Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study

Kuter, Irene; Gee, Julia Margaret Wendy; Hegg, Roberto; Singer, Christian F.; Badwe, Rajendra; Lowe, Elizabeth S.; Emeribe, Ugochi; Anderson, Elizabeth J.; Sapunar, Francisco; Finlay, Pauline; Nicholson, Robert Ian; Bines, José; Harbeck, Nadia

doi:10.1007/s10549-011-1947-7

Cited by 89 publications

(76 citation statements)

References 16 publications

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“…Investigators evaluating postmenopausal women with ER+ breast cancer who were receiving neoadjuvant endocrine therapy found that the ER downregulator fulvestrant decreased Ki67, ER and PR expression after 16 weeks of treatment in a dose dependent fashion (34). In a separate study of women who received neoadjuvant chemotherapy for breast cancer, tumor grade changed in 35%, ER, PR and HER2 expression in 43, 55 and 27% of cases, respectively (35).…”

Section: The Effects Of Treatmentmentioning

confidence: 99%

Reliable Biomarkers to Identify New and Recurrent Cancer

Sauter¹

2017

Eur J Breast Health

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The breast is the most frequent site of cancer among women in both developed and in developing countries (1). Breast cancer is the most frequent cause of cancer death in women from less developed countries and second most frequent (after lung cancer) among women in developed countries (1). It is increasing in incidence in the developing world due to increased life expectancy, increased urbanization and the adoption of western lifestyles (2). According to the World Health Organization (WHO), "Early detection in order to improve breast cancer outcome and survival remains the cornerstone of breast cancer control" (2).In 2017 approximately 41.070 U.S. women are projected to die from breast cancer (3). It is estimated that in 2011 508.000 women worldwide died of breast cancer (2). Although incidence rates are lower in developing regions than in Western Europe and North America, almost 50% of breast cancer cases and 58% of deaths occur in less developed countries (2). Breast cancer survival rates range from over 80% in many developed countries to below 40% in low-income countries (4). The low survival rates in less developed countries are due to later stage at disease presentation, as well as by the lack of adequate diagnosis and treatment facilities.Early detection is crucial to improving the survival of individuals with breast cancer, as survival is inversely related to disease stage (5). An invasive needle or surgical biopsy must be performed when an area of suspicion is identified in order to confirm the presence of malignancy, and most of these invasive biopsies will turn out to be benign (6). The development of non-invasive biomarkers that would distinguish between women with or without breast cancer is highly desirable.Twenty-one percent of all breast cancer deaths worldwide have been attributed to alcohol use, high body mass index (BMI), and physical inactivity (7). Thus, while some breast cancers may be prevented through lifestyle modification strategies, most cannot. Currently known risk factors address only a subset (up to half ) of risk for breast cancer. Biomarkers hold promise to aid breast cancer assessment. A highly predictive biomarker is stable, reproducible, sensitive, specific and easy to detect. Biomarkers can be assessed in tissue and/or body fluids. Eur J Breast Health 2017; 13: 162-7 DOI: 10.5152/ejbh.2017.3635 162 Reliable Biomarkers to Identify New and Recurrent Cancer ABSTRACTBreast cancer is the most frequent cancer detected throughout both the developing and the developed world. Its incidence is on the rise in the developing world. Great strides have been made in developing biomarkers to guide therapy for women diagnosed with breast cancer. Far fewer advances have occurred with biomarker development for the early diagnosis of breast cancer. Standard screening for new and recurrent breast cancer involves clinical breast exam and breast imaging. There are no Food and Drug Administration (FDA) approved noninvasive body fluid tests for the early detection of new or recurrent breast cancer...

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Section: The Effects Of Treatmentmentioning

confidence: 99%

Reliable Biomarkers to Identify New and Recurrent Cancer

Sauter¹

2017

Eur J Breast Health

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“…In the neoadjuvant setting, the use of fulvestrant is controversial, because of the slow response rate and possible non-response. In a phase Ⅱ randomized study, tumor response rates were 20.6% and 22.9%, according to the dosage of the drug [43] .…”

Section: Down-regulatorsmentioning

confidence: 99%

Current medical treatment of estrogen receptor-positive breast cancer

Lumachi

Santeufemia

Basso

2015

WJBC

168

126

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Approximately 80% of breast cancers (BC) are estrogen receptor (ER)-positive and thus endocrine therapy (ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of (1) ovarian function suppression (OFS), usually obtained using gonadotropinreleasing hormone agonists (GnRHa); (2) selective estrogen receptor modulators or down-regulators (SERMs or SERDs); and (3) aromatase inhibitors (AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs (i.e. , tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ , especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs (i.e. , fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type Ⅰ are permanent steroidal inhibitors of aromatase, while type Ⅱ are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs (i.e. , anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors (palbociclib) and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.

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“…In the metastatic setting, 500 mg fulvestrant, given as 2 Â 250 mg intramuscular injections, has been shown to offer additional benefit over the 250 mg dose with improved median overall survival (7,8). Recent analysis of presurgical data from a number of trials showed a dose-dependent effect on key biomarkers such as ER, progesterone receptor (PR), and Ki67 labeling index (9).…”

Section: Introductionmentioning

confidence: 99%

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive andESR1-Mutant Breast Tumors in Preclinical Models

et al. 2016

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Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERa, which is a potent and selective antagonist and downregulator of ERa in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity.Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERa protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER þ breast cells that could provide meaningful benefit to ER þ breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. Ó2016 AACR.

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Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study

Cited by 89 publications

References 16 publications

Reliable Biomarkers to Identify New and Recurrent Cancer

Reliable Biomarkers to Identify New and Recurrent Cancer

Current medical treatment of estrogen receptor-positive breast cancer

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive andESR1-Mutant Breast Tumors in Preclinical Models

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