scholarly journals The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2− Metastatic Breast Cancer: Biological Mechanisms and New Treatments

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1242 ◽  
Author(s):  
Daniele Presti ◽  
Erica Quaquarini
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Endocrine Resistance ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Endocrine Treatment ◽  
Response Predictors ◽  
New Treatments

Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice.

scholarly journals Efficacy of Bevacizumab-Capecitabine in Combination for the First-Line Treatment of Metastatic Breast Cancer

2011 ◽  
Vol 5 ◽  
pp. BCBCR.S7379 ◽  
Author(s):  
Stephen Dyar ◽  
Alvaro Moreno-Aspitia
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Orally Bioavailable ◽  
Regulatory Decisions ◽  
Phase Ii And Iii ◽  
Endothelial Growth Factor

There is an ongoing need for development of new chemotherapeutic regimens for metastatic breast cancer [mBC], especially when tumors lack therapeutic targets such as the estrogen or progesterone receptor [ER/PR], or the human epidermal growth factor receptor-2 [HER2]. Capecitabine is an orally bioavailable fluoropyrimidine approved for monotherapy in mBC, and bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor which has shown to be active in mBC and tolerable in combination with other chemotherapeutics. The combination of these two agents has been explored in multiple phase II and III clinical studies, with improvements in progression-free survival and overall response rates noted as compared to capecitabine monotherapy. However, the use of bevacizumab in combination with capecitabine and other chemotherapy agents for mBC remains beset with controversy due to safety concerns, cost issues, and pending regulatory decisions.

scholarly journals Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102

2018 ◽  
Vol 36 (16) ◽  
pp. 1556-1563 ◽  
Author(s):  
Noah Kornblum ◽  
Fengmin Zhao ◽  
Judith Manola ◽  
Paula Klein ◽  
Bhuvaneswari Ramaswamy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Objective Response ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Free Survival ◽  
Er Positive ◽  
Epidermal Growth

Purpose The mammalian target of rapamycin inhibitor everolimus targets aberrant signaling through the PI3K/AKT/mammalian target of rapamycin pathway, a mechanism of resistance to anti-estrogen therapy in estrogen receptor (ER)–positive breast cancer. We hypothesized that everolimus plus the selective ER downregulator fulvestrant would be more efficacious than fulvestrant alone in ER-positive metastatic breast cancer resistant to aromatase inhibitor (AI) therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase II study included 131 postmenopausal women with ER-positive, human epidermal growth factor receptor 2–negative, AI-resistant metastatic breast cancer randomly assigned to fulvestrant (500 mg days 1 and 15 of cycle 1, then day 1 of cycles 2 and beyond) plus everolimus or placebo. The study was designed to have 90% power to detect a 70% improvement in median progression-free survival from 5.4 months to 9.2 months. Secondary end points included objective response and clinical benefit rate (response or stable disease for at least 24 weeks). Prophylactic corticosteroid mouth rinses were not used. Results The addition of everolimus to fulvestrant improved the median progression-free survival from 5.1 to 10.3 months (hazard ratio, 0.61 [95% CI, 0.40 to 0.92]; stratified log-rank P = .02), indicating that the primary trial end point was met. Objective response rates were similar (18.2% v 12.3%; P = .47), but the clinical benefit rate was significantly higher in the everolimus arm (63.6% v 41.5%; P = .01). Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53% v 12%), fatigue (42% v 22%), rash (38% v 5%), anemia (31% v. 6%), diarrhea (23% v 8%), hyperglycemia (19% v 5%), hypertriglyceridemia (17% v 3%), and pneumonitis (17% v 0%), although grade 3 to 4 events were uncommon. Conclusion Everolimus enhances the efficacy of fulvestrant in AI-resistant, ER-positive metastatic breast cancer.

Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab in Patients With Metastatic Breast Cancer Pretreated With Trastuzumab

2010 ◽  
Vol 28 (34) ◽  
pp. 5110-5115 ◽  
Author(s):  
Fabrice Andre ◽  
Mario Campone ◽  
Ruth O'Regan ◽  
Corinne Manlius ◽  
Cristian Massacesi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Antitumor Activity ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Weekly Paclitaxel ◽  
Dose Escalation Study ◽  
Metastatic Setting

Purpose To determine the recommended dose of everolimus, a mammalian target of rapamycin inhibitor, combined with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2) –overexpressing metastatic breast cancer pretreated with trastuzumab. Methods In this phase Ib, multicenter, dose-escalation study, patients were treated with everolimus 5 mg/d, 10 mg/d, or 30 mg/wk in combination with paclitaxel (80 mg/m2 days 1, 8, and 15 every 4 weeks) and trastuzumab (2 mg/kg weekly). End points included end-of–cycle 1 dose-limiting toxicity (DLT) rate (primary end point), safety, relative dose intensity of study drugs, overall response rate (ORR), and pharmacokinetics. Results Of 33 patients enrolled, 31 were pretreated with taxanes, and 32 were resistant to trastuzumab. Patients received a median of two lines of chemotherapy in the metastatic setting (range, 0 to 17 lines). Three patients experienced cycle 1 DLTs: febrile neutropenia (5 mg/d), stomatitis (10 mg/d), and confusion (30 mg/wk). Grade 3 to 4 neutropenia was the most common toxicity observed (n = 17 patients [52%]). On the basis of observed DLTs and overall safety, 10 mg/d was recommended for additional development. Twenty-seven patients had measurable disease and were evaluable for efficacy. Among these patients, ORR was 44%. Overall disease was controlled for 6 months or more in 74%. Median progression-free survival was 34 weeks (95% CI, 29.1 to 40.7 weeks). Among 11 patients who were resistant to both trastuzumab and taxane, a similar level of antitumor activity was observed (ORR, 55%). Conclusion Everolimus combined with weekly paclitaxel and trastuzumab was generally well tolerated and had encouraging antitumor activity in patients with trastuzumab-pretreated and -resistant metastatic HER2-overexpressing breast cancer.

Systematic review and meta-analysis of post-progression outcomes in ER+/HER2- metastatic breast cancer after treatment with endocrine therapy and CDK 4/6 inhibitors within randomized clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1059-1059
Author(s):  
Elisabetta Munzone ◽  
Eleonora Pagan ◽  
Vincenzo Bagnardi ◽  
Emilia Montagna ◽  
Giuseppe Cancello ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Metastatic Breast Cancer ◽  
Endocrine Therapy ◽  
Fixed Effects ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Progression Free Survival

1059 Background: CDK4/6 inhibitors combined with endocrine therapy (ET) deeply transformed the treatment landscape of HR+/HER2− advanced breast cancer. After progression with the combination, there are no established guidelines for an optimal sequencing of the various therapeutic options. Data from randomized clinical trials (RCT) suggest that subsequent progression free survival (PFS2) was not compromised by the use of these drugs and time to subsequent chemotherapy (TTC) may be delayed. Therefore, we performed a meta-analysis to evaluate the benefit of such treatments on PFS2 and on delaying the TTC. Methods: We conducted a systematic literature search using PubMed to select all available randomized clinical trials of CDK4/6-inhibitors and ET reporting PFS2 or TTC data in first- or second-line therapy of HR+/HER2- pre- or postmenopausal metastatic breast cancer. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled hazard ratios (HR) for PFS2 and TTC with 95% confidence intervals (CI) using fixed-effects models. The pooled HRs for PFS and OS were also calculated. I2 was used to quantify heterogeneity between studies’ results. Results: Seven studies (PALOMA 1-2-3, MONALEESA 3-7, MONARCH 2-3) were included in our analyses (n = 3912 patients). A clear PFS2 benefit was observed in patients who received CDK 4/6 inhibitors + ET (pooled HR = 0.67, 95% CI = 0.61 to 0.74, I2 = 0.0%) and also a delay in subsequent TTC (pooled HR = 0.63, 95% CI = 0.58 to 0.70, I2 = 0.0%). As previously reported, the benefit in terms of PFS (pooled HR = 0.54, 95% CI = 0.50 to 0.59, I2= 0%) and OS (pooled HR = 0.77, 95% CI = 0.68 to 0.86, I2= 0%) was also confirmed. Conclusions: CDK4/6-inhibitors plus ET compared with ET alone improve PFS2, and TTC. The delay of chemotherapy can spare the patients toxicities, potentially improving the quality of life. Thus, the observed benefit in PFS2 may postpone the onset of endocrine resistance and may offer an additional therapeutic advantage in this setting.

D538G acquired mutation of estrogen receptor (ER) alpha: A novel mechanism of endocrine resistance in metastatic breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11578-e11578
Author(s):  
Ido Wolf ◽  
Keren Merenbakh ◽  
Tami Rubinek ◽  
Lior Soussan-Gutman ◽  
Baruch Klein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Transcriptional Activity ◽  
Novel Mutation ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Endocrine Treatment ◽  
Growth Factor Signaling ◽  
Development Of Resistance ◽  
Er Positive

e11578 Background: Resistance to endocrine therapy occurs in virtually all patients with ER-positive metastatic breast cancer (MBC) and is attributed to various mechanisms including loss of ER expression, altered activity of coregulators and cross-talk between the ER and growth factor signaling pathways. To our knowledge, acquired mutations of the ER have not been described as mediating endocrine resistance to endocrine treatment. Methods: Deep sequencing of the ER was conducted, as part of a commercially available next-generation sequencing of 182 cancer-related genes, on samples obtained from 10 heavily pre-treated, endocrine resistant patients with ER positive MBC. In one patient, a sample obtained at diagnosis was also available. Mutated ER was cloned and overexpressed in breast cancer cells. Transcriptional activity was tested using estrogen response element (ERE)-Luciferase construct, effects on viability were tested using MTT assays and computerized modeling was used to assess structural effects. Results: A novel mutation resulting in substitution of aspartic acid at position 538 to glycine was identified in 4 of 10 samples. Moreover, in one case in which samples were available prior to and following development of resistance, the D538G mutation was noted only in the latter sample. Structural modeling indicated that the substitution leads to a conformational change in the ligand binding domain which prevents binding of either estrogen or tamoxifen and mimics the conformation of activated receptor. Experiments in cell lines indicated constitutive ligand-independent transcriptional activity of the mutated receptor. Overexpression of the receptor in MCF-7 cells enhanced proliferation and conferred resistance to treatment with tamoxifen and fulvestarnt. Conclusions: We report here a novel mutation D538G of the ER in human breast cancer and demonstrate its role in mediating resistance to endocrine treatment. Our study also indicates, for the first time, acquired mutation of the ER as a novel mechanism of endocrine resistance. Further studies on larger populations and on less selected patients are needed in order to assess the accurate frequency of this novel mutation.

scholarly journals Cyclin-dependent kinase inhibitors: efficacy and safety

2019 ◽  
pp. 42-55 ◽  
Author(s):  
I. B. Kononenko ◽  
A. V. Snegovoi ◽  
V. Yu. Selchuk
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Hormone Receptor ◽  
Randomized Clinical Trials ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Endocrine Treatment ◽  
Cyclin Dependent Kinase

Breast Cancer is the most common type of cancer worldwide. Scientific advances and new ways of treating have significantly improved the prognosis of breast cancer in recent decades. The emergence of modern cyclin-dependent kinase (CDK) inhibitors has changed the treatment paradigm for metastatic hormone receptor (HR)-positive breast cancer. In the past four years, the CDK4/6 inhibitors, ribociclib, palbociclib and abemaciclib, received their first FDA approval for the treatment of Hormone Receptor (HR)- positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA, MONALEESA and the MONARCH randomized clinical trials, respectively. In the Russian standards for the treatment of metastatic HR positive and HER2-negative breast cancer are included two inhibitors of CDK4/6 – ribociclib, palbociclib. This review summarizes the background of clinical efficacy and potential toxicities seen with the use CDK4/6 inhibitors with endocrine treatment in pre- or postmenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer. Despite the similar toxicities, inhibitors of cyclin-dependent kinases differ in their severity and some types of adverse events. Most hematologic abnormalities seen with CDK4/6 inhibitors are not complicated and are adequately managed with standard supportive care and dose adjustments when indicated. This review focuses on the practical management of adverse events associated with CDK4/6 inhibitors.

scholarly journals Real-life prognosis of 5041 bone-only metastatic breast cancer patients in the multicenter national observational ESME program

2021 ◽  
Vol 13 ◽  
pp. 175883592098765
Author(s):  
Marion Bertho ◽  
Julien Fraisse ◽  
Anne Patsouris ◽  
Paul Cottu ◽  
Monica Arnedos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Real Life ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Breast Cancer Patients ◽  
Hormone Receptor Positive ◽  
Life Prognosis

Background: Bone-only (BO) metastatic breast cancer (MBC) is considered a more favorable entity than other MBC presentations. However, only few retrospective series and data from selected randomized controlled trials have been reported so far. Methods: Using the French national multicenter ESME (Epidemiological Strategy and Medico Economics) Data Platform, the primary objective of our study was to compare the overall survival (OS) of patients with BO versus non-BO MBC at diagnosis, with adjustment on main prognostic factors using a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1), describe treatment patterns, and estimate factors associated with OS. Results: Out of 20,095 eligible women, 5041 (22.4%) patients had BO disease [hormone-receptor positive (HR+)/human epidermal growth-factor-receptor-2 negative (HER2−), n = 4 102/13,229 (31%); HER2+, n = 644/3909 (16.5%); HR−/HER2−, n = 295/2 957 (10%)]. BO MBC patients had a better adjusted OS compared with non-BO MBC [52.1 months (95% confidence interval (CI) 50.3–54.1) versus 34.7 months (95% CI 34.0–35.6) respectively]. The 5-year OS rate of BO MBC patients was 43.4% (95% CI 41.7–45.2). They also had a better PFS1 [13.1 months (95% CI 12.6–13.8) versus 8.5 months (95% CI 8.3–8.7), respectively]. This observation could be repeated in all subtypes. BO disease was an independent prognostic factor of OS [hazard ratio 0.68 (95% CI 0.65–0.72), p < 0.0001]. Results were concordant in all analyses. Conclusion: BO MBC patients have better outcomes compared with non-BO MBC, consistently, through all MBC subtypes.

GEMOX: An Active Regimen for the Treatment of Luminal and Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer

Chemotherapy ◽  
2016 ◽  
Vol 62 (1) ◽  
pp. 30-33 ◽  
Author(s):  
Anna Rizzi ◽  
Francesca Aroldi ◽  
Paola Bertocchi ◽  
Tiziana Prochilo ◽  
Stefano Mutti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Complete Response ◽  
Salvage Regimen ◽  
Formidable Challenge ◽  
Heavily Pretreated ◽  
Major Reaction

Background: Pretreated metastatic breast cancer (MBC) remains a formidable challenge with unmet needs both in terms of prolonged survival and quality-of-life-related issues. Methods: We collected data from 27 MBC patients treated with gemcitabine and oxaliplatin (GEMOX) at our institution between June 2009 and April 2015. The patients were heavily pretreated, and all had previously been exposed to anthracyclines and taxanes. Results: We achieved a complete response in 1 patient (4%), a partial response in 7 patients (26%) and stable disease in 12 patients (44%), while 6 patients (22%) experienced progressive disease. The response of 1 patient (4%) could not be evaluated because she interrupted her treatment during the first cycle due to a major reaction to oxaliplatin. We observed grade 4 hypertransaminasaemia in only 1 patient (4%) and grade 2 neuropathy in 16 patients (59%). Grade 3 leuconeutropenia was observed in 5 patients (18%). The median progression-free survival was 5.9 months and the median overall survival was 9.6 months. Conclusions: GEMOX is an efficient and well-tolerated salvage regimen for MBC patients.

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