The impact of bilateral breast cancer on the prognosis of breast cancer: a comparative study with unilateral breast cancer

BACKGROUND: The clinical significance of bilateral breast cancer is unclear and its influence on prognosis is controversial. We assessed the impact of synchronous and metachronous bilateral breast cancer on the prognosis compared with unilateral breast cancer. METHODS: Between January 1, 1960 and December 31, 2001, 1,214 women were treated for primary operable breast cancers. Thirteen (1.1%) had synchronous bilateral breast cancer; 33 (2.7%) had a metachronous contralateral breast cancer. We compared age at operation, menopausal status, clinical stage, tumor size and histology, lymph node status, hormone receptor status, and use of adjuvant chemotherapy or hormone therapy, and we analyzed the impact of these factors on recurrence and survival in the 46 patients with bilateral breast cancer and the 1,168 patients with unilateral breast cancer. RESULTS: The 5-and 10-year disease-free survival rates, respectively, were 65% and 65% in metachronous cases, 85.7% and 64.3% in synchronous cases, and 77.9% and 72.1% in unilateral cases. There was no significant difference in overall survival among the three groups. On multivariate analysis, metachronous bilaterality, tumor size, lymph node status and adjuvant hormone therapy were each independent risk factors for recurrence, whereas bilaterality of breast cancer did not influence overall survival. CONCLUSIONS: Our data suggest that metachronous bilateral breast cancer is associated with shorter disease-free survival than synchronous bilateral or unilateral breast cancer, although overall survival does not differ among the 3 groups. Patients with metachronous bilateral breast cancer should be followed particularly closely in order to detect recurrence early and maximize quality of life.     

Long-term effects of adjuvant tamoxifen and/or radiotherapy. The South Sweden Breast Cancer Trial.

In a multicenter trial of adjuvant therapy in stage II breast cancer, 719 postmenopausal patients were randomized to one of three treatment regimens: radiotherapy only or in combination with adjuvant tamoxifen for one year, or adjuvant tamoxifen without radiotherapy. At twelve years of follow-up (median 9 years), no statistically significant differences in survival or recurrence-free survival were observed. However, the rate of loco-regional recurrency was lower among patients treated with both radiotherapy and tamoxifen. The rate of bilateral breast cancer was reduced in tamoxifen-treated patients whereas the rate of new primary malignancies other than breast cancer was somewhat higher in tamoxifen-treated patients. Adjuvant therapy in breast cancer may influence not only breast cancer recurrences and mortality but also later disease patterns and cause-specific mortality.     

Survival in bilateral breast cancer

The presence of bilateral invasive breast cancer places the patient in a state of double jeopardy. At Memorial Sloan-Kettering Cancer Center, the overall 10-year recurrence rate for unilateral Stage I breast cancer was 16%, whereas the recurrence rate for simultaneous, bilateral Stage I breast carcinoma was 29%: almost twice as high. The average 10-year survival of all patients with negative axillary nodes was 57%. In this retrospective analysis of 403 patients with bilateral primary operable breast cancer treated at Memorial Sloan-Kettering Cancer Center, significant differences were noted in the disease-free survival between patients with bilateral noninvasive cancer, bilateral invasive cancer, and the combination of invasive and in situ cancers. Bilateral intraductal cancer and lobular carcinoma in situ offered an excellent prognosis. The combination of preinvasive cancer on one side and infiltrating carcinoma on the other had the next best survival. The in situ lesion, when treated by mastectomy, did not alter the patients' life expectancy from that of the general population with unilateral breast cancer, thus indicating that surgeons should strive to detect breast cancer in its preinvasive form. The 5- and 10-year relapse-free survival of patients with bilateral invasive disease, regardless of axillary nodal status and tumor size, was 60% and 51%, respectively, for patients with a bilateral presentation and 54% and 38%, respectively, for carcinomas presenting metachronously. More important in determining prognosis, however, was the number of axillary nodes involved and the level of involvement. Invasion of bilateral axillary nodes at all levels predicted a poor prognosis. Because of this shortened survival, systemic adjuvant therapy should be considered for patients with bilateral invasive disease. The most common preinvasive breast cancer was lobular carcinoma in situ and the most frequently invasive tumor was infiltrating duct cancer. Since a contralateral breast cancer at the time of definitive treatment of the first side does not always present as a mass or with positive mammography, a random biopsy of the second breast is recommended. This should be done in the upper, outer quadrant and should include the subareolar area. With prompt adequate treatment, it is expected that survival from bilateral breast cancer should improve.     

Microtubule-associated protein-tau is a bifunctional predictor of endocrine sensitivity and chemotherapy resistance in estrogen receptor-positive breast cancer.

PURPOSE: The clinical outcome for patients with breast cancer is influenced by the metastatic competence of the cancer and its sensitivity to endocrine therapy and chemotherapy. A molecular marker may be prognostic of outcome or predictive of response to therapy, or a combination of both. EXPERIMENTAL DESIGN: We examined separately the prognostic and predictive values of tau mRNA expression in estrogen receptor (ER)-positive primary breast cancers in three patient cohorts. We used gene expression data from 209 untreated patients to assess the pure prognostic value of tau, data from 267 patients treated with adjuvant tamoxifen to assess predictive value for endocrine therapy, and data from 82 patients treated with preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide (paclitaxel/FAC) to assess predictive value for chemotherapy response. Wilcoxon rank sum test was used to compare tau expression between different outcome groups. RESULTS: Higher tau mRNA expression showed borderline nonsignificant association with better prognosis in the absence of systemic adjuvant therapy. Higher tau mRNA expression was significantly associated with no recurrence (at 5 and 10 years, P = 0.005 and P = 0.05, respectively) in patients treated with tamoxifen, indicating a predictive value for endocrine therapy. Tau expression was significantly lower in patients who achieved pathologic complete response to paclitaxel/FAC chemotherapy (P < 0.001). CONCLUSION: This study suggests that high tau mRNA expression in ER-positive breast cancer indicates an endocrine-sensitive but chemotherapy-resistant disease. In contrast, low tau expression identifies a subset of ER-positive cancers that have poor prognosis with tamoxifen alone and may benefit from taxane-containing chemotherapy.     

Current status of endocrine therapy for breast cancer

Endocrine therapy is usually indicated prior to chemotherapy as the first line therapy for metastatic breast cancer patients because of its milder toxicity. Patients who respond to a first-line endocrine therapy have a high chance of responding to a second-line endocrine therapy, and thus the responders to a first-line endocrine therapy would better be treated with second or third-line endocrine therapy. In the adjuvant setting, tamoxifen (antiestrogen) has been proven to improve the prognosis of both pre- and postmenopausal estrogen receptor positive breast cancer patients, and goserelin (LH-RH agonist) has been proven to improve prognosis in premenopausal women comparable to chemotherapy (CMF). Very recently, preliminary results have indicated that anastrozole (aromatase inhibitor) is superior to tamoxifen as adjuvant treatment for estrogen receptor positive postmenopausal breast cancer patients. In addition, the recent success of tamoxifen in a chemoprevention trial seems to have ushered in a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer.     

Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer.

BACKGROUND: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. METHODS: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. RESULTS: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ER-positive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P<.0001). CONCLUSIONS: Tamoxifen use appears to decrease the risk of ER-positive contralateral breast tumors, but it appears to increase the risk of ER-negative contralateral tumors.     

Contralateral primary tumors in breast cancer patients in a randomized trial of adjuvant tamoxifen therapy

Prophylactic treatment with the anti-estrogen tamoxifen may reduce the risk of breast cancer because estrogens are thought to act as promoters in the pathogenesis of the disease. This article presents results on the incidence of contralateral new primary tumors among 1846 postmenopausal breast cancer patients included in a randomized trial of adjuvant tamoxifen therapy for 2 or 5 years after surgery versus no adjuvant endocrine therapy. The median follow-up was 7 years (range, 3-13 years). There was a significant reduction of contralateral breast cancer in the 931 patients in the tamoxifen group versus that in the 915 control patients (29 versus 47 cases, respectively; P = .03). The cumulative incidence at 10 years in the tamoxifen group and the control group was 5% and 8%, respectively. Analysis of the relative hazard of contralateral tumor over time showed that the benefit with tamoxifen therapy was greatest during the first 1-2 years, but there was a continued risk reduction during the entire follow-up period, i.e., more than 10 years after cessation of treatment. There was no significant difference in the number of contralateral cancers in the patients randomly assigned to 2 or 5 years of treatment, but the 95% confidence interval of the relative hazard was wide. The proportion of estrogen receptor-negative contralateral breast cancers was higher in the tamoxifen group than in the control group. There was no difference, however, between the two groups in recurrence-free survival time from the diagnosis of the contralateral cancer.(ABSTRACT TRUNCATED AT 250 WORDS)     

The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy

Purpose To assess the benefit from adjuvant systemic tamoxifen therapy in breast cancer risk groups identified by the previously established prognostic 76-gene signature. Methods In 300 lymph node-negative (LNN), estrogen receptor-positive (ER+) breast cancer patients (136 treated with adjuvant tamoxifen, 164 having received no systemic adjuvant therapy), distant metastasis-free survival (DMFS) as a function of the 76-gene signature was determined in a multicenter fashion. Results In 136 tamoxifen-treated patients, the 76-gene signature identified a group of patients with a poor prognosis [hazard ratio (HR), 4.62; P = 0.0248]. These patients showed a 12.3% absolute benefit of tamoxifen in 10-year DMFS (HR, 0.52; P = 0.0318) compared with untreated high-risk patients. This represented a 71% increase in relative benefit compared with the 7.2% absolute benefit observed for all 300 patients without using the gene signature. In the low-risk group there was no significant 10-year DMFS benefit of tamoxifen. Conclusions The 76-gene signature defines high-risk patients who benefit from adjuvant tamoxifen therapy. Although we did not study the value of chemotherapy in this study, low-risk patients identified by the 76-gene signature have a prognosis good enough that chemotherapy would be difficult to justify. The prognosis of these patients is sufficiently good, in fact, that a disease-free benefit for tamoxifen therapy is difficult to prove, though benefits in terms of loco-regional relapse and a reduction in risk for contralateral breast cancer might justify hormonal therapy in these patients.     

Second cancers after conservative surgery and radiation for stages I-II breast cancer: identifying a subset of women at increased risk

PURPOSE: To assess the risk and patterns of second malignancy in a group of women treated with conservative surgery and radiation in a relatively contemporary manner for early-stage invasive breast cancer, and to identify a subgroup of these women at increased risk for a second cancer. METHODS AND MATERIALS: From 1978 to 1994, 1,253 women with unilateral Stage I-II breast cancer underwent wide excision, axillary dissection, and radiation. The median follow-up was 8.9 years, with 446 patients followed for >or= 10 years. The median age was 55 years. Sixty-eight percent had T1 tumors and 74% were axillary-node negative. Radiation was directed to the breast only in 78%. Adjuvant therapy consisted of chemotherapy in 19%, tamoxifen in 19%, and both in 8%. Factors analyzed for their association with the cumulative incidence of all second malignancies, contralateral breast cancer, and non-breast cancer malignancy were: age, menopausal status, race, family history, obesity, smoking, tumor size, location, histology, pathologic nodal status, region(s) treated with radiation, and the use and type of adjuvant therapy. RESULTS: One hundred seventy-six women developed a second malignancy (87 contralateral breast cancers at a median interval of 5.8 years, and 98 non-breast cancer malignancies at a median interval of 7.2 years). Nine women had both a contralateral breast cancer and non-breast cancer second malignancy. The 5- and 10-year cumulative incidences of a second malignancy were 5% and 16% for all cancers, 3% and 7% for contralateral breast cancer, 3% and 8%, for all second non-breast cancer malignancies, and 1% and 5%, respectively, for second non-breast cancer malignancies, excluding skin cancers. Patient age was a significant factor for contralateral breast cancer and non-breast cancer second malignancy. Young age was associated with an increased risk of contralateral breast cancer, while older age was associated with an increased the risk of a second non-breast cancer second malignancy. A positive family history increased the risk of contralateral breast cancer, but not non-breast cancer malignancies. The risk of a contralateral breast cancer increased as the number of affected relatives increased. Tamoxifen resulted in a nonsignificant decrease in contralateral breast cancer and an increase in non-breast cancer second malignancies. The 5-and 10-year cumulative incidences for leukemia and lung cancer were 0.08% and 0.2%, and 0.8% and 1%, respectively. There was no significant effect of chemotherapy or the regions treated with radiation on contralateral breast cancer or non-breast cancer second malignancy. The most common types of second non-breast cancer malignancies were skin cancers, followed by gynecologic malignancies (endometrial), and gastrointestinal malignancies (colorectal and pancreas). CONCLUSION: The 10-years cumulative incidence of a second cancer in this study was 16%. Young age and family history predicted for an increased risk of contralateral breast cancer, and older age predicted for an increased risk of non-breast cancer malignancy. The majority of patients treated with conservative surgery and radiation with or without adjuvant systemic therapy will not develop a second cancer. Long-term follow-up is important to document the risk and patterns of second cancer, and knowledge of this risk and the patterns will influence surveillance and prevention strategies.     

Evolving perspectives in contralateral breast cancer

Despite extensive publications reviewing contralateral breast cancer (CBC), the role of screening and preventative measures for contralateral tumours is controversial and optimal clinical management remains undefined. This paper addresses the incidence, the predisposing factors, the prevention and the treatment of bilateral breast cancer based on a review of the literature. Risk factors for CBC include young age at primary breast cancer diagnosis, hereditary breast cancer (due to a germline mutation), familial breast cancer (one or more affected relatives), radiation exposure at a young age, lobular carcinoma in situ (LCIS), lobular invasive carcinoma and multicentricity. Retrospective studies suggest that contralateral mammographic surveillance results in the early detection of breast cancer, but no clear survival benefit has been demonstrated. Trials of adjuvant tamoxifen in breast cancer patients have shown a reduction in the incidence of CBC in both pre- and postmenopausal women. In addition, breast cancer patients treated with ovarian ablation and prednisone have significantly reduced CBC versus controls. In patients with primary breast cancer there is no evidence that contralateral breast biopsies or contralateral prophylactic mastectomy reduce mortality. Randomised, prospective trials to determine optimal surveillance, prevention and treatment strategies for the contralateral breast in breast cancer patients have not been conducted. Based on the published literature, contralateral breast surveillance in breast cancer patients reasonably includes breast self-examination, regular physical examinations and annual mammography. In women who have no evidence of distant metastasis at the time of CBC diagnosis, we recommend that the CBC be treated in the same manner as a first breast cancer, taking into account prior local and systemic therapy.     

Is It Contralateral Axillary Metastasis or Occult Breast Cancer?: A Confusing Case Report

We report the case of a 43-year-old woman with primary left breast cancer presenting metastatic lymphadenopathy in the contralateral axilla. This patient represents a diagnostic and therapeutic challenge because primary breast cancer, occult contralateral breast cancer, and extra-mammary primary lesion can all be the source of the contralateral axillary metastasis. Left breast-conserving surgery, left sentinel lymph node biopsy, right breast mass excision, and right axillary lymph node dissection were performed. Immunohistochemical analysis revealed that the left breast cancer specimen was positive for estrogen receptor (ER) and progesterone receptor (PR), but negative for human epidermal growth factor receptor 2 (HER2). In contrast, the right axillary lymphadenopathy specimen was negative for ER and PR, but positive for HER2. Further investigation revealed no evidence of occult primary cancers or extra-mammary tumors. After surgical intervention, the patient was treated with adjuvant chemotherapy, adjuvant radiation therapy, and targeted therapy with trastuzumab. Two years after diagnosis, she is free of disease and presently being treated with tamoxifen.Key Words: Breast carcinoma, Occult primary tumor, Contralateral axillary lymph node metastasis, Immunohistochemistry     

Long-term outcome of adjuvant chemotherapy cyclophosphamide, mitoxantrone, and fluorouracil in women with breast cancer

The aim of the study is to report the long-term outcome and secondary tumours of early breast cancer patients of adjuvant CNF (cyclophosphamide, mitoxantrone, and 5-fluorouracil) chemotherapy. One hundred and ninety four patients, 185 primary early breast cancer and nine locoregionally recurrent breast cancer patients, were entered onto the trial between May 1986 and November 1993. The therapies included surgery, radiation therapy, adjuvant CNF chemotherapy, and tamoxifen according to hormonal status. Some of patients were treated twice with CMF (methotrexate). The median follow-up time was 12.9 years. Eighty nine (48%) primary breast cancers relapsed, and six locoregional breast cancers relapsed. After 5-10 years the relapse incidence decreased notably. Eighty three patients died of breast cancer, and nine of other causes. Two cases of leukemia, six cases of skin cancer, two cases of Hodgkin's disease, two cases of meningioma, and two cases of endometrial cancer were observed. This article confirms the feasibility of adjuvant CNF for early breast cancer patients. Questions of possible causability of secondary cancer have yet to be explored.     

Adjuvant Tamoxifen

Tamoxifen is a synthetic, nonsteroidal agent that was initially considered as an estrogen antagonist, but is now appreciated as having mixed activity at the estrogen receptor. The Early Breast Cancer Trialists Collaborative Group meta-analysis of 30 000 users of adjuvant tamoxifen confirms its clear and consistent benefit in the treatment of breast cancer in 55 clinical trials. Tamoxifen also reduces the incidence of contralateral, second primary breast cancers by approximately half within the adjuvant treatment setting. A large body of evidence confirms the pro-estrogenic effect of tamoxifen upon the endometrium, particularly in the post-menopausal patient. Several different studies report a relative risk of about 2.5 for developing endometrial cancer associated with tamoxifen use. Although the risk of endometrial cancer with tamoxifen is real and significant, it carries a high incidence of low-grade disease and a very low risk of death, and demonstrates a risk/benefit profile strongly in favor of tamoxifen therapy for the vast majority of women with early breast cancer. Comparing tamoxifen users with non-users also shows an increase in the prevalence of cataracts by approximately 14%. Changes in the fasting lipid levels lend support to the hypothesis that tamoxifen may be cardioprotective, although no trials yet demonstrate this benefit with certainty. The effect of tamoxifen upon coagulation and the vascular endothelium appear to mirror those of estrogen, with a relative increased hypercoagulability suggested by an increased incidence of deep vein thrombosis and pulmonary embolism. Among women over the age of 50, tamoxifen increases the risk of stroke, raising concerns regarding the use of tamoxifen in women with a history of thrombosis. Factors predicting a negative effect of tamoxifen on overall quality of life include age, ethnicity, income, prior adjuvant chemotherapy, social support, mental health status, and physical functioning.     

Incidence and risk factors associated with bilateral breast cancer in area with early age diagnosis but low incidence of primary breast cancer: analysis of 10-year longitudinal cohort in Taiwan

Summary This study aims to examine the incidence and risk factors of bilateral breast cancer in area with low incidence rate. A total of 120 and 1902 women with bilateral and unilateral breast cancers were enrolled; various factors, including those concerning their medical history and life style, were extracted. Using Kaplan–Meier method, we calculate the cumulative incidence of contralateral breast cancer. The results show as follows. The cumulative incidences of contralateral breast cancer at 1, 3, 5 years after diagnosis of first breast cancer were 1.15, 1.94, and 2.97%, respectively. The statistically significant risk factors included menopause (Hazard Ratio (HR) =1.56, (1.00–2.42)), invasive lobular carcinoma (HR=2.98, (1.35–6.56)), receiving chemotherapy (HR=2.21, (1.43–3.42)) and/or radiotherapy (HR=3.32, (2.19–5.05) and a protective factor was tamoxifen therapy (HR=0.5 (0.34–0.74). Size of the second occurred tumour (2.97 cm) tended to be smaller than the first one (3.58 cm) with borderline statistical significance (p=0.0731). Comparing to the existing data on Western countries, we find a higher risk for developing contralateral breast cancer in Taiwan where a low incidence of first breast cancer rate with early age diagnosis is noted. It suggests that first primary breast tumour with early age of onset and lobular carcinoma are found more likely to develop bilateral breast cancers.Tony Hsiu-Hsi Chen and King-Jen Chang equally contributed to this article.     

乳腺癌长期辅助性三苯氧胺治疗

对６３例激素受体阳性乳腺癌长期辅助性三苯氧胺治疗的疗效、安全性及预防乳腺第二原发癌的作用回顾性分析。可评仨者６１例。总的５年生存率、无瘤生存率分别为６５．６％和５４．５％。小于５０岁、５０岁及以上，绝经前、后，腋淋巴结阳性及阴性者５年生存率分别为５５．７％、７７．８％，５０．３％、７９．１％，６３．６％和８０．０％（各组Ｐ＜０．０５）。１例子宫内膜呈不典型性增生，１例发生对侧乳腺第二原发癌（１．６％）。表明长期辅助性三苯氧胺治疗能提高５年生存率，安全可靠，可预防乳腺第二原发癌，但应警惕子宫内膜癌发生。     

Postoperative adjuvant chemotherapy followed by adjuvant tamoxifen versus nil for patients with operable breast cancer: a randomised phase III trial of the European Organisation for Research and Treatment of Cancer Breast Group

BackgroundThe contribution of adjuvant tamoxifen in breast cancer patients after receiving adjuvant chemotherapy is not fully established. We investigated the impact of tamoxifen, given sequentially after completion of adjuvant chemotherapy in patients with operable breast cancer.Patients and methodsBetween March 1991 and June 1999, 1863 women with stages I–IIIA operable breast cancer who had undergone surgery and completed six cycles of adjuvant combination chemotherapy with either CMF, CAF, CEF, FAC or FEC were randomised to receive either tamoxifen 20 mg daily for 3 years or no further treatment. Irrespective of menstrual status and hormone receptor content of the primary tumour, patients were stratified by institute, chemotherapy scheme and age (above 50 years or younger). The main end-point was to detect a 5% increase in the 5 year survival (from 80% to 85%) in favour of antioestrogen therapy. Secondary end-points were relapse free survival (RFS), local control, incidence of second primary breast cancer and correlation of results with hormone receptor content.ResultsAfter exclusion of all patients from three sites because of inadequate documentation, a total of 1724 patients (93%) were analysed (Tam 861 and Control 863). At a median follow-up of 6.5 years, 5-year RFS on tamoxifen was 73% versus 67% in controls (p = 0.035). No difference was seen in overall survival. The benefit of tamoxifen therapy was mainly seen in the subgroup of patients with histologically documented positive axillary nodes (5-year RFS on tamoxifen 71% versus 64% in the control group, p = 0.044) and in patients with tumours expressing the ER and PR positive phenotype (5-year RFS on tamoxifen 77% versus 70% in the control group, p = 0.014).ConclusionsTamoxifen administered for 3 years after completion of adjuvant chemotherapy in this otherwise unselected group of patients for endocrine sensitivity had a limited impact on relapse and had no detectable effect on overall survival. The beneficial effect of tamoxifen is mainly confined to the subgroup of patients with node-positive disease and to patients with tumours expressing the ER and PR positive phenotype.     

Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5.

PURPOSE: Effective adjuvant treatment modalities in premenopausal breast cancer patients today include chemotherapy, ovariectomy, and tamoxifen administration. The purpose of Austrian Breast and Colorectal Cancer Study Group Trial 5 was to compare the efficacy of a combination endocrine treatment with standard chemotherapy. PATIENTS AND METHODS: Assessable trial subjects (N = 1,034) presenting with hormone-responsive disease were randomized to receive either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Stratification criteria included tumor stage and grade, number of involved nodes, type of surgery, and steroid hormone receptor content. Relapse-free survival (RFS) was defined as time from randomization to first relapse, local recurrence, or contralateral incidence, and overall survival (OS) as time to date of death. RESULTS: With a 60-month median follow-up, 17.2% of patients in the endocrine group and 20.8% undergoing chemotherapy developed relapses. Local recurrences emerged in 4.7% and 8.0%, respectively. RFS and local recurrence-free survival differed significantly in favor of endocrine therapy (P =.037 and P =.015), with a similar trend observed in OS (P =.195). CONCLUSION: Overall, our data suggest that the goserelin-tamoxifen combination is significantly more effective than CMF in the adjuvant treatment of premenopausal patients with stage I and II breast cancer.     

Use of goserelin in the treatment of breast cancer

Gonadotropin-releasing hormone analogs are, alongside tamoxifen, one of the most commonly used drugs in the treatment of pre-/perimenopausal endocrine-responsive breast cancer. Goserelin, as a principal agent of this class of drugs, is mainly investigated in clinical trials. The indirect comparison of goserelin with tamoxifen as a single drug in the adjuvant setting showed similar efficacy. Furthermore, goserelin is as effective as cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy, and total endocrine blockade as a combination of gonadotropin-releasing hormone analog and tamoxifen showed a comparable benefit with anthracycline-containing adjuvant chemotherapy. Goserelin administered after cessation of chemotherapy leads to a further improvement and may be equieffective as tamoxifen or a combination of both. Data concerning taxane-based and dose-dense chemotherapy as well as combination of gonadotropin-releasing hormone analogs with third-generation aromatase inhibitors are still lacking (ongoing suppression of ovarian function, tamoxifen and exemestane, and premenopausal endocrine-responsive chemotherapy trials). Moreover, duration of therapy with gonadotropin-releasing hormone analogs (2–3 years or longer) is still a matter of debate. Palliative endocrine treatment is standard in the first-line therapy of patients without life-threatening disease and endocrine-responsive breast cancer. Treatment decisions depend upon adjuvant endocrine pretreatment. Clinical data regarding ovarian protection by synchronous use of gonadotropin-releasing hormone in young breast cancer patients receiving chemotherapy are incoherent.     

Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80%, and following the first diagnosis the 10-year risk of contralateral breast cancer is approximately 30%. It has been shown that both tamoxifen and oophorectomy prevent contralateral breast cancer, but it is not clear whether there is a benefit in giving tamoxifen to women who have previously undergone an oophorectomy. Furthermore, the relative degree of protection in BRCA1 and BRCA2 carriers has not been well evaluated. We studied 285 women with bilateral breast cancer and a BRCA1 or BRCA2 mutation, and 751 control women with unilateral breast cancer and a BRCA1 or BRCA2 mutation in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of breast cancer and had been followed for as long as the case for a second primary breast cancer. The history of tamoxifen use for treating the first breast cancer was compared between bilateral and unilateral cases. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 for carriers of BRCA1 mutations (95% CI, 0.30-0.85) and was 0.42 for carriers of BRCA2 mutations (95% CI, 0.17-1.02). The protective effect of tamoxifen was not seen among women who had undergone an oophorectomy (OR = 0.83; 95%CI, 0.24-2.89) but this subgroup was small. In contrast, a strong protective effect of tamoxifen was apparent among women who were premenopausal or who had undergone natural menopause (OR = 0.44; 95% CI, 0.27-0.65).     

The Increasing Use of Prophylactic Mastectomy in the Prevention of Breast Cancer

Selected high-risk women without breast cancer choose to undergo bilateral prophylactic mastectomy (BPM) to reduce their risk of developing the disease. Several studies have reported that BPM significantly reduces, but does not eliminate, breast cancer risk. Few studies have reported rates or trends of BPM use. Patients with unilateral breast cancer are at increased risk for developing cancer in the normal contralateral breast. Some breast cancer patients choose contralateral prophylactic mastectomy (CPM) to prevent cancer in the contralateral breast. The risk of contralateral breast cancer is significantly reduced after CPM. Recent studies reported that CPM rates have markedly increased in recent years in the United States. Alternatives to CPM include surveillance with clinical breast examination, mammography, and, potentially, breast MRI. Endocrine therapy with tamoxifen or aromatase inhibitors significantly reduces the risk of contralateral breast cancer and may be more acceptable than CPM for some patients.