Hormone-dependent Metastatic Breast Cancer Research Articles

Abstract P074: STAT3 pathway in palbociclib resistance in breast cancer cell lines and the role of inhibitors such as tocilizumab and silymarin

Abstract Introduction Resistance to cyclin inhibitors such as palbociclib is a challenge in the treatment of hormone-dependent metastatic breast cancer. Likewise, triple negative tumors are resistant to these inhibitors. The role of the present research is to identify the role that the transcription factor STAT3 (antiapoptotic transcription factor) and the inhibitors of the STAT3 pathway, such as tocilizumab (interleukin 6 receptor inhibitor) and silymarin (extract of milk thistle containing silibinin, a STAT3 inhibitor), could have in this situation. Methods Breast cancer cell lines MCF-7 (positive for estrogen receptors) and MDA-MB-231 (triple negative) were cultured in DMEM + 10% FBS for 72 hours with different concentrations of palbociclib, tocilizumab and silymarin in order to obtain cell growth inhibition values ​​(IC50) in each compound and combinations of palbociclib with tocilizumab or silymarin. In these cases, the combination indexes (CI < 1 (synergy) and CI > 1 (antagonism)) were calculated using CompuSyn software. Likewise, an RNA extraction was carried out from the untreated cell lines to determine the basal expression levels of STAT3 by RT-qPCR. Results The IC50 of palbociclib in MCF-7 was 3.14 µM and in MDA-MB-231, 29.69 µM. The results of RT-qPCR for the basal expression of STAT3 revealed its absence of expression in MCF-7 and the presence of expression in MDA-MB-231, which could be related to the greater resistance to palbociclib of this last cell line. Tocilizumab did not present cytotoxicity per se and silymarin did not reach IC50 value in the cell lines studied (both compounds in doses up to 100 µM). Regarding the combinations of silymarin (50 µM and 75 µM) and palbociclib (0.1 µM and 1 µM), a synergistic effect (CI < 1) was detected in all the combinations studied in MCF-7 and in most of the same in MDA-MB-231 (except 75 µM silymarin and 0.1 µM palbociclib). However, in the case of the combination of tocilizumab (10 µM and 50 µM) and palbociclib (0.1 µM, 1 µM and 5 µM in MCF-7, and 5 µM, 10 µM and 25 µM in MDA-MB-231) synergy was only obtained in half of the combinations studied in both cell lines. Conclusion STAT3 factor could be related to resistance to cyclins in hormone-dependent breast cancer and to the lower sensitivity to these drugs observed in triple-negative breast cancer. The synergistic combination of palbociclib with silymarin, a STAT3 inhibitor, in both the hormone-sensitive and triple negative cell lines indicates that silymarin could help to enhance the effect of palbociclib in breast cancer and, even, help to reverse the resistance to this drug both in the hormone dependent and triple negative, although further studies would be needed to confirm this fact. Citation Format: Kevin Doello, Cristina Mesas, Víctor Amecua, Marco Fuel, Laura Cabeza, Raúl Ortiz. STAT3 pathway in palbociclib resistance in breast cancer cell lines and the role of inhibitors such as tocilizumab and silymarin [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P074.

Cáncer de mama avanzado receptor de estrógeno positivo: Manejo sistémico actual

Breast cancer is the leading cause of cancer death in Chilean women. While most patientes are cured, five percent of cases present with advanced disease initially and up to 20-30% of patients with localized disease may suffer systemic recurrences. The majority of breast neoplasms are dependent on the estrogenic stimulus, hence the deprivation of estrogen is the main therapeutic strategy. Recently, the use of molecular targeted therapies in combination with endocrine therapy has been successful in improving the survival outcomes of advanced breast cancer, with fewer side effects than those produced by conventional chemotherapy. Knowledge of the mechanisms of action of these new therapies, their toxicities, resistance pathways and patient selection to achieve the best therapeutic benefits are relevant aspects in the management of the disease. We present a review of the current state of management of hormone-dependent metastatic breast cancer with emphasis on the use of endocrine therapies combined with molecular therapies.

Efficacies of aromatase inhibitors in the treatment of hormone dependent metastatic breast cancer in postmenopausal women: a report of 148 cases

To evaluate the clinical efficacies of aromatase inhibitors in the treatment of postmenopausal metastatic breast cancer. A total of 148 postmenopausal women (including bilateral ovariectomy) with hormone dependent metastatic breast cancer receiving aromatase inhibitors (letrozole, anastrozole or exemestane) were analyzed retrospectively. Their clinical efficacies were evaluated. The median progression-free survival (PFS) was 6.5 months and the clinical benefit rate 63.5%. And the rates of PFS of patients on first-line and second-line or above treatments were 9.0 (95% CI: 6.95-11.05) and 3.0 months (95% CI: 1.8-10.1) respectively. The clinical benefit rates of two groups were 74.2% and 26.3% respectively. Aromatase inhibitors are both efficacious and well-tolerated for patients of postmenopausal metastatic breast cancer. It may be recommended as a first-line therapy for postmenopausal women with hormone dependent metastatic breast cancer.

Chromatographic separation of aminoglutethimide enantiomers on cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phase

Aminoglutethimide (AG) has been used clinically as a drug in the treatment of hormone-dependent metastatic breast cancer. It was reported that S-(-)-AG enantiomer had small activity and sometimes might cause side effects. Therefore, it was of great significance to obtain the high-purity R-(+)-AG by enantioseparation. In this work, aminoglutethimide enantiomers were separated by high performance liquid chromatography (HPLC) using an analytical column which was packed with cellulose tris(3,5-dimethylphenylcarbamate) stationary phase (Chiralcel OD-H). The solubilities of racemic AG in two different solvent compositions, n-hexane/ethanol and n-hexane/isopropanol, were measured, separately. The effects of alcohol content and monoethanolamine additive on the separation performance of racemic AG by HPLC were investigated. According to the experiments, n-hexane-ethanol (30:70, v/v) with 0.1% monoethanolamine additive was selected as the mobile phase. The separation factor, resolution, asymmetry factor, number of theoretical plates and maximum column capacity were measured and analyzed for the chromatographic separation of racemic AG at a flow-rate of 0. 6 mL/min and column temperature of 25-40 °C, with Chiralcel OD-H as stationary phase and n-hexane-ethanol (30:70, v/v) with 0. 1% monoethanolamine as mobile phase. This work provides the basic information of chromatographic separation for the batch and continuous production of aminoglutethimide enantiomers.

Prospective observational trial of re-antiestrogen therapy after becoming resistant to ethinylestradiol treatment in hormone-dependent metastatic breast cancer.

161 Background: After heavily treated estrogen deprivation therapy by aromatase inhibitors (AIs), an additional estrogen therapy may be useful in a certain condition. Furthermore, the estrogen therapy might sensitize a subsequent anti-estrogen therapy after the acquired resistance to estrogen. Methods: In the patients who obtained disease control (SD or more) by ethinylestradiol (EE2) therapy (1.5-3mg TID), the efficacy of anti-estrogen therapy using AI or fulvestrant was examined as a subsequent endocrine therapy. Primary endpoint was clinical benefit rate (CBR), and secondary endpoints were response rate (RR) and time to treatment failure (TTF). (Registration; UMIN000002831, prospective observational trial, sub-protocol analysis) Results: EE2 therapy was performed in 22 of postmenopausal breast cancer patients with ER-positive HER2-negative in primary or recurrent tumor, who had heavily pre-treated by endocrine therapies, including chemotherapies. At the median observation period of 13.6 months, RR of 41% (9/22) and CBR of 50% (11/22) were obtained (CR; 0, PR; 9, long SD; 2, SD; 4, PD; 3) and 4 patients withdrew this trial due to adverse events of early endocrine related symptoms and cerebral infarction. Although two patients were still ongoing, the median of duration of disease-control was 46 weeks (range; 23-62+). In thirteen patients who obtained disease control (SD or more) by EE2 therapy, fulvestrant for 6 patients or AI for 7 patients was used as a subsequent therapy. Fifty percent of fulvestrant group (3/6) and 43% of AI group (3/7) showed clinical benefit (PR or long SD). TTF of fulvestrant group was 15 weeks (median; range; 5-55+) and that of AI group was 19 weeks (median; range 5-33+). Furthermore, two patients who were responders to previous AI, got long SD to the subsequent EE2 re-treatment. Conclusions: EE2 therapy after resistance to estrogen deprivation therapy could be very useful, and a subsequent anti-estrogen therapy by AI or fulvestrant could be also effective in a certain condition. Thus, the changes of the endocrine environment by EE2 may induce the sensitization to hormone dependency in acquired hormone-resistant tumors. Clinical trial information: 000002831.

Antikörpertherapie in der Hämatologie und Onkologie – Teil 2*

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The Evolving Role of Aromatase Inhibitors in the Adjuvant Breast Cancer Setting

Third-generation aromatase inhibitors (AIs) have shown at least equivalent or superior efficacy to tamoxifen in the first-line treatment of women with hormone-dependent metastatic breast cancer. Similar results have been obtained in the neoadjuvant setting. These studies suggested that AIs may also have significant efficacy in the adjuvant setting, and evaluation against tamoxifen is ongoing. Unlike tamoxifen, which interferes with estrogen receptor-dependent gene expression, AIs prevent the formation of estrogen. Therefore, they do not have the mixed agonistic/antagonistic properties inherent in tamoxifen that cause the adverse events (thromboembolism, endometrial cancer) associated with this agent. In contrast, estrogen depletion may adversely affect bone density and lipid profile. The evaluation of AIs in the adjuvant setting is ongoing in eight major clinical trials. Many of these trials also have subprotocols designed to assess the safety of these agents. Although it will take many years to assess the full impact of adjuvant therapy with AIs, early results from the ATAC (Arimidex and Tamoxifen Alone or in Combination) trial with anastrozole have been reported, and a significant advantage in disease-free survival and the occurrence of contralateral breast cancer noted with the AI compared with tamoxifen. Early results with letrozole from the (J)MA-17 and BIG 1–98 trial (the International Breast Cancer Study Group trial) are expected to follow shortly. It is expected that the ongoing adjuvant trials will provide valuable information concerning efficacy, adverse-effect profile of long-term therapy, resistance to endocrine therapy and the usefulness of sequential treatment with multiple agents. A number of important questions will remain to be answered, however, including the length of time an AI should be administered after surgery and whether any one of the AIs would show superiority over the others in head-to-head comparison.

Factors affecting progression-free survival in hormone-dependent metastatic breast cancer patients receiving high-dose chemotherapy and hematopoietic progenitor cell transplantation: role of maintenance endocrine therapy.

We retrospectively analyzed the effect of maintenance endocrine therapy (MET) after high-dose chemotherapy with hematopoietic progenitor cell transplant (HDCT) on the progression-free survival (PFS) of patients with hormone-dependent metastatic breast cancer (MBC). One hundred and nine consecutive patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive MBC, who were progression free for at least 4 months after HDCT with cyclophosphamide, carmustine and thiotepa (CBT), were analyzed. Of these, 55 were non-randomly submitted to MET. After a median follow-up of 34.4 months (17.1-91.0), univariate analysis showed that MET was significantly associated with improved median PFS (31.1 vs 19.2 months, P = 0.022). Complete response to HDCT, pattern of metastatic spread, extent of the disease, single vs multiple metastatic sites, prior endocrine therapy for metastatic disease and prior exposure to any hormonal therapy (adjuvant and/or for the advanced disease) were also associated with PFS at univariate analysis. A multivariate Cox proportional hazard model was fitted to the data in order to correct the effect of MET for the other significant covariates. After correcting for these covariates, MET was still significant, predicting improved PFS (hazard ratio (HR) 0.580, 95% CI; 0.362-0.931). Administration of MET after optimal cytoreduction might result in increased efficacy of HDCT in hormone-dependent metastatic breast cancer.

Novel Mechanisms of Antiprogestin Action

Endocrine therapy used either prophylactically or therapeutically for the treatment of locally advanced or metastatic breast cancers offers many advantages to patients whose tumors contain functional estrogen (ER) and progesterone (PR) receptors. The range of treatments defined as endocrine include surgical ablation of endocrine glands, administration of pharmacologic doses of steroid hormones, chemical blockade of steroid hormone biosynthesis, and inhibition of endogenous steroid hormone action at the tumor with synthetic antagonists. The last of these approaches is the most widely used, making the antiestrogen tamoxifen the preferred first-line therapeutic agent for treatment of hormone-dependent metastatic breast cancer. The wide-spread use of tamoxifen reflects its efficacy and low toxicity, and the fact that it makes good physiological sense to block the local proliferative effects of estrogens directly at the breast. But are estrogens the only hormones with a proliferative impact on the breast and on breast cancers? This chapter focuses on evidence that progesterone also has proliferative actions in the breast; on preliminary data showing that progesterone antagonists may be new tools for the management of metastatic breast cancer; and on recent data suggesting that antiprogestin-occupied PR have novel mechanisms of action that bear on tissue specificity and development of hormone resistance.