Hormone-responsive Metastatic Breast Cancer Research Articles

Endocrine Therapy in the Current Management of Postmenopausal Estrogen Receptor-Positive Metastatic Breast Cancer.

Metastatic breast cancer (MBC) results in substantial morbidity and mortality for women afflicted with this disease. A majority of MBCs are hormone-responsive and estrogen receptor-positive, making endocrine therapy (ET) an integral component of systemic therapy. With a primary goal of minimizing the effects of estrogen on hormone-responsive MBC, ETs are among the first targeted treatments that aim to inhibit the influence of estrogen receptor activation on tumor proliferation. Several biochemical mechanisms have been the focus of drug development for treatment, including selective estrogen-receptor modulation, aromatase inhibition, and selective estrogen-receptor degradation. Treatments that exploit these mechanisms have improved survival and quality of life for women with MBC. However, in many cases, resistance to ET limits their effectiveness. Elucidation of the complex cellular signal cascades involved in the development of acquired resistance to ET and the interrelationship of growth factor signaling and estrogen responsiveness have characterized components of these pathways as attractive targets for drug development. Based on these insights and with the aim of overcoming hormone resistance, targeted therapies are emerging as useful treatments for MBC. This article reviews current endocrine treatments of MBC as well as recent and ongoing study of combination treatments and targeted therapies that interfere with cellular proliferation pathways as means of overcoming resistance. The Oncologist 2017;22:507-517 IMPLICATIONS FOR PRACTICE: This review provides medical oncologists and other oncology health care providers with a current understanding of the rationale for endocrine therapy in estrogen receptor-positive metastatic breast cancer and the efficacy and safety profile of available treatment options. Additionally, current concepts regarding the development of treatment resistance and the treatment strategies for overcoming resistance are discussed. Enhancing the current information and the understanding of these topics will assist clinicians in evaluating optimal treatment options for their patients.

Clinical and laboratory patterns during immune stimulation in hormone responsive metastatic breast cancer

This study clarifies the relationship between clinical and laboratory patterns, in endocrine-responsive metastatic breast cancer patients treated with a cyclic beta-interferon and interleukin-2 sequence added to anti-estrogens. In 31 patients, a regular laboratory and immunological assessment was made. During clinical benefit, as opposed to progression, a significant increase in the total number of lymphocytes, CD4+, CD8+, NK cells, CRP and IL-12 was confirmed. Also, a significant CEA, TPA, CA15.3 decrease occurred 24–72h after interleukin-2 administration. At the progression, both basally and after interleukin-2 stimulation, the mean values of CD4+ plus CD25+ cells were more than twice higher than during clinical benefit, with a decrease of CD4+ plus CD8+ (Teffector)/CD4+CD25+ (Treg) ratio. Moreover, a significant increase for CEA and for all 3 markers (standardized values) was found 24–72h after interleukin-2 administration. In patients who survived less than 5years, the Treg cell increase occurred at a significantly shorter time interval than in those who survived longer than 5years (20 vs 45.5months, respectively; P=0.001). These data show laboratory evidence of the effect of immunotherapy as well as that of hormone resistance occuring concomitantly with a laboratory pattern compatible with immune inhibition.

Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer according to prior therapy.

e11528 Background: Hormone therapy (HT) is limited by the onset of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) with the ER antagonist Fulvestrant (F) can overcome this resistance. The aim of this study was to evaluate the efficacy and tolerability of F in postmenopausal women with hormone-responsive (HR) metastatic breast cancer (MBC) previously treated with Tamoxifen (T) or Aromatase Inhibitors (AI). Methods: From May 2006 to July 2008 83 patients with HR MBC progressing after T or AI for adjuvant or metastatic disease receiving F 250 mg/month were identified. Median time to progression (TTP), overall survival (OS), clinical benefit rate (CBR) defined as the proportion of partial or complete responses (CR, PR) or stable disease (SD) lasting ‡6 months were analyzed. Results: Six, 32, 33 and 12 patients received F as 1st, 2nd, 3rd and 4thline of HT for MBC, respectively. Fulvestrant resulted in an overall CBR of 38.6% (32/83) with 0% CR, 9% PR, 30%SD, 56% PD. Disease was not evaluable in 4.8% of cases. Median TTP to F was 4.9 months (4 - 5.8; 95% C.I.) and OS was 20.1 months (15.8 - 24.4; 95% C.I.). Patients with visceral metastases and with more advanced lines of overall therapy had worse outcome (OR 3.13, 1.17-8.37, 95% C.I.; p 0.023 and OR 0.72, 0.54-0.96, 95% C.I.; p 0.025, respectively). However, Fulvestrant showed activity up to the fourth line of endocrine therapy regardless of number of metastatic sites and previous AI or T therapy. Overall treatment was well tolerated. Arthralgia, swelling, and myalgia were the most common adverse all were grade 1 or 2. No injection-related adverse events were reported. Conclusions: Fulvestrant is an active treatment in HR MBC previously challenged with HT. Safety profile is optimal and it may be a suitable option in extensively pre-treated patients. Further exploration of its use in this patient population is warranted.

Fulvestrant administered in two different schedules: Pharmacokinetics, biological markers, and activity.

e11026 Background: Fulvestrant (F) had a proved efficacy as second line endocrine therapy in menopausal patients with hormone-responsive metastatic breast cancer (HR-MBC). At 250 mg/monthly the pla...

Phase II Parallel Group Study Showing Comparable Efficacy Between Premenopausal Metastatic Breast Cancer Patients Treated With Letrozole Plus Goserelin and Postmenopausal Patients Treated With Letrozole Alone As First-Line Hormone Therapy

Goserelin and letrozole in premenopausal patients can result in clinical outcomes comparable to those obtained by letrozole alone in postmenopausal patients with metastatic breast cancer (MBC). A total of 73 patients with hormone-responsive MBC were included. Of those, 35 premenopausal patients received goserelin (3.6 mg subcutaneously every 28 days) plus letrozole (2.5 mg orally daily), and 38 postmenopausal patients received letrozole alone as their first-line endocrine therapy in a metastatic setting. Baseline characteristics were similar in the two groups, except for a younger age (median, 41 v 53.5 years; P < .001) and a shorter disease-free interval (median, 1.8 v 3.3 years; P = .03) in the premenopausal group. Clinical benefit rates were comparable between the two groups (77% v 74%; P = .77). With the median follow-up of 27.4 months, there was no statistical difference in the median time to progression between the two groups (9.5 months [95% CI, 6.4 to 12.1 months] v 8.9 months [95% CI, 6.4 to 13.3 months]). In patients who did not receive bisphosphonate, letrozole +/- goserelin caused a greater loss of bone mineral density at 6 months compared with that of patients receiving bisphosphonate treatment (premenopausal group, -16.7% v 53.9%; P = .002 and postmenopausal group, -13.3% v 17.4%; P = .04 at the lumbar spine). Clinical efficacies in premenopausal MBC patients with combined letrozole and goserelin therapy were comparable to those in postmenopausal patients treated with letrozole alone. Although letrozole +/- goserelin resulted in a modest increase in bone resorption, concurrent treatment with bisphosphonate could prevent bone loss at 6 months.

Single Nucleotide Polymorphisms of CYP19A1, rs10459592 and rs4775936 Predict Clinical Benefit of Letrozole in Patients with Metastatic Breast Cancer.

Abstract BackgroundThe CYP19A1 gene encodes the enzyme aromatase, which is involved in the production of estrogen in various tissues. We evaluated the efficacy of an aromatase inhibitor, letrozole in metastatic breast cancer patients according to DNA polymorphisms of the aromatase gene CYP19A1.Patients and methodsPatients (n=113) with hormone receptor positive metastatic breast cancer were treated with letrozole. Monthly GnRH agonist was added in premenopausal patients. DNA was isolated from peripheral blood samples and was genotyped for 50 polymorphisms of CYP19A1 by iPLEX Gold assay based on matrix-associated laser desorptional ionization, time-of-flight mass spectrometry.ResultsAmong 50 examined single nucleotide polymorphisms (SNP), 10 SNPs were revealed as monomorphic for Korean population. After trimming of the data using HWE test, rs10459592 (T/G) and rs4775936 (C/T), which were located in exon I.6 of CYP19A, were significantly associated in an over-dominant model with higher disease control rate (CR+PR+SD≥ 6months) (HR=2.82 [95% CI 1.21-6.59], p=0.0149; HR=2.62 [95% CI 1.12-6.10], p=0.0238, respectively). In linkage disequilibrium analysis, these were strongly linked (D'=1.0, r2=0.936), and subsequent haplotype analysis showed a statistical significance with regard to higher disease control rate (HR=2.61 [95% CI 1.12-6.1], p=0.0238). Median time to progression (TTP) with a median follow-up of 85.7 months (range 9.7-107.4 months) was improved in patients having over-dominant form of rs10459592 without statistical significance (median 7.74 months [95% CI 6.48-9.00] vs. median 12.07 months [95% CI 8.87-15.26], p=0.147). In multivariate analysis, rs10459592 (HR=2.81 [95% CI 1.12-7.06], p=0.027) was an independent factor affecting disease control rate besides age (HR=1.06 [95% CI 1.01-1.12], p=0.019) and HER2 positivity (HR=0.25 [95% CI 1.12-7.06], p=0.027).ConclusionIn patients with hormone responsive metastatic breast cancer treated with aromatase inhibitor, letrozole, the presence of SNPs in the exon I.6 of CYP19A1, rs10459592 and rs4775936 were significantly associated with improved treatment efficacy. Although further study is needed, our data present possible candidate markers for the letrozole treatment in metastatic breast cancer. (NCC grant number 0910320-1) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2117.

Excellent response to letrozole in brain metastases from breast cancer

Breast cancer with multiple parenchymal brain metastases carries an extremely poor outcome. Cranial radiotherapy improves survival by only a few months and the role of systemic therapy is marginal and largely unexplored. We report a patient with recurrent carcinoma of breast presenting with multiple bilateral cervical nodes and brain metastases manifesting as a right hemiparesis and facial nerve palsy, who was treated with palliative whole brain irradiation and letrozole. At the follow up at 20 months, neurological function had fully recovered, and both cerebral and extracerebral lesions had completely resolved, with calcification of the cerebral lesions. This report suggests that letrozole has beneficial effects both in extracranial and intracranial disease in hormone responsive metastatic breast cancer.

Clinical experience using fulvestrant in hormone responsive metastatic breast cancer

10749 Background: We report our clinical experience using the steroid estrogen receptor antagonist Fulvestrant to treat postmenopausal women with hormone sensitive metastasized breast cancer. We discuss the position of Fulvestrant in the endocrine treatment cascade, taking into account the new application guidelines for aromatase inhibitors. Methods: Data from 16 female patients and one male patient treated with Fulvestrant were analyzed. We describe the time point in the treatment cascade when Fulvestrant was administered and the resulting time to progression (TTP). The reviewed cohort was heterogeneous regarding the initial tumor size, the therapy and the progression of the tumor, respectively. The patients were 54 years of age at the time of diagnosis. The estrogen receptor was positive in all cases. Results: Fulvestrant was usually given as the last step in the endocrine treatment cascade (n = 14). The mean TTP was 5.7 months (n = 13). 3 patients are still under successful treatment with Fulvestrant. No common side effects as usually caused by endocrine therapies with Tamoxifen and aromatase inhibitors were documented. Conclusions: The specific estrogen receptor down-regulator Fulvestrant is a valid and well tolerated endocrine treatment option in heavily pre-treated and metastasized breast cancer patients (TTP 5.7 month). Also in the clinical situation of Tamoxifen resistant tumors, Patients could benefit from Fulvestrant. 3rd generation aromatase inhibitors are now used for the first-line treatment of breast cancer in postmenopausal women. Shifting the sequential endocrine therapy cascade might need a new positioning of Fulvestrant. No significant financial relationships to disclose.

First line hormonal treatment (HT) for metastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T) in postmenopausal patients (pts) - A randomized phase III trial of the EORTC Breast Group

515 Background: E is an aromatase inactivator, with demonstrated efficacy in MBC progressing under T, which remained standard 1st line HT over decades. The randomized EORTC phase II trial of E vs T, which showed promising activity in 1st line MBC (Ann. Oncol. 2003, 14: 1391–8) was extended in a phase III reported here, aiming at a true comparison of efficacy and tolerability of both drugs. Methods: Postmenopausal MBC pts with ECOG PS ≤2 and measurable, hormone responsive disease (ER &/or PgR + or unknown with disease free interval >2y) previously untreated with HT for MBC, were randomized to receive open label E 25mg or T 20mg daily. One prior chemotherapy (CT) for MBC was permitted. Prior adjuvant T was allowed if treatment free interval exceeded 6 mo. The trial was powered to detect an increase in median progression free survival (PFS, primary endpoint) of 3 mo in favor of E. Secondary endpoints were survival and tolerability. All analyses were intent to treat. Results: 382 pts accrued by 81 centers received E (190 pts) or T (192 pts). Both groups were balanced for median age (62.5), prior adjuvant CT (E 28%, T 29%) or CT for MBC (E 8%, T 7%), hormone receptor status, PS, prior adjuvant T (21% both) and dominant metastatic site (visceral E 48%, T 47%; bone E 35%, T 36%; soft tissue E 17%, T 17%). On 15/12/2003, 286 events (progression or death under treatment) and 136 deaths were reported. The median PFS is significantly longer under E than T (10.9 vs 6.7 months, p 0.04) with an HR of 0.79 (95% CI 0.62 - 0.99) in favor of E. Best response rates (%) under E were CR 7.4, PR 36.8, SD 27.4, PD 18.4, NE (not evaluable) 10.0; under T, CR 2.6, PR 26.6, SD 37.0, PD 27.6, NE 6.2). No pt withdrew due to toxicity. Grade 2–3 toxicities observed in ≥10% were bone pain (E 12%, T 18%), other pain (E 7%, T 14%) and hot flashes (E 5%, T 12%). Conclusions: E is a safe and highly active steroidal aromatase inactivator, superior to T in MBC. In view of its efficacy and excellent tolerance, E represents a good choice as first line therapy in hormone responsive MBC. Its safety profile makes E also attractive for use in the adjuvant and preventive settings. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Pfizer; Schering-Plough Pfizer

First line hormonal treatment (HT) for metastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T) in postmenopausal patients (pts) - A randomized phase III trial of the EORTC Breast Group

515 Background: E is an aromatase inactivator, with demonstrated efficacy in MBC progressing under T, which remained standard 1st line HT over decades. The randomized EORTC phase II trial of E vs T, which showed promising activity in 1st line MBC (Ann. Oncol. 2003, 14: 1391–8) was extended in a phase III reported here, aiming at a true comparison of efficacy and tolerability of both drugs. Methods: Postmenopausal MBC pts with ECOG PS ≤2 and measurable, hormone responsive disease (ER &/or PgR + or unknown with disease free interval >2y) previously untreated with HT for MBC, were randomized to receive open label E 25mg or T 20mg daily. One prior chemotherapy (CT) for MBC was permitted. Prior adjuvant T was allowed if treatment free interval exceeded 6 mo. The trial was powered to detect an increase in median progression free survival (PFS, primary endpoint) of 3 mo in favor of E. Secondary endpoints were survival and tolerability. All analyses were intent to treat. Results: 382 pts accrued by 81 centers received E (190 pts) or T (192 pts). Both groups were balanced for median age (62.5), prior adjuvant CT (E 28%, T 29%) or CT for MBC (E 8%, T 7%), hormone receptor status, PS, prior adjuvant T (21% both) and dominant metastatic site (visceral E 48%, T 47%; bone E 35%, T 36%; soft tissue E 17%, T 17%). On 15/12/2003, 286 events (progression or death under treatment) and 136 deaths were reported. The median PFS is significantly longer under E than T (10.9 vs 6.7 months, p 0.04) with an HR of 0.79 (95% CI 0.62 - 0.99) in favor of E. Best response rates (%) under E were CR 7.4, PR 36.8, SD 27.4, PD 18.4, NE (not evaluable) 10.0; under T, CR 2.6, PR 26.6, SD 37.0, PD 27.6, NE 6.2). No pt withdrew due to toxicity. Grade 2–3 toxicities observed in ≥10% were bone pain (E 12%, T 18%), other pain (E 7%, T 14%) and hot flashes (E 5%, T 12%). Conclusions: E is a safe and highly active steroidal aromatase inactivator, superior to T in MBC. In view of its efficacy and excellent tolerance, E represents a good choice as first line therapy in hormone responsive MBC. Its safety profile makes E also attractive for use in the adjuvant and preventive settings. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Pfizer; Schering-Plough Pfizer

Aromatase inhibitors as adjuvant therapy for breast cancer

The aromatase inhibitors are regarded as standard approaches to first- or second-line endocrine therapy in women with hormone-responsive metastatic breast cancer. Their efficacy and apparent lack of toxicity have led to their evaluation as adjuvant therapy. Although initial results with these agents in early breast cancer are promising, our collective long-term experience documenting tamoxifen's benefits and our uncertainty about the long-term effects of aromatase inhibitors suggest that it is too early to recommend their routine use in the adjuvant setting. However, anastrozole is also a reasonable therapeutic option in the adjuvant setting, particularly in individuals with a contraindication to tamoxifen such as those with thromboembolic disease or those who develop breast cancer while receiving tamoxifen or raloxifene (Evista) therapy. Anastrozole (Arimidex) was recently approved by the Food and Drug Administration for the adjuvant treatment of postmenopausal women with hormone-receptor-positive early breast cancer. Ongoing trials are assessing the potential role of aromatase inhibitors in the adjuvant, neoadjuvant, and preventive settings.

Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer

BackgroundWomen with hormone-responsive metastatic breast cancer (MBC) may respond to or have stable disease with a number of hormone therapies. We explored the efficacy and safety of the steroidal aromatase inactivator exemestane as first-line hormonal therapy in MBC in postmenopausal women. Patients and methodsPatients with measurable disease were eligible if they had received no prior hormone therapy for metastatic disease and had hormone receptor positive disease or hormone receptor unknown disease with a long disease-free interval from adjuvant therapy. They were randomized to tamoxifen 20 mg/day or exemestane 25 mg/day in this open-label study. ResultsBlinded independently reviewed response rates for exemestane and tamoxifen were 41% and 17%, respectively. Fifty-seven per cent of exemestane- and 42% of tamoxifen-treated patients experienced clinical benefit, defined as complete or partial response, or disease stabilization lasting at least 6 months. There was a low incidence of severe flushing, sweating, nausea and edema in women who received exemestane. One exemestane-treated patient had a pulmonary embolism with grade 4 dyspnea. ConclusionsExemestane is well tolerated and active in the first-line treatment of hormone-responsive MBC. An ongoing EORTC phase III trial is comparing the efficacy, measuring time-to-disease progression, of exemestane and tamoxifen.

Anastrozole: a selective aromatase inhibitor for the treatment of breast cancer.

The role of anastrozole, a new selective aromatase inhibitor, in treating hormone-responsive metastatic breast cancer is discussed. Treatment options for hormone-dependent breast cancer focus on interfering with the endocrine system in an attempt to modify the effects of estrogen. Tamoxifen is the drug of choice for primary endocrine therapy, but there is a need for agents with similar or greater efficacy and better tolerability. Anastrozole inhibits the conversion of androgens to estrogens by aromatase. Bioavailability studies have demonstrated almost complete absorption of anastrozole after oral administration. The drug's terminal half-life after multiple doses is 50 hours. Anastrozole is cleared principally by the liver. Clinical trials comparing anastrozole with megestrol acetate demonstrated no significant differences in clinical efficacy, although a follow-up study revealed a longer median overall survival rate in patients receiving anastrozole. The drug is well tolerated. Among the most frequently reported adverse effects are asthenia, hot flashes, headache, and back pain. The recommended dosage is 1 mg daily. The average wholesale cost of month's supply of anastrozole is $187.20, compared with approximately $100 for generic megestrol acetate or aminoglutethimide plus hydrocortisone. Although anastrozole will likely become the preferred second-line agent in the treatment of postmenopausal breast cancer in patients with disease progression after tamoxifen therapy, it is not a therapeutic alternative to aminoglutethimide on the basis of approved indications. Anastrozole and other aromatase inhibitors may have multiple applications in treating hormone-responsive breast cancer.