Endocrine Treatment Of Breast Cancer Research Articles

Role of SUSHI domain containing 3 (SUSD3) in breast cancer and aromatase inhibitor responsiveness

OBJECTIVE: Aromatase has been the most commonly used target for the hormonal treatment of breast cancer. We previously used microarray gene expression profiling on primary breast cancer tissues with or without a favorable response to an aromatase inhibitor (AI) to determine molecular predictors of clinical benefit. Sushi domain containing 3 (SUSD3) was among the top 3 differentially expressed genes from responders vs. non-responders to an AI. Thus, we investigated the function of SUSD3 in breast cancer. DESIGN: Real-time PCR validation of microarray analysis was performed. Breast and endometrial cancer cell lines were used to explore the correlation between ERα, PR and SUSD3 messenger RNA (mRNA). The regulation of SUSD3 expression after anti-estrogen, anti-progestin, estradiol (E2) and progesterone (P4) treatments was explored. The roles of ERα and PR in SUSD3 regulation were determined by knockdown of these receptors. MATERIALS AND METHODS: mRNA levels were determined by real-time PCR. Knockdown experiments were performed using small-interfering RNA (siRNA). Breast cancer cell lines were treated with anti-estrogen ICI 182780, anti-progestin ZK 98299, E2 and P4. RESULTS: SUSD3 mRNA expression was higher in responders of AI treatment (fold change 3.508 vs. 1, p= 0.0002) and in ERα/PR-positive tumors (fold change: 5.734 vs. 1, p< 0.0001). Elevated SUSD3 mRNA expression was found in highly PR-positive cell lines whereas decreased expression was found in ERα/PR-negative cell lines. E2 induced SUSD3 expression while ICI, ZK, or P4 decreased expression. siRNA knockdown of ERα or PR decreased SUSD3 mRNA levels. siRNA knockdown of SUSD3 decreased ERα and PR mRNA and protein levels. CONCLUSION: We demonstrate that estrogen, ERα, progesterone, and PR regulate SUSD3 both in vivo and in vitro in breast cancer tissues and cells. We postulate a short feedback loop whereby SUSD3 regulates ERα and/or PR expression and transcriptional function, and in turn, ERα and/or PR regulate SUSD3 expression.

Impact of body mass index (BMI) on endocrine therapy in premenopausal breast cancer patients: An analysis of the ABCSG-12 trial.

512 Background: Aromatase inhibitors (AIs) are effective as adjuvant endocrine treatment in breast cancer (BC) patients. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, BMI might have impact on the efficacy of AIs. In this retrospective analysis of ABCSG-12, we investigated the influence of BMI on the effectiveness of adjuvant endocrine therapy (tamoxifen versus anastrozole in combination with goserelin) in premenopausal BC patients. Methods: ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg q28d SC) in combination with anastrozole (ANA) or tamoxifen (TAM) ± zoledronic acid (ZOL, (4 mg IV q6mo) in premenopausal women with endocrine-responsive BC. BMI was calculated using the prospectively collected data on patients's height and weight at study entry. BMI definitions of the WHO were used: normal 18.5-24.9 kg/m2; overweight: BMI ≥ 25 kg/m2, underweight BMI ≤ 18.5 kg/m2). Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method, results were compared by using the log-rank test and Cox proportional hazard modelling. Results: 1,111 (64.0%) patients were normal weight and 573 (33.0%) were overweight. Fifty-two (3.0%) underweight patients were excluded from further analyses. At a median follow-up of 5 years, overweight patients treated with ANA showed significantly shorter DFS (HR 1.60, 95%CI 1.064 2.412 p = 0.02) and OS (HR 2.284, 95%CI 1.217 4.289 p = 0.008) compared to normal weight ANA patients. No differences in DFS or OS were observed between overweight and normal weight patients treated with TAM (p = 0.62 and p = 0.77, respectively). In overweight patients, ANA led to shorter DFS and OS compared to TAM (HR 0.625 95%CI 0.387 1.009 p = 0.052, and HR 0.336 95%CI 0.149 0.76, p = 0.006, respectively), whereas there was no difference regarding DFS (p = 0.53) and OS (p = 0.67) in the group of normal weight patients. Conclusions: BMI significantly impacts on the efficacy of anastrozole plus goserelin but not tamoxifen plus goserelin in the adjuvant endocrine treatment of premenopausal breast cancer patients, probably through influencing aromatase availability in fat tissue. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Novartis AstraZeneca, Novartis AstraZeneca, GlaxoSmithKline, Merck, Novartis, Roche

Gene expression profiling and prediction of response to hormonal neoadjuvant treatment with anastrozole in surgically resectable breast cancer

Aromatase inhibition (AI) is the most effective endocrine treatment for breast cancer in post-menopausal patients, but a percentage of hormone receptor-positive cancers do not benefit from such therapy: for example, about 20% of patients treated with anastrozole do not respond and it is still impossible to accurately predict sensitivity. Our main goal was to identify a robust expression signature predictive of response to neoadjuvant treatment with anastrozole in patients with ER+ breast cancer. At the same time, we addressed the question of delineating treatment effects and possible mechanisms of intrinsic resistance occurring in non-responder patients. We analyzed the transcriptome of 17 tru-cut biopsies before treatment and 13 matched surgical samples after 3 months treatment with anastrozole taken from ER+ breast tumors. Molecular profiles were related to clinical response data. Treatment with anastrozole was associated with a decreased expression of genes relating to cell proliferation and an increased expression of genes relating to inflammatory processes. There was also an enrichment of induction of T-cell anergy, positive regulation of androgen signalling, synaptic transmission and vesicle trafficking in non-responders, and of cell cycle inhibition and induction of immune response in responders. We identified an expression signature of 77 probes (54 genes) that predicted response in 100% of our cases. Five of them were able to accurately predict response on an independent dataset (P = 0.0056) of 52 ER+ breast cancers treated with letrozole. Ten fixed independent samples from the anastrozole study were also used for RT-qPCR validations. This study suggests that a relative small number of genes analysed in a pre-treatment biopsy may identify patients likely to respond to AI neoadjuvant treatment. This may have practical utility translatable to the clinics. Furthermore, it delineates novel mechanisms of intrinsic resistance to AI therapy that could be further investigated in order to explore circumventing treatments.

Mechanisms of resistance to hormonal treatment in breast cancer

Endocrine therapy is a cornerstone in hormone-dependent breast cancer treatment. Despite the effectiveness of this type of treatment, a significant percentage of tumours develop resistance, and hence, patients relapse. This raises the question of which mechanisms are activated by hormone-dependent tumours to become resistant to antihormonal therapy. The aim of this review is to summarise the current knowledge on structure and mechanisms of action of oestrogen receptors and the possible mechanisms of resistance known to date, focusing on the existing crosstalk between oestrogen receptor and growth factor receptor pathways as well as the influence of drug metabolism in its effectiveness. Finally, the clinical evidence of hormonal therapy resistance and the future directions for optimising breast cancer treatment is also discussed.

Aromatase inhibitors in adjuvant endocrine treatment of breast cancer: ending the debate of sequence or upfront?——interpretation of BIG 1-98 clinical trial

The third generation of aromatase inhibitors (AI) play an important role in the adjuvant treatment of hormonal positive postmenopausal breast cancer. Compared with tamoxifen, either upfront or sequential using of Al can both significantly improve the outcome of breast cancer patients. However, there is a continuous debate of sequence or upfront usage of Al in clinical applications. With the publication result of BIG 1-98 clinical trial and interpretation of the data, we can further recognize and optimize the usage of Al in breast cancer treatment. Key words: Breast neoplasms; Aromatase inhibitors; Neoadjuvant therapy

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct anti-estrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients.

Discussion about switch strategy in the adjuvant hormonal therapy of breast cancer: psychological aspects of physician–patient communication

BackgroundA survey of oncologists was conducted in Italy to evaluate the potential problems of physician–patient discussion about hormonal switch in the adjuvant therapy of breast cancer. Materials and methodsA questionnaire, including both closed and open-ended questions, was administered to 70 oncologists. Fifty-one of them returned completely filled questionnaires. ResultsForty-seven percent of the physicians reported difficulties in proposing the hormonal switch, and 60% stated that they found it difficult to make the therapeutic change acceptable to patients. The oncologist's barriers to propose the switch were related mostly to scientific and economic issues, such as the lack of certain advantages of aromatase inhibitors over tamoxifen (28%), their costs (14%) and their side-effects (34%). On the other hand, according to physicians, the patient's barriers to accept the therapeutic change were mainly due to psychological–relational factors, in particular the anxiety produced by the change (40%) and the bad patient–physician communication experienced in the past (26%). ConclusionsPatient–physician communication difficulties about switch strategy in the adjuvant hormonal treatment of breast cancer are, at least in part, related to psychological and relational factors. It is likely that training programs, improving doctor's communication skills, can overcome these problems.

News from endocrine treatment in breast cancer from the San Antonio Breast Cancer Symposium 2008

Endocrine treatment in combination with signal transduction inhibitors was a major concern of this year’s San Antonio Breast Cancer Symposium. Johnston gave the first plenary lecture on how to overcome endocrine resistance. He presented the first results of the EGF30008 trial: Lapatinib in combination with letrozole. The efficacy of aromatase inhibitors compared with tamoxifen for the treatment of hormone receptor-positive breast cancer has been the subject of numerous large-scale clinical trials. Henning Mouridsen from Denmark presented new results from the BIG-1-98 trial. Raimund Jakesz and M Goetz on behalf of the ABCSG presented the results of the ABCSG trials 8 and the pharmacogenetic and gene expression profiles and molecular grade index for the prediction of endocrine therapy.

An efficient steroid pharmacophore-based strategy to identify new aromatase inhibitors

Aromatase, an enzyme involved in the conversion of androgens into estrogens, is an important target for the endocrine treatment of breast cancer. Aromatase inhibition is usually achieved with steroids structurally related to the substrate of catalysis or, alternatively, with azole non-steroid compounds. Substituted androstenedione derivatives with Δ 1, Δ 6 and Δ 1,6 unsaturations and 6-alkyl/6-phenyl aliphatic substitutions, are among the most potent steroid aromatase inhibitors known to date. In this paper we have combined the common pharmacophoric and shape features of these molecules into a new pharmacophore model, useful for virtual screening of large compound databases. Small subsets of the best fitting anti-aromatase candidates were extracted from the NCI database and experimentally tested on an in vitro assay with human placental aromatase. New potent aromatase inhibitors were identified such as compounds 8 and 14. Considering the lack of a crystal structure for the aromatase enzyme, this ligand-based method is a valuable tool for the virtual screening of new aromatase inhibitors.

Key elements for discriminating selective estrogen receptor modulators and selective receptor estrogen down regulators: a molecular approach to classify antiestrogens.

Abstract Abstract #3036 Breast cancer is the most common type of malignancy among women in the world. About 60% of breast tumours express the oestrogen receptor alpha (ERα) and are considered hormone-responsive. Thus endocrine therapies have been the treatment of choice. However, the estrogen-like agonist effect of the available selective estrogen receptor modulators such as tamoxifen and the development of resistances require the development of new treatments that act through different mechanisms.&amp;#x2028; The objective of our study is to design new anti-estrogens and tools that can help to understand the molecular mechanisms involved in ligand dependent modulation or degradation of ERα. It has been proposed that ligand dependent ERα degradation of antagonist may result from the presence of an aliphatic side chain on a steroidal body. Our aim is to exploit the structural characteristics of anti-estrogens to create new compounds with different lateral side chains for the study of the relationship between structure and activity of antiestrogens.&amp;#x2028; We selected the following compounds: RU 39411, RU 58668, which have similar structures of the steroid body, but different side-chain motifs: RU 39411 has a side chain similar to that of Tamoxifen, while RU 58668 has one similar to Faslodex. The third compound, EM 652, has a body of intermediate structure between stilbestrol and oestradiol while the side chain is similar to that of Raloxifen.&amp;#x2028; First, we analysed the degradation of ERα in the presence of the different ligands: Fulvestrant and RU 58668 induce degradation of ERα,in a protasome dependent manner, while RU 39411 and EM 652 have the same effect as Tamoxifen and stabilize ERα. To further analyze the molecular mechanism we generated three mutants of ERα; L540Q (in H12 of ligand binding domain), K362A (interaction with co-activators,) and A350V-D351Y (interaction with side chain of antiestrogens).&amp;#x2028; Using transient transfection of the different mutant constructs of MDA-MB231(ER-negative) cells, we tested the effect of the ligands on gene expression of a luciferase reporter gene under the control of an estrogen inducible promoter and ligand-induced degradation of ER. Our results demonstrate that antiestrogens can be classified into two groups based on structure and function: Tamoxifen and RU39411 fall into a first group, and Faslodex and RU58668 into a second group. However EM 652 has an intermediate behavior. Preliminary results on stable cell lines show that results from transient transfections can be reproduced.and confirm the importance of the integrity of H12 for antagonist activity. Molecular modelisation demonstrates that variations in the structure of the ER ligand binding domain in the presence of different antiestrogens correlate with functional differences.&amp;#x2028; We have used molecular studies to screen and classify antiestrogen compounds into SERM or SERD with the aim to develop novel molecules for endocrine treatment of breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3036.

Menopause surveillance recommendations for patients with endocrine responsive breast cancer.

Abstract Abstract #1148 Background: Women aged under 55 receiving breast cancer treatment frequently experience temporary or permanent menopause as a result. Although defining menopause status in these patients is problematic it fundamentally influences subsequent medical management. No definitive data or consensus exists to guide what surveillance is required in these women, particularly with respect to treatment with aromatase inhibitors (AIs) and/or ovarian suppression and for contraceptive advice.The ENHANCE Group, first convened in Australia in 2006, consists of 19 members, comprising Medical Oncologists, Breast Surgeons, Endocrinologists, Gynaecologists and a Consumer Representative. The aim of the Group is to develop practical advice on the management of QoL and adverse event issues associated with hormonal therapy of breast cancer in areas where high-level evidence is insufficient to inform practice. The Group produces recommendations for healthcare professionals and information leaflets for patients. All recommendations are supported with the maximum evidence available together with broad expert opinion.&amp;#x2028; Methods:A review of the literature identified information regarding the definition of menopause, tests of menopause status and likelihood of menopause following different adjuvant chemotherapy regimens. Data on the likelihood of return of ovarian function was also identified. In addition, the use and benefit of ovarian function suppression and AIs for treatment of different subpopulations of breast cancer patients was reviewed. Using this review and expert opinion provided by members of the Group, an algorithm for determination of menopausal category was developed. Management recommendations, according to menopausal category were then determined.&amp;#x2028; Results:Five distinct menopause categories were identified: Premenopausal, Postmenopausal, Very Low, Low, and Moderate potential for ovarian function recovery. Menopausal status prior to adjuvant chemotherapy, type of adjuvant treatment, age, duration of amenorrhoea, oestradiol and FSH levels and use of tamoxifen determined placement into the categories. The algorithm includes suggested monitoring practice, both clinical and biochemical, for each of the menopause categories and guidance for patients who have had a hysterectomy. The recommendations indicate: (i)contraceptive advice according to age and menopause category; (ii)appropriate use of AIs with suggested monitoring practices; (iii)monitoring suggestions for patients where ovarian function suppression may be appropriate (iv)advice to be provided to patients to assist in monitoring menopausal status. A separate information sheet was developed to inform patients about menopause monitoring.&amp;#x2028; Conclusions:Ovarian function can return after a considerable period of amenorrhoea in patients undergoing systemic treatment for breast cancer. Return of ovarian function influences endocrine treatment of breast cancer, but it is often difficult to monitor accurately, and an appropriate schedule has not been investigated. Our work provides evidence-based recommendations (including expert opinion) for best practice in this area. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1148.

Results of the randomized phase II trial of adjuvant anastrozole versus anastrozole plus fulvestrant in hormone-receptor-positive postmenopausal breast cancer patients with bone marrow micrometastasis (ABCSG trial 21).

Abstract Abstract #4159 Purpose: Endocrine therapy is often the preferred therapeutic approach for patients (pts) with endocrine-responsive, invasive breast cancer. Bone marrow micrometastasis (BMM) is an established prognostic factor for early distant metastasis and cancer-related death. ABCSG-21 was designed to assess the predictive potential of BMM in an endocrine treatment setting.&amp;#x2028; Methods: To be eligible for the study, pts had to be postmenopausal and to have hormone-receptor-positive invasive early breast cancer; it was also mandatory that they had completed their primary breast cancer treatment (neoadjuvant/adjuvant chemotherapy, definitive surgery). Pts with HER2 overexpressing tumors were ineligible. Pts found to have BMM were randomized to receive treatment with either anastrozole 1 mg/day (standard; N=6) or anastrozole 1 mg/day plus fulvestrant 500 mg every 28 days with a loading dose (500 mg) at day 14 (experimental; N=7). The primary objective was to compare the frequency of events (presence of BMM, clinical recurrence and/or death) after 12 months of randomized treatment.&amp;#x2028; Results: The trial was closed after (i) 278 pts were screened, (ii) a BMM detection rate of 6.1% was found (17 of 278 pts), and (iii) 13 eligible BMM-positive pts (4.7%) had been randomized and treated (due to divergence of calculated [i.e. 15%] and actual [5%] risk ratio for the presence of BMM). Of the 17 BMM-positive pts, 65% had a T1 tumor, 60% had N0 disease, and 18% had G1 tumors. Despite small numbers, there were no significant differences in tumor size, frequency of lymph node metastasis, or tumor grading between pts with and without BMM at screening. A total of seven BMM positive pts have so far received 12 months of randomized treatment and also have had their scheduled second BM aspiration. All of these seven pts were BMM-negative at the second assessment, irrespective of study treatment received. No clinical recurrences and/or breast cancer-related deaths were observed.&amp;#x2028; Conclusions: As stated in a previous pooled analysis (Braun et al 2006 NEJM), the presence of BMM is not individually predictable using established histopathological criteria. Thus, to select pts for treatment because of an individually increased risk of recurrence, additional markers (e.g. BMM) need to be tested. The low frequency of BMM found in our study may have several explanations but may also support the conclusion that the risk of distant metastasis and/or disease-related death among postmenopausal hormone-receptor-positive pts is lower than that reflected by the standard algorithm of decision-making with respect to endocrine breast cancer treatment. Both standard and experimental treatments appear to be effective in eliminating residual tumor cells, allowing to conclude that the trial concept remains valid. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4159.

Sexual health issues in Sudanese women before and during hormonal treatment for breast cancer

Recent Sudanese studies have focused on depression and anxiety in women treated for breast cancer (BrCa). Less is known about whether such women suffer from sexual disturbances due to different cancer treatments. This study compares BrCa patients with a healthy control group and assessed the impact of cancer treatment types. The BrCa group included women treated for BrCa with mastectomies, chemotherapy and radiotherapy (N=100). Some received hormonal therapy (N=60) and others had not yet received it (N=40). The control group comprised women who had never had BrCa, non-BrCa (N=100). Outcomes were assessed using the Watts Sexual Function Questionnaire. It was found that many women treated for BrCa suffered from sexual disturbances before hormonal treatment while some regained sexual activity during hormonal treatment. Demographic data show negative correlation (P=0.03) between sexual function and age of the patients, positive correlation (P=0.002) between sexual function and educational level and positive correlation (P=0.031) as well between sexual function and the patient's length of marriage. This study helps to fill the gap in the literature about Sudanese women's sexuality, as many studies indicate the effect of some psychological disturbance (depression and anxiety) and ignoring the effect of sexual function in enhancing patient's quality of life.

Novel aspects in endocrine treatment of breast cancer

In recent years substantial improvements in the treatment of hormone responsive primary breast cancer have been achieved by the introduction of aromatase inhibitors (AIs). This demonstrates that withdrawal of estrogen might be superior to antagonism by the selective estrogen receptor modulator (SERM) tamoxifen. Increased efficacy of AIs could be explained by general inhibition of estrogen dependent mechanisms, not only those which are mediated by classical estrogen receptor (ER) that regulate tumor growth.

The promoter C specific ERα isoform is associated with tamoxifen outcome in breast cancer

Endocrine breast cancer treatment relies on estrogen receptor alpha (ERalpha) assessment, which does not predict response in all cases. We investigated whether ESR1 promoter C driven (ESR1_C) gene expression may shed light on endocrine responsiveness. We investigated archived tumor tissues of 211 patients. Transcript levels of ESR1_C and ESR1_exon3 (all transcripts) were quantified by real-time PCR. mRNA stability was assessed in actinomycin D treated MCF-7 cells. ERalpha protein was quantified using transiently transfected breast cancer cells. Low ESR1_C transcript levels were associated with better overall survival (P = 0.017). High levels of ESR1_C transcript were associated with non-favorable response in tamoxifen treated patients (HR = 2.48; CI 95% 1.24-4.99), an effect that was more pronounced in patients with ERalpha/PgR double-positive tumors (HR = 3.41; CI 95% 1.45-8.04). The ESR1_C isoform had a prolonged mRNA half-life and a more relaxed 5'-UTR structure compared to ESR1_A isoform. ESR1_C levels may aid in the discrimination of patients' endocrine responsiveness.

Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: a retrospective analysis of the ATAC trial

When the mechanism of action behind treatment toxicity reflects the intended effect on the treatment target, the toxicity might be a useful marker for efficacy. During endocrine treatment of breast cancer, the occurrence of symptoms related to oestrogen depletion or oestrogen blockade might thus be a predictor of treatment effectiveness. In this retrospective analysis, the relation between the reported incidence of vasomotor or joint symptoms and breast cancer recurrence in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial is assessed. Women with hormone-receptor-positive tumours who reported vasomotor or joint symptoms at the first follow-up visit (3 months) in the ATAC trial, (which assessed tamoxifen or anastrozole for adjuvant treatment of postmenopausal breast cancer), were compared with women without these symptoms to see if there was a relation between these symptoms and subsequent recurrence. The ATAC trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. 1486 of 3964 (37.5%) eligible women reported newly emergent vasomotor symptoms at the 3-month follow-up visit and had lower subsequent recurrence than those who did not report these symptoms (223 during 10 752 women-years of follow-up vs 366 during 11 573 woman-years of follow-up, respectively; hazard ratio [HR] 0.84 [95% CI 0.71-1.00], p=0.04; adjusted for age, body-mass index, previous hormone-replacement therapy, nodal status, tumour size, and tumour grade). A greater decrease in breast-cancer recurrence was seen for the 1245 of 3964 (31.4%) eligible women who reported new joint symptoms at the 3-month follow-up visit compared with those not reporting these symptoms (158 during 9242 women-years of follow-up vs 366 during 11 573 women-years of follow-up; adjusted HR 0.60 [0.50-0.72], p<0.0001). The appearance of new vasomotor symptoms or joint symptoms within the first 3 months of treatment is a useful biomarker, suggesting a greater response to endocrine treatment compared with women without these symptoms. Awareness of the relation between early treatment-emergent symptoms and beneficial response to therapy might be useful when reassuring patients who present with them, and might help to improve long-term treatment adherence when symptoms cannot be alleviated effectively.

Impaired Tamoxifen Metabolism Reduces Survival in Familial Breast Cancer Patients

Tamoxifen has been the mainstay adjuvant hormonal treatment for breast cancer for many years. Conversion of tamoxifen to its active metabolite, endoxifen, is reduced by low activity of the cytochrome P450 enzyme, CYP2D6. We examined the effect of reduced CYP2D6 activity on the response to tamoxifen in patients with familial early-onset breast cancer. We conducted a case note review and genotyping for the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*41 alleles in 115 patients (47 BRCA1, 68 BRCA2) with familial breast cancer who had been treated with 20-mg tamoxifen following surgery. Eight (7%) individuals had genotypes consistent with poor metabolizer status, and 4 (3.5%) individuals took CYP2D6 inhibitor drugs concomitant with their tamoxifen and were also considered poor metabolizer. Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient group with poor metabolizer CYP2D6 activity. However, a significant effect was confined to patients with BRCA2 mutations with a worse overall survival (median survival, 7 versus 28 years; P = 0.008; adjusted hazard ratio, 9.7). Poor metabolizer status for CYP2D6 predicts worse overall survival in patients with familial breast cancer. Therefore, CYP2D6 inhibitor drugs should not be prescribed concomitantly with tamoxifen. Prospective studies should be undertaken to establish the effect of CYP2D6 status on outcome in familial breast cancer patients treated with tamoxifen.

Regulation of breast cancer-associated aromatase promoters

By converting androstenedione to estrone, or testosterone to estradiol, aromatase is a key enzyme in estrogen biosynthesis. Encoded by a single gene CYP19, aromatase is expressed in various tissues, including ovary, placenta, bone, brain, skin, and adipose tissue, via partially tissue-specific promoters, and is essential for normal estrogen-dependent physiological functions. In disease-free breast tissue, aromatase mRNA is primarily transcribed from the weak promoter I.4 and maintained at low levels in breast adipose stromal fibroblasts. In breast cancer a distinct set of aromatase promoters, i.e. I.3, II, and I.7, is activated, leading to a marked increase in aromatase expression in breast tumors and breast adipose tissue adjacent to a breast tumor, and a consequent local overproduction of estrogen that promotes growth and progression of breast cancer. In addition, the total amount of promoter I.4-specific aromatase transcript in breast adipose fibroblasts may also be increased due to both cytokine-induced desmoplastic reaction and cytokine-stimulated promoter I.4 activity in breast cancer. Targeting aromatase has proven beneficial in treating breast cancer, since aromatase inhibitors are the most effective endocrine treatment of breast cancer to date. However, aromatase inhibitors cause major side effects such as bone loss and abnormal lipid metabolism, due to indiscriminate reduction of aromatase activity in all expression sites of the body. Therefore, inhibition of aromatase expression via breast cancer-associated aromatase promoters is a useful strategy to selectively block local aromatase production, and hence estrogen synthesis, in breast cancer. This review will summarize the significant findings on regulation of the breast cancer-associated aromatase promoters, and highlight the discovery of chemical compounds and nuclear receptor ligands that specifically inhibit activation of these aromatase promoters. Clinical side effects of these agents require development of new drugs with better specificity and efficacy, and epigenetic therapies with breast cancer tissue-selective aromatase siRNA-conjugated nanoparticles.

Effect of Exercise on Biomarkers, Fatigue, Sleep Disturbances, and Depressive Symptoms in Older Women With Breast Cancer Receiving Hormonal Therapy

To compare the effectiveness of a prescribed home-based walking exercise intervention with usual care in older women receiving hormonal treatment for breast cancer, and to examine relationships among levels of the cortisol, serotonin, interleukin-6, and bilirubin biomarkers and fatigue, sleep disturbances, and depressive symptoms. Longitudinal randomized clinical trial. A National Cancer Institute-designated cancer center in the southeastern United States. 20 women (aged 55 years or older) with breast cancer receiving hormonal treatment. Participants were randomized to a walking exercise intervention or usual care. Laboratory samples and the Pittsburgh Sleep Quality Index (PSQI), the Piper Revised Fatigue Scale, and the Center for Epidemiological Studies-Depression Scale were collected at the initial clinic visit and at 12 weeks from the groups. Questionnaires also were collected at weeks 2 and 14. Fatigue, sleep disturbances, depressive symptoms, biomarkers, and exercise. Effect of the exercise intervention on sleep scores was highly significant between groups. Exercise group scores on the PSQI decreased significantly over time (indicating improved sleep quality), although scores did not change significantly within the control group. Sleep actigraphy also showed significantly shorter actual wake time and less movement in the exercise group. Serotonin levels also were significantly affected by the intervention. Data suggest that a walking exercise intervention improves sleep in older women receiving hormonal treatment for their breast cancer. Serotonin levels may be a useful biomarker when assessing sleep disturbances in this group. Clinicians need to be aware that older women receiving hormonal treatment for their breast cancer may experience fatigue, sleep disturbances, and depressive symptoms. Homebased walking activity may reduce symptom severity in this group.

The prevalence and severity of urogenital symptoms in postmenopausal women receiving endocrine therapy for breast cancer

20551 Background: The urogenital side effects of endocrine therapy for breast cancer are well recognized but neither their prevalence nor severity is well described in the non-trial setting. These symptoms can negatively impact quality of life (QoL) and may seriously impact the efficacy of therapy if they compromise adherence to the recommended endocrine treatment. Methods: In this questionnaire study, we utilized a 5-point Likert type scale to assess the prevalence and severity of vulvovaginal and urinary tract symptoms and we also assessed the impact of these symptoms on sexual functioning (Sexual Activity questionnaire) and QoL (FACT-ES questionnaire) in a group of post-menopausal women receiving endocrine therapy for adjuvant or metastatic breast cancer. We also asked if women considered non- adherence to treatment due to adverse effects. Results: 252 post-menopausal women were surveyed, with median age 60 (range 32–91). All women were currently receiving endocrine treatment for breast cancer; 84% in the adjuvant and 16% in the metastatic setting. Tamoxifen was used by 30% of women and Aromatase inhibitors by 67%. Of the women surveyed, 63% reported some degree of urogenital symptoms related to their treatment. 48% reported symptoms of vaginal dryness, 32% dyspareunia, 26% vaginal discharge, 27% vaginal itching/irritation, 5% vaginal bleeding and 12% reported urinary symptoms. 48% of patients who reported vaginal dryness had severe/very severe symptoms. Only 9 patients admitted that they had considered discontinuing treatment because of urogenital side effects. Conclusions: Urogenital side effects are common and were found in 63% of patients. The most common urogenital side effect reported was vaginal dryness, which was reported as severe or very severe in 48%. Despite this degree of severity, only 9 patients reported considering discontinuing therapy because of these side effects. No significant financial relationships to disclose.