the DES arm or 16.7 years on the TAM arm. The overall objective response was 42% for DES and 33% for TAM (p=0.31) and the median duration of response was 11.8 months for DES and 9.9 months for TAM (p=0.38). Duration of response and progressionfree survival were not found to be significantly different between DES and TAM (p=0.32 and 0.65, respectively). The median survival was 3.0 years for DES vs. 2.4 years for TAM. The 5year survival was 35% for the DES arm and 16% for the TAM arm. Survival was significantly better for women on DES than for women on TAM (adjusted p=0.039). Review of records did not show any difference in pattern of treatment failure or subsequent treatments in the DES and TAM arms.Treatment with DES was more commonly associated with toxicity such as nausea, edema, vaginal bleeding, and cardiac problems, whereas hot flashes were commonly seen with TAM therapy.The initial treatment with DES is associated with increased survival. The basis of this survival advantage is not known. TAM still is the preferred agent in the treatment of metastatic breast cancer, but this trial underscores the fact that estrogens have activity and remain in the armamentarium for treatment of selected patients with metastatic breast cancer.     

A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer

Efficacy and safety of toremifene 60 and 240mg daily (TOR60 and TOR240) are compared to40 mg tamoxifen daily (TAM40) in postmenopausal womenwith advanced estrogen receptor (ER) positive or ERunknown breast cancer. The study is randomized andopen label in three parallel groups. Primary efficacyvariables are response rate and time to progression.WHO and ECOG criteria were used for measurableand nonmeasurable disease assessment, respectively. Safety was reportedaccording to WHO criteria. Altogether 463 patients wererandomized (157 to TOR60, 157 to TOR240, and149 to TAM40). By data cut-off, after 20.5months median follow-up time, over 70% of thepatients had experienced disease progression. Response rates are20.4%, 28.7%, and 20.8% in TOR60, TOR240, andTAM40, respectively. TOR60 and TAM40 show statistically equivalentefficacy and the difference between TOR240 and TAM40is not significant (P=0.112). Median timesto progression are 4.9 (TOR60), 6.1 (TOR240), and5.0 (TAM40) months and the corresponding hazard ratios(TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40are statistically equivalent and the difference between TOR240and TAM40 is not significant (P=0.374).All treatments were well tolerated. As a conclusion,TOR60 and TAM40 show equivalent clinical efficacy andtolerability. The higher dose of toremifene slightly butnot statistically significantly improves response rate and timeto progression. In postmenopausal women, toremifene 60 mgdaily is an effective and safe treatment ofadvanced ER-positive or ER-unknown breast cancer.     

Different types of postmenopausal hormone therapy and mammographic density in Norwegian women

Postmenopausal hormone therapy (HT) is associated with increased risk of breast cancer. The HTs used in Scandinavia is associated with higher risk estimates than those used in most other countries. Mammographic density is one of the strongest risk factors for breast cancer, and possibly an intermediate marker for breast cancer. We decided to examine the relationship between use of different types of HT and mammographic density in Norwegian women. Altogether, 1,007 postmenopausal participants in the governmental mammographic screening program were asked about current and previous HT use. Mammograms were classified according to percent and absolute mammographic density. Overall, current users of HT had on average 3.6% higher mean percent mammographic density when compared with never users (p < 0.001). After adjustment for age at screening, number of children and BMI in a multivariate model, women using the continuous estradiol (E(2)) plus norethisterone acetate (NETA) combination had a mean percent mammographic density significantly higher than never users (6.1% absolute difference). Those using the continuous E(2) plus NETA combination had an 4.8% (absolute difference) higher mean percent mammographic density after <5 years of use when compared with never users, while the corresponding number for >or=5 years of use was 7% (p-trend < 0.001). We found similar associations when absolute mammographic density was used as the outcome variable. In summary, our study shows a statistical significant positive dose-response association between current use of the continuous E(2) plus NETA combination and both measures of mammographic density.     

Patterns of failure in a randomized trial of adjuvant chemotherapy in postmenopausal patients with early breast cancer treated with tamoxifen.

BACKGROUND: We studied the effect of adjuvant anthracycline-based chemotherapy in postmenopausal patients with resected early breast cancer treated with adjuvant tamoxifen. PATIENTS AND METHODS: The trial included 835 patients with either axillary lymph node involvement, or tumors with histological grade II or III. They were randomized after local surgery to receive either tamoxifen (TAM group) or tamoxifen plus chemotherapy (TAM-CT group) consisting of six courses of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), or 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC). Radiotherapy was given after completion of adjuvant chemotherapy in the TAM-CT group and after surgery in the TAM group. RESULTS: The 5-year disease-free survival (DFS) rates were 73% in the TAM group and 79% in the TAM-CT group (log-rank test, P = 0.06). The 5-year overall survival rates were 82% and 87%, respectively (P = 0.06). The 5-year distant metastasis rates were 22% and 16% (P = 0.02), and the 5-year local recurrence rates were 6% and 4%, respectively (P = 0.23). There were no significant differences for contralateral breast cancer or other new primary malignancies. Chemotherapy tended to be more effective for patients who had tumors without estrogen receptors (trend test, P = 0.05). CONCLUSIONS: Anthracycline-based chemotherapy administered to postmenopausal patients receiving adjuvant tamoxifen gave a borderline significant benefit on overall and DFS, mainly by a reduction in distant metastases. Delaying radiotherapy after six courses of chemotherapy did not affect local control after up to 10 years of follow-up.     

Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer; A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N=94), the TAM+AG+H (N=83), and the TAM+FLU (N=81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p=0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are –9–19% and for TAM vs. TAM+FLU –4–25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM+FLU group, respectively (p=0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG+H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.     

Cost-effectiveness of switching to exemestane versus continued tamoxifen as adjuvant therapy for postmenopausal women with primary breast cancer

BACKGROUND: Sequential tamoxifen/exemestane therapy reportedly improves disease-free survival in women with primary breast cancer compared with continued tamoxifen therapy. The objective of the current study was to assess the cost-effectiveness of switching to exemestane after 2 to 3 years of tamoxifen versus continued tamoxifen in postmenopausal women with primary breast cancer for a total of 5 years of adjuvant therapy. METHODS: A Markov model based on the Intergroup Exemestane Study (IES) population compared switching to exemestane versus continued tamoxifen for 2.5 years of therapy and 5 years of postadjuvant therapy follow-up. Disease progression and hazards ratios (HR) for recurrence and survival were determined from datasets (IES and the Surveillance, Epidemiology, and End Results program of the National Cancer Institute) and from the published literature. An expert panel validated treatment patterns, outcomes, and resource utilization. Direct medical costs were included based on published sources. Cost-effectiveness ratios were determined, and extensive sensitivity analyses were conducted. RESULTS: Exemestane was found to be more effective than tamoxifen alone with regard to disease-free survival (2.6% absolute improvement), life-years gained (0.1028 LY), and quality-adjusted life-years gained (0.1195 QALY), at an additional cost of 2,889 Can dollars per person over 7.5 years. Incremental cost-effectiveness ratios were 28,119 Can dollars/LY gained and 24,185 Can dollars/QALY gained. The model was most sensitive to distant recurrence HR but was robust to variations in clinical, cost, and utility parameters. CONCLUSIONS: Switching to adjuvant exemestane after 2 to 3 years of tamoxifen is cost-effective in postmenopausal women with primary breast cancer.     

The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L).

BACKGROUND: The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L). PATIENTS AND METHODS: MA.17L is a substudy of MA.17, a randomized, double-blind, placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing approximately 5 years of prior adjuvant tamoxifen. Patients consenting to participate in this companion study had blood drawn and lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), triglycerides) evaluated at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial. RESULTS: Three hundred and forty seven women were enrolled in the study. The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months (P=0.049), in LDL cholesterol at 12 months (P=0.033) and triglycerides at 24 months (P=0.036). All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups. No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups. CONCLUSIONS: The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy.     

Femoral fractures in postmenopausal breast cancer patients treated with adjuvant tamoxifen

Summary The anti-estrogen tamoxifen is the prevalent endocrine treatment in postmenopausal breast cancer patients. However, nothing is known about the long-term effects of the drug on the skeleton as assessed by the occurrence of fractures.We investigated the occurrence of fractures of the femur in patients from a Danish Breast Cancer Cooperative Group (DBCG) trial initiated in 1977 by a linkage of data from the Danish National Registry of Patients with data from the DBCG registry. 1716 postmenopausal women with high-risk breast cancer were randomized to local radiotherapy with or without tamoxifen, 30 mg daily for 1 year.Fifty-one patients in the control group had one femoral fracture and 64 tamoxifen treated patients had one femoral fracture. Eleven patients in the control group had one trochanteric fracture compared to 27 patients in the tamoxifen group (logrank = 5.28, P = 0.022; hazard ratio = 2.12, 95% CL 1.12, 4.01).The results could not be explained by a longer survival in the tamoxifen group nor by bone metastases with pathological fractures.In conclusion, our study suggests that tamoxifen does not seem to offer protection against fractures in old age and may even increase the risk of fractures at particular sites. This hypothesis needs to be disproved or confirmed in other trials.     

The effect of clodronate and antioestrogens on bone loss associated with oestrogen withdrawal in postmenopausal women with breast cancer

In this study we report bone mineral density (BMD) changes during clodronate and antioestrogen treatment in women with breast cancer having discontinued hormone replacement therapy (HRT) at the time of operation compared to women who had not used HRT immediately before the operation. 61 postmenopausal women with operable breast cancer were treated with the adjuvant antioestrogen tamoxifen 20 mg or toremifene 60 mg daily for 3 years. All patients were randomized to clodronate (1.6 g daily orally) or control groups for 3 years. 23 patients had recently (recent users) and 38 never or not for at least 1 year before operation used HRT (non-users). BMD of lumbar spine and femoral neck were measured before antiresorptive therapy (antioestrogens and clodronate) and at 1, 2, 3 and 5 years thereafter. All patients were disease-free at the time of BMD measurements. Patients who had recently used HRT had more significant bone loss as compared to HRT non-users at 3 years in lumbar spine - 3.0% vs. + 1.2% (P< 0.001), but not in femoral neck - 0.4% vs. + 1.7% (P = 0.27). Adding 3-year clodronate treatment to antioestrogen therapy improved BMD marginally at 3 years: lumbar spine + 1.0% vs. -1.7% (P = 0.01) and femoral neck + 2.4% vs. -0.4% (P = 0.12). This was also seen at 5 years of follow-up, 2 years after termination of the antiresorptive therapy: HRT recent users vs. HRT non-users in lumbar spine -6.5% vs. +0.5% (P< 0.0001) and in femoral neck -4.8% vs. -1.5% (P = 0.38); and clodronate vs. controls in lumbar spine -1.0% vs. -3.2% (P = 0.06) and in femoral neck -0.1% vs. -5.2% (P = 0.001, respectively). The type of endocrine therapy (tamoxifen and toremifene) had no significant influence on BMD changes. We conclude from this study that postmenopausal women who have recently discontinued HRT experience more rapid bone loss than HRT non-users. Neither 3-year antioestrogen therapy alone nor antioestrogen together with clodronate could totally prevent the bone loss related to HRT withdrawal in lumbar spine, even though clodronate seemed to retard it.     

Elevated protein kinase C alpha expression may be predictive of tamoxifen treatment failure

We previously reported that stable transfection of protein kinase C alpha (PKCalpha) into T47D human breast cancer cells results in tamoxifen (TAM)-resistant tumour growth. Relevance of PKCalpha expression in clinical specimens was determined by comparing PKCalpha expression in tumours from patients exhibiting disease recurrence with patients remaining disease-free following TAM treatment. Our results suggest that PKCalpha expression may predict TAM treatment failure.     

Pharmacoeconomic analysis of adjuvant therapy with exemestane, anastrozole, letrozole or tamoxifen in postmenopausal women with operable and estrogen receptor-positive breast cancer

Objective To compare the efficiency of adjuvant therapy with aromatase inhibitors or with tamoxifen in postmenopausal women with operable breast cancer and positive estrogen receptors. Material and methods A cost-utility analysis was performed based on a Markov model, from the Spanish National Health Care System perspective, comparing the treatment with exemestane (EXE: 25 mg/day) or tamoxifen (TAM: 20 mg/day) after 2–3 years of monotherapy with TAM; anastrozole (ANA, 1 mg/day) or TAM (20 mg/day) without previous TAM therapy; and letrozole (LET: 2.5 mg/day) or placebo after 5 years of monotherapy with TAM. The follow-up of a hypothetical cohort of women starting treatment at 63 years of age was simulated during 10 and 20 years. The probabilities of transition between health states and quality adjusted life years (QALYs) were obtained from the literature, and the unit costs (∈ corresponding to 2004) from a Spanish database. Results After 10 and 20 years of follow-up, more QALYs per patient would be gained with the EXE scheme (0.230–0.286 and 0.566–0.708, respectively) than with ANA (0.114 and 0.285) and LET (0.176 and 0.474). The cost of gaining one QALY was lower with the EXE scheme (50,801–62,522 ∈ and 28,849–35,371 ∈ respectively) than with ANA (104,272 ∈ and 62,477 ∈) and LET (91,210 ∈ and 49,460 ∈). The result was stable for the cost per life-year gained (LYG) and in the sensitivity analysis. Conclusions The EXE scheme after TAM is more cost-effective than the ANA and LET schemes.     

Risk of early recurrence among postmenopausal women with estrogen receptor-positive early breast cancer treated with adjuvant tamoxifen

BACKGROUND: Adjuvant aromatase inhibitors (AIs), instead of or after tamoxifen, are effective in decreasing recurrence in postmenopausal women with estrogen receptor (ER)-positive breast cancer. An understanding of which patients are at risk of early recurrence while they are receiving tamoxifen may improve clinical decision making. METHODS: The patients who were included in this study were women aged >or= 50 years with early-stage, ER-positive breast cancer diagnosed between 1986 and 1999 and had been treated with tamoxifen. Characteristics of the patients with early recurrences (within 2.5 years of diagnosis), late recurrences (between 2.5 years and 5 years) and no recurrence within 5 years were compared. Logistic regression analyses were conducted to identify which groups were at risk of early recurrence. RESULTS: Among 3844 women, 304 women (7.9%) developed disease recurrence within 2.5 years. Higher than average rates of recurrence within 2.5 years were observed in cohorts with lymph node (N)-positive tumors (11.5%), grade 3 histology (14.3%), or low-positive ER levels, ie, 10-49 fmol/mg or 10%-20% staining (14.9%). In multivariate analyses, only pathologically N-positive tumors (1-3 vs 0 positive lymph nodes: odds ratio [OR], 1.6; 4-9 vs 0 positive lymph nodes: OR, 2.23 [P= .03]) and low-positive ER status (OR, 2.04; P= .01) were associated with recurrence within 2.5 years compared with recurrence between 2.5 years and 5 years. Other clinical and pathologic variables were not predictive of early recurrence. CONCLUSIONS: Subgroups of women with early ER-positive breast cancer may be identified who are at increased risk of recurrence within 2.5 years of diagnosis despite tamoxifen. It remains to be proven whether upfront AI therapy results in an advantage to these women.     

早期乳腺癌辅助内分泌治疗的原则与临床应用策略

辅助内分泌治疗早期乳腺癌大大提高了患者的长期生存率，业已成为激素受体阳性乳腺癌患者最重要的治疗手段。本文结合近年来的文献，对乳腺癌辅助内分泌的原则和策略作一介绍和评述。     

卡培他滨联合多西紫杉醇治疗转移性乳腺癌的临床观察

为了探讨卡培他滨和多西紫杉醇联合方案治疗转移性乳腺癌的疗效及不良反应,29例转移性乳腺癌患者接受卡培他滨和多西紫杉联合方案化疗。卡培他滨2·0g/m2,d1~d14;多西紫杉醇35mg/m2,d1、d8、d15。21d重复,化疗2个周期以上。结果示29例患者入选,2例出组,27例可供评价疗效,29例可评价不良反应。有效率为51·9%(14/27),获益率为88·9%(24/27);主要不良反应为手足综合征、皮肤色素沉着、白细胞减少、血小板减少、血红蛋白降低、恶心呕吐、口腔炎、腹泻、肝功能损害、脱发、心脏毒性、末梢神经毒性、过敏反应等。初步研究结果提示,对蒽环类药物和(或)紫杉醇治疗失败的转移性乳腺癌,卡培他滨联合多西紫杉醇是一种新的选择方案。     

Insights on adjuvant endocrine therapy for premenopausal and postmenopausal breast cancer

In 2005, cancer accounted for 13% of all deaths worldwide. Breast cancer is the number-one cause of cancer-related death among women in the USA, affecting 178,480 of them in 2007. As 75% of tumors in postmenopausal women and half in premenopausal women express estrogen receptor, endocrine therapy plays a significant role as a systemic treatment. Robust datasets have demonstrated the impact of tamoxifen in reducing breast cancer recurrence and mortality, regardless of the age of the patient. Other estrogen-deprivation strategies, such as aromatase inhibitors in postmenopausal women and luteinizing hormone-releasing hormone agonists in premenopausal women, are being increasingly used for estrogen receptor-positive breast cancer. This review discusses basic principles regarding endocrine therapy, the need for accurate estrogen receptor testing and the role of menopause in therapy selection.