Hormone Receptor-positive HER2-negative Metastatic Breast Research Articles

Elderly patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK4/6 inhibitors in a multicentre cohort

IntroductionCyclin-dependent kinases 4/6 inhibitors (CDK 4/6i) combined with endocrine therapy have become the gold standard in hormone receptor-positive (HR +) HER2-negative (HER2-) metastatic breast cancer (MBC). However, there is a significant lack of data regarding the efficacy and safety of these treatments in elderly patients. We present the results of a real-world data (RWD) cohort stratified by age at treatment initiation (≥ 70 years compared to patients < 70 years).MethodsClinico-pathological data of HR + HER2- MBC patients who were candidates for CDK4/6i therapy between January 2017 and December 2020 at the Institut Català d'Oncologia (Spain) were retrospectively collected. The primary goal was to assess Progression-Free Survival (PFS), Overall Survival (OS), and safety outcomes within this patient population.ResultsA total of 274 patients with MBC who received CDK4/6i treatment were included in the study. Among them, 84 patients (30.8%) were aged ≥ 70 years, with a mean age of 75, while 190 patients (69.2%) were under the age of 70, with a mean age of 55.7 years. The most frequently observed grade 3–4 toxicity was neutropenia, with similar rates in both the < 70 group (43.9%) and the ≥ 70 group (47.9%) (p = 0.728). The median Progression-Free Survival (mPFS) for the first-line CDK4/6i treatment was 22 months (95% CI, 15.4–39.8) in the < 70 group and 20.8 months (95% CI 11.2–NR) in the ≥ 70 group (p = 0.67). Similarly, the median PFS for the second-line CDK4/6i treatment was 10.4 months (95% CI, 7.4–15.1) and 7.1 months (95% CI 4.4–21.3) (p = 0.79), respectively. Median overall survival (mOS) was not reached either for the first- and second-line treatment.ConclusionsOur RWD suggests that elderly patients, when compared to those under 70, experience similar survival outcomes and exhibit comparable tolerance for CDK4/6i therapy.

Clinicopathological Evaluation of Patients with Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer Progressing on Endocrine Treatment: A Real-World Retrospective Study from a Regional Cancer Center

Metastatic breast cancer (MBC) is an incurable disease with the primary aim of treatment being the improvement of the patient's quality of life and the delay of disease progression. A substantial proportion of patients with hormone receptor (HR)-positive MBC eventually experience progression despite endocrine treatment. As endocrine resistance remains a significant challenge, we aim to comprehend the intricate relationship between clinicopathological characteristics and the utility of various parameters as predictive markers for hormonal treatment response. This study, conducted at a single center, is ambispective in nature and includes hormone receptor (HR)-positive, human epidermal growth factor 2–negative MBC patients who progressed while on endocrine treatment, selected through purposeful sampling. Nominal data were analyzed in terms of frequency distribution, and continuous variables were represented as median/mean ± standard deviation. Spearman's correlation test and chi-square test were employed to examine variable dependencies. Data comparisons were performed using the independent t-test, one-way analysis of variance, or Mann–Whitney's test. The majority of our study participants (n = 44, 64.70%) presented with de novo metastasis, while the remainder (n = 24, 35.29%) were patients who progressed from early-stage breast cancer to metastasis. The overall mean age of our study population at presentation was 47 ± 11 years. Patients with upfront stage 4 tumors presented at an older age, exhibited grade 2 tumors, had a higher frequency of bone-only metastasis, and experienced longer progression-free survival (PFS) compared to patients who progressed from the early stage to metastasis. Multiple visceral involvements had a significant negative impact on PFS in contrast to cases with single visceral or bone-only involvement. No significant associations with PFS were observed for the Ki-67 index, first-line chemotherapy, or endocrine therapy. The extent of metastasis to various organs emerged as the most influential factor in determining PFS. Consequently, we propose the necessity for larger prospective studies aimed at identifying superior or additional biomarkers.

Efficacy and clinical outcome of chemotherapy and endocrine therapy as first-line treatment in patients with hormone receptor-positive HER2-negative metastatic breast cancer.

Endocrine therapy (ET) and ET-based regimens are the preferred first-line treatment options for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (HR+/HER2- MBC), while chemotherapy (CT) is commonly used in clinical practice. The aim of this study was to investigate the efficacy and clinical outcome of ET and CT as first-line treatment in Chinese patients with HR+/HER2- MBC. Patients diagnosed with HR+/HER2-MBC between January 1st, 1996 and September 30th, 2018 were screened from the Chinese Society of Clinical Oncology Breast Cancer database. The initial and maintenance first-line treatment, progression-free survival (PFS), and overall survival (OS) were analyzed. Among the 1877 included patients, 1215 (64.7%) received CT and 662 (35.3%) received ET as initial first-line treatment. There were no statistically significant differences in PFS and OS between patients receiving ET and CT as initial first-line treatment in the total population (PFS: 12.0 vs. 11.0 months, P = 0.22; OS: 54.0 vs . 49.0 months, P =0.09) and propensity score matched population. For patients without disease progression after at least 3 months of initial therapy, maintenance ET following initial CT (CT-ET cohort, n = 449) and continuous schedule of ET (ET cohort, n = 527) had longer PFS than continuous schedule of CT (CT cohort, n = 406) in the total population (CT-ET cohort vs. CT cohort: 17.0 vs . 8.5 months; P <0.01; ET cohort vs . CT cohort: 14.0 vs . 8.5 months; P <0.01) and propensity score matched population. OS in the three cohorts yielded the same results as PFS. ET was associated with similar clinical outcome to CT as initial first-line treatment. For patients without disease progression after initial CT, switching to maintenance ET showed superiority in clinical outcome over continuous schedule of CT.

Efficacy of front-line treatment for hormone receptor-positive HER2-negative metastatic breast cancer with germline BRCA1/2 mutation.

Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation. The ESME metastatic breast cancer platform (NCT03275311) is a French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1). A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR [95% CI] 1.26 [1.03-1.55]). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR [95% CI] = 1.54 [1.03-2.32]) and PFS1 (adjusted HR [95% CI] 1.58 [1.17-2.12]) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 [0.88-1.41], p = 0.350; PFS1: 1.09 [0.90-1.31], p = 0.379). In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.

Prognostic Significance of Low HER2 Expression in Patients With Metastatic Hormone Receptor-positive Breast Cancer Treated With First Line CDK4/6 Inhibitors: A Greek Multicenter Real-world Data Analysis.

Low expression of HER2 has defined a new "HER2-low" subgroup of breast cancer with distinct clinicopathological characteristics and both prognostic and predictive implications. The impact of low HER2 expression in metastatic hormone receptor-positive HER2-negative breast cancer treated with first-line CDK4/6 inhibitors has not been studied. Using real-world patient data, we aimed to identify prognostic differences in this patient population according to HER2 expression with immunohistochemistry. We retrospectively analyzed 191 patients from 5 Oncology Department databases in Thessaloniki, Greece, with hormone receptor-positive HER2-negative metastatic breast cancer treated with CDK4/6 inhibitors in the first line, for whom detailed immunohistochemical HER2 data could be retrieved. Median progression-free survival was numerically different among the different HER2 subgroups (3.35 years for HER2 0 tumors, 2.18 years for HER2 +1 tumors, 1.74 years for HER2 +2/ISH-negative tumors), but this difference was not statistically significant (p=0.477). Median PFS was statistically significantly longer in patients without visceral metastases (5.45 years) compared to patients with visceral metastases (1.61 years) (p=0.017). Median PFS was also statistically significantly longer in patients taking an aromatase inhibitor (2.99 years) compared to patients taking fulvestrant (1.33 years) (p<0.0001). There were no statistically significant differences in the other subgroups examined. CDK4/6 inhibitors are equally effective as first-line treatment agents, regardless of the exact level of HER2 expression. Numerical differences, however, do exist among the different HER2 subgroups, and merit further evaluation in future studies to better study this phenomenon.

Prevention and correction of alpelisib-induced hyperglycemia (view of endocrinologist)

Alpelisib is a modern targeted drug for the treatment of patients with hormone receptor-positive HER2-negative metastatic breast cancer with a PIK3CA gene mutation. Blockade of PI3K can significantly increase progression-free survival, however, it is accompanied by adverse events, the most common of which is hyperglycemia. The article presents recommendations for risk estimation, prevention and correction of alpelisibinduced hyperglycemia.

Evolution of the CDK4/6 inhibitor abemaciclib: from palliative to adjuvant therapy. Clinical experience with abemaciclib in patients with hormone-receptor-positive, HER2-negative breast cancer

Introduction. Cyclin-dependent kinase 4/6 inhibitors are indicated in endocrine therapy for the treatment of hormone receptorpositive, HER2-negative, advanced, or metastatic breast cancer. In the recent past, abemaciclib made its debut as a combinatorial partner for adjuvant therapy in hormone-dependent breast cancer. This article demonstrates the analysis of our own experience of introducing abemaciclib into clinical practice.Aim. The aim of the study was to evaluate the preliminary results of treatment of patients with hormone receptor-positive HER2-negative metastatic breast cancer using abemaciclib outside the framework of clinical trials, in the real clinical practice of an oncological dispensary.Materials and methods. A retrospective analysis of the results of treatment was carried out in 27 patients who were prescribed abe-maciclib in various regimens and lines from April 2021 to January 2022 in the conditions of routine practice in the Krasnodar region.Results and discussion. Analysis of the total population of 27 patients at a median follow-up of 8 months showed that the median PFS was not reached. The one-year PFS was 68.8%. Treatment outcomes were independent of prescribing abemaciclib to treat baseline metastatic disease or breast cancer progression after previous radical treatment (p = 0.60). The PFS did not depend on the expression of progesterone receptors in the tumor tissue (p = 0.326) and the proliferative activity index Ki-67 (p = 0.618). Patients who received no more than 2 lines of previous drug treatment for a history of metastatic breast cancer had the greatest benefit from abemaciclib therapy (p = 0.001).Conclusions. Despite a relatively difficult group of patients (96% of patients with visceral metastases), abemaciclib has demonstrated efficacy and safety. The effectiveness did not depend on the analyzed factors: Ki-67, the level of expression of progesterone receptors, the type of metastatic disease (de novo metastatic or progressive breast cancer). In view of the best results, it is advisable to prescribe abemaciclib in the early lines of therapy.

Defining resistance mechanisms to CDK4/6 inhibition in hormone receptor-positive HER2-negative metastatic breast cancer (MBC) through a machine learning approach applied to circulating tumor DNA (ctDNA).

3055 Background: Although cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are a primary treatment for hormone receptor-positive/HER2 negative MBC, data regarding resistance mechanisms are still an unmet need. The aim of the study was to highlight new resistance pathways using machine learning (ML) to detect multiparametric patterns in complex datasets. Methods: The study retrospectively analyzed a cohort of 610 hormone receptor positive HER2 negative MBC patients (pts) at Northwestern University, Massachusetts General Hospital and Washington University in St. Louis between 2015-2020 with baseline ctDNA testing by Guardant360. Pathways were defined based on previous work (Sanchez-Vega F et al, Cell. 2018) (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Only pathogenic variants according to OncoKB were included in the models. Associations among single nucleotide (SNVs) and copy number (CNVs) variations, pathway classification and previous exposure to CDK4/6i were explored through logistic regression and Gradient boosted machines (GBMs) ML algorithm. Results: at baseline, 322 pts (52.8%) were previously treated with CDK4/6i. The most detected pathway alterations were SNVs in PI3K (37.1%), P53 (31.8%), ER (29.2%) and RTK (22.3%). After stepwise logistic regression, RB1, NF1 and ESR1 SNVs were associated with previous exposure to CDK4/6i (respectively OR: 3.55 P = 0.017; OR: 3.06 P = 0.026 and OR: 1.82 P &lt; 0.001), while SNVs in the ER pathway were associated with CDK4/6i (1.56 P &lt; 0.001). Two GBMs models were designed based on gene variants (training AUC: 0.695, cross validation AUC: 0.631) and oncogenic pathways (training AUC: 0.713, cross validation AUC: 0.619). The highest relative importance (RI) was observed for ESR1 SNVs (RI: 35.35), TP53 SNVs (RI: 11.33), NF1 SNVs (RI: 3.45), SMAD4 SNVs (RI: 3.39) and RB1 SNVs (RI: 3.33). Alterations at a pathway level with the highest RI were ER SNVs (RI: 33.50), P53 SNVs (RI: 14.98), PI3K SNVs (RI: 14.40), RTK SNVs (RI: 10.55), RTK CNVs (RI: 10.26), cell cycle CNVs (RI: 6.99), cell cycle SNVs (RI: 6.77) and RAS SNVs (RI: 6.54). Of the previously highlighted pathway alterations, a significant impact on PFS after ctDNA collection was observed among de novo pts treated with CDK4/6i (165 pts) for ER SNVs (P &lt; 0.0001), RTK SNVs (P = 0.0011), RTK CNVs (P = 0.0006), Cell cycle CNVs (P = 0.0010) and Cell cycle SNVs (P = 0.0143). No impact was observed on PFS for pts who had not received a CDK4/6i-based regimen. Conclusions: The combination of ctDNA-based datasets and machine learning algorithms defined novel resistance pathways for patients treated with CDK4/6i. Although preliminary, these results suggest that alterations of the ER, RTK and Cell cycle pathways might be crucial to optimize treatment strategy and drug development.

Maintenance endocrine therapy plus bevacizumab for advanced or metastatic breast cancer.

Endocrine therapy is the preferred option for patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar However, first-line chemotherapy is used in approximately half of this patient population, notably in the context of organ failure or resistance to endocrine therapy. 2 Werutsky G Reinert T Rosa ML Barrios CH Real-world data on first-line systemic therapy for hormone receptor-positive HER2-negative metastatic breast cancer: a trend shift in the era of CDK 4/6 inhibitors. Clin Breast Cancer. 2021; 21: e688-e692 Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar , 3 Jacquet E Lardy-Cléaud A Pistilli B et al. Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients. Eur J Cancer. 2018; 95: 93-101 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar In these patients, chemotherapy is frequently stopped, despite disease stabilisation, because of acute and cumulative toxic effects. 4 Giuliano M Schettini F Rognoni C et al. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019; 20: 1360-1369 Summary Full Text Full Text PDF PubMed Scopus (66) Google Scholar Switching to maintenance endocrine therapy after first-line induction chemotherapy has been proposed to improve disease control and to maintain quality of life (QOL). Switch maintenance therapy is regularly used in clinical practice, 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar , 3 Jacquet E Lardy-Cléaud A Pistilli B et al. Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients. Eur J Cancer. 2018; 95: 93-101 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar although clinical trials attesting to its relevance are scarce. 5 Ren W Yu Y Hong H et al. Clinical evidence of chemotherapy or endocrine therapy maintenance in patients with metastatic breast cancer: meta-analysis from randomized clinical trials and propensity score matching of multicentre cohort study. Cancer Res Treat. 2022; (published online Feb 4.)https://doi.org/10.4143/crt.2021.698 Crossref PubMed Google Scholar Moreover, the first-line combination of bevacizumab (an anti-angiogenic monoclonal antibody) plus chemotherapy has been shown in clinical trials to improve progression-free survival, although its effect on overall survival remains controversial. 6 Miyashita M Hattori M Takano T Toyama T Iwata H Risks and benefits of bevacizumab combined with chemotherapy for advanced or metastatic breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer. 2020; 27: 347-354 Crossref PubMed Scopus (7) Google Scholar These results have led to the consideration of this combination as an acceptable first-line strategy. 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar Similarly, bevacizumab plus endocrine therapy is efficacious in improving progression-free survival and overall survival while being well tolerated as a first-line treatment for advanced or metastatic breast cancer. 7 Martín M Loibl S Hyslop T et al. Evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for hormone receptor-positive metastatic breast cancer: a pooled analysis from the LEA (GEICAM/2006–11_GBG51) and CALGB 40503 (Alliance) trials. Eur J Cancer. 2019; 117: 91-98 Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar Switch maintenance endocrine therapy plus bevacizumab after bevacizumab plus paclitaxel in advanced or metastatic oestrogen receptor-positive, HER2-negative breast cancer (BOOSTER): a randomised, open-label, phase 2 trialSwitch to maintenance endocrine therapy plus bevacizumab with the possibility of weekly paclitaxel reinduction if needed is an efficacious alternative, with a better safety profile, to continuing weekly paclitaxel plus bevacizumab in patients with ER-positive, HER2-negative advanced or metastatic breast cancer who have responded to induction therapy. Full-Text PDF

Management of patients with hormone receptor-positive HER2-negative metastatic breast cancer: data of randomized trials and real-world evidence.

The Satellite Symposium of Novartis Pharma was held on January 28th,2022, within the framework of the RUSSCO Big Conference "Breast Cancer". It was dedicated to the diagnostics and treatment of patients with hormone receptor-positive HER2-negative advanced breast cancer (HR+/HER2- aBC). The information concerning two new observational studies was showed during the symposium: the retrospective analysis of the sequence of BC patients treatment in Moscow and the PROSPERITY study. The preliminary results of the data analysis concerning Moscow patients with breast cancer indicated the widespread practice of using endocrine therapy as an early-line treatment for HR+/HER2- aBC. Special attention was paid to new data concerning the use of Piqray (alpelisib) for the treatment of HR+/HER2- aBC with a PIK3CA mutation. The review of new results obtained in clinical trials and in clinical practice of the Loginov Moscow Clinical Research Center (Moscow) was made. The obtained data results indicate that alpelisib in combination with fulvestrant is effective after disease progression on CDK4/6 inhibitors, regardless of the duration of prior CDK4/6i therapy, as well as in patients who previously received fulvestrant. The duration of alpelisib treatment can be prolonged due to the competent approach to prevent and to control the adverse events.

Progression-free survival on endocrine therapy, before or after chemotherapy, in hormone receptor-positive HER2-negative metastatic breast cancer.

A major question when treating HR+/HER2- metastatic breast cancer (MBC) is whether early introduction of chemotherapy (CT) increases endocrine resistance. We aimed to describe progression-free survival (PFS) under first endocrine therapy (ET) depending on whether given before or after CT in a large nationwide cohort, in the pre-CDK era. The real-life retrospective ESME database includes all patients with MBC whose first-line treatment was initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. Our primary objective was to compare PFS from start of first ET in patients with HR+/HER2- MBC who received ET or CT first. We identified 6293 patients who received at least one ET line during their first two therapeutic lines for MBC. As first-line therapy, 3832 (60.9%) received ET alone (ET1 1st group), whilst 2461 (39.1%) received CT, including 2024 patients (32.2%) with maintenance ET after CT (ET1 after CT group). Median PFS under first ET was 12.4months (95% CI 11.9-13.1) in ET 1st group vs. 12.6months in ET1 after CT group (95% CI 12.1-13.4), HR 0.96 (95% CI 0.90-1.01, P = 0.1277). PFS under first ET appears identical whether prescribed before or after chemotherapy. These data suggest chemotherapy does not promote endocrine resistance.

Chemotherapy or endocrine therapy, first-line treatment for patients with hormone receptor-positive HER2-negative metastatic breast cancer in China: a real-world study.

BackgroundAlthough endocrine therapy (ET) is the preferred option for hormone receptor-positive HER2-negative metastatic breast cancer (HR+/HER2– MBC), chemotherapy (CT) is still commonly used. The objective of this real-world study was to present the actual choice of first-line treatment for patients with HR+/HER2– MBC and evaluate the consistency with guidelines in China.MethodsPatients with HR+/HER2– MBC between 1996 and September 2018 were identified from of the database of Chinese Society of Clinical Oncology Breast Cancer (CSCO BC). The statistical description was conducted to present the first-line treatment. Factors influencing the prescription of ET or CT were obtained using univariate and multivariate analysis. The consistency of the actual treatment with the guideline of Chinese Society of Clinical Oncology Breast Cancer (CSCO BC guideline) was evaluated.ResultsOf 1,877 patients, 662 (35.3%) received ET, and 1,215 (64.7%) received CT. ET proportion was only 25.4% in 1996–2005 and gradually increased to 44.6% in 2016–2018. Aromatase inhibitors (69% of ET) and taxane-based regimens (66% of CT) were the most commonly used ET and CT, respectively. Univariate and multivariate analysis showed that patients with age ≥60, distant relapse-free interval (DRFI) ≥24 months, ER+/PR+, bone metastasis only, or progression on (neo)adjuvant ET were preferably chosen for ET as first-line treatment. Factors associated with preferring CT were de novo stage IV, liver or lung metastasis. 17.2% of patients (322 cases) who had neither visceral metastasis nor progression on (neo)adjuvant ET wrongly received CT instead of ET, which is inconsistent with CSCO BC guideline. More than half of patients receiving CT discontinued their initial treatment due to adverse events and other non-disease progression reasons.ConclusionsAlthough high proportion of HR+/HER2– MBC patients received CT as first-line treatment in China, it is gratifying to see that the proportion of patients receiving ET has gradually increased. Our study revealed that 17.2% of patients were over-treated according to CSCO BC guideline, which may provide data to promote guideline adherence. The clinical application for ET should be appropriately expanded in first-line treatment, especially for patients without visceral disease and proof of endocrine resistance.

Abstract PS13-49: Effectiveness of platinum-based chemotherapy for hormone receptor-positive HER2-negative metastatic breast cancer

Abstract Background: Platinum-based chemotherapy (CT) regimens have activity in triple-negative breast cancer (TNBC), with overall response rates around 50%. The evidence for activity of these regimens for hormone receptor (HR)-positive breast cancer is scarce. We aimed to evaluate the effectiveness of platinum-based CT for HR-positive HER2-negative metastatic breast cancer. Methods: We evaluated, retrospectively, electronic medical records of patients with HR-positive HER2-negative metastatic breast cancer who have received, at least, 1 dose of platinum-based CT in the metastatic setting from Jan/2015 to May/2020 in a single cancer center. Data on clinical and demographic features, treatment, and outcomes were collected. The primary study endpoint was the clinical benefit rate at 3 months. Secondary endpoints were overall response rate, progression-free survival (PFS), overall survival (OS), and prognostic factors. Results: 244 patients were included. All patients were female, with a median age of 51.5 years, 59% were premenopause, 32.8% were metastatic at diagnosis, and 63.5% had ECOG-PS 0-1 by the time of platinum-based CT initiation. Although tests for hereditary breast and ovarian cancer were not available, 41% of patients met criteria for hereditary cancer testing. Most patients had invasive ductal carcinoma (90.2%), estrogen receptor &amp;gt;10% positive (92.2%), and progesterone receptor &amp;gt;10% positive (69.7%). Main sites of metastatic disease were bone (76.2%), lymph nodes (59.4%), lung (52.9%), and liver (62.7%). The majority of patients had received previous palliative systemic therapy before platinum-based CT; 36.5% had not received previous palliative endocrine therapy (ET), and 30.7% had not received previous palliative chemotherapy. The preferred platinum-based CT regimen was cisplatin plus gemcitabine (68.8%), and a small proportion received single-agent platinum-based CT (14.3%). Forty-three patients (17.7%) started platinum-based CT during hospitalization. Grade 3-4 treatment-related toxicities occurred in 40.9% of the patients. The clinical benefit rate at 3 months was 41.2% in the overall population, 46.7% when platinum-based CT was used as first-line CT, and 38.6% when used as subsequent CT line. Overall response rate was 26.7% in first-line platinum-based CT and 18.1% in subsequent CT line. Median PFS and OS were 3.2 months (95% CI 2.8 - 3.8) and 8.6 months (95% CI 6.8 - 9.9), respectively. One-year OS rate was 37.1% (95% CI 30.5 - 43.7%). Factors associated with worse OS were ECOG-PS 3-4 (HR 1.85, 95% CI 1.21-2.82, P=0.004), presence of liver metastases (HR 1.61, 95% CI 1.16-2.23, P=0.004), and platinum-based CT initiation during hospitalization (HR 1.74, 95% CI 1.18-2.56, P=0.005). Conclusion: Despite some activity of platinum-based CT for HR-positive HER2-negative metastatic breast cancer, especially as first-line CT, response rates were lower than historically observed in TNBC. Platinum-based CT was associated with poor PFS and OS outcomes. Negative prognostic factors for OS were ECOG-PS 3-4, presence of liver metastases, and initiation of the platinum-based CT during hospitalization. Citation Format: Lucas Fernando Uratani, Francesco Sansone Bermejo, Pedro HenriqueShimiti Hashizume, Renata Colombo Bonadio, Laura Testa. Effectiveness of platinum-based chemotherapy for hormone receptor-positive HER2-negative metastatic 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 PS13-49.

Patterns of treatment with everolimus exemestane in hormone receptor-positive HER2-negative metastatic breast cancer in the era of targeted therapy

BackgroundThere is currently no clinical trial data regarding the efficacy of everolimus exemestane (EE) following prior treatment with CDK4/6 inhibitors (CDK4/6i). This study assesses the use and efficacy of everolimus exemestane in patients with metastatic HR+ HER2− breast cancer previously treated with endocrine therapy (ET) or endocrine therapy + CDK4/6i.MethodsRetrospective analysis of electronic health record-derived data for HR+ HER2− metastatic breast cancer from 2012 to 2018. The proportion of patients receiving EE first-line, second-line, or third-line, and the median duration of EE prior to next line of treatment (TTNT) by line of therapy was calculated. OS for patients receiving EE first-line, second-line, or third-line, indexed to the date of first-line therapy initiation and stratified by prior treatment received, was calculated with Kaplan-Meier method with multivariable Cox proportional hazards regression analysis.ResultsSix hundred twenty-two patients received EE first-line (n = 104, 16.7%), second-line (n = 273, 43.9%) or third-line (n = 245, 39.4%). Median TTNT was 8.3 months, 5.5 months, and 4.8 months respectively. Median TTNT of EE second-line was longer following prior ET alone compared to prior ET + CDK4/6i (6.2 months (95% CI 5.2, 7.3) vs 4.3 months (95% CI 3.2, 5.7) respectively, p = 0.03). Similarly, EE third-line following ET alone vs ET + CDK4/6i in first- or second-line resulted in median TTNT 5.6 months (95% CI 4.4, 6.9) vs 4.1 months (95% CI 3.6, 6.1) respectively, although this was not statistically significant (p = 0.08). Median OS was longer for patients who received EE following prior ET + CDK4/6i. EE second-line following ET + CDK 4/6i vs ET alone resulted in median OS 37.7 months vs. 32.7 months (p = 0.449). EE third-line following ET + CDK4/6i vs prior ET alone resulted in median OS 59.2 months vs. 40.8 months (p < 0.010). This difference in OS was not statistically significant when indexed to the start of EE therapy.ConclusionThis study suggests that EE remains an effective treatment option after prior ET or ET + CDK4/6i use. Median TTNT of EE was longer for patients who received prior ET, whereas median OS was longer for patients who received prior ET + CDK4/6i. However, this improvement in OS was not statistically significant when indexed to the start of EE therapy suggesting that OS benefit is primarily driven by prior CDK4/6i use. EE remains an effective treatment option regardless of prior treatment option.

C-myc regulates the sensitivity of breast cancer cells to palbociclib via c-myc/miR-29b-3p/CDK6 axis

Palbociclib, a CDK4/6 inhibitor, has been granted accelerated approval by US FDA for hormone receptor-positive HER2-negative metastatic breast cancer. To determine potential biomarkers of palbociclib sensitivity to assist in patient selection and clinical development, we investigated the effects of palbociclib in a panel of molecularly characterized breast cancer cell lines. We quantified palbociclib sensitivity and c-myc expression in 11 breast cancer cell lines, 124 breast cancer samples, and The Cancer Genome Atlas database. We found non-TNBC subtypes were more sensitive to palbociclib than TNBC. Activation of c-myc led to differential palbociclib sensitivities, and further inhibition of c-myc enhanced palbociclib sensitivity. Moreover, we identified for the first time a c-myc/miR-29b-3p/CDK6 axis in breast cancer that could be responsible for c-myc-induced palbociclib insensitivity, in which c-myc activation resulted in downregulation of miR-29b-3p, further activated CDK6 and inhibited cell-cycle arrest at G1 phase. Moreover, downregulated (inactived) c-myc-induced oncogenic addiction could increase palbociclib efficacy, using both Xenograft model and patient-derived tumor xenograft (PDTX) model. Our finding extends the concept of combined blockade of the CDK4/6 and c-myc signaling pathways to increase palbociclib sensitivity, making c-myc a promising biomarker for palbociclib sensitivity in breast cancer.

Role of palbociclib in the treatment of hormone receptor-positive HER2-negative metastatic breast cancer. Generalizing results of randomized trials and real clinical practice

Palbociclib is the first-in-class drug of CDK 4/6 inhibitors group. The use of palbociclib in combination with endocrinotherapy (ET) opens up new possibilities for the treatment of metastatic hormone receptor-positive (HRP+) HER2-negative (HER2-) breast cancer (mBC). Palbociclib has gained world attention and is included in all clinical guidelines, both international and domestic, as a new standard of first- and second-line therapy of HRP+ HER2- mBC. The article presents the updated results of PALOMA-2 and PALOMA-3 studies and the results of use of palbociclib in combination with ET in real clinical practice.

CLO19-059: A Systematic Review and Meta- Analysis of Randomized Controlled Trials to Evaluate the Risk of Health-Related Quality of Life Events in Patients With Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Treated With CDK 4/6 Inhibitors

Background: Pain, fatigue, hot flushes, and rash significantly contribute to quality of life in breast cancer patients undergoing chemotherapy. Hormone receptor-positive breast cancer is a common entity among women worldwide. In cancer cells, CDK4/6 activity is over expressed, which can lead to amplification or overexpression of the genes encoding for CDK 4/6 or the cyclin D, ultimately leading to endocrine therapy resistance. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of health-related quality of life (HRQOL) events associated with CDK 4/6 inhibitors. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018. RTCs that mention HRQOL events as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95%CI. Random effects model was applied. Results: 8 RCTs (7 phase III and 1 phase II) with a total of 4,557 patients were eligible. The study arms used palbociclib/ribociclib/abemaciclib with letrozole or anastrozole or fulvestrant or other hormonal agent while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agent. The RR of all-grade side effects were as follows: fatigue, 1.226 (95% CI: 1.079–1.393; P=.002); back pain, 0.971 (95% CI: 0.844–1.117; P=.681); arthralgia, 0.978 (95% CI: 0.830–1.152; P=.790); headache, 1.046 (95% CI: 0.928–1.179; P=.459); alopecia, 2.635 (95% CI: 1.966–3.533; P&lt;.001); hot flushes, 0.901 (95% CI: 0.766–1.060; P=.210); and rash, 2.068 (95% CI: 1.604–2.666; P&lt;.001). The RR of high-grade side effects were as follows: fatigue, 3.487 (95% CI: 1.765–6.889; P&lt;.001); back pain, 1.364 (95% CI: 0.695–2.679; P=.367); arthralgia, 1.148 (95% CI: 0.509–2.593; P=.740); headache, 0.807 (95% CI: 0.303–2.147; P=.667); and rash, 3.018(95% CI: 0.954–9.554; P=.060). Conclusions: Our study showed that the risk of developing all grades of fatigue and any-grade alopecia and rash was significantly with CDK 4/6 inhibitors. Prompt intervention with good supportive care is required.

CLO19-052: Incidence of Ribociclib-Associated Cardiac Conduction Abnormalities in Patients With Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer: A Combined Analysis of 3 Phase III Randomized Controlled Trials

Introduction: Ribociclib, a cyclin-dependent kinase 4/6 inhibitor, has improved survival in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER 2)-negative advanced breast cancer. Despite remarkable efficacy, potential cardiac toxicities remain a concern. We undertook a combined analysis of randomized controlled trials (RCT) to estimate the incidence of prolongation of corrected QT interval (QTcF) associated with ribociclib. Methods: We performed systematic search of Embase, MEDLINE, and meeting abstracts till September 30, 2018, to find all phase 3 RCTs comparing ribociclib with other agents or placebo in patients with advanced breast cancer and reporting QTc prolongation as adverse event. Mantel-Haenszel method was used to calculate the pooled risk ratio (RR) and absolute risk difference (RD) with 95% CI. Fixed effects model was applied. Heterogeneity was assessed using I2 statistic. Results: Three phase III studies with 2,062 participants were included. Randomization ratio was 1 to 1 in MONALEESA-2 and 7 studies and 2 to 1 in MONALEESA-3 study. I2 statistic was 0, suggesting homogeneity across studies. Prolongation of QTcF &gt;60 msec from baseline was observed in 72 patients (61 had post-baseline QTcF &gt;480 msec) in ribociclib arm, compared to 7 in control arm. Pooled RR for prolongation of QTcF was 7.956 (95%CI: 3.683–17.187; P&lt;.001) and RD was 0.055 (95%CI: 0.040–0.070; P&lt;.001). The risk of having a post-baseline QTcF &gt;480 msec was significantly higher with ribociclib vs control (pooled RR, 4.002; 95%CI: 2.161–7.412; P&lt;.001; and RD, 0.039; 95%CI: 0.024–0.055; P&lt;.001). A total of 16 (1.38%) patients in the ribociclib arm had dose reduction, interruption, or discontinuation due to QTcF prolongation, as opposed to 3 (0.33%) in control arm. Pooled RR and RD were statistically significant at 4.204 (95%CI: 1.333–3.260; P=.014) and 0.012 (95%CI: 0.004–0.021; P=.006), respectively. Conclusion: Advanced breast cancer patients may have cardiac dysfunction due to prior cardiotoxic chemotherapies. In our meta-analysis, ribociclib was associated with significantly higher risk of QTc prolongation and the resultant dosing inconsistencies and discontinuation. Early detection of this potential adverse event and timely intervention are critical.

Abstract P1-16-04: Risk of venous thromboembolism with abemaciclib based regimen versus other CDK 4/6 inhibitor containing regimens in patients with hormone receptor-positive HER2-negative metastatic breast cancer

Abstract Background: Approximately 70% of patients with metastatic breast cancer (MBC) are hormone receptor (HR) - positive and the cyclin dependent kinases (CDK) along with their D-type cyclin catalysts, have been shown to play a role in mediating the resistance to endocrine therapy. Several CDK-targeted agents have been recently approved by FDA. Nevertheless, the risk of venous thromboembolism (VTE) with the use of different CDK 4/6 inhibitors has never been reported. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of VTE with abemaciclib based regimens versus other CDK 4/6 inhibitor containing regimens in patients with HR-positive HER2-negative MBC. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through February 2018. The randomized controlled trials that mention deep vein thrombosis and pulmonary embolism as adverse effects of CDK 4/6 inhibitor therapy were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR) and risk difference (RD) with 95% confidence interval (CI). Results: Five phase 3 studies and one phase 2 study with a total of 3,159 patients with HR-positive HER2-negative MBC were eligible for analysis. The study arms used palbociclib-letrozole, palbociclib-fulvestrant, ribociclib-letrozole, abemaciclib-fulvestrant, and abemaciclib-nonsteroidal aromatase inhibitors (either letrozole or anastrozole) while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant. The randomization ratio was 2 to 1 in PALOMA-2, PALOMA-3, MONARCH-2 and MONARCH-3 studies and 1 to 1 in PALOMA-1 and MONALEESA-2 trials. CDK 4/6 inhibitors were utilized as first line treatment in PALOMA-1, PALOMA-2, MONALEESA-2 and MONARCH-3. The I2 statistic for heterogeneity was 0, and the heterogeneity X2 (Cochran's Q) was 1 (P= 0.707), suggesting homogeneity among RCTs. The VTE incidence was 25 (3.255%) in the abemaciclib group vs 2 (0.520%) in the control group. The pooled relative risk for VTE was 6.222 (95% CI: 1.481 – 26.145, P = 0.013) and the absolute RD was 0.027 (95% CI: 0.013 – 0.042, P &amp;lt; 0.0001). In other CDK 4/6 inhibitor containing regimens, the VTE incidence was reported at 15 (1.243%) vs 2 (0.374%) in the control arm. The pooled RR for VTE was 2.312 (95% CI: 0.852 –6.272, P = 0.100) and the absolute RD was 0.008 (95% CI: - 0.000 – 0.017, P = 0.259). Conclusion: VTE is a major cause of morbidity and mortality and is particularly common in patients with breast cancer. Our meta-analysis demonstrated that the addition of abemaciclib to endocrine therapy notably contributed to a higher incidence of VTE with a relative risk of 6.22. However, no significant increase in the risk of VTE was noted in other CDK 4/6 inhibitor-based regimen. More randomized trials are required to determine the actual relation and definitive incidence of VTE among different CDK-targeted agents when added to endocrine therapy. Citation Format: Thein KZ, Ball S, Zaw MH, Quirch M, Hardwicke F, Awasthi S, Oo TH, Jones C. Risk of venous thromboembolism with abemaciclib based regimen versus other CDK 4/6 inhibitor containing regimens in patients with hormone receptor-positive HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-16-04.

Cyclin-dependent kinase 4/6 inhibitors: what have we learnt across studies, therapy situations and substances.

Cyclin-dependent kinases (CDK) are key regulatory enzymes that control cell cycle and cell division. In the recent years, new therapeutic options selectively targeting CDK 4 and 6 have shown promising clinical activity in several solid tumors. Since 2015, three CDK 4/6 inhibitors have been approved for treatment of hormone receptor-positive HER2-negative metastatic breast cancer: palbociclib, ribociclib and abemaciclib. These drugs share a common mechanism of action and have been evaluated in studies with a similar design. The following review gives a clinical overview of the CDK 4/6 inhibitors in breast cancer therapy and highlight current study data with regard to their antitumor efficacy and toxicities. In clinical trials in the first-line and later-line setting, palbociclib, ribociclib and abemaciclib in combination with endocrine therapy significantly prolonged progression-free survival. The most common adverse events during treatment with CDK 4/6 inhibitors are neutropenia, fatigue and gastrointestinal symptoms. CDK 4/6 inhibitors represent a valuable treatment option for patients with metastatic hormone receptor-positive HER2-negative breast cancer. Although the clinical efficacy of the three agents seems similar, their toxicity profiles differ. Therefore, the choice of a CKD 4/6 inhibitor depends on patient's characteristics and individual preferences. In the video, the author describes the content of the review and present the main topics discussed in the article (http://links.lww.com/COOG/A44).