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Patterns of Progression in Metastatic Estrogen Receptor Positive Breast Cancer: An Argument for Local Therapy.

ABSTRACT: Purpose:Despite advances in endocrine therapy (ET), metastatic estrogen receptor positive breast cancer (BrCA) remains incurable. Though the mechanisms of resistance to ET have been studied extensively, the anatomic pattern of disease progression remains poorly characterized. The purpose of this study was to characterize the pattern of progression for patients receiving ET for metastatic BrCA. Methods:The records of 108 patients with metastatic BrCA who progressed on ET were reviewed. Progression was characterized as follows: diffuse progression, progression in greater than 3 sites; oligoprogression, progression in fewer than 3 sites with prior diffuse metastases; and oligometastatic disease with progression, progression in 3 or fewer sites with prior limited metastases. Results:Seventy-four patients (69%) displayed only diffuse disease progression. Conversely, 23 patients (21%) displayed oligoprogression and 11 patients (10%) displayed oligometastases with progression at least once in their disease course. Further analysis of the patients with oligoprogression suggested that in 14 patients the sites of progression would have been amenable to local therapy. Conclusion:Oligoprogressive disease occurs in a significant subset of patients with metastatic BrCA treated with ET. These patients with oligoprogressive disease may be eligible for local therapy, potentially obviating the need to change of systemic therapy.

SUBMITTER: Kelly P

PROVIDER: S-EPMC5632870 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Patterns of Progression in Metastatic Estrogen Receptor Positive Breast Cancer: An Argument for Local Therapy.

Kelly Patrick P Ma Zhe Z Baidas Said S Moroose Rebecca R Shah Nikita N Dagan Roi R Mamounas Eleftherios E Rineer Justin J

International journal of breast cancer 20170925

<h4>Purpose</h4>Despite advances in endocrine therapy (ET), metastatic estrogen receptor positive breast cancer (BrCA) remains incurable. Though the mechanisms of resistance to ET have been studied extensively, the anatomic pattern of disease progression remains poorly characterized. The purpose of this study was to characterize the pattern of progression for patients receiving ET for metastatic BrCA.<h4>Methods</h4>The records of 108 patients with metastatic BrCA who progressed on ET were revie ...[more]

PMID: 29147583

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Project description:Metastatic breast cancer (MBC) results in substantial morbidity and mortality for women afflicted with this disease. A majority of MBCs are hormone-responsive and estrogen receptor-positive, making endocrine therapy (ET) an integral component of systemic therapy. With a primary goal of minimizing the effects of estrogen on hormone-responsive MBC, ETs are among the first targeted treatments that aim to inhibit the influence of estrogen receptor activation on tumor proliferation. Several biochemical mechanisms have been the focus of drug development for treatment, including selective estrogen-receptor modulation, aromatase inhibition, and selective estrogen-receptor degradation. Treatments that exploit these mechanisms have improved survival and quality of life for women with MBC. However, in many cases, resistance to ET limits their effectiveness. Elucidation of the complex cellular signal cascades involved in the development of acquired resistance to ET and the interrelationship of growth factor signaling and estrogen responsiveness have characterized components of these pathways as attractive targets for drug development. Based on these insights and with the aim of overcoming hormone resistance, targeted therapies are emerging as useful treatments for MBC. This article reviews current endocrine treatments of MBC as well as recent and ongoing study of combination treatments and targeted therapies that interfere with cellular proliferation pathways as means of overcoming resistance. The Oncologist 2017;22:507-517 IMPLICATIONS FOR PRACTICE: This review provides medical oncologists and other oncology health care providers with a current understanding of the rationale for endocrine therapy in estrogen receptor-positive metastatic breast cancer and the efficacy and safety profile of available treatment options. Additionally, current concepts regarding the development of treatment resistance and the treatment strategies for overcoming resistance are discussed. Enhancing the current information and the understanding of these topics will assist clinicians in evaluating optimal treatment options for their patients.

Project description:BackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer.MethodsWe measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERβ agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2-regulated genes.ResultsIn this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples.ConclusionOur results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer.

Project description:BACKGROUND:Approximately 70% of all breast cancers express the estrogen receptor, and are regulated by estrogen. While the ovaries are the primary source of estrogen in premenopausal women, most breast cancer is diagnosed following menopause, when systemic levels of this hormone decline. Estrogen production from androgen precursors is catalyzed by the aromatase enzyme. Although aromatase expression and local estrogen production in breast adipose tissue have been implicated in the development of primary breast cancer, the source of estrogen involved in the regulation of estrogen receptor-positive (ER+) metastatic breast cancer progression is less clear. METHODS:Bone is the most common distant site of breast cancer metastasis, particularly for ER+ breast cancers. We employed a co-culture model using trabecular bone tissues obtained from total hip replacement (THR) surgery specimens to study ER+ and estrogen receptor-negative (ER-) breast cancer cells within the human bone microenvironment. Luciferase-expressing ER+ (MCF-7, T-47D, ZR-75) and ER- (SK-BR-3, MDA-MB-231, MCF-10A) breast cancer cells were cultured directly on bone tissue fragments or in bone tissue-conditioned media, and monitored over time with bioluminescence imaging (BLI). Bone tissue-conditioned media were generated in the presence vs. absence of aromatase inhibitors, and testosterone. Bone tissue fragments were analyzed for aromatase expression by immunohistochemistry. RESULTS:ER+ breast cancer cells were preferentially sustained in co-cultures with bone tissues and bone tissue-conditioned media relative to ER- cells. Bone fragments analyzed by immunohistochemistry revealed expression of the aromatase enzyme. Bone tissue-conditioned media generated in the presence of testosterone had increased estrogen levels and heightened capacity to stimulate ER+ breast cancer cell proliferation. Pretreatment of cultured bone tissues with aromatase inhibitors, which inhibited estrogen production, reduced the capacity of conditioned media to stimulate ER+ cell proliferation. CONCLUSIONS:These results suggest that a local estrogen signaling axis regulates ER+ breast cancer cell viability and proliferation within the bone metastatic niche, and that aromatase inhibitors modulate this axis. Although endocrine therapies are highly effective in the treatment of ER+ breast cancer, resistance to these treatments reduces their efficacy. Characterization of estrogen signaling networks within the bone microenvironment will identify new strategies for combating metastatic progression and endocrine resistance.

Project description:Background:The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pretreated patients. Preclinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multicenter study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in postmenopausal women with moderately pretreated, estrogen receptor-positive, HER2 negative advanced breast cancer. Patients and methods:Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1 : 1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary end point was clinical benefit rate (CBR); secondary end points included progression-free survival (PFS). Results:Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% [95% confidence interval (CI): 41.5-63.7] for combination therapy, and 60% (95% CI: 47.8-72.9) for monotherapy. Median PFS was 10.8?months (95% CI: 5.6-12.7) for combination therapy, and 6.5?months (95% CI: 5.4-8.5) for monotherapy [hazard ratio (HR) 0.69; 95% CI: 0.4-1.1, exploratory P-value?=?0.12]. Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6?months (HR 0.53; 95% CI: 0.3-0.9, exploratory P-value?=?0.02), but not in those who received prior ET for ?6?months. Conclusion:Palbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET. Clinical trial information:NCT02549430.

Dataset Information

Patterns of Progression in Metastatic Estrogen Receptor Positive Breast Cancer: An Argument for Local Therapy.

Publications

Patterns of Progression in Metastatic Estrogen Receptor Positive Breast Cancer: An Argument for Local Therapy.

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