Targeted combination therapy with fulvestrant (FUL) for second-line (2L) treatment of hormone receptor-positive (HR+) advanced breast cancer (ABC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12527-e12527
Author(s):  
Ingrid A. Mayer ◽  
Ruth O'Regan ◽  
Noah Saul Kornblum ◽  
Kimberly L. Blackwell
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Targeted Therapies ◽  
Mammalian Target Of Rapamycin ◽  
Progression Free Survival ◽  
Poor Response ◽  
First Line ◽  
Hormone Receptor Positive ◽  
Active Research ◽  
Neo Adjuvant Chemotherapy

e12527 Background: FUL is the recommended 2L treatment for patients whose HR+ ABC progressed after aromatase inhibitor (AI) therapy. In first line ABC adding targeted therapy, eg. cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) palbociclib or ribociclib, or mammalian target of rapamycin inhibitor (mTORi) everolimus (EVE), to endocrine therapy (ET) has shown superior efficacy vs ET alone. The use of similar strategies to delay disease progression on ET in the 2L setting is an area of active research. Methods: PubMed and ClinicalTrials.gov were searched for trials investigating FUL + targeted therapies in 2L HR+ ABC. Search terms: (advanced OR metastatic) AND (breast cancer) AND (FUL OR faslodex) AND (2L OR relapse OR refractory OR resistant OR progression). Efficacy, adverse events (AEs) and quality of life were assessed. Results: 28 studies of FUL + targeted therapies in 2L ABC were found. Key randomized trials include 8 studies exploring FUL + CDK4/6i: palbociclib, ribociclib or abemaciclib. Palbociclib + FUL significantly improved progression-free survival (PFS) vs FUL in 2L HR+ ABC (p < 0.0001; PALOMA-3), AEs were manageable. Assessment of FUL + ribociclib (MONALEESA-3) or FUL + abemaciclib (MONARCH-2) in 2L HR+ ABC is ongoing. Ten studies are evaluating FUL + phosphatidylinositol 3-kinase (PI3K)/AKT/mTORi in 2L HR+ ABC. FUL + EVE significantly prolonged PFS vs FUL (p = 0.02; PrECOG 0102). Two trials evaluated buparlisib (pan-PI3K inhibitor [PI3Ki]) + FUL in HR+ ABC post-AI (BELLE-2) and post-mTORi (BELLE-3). In both trials, buparlisib + FUL improved PFS vs FUL in patients with PIK3CA-mutated tumors, FUL alone led to a poor response in this subgroup. However, pictilisib (pan-PI3Ki) + FUL did not improve PFS vs FUL even in the PIK3CA-mutated subgroup (FERGI). Ongoing phase 3 trials are exploring FUL + alpelisib (α-specific PI3Ki; SOLAR-1) or FUL + taselisib (β-sparing PI3Ki; SANDPIPER) in PIK3CA-mutant HR+ ABC. Pts who have progressed on AI, CDK4/6i or (neo)adjuvant chemotherapy are eligible for these studies. Data on FUL + other targeted therapies will also be discussed. Conclusions: Addition of targeted therapy to FUL demonstrates promising efficacy beyond first line.

Comparison of therapy benefit from standard anti-HER2 directed approaches in metastatic breast cancer (MBC) between initially HER2-positive patients and patients initially HER2-negative with switch to HER2-positive.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1040-1040
Author(s):  
Hans-Christian Kolberg ◽  
Özlem Yüksel ◽  
Peter A. Fasching ◽  
Sara Brucker ◽  
Hans Tesch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapies ◽  
Hormone Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Observation Time ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Free Survival ◽  
Hormone Receptor Positive

1040 Background: Metaanalyses have demonstrated that 5% of initially HER2 negative breast cancer patients switch to HER2 positive during the course of the disease. Whether there is a difference in benefit from standard HER2 targeted therapies between patients initially HER2 positive and patients switching from negative to positive is unclear. We used data from the PRAEGNANT registry to compare the outcome of those patients. Methods: PRAEGNANT is a prospective advanced breast cancer registry (NCT02338167) focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis compared progression-free survival (PFS) with standard HER2 targeted therapies between patients with tumors initially HER2 negative and switched to HER2 positive and patients with tumors that were initially HER2 positive adjusted for age and hormone receptor status. Results: At the time of this analysis 4061 patients with MBC were included in the PRAEGNANT registry, 49 of which met the requirements for this analysis. Median age was 56 (IQR 48-64) years and 87.8% of the patients were hormone receptor positive. At first diagnosis 15 patients were HER2 negative and 34 patients were HER2 positive. Within a median observation time of 9 months (95%CI: 3.8, 23.7) 35 PFS events occurred. Median observation time was 9 months (95% CI: 3.8, 23.7). Initially HER2 positive patients had a longer progression-free survival (HR = 0.49, 95% CI (0.24, 1.03), p = 0.07) as compared to initially HER2 negative patients switched to HER2 positive. The 1- and 2-year-PFS rates were also higher for patients initially HER2 positive: 1-year-PFS: 52% (95% CI: 36%, 73%) versus 26 % (95% CI: 12%, 52%); 2-year-PFS: 44% (95% CI: 29%, 67%) versus 19% (95% CI: 7%, 50%). Conclusions: Median PFS and 1- and 2-year PFS rate seem to be better in patients HER2 positive at initial diagnosis receiving standard HER2 directed therapies. Although our result has to be interpreted with caution because of the small cohort and the retrospective nature of our analysis, it justifies prospective research including the group of initially HER2 negative patients switched to HER2 positive as a distinct entity. Clinical trial information: NCT02338167 .

Treatment Algorithms for Hormone Receptor-Positive Advanced Breast Cancer: Applying the Results from Recent Clinical Trials into Daily Practice—Insights, Limitations, and Moving Forward

2013 ◽  
pp. e20-e27
Author(s):  
Sheridan Wilson ◽  
Stephen K. Chia
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Acquired Resistance ◽  
Mammalian Target Of Rapamycin ◽  
Real Life ◽  
Metastatic Breast ◽  
Predictive Biomarkers ◽  
Endocrine Treatment ◽  
First Line ◽  
Hormone Receptor Positive

Hormone receptor–positive (HR+) breast cancer is the most prevalent subtype of breast cancer in both early- and advanced-stage disease. Thus, the treatment of HR+ breast cancer has had the greatest global influence in improving clinical outcomes overall. Although the first-line metastatic breast cancer (MBC) trials comparing a third-generation aromatase inhibitor (AI) to tamoxifen have favored the AI, one of the challenges in translating these findings into clinical practice stems from the influence of prior adjuvant endocrine therapy, particularly the increasing use of adjuvant AIs today, on the choice of endocrine agent in the advanced setting because of the development of acquired resistance. Because the majority of patients enrolled into these studies were either endocrine-treatment naïve or exposed to tamoxifen only, the “real-life” applicability of the evidence is unclear. Because a superior dose of the selective estrogen receptor (ER) downregulator fulvestrant has now been established, its role as first-line therapy is being re-established. We are now starting to see the promise realized with blocking cross-talking growth factor pathways in addition to the ER pathway. The greatest efficacy is seen with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with exemestane and, perhaps to a lesser extent, anti-HER2–directed therapy in combination with an AI. Future gains will likely involve a greater understanding of the redundancy and compensation induced by blocking these pathways, trials involving blocking multiple pathways in addition to hormonal agents, and the molecular interrogation of the individual's tumor in search of predictive biomarkers and “actionable” genomic aberrations.

scholarly journals Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592094093 ◽  
Author(s):  
Pauline du Rusquec ◽  
Cyriac Blonz ◽  
Jean Sebastien Frenel ◽  
Mario Campone
Keyword(s):  
Breast Cancer ◽  
Cell Survival ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Intracellular Signaling ◽  
Pik3ca Mutation ◽  
Mammalian Target Of Rapamycin ◽  
Progression Free Survival ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

Recently many therapeutic classes have emerged in advanced hormone receptor-positive breast cancer, which is the leading cause of cancer death in women. In absence of visceral crisis, treatment relies on endocrine therapy combined with cyclin dependent kinase 4 and 6 inhibitor. Many mechanisms lead to resistance to endocrine therapy, including the activation of intracellular signaling pathways critical for cell survival. Approximately 70% of breast tumors harbor an alteration in the phosphoinositide 3 kinase (PI3K)/Akt pathway, leading to its hyper activation. This pathway is involved in the regulation of growth, proliferation and cell survival as well as in angiogenesis and is consequently a major target in the oncogenesis. An aberrant PIK3CA mutation is a common phenomenon in breast cancer and found in approximately 40% of patients with advanced hormone receptor-positive breast cancer. For the moment, the only positive trials showing a progression free survival benefit in this population are BOLERO-2 (2012), SOLAR-1 (2019), which tested everolimus, a mammalian target of rapamycin inhibitor, and alpelisib, a PI3K inhibitor, and led to their marketing authorization. However, many other inhibitors of this pathway are promising; nevertheless their development is actually limited by toxicity, mainly cutaneous (rash), digestive (diarrhea) and endocrine (diabetes).

Efficacy results from a multicenter phase II noncomparative two-arm pilot trial of bevacizumab with anastrozole or fulvestrant as first-line endocrine therapy for metastatic breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1091-1091
Author(s):  
M. S. Rubin ◽  
J. Barton ◽  
D. Shipley ◽  
E. Arrowsmith ◽  
N. Peacock ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Endocrine Therapy ◽  
Pilot Trial ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Poor Response ◽  
First Line ◽  
Eligibility Criteria ◽  
Her 2

1091 Background: Estrogen modulates angiogenesis via effects on endothelial cells with subsequent induction of vascular endothelial growth factor (VEGF). VEGF promotes tumor growth and is associated with poor response to antiestrogen therapy. This trial was designed to evaluate the progression-free survival (PFS) of bevacizumab (B) in combination with anastrozole (A) or fulvestrant (F) as first-line endocrine therapy (ET) in metastatic breast cancer (MBC). Methods: Eligibility criteria: no prior hormonal or chemotherapy for MBC, measurable or evaluable disease, normal LVEF, post-menopausal. Treatment: Arm A: anastrozole 1 mg po QD in pts who were a) ET naïve, b) ≥ 12 months from adjuvant ET, and c) intolerant of or progressed on prior tamoxifen. Arm B: fulvestrant 500 mg D1 and 250 mg D15 IM loading dose followed by 250 mg q28 days in pts who were a) < 12 months from adjuvant aromatase inhibitors (AIs), b) intolerant of or progressed on AIs, and c) MD's discretion. Bevacizumab 10 mg/kg IV D1 q2 weeks was given in both arms. Trastuzumab permitted in HER-2+ pts only. Response assessments were q8 weeks; pts were treated until disease progression or toxicity. Results: 79 pts were enrolled fromNovember 2006 to November 2008. 42 pts are evaluable for response and toxicity, Arm A - 25 pts and Arm B - 17 pts. Median age was 64, ECOG PS 0 - 55%, 1- 43 %, adjuvant chemo 27%, adjuvant hormonal -38%, hormone receptor status: ER+/PR+ 80%, ER+/PR- 14%, ER-/PR+ 2 %. HER-2+ 5 pts, 31% had ≥ 2 metastatic disease sites predominately lung and bone only disease - 40%. Median # cycles - 4. 24% achieved a partial response and 57% stable disease; 7 pts progressed. G3 hypertension (12%) was the most common toxicity. Median PFS for Arm A was 16.3 months and has not yet been reached for Arm B. Conclusions: Bevacizumab in combination with anastrozole or fulvestrant is feasible and well tolerated with no unanticipated toxicities. The addition of bevacizumab resulted in prolongation of the median PFS to16.3 months with anastrozole as compared to the 7–9 month historical control PFS reported for first-line AI monotherapy in MBC. Further evaluation of bevacizumab endocrine combinations is warranted. [Table: see text]

scholarly journals How I manage CLL with venetoclax-based treatments

Blood ◽  
2020 ◽  
Vol 135 (17) ◽  
pp. 1421-1427 ◽  
Author(s):  
William G. Wierda ◽  
Francesco Paolo Tambaro
Keyword(s):  
Targeted Therapy ◽  
B Cell ◽  
Targeted Therapies ◽  
Randomized Clinical Trials ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Continuous Exposure ◽  
First Line

Abstract Targeted therapies for chronic lymphocytic leukemia (CLL) include venetoclax, the oral inhibitor of B-cell lymphoma-2, and inhibitors of kinases in the B-cell receptor signaling pathway, like Bruton tyrosine kinase and phosphatidylinositol 3 kinase. Randomized clinical trials clearly demonstrated improved progression-free survival with targeted therapy over chemoimmunotherapy in first-line and treatment of relapsed/refractory CLL. Comparative trials of venetoclax-based vs other targeted therapies have not been conducted. Differentiating features and considerations with targeted therapies include goals of treatment and therapeutic approach as well as side effect and toxicity profiles. With targeted therapy options for first-line and relapsed CLL, it is ever more important to develop sound rationale and strategy for selecting first-line and treatment of relapsed disease and for long-term management of the disease, including therapeutic sequencing. Fixed-duration therapy with a treatment-free remission is a particularly appealing prospect, since it avoids continuous exposure to treatment and potential for toxicity. We discuss rationale and practical application of venetoclax in first-line and treatment of relapsed and refractory CLL. Venetoclax is highly active at achieving deep remission for most treated patients with CLL, including those with high-risk disease such as del(17p) CLL.

scholarly journals Targeted Therapy in HR+ HER2− Metastatic Breast Cancer: Current Clinical Trials and Their Implications for CDK4/6 Inhibitor Therapy and beyond Treatment Options

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5994
Author(s):  
Constanze Elfgen ◽  
Vesna Bjelic-Radisic
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Clinical Aspects ◽  
Hormone Receptor Positive ◽  
Patient Reported ◽  
Number Of Publications

A metastatic state of breast cancer (MBC) affects hundreds of thousands of women worldwide. In hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) MBC, cyclin-dependent kinase (CDK)4/6 inhibitors can improve the progression-free survival (PFS), as well as the overall survival (OS), in selected patients and have been established as first- and second-line therapies. However, as MBC remains uncurable, resistance to CDK4/6 inhibitors occurs and requires alternative treatment approaches. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. This review provides a summary and update on the clinical relevance, patient selection, ongoing trials of CDK4/6 inhibitors, and further targeted therapy options. It focuses on clinical aspects and practicability, as well as adverse events and patient-reported outcomes.

Immediate and long-term results of the first line chemotherapy in patients with metastatic triple negative breast cancer. Final analysis of randomized study

2020 ◽  
pp. 75-80
Author(s):  
S.A. Lyalkin ◽  
◽  
L.A. Syvak ◽  
N.O. Verevkina ◽  
◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Randomized Study ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Group 2 ◽  
Line Chemotherapy ◽  
Group 1

The objective: was to evaluate the efficacy of the first line chemotherapy in patients with metastatic triple negative breast cancer (TNBC). Materials and methods. Open randomized study was performed including 122 patients with metastatic TNBC. The efficacy and safety of the first line chemotherapy of regimens АТ (n=59) – group 1, patients received doxorubicine 60 мг/м2 and paclitaxel 175 мг/м2 and ТР (n=63) – group 2, patients received paclitaxel 175 мг/м2 and carboplatin AUC 5 were evaluated. Results. The median duration of response was 9.5 months (4.5–13.25 months) in patients received AT regimen and 8.5 months (4.7–12.25 months), in TP regimen; no statistically significant differences were observed, р=0.836. The median progression free survival was 7 months (95% CI 5–26 months) in group 1 and 7.5 months (95% CI 6–35 months) in group 2, p=0.85. Both chemotherapy regimens (AT and TP) had mild or moderate toxicity profiles (grade 1 or 2 in most patients). No significant difference in gastrointestinal toxicity was observed. The incidence of grade 3–4 neutropenia was higher in patients of group 2 (TP regimen): 42.8% versus 27% (р<0.05). Conclusions. Both regimens of chemotherapy (AT and TP) are appropriate to use in the first line setting in patients with metastatic TNBC. Key words: metastatic triple negative breast cancer, chemotherapy, progression free survival, chemotherapy toxicity.

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