Hormone-sensitive Breast Cancer Research Articles

Abstract P5-21-22: Palbociclib in highly pretreated metastatic ER-positive HER-2 negative breast cancer

Abstract Palbociclib, a first-in-class CDK 4/6 inhibitor, in combination with letrozole or fulvestrant is now licensed for the first or second line treatment of postmenopausal women with hormone-sensitive HER-2 negative metastatic breast cancer (MBC), but its activity in later lines is unknown. In Belgium, a compassionate Use Program (CUP) was temporarily established to provide palbociclib after at least 4 lines of systemic treatment for MBC. The UZ Leuven Multidisciplinary Breast Center included 82 patients in this CUP from September 28th 2015 to March 14th 2017. This analysis describes retrospectively collected efficacy (Revised RECIST guideline, version 1.1) and safety data from 68 patients with at least 6 months follow-up at the data cut-off point. The primary endpoint was clinical benefit, defined as being on treatment for at least 6 months (CR + PR + SD). Most of the patients (89.7%) used palbociclib in combination with letrozole. Other combinations are with tamoxifen (2.9%), fulvestrant (2.9%), exemestane (1.5%), anastrazole (1.5%) and megestrol (1.5%). At the data cut-off point, 18 patients are still on-treatment with palbociclib. The average duration of treatment is 5.7 months [range 2m- 17m]. The mean age of the patients was 66.3 years [range 34.8y – 85.9y] at the time of inclusion. Patients had had an average of 5.7 lines of systemic therapy [range 4 – 11 lines] before starting palbociclib, which was in 61.8% at least one line of chemotherapy. In this highly pretreated setting, 29 patients experienced stable disease lasting ≥ 6 months, resulting in an overall clinical benefit rate of 42.6%. 19.1% (13/68) showed stable disease for ≥ 9 months and 8% for ≥ 12 months. The subjective tolerance of the combination treatment was good, with 38% (26/68) of the patients discontinuing or delaying treatment following adverse events which were in the vast majority hematologic but asymptomatic. No factors predicting clinical benefit could be identified: use of chemotherapy before starting Palbociclib (p = 0.4644), age (p = 0.7029), time between primary breast cancer diagnosis and starting palbociclib (p = 0.1919) or time between first metastasis and starting palbociclib (p = 0.1108) and bone-only disease (p = 1,0000) were not significantly associated with clinical benefit at 6 months. These data not only support the findings of the PALOMA studies, but also show unexpectedly high clinical benefit and safety of palbociclib in heavily pretreated endocrine-resistant hormone receptor positive HER-2 negative advanced breast cancer. An update of these data will be presented. Citation Format: Hoste G, Punie K, Wildiers H, Neven P, Berteloot P, Van Nieuwenhuysen E, Han S, Concin N, Salihi R, Lefever I, Vergote I. Palbociclib in highly pretreated metastatic ER-positive HER-2 negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-22.

Abstract OT1-06-01: OPTIMA: A prospective randomized trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in early breast cancer

Abstract Background: Multi-parameter gene expression assays (MPAs) are widely used to estimate individual patient residual risk in hormone-sensitive HER2-negative node-negative early breast cancer, allowing patients with low risk to safely avoid chemotherapy. Evidence for MPA use in node-positive breast cancer is limited. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) aims to validate MPA's as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population. Methods: OPTIMA is a partially blinded multi-center, phase 3 randomized controlled trial with an adaptive two-stage design. The main eligibility criteria are women or men aged 40 or older with resected ER-positive, HER2-negative breast cancer and up to 9 involved axillary lymph nodes. Randomization is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment. Those with a “high risk” tumor MPA score receive standard management whilst those at “low risk” are treated with endocrine therapy alone. The preliminary phase (OPTIMA prelim) evaluated the performance of several MPAs to select a test to be used in the main efficacy trial based on economic analysis, and assessed the feasibility and acceptability of a large UK trial. OPTIMA prelim used Oncotype DX as the primary discriminator; the main trial will use Prosigna (PAM50) with Prosigna Score ≤60 defined as “low-risk”. The co-primary outcomes are (1) Invasive Disease Free Survival (IDFS) and (2) cost-effectiveness of test-directed therapy. Secondary outcomes include IDFS in “low-risk” patients, quality of life and additional survival measures. An integrated qualitative recruitment study will identify and address challenges to recruitment and informed consent. Tumor blocks from all consenting participants will be banked allowing the performance of alternative MPA technologies to be evaluated. Recruitment of 4500 patients will permit demonstration of 3% non-inferiority of test-directed treatment, with 5% significance and 85% power, assuming 3 years follow-up and a control arm 5-year IDFS of at least 85%. The addition of patients from OPTIMA prelim will allow non-inferiority to be assessed with 2.5% significance. Results: OPTIMA-prelim recruited 412 patients in 23 months from 35 sites with a 47% acceptance rate. The main study opened in January 2017. Early progress indicates that the recruitment target is achievable in the intended 46-month timescale through the participation of >100 sites Conclusion: OPTIMA, as one of two large scale prospective trials validating the use of test-guided chemotherapy decisions in node-positive early breast cancer, is expected to have a global impact on breast cancer treatment. Experience from OPTIMA prelim showed that patient advocate support and close engagement with sites will aid trial success. Funding: The project is funded in the UK by the NIHR HTA Programme (10/34/501). Views expressed are those of the authors and not those of the HTA Programme, NIHR, NHS or the DoH. Citation Format: Stein RC, Makris A, Hughes-Davies L, Macpherson IR, Hall PS, Cameron DA, Earl HM, Pinder SE, Poole CJ, Rea DW, McIntosh S, Harmer V, Morgan A, Rooshenas L, Conefrey C, Donovan JL, Hulme C, McCabe C, Stallard N, Campbell A, Higgins H, Bartlett JMS, Marshall A, Dunn JA. OPTIMA: A prospective randomized trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in early breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-06-01.

Surgical Oophorectomy is Ineffective Therapy in Women with Hormone-Receptor Positive Breast Cancer Who are in Historical, but Low-Progesterone Luteal Phase

The hormonal biology of the menstrual cycle has major relevance in the treatment of hormone-sensitive breast cancer. There are 500,000 new cases of hormone-receptor positive breast cancer in premenopausal women annually; 80% of these are among women in low- and middle-income countries. Surgical oophorectomy should play a major role in the treatment of these women. New data from two phase III clinical trials show that women who are in historical luteal phase, but have low progesterone levels at the times of their oophorectomy surgeries benefit little from this intervention. The unique sequence of hormonal signaling to micro-metastases which occurs in this situation offers a logical explanation for this observation. Because surgical oophorectomy is a safe and widely practical and affordable intervention, this new observation and explanation deserves the attention of the practicing global surgical community. Universal application of surgical oophorectomy treatment could save 100,000 lives of young women with breast cancer each year.

Growth of human breast cancers in Peromyscus.

ABSTRACTModeling breast cancer in general and hormone-sensitive breast cancer, in particular in mice, has several limitations. These are related to the inbred nature of laboratory mice, and do not allow adequate appreciation of the contribution of the host's genetic heterogeneity in tumor growth. In addition, the naturally low estrogen levels of mice makes estradiol supplementation obligatory for tumor growth. Here, we show that Peromyscus californicus, following cyclosporine-mediated immunosuppression, supports the growth of both MDA-MB-231 estrogen-independent and MCF7 estrogen receptor-positive breast cancers without exogenous estradiol supplementation. Tumor growth was inhibited by fulvestrant or letrozole, confirming that MCF7 xenografts remain hormone dependent in vivo and suggesting that P. californicus can be used as an alternative to conventional mice for the study of hormone-sensitive breast cancer. The fact that Peromyscus stocks are outbred also facilitates the study of breast cancer in genetically heterogenous populations.

The utility of anti-Müllerian hormone in the diagnosis and prediction of loss of ovarian function following chemotherapy for early breast cancer

AimChemotherapy results in permanent loss of ovarian function in some premenopausal women. Accurate identification in women with hormone-sensitive early breast cancer (eBC) would allow optimisation of subsequent endocrine treatment. We sought to assess whether analysis of anti-Müllerian hormone (AMH) using a sensitive automated assay could identify women who would not regain ovarian function after chemotherapy. MethodsData from women in the Ovarian Protection Trial in Premenopausal Breast Cancer Patients (OPTION) trial of goserelin (a gonadotrophin-releasing hormone (GnRH) analogue) for ovarian protection were analysed. Women were assessed for premature ovarian insufficiency (POI: amenorrhoea with elevated follicle-stimulating hormone (FSH)) at 24 months after diagnosis. The accuracy of AMH for the diagnosis of POI and its prediction from measurement at the end of chemotherapy was calculated. ResultsAMH below the level of detection showed good diagnostic accuracy for POI at 24 months (n = 73) with receiver operating characteristic (ROC) area under the curve of 0.86, sensitivity 1.0 and specificity 0.73 at the assay limit of detection. In women aged >40 at diagnosis who did not receive goserelin, AMH measured at end of chemotherapy also gave good prediction of POI at 24 months (area under the curve (AUC) 0.89 95% CI 0.75–1.0, n = 32), with sensitivity 0.91, specificity 0.82, diagnostic odds ratio (DOR) 42.8. FSH gave slightly lower AUC, and specificity was low at 0.55. Age but not tamoxifen impacted on AMH levels. ConclusionUsing this sensitive AMH assay, the finding of an undetectable AMH level in women aged >40 at the end of chemotherapy for eBC gave a good prediction that ovarian function would not return. This may allow alterations in post-chemotherapy endocrine management.

Abemaciclib Improves Outcome in Endocrine-Sensitive Breast Cancer

Abemaciclib Improves Outcome in Endocrine-Sensitive Breast Cancer

Endocrine Treatment of Breast Cancer: Current Perspectives, Future Directions

Breast cancer remains one of the major causes of death in women, and endocrine treatment is currently one of the mainstay of treatment in patients with estrogen receptor positive breast cancer. Endocrine therapy either slows down or stops the growth of hormone-sensitive tumors by blocking the body’s capability to yield hormones or by interfering with hormone action. In this paper, we intended to review various approaches of endocrine treatments for breast cancer highlighting successes and limitations. There are three settings where endocrine treatment of breast cancer can be used: neoadjuvant, adjuvant, or metastatic. Several strategies have also been developed to treat hormone-sensitive breast cancer which include ovarian ablation, blocking estrogen production, and stopping estrogen effects. Selective estrogen-receptor modulators (SERMs) (e.g. tamoxifen and raloxifene), aromatase inhibitors (AIs) (e.g. anastrozole, letrozole and exemestane), gonadotropin-releasing hormone agonists (GnRH) (e.g. goserelin), and selective estrogen receptor downregulators (SERDs) (e.g. fulvestrant) are currently used drugs to treat breast cancer. Tamoxifen is probably the first targeted therapy widely used in breast cancer treatment which is considered to be very effective as first line endocrine treatment in previously untreated patients and also can be used after other endocrine therapy and chemotherapy. AIs inhibit the action of enzyme aromatase which ultimately decrease the production of estrogen to stimulate the growth of ER+ breast cancer cells. GnRH agonists suppress ovarian function, inducing artificial menopause in premenopausal women. Endocrine treatments are cheap, well-tolerated and have a fixed single daily dose for all ages, heights and weights of patients. Endocrine treatments are not nearly as toxic as chemotherapy and frequent hospitalization can be avoided. New drugs in preliminary trials demonstrated the potential for improvement of the efficacy of endocrine therapy including overcoming resistance. However, the overall goals for breast cancer including endocrine therapy should focus on effective control of cancer, design personalized medical therapeutic approach, increase survival time and quality of life, and improve supportive and palliative care for end-stage disease.

Estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid in hormone sensitive breast cancer cells in vitro.

BackgroundZoledronic acid (ZA) has antiresorptive effects and protects from bone metastasis in women with early breast cancer. In addition, in postmenopausal women with endocrine responsive breast cancer ZA prolongs DFS. The exact mechanism is still unclear. We have therefore investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro.Materials and methodsUsing assays for cell proliferation (EZ4U, BrdU) and cell death (Annexin/PI), we have analyzed the dose-dependent antiproliferative and pro-apoptotic effects of ZA in two hormone sensitive cell lines (MCF-7 and T47D) and a hormone insensitive, triple negative cell line (MDA-MB-231) in the presence of 0, 1 and 10 nM estradiol.ResultsIn the absence of estradiol, ZA exerts dose-dependent antiproliferative and pro-apoptotic antitumor effects in both, hormone sensitive (MCF-7, T47D) and -insensitive (MDA-MB-231) breast cancer cell lines (p<0.0001). In the presence of estradiol, the antitumoral effect of ZA was significantly decreased only in the hormone sensitive MCF-7 and T47D cell lines (p = 0.0008 and p = 0.0008, respectively).ConclusionWe have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of ZA in hormone sensitive, but not in hormone insensitive breast cancer cell lines. Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal patients with hormone sensitive early breast cancer, which has been demonstrated clinically. We further hypothesize that endocrine insensitive tumors such as triple negative breast cancer (TNBC) should benefit from ZA irrespective of their menopausal status.

Improvement of Bone Physiology and Life Quality Due to Association of Risedronate and Anastrozole.

The endocrine therapy is the new frontiers of many breast cancers hormone sensitive. Hormone therapy for treating women with hormone receptor-positive cancer suppresses breast cancer growth either by reducing estrogen synthesis or by interfering with the action of estrogen within tumor cells. In this prospective randomized observational study we investigate the effect of adjuvant anastrozole in monotherapy or associated with risedronate on bone physiology and quality of life in postmenopausal, hormone-sensitive early breast cancer women at mild to moderate risk of fragility fractures.Methods : 84 women were randomly assigned to receive anastrozole alone (group A) or anastrozole plus oral risedronate (group A+R). At baseline and after 24 months lumbar spine (LS) and femoral neck (FN) BMD were evaluated with dual-energy x-ray absorptiometry and health-related quality of life (HRQoL) was examined using the short-form healthy survey.Results : After 24 months, the group A+R has showed a significant increase in T-score for LS (p < 0.05) and for FN (p < 0.05) whereas women of group A had a statistically significant rate of bone loss both in LS T-score (p < 0.05) and in FN (p < 0.05). A significant change in T-score BMD was seen for group A+R compared with group A at the LS (p = 0.04) and at FN (p = 0.04). Finally, group A+R showed an overall significant improvement of health profile (SF-36) in group A (p = 0.03).Conclusion : Postmenopausal breast cancer women with osteopenia during treatment with anastrozole have considerable risk of developing osteoporosis during the first 2 years; preventive measures such as healthy lifestyle and daily supplements of calcium and vitamin D alone seem to be insufficient in holding their bones healthy. Our findings suggest the usefulness of addition of risedronate in order to prevent aromatase inhibitors-related bone loss, not only in case of high-risk of fractures, but also for women at mild-moderate risk. This determines a significant improvement in bone health and a positive impact on HRQoL.

Proteasome 26S subunit PSMD1 regulates breast cancer cell growth through p53 protein degradation.

Endocrine therapy using antiestrogens and aromatase inhibitors is usually efficient to treat patients with hormone-sensitive breast cancer. Many patients with endocrine therapy, however, often acquire resistance. In the present study, we performed functional screening using short hairpin RNA library to dissect genes involved in antiestrogen tamoxifen resistance in MCF-7 breast cancer cells. We identified seven candidate genes that are associated with poor prognosis of breast cancer patients based on clinical dataset. The expression levels of six out of seven genes were higher in 4-hydroxytamoxifen (OHT) resistant MCF-7 (OHTR) cells compared with parental MCF-7 cells. Among the six selected genes, siRNA-mediated knockdown of PSMD1 and TSPAN12 markedly reduced the proliferation of OHTR cells. Notably, the knockdown of proteasome 26S subunit PSMD1 exhibited cell cycle arrest and the accumulation of p53 protein through inhibiting p53 protein degradation. In accordance with p53 accumulation, its target genes p21 and SFN were also upregulated by PSMD1 silencing. Taken together, PSMD1 was identified as a potential gene that plays a role in the development of tamoxifen resistance in breast cancer cells. These findings will provide a new insight for the mechanism underlying endocrine therapy resistance and a prognostic and therapeutic molecular target for advanced breast cancer.

Efficacy and safety of endocrine monotherapy as first-line treatment for hormone-sensitive advanced breast cancer: A network meta-analysis.

Endocrine therapy was recommended as the preferred first-line treatment for hormone receptor-positive (HR+, i.e., ER+ and/or PgR+), human epidermal growth factor receptor-2-negative (HER2-) postmenopausal advanced breast cancer (ABC), but which endocrine monotherapy is optimal lacks consensus. We aimed to identify the optimal endocrine monotherapy with a network meta-analysis. We performed a network meta-analysis for a comprehensive analysis of 6 first-line endocrine monotherapies (letrozole, anastrozole, exemestane, tamoxifen, fulvestrant 250 mg and 500 mg) for HR+ HER2- metastatic or locally advanced breast cancer in postmenopausal patients. The main outcomes were objective response rate (ORR), time to progression (TTP), and progression-free survival (PFS). Secondary outcomes were adverse events. We identified 27 articles of 8 randomized controlled trials including 3492 patients in the network meta-analysis. For ORR, the treatments ranked in descending order of effectiveness were letrozole > exemestane > anastrozole > fulvestrant 500 mg > tamoxifen > fulvestrant 250 mg. For TTP/PFS, the order was fulvestrant 500 mg > letrozole > anastrozole > exemestane > tamoxifen > fulvestrant 250 mg. We directly compared adverse events and found that tamoxifen produced more hot flash events than fulvestrant 250 mg. Fulvestrant 500 mg and letrozole might be optimal first-line endocrine monotherapy choices for HR+ HER2- ABC because of efficacious ORR and TTP/PFS, with a favorable tolerability profile. However, direct comparisons among endocrine monotherapies in the first-line therapy setting are still required to robustly demonstrate any differences among these endocrine agents. Clinical choices should also depend on the specific disease situation and duration of endocrine therapy.

Preservation of Fertility or Ovarian Function in Patients with Breast Cancer or Gynecologic and Internal Malignancies.

Because of the efficacy of systemic therapies, neoplasias which occur in pediatric and adolescent patients and in young adults have high cure rates. This means that fulfilling their wish to have children has become a more pressing concern, particularly among young women with malignant tumors. Premature ovarian failure is also a not insignificant problem as it has a lasting detrimental effect on quality of life. Every oncology patient who may potentially wish to have children should be informed about their options for preserving fertility prior to starting treatment. The rates of patient who received detailed briefing on this point remain low. This review presents the effects of different chemotherapeutic drugs on gonadal function together with an overview of currently valid recommendations on fertility preservation. Risk groups are defined and the specific approaches for malignancies of various organ systems are described. Cryopreservation of oocytes, fertilized embryos and ovarian tissue are fertility-preserving options for girls/young women. The data on the benefits of administering GnRH analogs for ovarian protection prior to starting chemotherapy are not clear. In postpubertal boys or male cancer patients, the standard approach is to cryopreserve sperm before starting therapy. The cryopreservation of testicular tissue is possible for prepubertal boys, however in-vitro sperm maturation is still in its experimental stages. This review also presents existing drug options for the preservation of ovarian function in oncology patients prior to chemotherapy, particularly for patients with (hormone-sensitive) breast cancer, and looks at the special issues of fertility-preserving surgery and radiation therapy in patients with gynecologic malignancies.

Abstract 5644: The emergence of resistance to tamoxifen in relation to menopausal status, HER-2 status, status of steroid receptor and lymph nodes metastases status

Abstract Background: The study used data from medical and counselling of patients who were diagnosed with hormonedependent breast cancer. Aim: The objective of the paper is to identify within a group of patients diagnosed with hormone sensitive breast cancer and those who have received adjuvant tamoxifen, and then to isolate the patients with whom the therapeutic effect of tamoxifen stopped. Methods: The study analyzed 153 patients in the period from 2005 to 2011, at the Public Health Institution Hospital, Sveti Vračevi" in Bijeljina. Resistance to tamoxifen was developed by 60 patients (39.2%) and 93 patients (60.8%) did not develop resistance to it. Results: More common emergence of resistance is in the premenopausal group of patients (p&amp;lt;0.001). Statistically significant difference in frequency of resistance to tamoxifen was observed in the group of patients with ER-/PrR+ status of steroid receptors (p&amp;lt;0.001). In relation to HER-2 status of diagnosed cancer, a statistically significant difference in frequency of resistance emergence during tamoxifen therapy in patients with HER2-positive status (p&amp;lt;0.001) was observed. We found that there is a statistically significant difference between patients with metastatic in lymph nodes compared to patients who had no metastases in lymph nodes (X2=39.494; p&amp;lt;0.001). Conclusions: The analysis of menopausal status of patients, status of ER/PgR receptors status, HER-2 status of diagnosed cancer and status of lymph nodes trying to sort out the parameters on the basis of which a group of patients who can be expected to develop resistance to tamoxifen could be differentiated. Note: This abstract was not presented at the meeting. Citation Format: Sinisa Maksimovic. The emergence of resistance to tamoxifen in relation to menopausal status, HER-2 status, status of steroid receptor and lymph nodes metastases status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5644. doi:10.1158/1538-7445.AM2017-5644

Abstract 3604: Effect of a new oral SERD AZD9496 on ER mediated signaling in xenograft model of postmenopausal breast cancer

Abstract Aromatase inhibitors (AIs) have made significant improvements in the treatment outcomes of patients with breast cancer. However, tumors may eventually acquire resistance. One of the proposed mechanisms of resistance to AIs is overexpression of ERα and cross-talk of ERα with growth factor receptors. Studies including our own have shown that downregulation of ER with fulvestrant may provide benefit in the treatment of AI-resistant breast cancer. Fulvestrant has been employed in the clinic as either first or second line treatment for ER positive breast cancers alone or in combination with AIs. Studies have suggested that further escalation of dose may provide further benefit. However, dose escalation of fulvestrant which is administered via intramuscular injection is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active SERD (selective estrogen receptor downregulator), AZD9496 was developed. We evaluated the effect of AZD9496 on the growth of hormone sensitive and anastrozole resistant breast cancer tumors using MCF-7Ca xenograft model of postmenopausal breast cancer. Mice bearing xenografts of MCF-7Ca were then treated with fulvestrant (1 mg/d-sc) or AZD9496 (5 mg/kg/d-po), alone or in combination with anastrozole (200μg/d-sc) for 23 weeks. Tumors were measured weekly and growth rate was calculated. AZD9496 was significantly better at inhibiting the growth of tumors compared to control (p&amp;lt;0.001) and anastrozole (p=0.04) while being equally effective as fulvestrant (p&amp;gt;0.99). In the second study, efficacy of AZD9496 was evaluated on against anastrozole resistant MCF-7Ca xenografts. Tumors were treated with anastrozole (200μg/d) for 13 weeks. During this time, the tumors initially regressed but eventually began to grow and had doubled in volume. At this time-point, they were regrouped to receive second line treatment. Single agent AZD9496 was marginally significant compared to continued anastrozole treatment (p=0.07). Nevertheless, second line treatment with AZD9496 was equally effective as fulvestrant (p=0.36). AZD9496 treatment was also equally effective in reducing the expression of ERα protein in MCF-7Ca xenografts as fulvestrant. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was not significantly different from mice that were treated with androstenedione (p=0.99). Furthermore, AZD9496 did not decrease the expression of ERα in the uterus, confirming its selectivity for mammary ERα. AZD9496 treatment was also able to reduce intratumoral aromatase activity. However, it was not due to direct inhibition of the enzyme, but due to reduction in ERα mediated signaling. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its oral bioavailability, selectivity for mammary ER, and ability to reduce aromatase activity while being equally effective as fulvestrant. Citation Format: Gauri J. Sabnis, Armina Kazi, Amanda Schech, Stephen Yu, Olga Golubeva, Angela Brodie. Effect of a new oral SERD AZD9496 on ER mediated signaling in xenograft model of postmenopausal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3604. doi:10.1158/1538-7445.AM2017-3604

Abstract 3862: In vivo chemopreventive of pseudosemiglabrin via inhibition of tumor angiogenesis and manipulation of hormones in estrogen-responsive breast cancer

Abstract Breast cancer is the most frequently diagnosed form of malignancy and the second leading cause of death in Western women. Mortality and most of the complications associated with breast cancer are due to metastasis developing in regional lymph nodes and in distant organs, including bone, lung, liver and brain. Chemopreventive is administration of chemical agents to prevent the initiational and promotional events associated with carcinogenesis. Some chemopreventive agents can prevent reaction or attacking molecules by different ways, these agents can suppress growth factors or signaling pathway. On this study we examined (-)-Pseudosemiglabrin (SSG) a natural compound extracted from Tephrosia apollinea on breast cancer cells and tumor vascularization in vitro and in vivo. Hormone sensitive breast cancer cell MCF-7 was found subtitle susceptible to SSG, it showed profound antitumorgeneis via inhibiting breast cancer cell migration, invasion and colony formation in vitro settings. In silico investigation of potential PARP inhibitor, SSG showed high binding affinity comparable to Rucaparib (standard PARP inhibitor). The natural compound significantly inhibited the sprouting of new blood vessels in ex vivo rat aorta ring assay; the antiangiogenic efficacy is perturbed by targeting VEGF expression and VEGFR phosphorylation. SSG completely inhibited the onset of breast cancer in animals pretreated with the compound. Molecular docking study showed that SSG binds to active site of Aromatase (the enzyme responsible for a key step in the biosynthesis of estrogens) with binding affinity better than standard aromatase inhibitor (Arimidex), moreover the compound has inhibitory activity against estrogen receptor in the breast cancer cells comparable to Tamoxifen. Our findings reveal that (-)-Pseudosemiglabrin can potentially be beneficial in preventing breast cancer in high-risk women or it can be adjuvant therapy with standard chemotherapy or even can be used for the treatment of women who have been diagnosed with breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Loiy E. Ahmed Hassan. In vivo chemopreventive of pseudosemiglabrin via inhibition of tumor angiogenesis and manipulation of hormones in estrogen-responsive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3862. doi:10.1158/1538-7445.AM2017-3862

Targeting Insulin Receptor in Breast Cancer Using Small Engineered Protein Scaffolds.

Insulin receptor (InsR) and the type I insulin-like growth factor (IGF1R) are homologous receptors necessary for signal transduction by their cognate ligands insulin, IGF-I and IGF-II. IGF1R mAbs, intended to inhibit malignant phenotypic signaling, failed to show benefit in patients with endocrine-resistant tumors in phase III clinical trials. Our previous work showed that in tamoxifen-resistant cells, IGF1R expression was lacking, but InsR inhibition effectively blocked growth. In endocrine-sensitive breast cancer cells, insulin was not growth stimulatory, likely due to the presence of hybrid InsR/IGF1R, which has high affinity for IGF-I, but not insulin. Combination inhibition of InsR and IGF1R showed complete suppression of the system in endocrine-sensitive breast cancer cells. To develop InsR-binding agents, we employed a small protein scaffold, T7 phage gene 2 protein (Gp2) with the long-term goal of creating effective InsR inhibitors and diagnostics. Using yeast display and directed evolution, we identified three Gp2 variants (Gp2 #1, #5, and #10) with low nanomolar affinity and specific binding to cell surface InsR. These Gp2 variants inhibited insulin-mediated monolayer proliferation in both endocrine-sensitive and resistant breast cancer, but did not downregulate InsR expression. Gp2 #5 and Gp2 #10 disrupted InsR function by inhibiting ligand-induced receptor activation. In contrast, Gp2 #1 did not block InsR phosphorylation. Notably, Gp2 #1 binding was enhanced by pretreatment of cells with insulin, suggesting a unique receptor-ligand-binding mode. These Gp2 variants are the first nonimmunoglobulin protein scaffolds to target insulin receptor and present compelling opportunity for modulation of InsR signaling. Mol Cancer Ther; 16(7); 1324-34. ©2017 AACR.

Surgical Oophorectomy Plus Tamoxifen Provides the Optimal Systemic Treatment for Pre-Menopausal Women with Hormone Sensitive Breast Cancer

Surgical Oophorectomy Plus Tamoxifen Provides the Optimal Systemic Treatment for Pre-Menopausal Women with Hormone Sensitive Breast Cancer

Fulvestrant 500 milligrams as endocrine therapy for endocrine sensitive advanced breast cancer patients in the real world: the Ful500 prospective observational trial.

The observational prospective trial herein presented aimed at evaluating the efficacy of fulvestrant 500 mg in the treatment of endocrine sensitive advanced breast cancer patients from the real world setting. The primary end point was clinical benefit rate (CBR). Secondary end points were overall survival (OS), progression free survival (PFS) and tolerability. One hundred sixty three patients were enrolled. At a median follow up of 20 months, the 61% of patients reached CBR, whose median duration was 10.8 months. Median PFS and OS were 7 and 35 months, respectively. Endocrine sensitive patients showed better PFS and OS. No relevant toxicity appeared when analyzing safety data. In multivariate analysis, visceral involvement, endocrine sensitivity and previous endocrine therapy were prognostic factor for PFS, whereas endocrine sensitivity and metastasis at diagnosis had prognostic relevance for OS. Estrogen receptor expression >50%, single metastatic site, and no prior endocrine therapy for advanced disease were predictive of CBR. In this prospective trial, fulvestrant 500 mg appeared to be a safe and active treatment and confirmed its efficacy in the daily clinical practice. A high percent expression of estrogen receptors (above 50%) was associated with higher CBR. Treatment was very well tolerated. Endocrine sensitivity had a major impact on treatment outcome. As expected, patients who had received first-line endocrine therapy for advanced disease exhibited worse outcome and a lower CBR.

Anti-tumor efficacy of new 7α-substituted androstanes as aromatase inhibitors in hormone-sensitive and resistant breast cancer cells

The majority of breast cancer cases are estrogen receptor positive (ER+). Although, third-generation aromatase inhibitors (AIs) are used as first-line treatment in post-menopausal women, they cause endocrine resistance and bone loss, which limits their success. Therefore, there is a demand to discover new potent molecules, with less toxicity that can circumvent these drawbacks. Our group has previously demonstrated that new 7α-substituted steroidal molecules, 7α-(2ξ,3ξ-epoxypropyl)androsta-1,4-diene-3,17-dione (3), 7α-allylandrost-4-ene-3,17-dione (6), 7α-allylandrost-4-en-17-one (9), 7α-allyl-3-oxoandrosta-1,4-dien-17β-ol (10) and 7α-allylandrosta-1,4-diene-3,17-dione (12) are potent AIs in placental microsomes. In this work, it was investigated their anti-aromatase activity and in vitro effects in sensitive and resistant breast cancer cells. All the steroids efficiently inhibit aromatase in breast cancer cells, allowing to establish new structure-activity relationships for this class of compounds. Moreover, the new AIs can inhibit breast cancer cell growth, by causing cell cycle arrest and apoptosis. The effects of AIs 3 and 12 on sensitive cells were dependent on aromatase inhibition and androgen receptor (AR), while for AI 9 and AI 10 were AR- and ER-dependent, respectively. In addition, it was shown that all the AIs can sensitize resistant cancer cells being their behavior similar to the sensitive cells. In summary, this study contributes to the understanding of the structural modifications in steroidal scaffold that are translated into better aromatase inhibition and anti-tumor properties, providing important information for the rational design/synthesis of more effective AIs. In addition, allowed the discovery of new potent 7α-substituted androstane molecules to inhibit tumor growth and prevent endocrine resistance.

Use of anastrozole in the chemoprevention and treatment of breast cancer: A literature review.

Aromatase inhibitors have emerged as an alternative endocrine therapy for the treatment of hormone sensitive breast cancer in postmenopausal women. The use of third-generation inhibitors represented by exemestane, letrozol and anastrozole is currently indicated. Anastrozole is a nonsteroidal compound and a potent selective inhibitor of the aromatase enzyme. Although a few studies have shown that its pharmacodynamic and pharmacokinetic properties may be affected by interindividual variability, this drug has been recently used in all configurations of breast cancer treatment. In metastatic disease, it is currently considered the first-line treatment for postmenopausal women with estrogen receptor-positive breast tumors. Anastrozole has shown promising results in the adjuvant treatment of early-stage breast cancer in postmenopausal women. It has also achieved interesting results in the chemoprevention of the disease. Therefore, due to the importance of anastrozole both for endocrine treatment and chemoprevention of hormone-sensitive breast cancer in postmenopausal women, we proposed the current literature review in the SciELO and PubMed database of articles published in the last 10 years.