Hormone Receptor-positive Advanced Breast Cancer Research Articles

Prognostic Factors for Overall Survival in Patients with Hormone Receptor-Positive Advanced Breast Cancer: Analyses From PALOMA-3.

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

18F]-Fluorodeoxyglucose Positron Emission Tomography/CT to Assess the Early Metabolic Response in Patients with Hormone Receptor-Positive HER2-Negative Metastasized Breast Cancer Treated with Cyclin-Dependent 4/6 Kinase Inhibitors

Introduction: Addition of cyclin-dependent 4/6 kinase (CDK4/6) inhibitors to endocrine therapy is standard of care in the treatment of women with advanced hormone receptor-positive HER2-negative breast cancer. However, the predictive factors for the treatment response to CDK4/6 inhibitor therapy are poorly elucidated. Early changes in the by [¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) uptake of tumors receiving different kinds of therapy have proven to reliably predict treatment outcomes in a variety of malignancies. Therefore, the feasibility of early metabolic response assessment to predict the long-term treatment response to CDK4/6 inhibitor therapy was evaluated in the present study. Methods: Eight patients underwent FDG-PET/CT before and after the initiation of CDK4/6 inhibitor therapy (ribociclib, palbociclib or abemcaciclib). CDK4/6 inhibitor therapy was combined with either aromatase inhibition or fulvestrant. The median interval between the treatment start (including baseline PET) and the follow-up PET examination was 14 days. Conventional radiographic staging was performed 3 months after the start of CDK4/6 inhibitor therapy. The percentual changes in molecular tumor volume, SUV_peak, the summed SUV_peak of up to 5 metastases (PERCIST-5), and total lesion glycolysis (TLG) were calculated for each patient. Results: Three patients showed progressive disease after 3 months of CDK4/6 inhibitor therapy, whereas 5 patients showed disease control (3 stable disease and 2 partial remission). Disease control was maintained in these patients (follow-up range 7–22 months). Patients with disease control had a significantly greater decline in TLG (–55.3 vs. 16.7%; p < 0.05). The same was true for the PERCIST-5 (–21.9 vs. 11.3%, p < 0.05). All patients with progressive TLG showed treatment failure and/or a poor outcome. Conclusion: Elevated TLG on early FDG-PET seems to be associated with long-term treatment failure and a poor outcome in patients undergoing CDK4/6 inhibitor therapy for metastatic breast cancer. Early findings indicate a potential prognostic value of early FDG-PET in this setting and warrant a prospective evaluation.

Everolimus and exemestane in hormone receptor-positive advanced breast cancer: A comprehensive cancer center’s experience.

e13017 Background: Activation of the mammalian target of rapamycin intracellular signaling pathway is one of the mechanisms of endocrine resistance in breast cancer. The addition of everolimus to exemestane improves progression-free survival (PFS) in patients with hormone receptor positive (HR+) advanced breast cancer (ABC) previously treated with nonsteroidal aromatase inhibitors (NSAIs). The aim of this study was to assess the effectiveness and safety of everolimus plus exemestane in patients with HR+ ABC. Methods: We retrospectively evaluated patients with HR+, HER2 negative ABC treated with everolimus/exemestane that recurred or progressed during/after treatment with NSAIs in a portuguese comprehensive cancer center. Study endpoints were PFS, overall survival (OS), overall response rate and adverse events. Results: Between April 2014 and September 2020, 63 female patients were treated with everolimus/exemestane. Median age was 59 years (36-79), and all had performance status ECOG ≤2. Seventeen (27.0%) patients had bone metastasis alone, 39 (61.9%) had bone and visceral metastasis, 25 (39.7%) had metastasis in 3 or more sites and 87.3% had previous hormone-sensitive disease. Before everolimus/exemestane, 61 (96.8%) patients were being treated with palliative endocrine therapy (alone or in combination with CDK4/6 inhibitors) or chemotherapy (ChT) and 2 (3.2%) patients were under adjuvant endocrine therapy. Median follow-up time was 12.8 months (1.4-74.6), with 39 patients alive. Overall response rate was 14.3% (1 complete response and 8 partial responses) and 45 patients had stable disease. Median PFS was 5.6 months (CI95% 2.4-8.8) and median OS was 25.4 months (CI95% 10.3-40.5). Subgroup analysis regarding PFS was statistically significant for previous treatment with CDK4/6 inhibitors (p = 0.026) and for site of metastasis (p = 0.025). In the subgroup of patients that previously underwent palliative ChT, median PFS was 4.0 months (CI95% 0.2-9.6) and median OS was 18.6 months (CI95% 8.2-29.0). For patients that did not receive previous palliative ChT, median PFS was 5.8 months (CI95% 3.8-7.8) and median OS was 43.5 months (CI95% 2.0-85.0). Grade 3 and 4 adverse events occurred in 21 (33.3%) patients, and were: nausea, anorexia, rash, headache, haematologic toxicity, hepatic cytolysis, hyperglycaemia, pneumonitis, oral mucositis and acute kidney failure with need for haemodialysis. Fifty-five (87.3%) patients suspended everolimus, 34 (54.0%) due to disease progression and 21 (33.3%) due to toxicity. Conclusions: Our results confirm the effectiveness and safety of everolimus/exemestane in real-world setting and support its use mainly before palliative ChT. Everolimus/exemestane in HR+ ABC is feasible in the clinic, with toxicity manageable under close surveillance.

Abstract GS4-02: E2112: Randomized phase 3 trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group

Abstract Background: Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with use of histone deacetylase (HDAC) inhibitors such as entinostat. The ENCORE 301 randomized phase II study reported an improvement in progression-free (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer. Protein lysine acetylation in peripheral blood mononuclear cells (PBMCs) was associated with prolonged PFS in the entinostat arm. Methods: E2112 is a multicenter randomized double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease had progressed on a non-steroidal AI in the adjuvant or metastatic setting (NCT02115282). Study participants were also required to have an ECOG performance status 0-1 with measurable or non-measurable (limited to 20% of the study population) disease. One prior chemotherapy for metastatic disease and prior treatment with fulvestrant and a CDK4/6 inhibitor was permitted but not required. Participants received exemestane 25mg po daily and entinostat (EE)/placebo (EP) 5mg po every week. Primary endpoints were PFS (central review) and OS. One-sided type 1 error 0.025 was split between two hypothesis tests: 0.001 for PFS test and 0.024 for OS. PFS tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS, 4.1 to 7.1 months); OS tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS, 22 to 29.3 months). Secondary endpoints included safety, objective response rate (ORR), and changes in protein lysine acetylation status in PBMCs (CD3+ T cells, CD14+ monocytes, CD19+ B cells, pan-leukocyte marker CD45+ cells, CD56+ NK cells) between C1D1 and C1D15 (integrated biomarker). Results: A total of 608 participants were randomized between March 2014 and October 2018 (305 EE, 303 EP), 98% enrolled in USA. Characteristics were well balanced between the arms. Median age was 63 years (range, 29-91), 99% female, 95% postmenopausal, 80% white and 15% black. A majority (84%) had disease resistant to AI in the metastatic setting at study entry, 78% had measurable disease and 60% visceral disease. Prior treatments included chemotherapy (60%), fulvestrant (30%), CDK4/6 inhibitor (35%), everolimus (3%). Median prior lines of chemotherapy was 1 (range, 0-4) and endocrine therapy was 2 (range, 1-7); in adjuvant/metastatic setting. Grade 3/4 adverse events in EE arm included neutrophil count decreased (20%), hypophosphatemia (14%), anemia (8%), white blood cell decreased (6%), fatigue (4%), diarrhea (4%), and platelet count decreased (3%). At final analysis, median PFS was 3.3 months (EE) versus 3.1 months (EP) (HR=0.87, 95% CI: 0.67, 1.13, p=0.30). Median OS was 23.4 months (EE) versus 21.7 months (EP) (HR=0.99, 95% CI: 0.82, 1.21, p=0.94). ORR was 4.6% (EE) and 4.3% (EP). The median fold change in lysine acetylation in PBMCs was approximately 1.5 in EE arm, and 1 in EP arm. Participants on EE had significantly higher increase in lysine acetylation by C1D15 than patients on EP (397 paired samples available for analysis, p&amp;lt;0.001 for all). Additional biomarker analyses will be presented at time of meeting. Conclusion: The combination of exemestane and entinostat did not improve survival in AI resistant advanced HR-positive, HER2-negative breast cancer. Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. Citation Format: Roisin M Connolly, Fengmin Zhao, Kathy D Miller, Min-Jung Lee, Richard L Piekarz, Karen L Smith, Ursa Brown-Glaberman, Jennifer S Winn, Bryan A Faller, Adedayo A Onitilo, Mark E Burkard, George T Budd, Ellis G Levine, Melanie E Royce, Peter A Kaufman, Alexandra Thomas, Jane B Trepel, Antonio C Wolff, Joseph A Sparano. E2112: Randomized phase 3 trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group [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 GS4-02.

Abstract PS5-06: Prospective testing for PIK3CA/AKT1/PTEN alterations in tumor tissue from 1440 patients with advanced hormone receptor-positive HER2-negative breast cancer (HR+/HER2- BC) or triple-negative breast cancer (TNBC) screened for the IPATunity130 randomized phase 3 trial

Abstract Background The PI3K/AKT signaling pathway plays a significant role in both HR+ BC and TNBC. IPATunity130 is a double-blind, placebo-controlled, randomized phase 3 trial of ipatasertib in combination with paclitaxel in patients with PI3K/AKT1/PTEN-altered HR+ or TNBC. A next-generation sequencing (NGS)-based assay from Foundation Medicine Inc. (FMI) was used to select patients prospectively for enrollment in this trial.Patients and methods An investigational clinical trial assay (CTA) of a composite 3-gene biomarker signature [Kim, Lancet Oncol 2017] based on the FoundationOne® CDx assay was used to identify patients with PI3K/AKT pathway-activated tumors as eligible for enrollment in IPATunity130 (NCT03337724). Qualifying alterations for the 3-gene signature (referred to as ‘biomarker-positive’) comprised activating mutations in PIK3CA and/or AKT1, and/or loss of function (LOF) alterations in PTEN represented by homozygous or heterozygous deletions, dominant-negative mutations, or inactivating mutations under loss of heterozygosity. Study sites were required to submit formalin-fixed paraffin-embedded archival or fresh biopsy tissue derived from primary or metastatic tumors for patient screening. IPATunity130 includes three independent cohorts: Cohort A (biomarker-positive TNBC); Cohort B (biomarker-positive HR+/HER2– BC); and Cohort C (biomarker-negative TNBC). Results In total, 1736 patients were screened, from whom 1690 samples were tested by FMI. Of these, 1475 (87%) produced a valid NGS result. The remaining 215 (13%) failed quality control for reasons including insufficient tissue, DNA yield, lab error, and computational failure. Alteration status for PIK3CA and/or AKT1 and/or PTEN was positive in 703 (49%) of 1440 CTA-evaluable samples. In the HR+/HER2– cohort, the breakdown of CTA-positive samples was 301/356 (85%) PIK3CA/AKT1 mutations and 86/356 (24%) PTEN LOF alterations. In TNBC, 183/347 (53%) had PIK3CA/AKT1 mutations and 193/347 (56%) had PTEN LOF alterations. CTA results according to baseline characteristics are shown overall and by subtype below. The most common mutations detected outside the 3-gene biomarker signature in the screened population were in the TP53, BRCA1, RB1, BRCA2, and NF1 genes in the TNBC cohort and the TP53, GATA3, CDH1, MAP3K1, and ESR1 genes in the HR+/HER2– cohort. In the HR+/HER2– cohort, 30 (14%) of 213 metastatic tumors had ESR1 mutations compared with 10/414 (2%) primary tumors. Tumor BRCA1 mutations were more common in patients aged ≤50 years whereas MAP3K1 mutations were more common in those aged &amp;gt;50 years.Conclusions IPATunity130 is the first reported pivotal trial to utilize the 3-gene biomarker CTA in HR+/HER2– BC and TNBC to screen for patients with PI3K/AKT pathway-activated tumors. The 3-gene biomarker CTA detected alterations in 49% of screened patients, with a higher prevalence of PIK3CA/AKT1/PTEN alterations in HR+/HER2– BC than TNBC. Additional analyses are planned to assess correlations between clinical outcomes and tumor characteristics. SubgroupPIK3CA/AKT1/PTEN alteration, n/N (%)OverallHR+/HER2–TNBCAll patient samples703/1440 (49)356/647 (55)347/793 (44)Age, years≤50219/475 (46)99/195 (51)120/280 (43)&amp;gt;50484/965 (50)257/452 (57)227/513 (44)Sample sourcePrimary456/941 (48)232/414 (56)224/527 (43)Metastatic222/448 (50)112/213 (53)110/235 (47)Geographic regionNorth America60/102 (59)33/49 (67)27/53 (51)Asia-Pacific172/330 (52)81/145 (56)91/185 (49)Europe301/633 (48)171/310 (55)130/323 (40)Rest of world170/375 (45)71/143 (50)99/232 (43) Citation Format: Heidi Savage, Wendy Lin, Mafalda Oliveira, Carlos Barrios, Joyce O’Shaughnessy, Nicholas Turner, Rebecca Dent, Steven J Isakoff, Shigehira Saji, Qinshu Lian, Denise Bradley, Sarah-Jayne Reilly, Heather Hinton, Matthew J Wongchenko, Aruna Mani, Sung-Bae Kim. Prospective testing for PIK3CA/AKT1/PTEN alterations in tumor tissue from 1440 patients with advanced hormone receptor-positive HER2-negative breast cancer (HR+/HER2- BC) or triple-negative breast cancer (TNBC) screened for the IPATunity130 randomized phase 3 trial [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 PS5-06.

Abstract OT-26-04: Solti-1801. Analysis of the efficacy of CDK4/6 inhibitors in combination with hormonal treatment in luminal breast cancer in relation to the intrinsic subtype and markers of immunity (CDK-PREDICT)

Abstract Introduction. The incorporation of cyclin-dependent kinase inhibitors 4 and 6 (CDK4/6 inhibitors) with endocrine therapy in patients with advanced hormone receptor-positive (HR+) breast cancer and without overexpression of the HER2 (HER2-) oncogene has demonstrated its efficacy improving progression-free survival (PFS), overall response rate (ORR) and, more recently, overall survival (OS). However, patients eventually progress due to resistance to treatment. To date, no clinical or molecular markers defining the HR +/HER2- patient population that obtains the greatest benefit from these drugs have been found, apart from estrogen receptor positivity. However, there are data from multiple retrospective analysis suggesting that within HR+/ HER2- disease, the non-luminal intrinsic subtypes (20-30% of these patients) have a worse prognosis and may not benefit from CDK4/6 inhibitors. Furthermore, the prognostic impact of tumor infiltrating lymphocytes (TILs) and gene expression related to the immune response in the context of HR + / HER2- advanced breast cancer have not been deeply investigated. Design. CDK-PREDICT is an observational, non-interventional, multicenter study that will include 114 patients with advanced breast cancer who have received, are receiving or are going to receive endocrine therapy plus a CDK4/6 inhibitor for, at least, 8 weeks as first-line treatment. The primary objective is to correlate the intrinsic subtypes (defined by PAM50) with the efficacy (measured as PFS) of CDK4/6 inhibitors + hormone therapy. As secondary objectives, the correlation of the intrinsic subtypes with ORR and with the histopathological characteristics of the tumor will be analyzed. In addition, the expression of immune response and cell cycle genes, as well as the presence of TILs, will be correlated with the intrinsic subtypes and with PFS and ORR. Overall, we aim to develop a predictive score combining clinical, genomic and immune expression data integrating tumor biology and microenvironment. For inclusion in the study, a metastatic sample taken within 90 days prior to CDK4/6 inhibitors treatment will be required. Once this sample has been collected, registered and assessed for quality, patients will be followed up every 6 months until disease progression, death or withdrawal from the study. This project has received a research grant from “Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad” (Spain) awarded within the National Research Program with reference PI 18/01408, co-funded with European Union ERDF funds (European Regional Development Fund). This study is included within the Biomarker program of SOLTI. Recruitment of this study started in June 2020. Citation Format: Pablo Tolosa, Tomás Pascual, Cristina Hernando, Sonia Servitja, María Fernández Abad, Rafael Villanueva, Fernando Henao, Javier Benítez, Laura Lema, Mario Martínez, Yolanda Ruano, Lucía Parrilla, Alejandra Bernardini, Ana María Roncero, Laia Paré, Jordi Canes, Fernando Salvador, Patricia Villagrasa, Aleix Prat, Eva Ciruelos. Solti-1801. Analysis of the efficacy of CDK4/6 inhibitors in combination with hormonal treatment in luminal breast cancer in relation to the intrinsic subtype and markers of immunity (CDK-PREDICT) [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 OT-26-04.

Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer: A Nation-Wide Multicenter Epidemiological Study in China.

BackgroundClinical guidelines generally recommend endocrine therapy (ET) as first-line treatment of hormone receptor-positive advanced breast cancer (HR+ ABC) whereas chemotherapy (CT) should be considered in the presence of life-threatening disease or limited clinical benefit after three sequential ET regimens. However, it is unclear if real-world clinical practice is in accordance with the current guidelines. This study was to present the real-world treatment patterns and ET regimens among HR+ ABC patients in China.MethodsUsing data from the Nation-wide Multicenter Retrospective Clinical Epidemiology Study of Female Advanced Breast Cancer in China (ClinicalTrials.gov identifier: NCT03047889), we investigated the clinicopathological characteristics, clinical profiles, and treatment patterns of HR+ ABC patients from January 2012 to December 2014.ResultsA total of 2,342 patients with HR+ ABC were included in this study. Our findings revealed that, in comparisons with those receiving initial CT (n = 1445), patients initiated ET (n =402) were significantly older, later recurrent after adjuvant treatment, with a lower rate of visceral involvement and a decreasing quantity of metastatic sites. A total of 1,308 patients received palliative ET while only 18.9% patients (n = 247) reached three lines of ET. Among patients completing more than one line of ET, the median treatment duration was 8 months for the first line, 6 months for the second line, and 3 months for the third line for patients receiving ET. In the advanced setting, the choices of palliative ET regimens were diverse, yet aromatase inhibitor (AI) monotherapy was still the overall mainstay of ET; in contrast, patients were less accessible to everolimus plus AI regimen in this population.ConclusionsLess than one quarter of patients initiated palliative ET for HR+ ABC in routine clinical practice. Patients who received multi-lines of ET experienced successive shorter durations following each line of therapy. This real-life data provides a solid overview of ET for HR+ ABC from China, indicating unmet need for treatment options that improve the effectiveness of endocrine therapy.

Deregulated Immune Pathway Associated with Palbociclib Resistance in Preclinical Breast Cancer Models: Integrative Genomics and Transcriptomics.

Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been widely used to treat advanced hormone receptor-positive breast cancer. Despite promising clinical outcomes, almost all patients eventually acquire resistance to CDK4/6 inhibitors. Here, we screened genes associated with palbociclib resistance through genomics and transcriptomics in preclinical breast cancer models. Palbociclib-resistant cells were generated by exposing hormone receptor-positive breast cancer cell lines to palbociclib. Whole-exome sequencing (WES) and a mRNA microarray were performed to compare the genomic and transcriptomic landscape between both palbociclib-sensitive and resistant cells. Microarray analysis revealed 651 differentially expressed genes (DEGs), while WES revealed 107 clinically significant mutated genes. Furthermore, pathway analysis of both DEGs and mutated genes revealed immune pathway deregulation in palbociclib-resistant cells. Notably, DEG annotation revealed activation of type I interferon pathway, activation of immune checkpoint inhibitory pathway, and suppression of immune checkpoint stimulatory pathway in palbociclib-resistant cells. Moreover, mutations in NCOR1, MUC4, and MUC16 genes found in palbociclib-resistant cells were annotated to be related to the immune pathway. In conclusion, our genomics and transcriptomics analysis using preclinical model, revealed that deregulated immune pathway is an additional mechanism of CDK4/6 inhibitor resistance besides the activation of cyclin E-CDK2 pathway and loss of RB, etc. Further studies are warranted to evaluate whether immune pathways may be a therapeutic target to overcome CDK4/6 inhibitor resistance.

Meta-analyses of phase 3 randomised controlled trials of third generation aromatase inhibitors versus tamoxifen as first-line endocrine therapy in postmenopausal women with hormone receptor-positive advanced breast cancer.

Four randomised controlled trials (RCTs) in postmenopausal women with advanced breast cancer (ABC) comparing aromatase inhibitors (AIs) versus the selective estrogen receptor modulator tamoxifen, each individually reported significantly longer progression-free survival (PFS) but none showed a significant difference in overall survival (OS). In these trials between 6.8% and 55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. Anonymised individual patient data were obtained from three RCTs, EORTC (exemestane versus tamoxifen), Study 0027 and Study 0030 (both anastrozole versus tamoxifen). For the remaining RCT (Femara Study PO25; letrozole versus tamoxifen), odds ratio (OR) or hazard ratio (HzR), with confidence intervals were obtained from the clinical study report, for patients with HR+ tumours, in addition to published data. In total, data were obtained from 2296 patients; 1560 (68%) had HR+ ABC. The OR for clinical benefit rate was 1.56, in favour of AIs (p<0.001). The duration of clinical benefit was not significantly increased by AIs (HzR0·88; p=0.08). For PFS the HzR (0.82) was in favour of AIs (p=0·007). However, for OS the HzR (1.05) was not significantly different between AIs and tamoxifen (p=0.42). Although third generation AIs put significantly more patients into 'clinical benefit', their tumours were not controlled for significantly longer. Overall, while this resulted in a significantly greater PFS in favour of the AIs, this did not translate into improvement in OS.

Phase II trial of humanized anti-Lewis Y monoclonal antibody for advanced hormone receptor-positive breast cancer that progressed following endocrine therapy

OBJECTIVES:The Lewis-Y antigen is expressed in 44%-90% of breast cancers (BCs). The expression of the antigen in carcinoma tissue differs from that in normal tissues. This study aimed to evaluate the clinical benefit of the humanized anti-Lewis Y monoclonal antibody, hu3S193, in advanced hormone receptor-positive and Lewis Y-positive BC after administration of endocrine therapy (ET).METHODS:A single-arm phase II study was conducted in seven centers. Patients with advanced hormone receptor-positive BC who failed first-line ET were included. The inclusion criterion was the observation of tumoral expression of the Lewis Y antigen during immunohistochemistry. The treatment comprised hu3S193 antibody administration at weekly intravenous doses of 20 mg/m2 for 8-week cycles. The primary endpoint was the clinical benefit rate. ClinicalTrials.gov NCT01370239.RESULTS:The study stopped accrual following an unplanned interim analysis as the hu3S193 antibody lacked sufficient activity to justify continuation of the study. Twenty-two patients were enrolled, of whom 21 were included in the efficacy analysis. The clinical benefit rate was 19%, with four patients presenting with stable disease after 24 weeks. One patient with prolonged stable disease received medication for over 2 years. No partial or complete responses were observed. The median time to progression and overall survival was 5.4 and 37.5 months, respectively.CONCLUSIONS:The humanized anti-Lewis Y monoclonal antibody, hu3S193, exhibited insufficient activity in this cohort. However, the possibility of activity in a more strictly selected subgroup of patients with higher levels of Lewis Y tumoral expression cannot be overlooked.

P16 methylation is a potential predictive marker for abemaciclib sensitivity in gastric cancer

Cell cycle control is often disrupted in gastric cancer (GC), making it an attractive therapeutic target. Abemaciclib is a specific CDK4/6 inhibitor that has been shown to improve treatment efficacy in hormone receptor-positive advanced breast cancer; however, its potential therapeutic value and predictive markers have not yet been revealed in GC. In this study, we investigated the efficacy of abemaciclib using preclinical GC models representing defined molecular subtypes from The Cancer Genome Atlas. In these 49 GC cell lines, Epstein–Barr virus (EBV) and high microsatellite instability (MSI-H)-type cell lines were p16 methylated and sensitive to abemaciclib; further, genomically stable (GS), and chromosomal instability (CIN)-type cell lines with p16 methylation and intact Rb were also found to be responsive. In addition, we found that GC patients with p16 methylation often displayed a poor prognosis. Collectively, these data provide a foundation for clinical trials to assess the therapeutic efficacy of abemaciclib in GC and suggest that p16 methylation could be used as a predictive marker to identify patients with GC who may benefit from abemaciclib-based therapies.

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

Is Universal Patient Access to Fulvestrant in Hormone Receptor-positive Advanced Breast Cancer Justified? A UK Retrospective Multicentre Study

Purpose: Fulvestrant is a selective oestrogen receptor (ER) downregulator used to treat postmenopausal women with hormone receptor-positive advanced breast cancer. Given that patient access to this drug across the UK is variable, we sought to investigate its efficacy.

CDK4/6 inhibitors and hormone therapy in hormone receptor-positive advanced breast cancer: Real-world data and intrinsic subtypes defined by PAM50.

e13035 Background: CDK 4/6 inhibitors plus hormone therapy(HT) has been approved by FDA and EMA for the treatment of hormone receptor positive HER2 negative advanced breast cancer (HR+/HER2-BC) with improvement in PFS consistently demonstrated in several clinical trials. Benefit in OS has also been demonstrated in Monaleesa3 and Monarch2 clinical trials. To date we don`t have real-world data and no single biomarker has been validated to identify subgroups that would benefit most from this new drugs. Methods: This is a multicenter, real life, observational study. From January 2015 to December 2019 we recruited 98 patients with immunohistochemical(IHC) HR+/HER2-BC treated with CDK4-6 inhibitor plus HT. All patients were classified into intrinsic molecular subtypes based on PAM50 signature done centrally in diagnostic/metastatic biopsies. Results: The clinical and treatment characteristic are in table. In IHC studies all population were classified as luminalA (40%) and LuminalB (60%) but we found HER2 enriched patients (6%) defined by PAM50. The median PFS for all population was 14 months and median PFS for Luminal A subtype was 12 months and 15 months for Luminal B with no statistically significant differences between them. Conclusions: Based on the results obtained, the intrinsic molecular subtype defined by PAM50 does not appear to be associated with differences in PFS in our study group. However, a study with a larger number of patients would be necessary. Inhibitors of CDK4/6, have established a central role in the management of HR+/HER2-BC. There is a clear benefit in PFS and OS but we still don’t know which patients will benefit from this therapy and who will not while the side effects such chronic neutropenia, QTC prolongation and diarrhea could have a negative impact on their quality of life. Its mandatory to explore a good biomarker to direct therapy. [Table: see text]

The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict efficacy of CDK 4/6 inhibitors in women with hormone receptor-positive/HER2-negative advanced breast cancer.

e13032 Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapies (ETs) are a mainstay of treatment for patients (pts) with hormone receptor-positive advanced breast cancer (HR+ aBC). Preclinical evidence indicates that their ability to stimulate antitumor immunity may crucially contribute to their anticancer activity. The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) reflect systemic inflammation and immune system functional status and could be associated with CDK 4/6 inhibitor efficacy in pts with HR+ aBC. Methods: A retrospective, monocentric study was performed to investigate the association between NLR or PLR, as measured at baseline and after the first three treatment cycles, and progression free survival (PFS) in HR+ aBC pts treated with CDK 4/6 inhibitors. The thresholds for NLR and PLR were defined using the maximally selected rank statistics. Cox proportional hazard model was used to evaluate the impact of these parameters on PFS at univariate and multivariable analysis. Results: We evaluated a total number of 162 pts. Of them 142 were treated with palbociclib, 17 with ribociclib and 3 with abemaciclib plus ETs between January 2017 and December 2019 at our Institution. NLR and PLR at baseline were not associated with PFS. Conversely, high NLR ( &gt; 3) and high PLR ( &gt; 323.6) after three treatment cycles were associated with significantly lower PFS (p = 0.011 and p = 0.013, respectively). Multivariable analysis confirmed an independent association between high NLR or PLR and lower PFS (aHR 3.66, 95% CI 1.44-9.33, p = 0.007 and aHR 2.79, 95% CI 1.36-5.70, p = 0.005, respectively). Conclusions: To the best of our knowledge this is the first study to show a significant association between high NLR or PLR values and lower PFS in HR+ aBC pts treated with CDK 4/6 inhibitors. The association was not present with baseline values but only when NLR or PLR were measured after three treatment cycles, suggesting potential immunomodulatory activity of CDK 4/6 inhibitors.

MON-LB128 Phosphoinositide 3-Kinase (PI3K) Inhibitor Induced Hyperglycemia With Alpelisib

Intorduction: Breast cancer is estimated to be the third leading cause of cancer-related death in women. A commonly mutated pathway in breast cancer is the phosphoinositide-3-kinase (PI3K) pathway. Newer agents inhibiting PI3K are now available for the treatment of advanced cancers. Metabolic complications of new onset diabetes/hyperglycemia and hyperlipidemia are commonly seen. The precise mechanism through which PI3K inhibitors cause hyperglycemia is unknown. We present a patient who developed hyperglycemia within 2 weeks of starting alpelisib. Clinical Case: A 68 y.o female with history of metastatic invasive lobular carcinoma of the right breast HR-positive, HER-2 negative who presents for evaluation of hyperglycemia. She was diagnosed with metastatic breast carcinoma and failed multiple treatment options. She was started on alpelisib 2 weeks prior and had no history of glucose intolerance. Her pretreatment HbA1c was 5.5% (n <5.7%). After initiation of alpelisib, fasting blood glucose ranged between 100-140 mg/dL (n 100-125 mg/dL), while post-prandial blood glucose ranged between 150-300 mg/dL (n <140 mg/dl). Her HbA1c rose to 7% (n <5.7%). She did not manifest any macrovascular or microvascular complications, but did have a family history of type 2 diabetes mellitus. After initially being started on metformin, the dose increased to 1500 mg daily with the addition of glimepiride 1 mg. She eventually achieved stable euglycemia on metformin alone.Conclusion: Hyperglycemia has been reported to commonly occur with PI3K inhibitor therapy, the mechanism of which is poorly understood. One purposed mechanism is the effect on AMP kinase pathway which may also affect the efficacy of metformin. Here, we present a case of new onset T2DM in the setting of HR-positive, HER-2 negative breast cancer effectively treated with metformin. Future studies are needed to establish the prevalence and incidence of drug-induced hyperglycemia in patients administered PI3K inhibitors, as well as the best management approach to ensuing hyperglycemia. Reference: André F, Ciruelos EM, Rubovszky G, et.al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019 May 16;380(20):1929-1940.Guena, E, Roda, D, Rafii, S. Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on phase I clinical trials. Br J Cancer. 2015;113:1541-1547Busaidy, NL, Farooki, A, Dowlati, A. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin Oncol. 2012;30:2919-2928.

32P The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict efficacy of CDK 4/6 inhibitors in women with hormone receptor-positive/HER2-negative advanced breast cancer

Preclinical evidence indicates that cyclin-dependent kinase (CDK) 4/6 inhibitors stimulate antitumor immunity, which may contribute to their anticancer activity. The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) reflect systemic inflammation and immune system functional status, and could be associated with CDK 4/6 inhibitor efficacy in patients (pts) with hormone receptor-positive advanced breast cancer (HR+ aBC).

Safety and efficacy of sirolimus combined with endocrine therapy in patients with advanced hormone receptor-positive breast cancer and the exploration of biomarkers

BackgroundWe performed a retrospective study on the efficacy and safety of sirolimus (an mTOR inhibitor) in hormone receptor (HR)-positive advanced breast cancer and searched for biomarkers to predict its efficacy. MethodsAll patients with HR-positive metastatic breast cancer treated with sirolimus plus endocrine therapy between December 2017 and July 2018 at the Cancer Hospital, Chinese Academy of Medical Sciences were consecutively and retrospectively reviewed. Mutations in circulating tumour DNA (ctDNA) were assayed for 1021 tumour-related genes via gene panel target capture-based next-generation sequencing. ResultsThirty-six patients with metastatic breast cancer treated with sirolimus plus endocrine therapy were included. The progression-free survival (PFS) rates between the sirolimus group and everolimus group were similar, and the median PFS was 4.9 months and 5.5 months, respectively (hazard ratio 1.56, 95% CI 0.86–2.81, P = 0.142). The objective response rate in the 36 patients was 19.4%, and the clinical benefit rate was 41.7%. Lipid metabolism disorder was the most common adverse event (69.4%), and 13.9% of patients had stomatitis. Most (94.4%) adverse events were grade 1–2. Twenty patients (55.6%) underwent ctDNA analysis before receiving sirolimus therapy. For patients who received less than 3 lines of chemotherapy, those with PI3K/Akt/mTOR pathway alterations had a better response to sirolimus than those without alterations, with a median PFS of 7.0 months vs 4.3 months (hazard ratio = 0.01, 95% CI 0.00–0.34, P = 0.010). ConclusionsSirolimus is a potentially effective treatment option for patients with HR-positive advanced breast cancer.

Oral Capecitabine-Vinorelbine is Associated with Longer Overall Survival When Compared to Single-Agent Capecitabine in Patients with Hormone Receptor-Positive Advanced Breast Cancer.

Background: Single-agent capecitabine (C) is a moderately effective chemotherapeutic compound in the treatment of patients with HER2-negative metastatic breast cancer (mBC). The capecitabine-vinorelbine (CV) combination is also used due to a good tolerability profile, but no studies have demonstrated its superiority over single-agent C. Methods: We conducted a retrospective analysis to compare overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and incidence of adverse events (AEs) in patients with HER2-negative mBC treated with CV vs. single-agent C. Results: Out of 290 patients included in this study, 127 (43.8%) received single-agent C, while 163 (56.2%) patients were treated with CV. Median PFS was similar in patients treated with single-agent C or CV, while CV was associated with significantly longer OS in patients with hormone receptor-positive (HR+) BC. This OS advantage was confirmed at multivariable analysis also after propensity score-based matching of patients according to relevant clinical or tumor characteristics. When compared with single-agent C, CV was associated with higher incidence of G3/G4 and any-grade nausea/vomiting, diarrhea and increased transaminases. Conclusions: While prospective studies are needed to confirm our findings, the potential OS advantage of CV over single-agent C in HR+ mBC patients must be weighed against a significantly higher incidence of AEs.

Abstract A18: Investigating CDK4/6 inhibition in triple-negative breast cancer

Abstract The purpose of our study is to investigate the immunologic effects of CDK4/6 inhibitors in triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype for which there are no targeted therapies. CDK4/6 inhibitors, including the recently FDA approved abemaciclib, show promising response rates in patients with advanced stage hormone receptor-positive (HR+) breast cancer. Our previous report established that CDK4/6 inhibitors promote antitumor immunity by inducing tumor cell antigen presentation by activating tumor endogenous retroviral elements, which induce type III interferon production and MHC-I upregulation (Goel, DeCristo, et al., Nature 2017). In addition, CDK4/6 inhibitors decrease T regulatory cell proliferation without affecting cytotoxic CD8 T-cell numbers. TNBC has been considered a poor candidate for CDK4/6 inhibitor therapy, as tumors often lose Rb protein expression, which is critical for CDK4/6 inhibitor-induced cell cycle arrest. However, reports show around 50%-70% TNBC still has intact RB. We found murine and human TNBC cell lines that express Rb to varying extents and decrease proliferation in vitro in response to abemaciclib. In our preclinical model of TNBC, abemaciclib induced tumor regression. Consistent with previous findings, TNBC tumor cells upregulated MHC-I upon abemaciclib treatment, suggesting increased antigen presentation. Tumor cell-surface PD-L1 was also increased with abemaciclib both in vitro and in vivo, as assessed by flow cytometry and RT-qPCR. These results are encouraging, since a recent trial evaluating αPD-L1 therapy (atezolizumab) reported enhanced progression-free survival in patients with PD-L1+ tumors. These data suggest the potential efficacy of CDK4/6 inhibitors in combination with αPD-L1 in the treatment of TNBC, as we previously reported in our Her2+ model. Abemaciclib also increased total CD8+ and CD4+ T cells and decreased PD1+ CD8 and CD4 cells in the spleen. Furthermore, total numbers of naive CD8+ and CD4+ T cells increased with abemaciclib treatment in the spleen, suggesting a favorable antitumor systemic immunologic effect. CDK4/6 inhibitors might therefore show efficacy in treating TNBC. Deeper analysis of the mechanisms involved in regulating PD-L1 and enhancing naive T cells should enable us to evaluate combination therapies using CDK4/6 inhibitors for this particularly deadly breast cancer subtype. Citation Format: Qiuchen Guo, Gregory J. Goreczny, Adam Maynard, Milos Spasic, Sandra S. McAllister. Investigating CDK4/6 inhibition in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A18.