Therapy For Advanced Breast Cancer Research Articles

Impact of coronavirus disease 2019 on the clinical diagnosis and treatment of breast cancer in China.

Impact of coronavirus disease 2019 on the clinical diagnosis and treatment of breast cancer in China.

Real-world data of fulvestrant as first-line treatment of postmenopausal women with estrogen receptor-positive metastatic breast cancer

Goals of endocrine therapy for advanced breast cancer (ABC) include prolonging survival rates, maintaining the quality of life, and delaying the initiation of chemotherapy. We evaluated the effectiveness of fulvestrant as first-line in patients with estrogen receptor (ER)-positive ABC with relapse during or after adjuvant anti-estrogenic therapy in real-world settings. Retrospective, observational study involving 171 postmenopausal women with ER-positive ABC who received fulvestrant as first-line between January 2011 and May 2018 in Spanish hospitals. With a median follow-up of 31.4 months, the progression-free survival (PFS) with fulvestrant was 14.6 months. No differences were seen in the visceral metastatic (14.3 months) versus non-visceral (14.6 months) metastatic subgroup for PFS. Overall response rate and clinical benefit rate were 35.2% and 82.8%. Overall survival was 43.1 months. The duration of the clinical benefit was 19.2 months. Patients with ECOG performance status 0 at the start of treatment showed a significant greater clinical benefit rate and overall survival than with ECOG 1–2. Results in real-world settings are in concordance with randomized clinical trials. Fulvestrant continues to demonstrate clinical benefits in real-world settings and appears be well tolerated as first-line for the treatment of postmenopausal women with ER-positive ABC.

Abstract PS7-49: Assessment of patient out-of-pocket cost for palbociclib therapy in advanced breast cancer

Abstract Assessment of patient out-of-pocket cost for palbociclib therapy in advanced breast cancerBackground:Palbociclib has demonstrated improved outcomes in patients with advanced hormone receptor positive (HR+)/human epidermal growth factor 2 (HER2) negative breast cancer when used in combination with endocrine therapy 1,2. The current average wholesale price of therapy with this medication class exceeds $190,000 per year (at full dose). Financial toxicity is a major concern in the oncology population and can decrease patient quality of life and may result in non-adherence 3,4. Our objective was to describe the out-of-pocket cost burden for patients treated with palbociclib. Methods:A retrospective review of patients newly initiated on palbociclib therapy between May 5, 2018 and May 30, 2019 was completed at our institution. Patients were included if they were 18 years of age and older, newly starting palbociclib for advanced or metastatic HR+/HER2- breast cancer, had US-based insurance, and received palbociclib from our internal specialty pharmacy. Cost information was collected utilizing dispensing reports and additional patient-specific information was obtained from the EHR. Descriptive statistics were performed on the collected data. Results:A total of 44 patients were included in the cost analysis. Primary sources of coverage for these patients included commercial insurance (n=13), Medicare (n=25), and state/federal insurance (n=6). We first assessed costs with primary insurance coverage alone. The sum of all the initial cycle out-of-pocket copays after primary insurance totaled $49,108. The median individual copay was $291, the range was $0 to $2,943, and 9 of the 44 patients had no copay after the primary insurance was applied. The impact of assistance programs, which include independent grant funding, copay cards, vouchers, and secondary Medicaid plans, was significant. After applying primary insurance and aid from assistance programs, the sum of all initial cycle out-of-pocket copays reduced from $49,108 to $3,172. After assistance, 33 of the 44 patients had an initial copay cost of $0. Over 90% of the out-of-pocket total was from two patients (one each with a copay of $2,467 and $497). Ultimately, Mayo Clinic Specialty Pharmacy helped patients avoid $45,851 in first cycle out-of-pocket copays, of which $41,079 and $4,772 were for Medicare and commercially-insured patients, respectively. Copay cost by type of insurance was assessed. All patients with commercial insurance (n=13) had no actual copay for the first cycle. Medicare patients (n=25) are not eligible for copay cards and had larger pre-assistance copays compared to commercial patients (median $2,454 vs. $45). Vouchers or grants were utilized by 16 out of 25 Medicare covered patients. State/Federal insurance included 2 Tricare and 4 Medicaid patients. While ineligible for copay card assistance, the copays for these patients were low, ranging from $0-$28. Standard Medicare D plans do not have an out of pocket maximum for the year. The catastrophic phase requires an ongoing copay of 5% of the total claim cost, resulting in approximately a $600 per month copay for the remainder of the calendar year during the study period. When combined with the first cycle cost of approximately $2500, the yearly out-of-pocket cost for a patient with a standard Medicare D plan is roughly $10,000. Conclusion:Patients initiating therapy with palbociclib are commonly faced with high out-of-pocket costs. The availability, eligibility, and use of financial assistance programs are imperative in decreasing the financial toxicity. Specialty pharmacies play an important role in obtaining financial assistance which leads to decreased out-of-pocket expenses for patients. Citation Format: Allison P Golbach, Matthew D Smith, Jodi L Taraba, Karthik V Giridhar. Assessment of patient out-of-pocket cost for palbociclib therapy in advanced breast cancer [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 PS7-49.

Abstract PS18-35: Disparities in reporting of race and participation by race in genomic studies

Abstract Background: Black/African American(B/AA) women are more likely to die of breast cancer as compared to White (Wh) women but are underrepresented in genomic research. Current genomic research that aims to classify breast cancer in order to personalize treatment in early breast cancer or to identify targets for therapy in advanced breast cancer fails to adequately represent B/AA women and other minority groups. This negatively impacts our current knowledge of breast cancer in non-Wh women and raises questions about the applicability of such testing in minority groups. Objective: To evaluate the frequency of race reporting and representation of non-White women in genomic studies. Methods: This a database study of all PubMed reported genomic testing studies to classify breast cancer for prognostic or predictive purposes. A PubMed search was conducted with articles from inception to the present with the following keyword search terms: “Breast Cancer Gene Expression Assay” AND “Race”, “PAM50” AND “Race”, “MammaPrint” AND “Race”, “Oncotype Dx” AND “Race”, “76 gene prognostic score” AND “Race”, Intrinsic Subtype” AND “Breast Cancer” AND “Race”. This search yielded 129 articles. 31 articles were removed due to lack of relevance. Results: Of the 98 articles remaining after applying inclusion/exclusion criteria, 39 (40%) failed to report race in their analysis. Of the remaining 59 articles, 57 (96.61%) included Wh participants in their study, 54 (91.53%) included B/AA participants, 13 (22.04%) included Hispanics/Latinos, and 20 (33.90%) included Asians. Two of the major clinical trials of widely used testing such as Oncotype Dx and MammaPrint but did not report race in the pivotal studies. The genomic studies that included B/AA women were more likely to be health services research studies. The genomic studies that focused on triple-negative breast cancer (TNBC) were also more likely to have B/AA participants that ranged from 6%-52% of participants. For Oncotype Dx testing, B/AA women were more likely to have a later stage at diagnosis. While the number of patients with low risk was similar in all race groups, B/AA women were more likely to have high Ki-67 with uncertain significance of these findings. Conclusions: A significant number of genomic studies did not report race and ethnicity. Racial and ethnic minorities continue to be under-represented in genomic research and this raises questions about the wider applicability of this research in these populations. Large clinical studies should specifically report the race and ethnicity of participants to inform decision making. In addition, funders should require reporting of race in genomic studies. Citation Format: Niloufar R Khanna, Niharika Dixit. Disparities in reporting of race and participation by race in genomic studies [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 PS18-35.

Abstract PS10-40: Real life efficacy of palbociclib and endocrine therapy in HR positive, HER2 negative advanced breast cancer

Abstract BackgroundPalbociclib, a highly selective inhibitor of CDK4/6, is indicated for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC), in combination with an aromatase inhibitor or with fulvestrant for patients who have progressed with an aromatase inhibitor, and in premenopausal women with a luteinising-hormone-releasing-hormone (LH-RH) agonist. Emerging real world data suggest that the efficacy of a palbociclib-based therapy is highly conserved. We report here the Institut Curie (IC) experience. Patients and methodsWe retrospectively reviewed all patients with HR+ HER2- ABC treated with a palbociclib-based therapy as 1st or 2nd line of therapy for ABC, from November 2016 to December 2018. Clinical, biological and imaging data were retrieved from IC electronic health record system. Data lock was December 31st 2020. Descriptive analyses, univariate and multivariate Cox regression analyses were performed. ResultsWe included 310 consecutive premenopausal (24.5%) and menopausal (75.5%) women. Median age was 61.8 years-old [23.5-92.1]. Among them, Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 59.7%, 1 in 32.1%, and 2 in 8.2% of patients (pts). The ABC diagnosis was de novo for 26.8%. There was at least one visceral lesion in 51.0% of pts, only bone lesions in 30.3%, 28.1% had three metastatic sites or more, and none of them have brain lesions. Previous treatments were chemotherapy (49.4%) and endocrine therapy (60.7%). Among pts pretreated by at least one endocrine therapy, 51.1% had shown prior sensibility, as defined by an absence of recurrence during adjuvant endocrine therapy or during 24 months after its completion, or an absence of progression during 6 months after the beginning of an endocrine therapy for a metastatic disease. Palbociclib was prescribed in the 1st line setting for 72.6% of pts and in the 2nd line setting for 27.4% of pts. The initial dose was 125 mg daily (95.2%). It was associated with an aromatase inhibitor (66.8%) or with fulvestrant (33.2%). LH-RH agonist was prescribed in 19.7% of pts. Denosumab was prescribed in 68.5% of pts with bone lesions. Median follow-up was 20.7 months (m). At 12 m from the initiation of palbociclib, 94.5% of the pts were alive. Median progression free survival was 23.4 m (95%CI: 21.6-NR) for pts without previous endocrine therapy, 22.7 m (95%CI: 14.7-NR) for pts who have shown endocrine sensibility, HR=1.2 (95%CI: 0.81-1.77), p=0.0027 and 13.4 m (95%CI: 10.7-20.8) for pts who have not shown endocrine sensibility, HR=1.88 (95%CI: 1.29-2.73), p=0.003. Although sensibility to previous endocrine therapy was a prognostic factor for progression free survival with the univariate analyse, it was not with the multivariate analysis. Three independent poor prognostic factors for progression free survival were identified: previous chemotherapy, HR=1.6 (95%CI: 1.12-2.29), p<0.001; initial ECOG performance status 2, HR=2.72 (95%CI: 1.55-4.79), p<0.001; and three or more metastatic sites, HR=1.61 (95%CI: 1.152.26), p<0.001. Hematologic grade 3-4 adverse events were neutropenia (72.3%), leukopenia (43.9%), anemia (3.2%) and thrombocytopenia (2.9%). Other adverse events observed (all grades) were infections (16.5%), stomatitis (13.9%) or alopecia (13.9%). At least one dose reduction occurred in 29.4% of pts and permanent discontinuation because of treatment toxicity was observed in 5.7% of pts. ConclusionIn a non-selected population of patients with HR+ HER2- ABC, the efficacy and safety data are strikingly similar to those previously reported. Palbociclib, in combination with hormone therapy, is a cornerstone treatment of HR+ HER2- metastatic breast cancer. Citation Format: Baptiste Porte, Matthieu Carton, Delphine Loirat, François-Clement Bidard, Linda Haroun, Audrey Bellesoeur, Youlia Kirova, Paul Cottu. Real life efficacy of palbociclib and endocrine therapy in HR positive, HER2 negative advanced breast cancer [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 PS10-40.

Trastuzumab emtansine of the treatment of HER2-positive breast cancer with brain metatases

Patients with brain metastases of HER2-positive breast cancer (BC) is a special group of patients who are difficult to treat and have a short life expectancy. The possibilities of whole brain radiotherapy, stereotactic radiosurgery and surgery in such patients are rather limited. Trastuzumab emtansine (T-DM1) showed potential activity in this subset of patients. T-DM1 is an antibody-chemical conjugate (ADC) that delivers directly to HER2-positive cancer cells, thereby limiting damage to healthy tissue. At this point, the efficacy of trastuzumab emtansine has been demonstrated in several randomized trials as a second and subsequent lines of therapy for advanced breast cancer with a favorable toxicity profile of the drug. This article describes a clinical case of a patient with luminal B HER-2 positive breast cancer who, underwent stereotactic radiosurgery and was treated with trastuzumab emtansine as a the second line of treatment for disease progression with metastatic brain lesions after trastuzumab/pertuzumab-containing therapy. Partial regression of metastases with long-term duration of the effect was achieved treatment with trastuzumab emtazine has been being continued for 24 months. Tolerability of therapy was good: thrombocytopenia 2 degree was the main among side effects. The effect has been persisted for 2 years and the patient continues the treatment. Discussion of the results of real clinical practice with well-known studies was carried out.

Real life efficacy of palbociclib and endocrine therapy in HR positive, HER2 negative advanced breast cancer

BackgroundPalbociclib is indicated for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC), in combination with endocrine therapy. Emerging real-life data suggest that the efficacy of a palbociclib-based therapy is highly conserved. We report the Institut Curie hospital experience. Patients and methodsWe retrospectively reviewed all patients with HR + HER2- ABC treated with a palbociclib-based therapy as first or second line for ABC, with an initial prescription from November 2016 to December 2018. Clinical, laboratory and imaging data were retrieved from electronic records. Data lock was December 31st, 2019. Descriptive analyses, univariate and multivariate Cox regression analyses were performed. ResultsWe included 310 consecutive patients. Median age was 61.8 years old. Palbociclib was prescribed in first line in 225 patients (72.6%). Before palbociclib-based therapy initiation, 122 patients (39.3%) were endocrine naive, 96 (31.0%) endocrine sensitive and 92 (29.7%) endocrine resistant. Median follow-up was 20.7 months. Median progression free survival (PFS) was 23.4 months (95%CI: 21.6-NR) in endocrine naive patients, 22.7 months (95%CI: 14.7-NR) in endocrine sensitive, and 13.4 months (95%CI: 10.7–20.8) in endocrine resistant. At 12 months from the initiation of palbociclib, 94.5% of patients were alive. By multivariate analysis, poor prognosis factors for PFS were identified in the endocrine naive/sensitive population: initial ECOG status 2, previous endocrine therapy for ABC, 3 metastatic sites or more. Toxicity profile was similar to previously published data. ConclusionIn a non-selected population of patients with HR + HER2- ABC, the efficacy and safety data are strikingly similar to those previously reported.

ACUTE ON CHRONIC DYSPNEA IN A PATIENT WITH METASTATIC BREAST CANCER ON ABEMACICLIB

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: We report a case illustrating the challenging diagnosis of interstitial pneumonitis caused by abemaciclib in an elderly woman with metastatic breast cancer. Lung toxicity is an uncommon but serious adverse effect of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors. Diagnosis is typically based on presentation, and non-contrast CT chest is the imaging modality of choice. Typical findings include ground-glass opacities with or without consolidation. The purpose of this case report is to highlight this uncommon toxicity of CDK4/6 inhibitors which requires high level of clinical suspicion for diagnosis. CASE PRESENTATION: A woman in the 8th decade of life with hormone-receptor positive, HER2 negative breast cancer with metastases to lungs and lumbar vertebrae, on treatment with abemaciclib and fulvestrant, was admitted to the hospital for exertional dyspnea for six weeks, with acute worsening to dyspnea at rest in the past one day. Prior to hospitalization, she had developed a fever three weeks after starting abemaciclib. She was treated for community-acquired pneumonia and COPD exacerbation, but had only partial relief of symptoms. CT chest showed ground glass opacities pronounced in right upper and middle lobes, with post-obstructive consolidation in left lower lobe, and soft tissue fullness around the left lower lobe bronchus and along the bronchovascular bundles suspicious for lymphangitic spread of tumor. Upon hospitalization, she was hypoxic and on 3 liters oxygen by nasal cannula. Repeat CT chest showed interval worsening of ground glass opacities in right upper lobe, new ground glass changes in left upper lobe, and worsening of left lower lobe consolidative change. Sputum cultures, fungal studies, and respiratory viral panel were negative. Symptoms improved with initiation of steroids. DISCUSSION: CDK 4/6 inhibitors are a relatively new class of drugs used in tandem with aromatase inhibitors or fulvestrant in the treatment of advanced hormone-receptor positive breast cancer. Diarrhea, nausea, fatigue, and pancytopenia were among common side effects noted in initial clinical trials. For our patient, a steroid course with taper was initiated, and the offending agent was held. A follow up CT scan three months later showed resolution of the ground glass opacities. This approach to management appears to be in line with the limited literature available. CONCLUSIONS: Our case documents an interesting diagnostic challenge in which a patient with developed pneumonitis in the setting of abemaciclib use. The diagnosis was delayed due to comorbid COPD and pneumonia, and confounded by partial resolution in symptoms with antibiotics. In September 2019, the FDA issued a safety warning that abemaciclib, palbociclib, and ribociclib may cause rare but severe pneumonitis. The temporal correlation between initiation of abemaciclib and development of symptoms remains unclear. Reference #1: Corona SP, Generali D. Abemaciclib: A CDK4/6 inhibitor for the treatment of HR+/HEeR2- advanced breast cancer. Drug Des Devel Ther. 2018;12:321-330. doi:10.2147/DDDT.S137783 Reference #2: Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. npj Breast Cancer. 2019;5(1):1-8. doi:10.1038/s41523-018-0097-z Reference #3: FDA warns about rare but severe lung inflammation with Ibrance, Kisqali, and Verzenio for breast cancer | FDA. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-severe-lung-inflammation-ibrance-kisqali-and-verzenio-breast-cancer. DISCLOSURES: No relevant relationships by Sameera Natarajan, source=Web Response No relevant relationships by Arjun Natarajan, source=Web Response

Precision Medicine for Breast Cancer Utilizing Circulating Tumor DNA: It Is in the Blood.

Liquid biopsy using blood components to assess circulating tumor DNA (ctDNA) is rapidly becoming a new standard-of-care technology in many tumor types, including breast cancer, due to the potential to provide predictive and prognostic information. The minimally invasive and repeatable nature of plasma based mutational testing is appealing for patients and facilitates enhanced disease monitoring. It is important for the clinician to understand the benefits and limitations of this emerging assay and the potential applications in breast cancer. Multiple technologies have been employed to assess breast cancer ctDNA with high sensitivity and specificity leading to assays that have been useful in research trials and are entering widespread clinical application. ctDNA analysis of breast cancer is of clinical utility today in selecting targeted therapy for advanced breast cancer, most notably by assessing PIK3CA mutations in hormone receptor-positive, HER2-negative disease. It will be employed in the near future in a variety of clinical settings including early detection of primary breast cancer, minimal residual disease after initial therapy, and use in advanced breast cancer for prognosis, early identification of non-response, and monitoring genomic markers of resistance.

The Influence of Pre-Existing Beta-Blockers Use on Survival Outcomes in HER2 Positive Advanced Breast Cancer: Pooled Analysis of Clinical Trial Data.

Introduction: Beta-blockers (BB) are commonly used to manage cardiovascular disease and may have benefits in controlling complications of anti-HER2 therapies. This study aimed to evaluate the association of pre-existing BB use with survival outcomes in patients initiating anti-HER2 therapy for advanced breast cancer (ABC).Materials and Methods: Data from clinical trials EMILIA, TH3RESA, MARIANNE, and CLEOPATRA was pooled. Cox proportional analysis was used to assess the association between pre-existing BB use with survival outcomes in patients initiating anti-HER2 therapies.Results: Of the 2,777 patients with HER2 positive ABC, 266 were using a BB at the time of anti-HER2 therapy initiation. BB use was associated with worse overall survival (OS) (adjusted HR = 1.27, 95% CI: 1.04–1.55). Sensitivity analysis in patients with pre-existing cardiovascular disease (CVD) also indicated that BB use was associated with worse OS (1.29, 1.02–1.63).Conclusion: In large high-quality data, BB use at the time of anti-HER2 therapy initiation for ABC was independently associated with worse OS, regardless of CVD status. The finding is contrary to pre-study hypotheses and findings in other BC subtypes. Future research should aim to gain a deeper understanding of the effects of BBs on specific BC subtypes, cancer types, and cancer treatments.

ABC4 Consensus: First Latin American Meeting-Assessment, Comments, and Application of Its Recommendations.

Breast cancer accounts for a high burden among all the neoplasms in Latin America, with more-advanced stages at presentation, which could result in high mortality rates. The 4th International Consensus Conference for Advanced Breast Cancer (ABC4) is focused on standardizing therapy for advanced breast cancer (ABC) and has held 5 meetings so far. ABC4 took place in Lisbon, Portugal, from November 2 to 4, 2017; however, the first Latin American ABC conference was held in Lima, Peru, from 18 to 19 May, 2018, chaired by Fatima Cardoso, MD, PhD. During these 2 days, the ABC4 consensus recommendations for advanced and locally advanced breast cancer were presented. Local treatment and systemic therapy were discussed with local experts, mainly focusing on anti–human epidermal growth factor receptor 2 therapy and newly approved drugs for hormone receptor–positive breast cancer, such as as CDK4/6, mammalian target of rapamycin, and poly (ADP-ribose) polymerase inhibitors for triple-negative breast cancer. The discussion focused additionally on access to drugs and ABC4 consensus recommendations as regards Latin American patients.

11P BioItaLEE: Comparative biomarker analysis of liquid biopsies and paired tissue samples of patients treated with ribociclib and letrozole as first-line therapy for advanced breast cancer (aBC)

BIOITALEE aims to study circulating tumor DNA (ctDNA) alterations, their evolution and association with clinical outcome in patients (pts) receiving ribociclib+letrozole as 1st-line treatment for aBC. Here we report the analysis of baseline liquid biopsy (LB) and tumor tissue samples (TS), and their comparison.

Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial

Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. Eli Lilly and Company.

Abstract P5-01-07: Bioitalee - Biomarker analysis on liquid biopsies of patients treated with ribociclib and letrozole as first-line therapy for advanced breast cancer (aBC) (NCT03439046)

Abstract Background: The primary objective of this phase IIIb, single arm trial is to study circulating tumor DNA (ctDNA) alterations, their evolution during treatment and association with clinical outcome in patients receiving ribociclib and letrozole as first-line therapy for aBC. Here we report baseline ctDNA mutational status and its correlation with clinical-pathological characteristics and response to treatment on the basis of first imaging evaluation. Methods: From February to December 2018, 287 post-menopausal patients (pts) with hormone receptor positive (HR+) and HER2 negative aBC were enrolled in 47 Italian Centers; 271 pts were suitable for biomarker analysis (Biomarker Analysis Set- BAS). Data on first imaging evaluation were available for 225 pts. Baseline liquid biopsies were analyzed both for Copy Number Variation (CNV) by Oncomine Pan-Cancer Cell-Free Assay (Thermo Fisher Scientific) and for Single Nucleotide Variant (SNV) using 533 amplicon custom AmpliSeq HD panel optimized for the detection of low abundance events in ctDNA. Variants were analyzed as both individual genes and as pre-defined pathways (n=10). Results: At BAS, median age was 66 years (range 47-86). At study entry, 60% (109) and 40% (162) of pts had recurrent and de-novo disease, respectively, with 43% (117) of pts with visceral and 24% (64) with bone-only involvement. At least one CNV alteration or a hotspot mutation was detected in 51% of patients. The most frequently altered genes were PIK3CA (22.14%), TP53 (15.50%), FGFR1 (6.64%), CCND1 (4.80%), CCND2 (4.80%), KMT2C (4.43%), MYC (4.06%), CDK4 (3.69%) AKT1 (3.32%), PTEN (3.32%), ERBB2 (2.58%), CCND3 (2.58%), APC (2.21%) and MAP2K4 (2.21%). More than one alteration was observed in 28% pts (either CNV or hotspots). Mutation in KTM2C or alterations in genes belonging to the “Estrogen Receptor nuclear function” (ERnf) pathway (i.e. KTM2C, ESR1, GATA3 and MYC) were more frequent in patients with recurrent vs. de novo disease (Odds Ratio [OR] =7.69, p=0.0499 for KTM2C; OR=2.70, p=0.0381 for ERnf). MYC copy number gain or alterations in the ERnf genes were more frequent in Estrogen Receptor positive (ER+)/Progesteron Receptor negative (PgR-) compared to ER+/PgR+ tumors (OR= 4.07, p=0.0361 for MYC; OR=3.36, p=0.0073 for ERnf). Copy number gain of FGFRs (FGFR1, 2 and 3) were more frequent in patients with visceral versus bone-only disease (OR=5.26, p=0.0144 for FGFRs) and in pts with more than three metastatic sites (OR=8.05, p=0.0052). At first imaging, the Clinical Benefit Rate (CBR, defined as CR + PR + SD) was 90%, with only 10% of pts showing early disease progression (PD). Thirty pts (11%) had at least one alteration in genes belonging to the CDK4/6 pathway (CCND1, RB1, CDK4 and 6, CDKN2A). These alterations were more frequent in the group of patients with early PD (OR=3.23, p=0.0272). MYC gain, TP53 mutations and alterations in the HER family genes (EGFR, ERBB2, 3 and 4) were also more frequent in pts with early PD compared with pts with CBR (OR 5.16, p=0.0280, OR 3.87, p=0.0058 and OR 4.40, p=0.0426, respectively). Conclusion: At the present analysis, alterations in KTM2C and ERnf seem to characterize recurrent vs de novo aBC while FGFRs are prevalent in patients with more aggressive disease. Interestingly, MYC gain, TP53 mutations, alterations in genes of the HER family and CDK4/6 pathway were more likely detected in patients with early PD suggesting these as potential markers of intrinsic resistance to first-line treatment with ribociclib and letrozole. Further analyses for biomarker dynamics and pharmacogenomics are ongoing. Citation Format: Michelino De Laurentiis, Luca Malorni, Giampaolo Bianchini, Roberta Caputo, Mario Giuliano, Alberto Zambelli, Fabio Puglisi, Lucia Del Mastro, Marco Colleoni, Filippo Montemurro, Giulia Bianchi, Ida Paris, Giacomo Allegrini, Laura Amaducci, Marina Elena Cazzaniga, Michele Orditura, Claudio Zamagni, Vincenzo Adamo, Valentina Guarnieri, Nicola Battelli, Maria Rosaria Valerio, Saverio Cinieri, Sara Bianchetti, Donatella Grasso, Daniela Castelletti, Diletta Valsecchi, Ettore Cotroneo, Grazia Arpino. Bioitalee - Biomarker analysis on liquid biopsies of patients treated with ribociclib and letrozole as first-line therapy for advanced breast cancer (aBC) (NCT03439046) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-07.

Abstract P2-17-01: Therapy of advanced breast cancer for patients with hormone receptor-positive/HER2-negative and HER2-positive tumors is changing in real life: First results from the prospective, national research platform OPAL for patients with advanced breast cancer in Germany

Abstract Introduction Tumor Registries give insight into routine treatment and complement the knowledge derived from randomized controlled trials (RCT), since characteristics of patients from RCTs often differ from those of patients in routine care. Furthermore, follow-up of patients in registries is generally longer which gives the possibility to analyze sequential treatments. Since 2007 the Tumor Registry Breast Cancer (TMK, NCT01351584) has prospectively collected data on treatment and outcome of patients with breast cancer in Germany. Among other topics, insights into “real-world” treatment and outcome and long-term observation of quality of life have been published. Since 2017 the registry platform OPAL (NCT03417115) has extended the work of the TMK by recruiting patients with advanced breast cancer (ABC) from all specialties (medical and gynecologic oncologists). The main aims are to observe the impact of novel treatments on patient outcome, and to identify areas for improvement of quality of care. Methods OPAL started in December 2017. Patients are prospectively recruited at start of their first systemic treatment for ABC. Follow-up continues until death or up to 5 years. There is no treatment specification. Detailed information on all (sequential) treatments, patient and tumor characteristics, physician-reported factors regarding treatment decision making, biomarker testing, outcomes (e.g. best response, progression-free and overall survival) are collected in a web-based data capture system with implemented checks for completeness and plausibility. Data are monitored by data management and on-site. Patient-reported outcomes (PROs) are collected at start of treatment and every 3 months thereafter. Patients can also give informed consent for their tumor samples to be used in future translational research (virtual biobank). All patient data remain in Germany. Here, first combined data from the TMK and OPAL (database as of 01.04.2019) are presented. Results Since 2007, 5076 patients have been recruited. Patients with ABC (n=2105, 434 since the start of OPAL) have a median age of over 60 years at start of treatment; about 60% have comorbidities. For patients with hormone-receptor positive (HRpos)/HER2 negative (HER2neg) ABC, first-line treatment has changed over the years. From 2007-11 (n=458) 60% of patients started with chemotherapy, decreasing to 48% in 2012-16 (n=528) and to 23% in 2018-19 (n=170) with 58% of patients now being treated with CDK4/6-inhibitor. First-line of HER2pos ABC has also changed from 79% of patients receiving trastuzumab (TRA) between 2007-12 (n=268) to 78% of patients receiving dual-blockade with TRA/pertuzumab in 2018-19 (n=97) and 10% receiving TRA only. About 25% of patients treated with TRA in 2018-19 received a biosimilar. Median overall survival (OS) of patients with start of first-line therapy between 2007-16 is currently 15 months for triple-neg (74% events), 34 months for HRpos/HER2neg (59% events), 40 months for HER2pos (52% events); median OS has not yet been reached for patients in OPAL. Conclusions For patients with HRpos/HER2neg ABC, a shift towards more endocrine therapy in the first-line setting, and a quick implementation of CDK4/6-inhibitors after their approval can be observed. In patients with HER2pos ABC, integration of trastuzumab biosimilars into routine care has started. Prognosis for patients with triple-negative ABC remains poor and new treatment options are urgently needed. OPAL together with TMK will allow to follow changes in treatment of patients with ABC in a “real world” setting in Germany, the application of sequential treatments, and their impact on clinical as well as patient-reported outcome. Citation Format: Elmar Stickeler, Nadia Harbeck, Marc Thill, Arnd Nusch, Marco Chiabudini, Lisa Kruggel, Martina Jänicke, Norbert Marschner, Mark-Oliver Zahn, Anja Welt, Achim Wöckel, Thomas Decker, OPAL Study Group. Therapy of advanced breast cancer for patients with hormone receptor-positive/HER2-negative and HER2-positive tumors is changing in real life: First results from the prospective, national research platform OPAL for patients with advanced breast cancer in Germany [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-17-01.

Abstract OT2-06-02: Phase 2 trial with safety-run in of gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive HER2 negative breast cancer

Abstract Background: Advanced triple negative breast cancer (TNBC) has a poor prognosis, with a median survival of approximately 12 months. Due to a lack of receptor targets, chemotherapy remains the mainstay of treatment. A subset of TNBC has defects in homologous recombination (HR) DNA repair due to germline BRCA mutations. Poly(ADP-ribose) polymerase (PARP) inhibitors have been shown to be an effective therapy in this subgroup. The phosphoinositide-3-kinase (PI3K) pathway inhibitors are also active in some breast cancers, lowering nucleotide pools required for DNA synthesis and S-phase progression. Preclinical studies suggest that PI3K stabilizes and preserves double strand break repair by interacting with the HR complex. Inhibition of PI3K/mTOR could impede PI3K interaction with the HR complex, thereby increasing dependency on PARP enzymes for DNA repair, and making this dual inhibition a rational combination. This trial is studying the safety and efficacy of combining the PI3K/mTOR inhibitor, gedatolisib, and the PARP inhibitor, talazoparib. Single-agent talazoparib is currently approved in advanced HER2 negative breast cancer with a germline BRCA 1/2 mutation. Trial design: This trial is designed with a safety run-in to determine the recommended phase 2 doses (RP2D) of the talazoparib and gedatolisib combination. The safety run-in will be followed by a phase II single-arm study of the combination, with 2 patient cohorts. Cohort A will be comprised of patients with advanced TNBC with negative or unknown germline BRCA1/2 status. Cohort B will be used for an exploratory analysis, comprised of patients with advanced HER2 negative breast cancer and a germline BRCA1/2 mutation. Eligibility Criteria: For the safety run-in phase, patients ≥18 of age with advanced breast cancer (defined as metastatic or unresectable) are eligible if they meet criteria for either cohort A or cohort B. For cohort A, all patients are required to have at least one line of prior systemic therapy for advanced breast cancer but no more than 2 lines of prior chemotherapy are allowed. For cohort B, no more than 2 lines of prior chemotherapy are allowed, with no limit on prior endocrine or targeted therapies. Patients with type I or poorly controlled diabetes are excluded due to the common side effect of hyperglycemia with gedatolisib. Specific aims: Primary objective of the safety run-in: Determine the RP2D of talazoparib in combination with gedatolisib in patients with advanced HER2 negative (triple negative or BRCA1/2 deficient) breast cancer. Primary objective of the phase II study: Estimate the objective response rate (ORR) in patients with BRCA1/2 negative, or unknown, advanced TNBC - Cohort A. Correlative analysis will include correlating the HR deficiency (HRD) score with clinical response in patients with TNBC. Statistical Methods: In the safety run-in, a 3+3 design will be used for dose escalation. Maximum tolerated dose (MTD) is decided when 6 patients are treated at a dose level with < 2 DLTs. The MTD will be the RP2D. The safety run-in (dose escalation) component will require 9-18 subjects. In the Phase II study, the primary endpoint for sample size justification is ORR for cohort A (TNBC). The null response rate of 5% will be compared to the alternative hypothesis of 20% ORR with a 1-sided alpha level of 0.1. Based on the exact binomial test, we propose 21 subjects to target a power level of 80%. ORR in cohort B is a secondary endpoint. Target Accrual: Our target accrual for the safety run-in is 9-18 participants. Assuming 10% of subjects will be not be evaluable for the primary outcomes, then the number of patients accrued to cohort A will be 24. Cohort B will remain at 12 since it is exploratory. Contact information: The study is being administered through the Big Ten Cancer Research Consortium and can be identified as BTCRC-BRE18-337. Citation Format: Sneha Phadke, Menggang Yu, Kathy Miller, Ami Shah, Oana Danciu, Kari Wisinski. Phase 2 trial with safety-run in of gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive HER2 negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-06-02.

Abstract P3-11-09: ARISTACAT - Aromatase inhibition plus minus saracatinib as advanced breast cancer therapy: A randomised phase II study of aromatase inhibition plus/minus the Src-inhibitor AZD0530 in post-menopausal women with advanced breast cancer

Abstract Background: Src, the first proto-oncogene to be described, is a non-receptor tyrosine kinase interacting with multiple oncogenic pathways, including cell proliferation, survival, angiogenesis and osteoclast activity. Src activation occurs in up to 40% of ER+ breast cancers, is linked with poor prognosis, and pre-clinically has been strongly implicated in endocrine resistance. Saracatinib (AZD0530) is a potent, oral selective Src inhibitor that enhances the anti-proliferative effect of endocrine agents in pre-clinical breast cancer models, preventing the development of endocrine-resistance and restoring endocrine sensitivity. In a murine model of prostate bony metastases saracatinib inhibits osteoclast activity, reducing bone resorption and the development and progression of bone lesions. Clinically, saracatinib is generally well-tolerated with mainly gastro-intestinal adverse events (AEs), clinically meaningful durations of stable disease as monotherapy, and partial responses observed in combination with other therapies. Methods: Multi-centre, placebo-controlled, double-blind, randomised phase II trial. Post-menopausal women with advanced/metastatic breast cancer suitable for 1st or 2nd second line hormonal treatment, were randomised to receive an aromatase inhibitor (AI) plus saracatinib 175mg mg/day or placebo. Patients were stratified as either (i) “AI-sensitive/naïve”, who received anastrazole 1mg daily ± saracatinib, or (ii) “prior-AI”, if they had progressed on a non-steroidal AI but were considered likely to retain some endocrine sensitivity, who received exemestane 25mg daily ± saracatinib. Other stratification factors were bone metastases, bisphosphonate use, performance status, and treatment centre. Treatment was until progression, intolerable toxicity or at the patient’s request. The primary endpoint was PFS; secondary endpoints were toxicity, ORR & OS; exploratory endpoints explored molecular correlates in on-treatment samples (including optional biopsies). Results: 140 patients were enrolled from 22 UK sites between August 2012 and April 2015 of whom 69 were in the “AI-sensitive/naïve” group and 71 in the “prior-AI” group; 134 patients were eligible for efficacy evaluation and 136 for safety. Interim safety data analyses by an IDMC identified no new safety signals. Treatment emergent AEs were generally low grade, the most frequent being fatigue (70%) and nausea (49%); AEs occurring significantly (p<0.05) more often with saracatinib were hypophosphataemia (40% vs 6%), rash (34% vs 12%), anorexia (43% vs 19%), vomiting (33% vs 15%) and diarrhoea (31% vs 16%). More patients receiving saracatinib had a dose reduction or stopped treatment due to toxicity (16% vs 10% and 5% vs 3%, respectively; n.s.). There was no indication of greater efficacy from the addition of saracatinib with respect to PFS (3.7 v 5.6 months; n.s.) or OS (24 vs 23 months; n.s.). ORR appeared lower with saracatinib (11% vs 31%) even when excluding non-evaluable patients. Effects were consistent in the “AI-sensitive/naïve” and “prior-AI” groups. Patients receiving saracatinib were no less likely to progress with bone metastases, while bisphosphonate use was associated with an increased PFS and OS across the trial population. Translational work underway includes assessing Src pathway suppression. Conclusions: Saractinib did not improve outcomes in post-menopausal women with advanced breast cancer treated with exemestane with numerically inferior p response rate and PFS, and no apparent beneficial effect on bone metastases. These data do not support further evaluation of saracatinib in combination with AIs. ARISTACAT - Abstract - San Antonio 2019 Citation Format: David Cameron, Stefan Symeonides, Murray Brunt, Peter Schmid, Simon Waters, Christopher Twelves, Peter Barrett-Lee, John Bartlett, Tammy Piper, Karen McAdam, Eve Macdonald Chisholm, Michelle Welsh, Robert Hill. ARISTACAT - Aromatase inhibition plus minus saracatinib as advanced breast cancer therapy: A randomised phase II study of aromatase inhibition plus/minus the Src-inhibitor AZD0530 in post-menopausal women with advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-09.

Abstract OT2-02-08: A phase 2 randomized, double-blind, placebo-controlled study of ribociclib or placebo in combination with endocrine therapy for the treatment of premenopausal and postmenopausal Chinese women with HR+, HER2−, advanced breast cancer

Abstract Background: Ribociclib (RIB) is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor that has demonstrated efficacy and safety in combination with endocrine therapy (ET) for the treatment of advanced breast cancer (ABC), but to date no studies have specifically evaluated RIB in a population in mainland China. This study aims to assess the efficacy and safety of RIB or placebo in combination with ET in premenopausal and postmenopausal Chinese patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2−) ABC. It is also designed to investigate the pharmacokinetics (PK) of RIB in combination with ET. Methods: In this phase 2 randomized, double-blind, placebo-controlled study, Chinese women with ABC will be included in a premenopausal or postmenopausal cohort (~150 patients each) and randomized 1:1 in each cohort to receive RIB or placebo. A further ~15 patients will be included in an open-label PK cohort. All patients must have HR+, HER2− ABC based on the most recently analyzed biopsy, with advanced disease not amenable to curative therapy. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (version 1.1) or at least 1 predominantly lytic bone lesion, and Eastern Cooperative Oncology Group performance status score (ECOG PS) < 2. Patients in the premenopausal cohort must be adult women who received no prior hormonal therapy and ≤ 1 line of chemotherapy (CT) for ABC and are eligible for ET. Patients in the postmenopausal and PK cohorts must be postmenopausal women who received no prior therapy (ET or CT) for ABC and are eligible for ET; patients who have received (neo)adjuvant therapy are eligible - if the prior neo(adjuvant) therapy included letrozole or anastrozole, the disease-free interval must be > 12 months from the completion of treatment until randomization. Exclusion criteria include previous CDK4/6 inhibitor therapy; symptomatic visceral disease or any disease burden rendering patients ineligible for ET; central nervous system metastases; known human immunodeficiency virus infection history; and clinically significant uncontrolled heart disease. Patients in the premenopausal cohort will be randomized to 600 mg RIB oral (3 weeks on/1 week off) or placebo, in combination with a nonsteroidal aromatase inhibitor (2.5 mg letrozole [LET] oral or 1 mg anastrozole oral, chosen by investigator) and 3.6 mg goserelin subcutaneous. Patients in the postmenopausal cohort will receive RIB or placebo in combination with LET; those in the single-arm PK cohort will receive RIB in combination with LET. The primary endpoint of the premenopausal and postmenopausal cohorts is progression-free survival. Secondary endpoints are overall survival, overall response rate, clinical benefit rate, time to response, duration of response, and time to deterioration in ECOG PS. The objectives for the PK cohort are to characterize PK parameters of the RIB + LET combination, and of the RIB metabolites. Citation Format: Zhimin Shao, Binghe Zu, Zhongsheng Tong, Qiang Liu, Wei Li, Li Cai, Kunwei Shen, Wenhe Zhao, Jin Yang, Chuan Wang, Woody Tang, Tingting Sun, Yu Han, Ruina Gao. A phase 2 randomized, double-blind, placebo-controlled study of ribociclib or placebo in combination with endocrine therapy for the treatment of premenopausal and postmenopausal Chinese women with HR+, HER2−, advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-08.

Post-mastectomy radiation therapy in breast cancer patients with 1-3 positive lymph nodes: No one size fits all.

Post-mastectomy radiation therapy (PMRT) is standard therapy for advanced breast cancer. However, given the lower risk of recurrence, PMRT administration remains controversial in select patients with limited nodal disease. We performed a review of the literature that focuses on the effect of PMRT in breast cancer patients with 1-3 positive lymph nodes, mainly examining loco-regional recurrence (LRR) and overall survival (OS). Most studies, including a large meta-analysis by the EBCTCG, showed a significant improvement in LRR rates among patients receiving PMRT. While most studies demonstrated a trend towards OS improvement, only few studies showed a statistically significant OS or breast cancer-specific survival benefit for PMRT. As such, individualized treatment decisions are recommended, taking into consideration clinicopathological findings. Future studies with large sample sizes and long follow-up times are still needed to better assess the role of PMRT in patients with limited nodal involvement.

Cyclin‑dependent kinase 4/6 inhibitors in combination with fulvestrant for previously treated metastatic hormone receptor‑positive breast cancer patients: A systematic review and meta‑analysis of randomized clinical trials

PurposeTo compare the efficacy and safety profile of the combination of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and fulvestrant versus fulvestrant alone in previously treated patients with advanced hormone-receptor positive breast cancer. MethodsPhase III randomized clinical trials (RCTs) were retrieved from a systematic review of electronic databases. A random-effect model was employed to determine the pooled hazard ratio (HR) for Progression-Free Survival (PFS) and Overall Survival (OS) using the inverse-variance method. The Mantel Haenszel method was used to calculate the pooled odds ratio (OR) for treatment-related side effects. Heterogeneity was measured using the tau-squared and I2 statistics. ResultsThree phase III RCTs (n = 1916) were included in the systematic review. Use of abemaciclib, palbociclib, or ribociclib in combination with fulvestrant was significantly associated with longer PFS compared to use of fulvestrant alone (HR: 0.53; 95%CI: 0.47–0.60; p<0.00001), with no significant heterogeneity found among trials. Similarly, OS was significantly longer for patients who received combination therapy in comparison with those allocated to receive fulvestrant alone (HR: 0.77; 95%CI: 0.67–0.89; p<0.0004). The overall odds ratio of serious adverse events (AE) was not significantly increased with the use of the combination therapy (OR: 1.51; 95%CI: 0.74–3.08), with significant heterogeneity found among trials (tau2=0.34; I2=86%; p = 0.0006). ConclusionThe addition of CDK 4/6 inhibitors (either abemaciclib, palbociclib, or ribociclib) to fulvestrant significantly improved PFS and OS in comparison with fulvestrant alone in patients previously treated with endocrine therapy for advanced breast cancer. No significant heterogeneity was found among CDK 4/6 inhibitors.