scholarly journals PI3Kinase Inhibition in Hormone Receptor-Positive Breast Cancer

2021 ◽  
Vol 22 (21) ◽  
pp. 11878
Author(s):  
Ajay Dhakal ◽  
Luna Acharya ◽  
Ruth O’Regan ◽  
Shipra Gandhi ◽  
Carla Falkson
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Pi3k Pathway ◽  
Molecular Target ◽  
Breast Cancer Treatment ◽  
Breast Cancers ◽  
Phosphatidylinositol 3 Kinase ◽  
Pi3k Inhibitors ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

Derangement of the phosphatidylinositol-3 kinase (PI3K) pathway is implicated in several subtypes of breast cancers. Mutation or upregulation of PI3K enhances cancer cells’ survival, proliferation, and ability to metastasize, making it an attractive molecular target for systemic therapy. PI3K has four isoforms, and several drugs targeting individual isoforms or pan-PI3K have been or are currently being investigated in clinical trials. However, the search for an effective PI3K inhibitor with a robust therapeutic effect and reasonable safety profile for breast cancer treatment remains elusive. This review focuses on the recently completed and ongoing clinical trials involving PI3K inhibitors as mono- or combination therapy in breast cancer. We review the salient findings of clinical trials, the therapeutic efficacy of PI3K inhibitors, and reported adverse effects leading to treatment discontinuation. Lastly, we discuss the challenges and potential opportunities associated with adopting PI3K inhibitors in the clinic.

scholarly journals Endocrine Therapy in Premenopausal Hormone Receptor–Positive Breast Cancer

2016 ◽  
Vol 12 (11) ◽  
pp. 1148-1156 ◽  
Author(s):  
Amye J. Tevaarwerk ◽  
Kari B. Wisinski ◽  
Ruth M. O’Regan
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Systemic Therapy ◽  
Hormone Receptor ◽  
Randomized Trials ◽  
Early Stage ◽  
Premenopausal Women ◽  
Breast Cancers ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

Systemic therapy for premenopausal women with hormone receptor–positive breast cancer has evolved in the last 5 years, but critical questions remain. Recent randomized trials have demonstrated a benefit for the addition of ovarian suppression to endocrine therapy in patients with breast cancers considered to be at high risk for recurrence, whereas those with lower-risk cancers seem to have a favorable outcome with tamoxifen alone. Two large randomized trials have demonstrated a benefit for extending adjuvant tamoxifen beyond 5 years. Currently the choice of systemic therapy is selected empirically but molecular profiling may, in the near future, provide a more conclusive means of selecting an endocrine therapeutic approach for premenopausal patients. Given that a significant subset of hormone receptor–positive cancers are intrinsically resistant to endocrine agents, as well as the finding that inhibiting cyclin-dependent kinases 4 and 6 and mammalian target of rapamycin appears to potentially reverse this resistance in patients with metastatic disease, evaluation of these agents in the early-stage setting is ongoing.

Obesity and Postmenopausal Hormone Receptor-positive Breast Cancer: Epidemiology and Mechanisms

Endocrinology ◽  
2021 ◽  
Author(s):  
Qianying Zuo ◽  
Shoham Band ◽  
Mrinali Kesavadas ◽  
Zeynep Madak Erdogan
Keyword(s):  
Breast Cancer ◽  
Potential Risk ◽  
Cancer Epidemiology ◽  
Breast Cancers ◽  
Breast Carcinogenesis ◽  
Postmenopausal Hormone ◽  
Hormone Receptor Positive ◽  
Breast Cancer Epidemiology ◽  
The Impact ◽  
Positive Breast Cancer

Abstract Obesity is a potential risk for several cancers, including postmenopausal, hormone dependent breast cancers. In this review, we will summarize recent studies on the impact of obesity on postmenopausal women’s health and discuss several mechanisms that were proposed to increase the risk of breast carcinogenesis.

scholarly journals ER-Negative Breast Cancer Is Highly Responsive to Cholesterol Metabolite Signalling

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2618 ◽  
Author(s):  
Samantha A Hutchinson ◽  
Priscilia Lianto ◽  
Hanne Roberg-Larsen ◽  
Sebastiano Battaglia ◽  
Thomas A Hughes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Target Genes ◽  
Cholesterol Metabolism ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Hormone Receptor Positive ◽  
Er Positive ◽  
Positive Breast Cancer

Interventions that alter cholesterol have differential impacts on hormone receptor positive- and negative-breast cancer risk and prognosis. This implies differential regulation or response to cholesterol within different breast cancer subtypes. We evaluated differences in side-chain hydroxycholesterol and liver X nuclear receptor signalling between Oestrogen Receptor (ER)-positive and ER-negative breast cancers and cell lines. Cell line models of ER-positive and ER-negative disease were treated with Liver X Receptor (LXR) ligands and transcriptional activity assessed using luciferase reporters, qPCR and MTT. Publicly available datasets were mined to identify differences between ER-negative and ER-positive tumours and siRNA was used to suppress candidate regulators. Compared to ER-positive breast cancer, ER-negative breast cancer cells were highly responsive to LXR agonists. In primary disease and cell lines LXRA expression was strongly correlated with its target genes in ER-negative but not ER-positive disease. Expression of LXR’s corepressors (NCOR1, NCOR2 and LCOR) was significantly higher in ER-positive disease relative to ER-negative, and their knock-down equalized sensitivity to ligand between subtypes in reporter, gene expression and viability assays. Our data support further evaluation of dietary and pharmacological targeting of cholesterol metabolism as an adjunct to existing therapies for ER-negative and ER-positive breast cancer patients.

Update of the Oxford Overview: New Insight and Perspectives in the Era of Personalized Medicine

2012 ◽  
pp. 71-79
Author(s):  
Kathleen I. Pritchard ◽  
Jonas Bergh ◽  
Harold J. Burstein
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Meta Analysis ◽  
Breast Cancers ◽  
Breast Cancer Therapy ◽  
Hormone Receptor Positive ◽  
Er Positive ◽  
Adjuvant Breast Cancer ◽  
Great Appreciation ◽  
Positive Breast Cancer

Overview: There is great appreciation for the heterogeneity of breast cancers, particularly of hormone-receptor positive breast cancers. A goal of modern oncology managing such heterogeneity is to determine how to individualize therapy based on the specific pathological and biological features of a given tumor. Two distinctive clinical literatures exist to guide treatment of hormone-receptor-positive breast cancer. The Oxford Overview, a seminal meta-analysis effort, has recently been updated, and suggests that nearly all patients with ER-positive tumors benefit from adjuvant endocrine therapy. In addition, the overview finds that nearly all subsets of patients with ER-positive tumors also benefit from modern adjuvant chemotherapy regimens. Meanwhile, retrospective subset analyses of specific trials or populations suggests that the benefits of chemotherapy are not so uniform, and in particular that molecular diagnostics assays can identify patients who do not warrant chemotherapy. This article will highlight recent data and controversies in personalizing adjuvant breast cancer therapy.

scholarly journals Phosphatidylinositol 3-Kinase and Antiestrogen Resistance in Breast Cancer

2011 ◽  
Vol 29 (33) ◽  
pp. 4452-4461 ◽  
Author(s):  
Todd W. Miller ◽  
Justin M. Balko ◽  
Carlos L. Arteaga
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinases ◽  
De Novo ◽  
Clinical Investigation ◽  
Endocrine Resistance ◽  
Pi3k Pathway ◽  
Antiestrogen Resistance ◽  
Phosphatidylinositol 3 Kinase ◽  
Positive Breast Cancer ◽  
Phosphatidylinositol 3

Although antiestrogen therapies targeting estrogen receptor (ER) α signaling prevent disease recurrence in the majority of patients with hormone-dependent breast cancer, a significant fraction of patients exhibit de novo or acquired resistance. Currently, the only accepted mechanism linked with endocrine resistance is amplification or overexpression of the ERBB2 (human epidermal growth factor receptor 2 [HER2]) proto-oncogene. Experimental and clinical evidence suggests that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway, the most frequently mutated pathway in breast cancer, promotes antiestrogen resistance. PI3K is a major signaling hub downstream of HER2 and other receptor tyrosine kinases. PI3K activates several molecules involved in cell-cycle progression and survival, and in ER-positive breast cancer cells, it promotes estrogen-dependent and -independent ER transcriptional activity. Preclinical tumor models of antiestrogen-resistant breast cancer often remain sensitive to estrogens and PI3K inhibition, suggesting that simultaneous targeting of the PI3K and ER pathways may be most effective. Herein, we review alterations in the PI3K pathway associated with resistance to endocrine therapy, the state of clinical development of PI3K inhibitors, and strategies for the clinical investigation of such drugs in hormone receptor–positive breast cancer.

Natural Compounds as Potential Regulators of the Phosphatidylinositol 3′ Kinase (PI3K) Pathway in Breast Cancer

2021 ◽  
Vol 11 (5) ◽  
pp. 524-538
Author(s):  
Anirban Roy ◽  
Indira Chakraborty ◽  
Aniruddha Banerji
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Pi3k Pathway ◽  
Akt Pathway ◽  
Breast Cancers ◽  
Phosphatidylinositol 3 Kinase ◽  
Lower Treatment ◽  
Pomolic Acid ◽  
Lower Treatment Cost ◽  
Phosphatidylinositol 3

Breast cancer is one of the most prevalent forms of cancer in women both globally and in India. Although breast cancer is characterized by different molecular subtypes, a majority of breast cancers appear to have mutations in the phosphatidylinositol 3′ kinase (PI3K)/ protein kinase B (Akt) pathway. Dysregulation of the PI3K/ Akt pathway in breast cancers plays important roles in promoting tumour growth, proliferation and invasion. Targeting PI3K mediated signalling cascades could be therefore of value for breast cancer treatment. Studies with synthetic inhibitors of the PI3K/ Akt pathway have yielded positive results but the efficacy shown by many of these inhibitors appear to be compromised by deleterious side effects. An alternative to syn-thetic inhibitors is the use of natural phytochemical compounds with anti-tumorigenic potential like apigenin, pomolic acid, resveratrol and its deriva-tives, curcumin, epigallocatechin-3 gallate and thymoquinone as potential inhibitors of PI3K/Akt signalling in breast cancer and such a strategy could lead to lesser side effects and a lower treatment cost. The current study ex-amines the importance of the PI3K pathway in breast cancer and discusses how regulation of aberrant signalling through this pathway by natural com-pounds could play an important role in breast cancer therapy.

Neratinib for the treatment of early-stage, hormone receptor-positive, HER2-overexpressed breast cancer

2020 ◽  
Vol 16 (17) ◽  
pp. 1165-1177
Author(s):  
Yolanda Jerez ◽  
Blanca Herrero ◽  
Marta Arregui ◽  
Blanca Morón ◽  
Miguel Martín ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitor ◽  
Early Stage ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Future Directions ◽  
Her2 Positive Breast Cancer ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

HER2-positive breast cancer accounts for 18–20% of all breast cancers. Despite significant advances and the currently available adjuvant treatments for management of the disease, approximately 25% of HER2-positive early-stage breast cancer patients show relapse and die. Neratinib is an irreversible tyrosine kinase inhibitor. Multiple studies have reported its significant antitumor activity in metastatic HER2-positive breast cancer. It is administered orally and has also been tested in the adjuvant setting. In this article, we present a comprehensive review of the pharmacokinetics and pharmacodynamics of neratinib as well as its clinical efficacy, with an emphasis on early HER2-positive breast cancer and suggestions for future directions for neratinib research.

scholarly journals Anastrozole Use in Early Stage Breast Cancer of Post-Menopausal Women

2009 ◽  
Vol 1 ◽  
pp. CMT.S9 ◽  
Author(s):  
Monica Milani ◽  
Gautam Jha ◽  
David A. Potter
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Estrogen Receptor ◽  
Hormone Receptor ◽  
Early Stage ◽  
Breast Cancers ◽  
Adjuvant Setting ◽  
Hormone Receptor Positive ◽  
Menopausal Women ◽  
Post Menopausal

The majority of breast cancers express the estrogen receptor and depend on estradiol (E2) for their growth. Hormonal therapy aims at depriving estrogen signaling either by using selective estrogen receptor modulators (SERM)–-that interfere with the binding of E2 to its receptor (ER)–-or aromatase inhibitors (AI)–-that block the aromatase-dependent synthesis of E2. While SERMs are recommended for both pre- and post-menopausal patients, AIs are indicated only for post-menopausal patients. For the past 20 years, the SERM tamoxifen has been considered the “gold standard” for the treatment of hormone receptor positive breast cancers. However, tamoxifen's role is now challenged by third generation AIs, such as anastrozole, which exhibit greater efficacy in the adjuvant setting in several recently reported trials. This review will focus on anastrozole's mechanism of action, dosing, pharmacology, pharmacokinetics, and clinical applications. It will briefly discuss the clinical trials that determined anastrozole's efficacy in the treatment of advanced breast cancer (ABC) and in the neo-adjuvant setting. Finally, it will present the clinical trials that established anastrozole as a frontline agent in the treatment of post-menopausal women with hormone receptor positive early breast cancer.

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