Use Of Adjuvant Tamoxifen Research Articles

Abstract S1-7: Lack of Correlation between Gene Variants in Tamoxifen Metabolizing Enymes with Primary Endpoints in the ATAC Trial.

Abstract Background. A number of studies have provided widely heterogeneous results for and against the hypothesis that genetic variants in drug metabolizing enzymes can influence patient response to tamoxifen. Most of these studies are confounded by relatively small numbers of patients, lack of comprehensive genotype information, lack of detailed clinical outcome data, and patient selection biases. The ATAC trial was a prospective randomized double-blind placebo-controlled trial designed to compare the adjuvant use of anastrozole versus tamoxifen for 5 years. The trial's detailed efficacy and safety data, long term (10-year) follow-up and high number of events make it an ideal setting for pharmacogenetic analyses. Here we report our initial findings testing for correlations with SNPs in CYP2D6 and UGT2B7, the primary enzymes responsible for the presumed activation and inactivation of tamoxifen, respectively, with clinical outcomes including any disease recurrence, distant recurrence, and overall survival. Methods: CYP2D6 genotype data for the 7 most common alleles were used to assign each patient a ‘score’ based on predicted allele activities from 0 (no activity) to 2 (high activity). Patients were also tested for the UGT2B7*2 variant, which has lower enzymatic activity and has been shown to correlate with higher serum endoxifen concentrations. All genotype determinations were made without knowledge of the patient's treatment assignment or outcomes. Results: Comprehensive CYP2D6 genotype data were obtained on 588 and 615 patients randomized to receive tamoxifen, and anastrozole, respectively. After median 10 years of follow-up, there were 115 recurrences in the tamoxifen cohort. We found no associations between any of the CYP2D6 scores and rates of recurrence in tamoxifen treated patients. A test for trend across CYP2D6 scores was not significant. In the anastrozole cohort, there were 92 recurrences, and there was no evidence of an association between CYP2D6 score with rates of recurrence. Likewise, there was no detectable association in either the tamoxifen or anastrozole group with UGT2B7 genotype alone or in combination with CYP2D6 score. Concomitant SSRI usage was recorded in these patients and is being assessed for possible impact on these results. Conclusion: These data from a large prospective clinical trial, with detailed outcome data and long-term follow-up do not support the hypothesis that patient with decreased CYP2D6 enzymatic activity receive less benefit from tamoxifen therapy compared to wild-type CYP2D6 patients. Variants in drug targets and estrogen signaling pathways may be the genetic basis for patient variability in anti-estrogen risk versus benefit profiles. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-7.

Cost-effectiveness analysis of 5 years of postoperative adjuvant tamoxifen therapy for korean women with breast cancer: Retrospective cohort study of the korean breast cancer society database

Objective: This study aimed to evaluate the cost-effectiveness of postoperative adjuvant tamoxifen therapy using data from a Korean breast cancer registry. Methods: In this retrospective, observational cohort study, patients were selected from the Korean Breast Cancer Society database. Women with stage I, II, or III breast cancer (diagnosed between 1981 and 2005), for whom information about tamoxifen use (20 mg/d for 5 years) and estrogen-receptor and/or progesterone-receptor status was available, were included. Cost-effectiveness was calculated from the perspective of Korean society. Using a decision analytic model based on standard clinical flow, incremental cost-effectiveness ratios (ICERs) for overall survival were calculated with stratification by disease stage and hormone-receptor status. One-way sensitivity analyses were also conducted. All results were represented as US dollars (US $1 ≈ 1000 Korean won, in year-2005 values). Results: A total of 17,579 patients were included in the analysis (10,694 tamoxifen users, 6885 nonusers). Among those with stage I or II breast cancer, ICERs for estrogen-receptor positive (ER+)/progesterone-receptor positive (PR+) tamoxifen users ranged from $739 to $1939. Tamoxifen use among those with either ER+ or PR+ status (but not both) remained cost-effective: $1217 to $3107 for 1 life-year gained. However, among estrogen-receptor negative (ER−)/progesterone-receptor negative (PR−) patients, tamoxifen use was more expensive and associated with shorter survival, and most ICERs were negative values, except for those aged ≥50 years (ICERs ranged from −$462 to −$3738 for 1 life-year gained). In contrast to those with stage I or II disease, tamoxifen use among patients with stage III disease was cost-effective regardless of hormone-receptor status. However, because of the small sample size, further studies are needed. Conclusions: In this analysis, postoperative adjuvant tamoxifen use was cost-effective for stage I or II ER+ and/or PR+ breast cancer, but not for ER−/PR− disease. Tamoxifen therapy appeared to be cost-effective for patients with stage III breast cancer regardless of hormone-receptor status. Seoul National University Hospital identifier: C-0702-019-198.

Does hormone receptor (HR) positivity affect the prognosis in breast cancers with human epidermal growth factor receptor 2 (HER2) overexpression?

e22091 Background: Biologically, there is an unclear issue about the role of HR positivity in HER2 positive breast cancer. These HER2(+)/ HR(+) pts were grouped into luminal B type apart from HER2(+)/ HR(-) pts in molecular profiling. However, from the clinical point of view, these pts have been categorized and been treated as either the only HER2(+) disease regardless of HR status or vice versa. Thus, we investigated the impact of HR status on clinical outcomes in HER2-overexpressed breast cancers. Methods: We retrospectively reviewed medical charts of HER2-positive breast cancer pts who underwent curative surgical resection from 1996 to 2001 in the Severance hospital, Korea. Demographic comparisons were performed by Chi-square tests. Tumor size, nodal stage, TNM stage, HR status, and adjuvant tamoxifen use were included in the Cox proportional hazards model. Results: Among the total 174 HER2-positive pts, HR (n=93) was positive in 53.5% (n = 93) and HR-positive tumors were more likely to be premenopausal (73% v 52%; P=0.01) and well- differentiated (grade 1or 2; 77% v 62%; P=0.04). There were no significant differences according to HR status in terms of tumor size, nodal stage, TNM stage, operation methods, and chemotherapy regimen. In these HER2-positive pts, the 5-year disease free survival (DFS) was longer in HR(+) pts than in HR(-) pts (DFS; 82.9% v 61.5%; P= 0.01). In a subset analysis, the 5-year DFS of HER2(+)/ER(+) pts without adjuvant tamoxifen (n=26) was not different from that of HER2(+)/ ER(-) pts (DFS; 57.7% v 61.5%; P= 0.32). However, the 5-year DFS of HER2(+)/ ER(+) pts with adjuvant tamoxifen was significantly prolonged compared with that of HER2(+)/ ER(-) pts (DFS; 91.5% v 61.5%; P< 0.001). In a multivariate analysis of DFS, tumor size and adjuvant tamoxifen use significantly affected DFS with an adjusted hazard ratio of 2.56 (95% CI, 1.2–4.9; P= 0.01) and 6.58 (95% CI, 2.8–20.3; P< 0.001), respectively. Conclusions: In an analysis of HER2-overexpressed breast cancer, the presence of HR itself did not affect the prognosis. However, most of the survival benefit seems to be driven from adjuvant tamoxifen therapy not the HR status itself. No significant financial relationships to disclose.

Choosing early adjuvant therapy for postmenopausal women with hormone-sensitive breast cancer: Aromatase inhibitors versus tamoxifen

Aims The aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole have demonstrated superior disease-free survival (DFS) over tamoxifen in several trials. As the choice of adjuvant endocrine treatment for early breast cancer (EBC) is evolving from tamoxifen to the AIs, this review compares the AIs with tamoxifen to help surgeons choose a treatment plan that provides the greatest reduction of recurrence risk for their patients. Methods MEDLINE was searched to identify relevant literature on the adjuvant use of tamoxifen and AIs in EBC. Results Despite the use of adjuvant tamoxifen, recurrence is a persistent threat to women with hormone-sensitive EBC. Trials of the AIs versus tamoxifen have established that patients benefit from longer DFS, and in some cases distant DFS, after the use of an AI as initial adjuvant therapy, as switch therapy following 2–3 years of tamoxifen, or as extended adjuvant therapy following 5 years of tamoxifen. The AIs are well tolerated, with a different safety profile than that of tamoxifen in all these settings. Trials addressing the optimal regimen and treatment duration for AIs are also underway. Conclusions The advantage in DFS associated with AIs over tamoxifen use should prompt physicians and patients to consider the use of an AI as the initial adjuvant endocrine therapy or, alternatively, switching patients who currently take tamoxifen to an AI for the remainder of adjuvant endocrine therapy. Prolonging the period of adjuvant therapy with letrozole after 5 years of tamoxifen reduces recurrence and is associated with a survival advantage in node-positive patients.

State of the art therapy for elderly patients with early-stage and locally advanced breast cancer

The global incidence of cancer is expected to increase dramatically in the coming years, due in part to ageing populations. Historically, elderly women with breast cancer have been excluded from clinical trials, making it difficult to develop evidence-based treatment guidelines. Ageing is a highly individualised process and age alone should not be used to deny treatment to otherwise appropriate patients. Comprehensive geriatric assessment (CGA), routinely used by geriatricians, is becoming increasingly relevant to oncology practice. CGA may have a direct effect on treatment decisions in breast cancer. While the role of adjuvant radiotherapy remains debated, surgery remains the best option for fit older patients. Data support the use of adjuvant tamoxifen for hormone receptor-positive disease, and the additional benefit of aromatase inhibitors remains to be fully determined. The benefits of adjuvant polychemotherapy, capecitabine or pegylated liposomal doxorubicin monotherapy are under evaluation in on-going phase III trials.

A case of synchronous relapse of breast cancer and uterine mullerian adenosarcoma after adjuvant tamoxifen in a pre-menopausal woman

20533 Background: Uterine müllerian adenosarcoma is a rare tumor of postmenopausal women. An increase in its incidence with the use of tamoxifen therapy for breast carcinoma is reported in several studies. Methods: We report a case of 42 years multigravida, premenopaused woman with breast carcinoma, who presented - after four years of use of adjuvant tamoxifen - a synchronous liver, bone, and lung metastasis of breast cancer with müllerian adenosarcoma. Results: Immunohistochemical stains on uterine tumor for estrogen and progesterone receptors showed positivity for both epithelial and stromal cells, actin, desmin and proliferative index (MIB-1) showed positivity for stromal cells only. The patient underwent a hysterectomy followed by palliative chemotherapy. The patient deceased at 14 months after her relapse because of progressive disease (cerebral, bone, liver and lung metastasis). Conclusion: Our case is the only one reported in the literature with synchronous relapse of the breast adenocarcinoma and a Müllerian adenosarcoma. Also it's of the rare cases occurring in a pre-menopaused woman since all except two cases were postmenopausal. [Table: see text] No significant financial relationships to disclose.

Adjuvant endocrine therapies for premenopausal women

Adjuvant endocrine treatment for premenopausal woman remains a controversial area in the therapeutical approach of early stages of breast cancer. Metaanalysis show that ovarian ablation and suppression produce, in a global way, significant benefits in terms of reduction of the risk of recurrence and death. Nevertheless, in the presence of adjuvant chemotherapy, the benefits of ovarian suppression or ablation are clearly reduced, probably in relation to the impact that amenorrhoea induced by chemotherapy. On the other hand, in premenopausal patients, the same metaanalysis show that the use of adjuvant tamoxifen produces benefits in disease- free survival and overall survival very similar to those observed in postmenopausal women. Additionally, the benefits from tamoxifen persist independently of whether or not adjuvant chemotherapy is being received. Thus, some of the questions to answer are: first, is there, in premenopausal women, an additional benefit when ovarian suppression is associated to tamoxifen? Second, it remains controversial if ovarian suppression must be indicated for all patients who receive chemotherapy or only those that have not reached amenorrhoea when adjuvant chemotherapy is completed. Moreover, although in the last decades more than 15,000 premenopausal patients have been included in specific trials of adjuvant endocrine therapy with ovarian suppression or ablation, the best modality of treatment has not been established, and what is more important, the role of its association with tamoxifen has not been completely defined. Many of these aspects remain controversial and the decision about the best therapeutical approach must be individualised in each patient.

Long-term pattern of disease recurrence among patients with early-stage breast cancer according to estrogen receptor status and use of adjuvant tamoxifen

Recent studies on the pattern of gene expression in estrogen receptor positive and negative tumours have revealed profound differences according to receptor status. However, it remains unclear if these differences reflect phenotypic traits in addition to sensitivity to endocrine therapy. This paper describes the long-term pattern of disease recurrence among ca. 2,600 pre- and post-menopausal patients with primary breast cancer according to estrogen receptor status. The study was based on patients with an operable, invasive breast cancer entered in one of three controlled clinical trials conducted by the Stockholm Breast Cancer Group. We selected those 2,562 patients who had been randomly allocated between adjuvant tamoxifen and no adjuvant systemic therapy. These patients had a known estrogen receptor status. Tamoxifen reduced locoregional (8.8% vs. 12.4%, hazard ratio (HR), 0.66; 95% CI, 0.52-0.83; P = 0.001, distant recurrences (17.2% vs. 20.2%, HR, 0.81; CI, 0.68-0.97; P = 0.018, as well as breast cancer death (18.7% vs. 23.7%, HR, 0.78; CI, 0.67-0.92; P = 0.002). Among patients not allocated to tamoxifen there was no significant differences in term of neither locoregional (12.4% vs. 12.4%, HR, 1; CI, 0.72-1.41; P = 0.98), nor distant metastases (18.5% vs. 20.7%, HR, 1.11;CI, 0.85-1.45; P = 0.46) according to ER status. The pattern of metastases was not different in ER positive comparison with ER negative. The results showed that the mentioned substantial differences in terms of gene expression appeared mainly to be related to endocrine sensitivity and not to metastatic potential. However, a slight advantage during the first five years for the ER positive versus ER negative patients in terms of cumulative incidence of events, suggested that ER negativity in some cases is correlated with an increased tumour growth rate.

Safety of tibolone in the treatment of vasomotor symptoms in breast cancer patients—Design and baseline data ‘LIBERATE’ trial

Many patients with a history of breast cancer (BC) will suffer from vasomotor symptoms, which can be induced or exacerbated by treatment with tamoxifen or aromatase inhibitors. The LIBERATE trial was designed as a randomized, double-blind, multicenter trial to demonstrate that tibolone 2.5 mg/day (Livial ®) is non-inferior to placebo regarding BC recurrence in women with vasomotor symptoms surgically treated for primary BC within the last 5 years. Secondary objectives are effects on vasomotor symptoms as well as overall survival, bone mineral density and health-related quality of life. Mean age at randomization was 52.6 years, and the mean time since surgery was 2.1 years. The mean daily number of hot flushes and sweating episodes was 7.3 and 6.1, respectively. For the primary tumor, Stage IIA or higher was reported for >70% of the patients. In subjects whose receptor status was known, 78.2% of the tumors were estrogen receptors positive. At randomization, tamoxifen was given to 66.2% of all patients and aromatase inhibitors to 7%. Chemotherapy was reported by 5% at randomization. The adjuvant tamoxifen use in LIBERATE allows a comparison with the Stockholm trial (showing no risk of BC recurrence associated with hormone therapy), which was stopped prematurely subsequent to HABITS. The LIBERATE trial is the largest, ongoing, well-controlled study for treatment of vasomotor symptoms in BC patients.

Towards optimal endocrine therapy for hormone-sensitive breast cancer: Initial versus sequential adjuvant aromatase inhibition

Patients with hormone-receptor-positive early breast cancer have a significant risk of recurrence despite the use of adjuvant tamoxifen. The third-generation aromatase inhibitors letrozole, anastrozole, and exemestane offer promise as alternative or additional therapy to tamoxifen. As extended adjuvant therapy following completion of 5 years of tamoxifen, letrozole further decreased the risk of recurrence compared with placebo. Compared with tamoxifen, both letrozole and anastrozole significantly reduced the risk of recurrence when used as initial adjuvant therapy, and in the short term both were better tolerated than tamoxifen. Anastrozole and exemestane both reduced the risk of relapse when started after 2–3 years of tamoxifen compared with continued tamoxifen treatment; the results of letrozole in this setting are expected in 2008. These data establish adjuvant aromatase inhibitors as effective alternatives to tamoxifen. Only limited data are currently available to inform the choice between an aromatase inhibitor as either initial adjuvant therapy or sequentially after tamoxifen. Future results from the Breast International Group (BIG) 1–98 trial will further clarify strategies for the adjuvant use of aromatase inhibitors. Here, we critically review the evidence for adjuvant use of aromatase inhibitors. Comparison is made between initial aromatase inhibition, switching, and extended adjuvant strategies. Practical recommendations are given for the endocrine treatment of post-menopausal breast cancer.

Clinicopathologic study of 56 patients with endometrial cancer during or after adjuvant tamoxifen use for their breast cancers

ObjectivesThe aim of this study was to describe the clinicopathologic features and prognosis of endometrial cancer patients diagnosed during or after tamoxifen treatment for breast cancer. MethodsFifty-six tamoxifen-related endometrial cancers were identified from 10 hospitals in Japan. Past users were defined as endometrial cancer patients diagnosed more than 12 months after the cessation of tamoxifen treatment for breast cancer. All other users were classified as recent users. ResultsAge at diagnosis of the endometrial cancer ranged from 29 to 81 years. Sixteen (29%) and 19 (34%) patients were nulliparous and overweight, respectively. When the patients were divided into two groups: 30 recent and 26 past users, the distribution of various clinical characteristics, except for age at the time of diagnosis for endometrial cancer and the interval between the diagnoses of two cancers, was similar for two groups. The daily dose, duration and cumulative dose also showed no significant difference between the two groups. Past users had histopathologically more invasive tumors showing prognostically more unfavorable subtypes than recent users. The background lesions including endometrial polyps and diffuse cystic changes were similar for the two groups. The cumulative 3-year survival was significantly worse for past users than for recent users (74.8% and 96.4%, respectively, P < 0.04). In multivariate analysis including recentness of tamoxifen use and age at diagnosis of endometrial cancer, the significance of past user disappeared. ConclusionsPast users had a worse prognosis of endometrial cancer with more invasive histologic features than recent users, probably because they included more elderly patients.

Changes in management techniques and patterns of disease recurrence over time in patients with breast carcinoma treated with breast-conserving therapy at a single institution.

The authors reviewed changes in the initial clinical presentation, management techniques, and patterns of disease recurrence over time (1981-1996) in patients with breast carcinoma treated with breast-conserving therapy (BCT) at a single institution. The goals of the current study were to determine the frequency and use of optimal local and systemic therapy techniques and to evaluate the impact of these changes on treatment efficacy. Six hundred seven patients with American Joint Committee on Cancer Stage I or II invasive breast carcinomas treated with BCT at William Beaumont Hospital (Royal Oak, MI) constituted the study population. All patients received at least an excisional biopsy of the primary tumor, an axillary lymph node staging procedure, and postoperative radiotherapy (RT) (a median tumor bed dose of 61 Gray [Gy] was administered). All sides were reviewed by one pathologist. Numerous clinicopathologic and treatment-related factors were analyzed to monitor changes that occurred over time. Changes in patterns of disease recurrence and treatment efficacy over time also were analyzed. Over the time period analyzed, changes at initial presentation included an increase in the mean age at diagnosis (age 56.1 years vs. 61.4 years; P < 0.001), a decrease in the number of patients with clinically palpable tumors (78% vs. 36%; P < 0.001), a decrease in the mean tumor size (2.2 cm vs. 1.6 cm; P < 0.001), but no change in the percentage of patients with negative lymph nodes (79% vs. 78%; P = 0.83). No differences over time were observed in mean tumor grade (2.0 vs. 1.9; P = 0.2) or the presence of angiolymphatic invasion (27% vs. 26%; P = 0.25). Changes in surgical management and pathologic assessment included the more frequent use of reexcision (46% vs. 81%; P < 0.001), larger mean total volumes of breast tissue specimens excised (115 cm3 vs. 189 cm3; P = 0.001), a larger percentage of patients with final negative surgical margins (74% vs. 97%; P < 0.001), and a small increase in the mean number of lymph nodes excised (13.8 lymph nodes vs. 14.1 lymph nodes; P = 0.01). The only other significant change in the pathologic management of patients over time included a doubling in the mean number of slides examined (10.6 slides vs. 21.1 slides; P < 0.001). Changes in adjuvant local and systemic therapy included an increase in the percentage of patients treated with > 60 Gy to the tumor bed (66% vs. 95%; P < 0.001), a doubling in the mean number of days from the last surgery to the start of RT (24 days vs. 50 days; P < 0.001), and a decrease in the use of regional lymph node RT (24% vs. 8%; P < 0.001). The use of adjuvant tamoxifen increased from 10% to 61% (P < 0.001). Finally, improvements were observed in the 5-year and 12-year actuarial rates of local disease recurrence (8% vs. 1% and 21% vs. 9%, respectively; P = 0.001) and distant metastases (12% vs. 4% and 22% vs. 9%, respectively; P = 0.006). No changes in the mean number of years to ipsilateral (6.5 years vs. 6.4 years; P = 0.59) or distant disease recurrence (4.6 years vs. 3.8 years; P = 0.73) were observed. The impact of screening mammography and substantial changes in surgical, pathologic, RT, and systemic therapy recommendations were observed over time in the study population. These changes were associated with improvements in 5-year and 12-year local and distant control rates and suggested that improvements in outcome can be realized through adherence to best practice guidelines and continuous monitoring of treatment outcome data.

Advances in Screening, Diagnosis, and Treatment of Breast Cancer

Advances in Screening, Diagnosis, and Treatment of Breast Cancer

Adjuvant treatment of breast cancer by concomitant hormonotherapy and radiotherapy: state of the art

Combining radiation and hormone therapy has become common clinical practice in recent years for locally advanced prostate cancer. The use of such concomitant therapy in the treatment of breast disease has been very infrequently reported in the literature, but such an application seems justified given the common hormonal dependence of breast cancer and the potential synergetic effect of these two treatment modalities. As adjuvant therapy, tamoxifen is the key drug in the hormonal treatment arsenal, providing a significant improvement in both local control and global survival rates. Aromatase inhibitors are currently being evaluated in this setting, and initial results are promising. In vitro, tamoxifen does not seem to offer a protective effect against radiation. In clinical use, the few available published studies confirm the superiority of the association of radiation with tamoxifen as opposed to radiation therapy alone in decreasing local recurrences of surgically removed breast tumors. Toxicity associated with such concomitant therapy includes mainly subcutaneous and pulmonary fibroses. However, subcutaneous fibrosis and its cosmetic impact on the treated breast are frequently described side effects of radiation therapy, and their incidence may actually be reduced when tamoxifen is associated. The evidence is less controversial for pulmonary fibrosis, which is more common with the concomitant therapy. The association of radiation and aromatase inhibitors has as of yet rarely been reported. Letrozole (Femara) has a radiosensitizing effect on breast-cancer cell lines transfected with the aromatase gene. Clinical data assessing this effect in vivo are not available. The FEMTABIG study (letrozole vs. tamoxifen vs. sequential treatment) did not specify the sequence of radiation and hormonal therapy. The ATAC study comparing the adjuvant use of anastrozole (Arimidex) and tamoxifen does not provide any information on the number of patients receiving radiation concomitant with the hormonal treatment, and in addition also does not specify the sequence of radiation and hormonal treatment. The TEAM study compared exemestane (Aromasine) and tamoxifen, but specified that hormonal treatment follow the completion of radiation therapy.

Prevalence of Endometrial Proliferation in Pipelle Biopsies in Tamoxifen-Treated Postmenopausal Women with Breast Cancer in Kuwait

Objective: To determine the prevalence of pathologic changes in the endometrium of tamoxifen-treated asymptomatic postmenopausal patients with breast cancer. Subjects and Methods: Fifty postmenopausal asymptomatic breast cancer patients with positive estrogen receptor status were treated with 20 mg of tamoxifen daily for a period of 5–60 months. The control group consisted of 30 asymptomatic postmenopausal breast cancer patients who were negative for estrogen receptor and therefore did not receive tamoxifen. Endometrial biopsies were performed using Pipelle endometrial suction curette at least 5 months after the study began. The endometrium was classified as atrophic (negative finding) and proliferative or hyperplastic (positive findings). The study and control groups were compared for demographic characteristics, risk factors for endometrial cancer, histological findings and the duration of tamoxifen treatment. Results: A significantly greater prevalence of endometrial abnormalities existed among the tamoxifen-treated than control patients (76 vs. 33%, p < 0.001). The abnormal endometrial changes were further demarcated in both groups into proliferative (54 vs. 26.7%, p = 0.02) and hyperplastic (22 vs. 6.6%, p = NS). In the study group, 63.6% of hyperplastic endometrium was simple hyperplasia and 36.4% was complex/no atypia hyperplasia, while in the control group all the cases were simple hyperplasia. No endometrial cancer was detected in either group. In addition, there was a positive association between the duration of tamoxifen exposure (<1 year vs. ≧1 year) and the endometrial abnormalities (46.6 vs. 88.6%, p = 0.003; proliferative 57.1 vs. 74.1%, p = 0.015; hyperplastic 42.8 vs. 25.8%, p = NS). Conclusion: The adjuvant use of tamoxifen is associated with significant time-dependent abnormal endometrial changes among patients with cancer of the breast.

Changing role of the oestrogen receptor in the life and death of breast cancer cells

The oestrogen receptor (ER) has proven to be an extraordinarily successful target for breast cancer treatment and prevention. The clinical use of tamoxifen, a nonsteroidal antioestrogen, demonstrated (1) that the strategic use of adjuvant tamoxifen in ER-positive patients could save lives and (2) that a selective ER modulator (SERM) could reduce the incidence of breast cancer in high-risk women. The ER is now the target for new and safer therapies such as the aromatase inhibitors and the pure antioestrogens that either block oestrogen synthesis or destroy the ER. However, the use of raloxifene, a SERM to prevent osteoporosis with the potential to prevent breast cancer has introduced a new dimension into preventive oncology. The widespread use of endocrine modulators (SERMs, aromatase inhibitors, and pure antioestrogens) raised the question of drug resistance. It is now clear that endocrine resistance can evolve through stages. Once a breast tumour becomes resistant to SERMs, the growth is stimulated by either the SERM or oestrogen. This is why an aromatase inhibitor is effective following SERM resistance and withdrawal. However, the extended use of repeated endocrine therapies now supersensitized the cells to oestrogen that causes apoptosis through the ER. We suggest that future clinical treatment strategies incorporate an ‘oestrogen purge’ to both enhance the actions of chemotherapy or completely reverse endocrine resistance and restore endocrine sensitivity. These new data build on the idea that breast cancer can be controlled as a chronic disease and will permit patients to live long and productive lives during targeted maintenance treatment.

Prophylaxis for venous thromboembolism during treatment for cancer: questionnaire survey

Venous thromboembolism is common in patients with cancer and is often the cause of death.1 Patients receiving treatment for cancer are at even greater risk of thromboembolism. Thromboembolism occurs in...

RESPONSE: Re: Trends in Use of Adjuvant Multi-Agent Chemotherapy and Tamoxifen for Breast Cancer in the United States: 1975-1999

RESPONSE: Re: Trends in Use of Adjuvant Multi-Agent Chemotherapy and Tamoxifen for Breast Cancer in the United States: 1975-1999

Predictive value of tumour cell proliferation in locally advanced breast cancer treated with neoadjuvant chemotherapy

We previously reported that defects in apoptotic pathways (mutations in the TP53 gene) predicted resistance to doxorubicin monotherapy. The aim of this study was to evaluate whether cell proliferation, as assessed by mitotic frequency and Ki-67 levels, may provide additional predictive information in the same tumours and to assess any potential correlations between these markers and mutations in the TP53 gene and erbB-2 overexpression. Surgical specimens were obtained from ninety locally advanced breast cancers before commencing primary chemotherapy consisting of weekly doxorubicin (14 mg/m 2) for 16 weeks. 38% of the patients had a partial response (PR) to therapy, 52% had stable disease (SD) while 10% had progressive disease (PD). Univariate analysis showed a significant association between a high cell proliferation rate (expressed as a high mitotic frequency) and resistance to doxorubicin ( P=0.001). Further analyses revealed this association to be limited to the subgroup of tumour expressing wild-type TP53 ( P=0.016), and TP53 mutation status was the only factor predicting drug resistance in the multivariate analyses. The finding that a high mitotic frequency, as well as a high Ki-67 staining, correlated to TP53 mutations ( P=0.001 for both), suggests TP53 mutations are the key predictor of drug resistance, although cell proliferation may play an additional role in tumours harbouring wild-type TP53. Regarding overall (OS) and relapse-free survival (RFS), multivariate analyses (Cox' proportional hazards regression) revealed a high histological grade and negative oestrogen receptor (ER) status to be the variables that were most strongly related to breast cancer death ( P=0.001 and P=0.001, respectively). A key reason for this difference with respect to the factors predicting chemotherapy resistance could be due to the adjuvant use of tamoxifen in all patients harbouring ER-positive tumours.

Can we select which patients with small breast cancers should receive adjuvant chemotherapy?

To identify the risk of systemic metastases from T1a and T1b N0 breast cancers in patients treated in an academic center, and to seek factors to identify the patients at greatest risk of such failure. With the demonstration that adjuvant chemotherapy reduces the death rate from breast cancer by roughly one quarter across all risk groups, controversy has reigned regarding possible exclusions from therapy. T1a and T1b N0 tumors (1-cm diameter and smaller with negative axillary nodes) have been considered at low risk for metastasis since the report from Memorial Sloan-Kettering Cancer Center of a 90% survival rate at 10 years. Subsequent reports have suggested an even more favorable prognosis for this group. However, consensus statements advise selecting some of these women for treatment, and many do receive adjuvant chemotherapy. Sequential patients with breast cancer at the Emory Clinic were prospectively staged and followed up for outcome. The records of patients with T1a and T1b N0 tumors were reviewed for exact tumor diameter, grade, receptor status, adjuvant therapy, and outcome. A corrected data set was stripped of patient identifiers and analyzed by Kaplan-Meier methods. Subgroups were formed based on tumor grade (1 vs. 3), adjuvant chemotherapy (use vs. no use), and adjuvant tamoxifen (use vs. no use) and were compared via log-rank tests. Two hundred eighty-two women were identified. Two developed metastatic disease and one experienced a local failure after breast-conserving treatment. The estimated disease-free survival rate at 10 years was 98.7%. With only two distant failures and one local failure, there was no significant difference by grade, receptor status, or use of adjuvant chemotherapy or tamoxifen. The risk of systemic failure from such tumors barely exceeded 1% at 10 years. Unless future studies can identify a subgroup at higher risk, the cognitive changes associated with cytotoxic chemotherapy or the loss of estrogen involved do not appear to have sufficient offsetting benefit to warrant chemotherapy for this group of women.