scholarly journals Pure oestrogen antagonists for the treatment of advanced breast cancer

2006 ◽  
Vol 13 (3) ◽  
pp. 689-706 ◽  
Author(s):  
Anthony Howell
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Partial Agonist ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Phase Iii ◽  
Cross Resistance ◽  
Phase Ii Trials ◽  
Line Setting

For more than 30 years, tamoxifen has been the drug of choice in treating patients with oestrogen receptor (ER)-positive breast tumours. However, research has endeavoured to develop agents that match and improve the clinical efficacy of tamoxifen, but lack its partial agonist effects. The first ‘pure’ oestrogen antagonist was developed in 1987; from this, an even more potent derivative was developed for clinical use, known as fulvestrant (ICI 182,780, ‘Faslodex’). Mechanistic studies have shown that fulvestrant possesses high ER-binding affinity and has multiple effects on ER signalling: it blocks dimerisation and nuclear localisation of the ER, reduces cellular levels of ER and blocks ER-mediated gene transcription. Unlike anti-oestrogens chemically related to tamoxifen, fulvestrant also helps circumvent resistance to tamoxifen. There are extensive data to support the lack of partial agonist effects of fulvestrant and, importantly, its lack of cross-resistance with tamoxifen. In phase III studies in patients with locally advanced or metastatic breast cancer, fulvestrant was at least as effective as anastrozole in patients with tamoxifen-resistant tumours, was effective in the first-line setting and was also well tolerated. These data are supported by experience from the compassionate use of fulvestrant in more heavily pretreated patients. Further studies are now underway to determine the best strategy for sequencing oestrogen endocrine therapies and to optimise dosing regimens offulvestrant. At present, and for the foreseeable future, fulvestrant is the only oestrogen antagonist with no agonistic effects licensed for the treatment of advanced breast cancer in postmenopausal women. Other similar oestrogen antagonists are undergoing research and development, with a few currently being evaluated in phase II trials.

Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

2016 ◽  
Vol 34 (25) ◽  
pp. 2961-2968 ◽  
Author(s):  
Charlotte Fribbens ◽  
Ben O’Leary ◽  
Lucy Kilburn ◽  
Sarah Hrebien ◽  
Isaac Garcia-Murillas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Advanced Breast Cancer ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Phase Iii ◽  
Wild Type ◽  
Estrogen Receptor Positive ◽  
Esr1 Mutations ◽  
The Impact

Purpose ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor–positive advanced breast cancer. Materials and Methods In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. Results In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). Conclusion ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.

Multicenter phase II efficacy trial of toremifene in tamoxifen-refractory patients with advanced breast cancer.

1993 ◽  
Vol 11 (2) ◽  
pp. 345-350 ◽  
Author(s):  
C L Vogel ◽  
I Shemano ◽  
J Schoenfelder ◽  
R A Gams ◽  
M R Green
Keyword(s):  
Breast Cancer ◽  
Treatment Failure ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Stable Disease ◽  
Objective Response ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Cross Resistance ◽  
High Dose

PURPOSE To explore further the efficacy of high-dose toremifene in patients with advanced breast cancer who had failed to respond to tamoxifen or whose disease had progressed on tamoxifen. PATIENTS AND METHODS One hundred two perimenopausal or postmenopausal women with metastatic breast cancer refractory to tamoxifen were entered onto a phase II clinical trial of toremifene at a dose of 200 mg/d. The study patients consisted of 28 primarily refractory patients; 43 patients who had relapsed after a prior tamoxifen response; and 31 patients who had relapsed while receiving adjuvant tamoxifen. This was a heavily pretreated group of patients, with 65% having failed chemotherapeutic attempts and 72% having failed two or more hormonal therapies. Forty-nine percent of patients had visceral dominant disease. RESULTS The objective response rate was 5% (95% confidence interval [CI], 3% to 7%). The median time to treatment failure (TTF) was 10.9 months for the five responders. An additional 23% of patients had stable disease for a median TTF of 7.8 months, whereas the patients who experienced treatment failure had a median TTF of 2.1 months. Whether those patients with stable disease derived clinical benefit or simply had slow progression in an intrinsically indolent disease presentation is uncertain. Common toxicities were generally mild and similar to those encountered with tamoxifen. CONCLUSION We conclude that there is major cross-resistance between tamoxifen and toremifene and that only occasional tamoxifen-refractory patients will have objective responses to toremifene.

Fulvestrant ('Faslodex')--a new treatment option for patients progressing on prior endocrine therapy.

2002 ◽  
pp. 267-276 ◽  
Author(s):  
C Morris ◽  
A Wakeling
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Advanced Breast Cancer ◽  
Postmenopausal Women ◽  
Endocrine Therapy ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Phase Iii ◽  
Hormone Receptor Positive

Since its introduction more than 30 years ago, tamoxifen has been the most widely used endocrine therapy for the treatment of women with advanced breast cancer. More recently, a number of alternative endocrine treatments have been developed, including several selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and, most recently, fulvestrant ('Faslodex'). Fulvestrant is an estrogen receptor (ER) antagonist, which, unlike the SERMs, has no known agonist (estrogenic) effect and downregulates the ER protein. Tamoxifen is effective and well tolerated, although the non-steroidal AIs, anastrozole and letrozole, are more effective treatments for advanced disease than tamoxifen. Fulvestrant has recently gained US Food and Drug Administration approval for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. In two global phase III clinical trials fulvestrant was at least as effective and as equally well tolerated as anastrozole for the treatment of postmenopausal women with advanced and metastatic breast cancer. In a retrospective analysis of the combined data from these trials, mean duration of response was significantly greater for fulvestrant compared with anastrozole. These new hormonal treatments expand the choice of endocrine therapy for women with advanced breast cancer and offer new options for sequencing and combining treatments.

scholarly journals Ixabepilone as Monotherapy or in Combination with Capecitabine for the Treatment of Advanced Breast Cancer

2011 ◽  
Vol 5 ◽  
pp. BCBCR.S5331 ◽  
Author(s):  
Katherine H. Rak Tkaczuk
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Response Rate ◽  
Locally Advanced Breast Cancer ◽  
Single Agent ◽  
Locally Advanced ◽  
Advanced Breast ◽  
Prior Exposure ◽  
Phase Iii ◽  
Overall Response

Breast Cancer is the most prevalent cancer in the world with 4.4 million survivors up to 5 years following the diagnosis. 1 In the US alone approximately forty thousand women die annually of metastatic breast cancer (MBC). Despite many effective systemic treatment options approximately 50% of women with MBC succumb to the disease within 24 months of the diagnosis. 2 Ixabepilone is a novel, first in class member of the epothilone class of antineoplastic agents. Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and Capecitabine. Ixabepilone is also indicated in combination with Capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixabepilone was extensively studied as a single agent in patients with MBC and was found to be effective and well tolerated with a predictable and manageable safety profile. Not surprisingly prior exposure to anthracyclines and taxanes affects significantly the potential for response to therapy with single agent Ixabepilone in metastatic setting. MBC patients with taxane resistant MBC have objective response rate (RR) of 12%, patients with prior low exposure to taxanes and/or resistance RR = 22%, Ixabepilone treatment after adjuvant anthracycline therapy exposure renders RR = 42% and in Taxane naïve patients RR = 57%. In two large phase III studies of Ixabepilone + Capecitabine versus Capecitabine alone, progression free survival (PFS) and overall response rates (RR) were higher in the combination treatment arms, but no survival advantage was seen overall. Treatment with Ixabepilone + Capecitabine in a phase II study resulted in an overall response rate (ORR) of 23% in ER/PR/HER2 negative, triple-negative breast cancer patients (TNBC) while ORR of 31% was seen in a preplanned pooled analysis of TNBC in the phase III trials of Ixabepilone + Capecitabine. Significantly prolonged median PFS was seen for TNBC treated with the combination of Ixabepilone + Capecitabine compared to Capecitabine alone 4.2 vs. 1.7 months respectively. Ixabepilone as single agent appears to show excellent antitumor activity in patients with TNBC MBC. Addition of Ixabepilone to Capecitabine results in approximately doubling in median PFS for TNBC versus Capecitabine alone. Single agent Ixabepilone is generally well tolerated, and its toxicity profile does not overlap with that of Capecitabine and therefore depending on prior exposure to chemotherapy both single agent Ixabepilone or in combination with Capecitabine can be used safely and effectively for treatment of advanced breast cancer.

scholarly journals Trends in incidence, molecular diagnostics, and treatment of patients with breast cancer in Kazakhstan, 2014-2019

2021 ◽  
Vol 62 (4) ◽  
pp. 16-23
Author(s):  
O. Shatkovskaya ◽  
D. Kaidarova ◽  
Z. Dushimova ◽  
M. Sagi ◽  
R. Abdrakhmanov
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Hormone Therapy ◽  
Molecular Diagnostics ◽  
Breast Cancer Incidence ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Breast Cancer Diagnosis ◽  
Advanced Breast ◽  
Ki 67

Relevance: Globocan reported 4,390 new breast cancer cases and 1,654 deaths from breast cancer in the Republic of Kazakhstan (RK) in 2020. Molecular diagnostics of breast cancer includes the determination of Hormone Receptor (HR), HER2, and Ki-67 status to detect patients with HR-positive tumors and administer effective treatment. Methods: This observational study included a retrospective analysis of incidence, molecular diagnostics, and treatment regimens in women with a confirmed breast cancer diagnosis aged 18 years old and older, registered in the RK Electronic Registry of Cancer Patients (ERCP) from 1 January 2014 till 31 December 2019. Results: In the study period (2014 to 2019), the number of breast cancer cases registered annually has doubled. The incidence increased by 46.9%. The share of locally advanced and advanced forms of breast cancer has decreased. The proportion of Luminal type A (HR+/HER2-) among newly diagnosed patients ranged from 17.9% to 30%. Chemotherapy and endocrine therapy with goserelin, buserelin, leuprorelin, and fulvestrant are standard first- and second-line treatments for HR+ breast cancer. Since fulvestrant indications have been expanded, more than 50% of patients with HR-positive advanced breast cancer receive fulvestrant as the first-line therapy. Conclusion: Breast cancer incidence growth and a decrease in the share of locally advanced and advanced breast cancer cases in the RK could be attributed to increased coverage of eligible women aged 40 to 70 with breast cancer mammographic screening. Although international guidelines support the administration of hormone therapy with or without targeted therapy in women with HR-positive, HER2-metastatic breast cancer, upfront use of chemotherapy remains common in the RK even in the absence of visceral crisis. The use of CDK4/6 inhibitor palbociclib in combination with hormone therapy has become routinely available since 2019.

A Randomized Trial of Chemotherapy with or without Estrogenic Recruitment in Locally Advanced Breast Cancer

1997 ◽  
Vol 83 (5) ◽  
pp. 829-833 ◽  
Author(s):  
Editta Baldini ◽  
Giovanni Gardin ◽  
Piergiorgio Giannessi ◽  
Fulvio Brema ◽  
Alessandra Camorriano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Locally Advanced Breast Cancer ◽  
Objective Response ◽  
Locally Advanced ◽  
Dose Intensity ◽  
Advanced Breast ◽  
Phase Iii ◽  
Pathologic Features ◽  
Significant Difference

The present phase III trial was carried out to verify whether a kinetic recruitment induced by low doses of diethylstilbes-trol (DES) could increase the killing efficacy of chemotherapy in patients with locally advanced breast cancer. One-hundred and seventeen untreated patients with locally advanced breast cancer (stage IIIA/IIIB) were randomized to receive 3 courses of primary chemotherapy consisting of cyclophosphamide (600 mg/m2 i.v.), doxorubicin (50 mg/m2 i.v.) and fluorouracil (600 mg/m2 i.v.) (CAF) on day 1, or DES-CAF (DES, 1 mg orally days 1-3, CAF on day 4). The courses were repeated every 3 weeks. The patients who achieved an objective response were submitted to mastectomy followed by 3 courses of CAF alternated with 3 courses of CMF (cyclophosphamide, 600 mg/m2 i.v.; methotrexate, 40 mg/m2 i.v.; fluorouracil, 600 mg/m2 i.v.), with or without DES. The two treatment arms were well balanced in terms of clinical and pathologic features. There was no significant difference in response rates to induction chemotherapy between the two treatment arms (objective response rate, 63.3% for CAF and 56.1% for DES-CAF). Median overall survival was 49 and 47 months and median progression-free survival was 24 and 21 months for CAF and DES-CAF patients, respectively. Toxicity was not significantly different in the two groups, with the exception of leukopenia: DES chemotherapy was significantly more myelotoxic than the standard treatment, which resulted in a significant reduction in the actual dose intensity. In spite of the attractive experimental evidence, we conclude that so far there is no clinical advantage in the combination of estrogen and chemotherapy. Further research is needed to investigate different schedules of chemotherapy and hor-mones, or to test the possibility of combining various mitogens.

Fulvestrant in advanced breast cancer following following failure of tamoxifen and a third generation aromatase inhibitor

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1073-1073
Author(s):  
J. Wang ◽  
S. Jain ◽  
W. Heller ◽  
D. Mackie ◽  
V. Watson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Advanced Breast Cancer ◽  
Aromatase Inhibitor ◽  
Endocrine Therapy ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Third Generation

1073 Background: Endocrine therapy is a key modality in the management of estrogen receptor positive metastatic breast cancer. Fulvestrant (ICI 182,780) is an estrogen receptor downregulator. It has previously been shown to be as effective as anastrozole in patients who had previously progressed on tamoxifen. Methods: A retrospective study was carried out of metastatic breast cancer patients treated at Charing Cross Hospital between 2002–2005 who had received fulvestrant following treatment failure with tamoxifen and a third generation aromatase inhibitor. All patients were postmenopausal and received fulvestrant 250mg IM every 28 days. Measurable disease was assessed by response evaluation criteria in solid tumors (RECIST). Results: A total of 45 patients were identified with a median age of 60 (range 36 to 90). The ER status was known in 95% (n=43) of patients and was positive in all cases, it was unknown in 2% (n=2). At the time of commencing fulvestrant, 96% (n=43) had metastatic disease and 4% (n=2) locally advanced disease. All patients had received at least 2 lines of prior endocrine therapy (including adjuvant therapy), at time of starting fulvestrant the median number of prior regimens was 3 (range 3–5). Fulvestrant was administered for a median of 4 months (range 1 to 20 months), with 4 patients currently still receiving therapy as of 1 November 2006. Of the 45 patients, 2.2% (n=1) achieved a partial response, while 31% (n=14) achieved stable disease for at least 6 months. Thus, 33.3% (n=15) obtained clinical benefit (defined as PR or SD for at least 6 months). The response rates based on line of therapy will be presented. Of the 45 patients, 41 were evaluable for survival data. The median survival of the remaining patients from the start of fulvestrant therapy was 9 months (range 1 to 48 months). Of the 44 patients, 14% (n=6) remain alive. The treatment was well tolerated and toxicity data will be presented. Conclusions: Fulvestrant is well tolerated and is efficacious as treatment for advanced breast cancer that has failed tamoxifen and a third generation aromatase inhibitors. No significant financial relationships to disclose.

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