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Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy.

ABSTRACT: CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease. A combined analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (PFS and ORR in patients with measurable disease) were examined for patient subgroups corresponding to each significant prognostic factor. Analysis of clinical factors confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor status, performance status, treatment-free interval (TFI) from the end of adjuvant ET, and time from diagnosis to recurrence. Prognosis was poorer in patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or short TFI (<36 months). Benefit (PFS hazard ratio, ORR increase) from abemaciclib was observed in all patient subgroups. Patients with indicators of poor prognosis had the largest benefit from the addition of abemaciclib. However, in MONARCH 3, for patients with certain good prognostic factors (TFI???36 months, bone-only disease) ET achieved a median PFS of >20 months. These analyses identified prognostic factors and demonstrated that patients with poor prognostic factors derived the largest benefit from the addition of abemaciclib.

SUBMITTER: Di Leo A

PROVIDER: S-EPMC6299082 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy.

Di Leo Angelo A O'Shaughnessy Joyce J Sledge George W GW Martin Miguel M Lin Yong Y Frenzel Martin M Hardebeck Molly C MC Smith Ian C IC Llombart-Cussac Antonio A Goetz Matthew P MP Johnston Stephen S

NPJ breast cancer 20181218

CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal a ...[more]

PMID: 30588487

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Project description:Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity.In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed.Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001).Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).

Project description:BackgroundThis analysis investigated whether baseline characteristics affect the survival benefit derived from palbociclib-fulvestrant and the optimal timing of cyclin-dependent kinase 4/6 inhibitor therapy for advanced breast cancer (ABC) in patients from PALOMA-3.Patients and methodsIn total, 521 patients were randomized 2:1 to receive palbociclib (125 mg/day, 3/1 schedule)-fulvestrant (500 mg, intramuscular injection, on days 1 and 15 of cycle 1, and then day 1 of each subsequent cycle) or matching placebo-fulvestrant. Median overall survival (OS) and progression-free survival were estimated using the Kaplan-Meier method.ResultsMultivariable analysis identified endocrine sensitivity, nonvisceral disease, no prior chemotherapy for ABC, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 as significant prognostic factors for OS. Patients without chemotherapy for ABC had fewer prior lines of treatment in any setting and in the ABC setting versus patients with prior chemotherapy for ABC (two or fewer prior systemic therapies: 69% vs. 42%; no more than one prior line for ABC: 82% vs. 33%, respectively). Median OS was prolonged with palbociclib-fulvestrant in patients without prior chemotherapy for ABC (39.7 vs. 29.5 months; hazard ratio, 0.75; 95% confidence interval [CI]: 0.56-1.01) and was similar in patients with prior chemotherapy for ABC (25.6 vs. 26.2 months; hazard ratio, 0.91 [95% CI: 0.63-1.32]) versus placebo-fulvestrant.ConclusionPrognostic factors for OS included endocrine sensitivity, nonvisceral disease, ECOG PS of 0, and no prior chemotherapy for ABC. Exploratory analyses suggest improved OS with palbociclib-fulvestrant versus placebo-fulvestrant in patients with no prior chemotherapy for ABC, prior endocrine sensitivity, and fewer prior regimens of systemic therapy. (Clinical trial identification number: NCT01942135).Implications for practicePrognostic factors for overall survival in HR+/HER2- advanced breast cancer (ABC) include the absence of prior chemotherapy in the advanced setting, endocrine sensitivity, nonvisceral disease, and an ECOG performance status of 0. Improved overall survival benefit was observed with palbociclib-fulvestrant versus placebo-fulvestrant in patients (regardless of menopausal status or visceral involvement) with no prior chemotherapy for ABC, with prior endocrine sensitivity, and fewer prior regimens of systemic therapy. Progression-free survival was prolonged with palbociclib across subgroups (regardless of chemotherapy exposure in ABC). These exploratory findings suggest that patients may receive greater clinical benefit from palbociclib-fulvestrant if they receive the combination before chemotherapy in the advanced setting.

Project description:Importance:Steroid hormone receptors, including estrogen receptor (ER) and progesterone receptor (PR), are crucial biomarkers in breast cancer (BC). However, limited data are available regarding single hormone receptor-positive (ER-positive/PR-negative and ER-negative/PR-positive) subtypes, rendering treatment decision and survival forecast difficult in patients with these BC subtypes. Objective:To investigate the clinicopathological characteristics and BC-specific survival (BCSS) of patients with single hormone receptor-positive BC. Design, Setting, and Participants:In this cohort study, data on patients diagnosed with BC between 1990 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results database (N = 1 158 032). Patients lacking information on ER status, PR status, or BCSS were excluded (n = 334 633). Comparisons were performed between single hormone receptor-positive BC and double hormone receptor-positive/double hormone receptor-negative BC. The dates of analysis were September 1, 2018, to June 31, 2019. Main Outcomes and Measures:The BCSS of patients with single hormone receptor-positive BC. Results:This cohort study included 823 399 patients with BC (818 002 women and 5397 men). The median (range) age at diagnosis was 60 (8-108) years, and the median (range) follow-up duration was 71 (0-311) months. The percentages of ER-positive/PR-positive, ER-positive/PR-negative, ER-negative/PR-positive, and ER-negative/PR-negative cases were 67.2%, 12.2%, 1.6%, and 19.0%, respectively. Single hormone receptor-positive subtypes showed distinct clinical characteristics compared with double hormone receptor-positive/double hormone receptor-negative subtypes. Multivariable Cox proportional hazards regression analysis showed that patients with ER-positive/PR-negative (hazard ratio [HR], 1.36; 95% CI, 1.34-1.38) and ER-negative/PR-positive (HR, 1.61; 95% CI, 1.55-1.67) tumors had worse BCSS than patients with the ER-positive/PR-positive subtype. In contrast, patients with ER-positive/PR-negative (HR, 1.27; 95% CI, 1.24-1.29) and ER-negative/PR-positive (HR, 1.07; 95% CI, 1.03-1.11) tumors had better BCSS than patients with the ER-negative/PR-negative subtype. The BCSS was statistically significantly worse in patients with ER-negative/PR-positive tumors than in patients with ER-positive/PR-negative tumors (HR, 1.18; 95% CI, 1.14-1.23). Conclusions and Relevance:In this cohort study, statistically significant distinctions between survival rates of patients with single hormone receptor-positive BC vs double hormone receptor-positive/double hormone receptor-negative BC were observed. Different strategies may be required for patients with single hormone receptor-positive tumors to ensure optimal treatment and maximum benefits from therapies.

Project description:PurposeAdvanced breast cancer is a heterogeneous disease with several well-defined subtypes, among which, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) is most prevalent. Determination of HR and HER2 status influences prognosis and, thus, disease management. Although literature on these prognostic factors exist, especially in the early breast cancer setting, it remains unclear to what extent these factors can guide clinical decision-making in the advanced disease setting. Therefore, we sought to identify the strength and consistency of evidence for prognostic factors in patients with HR+/HER2- advanced breast cancer.MethodsA systematic literature review (SLR) of the major electronic databases was conducted in November 2018 for primary research studies published since 2010. Endpoints of interest were tumor response, progression-free survival (PFS), overall survival (OS), and breast cancer-specific survival (BCSS).ResultsSeventy-nine studies were included wherein all patients were diagnosed with advanced breast cancer and ≥50% of the population were HR+/HER2-. OS was the most commonly assessed endpoint (n=67) followed by PFS (n=33), BCSS (n=5) and tumor response (n=3). The prognostic factors with strongest evidence of association with worse OS were negative progesterone receptor status, higher tumor grade, higher circulating tumor cell (CTC) count and higher Ki67 level, number of metastatic sites (eg multiple vs single) and sites of metastases (eg presence of liver metastases vs absence), shorter time to recurrence or progression to advanced breast cancer, poor performance status, prior therapy attributes in the early or metastatic setting (type of therapy, treatment line, response of prior therapy), and race (black vs white). The prognostic factors that had strongest evidence of association with PFS included CTC count, number and sites of metastases, and absence of prior therapy or higher lines of therapy in the early or metastatic setting. The directionality of association was consistent for all prognostic factors except between lymph node and OS, and de novo metastatic breast cancer and PFS.ConclusionMultiple disease, treatment, and patient-related prognostic factors impact survival, particularly OS, in patients with HR+/HER2- advanced breast cancer. Treatment outcomes can vary considerably due to these factors. Understanding poorer prognostic factors for patients can result in improved clinical decision-making.

Project description:OBJECTIVE:To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. STUDY SELECTION AND DATA ABSTRACTION:Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. DATA SYNTHESIS:In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a "breakthrough therapy" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001). CONCLUSIONS:Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer.

Project description:BackgroundCanAssist-Breast is an immunohistochemistry based test that predicts risk of distant recurrence in early-stage hormone receptor positive breast cancer patients within first five years of diagnosis. Immunohistochemistry gradings for 5 biomarkers (CD44, ABCC4, ABCC11, N-Cadherin and pan-Cadherins) and 3 clinical parameters (tumor size, tumor grade and node status) of 298 patient cohort were used to develop a machine learning based statistical algorithm. The algorithm generates a risk score based on which patients are stratified into two groups, low- or high-risk for recurrence. The aim of the current study is to demonstrate the analytical performance with respect to repeatability and reproducibility of CanAssist-Breast.MethodsAll potential sources of variation in CanAssist-Breast testing involving operator, run and observer that could affect the immunohistochemistry performance were tested using appropriate statistical analysis methods for each of the CanAssist-Breast biomarkers using a total 309 samples. The cumulative effect of these variations in the immunohistochemistry gradings on the generation of CanAssist-Breast risk score and risk category were also evaluated. Intra-class Correlation Coefficient, Bland Altman plots and pair-wise agreement were performed to establish concordance on IHC gradings, risk score and risk categorization respectively.ResultsCanAssist-Breast test exhibited high levels of concordance on immunohistochemistry gradings for all biomarkers with Intra-class Correlation Coefficient of ≥0.75 across all reproducibility and repeatability experiments. Bland-Altman plots demonstrated that agreement on risk scores between the comparators was within acceptable limits. We also observed > 90% agreement on risk categorization (low- or high-risk) across all variables tested.ConclusionsThe extensive analytical validation data for the CanAssist-Breast test, evaluating immunohistochemistry performance, risk score generation and risk categorization showed excellent agreement across variables, demonstrating that the test is robust.

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Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy.

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Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy.

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