Predictors of fulvestrant long-term benefit in hormone receptor-positive/HER2 negative advanced breast cancer.
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ABSTRACT:
SUBMITTER: Torrisi R
PROVIDER: S-EPMC9329443 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose: This single-arm, open-label phase II study evaluated the safety and efficacy of taselisib (GDC-0032) plus fulvestrant in postmenopausal women with locally advanced or metastatic HER2-negative, hormone receptor (HR)-positive breast cancer.Patients and Methods: Patients received 6-mg oral taselisib capsules daily plus intramuscular fulvestrant (500 mg) until disease progression or unacceptable toxicity. Tumor tissue (if available) was centrally evaluated for PIK3CA mutations. Adverse events (AE) were recorded using NCI-CTCAE v4.0. Tumor response was investigator-determined using RECIST v1.1.Results: Median treatment duration was 4.6 (range: 0.9-40.5) months. All patients experienced ?1 AE, 30 (50.0%) had grade ?3 AEs, and 19 (31.7%) experienced 35 serious AEs. Forty-seven of 60 patients had evaluable tissue for central PIK3CA mutation testing [20 had mutations, 27 had no mutation detected (MND)]. In patients with baseline measurable disease, clinical activity was observed in tumors with PIK3CA mutations [best confirmed response rate: 38.5% (5/13; 95% CI, 13.9-68.4); clinical benefit rate (CBR): 38.5% (5/13; 95% CI, 13.9-68.4)], PIK3CA-MND [best confirmed response rate: 14.3% (3/21; 95% CI, 3.0-36.3); CBR: 23.8% (5/21; 95% CI, 8.2-47.2)], and unknown PIK3CA mutation status [best confirmed response rate: 20.0% (2/10; 95% CI, 2.5-55.6); CBR: 30.0% (3/10; 95% CI, 6.7-65.2)].Conclusions: Taselisib plus fulvestrant had clinical activity irrespective of PIK3CA mutation status, with numerically higher objective response rate and CBR in patients with PIK3CA-mutated (vs. -MND) locally advanced or metastatic HER2-negative, HR-positive breast cancer. No new safety signals were reported. A confirmatory phase III trial is ongoing. Clin Cancer Res; 24(18); 4380-7. ©2018 AACR.
| S-EPMC6139036 | biostudies-literature
Project description:BACKGROUND:In the phase III MONARCH 2 study (NCT02107703), abemaciclib plus fulvestrant significantly improved progression-free survival (PFS) versus placebo plus fulvestrant in patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer (ABC). This study assessed patient-reported pain, global health-related quality of life (HRQoL), functioning, and symptoms. MATERIALS AND METHODS:Abemaciclib or placebo (150 p.o. mg twice daily) plus fulvestrant (500 mg, per label) were randomly assigned (2:1). The modified Brief Pain Inventory, Short Form (mBPI-sf); European Organization for Research and Treatment of Cancer (EORTC) QoL Core 30 (QLQ-C30); and Breast Cancer Questionnaire (QLQ-BR23) assessed outcomes. Data were collected at baseline, cycle 2, every two cycles 3-13, thereafter at every three cycles, and 30?days postdiscontinuation. Longitudinal mixed regression and Cox proportional hazards models assessed postbaseline change and time to sustained deterioration (TTSD) by study arm. RESULTS:On-treatment HRQoL scores were consistently maintained from baseline and similar between arms. Patients in the abemaciclib arm (n =?446) experienced a 4.9-month delay in pain deterioration (mBPI-sf), compared with the control arm (n =?223), and significantly greater TTSD on the mBPI-sf and analgesic use (hazard ratio, 0.76; 95% CI, 0.59-0.98) and QLQ-C30 pain item (hazard ratio, 0.62; 95% CI, 0.48-0.79). TTSD for functioning and most symptoms significantly favored the abemaciclib arm, including fatigue, nausea and vomiting, and cognitive and social functioning. Only diarrhea significantly favored the control arm (hazard ratio, 1.60; 95% CI, 1.20-2.10). CONCLUSION:HRQoL was maintained on abemaciclib plus fulvestrant. Alongside superior PFS and manageable safety profile, results support treatment with abemaciclib plus fulvestrant in a population of patients with endocrine-resistant HR+, HER2-negative ABC. IMPLICATIONS FOR PRACTICE:In MONARCH 2, abemaciclib plus fulvestrant demonstrated superior efficacy and a manageable safety profile for patients with in hormone receptor-positive (HR+), HER2-negative (-) advanced breast cancer (ABC). Impact on health-related quality of life (HRQoL) is important to consider, given the palliative nature of ABC treatment. In this study, abemaciclib plus fulvestrant, compared with placebo plus fulvestrant, significantly delayed sustained deterioration of pain and other patient-reported symptoms (including fatigue, nausea, vomiting), and social and cognitive functioning. Combined with demonstrated clinical benefit and tolerability, the stabilization of patient-reported symptoms and HRQoL further supports abemaciclib plus fulvestrant as a desirable treatment option in endocrine resistant, HR+, HER2- ABC.
| S-EPMC7011625 | biostudies-literature
Project description:Prior to availability of anti-HER2 therapies, HER2-positive metastatic breast cancer (MBC) was associated with a poor prognosis. Prospective randomized trials have demonstrated survival benefit from anti-HER2 treatments. Anecdotal observations have suggested that a small but meaningful fraction of patients with HER2-positive MBC may be "exceptional responders" with long survival. We hypothesized that demographic and/or clinicopathologic characteristics can be identified to distinguish short-term from long-term survivors. A retrospective, single-institution review of 168 patients with HER2-positive MBC who received treatment with anti-HER2 therapy in the metastatic setting was performed. Cox proportional hazards analysis was used to assess factors associated with long-term survival. Median overall survival from the time of breast cancer recurrence was 3.9 years (95 % CI 3.4-5.2). From the time of diagnosis of MBC, 56 (33 %) survived for 5 or more years and 12 (7 %) survived more than 10 years. Of the 66 patients diagnosed with central nervous system metastases, 9 (14 %) survived more than 5 years following that diagnosis. Younger age at diagnosis, lower stage, hormone receptor positive status, and only having one organ involved at diagnosis were associated with longer survival. Four patients discontinued anti-HER2 therapy and are without evidence of progression of disease after a median 7.4 years (0.2-12.0) since stopping therapy. In a cohort of patients with HER2-positive MBC treated primarily with trastuzumab and lapatinib, 7 % of patients were "exceptional responders." Combining these clinical factors with molecular determinants of prolonged survival may provide insights for individualizing treatment selection.
| S-EPMC4895232 | biostudies-literature
Project description:The Breast Cancer Test (BCT) score has been validated for its ability to predict the risk of distant metastasis in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. This study aimed to examine the value of the BCT score for predicting the benefit of adjuvant chemotherapy for Korean women with hormone receptor-positive, HER2-negative, lymph node-negative breast cancer. The study included 346 patients treated with either hormone therapy alone (n = 203) or hormone therapy plus chemotherapy (n = 143), and compared patient survival between the two treatment groups. The effect of BCT score on patient survival by treatment group was assessed using Cox proportional hazards models. Based on the results, the BCT score was prognostic for distant metastasis-free survival and breast cancer-specific survival in the hormone therapy alone group. There was no significant difference between the treatment groups in terms of 10-year distant metastasis-free survival in the overall patient population. However, when patients were classified as low risk (n = 266) and high risk (n = 80) according to the BCT score, addition of adjuvant chemotherapy to hormone therapy for patients classified as BCT high-risk group led to a significant improvement in 10-year distant metastasis-free survival, from 65.4% to 91.9% (hazard ratio, 0.18; 95% confidence interval, 0.05-0.64; P = 0.003); in contrast, there was no benefit for the BCT low-risk group. The stratification of patients according to the BCT score also identified clinically high-risk patients who may not benefit from chemotherapy. Results were similar for breast cancer-specific survival. In conclusion, the BCT score was not only of prognostic value but was also a predictor of chemotherapy benefit for Korean patients with hormone receptor-positive, HER2-negative, lymph node-negative breast cancer.
| S-EPMC6248959 | biostudies-literature
Project description:Palbociclib has been shown to be a highly effective therapy in hormone receptor positive metastatic breast cancer when used in combination with letrozole or fulvestrant. Grade 3/4 neutropenia is a common side effect although febrile neutropenia is relatively uncommon. Insufficient data exist to describe the hematological safety of palbociclib in African American women (AAW) known to have a high incidence of benign ethnic neutropenia (BEN). PALOMA 1, 2 and 3, the initial phase II/III studies that led to the U.S. Food and Drug Administration (FDA) approval of palbociclib in metastatic breast cancer, only included participants with baseline absolute neutrophil count (ANC) of 1500/mm3 or higher. African American women (AAW) were underrepresented in the PALOMA trials and this may be partially explained by strict requirements for minimal ANC ?1500/mm3. The ANC of 1500/mm3 for initiation of treatment in those with BEN has been previously challenged. In this study, we propose to lower the ANC cutoff for enrollment to 1000/mm3. PALINA (NCT02692755) is a phase II, single arm, multicenter clinical trial that will enroll 35 patients. The primary endpoint is to assess the proportion of patients who complete therapy without the development of febrile neutropenia or treatment discontinuation due to neutropenia. The secondary endpoints include number of patients who required dose delays or dose reductions in palbociclib attributed to neutropenia, rate of grade 3/4 neutropenia, clinical benefit rate at 24 weeks, the association between metabolite and exosomal signature with disease response and the association between baseline ANC prior to cancer diagnosis and the Duffy Null polymorphism (SNP rs2814778) with hematological safety. PALINA will provide important information about the hematologic safety of palbociclib in AAW with advanced breast cancer.
| S-EPMC6042467 | biostudies-literature
Project description:Fulvestrant 500 mg is standard of care for endocrine therapy-naive or pretreated women with hormone receptor-positive (HR+) metastatic breast cancer (MBC). This study was conducted to explore the potential factors and duration of last endocrine therapy as predictors for the efficacy of fulvestrant 500 mg on Chinese patients in real-world practice. Two hundred and fifty-two MBC patients who were treated with fulvestrant 500 mg consecutively between January 2011 and December 2015 in our institute were included in this study. Efficacy outcomes included progression-free survival (PFS), overall survival (OS), and clinical benefit rate (CBR). The optimal cut-off value for duration of last endocrine therapy was determined by survival ROC analysis. Adverse events were graded according to NCI-CTC AE 4.0. Fulvestrant 500 mg demonstrated a median PFS of 5.8 months (95%CI 4.6-6.9), and a median OS of 35.9 months (95%CI 30.2-41.4). CBR was 41.3% (95%CI 35-47). Liver metastasis, bone alone metastasis, lines of endocrine therapy for MBC, and sensitivity to last endocrine therapy were statistically significant in the Cox multivariate analysis (P values of 0.022, 0.02, 0.03, and 0.038, respectively). The optimal cut-off values for duration of last endocrine therapy to predict the efficacy of fulvestrant 500 mg were 25.08 months for adjuvant endocrine therapy and 5.17 months for first-line endocrine therapy, which showed no difference in prediction power with ABC clinical definition. Patients with prior adjuvant endocrine therapy ?25.08 months or first-line therapy?5.17 months reached a longer PFS of fulvestrant (p = 0.04). Six patients discontinued the treatment due to intolerable adverse events. Patients with the duration of prior endocrine therapy longer than optimal cut-off points indicate better PFS of fulvestrant. Liver metastasis, bone alone metastasis, line of fulvestrant, and sensitivity to last endocrine therapy were also predictors for response of fulvestrant. ClinicalTrials.gov Identifier: NCT03708432.
| S-EPMC7724295 | biostudies-literature
Project description:Background: HER2-positive advanced breast cancer (ABC) is associated with significant heterogeneity in long-term disease control and survival. Prognostic models for HER2-positive ABC patients considering first-line pertuzumab, trastuzumab, and docetaxel have not been evaluated. Methods: A pre-treatment prognostic model for progression-free survival (PFS) and overall survival (OS) was developed for HER2-positive ABC patients initiating first-line pertuzumab, trastuzumab, and docetaxel using clinicopathological data from the randomized clinical trial CLEOPATRA (n = 408). Cox proportional hazard analysis with a backwards deletion process was used. Results: Metastatic sites count (<3 vs. ? 3) and lactate dehydrogenase (LDH) (? ULN vs. >ULN) were identified as common pre-treatment risk predictors for PFS and OS (P < 0.05). Based on these two factors, patients can be characterized as one of three prognostic groups (good = 0 factors; intermediate = 1 factor; poor = 2 factors). The prognostic groups were associated with significantly different PFS (P < 0.001), with 3-year PFS probabilities of 44% (36-55), 28% (22-36), and 17% (11-29) for the good, intermediate and poor prognostic groups, respectively. Similarly, there was significant differences in OS (P < 0.001), with 4-year OS probabilities of 75% (95% CI: 67-84), 60% (53-68) and 31% (21-45) for the good, intermediate and poor prognostic groups, respectively. Conclusions: Pre-treatment prognostic groups identified for HER2-positive ABC patients initiating first-line pertuzumab, trastuzumab, and docetaxel had significantly different long-term disease control and survival outcomes.
| S-EPMC6713878 | biostudies-literature
Project description:Nearly 75% of breast cancers are hormone receptor-positive (HR+) and human epidermal growth factor receptor type 2-negative (HER2-), making endocrine therapy the mainstay of treatment for HR+ and HER2- combination. Although endocrine therapy, such as therapy with fulvestrant, is widely used in the clinic, endocrine resistance (primary or secondary) is inevitable and poses a serious clinical concern. However, the therapeutic landscape of HR+/HER2- breast cancer is rapidly changing and evolving. In recent years, molecular insights into the genome of HR+/HER2- breast cancer have helped to identify promising targets, such as alterations in signaling pathways [phosphatidylinositide 3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR)], dysregulation of the cell cycle (CDK4/6), and identification of new ESR1 mutations. These insights have led to the development of newer targeted therapies, which aims at significantly improving survival in these patients. This review summarizes the role and rationale of fulvestrant when used as a monotherapy or in combination with targeted therapies in patients with HR+/HER2- advanced breast cancer. We also discuss other novel agents and potential future combination treatment options.
| S-EPMC6536994 | biostudies-literature
Project description:BACKGROUND:Fulvestrant, a selective estrogen receptor degrader, is approved for first- and second-line treatment of postmenopausal women with hormone receptor-positive advanced breast cancer (ABC). METHODS:Meta-analysis of randomized controlled trials (RCTs) evaluating fulvestrant 500 mg in postmenopausal hormone receptor-positive ABC, to evaluate differences in clinical benefit rate (CBR; proportion of patients experiencing best overall response of complete response, partial response, or stable disease for ≥ 24 weeks) between fulvestrant 500 mg and comparator endocrine therapies. Odds ratios (OR) and 95% confidence intervals (CI) for CBR were calculated; fixed effects (FE) models were constructed (first- and second-line data, alone and combined). RESULTS:Six RCTs were included. Four studies evaluated fulvestrant 500 mg vs. fulvestrant 250 mg; two evaluated fulvestrant 500 mg vs. anastrozole 1 mg. In total, 1054 and 534 patients were included (first- and second-line treatment, respectively). Analysis of OR and 95% CI of CBR by therapy line favored fulvestrant 500 mg vs. comparator therapy. Assessing all results combined in the FE model indicated significant improvement in CBR with fulvestrant 500 mg vs. comparator treatments (OR 1.33; 95% CI 1.13-1.57; p = 0.001). Restricting the FE model to therapy line demonstrated significant improvement in CBR vs. comparator treatments (OR 1.33; 95% CI 1.02-1.73; p = 0.035) for first-line, and a trend to improvement vs. comparator treatments (OR 1.27; 95% CI 0.90-1.79; p = 0.174) for second-line. CONCLUSIONS:In postmenopausal patients with hormone receptor-positive ABC, fulvestrant 500 mg first-line was associated with significantly greater CBR (more patients benefiting from treatment) vs. comparator endocrine therapy.
| S-EPMC6821663 | biostudies-other
Project description:Gene expression data of HER2+ breast tumor samples Increasing evidence indicates that a subset of patients with HER2-positive breast cancer may achieve significant clinical benefit with anti-HER2 targeted therapy without chemotherapy. Thus, identification of biomarkers of long-term benefit from anti-HER2 agents is needed, especially in the metastatic setting. In the HERLAP study (NCT00842998), patients with HER2-positive metastatic breast cancer were randomized to trastuzumab or lapatinib as first-line therapy. Patients showing radiological signs of tumor regression after 8 weeks of treatment were allowed to continue on single agent anti-HER2 therapy until disease progression. Chemotherapy was added to anti-HER-2 therapy in patients failing to achieve tumor regression at the 8-week evaluation and those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded in 17 primary tumor samples. The research-based PAM50 intrinsic subtypes were also identified. The association of the expression of each biomarker with clinical outcome endpoints was evaluated. Nineteen patients were enrolled. In 4 patients (21.1%) we observed disease control lasting longer than 12 months with single agent anti-HER2 therapy (range 14.9-38.8 months). High expression of 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were found significantly associated with 8-week overall response rate and with the duration of disease control during single agent anti-HER2 therapy. Conversely, high expression of luminal-related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile, was found associated with reduced benefit from single agent anti-HER2 therapy. Conclusions: Our data indicate that gene expression-based biomarkers can identify patients with HER2-positive metastatic breast cancer that benefit substantially from single agent chemo-free anti-HER2 targeted therapy. In the study presented here, a well-defined cohort of 21 breast cancer cases from the HERLAP trial, was used to acquire expression profiles of a total of 105 unique genes
2013-10-25 | E-GEOD-46350 | biostudies-arrayexpress