Adjuvant Antiestrogen Therapy Research Articles

Breast Cancer Index Identifies Early-Stage Estrogen Receptor–Positive Breast Cancer Patients at Risk for Early- and Late-Distant Recurrence

Residual risk of relapse remains a substantial concern for patients with hormone receptor-positive breast cancer, with approximately half of all disease recurrences occurring after five years of adjuvant antiestrogen therapy. The objective of this study was to examine the prognostic performance of an optimized model of Breast Cancer Index (BCI), an algorithmic gene expression-based signature, for prediction of early (0-5 years) and late (>5 years) risk of distant recurrence in patients with estrogen receptor-positive (ER(+)), lymph node-negative (LN(-)) tumors. The BCI model was validated by retrospective analyses of tumor samples from tamoxifen-treated patients from a randomized prospective trial (Stockholm TAM, n = 317) and a multi-institutional cohort (n = 358). Within the Stockholm TAM cohort, BCI risk groups stratified the majority (∼65%) of patients as low risk with less than 3% distant recurrence rate for 0 to 5 years and 5 to 10 years. In the multi-institutional cohort, which had larger tumors, 55% of patients were classified as BCI low risk with less than 5% distant recurrence rate for 0 to 5 years and 5 to 10 years. For both cohorts, continuous BCI was the most significant prognostic factor beyond standard clinicopathologic factors for 0 to 5 years and more than five years. The prognostic sustainability of BCI to assess early- and late-distant recurrence risk at diagnosis has clinical use for decisions of chemotherapy at diagnosis and for decisions for extended adjuvant endocrine therapy beyond five years.

Abstract P2-13-08: Comparison of Compliance to Anti Estrogen Therapy in Patients with Early Breast Cancer followed at Tertiary Centers versus Through Family Physicians and Primary Surgeons: A Practice Review

Abstract Background: Poor adherence or non-compliance to pharmacologic therapies in chronic diseases is a major clinical problem. Adherence to adjuvant anti-estrogen therapies among patients with early breast cancer (EBC) is variable as reported in different clinical trials. Cancer centres, at present, frequently refer patients with EBC on adjuvant anti-estrogen therapy back to their surgeons and family doctors for follow up. In order to find any difference in compliance for such patients, we reviewed patients followed by their primary surgeons and family doctors (peripheral cohort) for adherence and compared them to patients regularly followed in the cancer center (central cohort). Patients and Methods: Women with EBC receiving anti-estrogen therapy were identified from breast cancer database at London Regional Cancer Program LRCP). A standardized telephone interview was conducted with patients. We assumed that adherence in the central cohort will be 20% higher than the peripheral cohort. Patient are considered adherent if they took more than 80%, Non-adherent if they took less than 50% and semi-adherent if they took 50–80% of the prescribed medication. Results: We recruited a total of 160 patients (80 patients in each cohort). Seventy seven (96.3%) patients in central cohort were compliant and 76 (95%) patients were compliant in the peripheral cohort. The HR was 0.7 (p >.999) Conclusion: From our retrospective review, we did not observe any significant difference in the adherence to adjuvant anti-estrogen therapy in patients with EBC. The present process of discharging such patients to surgeons and family physicians for follow up does not seem to affect their compliance. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-08.

Risk of Colorectal Adenomas in Women with Prior Breast Cancer

Longer life expectancy in patients with prior breast cancer may increase their risk of developing other primary cancers, including colorectal cancer (CRC). Whether the risk of developing CRC in this patient population is higher in comparison to those with no prior cancer remains unclear. The purpose of this study was to compare the prevalence of colorectal adenomas and any CRC in breast cancer survivors with those who have no history of prior cancer and assess any difference with use of antiestrogen therapy. We compared the prevalence of colorectal cancer and adenomas in breast cancer survivors with that of a group of matched controls. Eligible survivors were ≤85 years of age; had initially been diagnosed with stage 0, I, II, or III breast cancer; had completed all cancer treatments with the exception of adjuvant antiestrogen therapy; and had no evidence of recurrence on follow-up. We used the screening colonoscopy database at our institution to identify age-, sex-, and race-matched controls with no history of cancer. We identified 302 study-eligible breast cancer survivors and 302 matched controls. No colorectal cancers were found in either group. Forty-one breast cancer survivors and 30 controls had tubular adenomas; four survivors and three controls had villous adenoma; and eight survivors and ten controls had advanced adenoma. Multivariate regression analysis revealed that adjuvant antiestrogen therapy was not significantly associated with an increased risk of advanced adenoma. The prevalence of colorectal adenomas in breast cancer survivors and controls was similar. Breast cancer survivors, including those receiving adjuvant antiestrogen therapies may follow the colorectal screening guidelines used for average-risk population.

Potential implications of adjuvant endocrine therapy for the oral health of postmenopausal women with breast cancer

Current adjuvant treatment modalities for breast cancer that express the estrogen receptor or progesterone receptor include adjuvant anti-estrogen therapies, and tamoxifen and aromatase inhibitors. Bone, including the jaw, is an endocrine-sensitive organ, as are other oral structures. This review examines the potential links between adjuvant anti-estrogen treatments in postmenopausal women with hormone receptor positive breast cancer and oral health. A search of PubMed, EMBASE, CENTRAL, and the Web of Knowledge was conducted using combinations of key terms "breast," "cancer," "neoplasm," "Tamoxifen," "Aromatase Inhibitor," "chemotherapy," "hormone therapy," "alveolar bone loss," "postmenopausal bone loss," "estrogen," "SERM," "hormone replacement therapy," and "quality of life." We selected articles published in peer-reviewed journals in the English. The authors found no studies reporting on periodontal diseases, alveolar bone loss, oral health, or oral health-related quality of life in association with anti-estrogen breast cancer treatments in postmenopausal women. Periodontal diseases, alveolar bone density, tooth loss, and conditions of the soft tissues of the mouth have all been associated with menopausal status supporting the hypothesis that the soft tissues and bone of the oral cavity could be negatively affected by anti-estrogen therapy. As a conclusion, the impact of adjuvant endocrine breast cancer therapy on the oral health of postmenopausal women is undefined. The structures of the oral cavity are influenced by estrogen; therefore, anti-estrogen therapies may carry the risk of oral toxicities. Oral health care for breast cancer patients is an important but understudied aspect of cancer survivorship.

Comparison of adherence to antiestrogen therapy in patients with early breast cancer followed at tertiary centers versus through family physicians and primary surgeons: a practice review

SUMMARY Background: Poor adherence or noncompliance to pharmacologic therapies in chronic diseases is a major clinical problem. Adherence to adjuvant antiestrogen therapies among patients with early breast cancer (EBC) is variable, as reported in different clinical trials. Canadian cancer centers, at present, frequently refer patients with EBC on adjuvant antiestrogen therapy back to their surgeons and family doctors for follow-up. In order to find any difference in adherence for such patients, we reviewed patients followed by their primary surgeons and family doctors (peripheral cohort) for adherence and compared them with patients regularly followed in the cancer center (central cohort). Patients & methods: Women with EBC receiving antiestrogen therapy were identified from the breast cancer database at the London Regional Cancer Program. A telephone interview was conducted with patients. We assumed that adherence in the central cohort will be 20% higher than the peripheral cohort. Patients were considered adherent if they took more than 80% of the prescribed medication, nonadherent if they took less than 50% of the prescribed medication and semiadherent if they took 50–80% of the prescribed medication. Results: We recruited a total of 160 patients (80 patients in each cohort). Seventy-seven (96.3%) patients in the central cohort were reportedly adherent and 76 (95%) patients were adherent in the peripheral cohort. The hazard ratio was 0.7 (p > 0.999). Conclusion: We did not observe any significant difference in the reported adherence to adjuvant antiestrogen therapy in patients with EBC. The present process of discharging such patients to surgeons and family physicians for follow-up does not seem to affect their adherence.

P2.16 Estrogen Receptors Alpha and Beta as Targets for Non-Small Cell Lung Cancer Hormonal Therapy

ABSTRACT Background Recent investigations demonstrate important role of estrogens in occurrence and progression of non-small cell lung cancer (NSCLC) as well as prognostic value of estrogen receptors (ER) alpha and beta in the tumor tissue. But the data about ER expression in the NSCLC differ significantly because of using semiquantitative methods for estimation only. To answer the question what is the significance of each type of the receptor as potential targets for antiestrogen therapy we have studied ERalpha and ERbeta expression in the NSCLC using the quantitative immunofluorescence methodology developed previously. Materials and methods NSCLC surgical specimens (97) were analyzed by flowcytometry. Primary antibodies were: anti-ERbeta 14C8, mouse IgG2a and IgG1 (Abcam); anti-ERalpha 1D5 (DAKO). Secondary antibody - FIT?-conjugated anti-mouse-IgG (F2772,Sigma). Number of specifically fluorescent cells was analyzed with Kolmogorov-Smirnov statistical approach. Three levels of ERbeta expression were compared: high - more than 50 % of the specifically fluorescent cells; moderate - 30-49 %; low - less than 30 %. Results 1.Expression of ERalpha and beta was reviled in about 90 % of NSCLC specimens. 2.Median of ERalpha level (22 %) was in 1·7-fold less then ERbeta level (37 %, p = 0,000002). 3.In women median of ERbeta level, but not ERalpha, was in 1·6-fold higher than in men (p = 0,008). 4.ERbeta level in men (32 %) and women (50 %) was higher in adenocarcinomas as compared with squamous-cell carcinomas in men (28 %): p = 0,0001 and 0,013 respectively. 5.ERalpha level in men (27 %) and women (22 %) was higher in adenocarcinomas as compared with squamous-cell carcinomas in men (16 %): p = 0,0003 and 0,016 respectively. 6. High and moderate level of ERbeta was revealed in 61 % of cases, while ERalpha - in 28 % only. 7. It was no coexpression of high ERalpha with low ERbeta level or any ERalpha expression with no ERbeta. Conclusion NSCLC is characterized by expression of ERbeta and ERalpha that is higher in adenocarcinomas than in squamous-cell carcinomas. ERbeta have main clinical relevance as potential target for antiestrogen therapy, because of higher level and frequency of expression than ERalpha. Generally, about half of adenocarcinoma and one third of squamous-cell carcinoma patients could benefit from adjuvant antiestrogen therapy. Supported by RFBR (Grants 10-04-00551-?,12-04-00028-?).

310 Breast Density Change as a Predictive Surrogate of Adjuvant Anti-estrogen Therapy Response in Estrogen Receptor Positive Breast Cancer

310 Breast Density Change as a Predictive Surrogate of Adjuvant Anti-estrogen Therapy Response in Estrogen Receptor Positive Breast Cancer

Prognostic or Predictive? It's Time to Get Back to Definitions!

TO THEEDITOR: I read with great interest the study of Peck et al 1 assessing the correlation of nuclear localized and tyrosine phosphorylated Stat5 expression in breast cancer with outcome. The authors claimed in the Discussion section that their results “revealed a strong predictive value of Nuc-pYStat5 for response to antiestrogen therapy.” I believe that this statement is misleading. In the literature, there is frequently some confusion about the definitions of the terms “prognostic” and “predictive.” A prognostic factor is a clinical or biologic characteristic that is objectively measurable and that provides information on the likely outcome of the cancer disease in an untreated individual. Such prognostic markers are helpful for identifying patients with cancer who are at high risk of metastatic relapse and therefore potential candidates for adjuvant systemic treatments. In contrast, a predictive factor is a clinical or biologic characteristic that provides information on the likely benefit from treatment (either in terms of tumor shrinkage or survival). Such predictive factors can be used to identify subpopulations of patients who are most likely to benefit from a given therapy. Importantly, prognostic factors define the effects of patient or tumor characteristics on the patient outcome, whereas predictive factors define the effect of treatment on the tumor. By analyzing the impact of Stat5 status on the survival of patients with lymph node–negative breast cancer who did not receive adjuvant therapy, the authors have clearly demonstrated the prognostic value of this biomarker in this setting. Indeed, patients with low Nuc-pYStat5 expression had a significantly higher risk of disease recurrence and of dying from breast cancer than patients with high Nuc-pYStat5 expression. To analyze the potential predictive value of Stat5 status for response to estrogen therapy, the authors used the same methodology in patients with node-negative and node-positive breast cancer who received adjuvant antiestrogen therapy. They found a significant correlation between low levels of Nuc-pYStat5 and poor breast cancer– specific survival and therefore concluded that Stat5 expression status was predictive of response to hormonal therapy. This conclusion is not accurate. By using such a methodology, the authors proved only that Stat5 status also had a prognostic value in patients managed with antiestrogen. However, this does not indicate that Stat5 can be used as a predictive biomarker to select patients who are more likely to benefit from hormonal treatment. The only way to demonstrate a predictive value of Stat5 status for benefit of hormonal treatment in the adjuvant setting would be to retrospectively or prospectively analyze the data from a randomized controlled trial comparing hormonal therapy versus placebo or versus a regimen devoid of antiestrogen drugs. Only with that kind of study can it be demonstrated that the benefit of hormonal therapy is limited to patients with high Stat5 expression and that Stat5 status can even be considered as a predictive factor. Although prognostic marker validation is relatively easy and can be established by using data from retrospective series, more stringent criteria are required for the validation of predictive biomarkers. 2 With regard to the predictive value of Stat5 status for hormonal therapy in breast cancer, the study design chosen by Peck et al 1 does not fit these criteria.

Is gene array testing to be considered routine now?

There are five multi-gene expression based prognostic tests for breast cancer offered as reference lab tests - Mammaprint, MapQuant Dx, OncotypeDx, PAM50 Breast Cancer Intrinsic Subtype Classifier, and Theros Breast Cancer Index. Each claims to provide additional prognostic information beyond conventional prognostic markers and to aid in determining who should receive systemic therapy. Evidence for their clinical utility was reviewed to determine whether any of them should be considered as routine clinical test. Peer reviewed publications, meeting abstracts, and information provided by company web sites have been reviewed to compile information regarding their clinical utility according to the following criteria; (1) Analytical validity and regulatory approval of the reference lab test. (2) Level of evidence for clinical utility. (3) Whether published evidences support prognostic and/or predictive claim. While published evidences for clinical claims for OncotypeDx and Mammaprint used reference lab tests, and the supporting evidences for other tests come from academic assays before being converted to reference lab tests, results from two large randomized clinical trials testing the clinical utility of OncotypeDx and Mammaprint are still several years away and until that time none of the markers would reach level I evidence by Marker Utility Grading System. However Oncotype Dx has reached a level IB evidence according to Simon modification to Marker Utility Grading System. Therefore OncotypeDx may be considered for routine clinical use as an adjunct to clinical and pathological information and has been incorporated into clinical guidelines in USA. While Mammaprint, MapQuantDx, and PAM50 have been repeatedly demonstrated to provide robust prognostic information, evidence for its worth as a predictive marker for chemotherapy benefit is yet to come from randomize clinical trials and therefore its utility is limited to prognostication. Meta-analysis of publicly available microarray based gene expression studies demonstrated that gene expression assays provide similar information and the most important information they provide is the proliferation activity. In untreated population, the prognostic impact of proliferation genes is limited to ER+HER2- subset since HER2+ or ER-HER2- subsets are associated with high proliferation activity. Therefore the clinical utility of these gene expression based tests is mainly for ER+HER2- subset. Since they are usually treated with adjuvant anti-estrogen therapies, for their clinical utility, demonstration of the interaction between the gene expression markers and chemotherapy in anti-estrogen treated cohort in a randomized clinical trial would be required. While OncoytpeDx is the only test supported by studies in a randomized clinical trial for adjuvant chemotherapy, other gene expression based tests are expected to provide similar information. Gene expression profiling assays as more reproducible and precise surrogates for tumor grade (MapQauntDx and Theros Breast Cancer Index) are very promising assays. However, absence of definitive predefined cut-off for defining the subset that benefit from chemotherapy validated in cohorts from randomized trials limit their clinical application.

Abstract A18: Inflaming breast cancer development: Expression of aromatase is increased by TNFα via the early growth response genes

Abstract Introduction: Breast cancer remains the leading cause of cancer-related death in Western women. In postmenopausal cases, up to 70% of tumors are classed as estrogen receptor positive (ER+), dependent on estrogen for continued growth and proliferative advantage. Adjuvant antiestrogen therapies are considered the cornerstone approach to the treatment of such tumors, and as such research is ongoing to maximize the effectiveness of drug treatments. The major source of estrogens for growth of ER+ breast cancers is local conversion of androgen precursors by the enzyme P450 aromatase. Inflammatory factors such as tumor necrosis factor-α (TNFα) stimulate transcription of the CYP19A1 gene that encodes aromatase, via its adipose-specific promoter I.4 (PI.4). The pathways by which this is achieved are not fully understood. Increased concentrations of TNFα are frequently detected within the stromal and epithelial compartments of an ER+ breast tumor microenvironment, contributing to a more invasive tumor fed by the increases in local estrogen production which are, in part, being driven by this critical cytokine. This study aims to identify the mechanisms underlying TNFα-dependent aromatase induction in the context of estrogen-dependent breast cancer. Methods: A custom gene array was performed to assess mRNA changes in primary human breast adipose fibroblasts (BAFs) that had been treated for 1 hr with 5ng/ml TNFα. This data was validated by qRT-PCR. Luciferase reporter assays were performed in C0S7 cells and EMSA assays were carried out using γP-32 detection. Results: A custom array showed that mRNA expression of the early growth response gene Egr1 was increased in BAFs that had been treated for 1 hr with TNFα. The family of early growth response genes Egr1, Egr2, Egr3 and Egr4 were all found to be significantly upregulated in a time-dependent manner in response to TNFα treatment, as validated by qRT-PCR. This occurs via induction of the NFkB pathway, as Egr mRNA induction was reduced in a dose-dependent manner upon pathway inhibition with the IKK-inhibiting compound BAY-11-7082. Egr2, Egr3 and Egr4 were able to induce Pl.4-driven luciferase reporter activity, with Egr2 proving to be the most potent activator. Serial 5′ deletion analysis of the 1 kb PI.4 promoter region revealed that the Egr2-induced promoter activity was mediated by a 41 bp sequence at the 3′ end, a region that did not contain any putative Egr binding sites. EMSA confirmed that there was no binding of any of the four Egr transcription factors to the 41 bp region. Mutagenesis of the 41 bp fragment is being carried out to narrow down the specific region of interest, and novel transcription factor binding sites will be confirmed with further luciferase assays and EMSA. Conclusion: We have elucidated a novel pathway by which TNFα is able to induce aromatase expression and thus estrogen biosynthesis in the breast via induction of the NFkB pathway and early growth response genes. Understanding TNFα signalling and the transcription factors it activates to turn on PI.4 CYP19A1 expression in BAFs is vital to the understanding of breast cancer pathology. These insights may help in the development of diagnostic tools or novel therapeutics in order to tackle the growing instances of this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A18.

Does Adjuvant Antiestrogen Therapy Affect Cognitive Function in Women with Hormone-Sensitive Breast Cancer?

Adjuvant endocrine therapy with tamoxifen or aromatase inhibitors (AIs) is widely prescribed after initial treatment for hormone-sensitive breast cancer — but we know little about the effects of such antiestrogen therapy on cognitive function. Researchers performed neuropsychological assessments in 179 postmenopausal Dutch women (mean age, 68) with estrogen- or progesterone-receptor–positive breast cancer who were enrolled in an international …

Weight changes in breast cancer survivors who received adjuvant antiestrogen therapy

6588 Background: Antiestrogen therapy has dramatically improved breast cancer survival rates but weight gain may be problematic. Studies evaluating antiestrogen therapy-related weight gain have yielded mixed results. Our primary objective was to evaluate weight changes in female breast cancer survivors (BCS) who received adjuvant anti-estrogen therapy for stage 0-III breast cancer. Methods: A retrospective chart review was conducted to evaluate weight changes in female chemo naive BCS receiving anti-estrogen therapy. Weights at initiation of hormonal therapy and at 6, 12, 24, and 36 months of follow-up were recorded. Median weight changes were calculated and were compared with Wilcoxon's signed rank test or the Kurskall-Wallis test. Results: A total of 622 women were included. The majority were white (77%), had stage I disease (78%), and were postmenopausal (82%). The median age at diagnosis was 59 years (range, 26–87). Median weight at initiation of hormonal therapy among premenopausal women was 65 kg (range 45.4–122.9). Median weight gain in this group was 0.4 kg (p = 0.009), 0.7 kg (p = 0.013), 1.9 kg (p = 0.0001), and 2.4 kg (p < 0.0001) at 6, 12, 24, and 36 months respectively. Among post-menopausal women, median weight at initiation of therapy was 71.7 kg (range 41.5–152.0) and median weight gain was 0.5 kg (p < 0.0001), 1 kg (p < 0.0001), 0.85 kg (p = 0.001), and 0.85 kg (p = 0.004) at 6, 12, 24, and 36 months respectively. Premenopausal patients had significantly more weight gain at 24 (p = 0.041) and 36 months (p = 0.005), as compared to postmenopausal patients. Among premenopausal women, 110/111 were treated with tamoxifen. Among post-menopausal women (n = 510), hormonal therapy was as follows: unknown n = 28 patients, tamoxifen n = 312, and AI n = 170. Overall, BCS treated with tamoxifen vs an AI had significantly more weight gain at 24 (p = 0.003) and 36 months (p = 0.009). Conclusions: Premenopausal patients are at higher risk for weight gain than postmenopausal patients. Further prospective research is warranted examining weight gain as a long-term side effect of anti-estrogen therapy in BCS. No significant financial relationships to disclose.

Bone Densitometry and Treatment for Osteoporosis in Older Men

WHEL study enrolled 756 participants with estrogen receptor– negative tumors, with 188 in the first year since diagnosis. The a priori analysis plan of the WHEL study included evaluating effects of interactions between diet group and key covariates (including hormone receptor status of the original tumor and years from diagnosis to randomization) on additional breast cancer events. These were presented in Table 4 of our article. Breast cancer event rates among estrogen receptor–negative women were 20% in the nonintervention arm and 21% in the intervention arm (hazard ratio, 1.08; 95% confidence interval, 0.79-1.48; P=.63). There was no intervention effect on additional breast cancer events among strata defined by years from diagnosis to randomization (P=.50 by likelihood ratio test). Thus, the lack of effect of the WHEL intervention in estrogen receptor–negative patients is not explained by issues of study power or design. Regardingdifferences in the studygroups,wenoted theslight imbalance in the percentage of women who received adjuvant antiestrogen therapy (intervention, 69.4% vs comparison, 65.3%) and those who had a bilateral oophorectomy (intervention, 14.6% vs comparison, 11.4%). Hence, we adjusted for these variables in addition to following the original analysis plan. As shown in Figure 2 of our article, both unadjusted and adjusted hazard ratios for intervention effect yielded similar results. Most importantly, these initial differences in study group would, if anything, have favored an intervention effect, thus strengthening our study conclusions. The WINS investigators concluded that decreasing dietary fat intake may reduce breast cancer recurrence. Such an effect was not confirmed in the WHEL study, although at baseline the study population consumed less than 30% energy from fat. Another possible explanation for the discrepancy is that the WINS intervention appeared to result in moderate weight loss (2.3 kg at 1 year), which might be expected to reduce recurrences. There was less than a 1-kg weight difference between the WHEL study groups throughout the study.

Associations of genetic variants in the estrogen receptor coactivators PPARGC1A, PPARGC1B and EP300 with familial breast cancer

The mitogen effect of the ovarian steroid estrogen is a strong risk factor for breast cancer development. This effect is mainly mediated by the estrogen receptor alpha, a hormone inducible transcription factor, which activates gene expression through recruiting multiple coactivators, such as PPARGC1A, PPARGC1B and EP300. We tested the hypothesis that non-conservative, putative functional amino acid exchanges in PPARGC1A, PPARGC1B and EP300 act as low-penetrance familial breast cancer risk factors. The analysis of 816 BRCA1/2 mutation-negative familial breast cancer patients and 1012 controls revealed an association of the PPARGC1A Thr612Met polymorphism with familial breast cancer (OR = 1.35, 95% CI 1.00-1.81, P = 0.049), high-risk familial breast cancer (OR = 1.51, 95% CI 1.08-2.12, P = 0.017) and bilateral familial breast cancer (OR = 2.30, 95% CI 1.24-4.28, P = 0.009). Logistic regression analyses of the PPARGC1B Ala203Pro variant showed an increased familial breast cancer risk of heterozygous and homozygous variant allele carriers (OR = 1.48, 95% CI 1.15-1.91, P = 0.002). The genotype-combination analysis of the associated PPARGC1A Thr612Met variant and the associated PPARGC1B Ala203Pro variant suggests an allele dose-dependent breast cancer risk (P(trend) = 0.0004). Our results indicate for the first time the importance of inherited variants in the estrogen receptor coactivator genes PPARGC1A and PPARGC1B for familial breast cancer susceptibility. Owing to their impact on estrogen signaling, these polymorphisms might also influence adjuvant anti-estrogen therapy, using agents such as tamoxifen and raloxifen, and outcome of breast cancer patients.

Adverse outcome and resistance to adjuvant antiestrogen therapy in node-positive postmenopausal breast cancer patients—The role of p53

The prognostic and predictive relevance of p53 immunoreactivity is used here as a tentative approach for defining more accurately the benefit of adjuvant hormonal therapy in postmenopausal node-positive breast cancer patients. Ninety-seven postmenopausal patients with axillary lymph node metastasis were treated with an antiestrogen for a period of 3 years after primary surgery and radiotherapy. The p53 status of the primary tumor was assessed by immunohistochemistry and 24% of the samples showed positive expression of p53. Within the average follow-up time of 59 months, disease recurrence was diagnosed in 34 patients (35%). Multivariate analysis showed high clinical stage, negative estrogen receptor status and p53 positivity to be independent prognostic factors predicting both shortened disease-free survival and worse overall survival. p53 immunoreactivity was associated with worse clinical outcome irrespective of hormone receptor status. The data suggest that adjuvant therapy with antiestrogens is insufficient in this patient population with p53-positive tumors.

Phase III, Multicenter, Double-Blind, Randomized Study of Letrozole, an Aromatase Inhibitor, for Advanced Breast Cancer Versus Megestrol Acetate

To compare two doses of letrozole (0.5 mg and 2.5 mg every day) and megestrol acetate (40 mg qid) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. This double-blind, randomized, multicenter, multinational study enrolled 602 patients, all of whom were included in the primary analysis in the protocol. Patients had advanced or metastatic breast cancer with evidence of disease progression while receiving continuous adjuvant antiestrogen therapy, had experienced relapse within 12 months of stopping adjuvant antiestrogen therapy given for at least 6 months, or had experienced disease progression while receiving antiestrogen therapy for advanced disease. Tumors were required to be estrogen receptor- and/or progesterone receptor-positive or of unknown status. Confirmed objective response rate was the primary efficacy variable. Karnofsky Performance Status and European Organization for Research and Treatment of Cancer quality-of-life assessments were collected for 1 year. There were no statistically significant differences among the three treatment groups for overall objective tumor response. Patients treated with letrozole 0.5 mg had improvements in disease progression (P =.044) and a decreased risk of treatment failure (P =.018), compared with patients treated with megestrol acetate. Letrozole 0.5 mg showed a trend (P =.053) for survival benefit when compared with megestrol acetate. Megestrol acetate was more likely to produce weight gain, dyspnea, and vaginal bleeding, and the letrozole groups were more likely to experience headache, hair thinning, and diarrhea. Given a favorable tolerability profile, once-daily dosing, and evidence of clinically relevant benefit, letrozole is equivalent to megestrol acetate and should be considered for use as an alternative treatment of advanced breast cancer in postmenopausal women after treatment failure with antiestrogens.

Matrix metalloproteinase-2 (MMP-2) is associated with the risk for a relapse in postmenopausal patients with node-positive breast carcinoma treated with antiestrogen adjuvant therapy.

Node-positive breast carcinoma is an aggressive disease. Postmenopausal patients benefit from antiestrogen adjuvant therapy. Predictive markers could, however, be useful in selecting these patients for different modalities of adjuvant therapy. Recently, we showed that MMP-2 (72 kD type IV collagenase/gelatinase A) is correlated with unfavorable prognosis in premenopausal breast carcinoma patients. Expression of the immunoreactive protein for MMP-2 was evaluated prospectively in this study in paraffin tissue sections from primary tumors of 100 postmenopausal, node-positive breast carcinoma patients treated with an adjuvant antiestrogen therapy. A specific MMP-2 monoclonal antibody in an avidin-biotin immunohistochemical staining was used. Sixty nine percent of the samples were MMP-2 positive. Eighty three percent of the MMP-2 negative patients lived for 5 years without a recurrence, while only 67% of the patients with an MMP-2 positive primary tumor were recurrence-free at that time (p < 0.05; log rank analysis). MMP-2 positivity showed a significant correlation with shortened survival in patients with a small primary tumor (T1-2) and a low axillary tumor burden. One hundred percent of these patients with an MMP-2 negative breast carcinoma survived for 5 years, compared to 73% of the MMP-2 positive cases alive at that time (p = 0.02). In conclusion, we show here that MMP-2 is a prognostic indicator in postmenopausal patients with node-positive breast carcinoma with a low tumor burden, and that it predicts a risk for failure in antiestrogen adjuvant therapy. It might have predictive value in selecting the most efficient adjuvant therapy in this set of patients.

Cost Effectiveness of Letrozole in the Treatment of Advanced Breast Cancer in Postmenopausal Women in the UK

To simulate the treatment of postmenopausal women with advanced breast cancer from second-line hormone therapy to death, and to generate estimates of the cost and effectiveness of letrozole and megestrol in order to determine the incremental cost effectiveness of letrozole, expressed as cost per life-years gained. A decision-analytic model, using Markov process techniques, was designed to evaluate the lifetime clinical and economic consequences of treatment with letrozole compared with standard care with megestrol. The model was based on clinical trial results showing a clear advantage of letrozole in terms of time to progression and duration of response. The setting of the study was that of the UK healthcare system in 1996. A hypothetical cohort of patients, identical to the patients recruited for the AR/BC2 clinical trial, who were postmenopausal women with advanced breast cancer who had previously failed to respond to first-line or adjuvant anti-estrogen therapy. The dosages of medications were 2.5 and 160 mg/day for letrozole and megestrol, respectively. The analysis covered the period from treatment initiation until death (lifetime model). Effectiveness was expressed as survival and time without progression, and the model also included all relevant economic measures. Based on the model, the average survival time of the letrozole group was 2.1 years (25.3 months) versus 1.9 years (21.5 months) for the megestrol group, a gain in survival of 2.4 months (10.5%). The average time without progression, cumulatively calculated over the different treatment options, amounted to 20.2 months for letrozole and 17.8 months for megestrol, an increase of 13.7% for the former patients. The total average cost per patient for the treatment of advanced breast cancer starting from second-line hormone therapy until death was higher in the letrozole group at 7547 Pounds versus 6820 Pounds for the megestrol group (discounted at an annual rate of 5%), leading to an incremental cost-effectiveness ratio of 3588 Pounds per life-year gained (1996 values). Based on the assumptions used in this model, letrozole offers a suitable alternative to megestrol in the treatment of second-line hormone therapy.

Estradiol modulation of plasminogen activator production in organ cultures of human breast carcinomas: Correlation with clinical outcome of anti‐estrogen therapy

We have studied the estradiol sensitivity of primary human breast carcinomas in organ culture in a prospective pilot series of 109 tumors. The effect on plasminogen activator (PA) production was used as the end-point of estrogen action. We found that: (i) All tumors secreted detectable levels of urokinase-type PA (uPA); the level of basal uPA production was markedly heterogeneous but showed a weak association with the level of estrogen receptor positivity (p = 0.049). (ii) Only 23.5% of the tumors secreted tissue-type PA (tPA) in addition to uPA; a higher proportion of these tumors had histological characteristics indicative of good prognosis (18% vs. 3% of tumors secreting only uPA). (iii) Estradiol modulated uPA production and this effect was receptor-mediated. (iv) Responsiveness to estradiol was limited to a subset (25 of 60 or 41.7%) of estrogen and progesterone-receptor-positive tumors. (v) Of 20 evaluable patients with lymph-node and receptor-positive breast cancer who received adjuvant anti-estrogen therapy, 11 were identified as estradiol-sensitive by the in vitro PA assay; of these, 10 had no evidence of disease after a median follow-up period of 3+ years. In contrast, of 9 patients with tumors identified as estradiol-insensitive, 4 developed metastases within 3+ years of follow-up. (vi) Consistent with the previously reported inhibitory effect of corticosteroids on uPA production in organ cultures of human tumors, the basal culture level of uPA produced by tumors from patients receiving corticosteroids at the time of surgery was significantly lower than the level of uPA in the remaining tumors (p = 0.029). Also, tumors from patients receiving thyroid hormone, known to stimulate uPA in vitro, showed a slight trend toward increased production of uPA. These results show that hormone effects on tumor PA production are qualitatively similar in organ culture and in the host. This and the emerging individual correlation between sensitivity to estradiol in vitro, as determined by PA, and the clinical effectiveness of anti-estrogen therapy, underscore the potential usefulness of the organ culture approach.

Adjuvant Antiestrogen Therapy for Breast Cancer: Past, Present, and Future

Laboratory investigations using animal models of breast cancer growth have indicated that the antiestrogenic compound tamoxifen is a tumoristatic agent. It is therefore effective in suppressing, rather than destroying, the breast tumor. Its use as an adjuvant in breast cancer management has been successful, with a proportion of women benefiting from long periods of tamoxifen treatment. All the initial studies recruited postmenopausal women, but tamoxifen is now proposed for the treatment of premenopausal women for an extended time. Naturally, there are many aspects of the toxicology of tamoxifen to consider; however, careful monitoring of clinical trials will determine the safety of the drug for the general patient population.