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Treatment-induced bone loss and fractures in cancer patients undergoing hormone ablation therapy: efficacy and safety of denosumab.

Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density

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… Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST Study. Ann Oncol. 2010;21:2188–94. doi: 10.1093/annonc/mdq217. 101. Shapiro CL, Halabi S, Hars V, et al. … Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol. 2007;25:829–36. doi: 10.1200/JCO.2005.05.3744. 111. Bundred NJ, Campbell ID, Davidson N, et al. …

Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention.

The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstre

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… The patients had been enrolled in a phase II study of letrozole or letrozole and cyclphosphamide. Either letrozole or letrozole plus cyclophosphamide-treated patients displayed a reduction in PI3K and P-mTOR expression. … A diagram of the effects of letrozole on ER and PI3K/PTEN/Akt/mTORC signaling and letrozole-resistance is presented in Figure 4 . …

Comparative analysis of Denosumab and Zoledronic acid in advanced breast cancer patients receiving CDK4/6 inhibitors.

A comparative analysis of Denosumab (DMAB) and Zoledronic Acid (ZA) was conducted in a real-world cohort of 864 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer with bone metastases, who were undergoing CDK4/6 inhibitors plus endocrine therapy. We evaluated the time to first skeletal-related events (SREs), progression-free survival (PFS), and overall survival (OS). To adjust for confounding variables, we utilized propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methodologies. In the unadjusted

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… Overall survival with Ribociclib plus letrozole in advanced breast cancer N Engl J Med 386 2022 942 950 35263519 10.1056/NEJMoa2114663 14 Slamon D.J. … Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial Eur J Cancer 118 2019 178 186 31164265 10.1016/j.ejca.2019.05.004 31 Ho D. Imai K. King G. Stuart E.A. …

Cancer treatment-induced bone loss.

Cancer treatment-induced bone loss (CTBL) is associated with anti-tumor treatments, including endocrine therapies, chemotherapeutic treatments, radiotherapy, glucocorticoids, and tyrosine kinase inhibitors. Osteoporosis, characterized by the loss of bone mass, can increase the risk of fractures, leading to mortality and long-term disability, even after cancer remission. Cancer and osteoporosis have marked clinical and pathogenetic similarities. Both have a multifactorial etiology, affect the geriatric population, and markedly influence quality of life. Lifestyle management, including calcium a

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… | 60 | +6.2% vs. −2.7% a) ZO-FAST [ 99 ] | Zoledronate | 1,065 | Intravenously, 4 mg every 6 months | Letrozole | 60 | +4.3% vs. −5.4% a) E-ZO-FAST [ 100 ] | Zoledronate | 527 | Intravenously, 4 mg every 6 months | Letrozole | 12 | +2.7% vs. −2.7% a) ABCSG12 [ 36 , 101 ] | Zoledronate | 404 | Intravenously … Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009;361:766–776. doi: 10.1056/NEJMoa0810818. 29. Coleman RE, Banks LM, Girgis SI, et al. …

A Comparison of the Efficacy and Safety of Denosumab and Zoledronic Acid in Patients with Bone Metastatic Breast Cancer Receiving CDK4/6 Inhibitor Therapy.

Background and Objectives: Bone metastases in patients can cause significant quality-of-life declines due to skeletal-related events (SREs). SRE is defined as the occurrence of radiotherapy for bone pain, pathologic fracture, bone surgery, spinal cord compression, or hypercalcemia. Bone-modifying agents (BMAs), such as denosumab and zoledronic acid, are crucial in reducing the frequency and severity of SREs. The inhibition of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has emerged as the standard treatment for hormone receptor-positive metastatic breast cancer, demonstrating significant im

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… Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann. Oncol. 2018;29:1541–1547. doi: 10.1093/annonc/mdy155. 13. … Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N. Engl. J. Med. 2022;386:942–950. doi: 10.1056/NEJMoa2114663. 15. Tang H., Yeo D., De Souza K., Ahmad O., Shafiq T., Ofor O., Anand A., Karim S., Khan S., Madhusudan S. …

The anti-tumour effects of zoledronic acid.

Bone is the most common site for metastasis in patients with solid tumours. Bisphosphonates are an effective treatment for preventing skeletal related events and preserving quality of life in these patients. Zoledronic acid (ZA) is the most potent osteoclast inhibitor and is licensed for the treatment of bone metastases. Clodronate and pamidronate are also licensed for this indication. In addition, ZA has been demonstrated to exhibit antitumour effect. Direct and indirect mechanisms of anti-tumour effect have been postulated and at many times proven. Evidence exists that ZA antitumour effect i

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… Aromatase-expressing breast cancer cells were treated with letrozole (100 nM) and ZA(10 μM) either simultaneously or in sequence, each for 24 h. Letrozole and ZA induce levels of apoptosis in breast cancer cells in vitro that are significantly greater compared with treatment with each drug alone. … Combined effects of the bisphosphonate, zoledronic acid and the aromatase inhibitor letrozole on breast cancer cells in vitro: evidence of synergistic interaction. Br J Cancer. 2010;102(6):1010–1017. doi: 10.1038/sj.bjc.6605579. 20. …

The incidence and relative risk of adverse events in patients treated with bisphosphonate therapy for breast cancer: a systematic review and meta-analysis.

BACKGROUND: Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival. However, the risk of adverse events associated with bisphosphonate therapy for breast cancer remains poorly defined. METHODS: A literature search was conducted using the PubMed, EMBASE, Cochrane and Web of Science libraries. Risk ratio (RR) was calculated to evaluate the adverse events of the meta-analytic results. Osteonecrosis of the jaw (ONJ) incidence was calculated using the random effect model (D+L pooled) for meta-analysis. RESULTS: A total of 47 studies com

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… J Clin Oncol 2005 ; 23 : 3314 – 3321 . 15738536 10.1200/JCO.2005.05.116 33 Brufsky A Harker WG Beck JT et al Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer . … Oncology 2011 ; 81 : 298 – 305 . 22156381 10.1159/000334456 35 Takahashi S Iwase T Kohno N et al Efficacy of zoledronic acid in postmenopausal Japanese women with early breast cancer receiving adjuvant letrozole: 12-month results . …

Optimizing clinical benefits of bisphosphonates in cancer patients with bone metastases.

Bisphosphonates are important treatments for bone metastases. Considerations for optimizing the clinical benefits of bisphosphonates include efficacy, compliance, and safety. Several bisphosphonates are approved for clinical use; however, few have demonstrated broad efficacy in the oncology setting and been compared directly in clinical trials. Among patients with bone metastases from breast cancer, the efficacy of approved bisphosphonates was evaluated in a Cochrane review, showing a reduction in the risk of skeletal-related events (SREs) ranging from 8% to 41% compared with placebo. Between-

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… In another study with immediate or delayed treatment with zoledronic acid, 4 mg biannually, for 5 years in patients with BC receiving letrozole, immediate zoledronic acid increased BMD at 12 months compared with delayed treatment ( p < .0001 for both) [ 47 ]. … Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. Cancer. 2008;112:1001–1010. doi: 10.1002/cncr.23259. 48. Pant S, Shapiro CL. …

Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.

The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)

The bone-muscle connection in breast cancer: implications and therapeutic strategies to preserve musculoskeletal health.

Breast cancer and its therapies frequently result in significant musculoskeletal morbidity. Skeletal complications include bone metastases, pain, bone loss, osteoporosis, and fracture. In addition, muscle loss or weakness occurring in both the metastatic and curative setting is becoming increasingly recognized as systemic complications of disease and treatment, impacting quality of life, responsiveness to therapy, and survival. While the anatomical relationship between bone and muscle is well established, emerging research has led to new insights into the biochemical and molecular crosstalk be

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… Preclinical models of mice undergoing OVX found a similar reduction in lean mass with the AI letrozole treatment compared to placebo, but a significant reduction in muscle specific force of the extensor digitorum longus muscle in those mice treated with both OVX and the AI ( p < 0.05) [ 12 ]. … Geisler J Haynes B Anker G Dowsett M Lonning PE Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study J Clin Oncol 2002 20 3 751 757 10.1200/JCO.2002.20.3.751 11821457 7. …

Unveiling the Link Between Breast Cancer Treatment and Osteoporosis: Implications for Anticancer Therapy and Bone Health.

Background: The interplay between breast cancer treatment and osteoporosis has important consequences for anticancer therapy and patient bone health. Many breast cancer therapies involve hormonal treatments that lower estrogen levels, which can lead to an increased risk of osteoporosis due to reduced bone mineral density. Aromatase inhibitors, chemotherapy, and surgeries such as oophorectomy can further aggravate bone loss, highlighting the necessity of prioritizing bone health during cancer treatment. Objective: This review is aimed at investigating the complex relationship between breast can

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… The three selective AIs used to treat postmenopausal women with breast malignancies expressing the ER and/or PR are anastrozole, exemestane, and letrozole. Women receiving AIs experience a lumbar spine BMD loss of 2%–3% [ 147 ]. … Bone mineral density in breast cancer patients treated with adjuvant letrozole, tamoxifen, or sequences of letrozole and tamoxifen in the BIG 1-98 study (SAKK 21/07) Annals of Oncology . 2012;23(6):1474–1481. doi: 10.1093/annonc/mdr448. 133. Mills E. G., Yang L., Nielsen M. …

Targeting translation initiation in breast cancer.

Over the past 20 years, a better understanding of cancer biology, screening for early detection, improved adjuvant treatment, and targeted therapies have decreased the rate of breast cancer deaths. However, resistance to treatment is common, and new approaches are needed. Deregulation of translation initiation is associated with the commencement and progression of cancer. Often, translation initiation factors are overexpressed and the related signaling pathways activated in human tumors. Recently, a significant number of inhibitors that target translation factors and pathways have become avail

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… In another phase II trial, 270 postmenopausal women with operable estrogen receptor–positive breast cancer received neoadjuvant treatment with letrozole (a nonsteroidal aromatase inhibitor) with or without everolimus. … Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 2009; 27:2630 - 7; http://dx.doi.org/ 10.1200/JCO.2008.18.8391; PMID: 19380449 146. …

Recent advances in anti-angiogenic therapy of cancer.

Since angiogenesis is critical for tumor growth and metastasis, anti-angiogenic treatment is a highly promising therapeutic approach. Thus, for over last couple of decades, there has been a robust activity aimed towards the discovery of angiogenesis inhibitors. More than forty anti-angiogenic drugs are being tested in clinical trials all over the world. This review discusses agents that have approved by the FDA and are currently in use for treating patients either as single-agents or in combination with other chemotherapeutic agents.

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… In combination with chemoendocrine therapy (including capecitabine and vinorelbine, and letrozole) bevacizumab treatment significantly decreased the percentage of viable circulating endothelial cells and prevented the chemotherapy-induced mobilization of circulating progenitors [ 45 ]. … Combination treatments for breast cancer with aromatase inhibitor [ 113 ] and letrozol [ 114 ] are also being evaluated. Rapamycin treatment brought partial responses (>50% reduction in the absolute number of blood blasts) and stable disease in adult refractory/relapsed AML [ 115 ]. …

Intrauterine insemination performance characteristics and post-processing total motile sperm count in relation to live birth for couples with unexplained infertility in a randomised, multicentre clinical trial.

STUDY QUESTION: Are intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related t … trial determined live birth rates following IUI after ovarian stimulation with clomiphene citrate, letrozole or gonadotropins in 854 couples with unexplained infertility. It was conducted between 2011 and 2014, and couples could undergo up to four consecutive treatment cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMIGOS was an NIH-sponsored Reproduct …

Practical consensus recommendaton for adjuvant bone-modifying agents in breast cancer.

Bone-modifying therapy is a primary research interest in breast cancer. Several features contribute to the importance of the bone environment in the management of breast cancer. Firstly, bone metastases represent the most common site of breast cancer metastases and secondly, the emergence of cancer treatment-induced bone loss (CTIBL) among breast cancer survivors and patients is of increasing concern. In the adjuvant setting, bisphosphonates can be given to prevent and treat tumor therapy-induced bone loss in premenopausal and postmenopausal women and, owing to their beneficial effect on bone

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… Recent data suggest that the steroidal AI exemestane may result in less BMD loss and potentially reduced fracture risk compared to the non-steroidal AIs, anastrozole and letrozole.[ 35 ] Cytotoxic chemotherapy is the only standard adjuvant treatment option for women with hormone receptor negative breast … J Clin Oncol 2008 26 4859 61 18725646 10.1200/JCO.2008.18.0851 33 Perez EA Josse RG Pritchard KI Ingle JN Martino S Findlay BP Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: A companion study to NCIC CTG …

Non-conventional dosing of oral anticancer agents in oncology and malignant haematology: a systematic review protocol.

BackgroundRecent advances in cancer therapeutics have resulted in significantly improved overall survival and progression-free survival for patients. Targeted oral systemic anticancer therapies (SACT) offer a range of treatment approaches that differ from traditional cytotoxic chemotherapy: non-cytotoxic oral SACT target malignant disease continuously, have less broad and more favourable safety profiles, which can improve patients' quality of life (QoL). Toxicities associated with daily oral SACT administration can, however, result in non-adherence and a reduced QoL. Non-conventional dosing of

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… Search terms for hormone modulators are: anastrozole, exemestane, letrozole, tamoxifen, toremifene, abiraterone, bicalutamide, cyproterone, enzalutamide, flutamide, medroxyprogesterone, megestrol, norethisterone, diethylstilbestrol, and ethinylestradiol. … nilotinib or nintedanib or olaparib or osimertinib or panobinostat or pazopanib or ponatinib or regorafenib or ruxolitinib or sorafenib or sunitinib or temsirolimus or trametinib or vandetanib or vemurafenib or vismodegib or thalidomide or lenalidomide or pomalidomide or anastrozole or exemestane or letrozole …

Protection of bone in premenopausal women with breast cancer: focus on zoledronic acid.

Maintaining bone health is important for patients with breast cancer (BC), the most commonly diagnosed cancer in American women. Indeed, bone loss is common throughout the BC disease continuum. In the metastatic BC setting, patients are likely to develop bone metastases, a painful complication that can lead to potentially debilitating skeletal-related events. Bone health is equally important for patients with early BC. During adjuvant therapy for early BC, the largest challenge to bone health is from accelerated bone mineral density (BMD) loss. Although decreased BMD is well recognized in olde

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… Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis N Engl J Med 2007 356 18 1809 1822 17476007 10.1056/NEJMoa067312 38 Brufsky AM Harker WG Beck JT Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole … Cancer 2012 118 5 1192 1201 21987386 10.1002/cncr.26313 39 Eidtmann H de Boer R Bundred N Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST Study Ann Oncol 2010 21 11 2188 2194 20444845 10.1093/annonc/mdq217 40 …

T-Regulatory Cells In Tumor Progression And Therapy.

Regulatory T cells (Tregs) are important members of the immune system regulating the host responses to infection and neoplasms. Tregs prevent autoimmune disorders by protecting the host-cells from an immune response, related to the peripheral tolerance. However, tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response. Thus, Tregs are a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. This has prompted the development of novel adjuvant therapies that obviate their negative effects thereby enhancing the therapeutic ef

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… However tumor regression evident in patients treated with the combination. 180 Chemotherapeutic Agents Estrogen Aromatase Inhibitors Breast cancer/ Human Phase II Significant reduction in Tregs following letrozole and letrozole-cyclophosphamide treatments. … However tumor regression evident in patients treated with the combination. | 180 Chemotherapeutic Agents Estrogen | Aromatase Inhibitors | Breast cancer/ Human Phase II | Significant reduction in Tregs following letrozole and letrozole-cyclophosphamide treatments. …

Revolutionizing ovarian cancer therapy by drug repositioning for accelerated and cost-effective treatments.

Drug repositioning, the practice of identifying novel applications for existing drugs beyond their originally intended medical indications, stands as a transformative strategy revolutionizing pharmaceutical productivity. In contrast to conventional drug development approaches, this innovative method has proven to be exceptionally effective. This is particularly relevant for cancer therapy, where the demand for groundbreaking treatments continues to grow. This review focuses on drug repositioning for ovarian cancer treatment, showcasing a comprehensive exploration grounded in thorough in vitro

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… In a phase II trial involving 50 patients with relapsed ovarian cancer, the antitumor activity of letrozole was assessed using Union International Contre Cancer (UICC) and CA125 (cancer antigen 125) marker criteria. … Finally, a 2.5 mg daily oral dose of letrozole was administrated to thirty-three women with recurrent ER+ epithelial ovary or peritoneum carcinoma enrolled in a phase II trial ( 253 ). …

Recent Progress in CDK4/6 Inhibitors and PROTACs.

Cell division in eukaryotes is a highly regulated process that is critical to the life of a cell. Dysregulated cell proliferation, often driven by anomalies in cell Cyclin-dependent kinase (CDK) activation, is a key pathological mechanism in cancer. Recently, selective CDK4/6 inhibitors have shown clinical success, particularly in treating advanced-stage estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This review provides an in-depth analysis of the action mechanism and recent advancements in CDK4/6 inhibitors, categorizing them based

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… Furthermore, 40 months later, over 70% of patients in the combination of palbociclib and letrozole group in this study experienced tumor progression during treatment. … Palbociclib and letrozole in advanced breast cancer N. Engl. J. Med. 2016 375 1925 1936 10.1056/NEJMoa1607303 27959613 …