Receptor 2-negative Metastatic Breast Cancer Research Articles

Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer.

Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer.

First-line treatment with a cyclin-dependent kinase 4/6 inhibitor combined with an aromatase inhibitor for hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer: Population-based outcomes for patients treated in Alberta, Canada.

e13020 Background: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in combination with an aromatase inhibitor (AI) has emerged as the standard first line treatment in patients with hormone receptor positive, human epidermal growth factor receptor-2 (HER-2) negative metastatic breast cancer (MBC). In this analysis, we describe population-based outcomes for first-line treatment with a CDK4/6i combined with an AI. Methods: All patients who were prescribed CDK4/6i + AI from January 2016 through June 2019 in a large Canadian province were included. Descriptive statistics were used to summarize patient demographics, tumor and treatment characteristics. Survival distributions were estimated using the Kaplan-Meier method. Multivariate analysis (MVA) using a Cox proportional hazards model was constructed to examine associations between potentially prognostic clinical variables and progression free survival (PFS). Results: A total of 316 patients were included. Median age was 61 years (interquartile range, 53-70 years), 82% were postmenopausal women, 39% had de novo MBC, and 48% had non-visceral disease. Palbociclib was prescribed in 94% of patients and the remaining patients received ribociclib. The CDK4/6i was dose-reduced upfront or during treatment in 47%. While 70% of the patients discontinued treatment due to progression, 30% stopped due to toxicity/patient preference/physician recommendation. With a median follow-up of 28.1 months, the median PFS was 37.9 months (95% CI, 26.7-NR). In the MVA, PR-negative tumour (HR, 2.37; 95% CI, 1.45-3.88; P = 0.001) and dose reduction of the CDK4/6i (HR, 1.51; 95% CI, 1.06-2.16; P = 0.022) predicted worse PFS. Median overall survival (OS) was not reached. The 30-month and 36-month OS rates were 74% and 68%, respectively. Of patients who progressed (n = 131), 89% received second-line treatment (chemotherapy in 46%, single agent hormonal therapy in 35%, hormonal therapy plus a targeted agent in 15%, and other in 4%). Median time to progression on second line chemotherapy was 9.0 (5.8-17.6) months and second line hormonal therapy +/- targeted agent was 4.0 (3.4-8.6) months (P = 0.012). Conclusions: The real-world outcomes of first-line use of CDK4/6i and AI are encouraging. PR negative tumors and dose reduction appear to be negative prognostic markers. CDK4/6i + AI as first-line treatment for HR-positive, HER2-negative MBC in Alberta is justified based on favorable PFS and early OS outcomes.

Characterizing demographics, clinical, and genomic characteristics for U.S. patients with HR+, HER2- metastatic breast cancer following progression on a CDK4 and 6 inhibitor.

1015 Background: Cyclin-dependent kinases 4 and 6 inhibitors (CDK4 & 6i) have advanced the therapeutic landscape for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, there is an unmet need for treatment strategies following progression on CDK4 & 6i +/- endocrine therapy (ET). The objective of this analysis is to aid in the development of post-progression treatment by characterizing genomic profiles of tumor biopsies after progression on a CDK4 & 6i +/- ET. Methods: This is a retrospective study comparing two cohorts of US patients (pts) diagnosed with HR+, HER2- MBC since January 2011. One cohort underwent biopsy following progression on a CDK4 & 6i +/- ET (Cohortpost) while the second cohort underwent biopsy with no evidence of CDK4 & 6i treatment (Cohortpre). Tumor tissue was analyzed using the next generation sequencing Tempus xT assay that analyses 595 cancer-related genes. Of 595 molecularly profiled pts, 369 had sufficient medical record data to be eligible for this analysis. Patient characteristics at metastatic diagnosis and CDK4 & 6i initiation were described. For genomic profile comparison, Mann-Whitney U-test was used for continuous variables such as tumor mutation burden (TMB) with significance at P < 0.05; Chi-square or Fishers' exact test was used as appropriate for categorical variables including mutation frequency, with significance at false discovery rate (FDR) < 0.2. Results: Of 369 pts, 177 (48%) were in Cohortpre and 192 (52%) were in Cohortpost. Overall, the mean age at the time of MBC diagnosis was 59 and 55 years, respectively; 47% and 66% of patients had evidence of prior chemotherapy or ET; and 30% and 25% had de novo stage IV MBC. The most common biopsy site was liver, occurring in 38% of pts overall (Cohortpre, 23%; Cohortpost, 52.6%). The xT assay results indicated that pts in Cohortpost had significantly higher TMB compared to patients in Cohortpre (median 2.92 vs 1.67, P < 0.0001). A subset of patients with liver mets across both cohorts (n = 141) showed a similar, but nonsignificant trend (median 2.92 vs 2.08, P = 0.0565). Additionally, pts in Cohortpost had a higher ESR1 alteration frequency compared to Cohortpre (mutations: 32.29% vs 9.60%, FDR < 0.0001; fusions: 7% vs 3%, P = 0.1420). No significant differences were noted in TP53, CCNE1, CCND1, RB1, CDK4, and CDK6 between cohorts. Conclusions: These findings describe clinical characteristics and specific genomic alterations noted after progression on CDK4 & 6i +/- ET. Further analyses will evaluate timing of resistance, mutational and transcriptomic signatures. This may aid in understanding mechanisms of progression associated with CDK4 & 6i +/- ET, ultimately contributing to development of treatment options post progression.

AMEERA-1: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).

1058 Background: AMEERA-1 (NCT03284957) investigates amcenestrant, an oral SERD, as monotherapy and combined with targeted therapies in ER+/HER2– mBC. Here we report data from dose escalation (Part C) and dose expansion (Part D) of amcenestrant + palbo. Methods: Patients (pts) were postmenopausal women with ER+/HER2– mBC and ≥ 6 mos prior advanced endocrine therapy (ET) or adjuvant (adj) ET resistance (relapse on adj ET started ≥ 24 mos ago or < 12 mos after completing adj ET). Prior chemotherapy (≤ 1) for advanced disease was allowed; targeted therapies were not except ≤ 1 CDK4/6i in Part C. Part C assessed dose-limiting toxicities (DLTs) and aimed to establish the recommended phase 2 dose (RP2D) for amcenestrant (200 or 400 mg once daily [QD], in 28-day cycles) in combination with palbo (125 mg QD for 21 days on/ 7 days off). Safety (treatment-emergent adverse events [TEAEs] and lab abnormalities per CTCAE v4.03) and pharmacokinetics (PK) were evaluated. Antitumor activity at the RP2D for amcenestrant + palbo was evaluated in a subset of Part C pts and Part D, according to RECIST v1.1, determined locally by investigators. Results: Feb 8, 2021 data cutoff. In Part C (n = 15; 200 mg: 9; 400 mg: 6), no DLTs occurred and amcenestrant 200 mg QD was selected as the RP2D with palbo, based on PK and safety data. In the pooled safety population at the RP2D (n = 39; Part C: 9; Part D: 30), median (range) age was 59 y (33–86) with ECOG PS 0 (74.4%) or 1 (25.6%) and 2 (1–6) organs involved. Immediate prior therapy was neo/adj (41.0%, all ET resistant) or advanced (59.0%, range 1–4 lines). Median (range) exposure was 32 wks (1–66) with 59.0% pts on ongoing therapy. No amcenestrant dose reductions occurred; 25.6% had ≥ 1 palbo dose reduction. Most common non-hematological TEAEs related to amcenestrant were Grade 1–2 nausea and fatigue (17.9% each), asthenia and hot flush (10.3% each); to palbo were fatigue (30.8%), nausea (25.6%), asthenia and dysgeusia (10.3% each). Two pts discontinued due to AEs. The majority (94.9%) had neutrophil count decrease (53.8% Grade ≥ 3). Preliminary antitumor activity after at least 6 cycles of therapy (unless early treatment discontinuation) is reported in the table below. Conclusions: In pts with ER+/HER2– mBC, safety at the RP2D of amcenestrant + palbo was favorable, with no safety signals of bradycardia or eye disorders. Preliminary antitumor activity was observed (ORR: 31.4% and CBR: 74.3%). Clinical trial information: NCT03284957 .[Table: see text]

CYCLONE 1: A phase 2 study of abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a novel hormonal agent and taxane-based chemotherapy.

TPS5086 Background: In cancer cells, the cyclin-dependent kinases 4 and 6 (CDK4 & 6)/retinoblastoma protein (Rb) pathway is commonly altered, resulting in uncontrolled cell cycle entry and proliferation. CDK4 & 6 inhibitors represent a major advance in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC or MBC, respectively). Abemaciclib is an oral selective inhibitor of CDK4 & 6 administered on a continuous dosing schedule, approved in combination with endocrine therapy for HR+, HER2- ABC or MBC. In addition, abemaciclib is also approved by the FDA as monotherapy for HR+, HER2- ABC or MBC following endocrine therapy and prior chemotherapy in the metastatic setting. Similar to the estrogen receptor signaling pathway in breast cancer cells, there is evidence that the androgen receptor axis activates CDK4 & 6 to sustain prostate cancer cell proliferation and survival. Preclinical studies in prostate cancer cell lines and xenograft models showed that abemaciclib exhibits single agent activity by inducing cell cycle arrest and tumor growth inhibition. Clinical activity of abemaciclib in combination with abiraterone and prednisone is investigated in a randomized phase 2 study in the first-line mCRPC setting (CYCLONE 2, NCT03706365). Despite recent advances, management of heavily pretreated mCRPC remains a major clinical challenge. Herein, we hypothesize that mCRPC patients whose disease progressed after novel hormonal agents (NHA) and taxane therapies may derive therapeutic benefit from single agent abemaciclib. Methods: CYCLONE 1 is a phase 2, single-arm, multicenter study to assess the safety and efficacy of abemaciclib monotherapy in 40 patients with mCRPC progressing after ≥1 NHA and 2 taxane regimens. Patients will be enrolled at time of prostate specific antigen (PSA) or radiographic progression per PCWG3 criteria and have at least 1 measurable lesion per RECIST 1.1. Metastatic tumor tissue (fresh biopsy or archival material <12 weeks) is required at baseline for biomarker analysis. Patients will receive abemaciclib 200 mg twice daily until unacceptable adverse events or disease progression. The primary objective is investigator-assessed objective response rate (ORR). Key secondary objectives include safety, radiographic progression-free survival, overall survival, PSA response rate, time to PSA progression, time to symptomatic progression, Ki-67 expression, patient-reported outcomes, and pharmacokinetics. Assuming an ORR of 15%, the study has over 73% power to observe a response rate of at least 12.5%. Accrual began in January 2021. Clinical trial information: NCT04408924.

Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients’ prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Local Laboratory Testing of Germline BRCA Mutations vs. Myriad: A Single-Institution Experience in Korea.

Genetic diagnosis for human epidermal growth factor receptor 2-negative metastatic breast cancer patients with the germline BRCA (gBRCA) mutation has been emphasized since the development of polyadenosine diphosphate-ribose polymerase inhibitors. Myriad Genetics, Inc.’s (Salt Lake City, UT, USA) companion diagnostics service is almost exclusively used for genetic testing. The aim of this study was to compare the results of germline BRCA mutation tests returned by a local laboratory and those performed by Myriad. Between April 2014 and February 2018, 31 patients with gBRCA 1/2 mutation test results from both Samsung Medical Center (Seoul, Korea) and Myriad were enrolled. “Discordant: Opposite classification” was observed for only one among 27 (3.7%). This discrepancy was due to the detection of a deleterious large genomic rearrangement of BRCA 1 by Myriad. Samsung Medical Center performed multiple ligation-dependent probe amplifications (MLPA) to detect large genomic rearrangements only in high-risk patients. This one case was not suspected as high risk and MLPA was not performed. The concordant rate was 74.1% for all 27 patients. “Discordant: Laboratory’s uncertain classification” was found in 22.2% of the sample (six patients). All discrepancies were generated during interpretation of BRCA 2 gene sequencing. Further studies and standardization of genetic testing for BRCA 1/2 genes are required.

Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1

Abstract Background SERDs belong to a class of ER-targeted therapies that antagonize and degrade ERs, including in ER-dependent tumors resistant to other endocrine therapies (ET). This study (AMEERA-1; NCT03284957) investigates SAR439859, an oral SERD, as monotherapy and (in ongoing cohorts) in combination with targeted therapies in patients (pts) with ER+/HER2- mBC. Here we report updated safety and antitumor activity with SAR439859 monotherapy, including exploratory analyses by prior therapy and ESR1 status. Methods This open-label, phase 1/2, first-in-human study assessed SAR439859 as monotherapy in Parts A (dose escalation 20-600 mg once daily [QD]) and B (dose expansion with recommended dose at 400 mg QD). Eligible pts were heavily pre-treated, postmenopausal women with ER+/HER2- mBC and measurable disease who received ≥6 months of prior ET in the advanced setting. Prior chemotherapy, mammalian target of rapamycin inhibitors (mTORi) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for advanced disease were allowed. This analysis pooled data from pts receiving SAR439859 ≥150 mg (Part A) and 400 mg (Part B), administered in 28-day cycles. Antitumor activity was assessed by the objective response rate and clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] ≥24 weeks) per RECIST v1.1, determined by investigators. Analyses by prior therapy and baseline ESR1 mutation status were performed. Safety was also evaluated. Results Pts (n = 62; Part A: 13; Part B: 49) had a median age of 63 (range 37-88) years and ECOG PS 0 (59.7%) or 1 (40.3%); 93.5% had visceral metastases. Pts had a median of 2 (range 1-8) prior lines of therapy in the advanced setting (48.4% had ≥3 prior lines): all had prior ET and 72.6% had prior targeted therapy. SAR439859 monotherapy showed antitumor activity in the response-evaluable population (n = 59) and in subset populations with ≤3 prior lines (n = 33) or without prior mTORi, CDK4/6i, or SERD (n = 14) (Table 1). For pts with ESR1 status (n = 58), CBR with SAR439859 was comparable in ESR1 wild-type (36.7%) and mutant mBC (32.1%), with similar results in subpopulations. Treatment-related adverse events (TRAEs) occurred in 62.9% of pts (all grade 1-2); none resulted in SAR439859 discontinuation. Most frequent TRAEs were hot flush (16.1%); constipation and arthralgia (each 9.7%); decreased appetite, vomiting, diarrhea and nausea (each 8.1%); and fatigue (6.5%). Conclusions Among heavily pre-treated pts, SAR439859 demonstrated antitumor activity, similar to historical single-agent fulvestrant activity in less heavily pre-treated pts with advanced/mBC (2L+ setting; no prior targeted agents) (indirect comparison). In both subsets of pts with fewer prior advanced lines of therapy, SAR439859 showed trends of greater clinical activity versus historical fulvestrant activity. SAR439859 had a favorable safety profile with limited TRAEs. No safety signals of cardiac or ocular toxicities were observed. Ongoing parts of the study are investigating SAR439859 in combination with targeted therapies. Based on the monotherapy results, a randomized phase 2 study is investigating SAR439859 compared with physician’s choice in a 2L+ setting (AMEERA-3; NCT04059484). Funding: Sanofi. Antitumor activity overall and in subpopulations by prior lines of therapy (Parts A+B)Overall population (A+B)≤3 Prior advanced linesWithout prior targeted therapy(n = 59)a(n = 33)b(n = 14)cBOR, n (%)–CR000–PR5 (8.5)5 (15.2)3 (21.4)–SD24 (40.7)15 (45.5)8 (57.1)–PD30 (50.8)13 (39.4)3 (21.4)ORR, n (%)5 (8.5)5 (15.2)3 (21.4)CBR, n (%)20 (33.9)14 (42.4)9 (64.3)aPooled cohort (A ≥150 mg QD + B);bSubset of pooled cohort with ≤3 prior lines in the metastatic setting, including ≤1 of either prior chemotherapy or CDK4/6i and no prior mTORi; cSubset of pooled cohort with no prior mTORi, CDK4/6i, or fulvestrant.BOR, best overall response; CBR, clinical benefit rate; CR, complete response; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. Citation Format: Hannah M Linden, Mario Campone, Aditya Bardia, Gary A Ulaner, Alice Gosselin, Séverine Doroumian, Vasiliki Pelekanou, Marina Celanovic, Sarat Chandarlapaty. A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-08.

Abstract PS10-46: Real-world patient characteristics, utilization patterns, and outcomes of US patients with HR+/HER2- metastatic breast cancer treated with abemaciclib

Abstract Background Abemaciclib is the most recent oral cyclin-dependent kinase 4 and 6 inhibitor (CDK4&6i) to receive FDA approval to treat hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC). We used administrative claims data to describe patient characteristics, real-world utilization patterns, and outcomes in a US patient cohort upon initiating abemaciclib treatment for HR+, HER2- MBC.Methods This retrospective observational study analyzed medical and pharmacy claims from the IBM® MarketScan® Research Databases (Commercial and Medicare Supplemental) between 1-Jan-2007 to 31-Jan-2020. Patients (≥18 years) newly initiating abemaciclib between 1-Sept-2017 and 31-Oct-2019 were included if they had ≥2 breast cancer diagnoses, ≥2 secondary neoplasm diagnoses, evidence of HR+ disease, continuous enrollment ≥6 months before and ≥90 days after abemaciclib initiation (index date), and absence of therapies suggesting HER2 positivity. Patients were grouped by concomitant therapy (+aromatase inhibitor [AI], +fulvestrant [F], 200mg abemaciclib monotherapy [200mgMono], or +other), and stratified by prior CDK4&6i use (yes/no). Line of therapy (LoT) and reason for discontinuation were not able to be determined from this dataset. Baseline demographic, clinical, and treatment characteristics were summarized with descriptive statistics. Kaplan-Meier methods assessed time-to-discontinuation, defined as a gap of 60-days without an abemaciclib fill, following exhaustion of days’ supply from prior fills, or initiation of a different CDK4&6i (ie, palbociclib or ribociclib).Results There were 454 patients included in this analysis (mean [SD] age=57.7 years [10.8]; 98.9% female). Prevalence of new abemaciclib initiators was 29.3% (n=133) in the +AI group, 35.0% (n=159) in the +F group, 10.4% (n=47) in the 200mgMono group, and 25.3% (n=115) in the +other group. Prior CDK4&6i use within each regimen ranged from 37.6% (+AI) to 60.0% (+other). Visceral metastases were present in 50.4% in the +AI group; 49.7% in the +F group; 55.3% in the 200mgMono group; and 47.8% in the +other group. Nearly 75% (n=331) of all abemaciclib initiators began treatment with a 150 mg dose. Chemotherapy use in the 6-month pre-index period was observed for 18.8% in the +AI group; 21.4% in the +F group; 51.1% in the 200mgMono group; and 21.7% in the +other group. Median length of follow-up for all abemaciclib initiators was 321 days (IQR 195-482). Among those without prior CDK4&6i use, the median time-to-discontinuation for the +AI group was not reached (NR) (95% CI, 430 days-NR), the +F group was 531 days (95% CI, 281-NR), the 200mgMono group was 141 days (95% CI, 80-NR), and the +other group was 392 days (95% CI, 300-NR). In the subset with prior CDK4&6i use, the median time-to-discontinuation for the +AI group was 196 days (95% CI, 125-NR), the +F group was 146 days (95% CI, 93-225), the 200mgMono group was 140 days (95% CI, 86-NR), and the +other group was 191 days (95% CI, 113-280).Conclusion These real-world data complement pivotal abemaciclib clinical trial results by examining abemaciclib use among a more heterogeneous patient population in a clinical practice setting. The sizeable number of patients with prior CDK4&6i use, visceral metastases, and prior chemotherapy at abemaciclib initiation suggests many patients had very advanced disease and/or were in later stages of their treatment paradigm. Claims data lack many variables of clinical relevance needed to fully understand disease severity in the study population, such as LoT and degree of endocrine sensitivity; these limitations should be considered when interpreting CDK4&6i administrative claims studies. Citation Format: Kimberly R. Saverno, Julie Beyrer, Emily Nash Smyth, Hamad Abedtash, Angelo DeLuca, Yajun Emily Zhu, Sarah Rybowski. Real-world patient characteristics, utilization patterns, and outcomes of US patients with HR+/HER2- metastatic breast cancer treated with abemaciclib [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-46.

Patterns of treatment and outcome of palbociclib plus endocrine therapy in hormone receptor-positive/HER2 receptor-negative metastatic breast cancer: a real-world multicentre Italian study.

Background:The CDK4/6 inhibitor palbociclib combined with endocrine therapy (ET) has proven to prolong progression-free survival (PFS) in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). Few data are available regarding the efficacy of such a regimen outside the clinical trials.Patients and methods:This is a multicentre prospective real-world experience aimed at verifying the outcome of palbociclib plus ET in an unselected population of MBC patients. The primary aim was the clinical benefit rate (CBR); secondary aims were the median PFS, overall survival (OS) and safety. Patients received palbociclib plus letrozole 2.5 mg (cohort A) or fulvestrant 500 mg (cohort B).Results:In total, 191 patients (92 in cohort A, 99 in cohort B) were enrolled and treated, and 182 were evaluable for the analysis. Median age was 62 years (range 47–79); 54% had visceral involvement; 28% of patients had previously performed one treatment line (including chemotherapy and ET), 22.6% two lines and 15.9% three. An overall response rate of 34.6% was observed with 11 (6.0%) complete responses and 52 (28.6%) partial responses. Stable disease was achieved by 78 patients (42.9%) with an overall CBR of 59.8%. At a median follow-up of 24 months (range 6–32), median PFS was 13 months without significant differences between the cohorts. When analysed according to treatment line, PFS values were significantly prolonged when palbociclib-based therapy was administered as first-line treatment (14.0 months), to decrease progressively in second and subsequent lines (11.7 and 6.7 months, respectively). Median OS was 25 months, ranging from 28.0 months in 1st line to 18.0 and 13.0 months in 2nd and subsequent lines, respectively.Conclusions:Our data indicate that palbociclib plus ET is active and safe in HR+/HER2− MBC, also suggesting a better performance of the combinations in earlier treatment lines.

Abemaciclib, a third CDK 4/6 inhibitor for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer

ABSTRACT Introduction The field of metastatic luminal breast cancer (hormone receptor positive, HER-2 negative) is dynamic and evolving, harboring some of the most significant therapeutic advances in medical oncology. Over the last decade, many pivotal trials showed excellent results with drastic improvements in survival as well as the quality of life of metastatic luminal breast cancer patients. Areas covered The successful inhibition of the cyclinD/cyclin-dependent kinases 4 and 6 (CDK4/6)–retinoblastoma protein (RB) pathway with potent CDK4/6 inhibitors improved the outcome of advanced luminal breast cancers. Abemaciclib is the third CDK 4/6 inhibitor arriving to the market after palbociclib and ribociclib. Here, we describe the biology of the CDK4/6 pathway and summarize clinical data of previously published pivotal trials emphasizing the efficacy and toxicity of abemaciclib. The aim was to define its place in the current guidelines and to make a brief comparison with other available drugs of same class in the absence of cross trials comparison. Expert opinion As there are no available biomarkers to predict response or resistance to abemaciclib, the promising overall survival data of MONARCH-2 could possibly impact the clinician’s choice to optimize treatment for endocrine-resistant metastatic breast cancer.

Clinical Outcomes of 130 Patients with Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Treated with Palbociclib plus Endocrine Therapy and Subsequent Therapy: A Real-World Single-Center Retrospective Study in China

BackgroundThis retrospective single-center study conducted in China aimed to investigate the clinical outcomes of patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) treated with palbociclib plus endocrine therapy (ET) and subsequent therapy.Material/MethodsEligible patients were women with HR+ and HER2− MBC who initiated palbociclib plus ET between September 2016 and August 2019 at Fudan University Shanghai Cancer Center. Clinical characteristics and efficacy data were retrospectively recorded from the electronic medical record system.ResultsIn total, 130 patients were included in the study, of whom 87.0% of patients started palbociclib on 125 mg/day, 8.5% of patients had dose reduction, and 2.3% of patients discontinued the treatment because of toxicity. Overall, the disease control rate was 77.4% and clinical benefit rate was 63.4%. After a median follow-up period of 10.6 months, the median progression-free survival was 9.2 months. There was limited efficacy in patients who received palbociclib as no less than a fourth line of ET, except for patients who added palbociclib to the ET, which they had acquired resistance to. After disease progression on palbociclib, further treatment with chemotherapy and ET had similar efficacy (P=0.571).ConclusionsThe findings from this real-world single-center study in China showed that treatment with palbociclib plus ET exhibited favorable efficacy and good tolerance in patients with HR+ and HER2− MBC, even in patients who were initially resistant to endocrine therapy, and there was no difference in outcomes between subsequent treatment with chemotherapy and ET.

Clinical Challenges in the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: A Literature Review.

Endocrine therapy (ET) is integral to the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). Aromatase inhibitors (AIs; e.g., anastrozole, letrozole, exemestane), selective estrogen receptor modulators (e.g., tamoxifen), and the selective estrogen receptor degrader, fulvestrant, inhibit tumor cell proliferation by targeting ER signaling. However, the efficacy of ET could be limited by intrinsic and acquired resistance mechanisms, which has prompted the development of targeted agents and combination strategies. In recent years, the treatment landscape for HR+, HER2− MBC has evolved rapidly. AIs, historically the first-line treatment for postmenopausal patients with HR+, HER2− MBC, have been challenged by more effective ET, such as fulvestrant alone or in combination with an AI, and the cyclin-dependent kinase (CDK)4/6 inhibitors, which have increasingly become the new standard of care. For endocrine-resistant disease (≥ second-line), clinical trials demonstrated that the mammalian target of rapamycin inhibitor, everolimus, enhanced the efficacy of exemestane or fulvestrant after progression on an AI. CDK4/6 inhibitors in combination with fulvestrant have demonstrated superior progression-free survival and overall survival versus fulvestrant alone. Recently, the combination of fulvestrant with alpelisib in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) mutated HR+, HER2− MBC following progression on or after ET was approved, based on the SOLAR-1 study. However, the optimal sequencing of treatments is unknown, especially following disease progression on a CDK4/6 inhibitor. This review aims to provide practical guidance for the management of HR+, HER2− MBC based on available data and the utility of genomic biomarkers, including germline breast cancer genes 1 and 2 (BRCA1/2) mutations, and somatic estrogen receptor alpha gene (ESR1), HER2, and PIK3CA mutations.

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP)

BackgroundThis study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patients and methodsPatient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. ResultsA total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7–7.0) and the median overall survival was 19.0 months (95% CI 16.4–21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37–2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. ConclusionsPalbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.

Early Changes of the Standardized Uptake Values (SUVmax) Predict the Efficacy of Everolimus-Exemestane in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.

Simple SummaryThe combination of everolimus and exemestane was FDA approved after BOLERO-2 clinical trial results for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (HR+ mBC), progressing on a prior therapy with a non-steroideal aromatase inhibitor. However, there are no predictive biomarkers for tumor sensitivity or resistance to everolimus-based treatment. The aim of our retrospective study was to investigate the potential role of FDG-PET SUV (ΔSUV%) as a predictive biomarker for a long-term clinical benefit. We found in a homogenous population of 31 patients two precocious ∆SUV% thresholds capable of identifying HR+ HER2-mBC patients achieving long-term benefit or long-term survival (36 month-OS) during everolimus-exemestane therapy. Based on these results, ∆SUV, as PET-based biomarker, provides additional information on which patients are most likely to benefit from everolimus with exemestane-based therapy over a long-term period. FDG-PET is a useful and minimally invasive tool that could be used for making a decision on personal treatment enhancing benefit while reducing collateral effects.Background: The mTORC1 inhibitor everolimus has been approved in combination with the aromatase inhibitor exemestane for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (HR+ mBC) progressing on prior therapy with a non-steroidal aromatase inhibitor. To date, no predictive biomarkers of tumor sensitivity/resistance for everolimus-based treatments have been identified. We hypothesized that precocious changes in the Standardized Uptake Volume (∆SUV%), as assessed by 18F-Fluorodeoxyglucosepositron-emission tomography (18F-FDG PET/CT), may be a marker of everolimus efficacy. Methods: This was a retrospective study including 31 HR+ HER2- patients treated with everolimus and exemestane in two Italian centers between 2013 and 2018. The objective of the study was to investigate ∆SUV% as a predictive marker of everolimus antitumor efficacy. 18F-FDG PET/CT scans were performed at baseline and after three months of treatment. Patients were defined as long responders (LRs) if disease progression occurred at least 10 months after treatment initiation and long survivors (LSs) if death occurred later than 36 months after starting therapy. ROC analysis was used to determine the optimal cut-off values of ∆SUV% to distinguish LRs from non-LRs and LSs from non-LSs. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier method. Results: The SUVmax values decreased significantly from baseline to 3 months after therapy (p = 0.003). Dynamic changes of SUVmax (Delta SUV) had a higher accuracy in discriminating long-responders from non-long-responders (AUC = 0.67, Delta SUV cut-off = 28.8%) respects to its ability to identify long survivors from no-long survivors (AUC = 0.60, Delta SUV cut-off = 53.8%). Patients were divided into groups according to the Delta SUV cut-offs and survival outcomes were evaluated: patients with a decrease of ∆SUV% ≥ 28.8% had significantly better PFS (10 months-PFS: 63.2%, 95% CI: 37.9–80.4% and 16.7%, 95% CI: 2.7–41.3% respectively, p = 0.005). As regard as OS, patients with ∆SUV% ≥ 53.8% had longer OS when compared to patients with ∆SUV% < 53.8% (36 month-OS: 82.5% vs. 45.9% vs. p = 0.048). Conclusion: We found two precocious ∆SUV% thresholds capable of identifying HR+ HER2-mBC patients, which would achieve long-term benefit or long-term survival during everolimus-exemestane therapy. These results warrant further validation in prospective studies and should be integrated with molecular biomarkers related to tumor metabolism and mTORC1 signaling.

Optimizing care for younger women with hormone receptor-positive, HER2-negative metastatic breast cancer.

Treatment strategies for hormone receptor-positive (HR+ ), human epidermal growth factor receptor 2-negative (HER2- ) metastatic breast cancer in young women (<40 years at diagnosis) have traditionally been extrapolated from data obtained from trials conducted either exclusively or predominantly in the postmenopausal setting. These young patients are usually treated with ovarian function suppression (OFS) + endocrine therapy (ET) ± targeted therapy, except if there is a concern about endocrine resistance or a need to gain rapid disease control due to the onset of visceral crisis. This review examines evidence that supports the use of a cyclin-dependent kinase 4/6 inhibitor, in combination with OFS and ET, when treating premenopausal or perimenopausal women with HR+ /HER2- metastatic breast cancer. This includes data from the MONALEESA-7 study (treating only premenopausal/perimenopausal women in the first-line setting), and the results of subgroup analyses from the PALOMA-3 and MONARCH-2 trials. We also consider a number of age-specific challenges that younger breast cancer patients can face, highlighting the importance of a multidisciplinary approach to ongoing care.

Real-world Outcomes of Cyclin-dependent Kinase Inhibitors Continued Beyond First Disease Progression in Hormone Receptor-positive Metastatic Breast Cancer

BackgroundCDK4/6 inhibitors (CDK4/6i), in combination with aromatase inhibitors, are United States Food and Drug Administration-approved for the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). The effectiveness of continuing them beyond first disease progression (PD) is currently unknown. This retrospective study evaluated the impact of the continuation of CDK4/6i beyond first PD in HR+/HER2− MBC using real-world experience. Patients and MethodsA single-institution retrospective review of patients with HR+ MBC who received CDK4/6is from 2015 to 2018 and where CDK4/6is were continued beyond first PD. The primary outcome was progression-free survival (PFS) after initial PD on CDK4/6i therapy. ResultsThirty women with HR+/HER2− MBC met eligibility criteria. Patients were identified from a prospective database of patients at the Cleveland Clinic Foundation who were prescribed CDK4/6is. The median age and follow-up duration were 47.5 years and 27 months, respectively. Most patients received palbociclib (PA)/letrozole as initial therapy (67%), followed by PA/fulvestrant (23%), and PA/other aromatase inhibitor (20%), and abemaciclib with either fulvestrant or letrozole (6%). As of January 31, 2019, 25 (83.3%) patients were still alive, and 19 (63%) patients had progressed. The estimated median PFS for continued CDK4/6i use beyond the first PD was 11.8 months (95% confidence interval, 5.34-13.13 months). ConclusionsAmong a small cohort of patients with HR+ MBC in a non-clinical trial setting, continuation of CDK4/6i-endocrine treatment post initial PD was associated with a median PFS of about 12 months. Formal randomized clinical trials evaluating the continuation of CDK4/6is beyond the first PD are currently ongoing and will provide more answers to this important clinical question.

Optimizing the management of HER2-negative metastatic breast cancer in the era of PARP inhibitors-proceedings from breast cancer expert group meeting.

The therapeutic landscape of human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents such as poly-ADP ribose polymerase inhibitors (PARPi), novel chemotherapeutic agents, immunotherapy, and endocrine therapies. In this scenario, optimizing the appropriate treatment sequence is a daunting task for clinicians. To develop evidence-based answers to key clinical questions on treatment selection and appropriate treatment sequence for the management of patients with HER2- mBC in the era of PARPi, a breast cancer expert group meeting was convened. The expert panel comprised of eight key opinion leaders from Argentina, Brazil, Colombia, Egypt, Mexico, Moscow, South Korea, and the United Arab Emirates, who convened and reviewed the literature, discussed the clinical practices across the participating regions, and formulated answers to key clinical questions for optimizing the management of HER2- mBC. In this review, evidence-based answers have been provided pertaining to (I) the specific mBC population to be considered for BRCA testing, optimal time point of BRCA testing, and genetic counselling in mBC patients; (II) the role of PARPi versus platinum therapy in HER2- mBC patients in the metastatic setting; (III) sequencing treatment in metastatic triple-negative breast cancer (TNBC) and hormone receptor-positive HER2- mBC patients, and defining the place of PARPi in the sequencing algorithms; and (IV) the need for a breast cancer registry for patients with HER2- mBC. This expert review will serve as a comprehensive guide to clinicians for optimizing BRCA testing and managing patients with BRCA mutation (BRCAm) and HER2- mBC. The data collected from the proposed HER2- mBC registry will help understand the treatment practices, identify unmet needs, and develop strategic policies regionally to help improve access to optimized care of HER2- mBC.

Optimizing Palbociclib Therapy Across the Age Spectrum: Hypothetical, Illustrative Case Scenarios in HR+, HER2-Metastatic Breast Cancer.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in combination with endocrine therapy are a preferred treatment option for premenopausal and postmenopausal women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (mBC). Palbociclib is a potent, first-in-class oral inhibitor of CDK4/6. To provide optimal care to patients with HR+/HER2– mBC receiving palbociclib, advanced practitioners require a thorough understanding of the efficacy and adverse event (AE) profile of palbociclib as well as the diverse characteristics and support needs of patients eligible for palbociclib treatment. This Grand Rounds uses two hypothetical patient scenarios to illustrate core issues in the management of premenopausal and postmenopausal patients receiving palbociclib-based therapy for mBC. In addition to providing an overview of key efficacy and safety data, each case offers practical guidance on providing individualized, patient-centered care, the identification and management of treatment-related AEs, management of concomitant medications, and best practices to promote adherence to therapy.

Abemaciclib▼ for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer

Abemaciclib▼ for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer