Neoadjuvant endocrine therapy in primary breast cancer

Neoadjuvant chemotherapy has been employed increasingly in operable breast cancer during recent years. Several randomized trials showed that the chances of breast conserving therapy are being enhanced, and that survival was not compromised by primary systemic therapy compared to adjuvant treatment. Apart from the surgical advantages of tumor downstaging and breast conservation, therapy upfront might offer the chance to predict subsequent response of an individual patient to a given agent in the adjuvant setting. Furthermore, by investigating pre- and posttreatment tumor specimens, the neaodjuvant setting might help to evaluate new predictive biological markers, assess biologic effects of new treatments, and gain insight into molecular mechanisms. For postmenopausal patients with receptor-positive disease who cannot tolerate the toxicities of chemotherapy regimens or are not eligible for immediate surgery, endocrine treatment is emerging as an attractive alternative in the neoadjuvant setting. The new third-generation aromatase inhibitors letrozole and anastrozole have been compared to tamoxifen in 3 well-designed randomized neoadjuvant phase III trials (PO24, IMPACT, and PROACT). These studies showed significantly higher response rates for letrozole than for tamoxifen, and comparable ones for anastrozole. Thus, the primary use of an aromatase inhibitor seems a feasible and safe treatment option for postmenopausal women with early-stage breast cancer who do not wish to or are unable to undergo immediate surgery or preoperative chemotherapy. Further neoadjuvant endocrine trials should help us to elucidate the cross-talk between the different signal transduction pathways and their role in endocrine resistance.     

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.     

Risk for second primary non-breast cancer in pre- and postmenopausal women with breast cancer not treated with chemotherapy, radiotherapy or endocrine therapy

Introduction

We investigated the risk for a second primary cancer in pre- and postmenopausal women with breast cancer treated by surgery alone, to assess the importance of non-treatment factors and menopausal status.

Patients and methods

The cohort comprised 14,151 women with breast cancer diagnosed during 1977-2006, who did not receive radiotherapy or systemic adjuvant therapy. They were identified in the nationwide clinical database of the Danish Breast Cancer Cooperative Group. The women were followed for a second primary cancer other than breast cancer in the Danish Cancer Registry, and risk was quantified as standardised incidence ratios (SIRs).

Results

Women with breast cancer diagnosed before menopause had an 18% greater overall risk for a second primary non-breast cancer than the general female population (95% confidence interval [CI], 1.06-1.32). The excess was confined to cancers of the endometrium (1.5; 95% CI, 1.0-2.0) and ovaries (1.8; 95% CI, 1.2-2.4). Rare histological subtypes of breast cancer were associated with these two cancer sites. Women with breast cancer after menopause had no overall excess risk for a second cancer (SIR, 0.98; 95% CI, 0.92-1.04).

Conclusion

An excess risk for second non-breast cancers related to non-treatment factors is seen primarily in breast cancer patients who were premenopausal at diagnosis.     

Cost-effectiveness of endocrine therapy versus radiotherapy versus combined endocrine and radiotherapy for older women with early-stage breast cancer

PurposeTo evaluate the cost-effectiveness of endocrine therapy (ET), radiation therapy (XRT), and combination ET + XRT as post-surgical treatment for older women with early-stage breast cancer from the societal perspective.MethodsWe constructed a Markov state-transition model consisting of three mutually exclusive health-states: Disease-Free, Recurrence, or Death. Osteoporotic fracture, radiation-induced breast fibrosis, and radiation pneumonitis were modeled as treatment-related adverse events (AEs). Cancer registry-linked-Medicare data were used to assess probability of recurrence and total costs, after propensity adjustment to account for treatment selection, among women aged >65 years diagnosed with estrogen receptor positive or progesterone receptor positive (ER+/PR+) breast cancer receiving ET, XRT, or ET + XRT in 2007–2011. Following randomized controlled trials, overall survival was assumed equivalent, but locoregional recurrence varied. Indirect costs and health-state utilities were literature-driven and varied in sensitivity analyses. Costs and outcomes were discounted at 3% annually.ResultsIn a cohort of 10,000 women over ten years, we estimated 1620 total recurrences in the ET-only group, 1296 in the XRT-only group, and 1076 with ET + XRT. Compared to ET-only, the base-case incremental cost-effectiveness ratio (ICER) was $10,826 per quality-adjusted life-year (QALY)-gained for XRT-only and $26,834/QALY-gained for ET + XRT. Similarities in cost and effectiveness between treatments led to highly sensitive results. We also present clinically-relevant patient preference scenarios for recurrence risk-averse patients and near-term AE risk-averse patients.ConclusionsThe cost-effectiveness of regimens including ET and/or XRT in older women with early-stage breast cancer is sensitive to small differences in costs, as well as risk of, and utilities associated with, locoregional recurrence, suggesting that patient preferences concerning treatment benefits and risks should be considered by physicians.     

Preoperative chemotherapy and endocrine therapy in patients with breast cancer

This review focuses on the aims, results, advantages, and possible disadvantages of preoperative chemotherapy and endocrine therapy. We present the recent improvements in terms of pathologic response rates that have resulted from new combinations of drugs. The change of established prognostic factors during neoadjuvant treatment, the need for new markers, and the consequences in terms of clinical decision-making are demonstrated. We discuss the risk of local relapse after breast-conserving surgery, which was made feasible by preoperative chemotherapy. A short overview of current neoadjuvant cytostatic, endocrine, and immunotherapy trials is provided. Future opportunities for tailoring therapy to each individual patient based on early information from the primary tumor are discussed. Important considerations and results of recent endocrine trials that analyzed possible tamoxifen-resistance in subgroups are reported. New opportunities exist to evaluate the efficacy of new cancer drugs more rapidly in the neoadjuvant setting than in the metastatic and adjuvant setting. This approach offers the possibility of monitoring prognostic markers in the primary tumor before, during, and after treatment with specific chemotherapeutic agents. With respect to recent findings of gene-array techniques, it is likely that the advances in this technology will lead to improved prognostic statements. It will show the influence of therapy on gene expression profiles in the course of treatment and might enable us to identify chemoresistance of specific tumors rather early. This could potentially lead to a new direction of cancer therapy.     

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

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

乳腺癌患者应用内分泌药物治疗后合并脂肪肝的临床分析

目的：分析乳腺癌患者应用内分泌药物后发生脂肪肝的机理及预防。方法：收集住院及门诊服用内分泌药物治疗的乳腺癌患者,通过血脂、腹部CT或B超检查,探讨合并脂肪肝的机理。结果：107例患者均有不同程度的脂肪肝发生,轻度脂肪肝42例,中度脂肪肝37例,重度脂肪肝28例。中断内分泌治疗13例。最早发生脂肪肝服药3月,最晚服药近2年,平均13月。结论：乳腺癌服用内分泌治疗的患者应注意预防脂肪肝的发生并给予及早的干预治疗。     

乳腺癌化疗致闭经的利弊及随后的内分泌治疗

化疗致闭经是一个客观过程，影响因素基本明确，而且对激素受体阳性的患者，化疗致闭经可改善无病生存和总生存，所以对一些预后好和希望保留卵巢功能的患者我们可以进行干预尽可能保护卵巢功能；而对一些高危、预后差的患者，如果化疗未致闭经，可以采用进一步卵巢抑制的方法，以达到闭经，从而获得更好的疗效，这是一个客观、容易观察的指标。     

Recent progress in endocrine therapy of patients with breast cancer

Endocrine therapy of breast cancer was reviewed historically, and growth or regression of the tumor in relation to estrogen level in pheripheral blood was elucidated. Discovery of anti-estrogens has brought big revolution in the therapy of breast cancer. Recent developments of GnRH analogue and inhibitor of steroidgenesis are expected to give us more useful tools for the treatment of the disease. Combinations of such hormonal drugs with different action mechanisms will be resulted in better prognosis of breast cancer patients.     

Chemohormonal therapy and endocrine function in breast cancer patients

The administration of CMFVP (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) results in profound alterations in hormonal profiles of premenopausal women due to a reduction in ovarian and adrenal secretion of estrogens and androgens. Cytotoxic chemotherapy results in ovarian suppression as documented by decreases in estradiol with concomitant elevations in pituitary gonadotrophins, whereas the addition of prednisone to the cytotoxic regimen results in significant decreases in androgen levels due to adrenal suppression. In postmenopausal women, CMFVP also results in significant decreases in estrogens and estrogen precursors due to suppression of adrenal steroid metabolism. Continuous low-dose prednisone administration during cytotoxic chemotherapy appears to be more effective than an intermittent high-dose schedule in achieving and sustaining adrenal suppression. However, complete elimination of adrenal steroidogenesis does not occur in all cases since measurable amounts of adrenal steroids remain in the serum throughout chemohormonal therapy. The administration of tamoxifen plus CMFVP is associated with hyperestrogenemia in younger premenopausal patients which persists until the onset of ovarian suppression.     

晚期转移性乳腺癌内分泌治疗进展

晚期转移性乳腺癌患者由于体质差,对二次手术和化疗一般不能耐受.内分泌治疗由于副作用小,缓解率高,为广大医患所接受,特别是雌激素受体(ER)或孕激素受体(PR)阳性的患者,其治疗效果甚至优于化疗.由于雌激素来源的不同,绝经前后内分泌治疗药物选择有所不同.现综述晚期转移性乳腺癌内分泌治疗的现状.     

A case of advanced breast cancer successfully treated with primary endocrine therapy

We present a case of a premenopausal woman with advanced hormone-sensitive breast cancer who was successfully treated with primary endocrine therapy consisting of ovarian ablation followed by a combined endocrine regimen of the aromatase inhibitor fadrozole 2 mg daily and tamoxifen 20 mg daily. During the 5 months treatment period, PR evaluation of the loco-regional lesions was performed The patient then underwent mastectomy with axillary lymph node dissection followed by fadrozole and tamoxifen therapy. Throughout the treatment course, no adverse events were encountered and the patient has been enjoying a favorable quality of life. As shown by this case, primary endocrine therapy is a promising treatment option for hormonesensitive breast cancer. However, this modality should be continued to be regarded as experimental.     

Adjuvant radiotherapy and risk of contralateral breast cancer.

BACKGROUND: The risk of contralateral breast cancer is increased twofold to fivefold for breast cancer patients. A registry-based cohort study in Denmark suggested that radiation treatment of the first breast cancer might increase the risk for contralateral breast cancer among 10-year survivors. PURPOSE: Our goal was to assess the role of radiation in the development of contralateral breast cancer. METHODS: A nested case-control study was conducted in a cohort of 56,540 women in Denmark diagnosed with invasive breast cancer from 1943 through 1978. Case patients were 529 women who developed contralateral breast cancer 8 or more years after first diagnosis. Controls were women with breast cancer who did not develop contralateral breast cancer. One control was matched to each case patient on the basis of age, calendar year of initial breast cancer diagnosis, and survival time. Radiation dose to the contralateral breast was estimated for each patient on the basis of radiation measurements and abstracted treatment information. The anatomical position of each breast cancer was also abstracted from medical records. RESULTS: Radiotherapy had been administered to 82.4% of case patients and controls, and the mean radiation dose to the contralateral breast was estimated to be 2.51 Gy. Radiotherapy did not increase the overall risk of contralateral breast cancer (relative risk = 1.04; 95% confidence interval = 0.74-1.46), and there was no evidence that risk varied with radiation dose, time since exposure, or age at exposure. The second tumors in case patients were evenly distributed in the medial, lateral, and central portions of the breast, a finding that argues against a causal role of radiotherapy in tumorigenesis. CONCLUSIONS: The majority of women in our series were perimenopausal or postmenopausal (53% total versus 38% premenopausal and 9% of unknown status) and received radiotherapy at an age when the breast tissue appears least susceptible to the carcinogenic effects of radiation. Based on a dose of 2.51 Gy and estimates of radiation risk from other studies, a relative risk of only 1.18 would have been expected for a population of women exposed at an average age of 51 years. Thus, our data provide additional evidence that there is little if any risk of radiation-induced breast cancer associated with exposure of breast tissue to low-dose radiation (e.g., from mammographic x rays or adjuvant radiotherapy) in later life.     

Survival improvement in hormone-responsive young breast cancer patients with endocrine therapy

Purpose

Breast cancer (BC) is the most frequent cancer among women in developed countries. Physical activity (PA), body mass index (BMI), and alcohol intake have been identified as relevant lifestyle modifiable risk factors for post-menopausal BC. We aimed to evaluate the role of these factors in modulating post-menopausal BC risk and to estimate the proportion of BC cases attributable to low PA, high BMI, and alcohol taking into account non-modifiable factors.

Methods

In the Italian section of the EPIC study, 15,010 post-menopausal women were recruited and provided information about dietary and lifestyle habits including PA, smoking, reproductive history, and anthropometric measurements. During 14.8 years of median follow-up, 672 incident BC cases (607 invasive and 65 in situ) were identified.

Results

In multivariate models, inverse associations with BC risk emerged for increasing level of total (p trend 0.02), leisure time (p trend 0.04), and occupational (p trend 0.007) PA. High BMI (HR 1.21; 95% CI 1.02–1.43 and HR 1.33; 95% CI 1.06–1.65 for overweight and obesity, respectively) and alcohol consumption higher than 10 g/day (HR 1.30; 95% CI 1.09–1.54) were associated with BC risk. We estimated that 30% (95% CI 8–50%) of post-menopausal BC cases would be avoided through an increase of leisure time PA, a BMI below 25.0, and consuming no more than one drink/day.

Conclusions

This large study carried out in Mediterranean women confirms the role of PA, BMI, and alcohol consumption in modulating post-menopausal BC risk and supports the potential benefits obtainable by modifying these lifestyle factors.

     

Local relapse in primary breast cancer patients with unexcised positive surgical margins after lumpectomy, radiotherapy and chemoendocrine therapy

Background: Inadequate surgical excision with residual involvement of resection margins by tumour after breast conservation results in increased local recurrence rates. To reduce this risk positive margins are, therefore, usually excised. Systemic treatment with tamoxifen or chemotherapy reduces local recurrence, along with radiotherapy. However, no studies to date have examined the correlation between chemoendocrine treatment, together with radiotherapy, and local relapse in patients with unexcised involved resection margins, having had breast conservation treatment.Patients and methods: The histopathology reports were reviewed of 184 patients who were treated from June 1991 to August 1995 within our randomised study of neoadjuvant versus adjuvant chemoendocrine therapy with mitozantrone and methotrexate (2M) ± mitomycin-C (3M) and tamoxifen, used concurrently with radiation following conservation surgical treatment. Histological resection margin was considered positive if ductal carcinoma in situ (DCIS) or invasive carcinoma was present microscopically less than 1mm from the excision margin.Results: Although 38% of patients had unexcised microscopically involved margins, local relapse rate as first site of relapse was only 1.9% after a median follow up of 57 months. There was no difference in distant relapse (P = 0.2) and survival (P = 0.5) between the positive and negative margins groups.Conclusions: The presence of positive unexcised margins does not have a significant effect on outcome in patients who are treated with chemoendocrine therapy together with radiotherapy. Further clinical trials are required.     

Chemo/endocrine therapy for breast cancer patients

Standard adjuvant chemo/endocrine therapy for breast cancer patient is based upon St. Gallen's consensus 1998. Recent development in the field of adjuvant chemo/endocrine therapy is an usage of LH-RH analogue with tamoxifen for premenopausal hormone receptor positive women, and also an emerging role of taxans. Orally given 5-FU derivatives may work in adjuvant settings. The third generation aromatase inhibitors have established their role in second line hormone therapy for the advanced or recurrent breast cancer patients. High dose chemotherapy should not be used in outside clinical trials.