Hormone Receptor-positive Advanced Breast Cancer Research Articles

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.

Abstract P5-11-19: Ribociclib for the treatment of hormone receptor-positive refractory advanced breast cancer: Managed access programme in Turkey

Abstract Background: Ribociclib combined with endocrine therapy (ET) have demonstrated efficacy in patients with hormone receptor (HR) positive advanced breast cancer (ABC) who experienced progression during prior ET. However, there are scarce data chemo-endocrine refractory patients with ribociclib. We analyzed the efficiency and safety of ribociclib from the real world evidence in this heavily treated group of patients in Managed Access Programme (MAP). Methods: MAP launched in Turkey, between October 2017 and March 2018. We retrospectively analyzed survival outcomes and toxicities of 52 patients from this programme. Results: The median age of the total population was 54.5 years (28-76 years) and 71.2% (n=37) of the patients were postmenapousal. Median estrogen receptor and progesterone receptor positivity were 90% (15-100) and 25% (0-100), respectively. Median Ki67 was 25% (3-90%). 46.2% and 73.1% of the patients had adjuvant chemotherapy and ET, respectively. Denovo metastatic disease was detected 28.8% of the patients. Visceral disease (lung, liver, and others) was present in 21 patients (40.3%), and 16 (30.8%) had bone-only disease. Median treatment line of ABC before ribociclib was 4 (1-9). ET was performed 36.5% and 38.4% for the first and second line treatment of ABC, respectively. Most of the patients (71.5%) treated anthracycline and taxanes before ribociclib. Ribociclib combined with ET in the majority of the patients; aromatase inhibitors (51.9%), fulvestrant (26.9%) and tamoxifen (3.8%). However, 4 patients were receiving ribociclib monotherapy. As of May 21, 2019, 26.9% (n=14) of patients were still receiving treatment. Objective response rate was 38.4% (n=20) and additional 18 (34.6%) stable diseases were detected. Median progression free survival and overall survival were 5 months (3.9-6.1 months) and 15.2 months (13.7-16.8 months), respectively. While 48.1% of the patients treated with chemotherapy after ribociclib failure, only two patients treated with ET after ribociclib failure. Ribociclib was generally well tolerated all the study population, grade 2 emesis was developed only two patients. Grade 3/4 neutropenia was developed in 36.5% of the patients. There was no febrile neutropenia. Urosepsis (n=1) and grade 4 thrombocytopenia (n=1) were developed in seperate patients. A prolongation of QTcF from baseline occurred in two patients. Dose reductions occurred in 21.2% (n=11) of the patients. There was 3 deaths during treatment. Conclusions: Ribociclib is an effective agent with tolerable safety profile even in the heavily pretreated patients with HR positive ABC especially combined with ET. Citation Format: Umut Demirci, Erhan Gokmen, Yesim Eralp, Seyda Gunduz, Sema Sezgin Goksu, Taner Korkmaz, Osman Kostek, Serdar Turhal, Semra Paydas, Sevgi Topcu, Burcu Cakar, Bulent Karabulut, Ozgur Tanrıverdi, Burcak Karaca, Gulhan Ipek Deniz, Ozkan Alan, Fatma Paksoy Turkoz, Gul Basaran. Ribociclib for the treatment of hormone receptor-positive refractory advanced breast cancer: Managed access programme in Turkey [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-19.

Abstract P1-03-06: Development of patient-derived xenograft tumor models and 3D spheroid culture from advanced hormone receptor-positive inflammatory breast cancer patients for evaluation of new therapeutics

Abstract Background: Breast cancer (BC) is a heterogeneous disease comprising different clinical, histopathological, and molecular subtypes. Hormone receptor-positive (HR+) advanced BC cancer, in particular the inflammatory BC (IBC) represents a significant clinical challenge because of the development of endocrine resistance during either adjuvant or metastatic treatment translating to poor outcome. We aim to develop unique PDX tumor models and 3D spheroid/organoid cultures that recapture advanced IBC using pleural effusions or/and circulating tumor cells (CTCs) as tumor resource and that can help understand the mechanism of IBC metastasis for new drug development. Methods: Five samples of pleural effusion-derived tumor cells or circulating tumor cells (CTCs) from three advanced IBC patients were obtained from Northwestern Memorial Hospital to establish IBC PDX tumor model in immunodeficient NSG female mice via subcutaneous or breast fat pad xenografting and develop the derived 3D organoid/spheroid cultures for anti-cancer drug evaluation. STR profiling against with original patient tumor DNA was conducted to confirm the tumor authentication. Results: Three developed IBC PDX tumor models (one HR+-IBC and two triple negative (TN)-IBC) were demonstrated by pathology to have highly heterogeneous characteristics and metastatic features similar to the original patient tumor. NSG mice xenografted with original TN-IBC pleural effusion, or derived spheroid cultures with varying passage numbers (<3 passages or >6 passages) manifested different inflammatory clinical symptoms. Mice xenografted with one case of original TN-IBC pleural effusion cells (~40% of tumor-associated macrophages and ~60% of tumor cells) developed palpable tumors and was shown to have the most IBC-like characteristics including reddish skin and ulcerative lesions. They were sacrificed 2 months after xenograft due to declining health. Mice xenografted with >6 passages or <3 passages of spheroid cultures manifested little to moderate skin lesions and developed tumor sizes of ~1 cm within 2-3 months while having a longer life span. Liver and lung metastases were observed in the breast fat pad of xenografted PDX tumor mice with one case of original HR+-IBC pleural effusion. 3D tumor spheroid/organoid cultures were successfully established from original IBC pleural effusion or/and IBC PDX tumor cultures. Spheroid generated from HR+-IBC pleural effusion showed phenotypic plasticity: the HR+-IBC spheroid cells display both tumor and macrophage cell characteristics and spheroid cultures can convert to adhesive cell phenotypes with addition of condition media. These spheroid/organoid cultures are used for evaluation of new drug strategies such as selectively targeting ER degraders (SERDS), CDK4/6 inhibitor, or Tyrosine kinase inhibitors for treatment of HR+-IBC or TN-IBC. Conclusions: Our results suggested 3D spheroid cultures and PDX tumor models from advanced IBC recapture aggressive features of the disease and can be an ideal model for the mechanism study of metastatic advanced IBC and preclinical testing of novel agents in IBC and endocrine resistant disease. Citation Format: Wenan Qiang, Zhangfeng Zhong, Pamela Monahan, Kristy Tse, Youbin Zhang, Qiang Zhang, Lorenzo Gerratana, Andrew Davis, Demirkan Gursel, Reiner Bleher, Jian-Jun Wei, Charles D. James, Thomas V. O’Halloran, Massimo Cristofanilli. Development of patient-derived xenograft tumor models and 3D spheroid culture from advanced hormone receptor-positive inflammatory breast cancer patients for evaluation of new therapeutics [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-06.

Abstract OT2-02-07: Fulvestrant with additional palbociclib in advanced or metastatic hormone receptor-positive HER2-negative breast cancer after progression to fulvestrant monotherapy: JBCRG- M07 (FUTURE trial)

Abstract Background: Fulvestrant is one of the standard treatments for first- and second-line endocrine therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC). Palbociclib inhibits cyclin dependent kinase (CDK) 4 and CDK6 in vitro, resulting in loss of RB1 phosphorylation. Palbociclib has high activity in HR-positive breast cancer cell lines and is synergistic in combination with endocrine therapies. The PALOMA-3 trial enrolled patients with metastatic estrogen receptor (ER)-positive breast cancer with resistance to aromatase inhibitor. The results demonstrated that palbociclib combined with fulvestrant was associated with significantly longer progression-free survival (PFS) than fulvestrant alone. However, patients in the trial reported higher rates of adverse events, such as neutropenia and alopecia, compared with fulvestrant monotherapy. We investigate in this prospective cohort study that the addition of palbociclib to fulvestrant is effective and safe in HR-positive and HER2-negative advanced breast cancers that progressed during fulvestrant monotherapy. Specific Aims: Primary objective: To observe the PFS in patients with resistance to fulvestrant monotherapy who were treated with fulvestrant plus palbociclib. Secondary Objective: To observe the PFS in patients treated with fulvestrant as the first and second line therapy. We also aim to observe overall survival and safety. A prospective translational research is also planned to assess the correlations between biomarkers and response. Trial Design: Single arm exploratory trial Eligibility Criteria: Eligible patients must have historically confirmed ER-positive and HER2-negative MBC who received fulvestrant as first or second line therapy. Prior chemotherapy in the neoadjuvant and adjuvant settings and up to one line of chemotherapy in MBC is permissible. Patients who received CDK4/6 inhibitor as metastatic therapy are excluded. Statistical Design: We aim to set the lowest limit of the therapeutic effect at a median PFS of 5 months, which is the value reported in the PALOMA-3 study. If we assume that the expected median PFS is 8 months, at least 63 patients are required to reject the null hypothesis (5 months) with a power of 80% under a one-sided alpha at 0.05. The length of the accrual period and follow-up period are set at 12 and 18 months, respectively. Target Accrual: First registration: 200 patients with fulvestrant monotherapy as the first and second line setting. Second registration: 70 patients with combined palbociclib and fulvestrant. (UMIN 000029294) Citation Format: Kokoro Kobayashi, Naoki Niikura, Shigehira Saji, Takayuki Iwamoto, Nobutaka Iwakuma, Yuichiro Kikawa, Norikazu Masuda, Kenichi Watanabe, Takashi Takeshita, Mari Oba, Shinji Ohno. Fulvestrant with additional palbociclib in advanced or metastatic hormone receptor-positive HER2-negative breast cancer after progression to fulvestrant monotherapy: JBCRG- M07 (FUTURE trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-07.

Abstract P3-08-01: MONARCH 2: Interim analysis of overall survival in patients with poor prognostic factors

Abstract Background: In MONARCH 2 (M2), abemaciclib, an oral selective cyclin dependent kinase 4 & 6 inhibitor, demonstrated significant progression-free survival (PFS) improvement in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer when added to fulvestrant. Treatment with abemaciclib plus fulvestrant provided a statistically significant and clinically meaningful median overall survival (OS) benefit of 9.4 months (hazard ratio 0.757; 95% confidence interval, 0.606, 0.945; p=0.0137).1 High grade tumors, progesterone receptor (PgR) negativity, liver metastases, and absence of bone-only disease were identified as independent poor prognostic disease characteristics.2 In a retrospective analysis of M2, among subgroups analyzed, patients within those poor prognostic subgroups numerically received the largest improvement from the addition of abemaciclib to endocrine therapy (ET) with PFS hazard ratios in the range of 0.4 to 0.5.2 Methods: M2 (NCT02107703) was a global, randomized, double-blind Phase 3 trial of abemaciclib + fulvestrant (N=446) or placebo + fulvestrant (N=223) in women with ET resistant HR+, HER2- advanced breast cancer. Investigator-assessed PFS was the primary objective and OS was a key secondary endpoint. Here, we present exploratory OS results conducted within the previously described prognostic subgroups.2 Hazard ratios were estimated using Cox models with a test of interactions of subgroups with treatment performed. Results: As of the data cut-off (20 June 2019), OS prolongation was consistent across all subgroups; a numerically greater OS effect was observed in patients with previously identified negative prognostic factors including patients with high tumor grade, PgR negativity, baseline liver metastases, and absence of bone-only metastases, relative to their complementary subgroups (Table). However, no statistically significant interaction between these prognostic factors and treatment effect were observed. Similar to OS, a more pronounced effect for abemaciclib plus fulvestrant for patients with high tumor grade, PgR negativity, baseline liver metastases, and absence of bone-only metastases was also observed when examining the time to chemotherapy or death, whichever is earlier (chemotherapy free survival [CFS]). Conclusions: Consistent with the statistically significant and clinically meaningful benefit observed in the overall study population, abemaciclib plus fulvestrant improved OS across all exploratory subgroups, with the largest OS effects observed in patients with poor prognostic factors, consistent with previously reported PFS data. Refernces: 1. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: Overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer. Abstract to be presented at: European Society for Medical Oncology 2019; Barcelona, Spain. 2. Di Leo A, O’Shaughnessy J, Sledge GW Jr, et al. Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy. NPJ Breast Cancer. 2018;4:41. Abbreviations: CFS, chemotherapy free survival; HR, hazards ratio; N, number in overall study population; n, number in specified subgroup; OS, overall survival; PgR, progesterone receptor. n (%) N=669Overall Survival Hazard Ratio (95% CI)Chemotherapy Free Survival Hazard Ratio (95% CI)Tumor gradeHigh169 (25.26)0.66 (0.44, 1.01)0.52 (0.36, 0.75)Low/intermediate345 (51.57)0.79 (0.58, 1.08)0.78 (0.60, 1.02)Unknown155 (23.17)0.83 (0.52, 1.31)0.50 (0.34, 0.76)PgR statusNegative141 (21.08)0.66 (0.41, 1.05)0.59 (0.39, 0.89)Positive509 (76.08)0.79 (0.61, 1.01)0.68 (0.55, 0.85)Baseline liver metastasesYes174 (26.01)0.73 (0.49, 1.08)0.60 (0.42, 0.85)No495 (73.99)0.76 (0.58, 0.99)0.64 (0.51, 0.81)Bone-only metastasesYes180 (26.91)0.91 (0.56, 1.46)0.69 (0.46, 1.01)No486 (72.65)0.72 (0.57, 0.93)0.64 (0.52, 0.80) Citation Format: Patrick Neven, Stephen Johnston, Masakazu Toi, Joohyuk Sohn, Kenichi Inoue, Xavier Pivot, Olga Burdaeva, Meena Okera, Norikazu Masuda, Peter A Kaufman, Han Koh, Eva-Maria Grischke, PierFranco Conte, Yi Lu, Nadine Haddad, Karla Hurt, Antonio Llombart-Cussac, George W Sledge. MONARCH 2: Interim analysis of overall survival in patients with poor prognostic factors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-01.

Abstract P5-11-03: Practice patterns and outcomes of post progression treatment after CDK 4/6 inhibitors

Abstract Background: CDK 4/6 inhibitors have become frontline treatment for patients (pts) with advanced hormone receptor (HR) positive breast cancer. There is limited data regarding post-progression outcomes in pts receiving CDK 4/6 inhibitors as standard of care. In this study, we analyzed treatment patterns and clinical outcomes of post-progression treatment in pts with advanced HR positive breast cancer after receiving CDK 4/6 inhibitors. Methods: Pts with metastatic breast cancer receiving CDK 4/6 inhibitors who received treatment after progression were identified from a cohort of pts at MDACC. Pts receiving CDK 4/6 inhibitors in a clinical trial were excluded. Clinical and demographic data as well as progression-free survival (PFS) was collected. Data was analyzed using Fischer's exact test for categorized variables and T test/Wilcoxon rank-sum test for continuous variables. PFS was analyzed using the Kaplan Meier method. Results: 206 pts who met eligibility criteria were included. Median age at metastatic diagnosis was 56 years-old and the majority of pts were white (n=160, 77.7%) with a pre- treatment performance status of 0 (n=168, 81.6%). The largest fraction of pts (n=98, 47.6%) received a chemotherapy agent following progression on a CDK 4/6 inhibitor while 19.4% (n=40) received endocrine therapy, 21.8% (n=45) received a biologic, 6.3% (N=13) received a different CDK 4/6 inhibitor and 4.9% (n=10) received an investigational therapy. The majority of pts who progressed on a subsequent agent had visceral progression (n=193, 93.7%). The median time to progression on an agent after CDK 4/6 inhibitor was 122 days. There was no statically significant difference in time to progression after CDK 4/6 inhibitor between pts receiving different classes of therapies, including CDK 4/6 inhibitors and investigational therapies (p=0.3). Conclusion: Pts in our cohort were more likely to receive chemotherapy following progression on a CDK 4/6 inhibitor. Reassuringly, there was no significant difference between time to progression on different agents. As CDK 4/6 inhibitors become frontline therapy for HR positive metastatic breast cancer, it is important to evaluate the sequencing of therapies as well as outcomes on subsequent agents. Citation Format: Katherine Keaney Clifton, Akshara Singareeka Raghavendra, Min Yi, Jennifer Litton, Debu Tripathy, Meghan Karuturi. Practice patterns and outcomes of post progression treatment after CDK 4/6 inhibitors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-03.

High-Dose Toremifene as a Promising Candidate Therapy for Hormone Receptor-Positive Metastatic Breast Cancer with Secondary Resistance to Aromatase Inhibitors.

There are currently no established second- and later-line therapies for postmenopausal women with hormone receptor-positive advanced or metastatic breast cancer. We examined the efficacy of high-dose toremifene (HD-TOR) for this patient group and whether aromatase inhibitor (AI) resistance influences HD-TOR treatment outcome. This retrospective analysis investigated the outcomes of 19 women with postmenopausal hormone-sensitive recurrent or metastatic breast cancer who received HD-TOR, defined as 120 mg daily from 2012 to 2016. The median follow-up duration was 9.67 months. The overall response rate (ORR) and clinical benefit rate (CBR) were compared between various clinical subgroups, including patients exhibiting primary or secondary AI resistance as defined by the timing of recurrence or progression. Time to treatment failure (TTF) was estimated by the Kaplan–Meier method and compared between subgroups by the log-rank test. The overall ORR was 21.1%, and the CBR was 31.6%. CBR was significantly higher for patients without liver metastasis (50% vs. 0%, p = 0.044). Nine cases exhibited primary and eight cases secondary AI resistance. Both ORR and CBR were higher in patients with secondary AI resistance (25% vs. 0%, p = 0.087; 38% vs. 11%, p = 0.29). The median TTF was 6.2 months in the entire AI-resistant group (n = 17) and was longer in the secondary resistance subgroup than in the primary resistance subgroup (8.40 vs. 4.87 months; log-rank: p = 0.159). High-dose TOR appears to be most effective for postmenopausal breast cancer cases with secondary resistance to AIs, cases without prior AI treatment, and cases without liver metastasis. The detailed mechanisms of AI resistance and the clinical features of responsive cases need to be further clarified to identify the best candidates for HD-TOR.

First-line endocrine therapy for postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a systematic review and meta-analysis

BackgroundIn establishing the 2018 Breast Cancer Practice Guidelines of the Japan Breast Cancer Society, we explored the optimal first-line endocrine therapy for advanced postmenopausal hormone receptor-positive breast cancer.MethodsWe performed a systematic review of relevant reports from randomized-controlled studies published prior to November 2016 found using medical journal search engines. The main outcomes which we evaluated were progression-free survival (PFS), objective response rate (ORR), disease control rate (CBR), and toxicity.ResultsFour controlled trials comparing aromatase inhibitors (AI) and cyclin-dependent kinase (CDK)4/6 inhibitor combination therapy to AI monotherapy, and two controlled trials comparing anastrozole to fulvestrant 500 mg were analyzed. AI/CDK4/6 inhibitor combination therapy significantly improved PFS (Risk Ratio: 0.67, 95%CI 0.60–0.73), increased ORR (Risk Difference: 0.11, 95% CI 0.07–0.16), and increased CBR (Risk Difference: 0.11, 95% CI 0.07–0.15), compared with AI monotherapy. Patients who received this combination therapy had a higher grade ≥ 3 adverse event rate more than those who received AI monotherapy (Risk Difference: 43%, 95%CI: 0.39–0.47). Fulvestrant 500 mg alone significantly improved PFS (risk ratio: 0.85, 95%CI 0.72–0.98), but ORR and CBR were similar to those of anastrozole alone.ConclusionIn the first-line treatment for advanced postmenopausal hormone receptor-positive breast cancer, a combination therapy of CDK4/6 inhibitors and AI showed significant improvement of PFS, ORR, and CBR but with significant increased toxicities compared with AI alone. Fulvestrant 500 mg monotherapy significantly prolonged PFS compared with AI monotherapy. We must wait for the results of the studies with longer follow-up period.

Anastrozole plus fulvestrant vs. anastrozole alone for hormone receptor-positive advanced breast cancer: a meta-analysis of randomized controlled trials.

For patients with hormone receptor (HR)-positive advanced breast cancer, whether the combination of anastrozole and fulvestrant is more effective than anastrozole alone is controversial. Our meta-analysis aimed to compare the efficacy and safety of the two therapies. We retrieved relevant studies in Embase, the Cochrane Library, Ovid MEDLINE, PubMed, ScienceDirect, Web of Science, Scopus, and Google Scholar. The primary outcomes were overall survival (OS) and progression-free survival (PFS). The secondary outcomes were the disease control rate (DCR), the objective response rate (ORR), and adverse events (AEs). Five articles based on 4 randomized controlled trials containing 2146 patients were identified in our meta-analysis. The combination group had better efficacy in the endpoints of OS (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.74-0.99, p = 0.03) and PFS (HR 0.87; 95% CI 0.77-0.97, p = 0.02). Regarding the ORR, DCR, total AEs and grade 3-5 AEs, we found no difference between the two treatments. The combination group showed a clearly higher rate of treatment discontinuations (95% CI 1.05-3.60, p = 0.03) and AEs leading to death (95% CI 1.12-9.11, p = 0.03). The subgroup analysis of AEs showed an increased incidence of extremity or muscle pain, hematologic effects, gastrointestinal disorders, and hot flashes in the combination group. For HR-positive advanced breast cancer patients, the combination of anastrozole and fulvestrant appears to be superior to anastrozole alone in extending PFS and OS, despite relatively serious AEs.

Efficacy of Palbociclib and Endocrine Treatment in Heavily Pretreated Hormone Receptor-positive Her2-negative Advanced Breast Cancer: Retrospective Multicenter Trial

Efficacy of Palbociclib and Endocrine Treatment in Heavily Pretreated Hormone Receptor-positive Her2-negative Advanced Breast Cancer: Retrospective Multicenter Trial

Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer.

Recently many therapeutic classes have emerged in advanced hormone receptor-positive breast cancer, which is the leading cause of cancer death in women. In absence of visceral crisis, treatment relies on endocrine therapy combined with cyclin dependent kinase 4 and 6 inhibitor. Many mechanisms lead to resistance to endocrine therapy, including the activation of intracellular signaling pathways critical for cell survival. Approximately 70% of breast tumors harbor an alteration in the phosphoinositide 3 kinase (PI3K)/Akt pathway, leading to its hyper activation. This pathway is involved in the regulation of growth, proliferation and cell survival as well as in angiogenesis and is consequently a major target in the oncogenesis. An aberrant PIK3CA mutation is a common phenomenon in breast cancer and found in approximately 40% of patients with advanced hormone receptor-positive breast cancer. For the moment, the only positive trials showing a progression free survival benefit in this population are BOLERO-2 (2012), SOLAR-1 (2019), which tested everolimus, a mammalian target of rapamycin inhibitor, and alpelisib, a PI3K inhibitor, and led to their marketing authorization. However, many other inhibitors of this pathway are promising; nevertheless their development is actually limited by toxicity, mainly cutaneous (rash), digestive (diarrhea) and endocrine (diabetes).

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

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

An evidence-based review of the outcome of fulvestrant plus a targeted agent versus fulvestrant alone in treating hormone receptor-positive endocrine therapy-resistant metastatic breast cancer.

Fulvestrant is approved for the hormone receptor-positive advanced metastatic breast cancer (MBC) patients during or after prior endocrine treatment. The adding of a targeted agent to fulvestrant has improved the outlook for these patients from recent studies. However, these results were still under investigation, the analysis was undertaken to assess the clinical outcomes of the fulvestrant-based combination therapy compared with fulvestrant monotherapy. I systematically searched electronic databases to identify eligible literatures till January 2019. Randomized-controlled trials (RCTs) assessing the efficacy of a targeted agent to fulvestrant with fulvestrant mono-therapy in MBC patients who are refractory to or intolerant of prior endocrine therapy were included. Six RCTs were included in this analysis. The group of a targeted agent to fulvestrant was significantly improved overall survival (OR = 0.86, 95%CI = 0.76-0.97, P = 0.02), progression-free survival (OR = 0.66, 95%CI = 0.54-0.81, P < 0.0001), as well with the objective response rate (OR = 2.30, 95%CI = 1.67-3.18, P < 0.00001), respectively. However, there are more adverse effects with the combination group (OR = 6.71, 95%CI = 5.58-8.06, P < 0.00001). Pooled results indicate that adding a targeted agent to fulvestrant prolonged OS, PFS and ORR in relapse or metastatic hormone receptor-positive breast cancer after prior endocrine therapy. Combination of fulvestrant with a targeted agent was associated with more frequent grade 3/4 toxicities. Further research is needed to develop a database of reliable biomarkers and their individual impact on the fulvestrant-based combination treatments.

323P - Endocrine therapy alone versus targeted combination strategy as first line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trials

BackgroundCombined endocrine/targeted approaches have been investigated as first-line treatment in hormone receptors positive metastatic breast cancer (BC). Randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged >65 years) are under represented in most of the trials. Due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in elderly women. MethodsThis meta-analysis included first line phase II/III randomized published trials comparing ET to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged > 65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Prospero registration number: CRD42019120215. Results8 studies were included: 4 (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found. ConclusionsThe novel experimental strategies showed an improvement in PFS in elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone, the magnitude of PFS benefit is age-independent. To define the role of novel agents, future trials should be designed taking in account not only the age, but also adequate geriatric assessment and comorbidity status. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureL. Cortesi: Speaker Bureau / Expert testimony: Astazeneca; Speaker Bureau / Expert testimony: Pierre Fabre Pharma. F. Piacentini: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pfizer. S. Cascinu: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly. L. Moscetti: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis. All other authors have declared no conflicts of interest.

Therapeutic Drug Monitoring of Everolimus in Oncology: Evidences and Perspectives.

Everolimus is a mammalian target of rapamycin (m-TOR) inhibitor that has been approved for the treatment of hormone receptor-positive advanced breast cancer, metastatic renal cancer, and neuroendocrine tumors. Although therapeutic drug monitoring (TDM) of everolimus is well established in the transplantation field, it is not currently performed in oncology. The last consensus conference about the TDM of everolimus states that for the use of everolimus in oncology, "further studies are required to determine the clinical utility of TDM for everolimus in oncology settings." In this review, the authors will discuss the current evidences and perspectives, based on observational studies available, in favor of the TDM of everolimus in oncology focusing on (1) the management of everolimus in routine practice, (2) the prerequisites for TDM of everolimus in oncology, (3) the pharmacodynamics (including a description of the biomarker of resistance and mutations in m-TOR), and (4) a general outlook.

Overexpression of TK1 and CDK9 in plasma-derived exosomes is associated with clinical resistance to CDK4/6 inhibitors in metastatic breast cancer patients.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve progression-free survival (PFS) in patients with hormone receptor-positive (HR+) advanced breast cancer. However, a better knowledge of predictive biomarkers of response and resistance to CDK4/6i is needed. Therefore, the present article addresses the role of the mRNA expression of thymidine kinase 1 (TK1), CDK4, 6 and 9 in plasma-derived exosomes and their relevance in the pharmacologic activity of CDK4/6i. Blood samples of 40 HR+/HER2- advanced breast cancer patients were collected before (T0) the administration of palbociclib plus hormonal therapy and after 3 months (T1). RNA was isolated from exosomes and analysed for the expression of TK1, CDK 4, 6 and 9 by digital droplet PCR (ddPCR). A higher value of TK1 copies/ml at baseline (T0) was significantly associated with the number of previous lines of chemotherapy (p = 0.009). In patients with PD, a significant increase was observed in the number of copies/ml of TK1 (p = 0.01) and CDK9 (p = 0.03) comparing T1 vs. T0 values. No significant correlations between response to treatment and clinical parameters were found at univariate analysis. High baseline CDK4 expression was significantly correlated with longer PFS in patients treated with fulvestrant + palbociclib (low versus high: 6.45months vs. not reached, p = 0.01). The present study demonstrates that, in plasma-derived exosomes, highbaseline CDK4 mRNA levels are associated with response to palbociclib plus hormonal therapy, while the increase in TK1 and CDK9 mRNA copies/ml is associated with clinical resistance.

Fulvestrant in hormone receptor-positive advanced breast cancer: A UK retrospective multicenter study.

e12525 Background: Fulvestrant is a selective oestrogen receptor (ER) down regulator used to treat hormone receptor-positive advanced breast cancer in postmenopausal women. It is used at various time points in treatment. However, variations in funding across the UK limit universal patient access to fulvestrant. We sought to investigate its use and efficacy in UK clinical practice. Methods: Medical records of 458 patients with ER positive advanced breast cancer treated with fulvestrant between August 2011 and November 2018 at ten UK centres were reviewed. Demographics and treatment responses were recorded. Efficacy was analysed by progression free survival (PFS), clinical benefit rate (CBR) and overall survival (OS) with alive patients censored to December 2018. Results: Of the 445 patients with analysable data, median age was 70 (range 21-95). ECOG performance status was 0-1 in 70% (n = 285). Bone was most commonly involved (73%, n = 323), 307 (69%) had visceral involvement and 228 (51%) had nodal metastases. Both locally advanced and metastatic patients had received a median 2 (range 0 – 5 for all patients) prior endocrine therapy lines and 0 (range 0 – 6) prior chemotherapy lines. Fulvestrant was the first line treatment in 49 (11%). Median duration of fulvestrant use was 5 months (range 1-88). Overall, median PFS was 6 months. This increased to 7 months in absence of visceral disease, in whom 22% of patients achieved a prolonged PFS extending to 30 months. Fulvestrant produced a CBR of 41% in 355 patients assessed, of which 16% partially responded. First radiological assessment occurred at median 3 months (range 1-37). Progressive disease accounted for 82% of discontinuation compared to 4% owing solely to adverse events in 341 assessed patients. Median OS for the whole cohort was 23 months. Conclusions: This is one of the largest studied patient cohorts treated with fulvestrant. This heavily pre-treated population reflects real life fulvestrant use. Reassuringly the results confirm its clinical benefit in maintaining disease response. Given its potential synergistic action with other systemic agents, fair access to this highly active drug for all patients is as important now as ever before.

Endocrine-based targeted combination versus endocrine therapy alone as first-line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trials.

1046 Background: Combined endocrine approaches have been widely investigated as first-line treatment in hormone receptors positive metastatic breast cancer. In particular, multiple randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged ≥65 years) are under represented in most of the clinical studies. Moreover, due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in women aged ≥65 years. Methods: This meta-analysis included first line phase II/III randomized published trials comparing (ET) to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged ≥65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Results: 8 studies were included in the analysis. 4 trials (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found in elderly population subgroup. Conclusions: The novel experimental combo-strategies in the first line setting showed an improvement in PFS in the subgroup of elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone. The magnitude of PFS benefit due to addition of CDK4/6 inhibitors to ET is age-independent.

Assessing treatment benefits with CDK4/6i+ET for hormone receptor-positive advanced breast cancer: A network meta-analysis.

e12543 Background: Previously, the treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (aBC) has relied solely on endocrine therapy (ET). Unfortunately, almost all tumors developed resistance to ET. Although cyclin-dependent kinase inhibitors (CDKi)+ET clearly improve several clinical outcomes, many relevant questions remain unanswered: is there a benefit in (i) overall survival (OS) (ii) progression-free survival (PFS), and (iii) which CDKi is the best. Methods: A systematic review was performed to identify trials that compared CDKi+ET versus ET alone for HR+/HER2-aBC. Pooled meta-estimates were generated to assess CDKi+ET OS benefit and PFS benefit. Bayesian network meta-analysis was performed to compare each CDKi in terms of PFS, clinical benefit rate (CBR), response rate (RR) and toxicity. Results: 2,523 studies were screened and 8 studies satisfied the inclusion criteria. There was a trend for OS benefit with CDKi+ET compared to ET alone with 97% posterior probability that CDKi+ET is better than ET alone and HR 0.81 (95% CrI 0.66-1.00). CDKi+ET also showed &gt; 99% probability of better than ET alone in both first and second-line settings in terms of PFS, RR, and CBR with PFS HR 0.56 (0.47-0.66) first line, 0.49 (0.39-0.60) second-line; RR OR 1.61 (1.29-1.97) first-line, 2.58 (1.71-3.80) second-line; CBR OR 1.75 (1.38-2.25) first-line, 2.38 (1.65-3.37) second-line. Ribociclib and abemaciclib showed weak-moderate evidence of better PFS and RR compared to palbociclib (64% to 81% posterior probability of superiority). There was no evidence of differences between ribociclib and abemaciclib. Palbociclib achieved better CBR compared to ribociclib and abemaciclib, although this difference may be related to the poor performance of placebo arm in studies that used palbociclib. In terms of safety, abemaciclib caused less neutropenia, but more diarrhea than ribociclib and palbociclib. Deep vein thrombosis was less frequent with ribociclib. Conclusions: CDKi+ET was 97% superior in terms of OS and &gt; 99% superior in terms of PFS, RR, and CBR compared to ET alone. Further studies are necessary in order to find the best agent and the best sequencing of CDKi for HR+/HER2- aBC treatment.