Endocrine Monotherapy Research Articles

CLINICAL STUDY OF THE PROSTATE CANCERS WITH A SERUM PROSTATE SPECIFIC ANTIGEN LEVEL OF MORE THAN 100 ng/ml AT THE FIRST DIAGNOSIS

In patients with prostate cancer high serum prostate specific antigen (PSA) at diagnosis was generally regarded as a strong impression of advanced disease with distant metastasis and poor prognosis. (Objective) We reported a retrospective study of prognostic factor and Overall survival (OS) in patients with prostate specific antigen (PSA) level of greater than 100 ng/ml (PSA≥100 ng/ml). (Subjects and methods) Between January 2002 and December 2015, 60 patients were diagnosed prostate cancer with PSA≥100 ng/ml and performed hormonal monotherapy at Kanazawa Medical University hospital. We evaluated initial PSA level, Gleason score, Gleason Grading Group, clinical stage, site of metastasis, PSA nadir level, Time to PSA nadir (TTN), serum Hemoglobin (Hb) level, serum C-Reactive Protein (CRP) level, serum Lactate Dehydrogenase (LDH) level, serum Alkaline Phosphatase (ALP) level, clinical passage and survival time. (Results) The median age of the patients was 73 years old (54-90) and the initial PSA levels ranged from 100 ng/ml to 15,823 ng/ml (median 390).Prognostic factors of overall survival were site of metastasis, Gleason score, Gleason Grading Group, PSA nadir level, TTN, serum CRP level, serum LDH level and serum ALP level at the diagnosis. In multivariate analysis serum LDH level remained an independent predictor of OS.

High-dose prednisone therapy for infantile spasms and late-onset epileptic spasms in China: The addition of topiramate provides no benefit

PurposeTo compare the clinical efficacy of high-dose prednisone monotherapy and the combination of hormone and moderate-dose topiramate (TPM) therapy in children with infantile spasms (IS) and late-onset epileptic spasms (ES), and to evaluate whether the addition of TPM would provide more benefits for patients. MethodsAll patients were assigned to receive either high-dose prednisone alone (the maximum doses was 60 mg a day) or high-dose prednisone with TPM (the moderate doses was 5 mg/kg/day). The primary outcome was the proportion of children who achieved cessation of spasms at day-49 or day-56 after initial treatment (the minimum duration of treatment were 49 days). Results77 patients were randomly divided into two groups. The control rate of spasms on day-14 in hormone monotherapy was similar to combination therapy (71.8% vs 76.3%, p = 0.796). The cessation of spasms rate of patients on day-49 or day-56 was also similar between the two groups (71.8% vs 65.8%, p = 0.569). After 4 months, the cessation of spasms rate of patients in the group of hormone monotherapy was higher than the group of combination therapy, but there was no significant difference (61.5% vs 50.0%, p = 0.308). ConclusionThe efficacy of the combination therapy was not better than that of the monotherapy in achieving spasm freedom at 14-days, 49-days or 56-days and day-120 in the patients. Adding-on moderate-dose TPM did not help more children achieve spasm freedom and provided no benefit for prevention of IS and late-onset ES in short term. Higher-dose regimens of TPM might be more effective.

Hormone Therapy for Cancer Is a Risk Factor for Relapse of Inflammatory Bowel Diseases

Background & Aims:Exposure to hormone contraception has been associated with an increased risk of relapse of inflammatory bowel diseases (IBD). Little is known about the effects of cancer therapies, specifically hormone therapies, on the course of IBD.Methods:We conducted a retrospective cohort study, collecting data from 5 medical centers on patients with IBD who received a subsequent diagnosis of breast or prostate cancer from 1997 through 2018. For patients with quiescent IBD at their cancer diagnosis, the primary outcome was relapse of IBD. For patients with active IBD at their cancer diagnosis, the primary outcome was IBD remission.Results:Our analysis included 447 patients with IBD (44% with Crohn’s disease, 53% with ulcerative colitis, and 3% with IBD-unclassified) who had either breast (78%) or prostate (22%) cancer. At their cancer diagnosis, 400 patients (90%) had inactive IBD, and 47 (10%) had active IBD. Among patients with inactive IBD, 112 (28%) developed active IBD. Previous exposure to steroids, immunomodulators, or biologics was associated with IBD relapse following a cancer diagnosis (hazard ratio [HR] for steroids, 1.79; 95% CI, 1.18–2.71; HR for immunomodulators, 2.22; 95% CI, 1.38–3.55; HR for biologics, 1.95; 95% CI, 1.01–5.36). Hormone monotherapy (HR, 2.00; 95% CI, 1.21–3.29) and combination cytotoxic and hormone therapy (HR, 1.86; 95% CI, 1.01–3.43) was associated with IBD relapse. Among 34 patients who received only cytotoxic chemotherapy, 75% remained in remission from IBD at 250 months compared with 42% of those who received hormone monotherapy (log rank=0.02). Among patients with active IBD at their cancer diagnosis, 14 (30%) entered remission from IBD, but there were no significant factors of achieving IBD remission.Conclusions:In a multicenter retrospective study, we found that patients with IBD and breast or prostate cancer who receive hormone therapy have an increased risk for relapse of IBD and related adverse outcomes.

Monitoring the Early Response of Fulvestrant Plus Tanshinone IIA Combination Therapy to Estrogen Receptor-Positive Breast Cancer by Longitudinal 18F-FES PET/CT.

Endocrine monotherapy of breast cancers is generally hampered by the primary/acquired resistance and adverse sides in clinical settings. Herein, advantaging the multitargeting antitumor effects and normal organ-protecting roles of Chinese herbal medicine, the aim of this study was to investigate the enhanced synergistic efficacy of fulvestrant plus Tan IIA combination therapy in ER-positive breast cancers and to monitor the early response by longitudinal 18F-FES PET/CT imaging. The experimental results showed FUL + Tan IIA combination therapy significantly inhibited tumor growth of ER-positive ZR-75-1 tumor xenografts and exhibited distinct antitumor effects at an earlier time point after treatment than did the monotherapy of FUL or Tan IIA. Moreover, 18F-FES PET/CT imaging competently monitored the early response of FUL + Tan IIA combination therapy. The quantitative 18F-FES %ID/gmax in vivo was further confirmed by and correlated well with ERα expression ex vivo. In conclusion, the synergic effect of FUL + Tan IIA combination therapy to ER-positive breast cancers was verified in the preclinical tumor models and the early treatment response could be monitored by 18F-FES PET/CT.

Adjuvant endocrine monotherapy (ET) versus adjuvant breast radiation (RT) alone in healthy older women with stage I, estrogen receptor-positive (ER+) breast cancer: An analysis of the National Cancer Database (NCDB).

519 Background: The NCCN guidelines state that breast RT may be omitted in patients > 70 years of age with ER+, clinically node-negative, T1 breast cancer (BC) who receive adjuvant ET. Available data on older patients notes that local relapses are the most frequent site of failure, and distant relapse rates are low. The side effects of ET are not inconsequential and negatively affect QOL. The objectives of this study are to examine clinical outcomes including overall survival (OS) in women ≥70 years of age treated by lumpectomy(L)+ET and L+RT in the NCDB. Methods: The 2004-2013 NCDB includes 76,431 women ≥70 years with ER+ stage I BC who underwent L, and had a minimum one year follow up. Women who received no adjuvant therapy, both ET+RT, or any chemotherapy were excluded. To limit the analysis to healthy women, we excluded subjects with a Charlson comorbidity index > 0. We identified 24,572 patients who received either adjuvant ET monotherapy or adjuvant RT alone. Among these, 46% (11,313) received ET and 54% (13,259) breast RT. Overall median follow up was 57 months (range: 12-143 months). Analysis of OS between the 2 treatment groups was performed using Kaplan-Meier statistics and Cox proportional hazards regression; propensity weighting was used to balance covariates across the 2 treatment groups. Results: After propensity weighting, demographic covariates including age, race, insurance, and facility type were balanced between the 2 treatment groups. The median OS for ET was 125.9 months (95% CI 120.1-131.8), and 127.2 months for RT (95% CI 124.5-131.7) (p < 0.0001). The weighted hazard of death was 11.7% less in women receiving RT compared to ET (HR 0.883, 95% CI 0.834-0.936, p < 0.0001). Conclusions: To our knowledge, this is the first large study comparing RT and ET monotherapy in healthy older women with stage I, ER+ BC. The OS with RT alone is not inferior to ET alone, and in this study population is noted to be better. While this analysis has various limitations not dissimilar from other NCDB database studies, our observations are encouraging and warrant further research with prospective studies.

Real-world effectiveness of ribociclib + aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line treatment in postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Baseline data from the RIBANNA study.

e12520 Background: Ribociclib, a selective CDK4/6 inhibitor, in combination with an aromatase inhibitor (AI) is approved for the treatment of HR+/HER2- advanced breast cancer (aBC) (locally advanced or metastatic). Real-world evidence for the effectiveness, safety and tolerability of ribociclib + AI in routine clinical practice is needed to support its use. Methods: RIBANNA (CLEE011ADE03) is a non-interventional study running in Germany since October 2017 involving up to 3020 postmenopausal patients receiving ribociclib + AI, endocrine monotherapy (ET), or chemotherapy (CT) as first-line treatment for HR+/HER2- aBC, prescribed in line with German guidelines. Data are collected from clinical practice in all three cohorts. Further lines of treatment are documented to examine outcomes of sequential therapy. Results: 461 patients enrolled to October 9, 2018 (Table). First-line mean daily ribociclib dose was 382 mg including and 540 mg excluding dose interruptions; mean duration of exposure to ribociclib: 128 days. Ribociclib was given in combination with anastrozole (8%), exemestane (7%), and letrozole (83%); ET comprised a selective estrogen receptor degrader (25%), nonsteroidal AI (64%), steroidal AI (5%), and a selective estrogen receptor modulator (7%); CT included taxane-based monotherapy (30%) or combination therapy (27%), anthracycline-based combination therapy (5%), other monotherapy (23%) or other combination therapy (13%). Conclusions: Population characteristics from the RIBANNA study show a diverse group of patients from a real-world setting of ribociclib treatment. Baseline demographics and characteristics. Clinical trial information: CLEE011ADE03. [Table: see text]

Cost-Effectiveness Analysis of Fulvestrant 500mg in Endocrine Therapy-Naïve Postmenopausal Women with Hormone Receptor-Positive Advanced Breast Cancer in the UK.

IntroductionThe selective estrogen receptor degrader fulvestrant is approved for the first-line treatment of postmenopausal patients with hormone receptor-positive (HR+), locally advanced or metastatic breast cancer who have not received prior endocrine therapy. We evaluated the cost-effectiveness of fulvestrant versus comparator treatments in endocrine therapy-naïve patients with locally advanced or metastatic breast cancer.MethodsA three-health-state (progression free, progressed disease, and death) partitioned survival model from the UK National Health Service and Personal Social Services perspective was developed to extrapolate study data for the cumulative probability of progression-free survival and overall survival to a lifetime (30-year) horizon. Relative comparator data were derived from a systematic literature review-informed network meta-analysis. Sensitivity analyses were applied to assess the impact of uncertainty in the parameter input values on the results.ResultsOver a lifetime horizon (30 years), the incremental cost (British pounds sterling) per patient associated with fulvestrant treatment was £18,867 versus anastrozole, £23,097 versus letrozole, and £17,131 versus tamoxifen, with incremental quality-adjusted life-years of 0.55, 0.77, and 0.76, respectively, and incremental cost-effectiveness ratios of £34,109, £29,827, and £22,532, respectively. The largest difference in costs between fulvestrant and the comparators was related to treatment costs.ConclusionsResults suggest that fulvestrant could potentially be a cost-effective option compared with other endocrine monotherapies (anastrozole, letrozole, and tamoxifen) for treating endocrine therapy-naïve, postmenopausal women with HR+, locally advanced or metastatic breast cancer.Electronic supplementary materialThe online version of this article (10.1007/s41669-019-0134-3) contains supplementary material, which is available to authorized users.

Abstract P4-14-12: Outcomes in hormone receptor positive, invasive lobular cancer in the era of endocrine monotherapy

Abstract Background:Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancers and is clinically and biologically distinct from invasive ductal carcinoma (IDC). Despite that, women with early stage ILC are often treated similarly to IDC. However, several retrospective studies suggest that patients (pts) with ILC may not derive survival benefit from the addition of chemotherapy to endocrine therapy relative to pts with IDC. The purpose of our study was to compare outcomes of pts with ILC treated with chemotherapy with those who received endocrine monotherapy. Methods: A retrospective review of pts with ILC or pleomorphic lobular carcinoma treated at the Ohio State University James Cancer Center from 2004-2014 was performed. Clinico-pathologic characteristics, treatment summary and clinical outcomes were collected. Distant disease-free survival (DDFS) was defined as time from diagnosis to the first distant metastases or death and overall survival (OS) was the time from diagnosis to death or last known follow up. DDFS and OS curves were created using Kaplan-Meier methods and compared using log-rank tests. Cox proportional hazard models were used to calculate univariate and multi variable hazard ratios (HR) for OS and DDFS. Results: We identified 379 pts with early stage ILC (stage I: 43% (162/379), stage II: 34% (127/379), stage III: 22% (84/379), unknown: 1% (6/379)). The majority of pts were post-menopausal (79%), Caucasian (92%) and ER+/PR+ (87%) and HER2 negative (96%). One hundred seventy six pts (46%) received chemotherapy and 189 (50%) pts received endocrine therapy alone. Pts who received chemotherapy had stage II or III disease, positive lymph nodes and grade 2 or 3 tumors; while pts who received endocrine monotherapy had stage I disease, negative lymph nodes and grade 1 or 2 tumors. We found a 51% decrease in chemotherapy (from 63% to 31%) and an increase in endocrine monotherapy use (from 34% to 65%) between 2004-2010 and 2011-2014. One hundred thirty two pts were evaluated with Oncotype DX, of which 76% (100/132) were node negative with the majority having a low recurrence score (low: 64%; intermediate: 33%; high: 3%). The use of Oncotype DX increased from 21.1% in 2004-2010 to 47.9% in 2011-2014. We found that 112 of 149 pts with at least 5 years follow up (75.2%) successfully completed five or more years of endocrine therapy. Univariate cox models showed worse DDFS HRs for type of therapy and node status (HR: 2.36, p=0.005, HR: 4.16, p<0.001, respectively). However, the HR for therapy was no longer significant when adjusting for age, grade, and nodal involvement (HR = 1.19, 95% CI: 0.56 – 2.52, p=0.646). Nodal involvement remained significant (HR= 3.56, 95% CI: 1.64-7.70, p=0.001) after adjusting for therapy, age and grade. No significant difference in OS was found between endocrine monotherapy and chemotherapy (p=0.426, log-rank test). Conclusion: We found no difference in DDFS between endocrine monotherapy and chemotherapy after adjusting for age, grade, and nodal involvement in pts with early stage ILC. This supports the hypothesis that ILC may not derive a significant benefit from the addition of chemotherapy. We need more prospective clinical trials considering histology to better understand how best to treat ILC. Citation Format: Williams N, Liu J, Stephens J, Palettas M, Boutrid H, Sardesai S, Reinbolt R, Stover D, VanDeusen J, Noonan A, Wesolowski R, Lustberg M, Ramaswamy B. Outcomes in hormone receptor positive, invasive lobular cancer in the era of endocrine monotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-12.

Abstract OT3-02-01: RIBANNA — Real-world evidence of ribociclib plus aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line therapy for postmenopausal women with HR+, HER2– advanced breast cancer (aBC)

Abstract Background: In the pivotal phase 3 MONALEESA-2 trial, ribociclib, a highly selective oral CDK4/6 inhibitor in combination with letrozole significantly prolonged progression-free survival (PFS) compared to letrozole alone. In the year 2017, based on the results of MONALEESA-2, ribociclib in combination with an aromatase inhibitor (AI) was approved for the treatment of HR+, HER2– aBC in postmenopausal women with no prior therapy for their advanced disease (first-line treatment). Beyond phase 3 trials, further data for ribociclib are now becoming available from the phase 3b trials, RIBECCA and COMPLEEMENT-1, involving approximately 500 and 3000 patients with aBC, respectively. However, real-world evidence for the effectiveness, safety, and tolerability of ribociclib + AI in the routine clinical practice is needed to further support the use of this combination in the first-line therapy. Methods: RIBANNA is a non-interventional study, which started in October 2017 and plans to enroll 3020 patients across ˜400 sites in Germany. Postmenopausal women diagnosed with aBC will be enrolled into 3 cohorts (cohort 1: ribociclib + AI; cohort 2: endocrine monotherapy; and cohort 3: chemotherapy). Across all cohorts, patients will be treated in accordance with the respective German-prescribing guidelines. Data related to efficacy (with PFS as the primary efficacy criterion), safety, tolerability, duration of therapy, and impact on quality of life (QoL) will be collected. QoL will be assessed using the validated patient questionnaires. This study was especially designed to analyze the patient data from sequential lines of therapy in all three cohorts over a period of up to 7 years. For this purpose, RIBANNA will collect the data on each line of treatment and the reason for changing treatment in all 3 cohorts. The same accounts for QoL, which will also be assessed periodically, regardless of disease progression and initiation of subsequent therapies. RIBANNA is the first study to provide the real-world evidence regarding treatment of HR+, HER2− aBC with the CDK4/6 inhibitor, ribociclib. This study includes 3 treatment cohorts (ribociclib + AI, endocrine monotherapy, and chemotherapy) with subsequent treatment algorithms and assessment of QoL over the entire study period. Citation Format: Wöckel A, Fasching PA, Guderian G, Heim J, Jackisch C, Lück H-J, Lüftner D, Marmé F, Reimer T, Decker T. RIBANNA — Real-world evidence of ribociclib plus aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line therapy for postmenopausal women with HR+, HER2– advanced breast cancer (aBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-01.

Abstract PD9-06: Paired pre- and post-treatment DNA sequencing identifies genomic alterations mediating clinical resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer

Abstract Background: The combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6 inh) and endocrine therapy have changed the treatment paradigm for hormone receptor-positive metastatic breast cancer (HR+ MBC). Three CDK 4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are now approved for HR+ MBC in combination with either an aromatase inhibitor (AI) or fulvestrant (a selective estrogen receptor degrader, SERD) after demonstrating significant improvement in progression-free survival compared to endocrine monotherapy. However, both primary and secondary resistance has been observed clinically, and the mechanisms of such resistance are not well understood. Here we describe emergence of molecular alterations following treatment with the combination of CDK 4/6 inhibitors and endocrine therapy. Methods: We evaluated molecular alterations by next-generation sequencing (NGS) prior to and following treatment with CDK 4/6 + endocrine therapy pre and post CDK inh among patients with HR+ MBC. We performed circulating tumor (ct) DNA analysis via the Guardant360 assay, an NGS-based assay that identifies potential tumor-related (somatic) genomic alterations through sequencing of the critical exons within 73 cancer-related genes, and/or tissue-based genomic analysis utilizing our institutional NGS platform (SNaPshot), which targets hotspots and exons in 89 genes. Results: A total of 33 HR+ MBC patients had paired pre/post CDK 4/6 tissue/liquid biopsies. 19 (57.6%) received palbociclib and 14 (42.4%) ribociclib, with 25 (75%) receiving an AI and 8 (24%) a SERD. Eight patients (24.2%) were first line. The median duration of response was 8 months (range 1-35 months). The most common acquired alterations at the time of progression that were not present in the pre-treatment specimens included mutations in ESR1 (30.3%), TP53 (30.3%), RB1 (12.1%) and PIK3CA (9.1%), and FGFR1 amplification (27.3%). We then evaluated these results in a subset of patients (N=17) who had paired pre/post liquid biopsies only and found similar results. We observed alterations in oncogenic pathways both upstream and downstream of CDK 4/6-cyclin-D complex (N=17), including upstream receptor tyrosine kinase alterations (29.4%), PI3K/AKT/mTOR alterations (5.9%), and MAPK alterations (17.6%), as well as downstream cell-cycle (35.3%) and DNA repair gene alterations (17.6%). Furthermore, 58.8% of patients had more than one acquired potential driver mutation, and 41.2% had both upstream and downstream alterations possibly reflecting emergence of different subclones and tumor heterogeneity under selective pressure from CDK 4/6 inhibitors. Conclusion: Both upstream and downstream genomic alterations may mediate acquired clinical resistance to CDK 4/6 inhibitors, reflecting genomic evolution and diversification after exposure to CDK 4/6 inhibitors. Additional studies are needed to confirm these findings and develop potential therapeutic strategies to overcome clinical resistance to CDK 4/6 inhibitors for patients with MBC. Citation Format: Spring LM, Haddad S, Malvarosa G, Vidula N, Juric D, Iafrate AJ, Ellisen LW, Moy B, Isakoff SJ, Bardia A. Paired pre- and post-treatment DNA sequencing identifies genomic alterations mediating clinical resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD9-06.

Abstract P2-07-05: A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced stage breast cancer treated with first-line endocrine therapy

Abstract Purpose: Endocrine based therapy is an effective strategy to manage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, nearly all patients exhibit/develop either de novo or acquired resistance. While prognostic biomarkers of endocrine responsiveness are well established for the adjuvant treatment in ER+ breast cancer, less is known regarding prognostic and predictive biomarkers of response in the first line ABC setting. We sought to develop a clinical calculator based on clinical criteria for predicting progression-free survival (PFS) and overall survival (OS) of women with HR+/HER2- ABC who will be receiving endocrine monotherapy as first-line treatment for ABC. Methods: The development of the clinical calculator will be based on data from modern clinical trials in women with HR+/HER2- ABC. The studies to be included in the final analyses are given in Table 1. The control arm data from trials1-6 will form the training dataset (N = 1,223) and be used to construct the clinical prediction models. Variables considered include age, race, ECOG status, disease measurability, body mass index, disease-free interval, number of metastatic sites, locations of metastatic sites, prior endocrine therapy, and prior chemotherapy. Missing values will be imputed using single imputation with all variables included in the imputation model. For continuous variables, restricted cubic splines will be used to determine if non-linear effects may be more appropriate. The Lasso regression will be used as a variable selection technique to reduce the dimensionality of covariates; initially all pairwise interactions will be included in the model. Following Lasso regression, the multivariable Cox proportional hazards models will be constructed for PFS and OS including only variables retained in Lasso. The final model will be internally validated for discrimination and calibration using 10-fold cross-validation. External validation will be performed using control arm data from EGF 30008 (N = 536). Results: To date, control arm data from four trials (trials 1-4) have been received. The preliminary results presented here are based on pooled data from C40503 and LEA, for which data elements have been harmonized. Models for predicting PFS and OS have good calibration and are associated with bias-corrected C-indices of 0.61 and 0.65, respectively. These models will be updated using pooled data from trials 1-6. Conclusions: Our preliminary data demonstrate that clinical calculators based on baseline clinical factors can provide accurate prediction of PFS and OS in patients with HR+/HER2- ABC treated with first-line ET. If validated, these tools may be used for risk stratification in future clinical trials and to identify patients who may require more or less aggressive therapy. Table 1:Studies to be includedTrial NumberTrial NameTrial PISample Size in Control Arm1C40503Maura Dickler152 (letrozole)2LEAMiguel Martin179 (letrozole)3FACTJonas Bergh188 (anastrozole)4FALCONJohn Robertson194 (anastrozole)5S0226Rita Mehta345 (anastrozole)6MONARCH 3Matthew Goetz165 (nonsteroidal AI)7EGF 30008Stephen Johnston536 (letrozole) Citation Format: Polley M-YC, Dickler MN, Johnston S, Goetz MP, de la Haba J, Loibl S, Mehta RS, Bergh J, Roberston J, Barlow W, Liu H, Tenner K, Martin M. A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced stage breast cancer treated with first-line endocrine therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-05.

Abstract P1-18-04: CTCs and SUV to predict the efficacy of the bone-specific radiopharmaceutical agent radium-223 dichloride combined with hormonal therapy for hormone receptor-positive bone-dominant breast cancer metastasis

Abstract Background: Radium-223 dichloride (Ra-223) is a targeted alpha particle-based radiotherapeutic that has a localized cytotoxic effect on bone metastases. We sought to determine whether the circulating tumor cell (CTC) count and the presence of CTCs in epithelial-mesenchymal transition (EMT-CTCs) along with the standardized uptake value (SUV) on positron emission tomography-computed tomography (PET/CT) scans predict the efficacy of combined Ra-223 and hormonal therapy in patients with hormone receptor (HR)-positive bone-dominant metastatic breast cancer. Patients and Methods: In this single-center phase 2 study (NCT02366130), 36 patients received Ra-223 (55 kBq/kg intravenously) on day 1 and then every 4 weeks for six cycles. Patients also received a standard care endocrine monotherapy. One non-bone metastatic site was allowed. The number of prior endocrine therapies was not limited and one prior chemotherapy was allowed for metastasis. Response was evaluated using the PET Response Criteria in Solid Tumors (PERCIST) with PET/CT at baseline, 6 and 9 months (mo) later. The CTC count (CellSearch) and the presence of EMT-CTCs (AdnaTest) was determined at baseline, 6 and 9 mo later. Progression-free survival (PFS) time was calculated to evaluate efficacy. Results: Seven patients (20%) had a non-bone metastatic site. The median number of prior therapies for metastasis was 1 (range, 0-4). Six patients (17%) received chemotherapy. The median CTC count at baseline was 4 (range, 0-306). Only four patients (11%) were positive for EMT-CTCs at baseline. The median follow-up time was 14.7 mo (95% confidence interval [CI], 13.2 mo-not reached [NR]). The disease control rate at 9 mo was 46% in 33 patients who reached 9 mo or progressed up to 9 mo. The tumor response rate at 6 mo was 52% (complete/partialresponse rate; 22/30 %) in 27 patients whose disease was evaluable using PERCIST. The SUV on PET/CT decreased significantly at 6 and 9 mo after baseline (average decreases of 1.5 (p=0.0004) and 2.5 (p=0.0054), respectively). The median PFS duration was 7.4 mo (95% CI, 4.8 mo-NR). The median bone PFS was 16 mo (95% CI, 7.3 mo-NR). Patients with bone-only metastasis (N=28, 80%) had a significantly longer median PFS duration than did patients with non-bone metastases at baseline (N=7, 20%) (13.8 mo versus 4.5 mo; p=0.017). Patients without prior treatment (N=12, 34%) tended to have longer median PFS durations than did those who underwent prior treatment (N=23, 66%) (16.8 mo versus 4.8 mo; p=0.1865). Also, patients with <5 CTCs at baseline (N=19, 54%) tended to have longer median PFS durations than did those with ≥5 CTCs (N=16, 46%) (13.8 mo versus 4.8 mo; p=0.1277). EMT-CTCs status did not predict efficacy. Conclusions: Bone-only metastatic breast cancer and SUV suppression by Ra-223 are predictive of efficacy. Patients with baseline <5 CTC count tended to have better outcomes than did those with ≥5 CTCs. Combined treatment with Ra-223 and a hormonal agent is especially effective at controlling bone metastasis in patients with HR-positive breast cancer. Bone-only metastatic disease and CTC count should be factored in future clinical trial designs. Citation Format: Ueno NT, Tahara RK, Reuben JM, Gao H, Saigal B, Fujii T, Lucci A, Ibrahim NK, Damodaran S, Shen Y, Liu DD, Hortobagyi GN, Tripathy D, Lim B, Chasen BA. CTCs and SUV to predict the efficacy of the bone-specific radiopharmaceutical agent radium-223 dichloride combined with hormonal therapy for hormone receptor-positive bone-dominant breast cancer metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-18-04.

Abstract P4-09-06: Analyzing the changes in the HR+/HER2- metastatic breast cancer (mBC) landscape since the arrival of CDK4/6 inhibitors with machine learning and visual analytics

Abstract BACKGROUND: The real-world impact of CDK4/6 inhibitor use on HR+/HER2- mBC treatment sequencing, treatment response, and therapeutic utilization is limited. This study sought to describe treatment sequencing and response pre- and post-FDA approval of CDK4/6 inhibitors by conducting a traditional observational study approach and supplementing with a machine-learning methodology. METHODS: Female patients ≥18yrs were identified in the MarketScan Commercial and Medicare Supplement databases with continuous enrollment for at least 12 months pre-index, ≥2 medical claims for a BC diagnosis and ≥2 medical claims for metastatic disease (earliest=index date), and who had no treatment at any time with HER2 targeted therapy. Patients were excluded if they had received CDK4/6 or everolimus treatment prior to index. Treatment was stratified by line of therapy pre- and post- first CDK4/6 approval (February 3, 2015). We identified treatment patterns with standard distributions and visual analytics. Response to therapy and utilization was analyzed with prediction models and IBM Watson® machine learning population comparison models. RESULTS: A total of 19,558 patients were eligible for the study with a mean age at diagnosis of mBC of 62 (SD 13). Prior to first CDK4/6 inhibitor approval, anastrazole and letrozole monotherapies were most likely to be identified as both first and second line treatment. Following approval of the first CDK4/6 inhibitor in 2015, CDK4/6 inhibitors were observed as a first line treatment in 25% of patients, and as second line treatment in 24% of patients. Of patients diagnosed following the first CDK4/6 inhibitor approval, 44% of patients were exposed to endocrine therapy and 10% were exposed to chemotherapy in the pre-index period. Patients receiving CDK4/6 inhibitors in combination with endocrine therapy as first line treatment were observed to have a longer progression free survival time than patients receiving endocrine monotherapy. Visual analytics demonstrate a large variation in treatment sequencing, especially after first line therapy. Machine learning and prediction models identified a strong secular bias in the use of CDK4/6 and a signal for improved treatment response in patients with no exposure to endocrine therapies in the pre-index period. CONCLUSIONS: The mBC treatment landscape has changed significantly with the introduction of CDK4/6 inhibitors, which may be expected to impact long-term outcomes. Visual analytics and machine learning approaches can improve clinical insight. These approaches can help with identifying patient and clinical characteristics that predict response and utilization as well as appropriate treatment selections across lines of therapy. Citation Format: Meade D, Hensley Alford S, Mahatma S, Malangone-Monaco E, Boulanger L, Tkacz J, Turner SJ, Chen S, Manson S, Mejia S, Buleje I, Madan P, Kim G, Fowler R, Basar A. Analyzing the changes in the HR+/HER2- metastatic breast cancer (mBC) landscape since the arrival of CDK4/6 inhibitors with machine learning and visual analytics [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-09-06.

Abstract P2-08-34: The network metanalysis of data from PALOMA 2, MONALEESA 2, MONARCH 3, FALCON, SWOG and FACT trials: Progression free survival (PFS) benefit from first-line endocrine-based therapies in postmenopausal women with HR+ HER2- metastatic breast cancer (MBC) according to different prognostic subgroups

Abstract Background The three classes of Cycline Dependend Kinase (CDK) 4/6 inhibitors, Palbociclib (P), Ribociclib (R) and Abemaciclib (A), in combination with non-Steroidal Aromatase Inhibitors (nSAIs) showed improvement on Progression Free Survival (PFS) in patients with HR+/HER2- MBC compared to AIs monotherapy. Fulvestrant (F) also showed a PFS benefit over AIs in first-line setting of endocrine naive patients (pts) which was even greater in pts whithout visceral disease. The absence of direct comparison between F and CDK 4/6 combination therapies and their less favorable toxicity profile generated great interest in the identification of a specific subgroup of pts based on clinical and pathological factors for decision-making in the use of endocrine monotherapy. This analysis combines data from six randomized phase III trials investigating the role of endocrine-based therapies in the first-line setting of HR+/HER2- MBC to identify clinical factors in the choice among available drugs. Methods A Bayesian network meta-analysis was carried out for PFS; Hazard Ratio (HR) and 95% CI were reported. Potential treatment effect modifying covariates were investigated using sub-group analysis, stratifying by age, ECOG, ethnicity, prior chemotherapy or endocrine therapy exposure, measurable disease at the time of metastasis occurrence, visceral or bone only disease, time from the initial diagnosis of breast cancer to the metastasis onset. Data analysis was performed using R Statistical Software version 3.5.0 Results In the absence of direct comparison between CDK 4/6 inhibitors + nAIs and F endocrine-based therapies, all these therapeutic options resulted in significant PFS benefit compared to nAIs monotherapy (HR: 0.74; 95% CI 0.67-0.80). However, among the three classes of CDK 4/6 inhibitors and F a significant longer PFS was observed according to some clinical-pathological factors as followed reported: from P + nAIs in “bone only” disease (HR 0.47; CI 0.25-0.86); from A + nAis in “de novo” subgroup (HR 0.60; CI 0.37-0.97), in “Asian” population (HR 0.37; CI 0.16-0.85) and “non visceral” disease (HR 0.48 CI 0.25-0.89); from R + nAIs in “de novo” subgroup (HR 0.55; CI 0.32-0.95) and in “visceral” disease (HR 0.66 CI 0.45-0.96); from all the three combination strategies (A, P and R) in “prior endocrine” exposure subgroup (HR 0.47 CI 0.25-0.87; HR 0.60 CI 0.45-0.80; HR 0.64 CI 0.41-1.0, respectively). Even though no significant PFS benefit was observed in the remaining subgroups, combined CDK 4/6 strategies appeared more effective than F according to relative HR. Conclusions CDK 4/6 inhibitors endocrine-based therapies as first-line treatment for postmenopausal women with HR+/HER2- MBC showed PFS improvement, regardless of prognostic subgroup and additionally advantage was emerged by indirect comparison with F. Further direct comparative studies are needed to explore greater benefits from different therapeutic options. Citation Format: Rossi V, Giannarelli D, Berchialla P, Montemurro F, Ferretti G, Nistico' C, Vigna L, Cognetti F, Fabi A. The network metanalysis of data from PALOMA 2, MONALEESA 2, MONARCH 3, FALCON, SWOG and FACT trials: Progression free survival (PFS) benefit from first-line endocrine-based therapies in postmenopausal women with HR+ HER2- metastatic breast cancer (MBC) according to different prognostic subgroups [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-34.

Abstract P6-18-38: Treatment patterns and sequences among pre-menopausal women with HR+/HER2- metastatic breast cancer: A chart review study

Abstract Background: Recently, a novel class of treatments, CDK4/6 inhibitors, has been approved, and is now recommended for pre-menopausal women with HR+/HER2- metastatic breast cancer (mBC). This study examined prevailing treatment patterns and sequencing among premenopausal women with mBC treated in clinical practice. Methods: Patient-level data were collected from patient charts in May 2018 from 30 oncologists, mostly from community practice, in the US. Treatment sequences and patterns were assessed for pre-menopausal women diagnosed with HR+/HER2- mBC between January 2015 and January 2017 (with a minimum of 1 year of follow-up). Results: Data were collected on 201 pre-menopausal women with HR+/HER2- mBC. In first-line therapy for mBC, 52.7% of the patients received a CDK4/6 inhibitor-based regimen, 23.4% received endocrine monotherapy, 20.9% received a chemotherapy-based regimen, and the remaining 3.0% received an everolimus-based regimen. The majority of patients who received a CDK4/6 inhibitor received it in combination with an AI (73.6%), fulvestrant (11.3%), or tamoxifen (6.6%). Approximately half of all patients (51.2%) received an ovarian suppression agent during first-line therapy. Overall, median time on treatment from Kaplan Meier (KM) analysis for first-line therapy was 16.1 months. Most common reason for discontinuing first line was disease progression or suboptimal response (79.0% of patients who discontinued); another common reason was the completion of the planned duration of therapy (12.6%). Among the 106 patients who received a CDK4/6 inhibitor in the first line, median time on treatment from KM analysis was 26.8 months. Main reason for CDK4/6 inhibitor discontinuation was disease progression or suboptimal response (90.2% of patients who discontinued). For the 109 patients for whom we observed a second-line therapy, treatment sequences are presented in Table 1. Median time on treatment for second and third line therapy was 9.6 and 7.8 months, respectively. Conclusion: Following the introduction of novel CDK4/6 inhibitor treatments in the mBC setting, we observed that approximately half of pre-menopausal patients received a CDK4/6-based regimen in the first line of therapy. Top 5 treatment sequences in pre-menopausal HR+/HER2- mBC patients (n=109)Treatment SequenceN(%)CDK4/6 - ET -> Everolimus - ET21(19.3%)Chemo -> Chemo16(14.7%)CDK4/6 - ET -> Chemo13(11.9%)ET -> CDK4/6 - ET13(11.9%)Chemo -> CDK4/6 - ET10(9.2%)ET: endocrine therapy; Chemo: chemotherapy; -> indicates a change to the next line of therapy. Percentages calculated among patients with at least 2 lines of therapy Citation Format: Dalal AA, Goldschmidt D, Romdhani H, Kelkar S, Guerin A, Wang H, Caria N, Sawhney A, O'Shaughnessy J. Treatment patterns and sequences among pre-menopausal women with HR+/HER2- metastatic breast cancer: A chart review study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-38.

Why upfront use of CDK inhibitors for the treatment of advanced breast cancer may be wasteful, and how we can increase their value

Three Cyclin Dependent Kinase 4/6 (CDK) inhibitors have been approved by the United Stated Food and Drug Administration for front line treatment of advanced hormone receptor positive breast cancer based on improvements in progression free survival against endocrine monotherapy. Two clinical trials have so far reported results on overall survival but both are negative. CDK inhibitors are usually tolerated well but they do add to inconvenience and cost - for example, grade III-IV neutropenia occur at a frequency of over 60% requiring frequent blood work at least during the initial months of treatment. These drugs cost over $ 13,500 for a 4-week cycle in the United States, and are responsible for billions of dollars annually in drug cost alone. Importantly, many women with metastatic breast cancer do well for a long time with endocrine therapy alone and CDK inhibitors do not have a predictive marker. Selective use of these agents in later lines may improve substantially the convenience and cost without compromise in overall outcome. However, with results demonstrating impressive improvements in PFS published in major medical journals coupled with patients' natural desire for “best available” options, the trend among oncologists is to prescribe these drugs as the default front-line treatment. In this commentary I caution readers against over interpretation of results from the CDK inhibitor trials, describe adverse consequences of routine front-line use, and explain why selective use in later line may yield a higher value.

The impact of ethnicity on efficacy and toxicity of cyclin D kinase 4/6 inhibitors in advanced breast cancer: a meta-analysis.

Adding cyclin-dependent kinase (CDK) 4/6 inhibitor to endocrine therapy improves progression-free survival (PFS) in advanced breast cancer but the impact of ethnicity on efficacy and toxicity is unclear. We aimed to estimate the relative treatment efficacy and toxicity of endocrine therapy with and without CDK4/6 inhibitors, and compare between Asian/non-Asian subgroups. This meta-analysis included published first-line randomized trials comparing CDK4/6 inhibitor-endocrine therapy versus endocrine monotherapy. Hazard ratios (HR) and 95% confidence intervals (CI) for the overall population and Asian/non-Asian subgroups were extracted. The inverse-variance-weighted method was used to pool treatment estimates of PFS. Four trials (N = 2499) were included. Patients received combination CDK4/6 inhibitor-endocrine therapy (N = 1441; ribociclib, [46.4%]; palbociclib, [30.8%]; or abemaciclib, [22.8%]) versus endocrine monotherapy (N = 1058). CDK4/6 inhibitor-endocrine therapy was associated with prolonged PFS compared with endocrine monotherapy (HR 0.56; 95% CI 0.50-0.62). In Asians (N = 492), PFS HR was 0.39 (95% CI 0.29-0.51, P < 0.0001). In non-Asians (N = 2007), PFS HR was 0.62 (95% CI 0.54-0.71, P < 0.0001). There was a significant treatment-by-ethnicity interaction (P = 0.002). Toxicity data by ethnic subgroup were only available from two trials (n = 1334) with no convincing evidence that the risk of toxicity between CDK4/6 inhibitor-endocrine therapy and endocrine monotherapy varied by ethnicity. Adding CDK4/6 inhibitor to endocrine therapy prolongs PFS compared to endocrine therapy alone as first-line treatment in advanced breast cancer. The magnitude of PFS benefit is ethnicity-dependent but there is no interethnic differences in relative treatment-related toxicities. These findings may assist in the design and interpretation of trials, inform economic analyses, and stimulate pharmacogenomic research.

ISY3-4 - Issue to be solved in the near future to determine optimal sequential endocrine therapy in metastatic breast cancer

Main objective in palliative therapy for patients with metastatic breast cancer (MBC) is prolonged survival and maintenance of quality of life. In ER-positive/HER2-negative MBC, sequential endocrine therapy is one of the most important treatment strategy for patients who have hormone-responsive and no life-threatening disease. However, the optimal sequential endocrine therapy is not established. Aromatase inhibitor, selective ER modulator, selective ER down-regulator and CDK4/6 inhibitor + aromatase inhibitor are candidates as 1st line endocrine therapy for postmenopausal patients. There is also no clear guidance on subsequent treatment. From the results of several clinical trials, it may be better to sequentially use alternate drugs with different mechanism of action in sequential endocrine monotherapy. However, the advent of CDK4/6 inhibitors have resulted in a paradigm shift in the treatment of ER-positive/HER2-negative metastatic breast cancer. In this presentation, I would like to discuss about 4 issues to be solved in endocrine therapy for postmenopausal ER-positive/HER2-negative metastatic breast cancer. First, should CDK4/6 inhibitor in combination with endocrine agent be used as part of sequential endocrine therapy for all patients? Second, whether CDK4/6 inhibitor are more effective for use in 1st line therapy or subsequent treatment? Third, when using a CDK4/6 inhibitor after 1st line endocrine monotherapy, should it be changed to another endocrine agent or the same endocrine drug? Fourth, what is the optimal treatment in patients who have progressed during or after CDK4/6 inhibitor administration?

282TiP - Real-world effectiveness of ribociclib + aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line treatment in postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: The RIBANNA study

282TiP - Real-world effectiveness of ribociclib + aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line treatment in postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: The RIBANNA study

Treatment and Monitoring Patterns Among Premenopausal Women with HR+/HER2- Advanced Breast Cancer.

Premenopausal women with hormone receptor positive (HR+) and human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (aBC) often present with aggressive tumor types that lead to poor prognosis, high rates of recurrence, and mortality. Although clinical guidelines provide evidence-based recommendations for optimal treatment and monitoring, there is a dearth of information regarding treatment and monitoring patterns in clinical practice. In this study, we describe treatment and monitoring patterns among premenopausal women with HR+/HER2- aBC in real-world practice. A large US claims database was used to describe treatment patterns for patients in first, second, and third lines of therapy. Treatment monitoring included complete blood count (CBC), liver function test (LFT), and electrocardiogram (EKG) monitoring, described for the first three lines of therapy, and separately for patients receiving endocrine monotherapy (ET) and chemotherapy. Among 3203 patients, chemotherapy was the most common treatment used in first-line (63.6%) and second-line therapy (66.9%). ET was used in 34.4, 30.1, and 73.6% of patients in first, second, and third lines of therapy, respectively. The two most common treatment sequences were a single line of ET (27.3%), and two consecutive lines of chemotherapy followed by a line of ET (19.3%). Patients receiving chemotherapy were monitored with CBC on average more than two times per month, and for LFT one to two times per month. Patients receiving ET were monitored with CBC and LFT on average once every 2-3months. Overall, approximately 20% of patients were monitored with an EKG at some point during each line of therapy. A considerable proportion of premenopausal women with aBC received first- and second-line chemotherapy, which appears inconsistent with current clinical guidelines. The observed treatment heterogeneity points to a lack real-world consensus on the management of premenopausal women with HR+/HER2- aBC. Novartis Pharmaceuticals Corporation.