Drugs In Metastatic Breast Cancer Research Articles

Abstract PO2-05-12: Retrospective analysis on therapeutic efficacy and predictive indicators of eribulin plus anti-angiogenic drugs for metastatic breast cancer

Abstract Background: Eribulin has been widely used for the treatment of metastatic breast cancer (MBC). It has been found that eribulin can work in synergy with Bevacizumab or Anlotinib to achieve anti-angiogenic effects and possible synergistic enhancement. To optimize the efficacy of eribulin usage in late-line MBC patients, it is essential to delve deeper into the effects of combined treatments and gather more real-world clinical outcomes. Therefore, we evaluated the efficacy and safety of eribulin plus the anti-angiogenic drugs in late-line MBC patients. Objective: This study aims to retrospectively analyze the therapeutic efficacy and safety of eribulin plus anti-angiogenic drugs in treating metastatic breast cancer and explore predictive indicators of the therapeutic efficacy of eribulin in treating MBC. Methods: A retrospective review study was performed. 40 Patients diagnosed with MBC and treated with eribulin in Xi’an international medical center hospital from May 2020 to May 2021 were enrolled in this study. Patients were evaluable for this study and divided into two groups based on whether they received eribulin monotherapy or combined therapy. 22 patients were treated with eribulin monotherapy, and 18 were treated with eribulin and anti-angiogenic drugs (Bevacizumab and Anlotinib). Patients’ treatment parameters and characteristics were recorded. The Kaplan-Meier method was used to calculate the median PFS and corresponding 95% confidence interval (CI), and the Cox regression model was used for multivariate analysis of predictive indicators. The Fisher exact probability test was used to compare the difference in adverse reactions between the two groups, with a level of significance set at p-value < 0.05. Results: All study patients have an average of 5 treatment lines and a median progression-free survival (mPFS) of 4.2 months. The eribulin plus anti-angiogenic drug treatment group had a significantly prolonged mPFS compared to the group without anti-angiogenic drug treatment (7.0 months vs 2.0 months, p < 0.001, log-rank). Multivariate analysis identified that the combination of anti-angiogenic therapy (HR = 0.043, p = 0.004) and the occurrence of grade 3-4 neutropenia after treatment were two predictive factors for longer PFS (HR = 0.322, p = 0.009). In contrast, prior resistance to taxanes was predictive of shorter PFS (HR = 4.583, p = 0.019). Other factors, including age, Eastern Cooperative Oncology Group (ECOG) performance status, hormone receptor (HR) type, expression status, human epidermal growth factor receptor-2 (HER-2) expression status, Ki-67 level, number of metastatic lesions, and number of prior lines of Eribulin therapy, were not significantly associated with PFS. The results of Fisher’s exact test show that there was no significant increase in treatment-related adverse events (all grades) after combination with anti-angiogenic drugs. Conclusion: A combination of eribulin and anti-angiogenic therapy has significantly prolonged mPFS in the treatment of MBC patients. Other factors such as prior non-taxane resistance, grade 3-4 neutropenia occurrence after treatment, and combined anti-angiogenic therapy can be used as biomarkers for predicting treatment efficacy. The adverse events are manageable and the safety of combined therapy can be guaranteed. Therefore, the eribulin plus anti-angiogenic combination may act as a potential therapy for late-line MBC patients with clinically beneficial therapeutic effects. Keywords: metastatic breast cancer, eribulin, anti-angiogenic therapy, retrospective analysis Citation Format: Junmei Zhang, Xuezheng Wang, Hongjuan Du, Yan Xue. Retrospective analysis on therapeutic efficacy and predictive indicators of eribulin plus anti-angiogenic drugs for metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-12.

Abstract PO4-10-12: Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023

Abstract Title: Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023 Background: The number of FDA-approved genome-targeted cancer drugs for metastatic breast cancer has increased, providing the potential for personalized therapy. To help physicians, patients, and policymakers differentiate meaningful from trivial innovation in this field, we assessed the validity of the targets and value of the outcomes used in the pivotal trials supporting approval. Methods: We analyzed trials supporting genome-targeted breast cancer drugs FDA-approved between 2006-2023, defined as those using a genomic test in which the drug targeted a given genomic alteration. From FDA drug labels and trial reports, we extracted characteristics of pivotal trials. For Accelerated Approvals—a special FDA program allowing approval based on unvalidated surrogate measures—if the drug later received traditional approval based on a confirmatory trial, only the latter was analyzed. Strength of evidence supporting molecular targetability was evaluated using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). Clinical benefit for approved indications was assessed using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets qualifying for ESCAT category level I-A or I-B associated with ESMO-MCBS grade 4 or 5 were rated as high-benefit genomic-targeted breast cancer treatments. Results: Fifteen genome-targeted drugs covered 17 indications and targeted 8 driver alterations. Among the 17 pivotal trials supporting these indications, most were randomized (11, 65%), phase 3 (11, 65%) and open-label (14, 82%). The most common primary endpoint leading to approval (10, 59%) was progression-free survival. Eleven trials (65%) had a I-A ESCAT targetability, 5 (29%) had a I-C targetability score and 1 (6%) was categorized as II-A. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations, and ESR1 mutation were classified as tier I-A due to randomized trials demonstrating the effectiveness of approved targeted therapies in patients with these alterations. RET fusions, NTRK fusions, and microsatellite instability were classified as tier I-C, while high-tumor mutational burden was categorized as tier II-A. Eighteen percent of trials (3/17) demonstrated ESMO-MCBS grades 4-5. Overall, 3 of 17 (18%) indications had high-benefit genomic-based cancer treatments. Conclusions: Among molecular-targeted cancer therapies approved for metastatic breast cancer, fewer than a fifth demonstrated substantial patient benefits at approval. Benefit frameworks like ESCAT and ESMO-MCBS can help stakeholders identify therapies with the greatest potential. Citation Format: Ariadna Tibau, Thomas J. Hwang, Consolacion Molto Valiente, Jerry Avorn, Aaron Kesselheim. Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-12.

Estimating the Potential Benefits of Confirmatory Trials for Drugs with Accelerated Approval: A Comprehensive Value of Information Framework.

The US Food and Drug Administration's Accelerated Approval (AA) policy provides a pathway for patients to access potentially life-saving drugs rapidly. However, the use of surrogate endpoints, single-arm designs, and small sample sizes in preliminary trials that support AAs can lead to uncertainty regarding the clinical benefits of such drugs. This study aims to develop a comprehensive value of information (VOI) framework for assessing the potential benefits of future confirmatory trials, accounting for the various uncertainties inherent in preliminary trials. I formulated an expected value of information from confirmatory trial (EVICT) metric, which evaluates the potential benefits of a confirmatory trial that would reduce those uncertainties by using a clinically meaningful endpoint, a randomized control, and increased sample size. The EVICT metric can quantify the expected benefits of a well-designed confirmatory trial or an inadequately designed one that continues to use surrogate endpoints or single-arm design. The framework was illustrated using a hypothetical AA drug for metastatic breast cancer. The case study demonstrates that a highly uncertain preliminary trial of an AA drug was associated with a substantial EVICT. A confirmatory trial with an increased sample size for this AA drug, utilizing a clinically meaningful endpoint and randomized control, yielded a population-level EVICT of $12.6 million. Persistently using a surrogate endpoint and single-arm trial design would reduce the EVICT by 60%. This framework can provide accurate VOI estimates to guide coverage policies, value-based pricing, and the design of confirmatory trials for AA drugs.

Taxane rechallenge during metastatic disease in HER-2 negative breast cancer patients: Clinical activity, tolerance and survival results

BackgroundTaxanes are major drugs for metastatic breast cancer (MBC) treatment, and are generally well tolerated, making them attractive for therapeutic reintroduction (rechallenge) during metastatic course. In view of the paucity of current literature, we questioned the usefulness of taxane rechallenge in a population of patients previously treated with taxanes in a metastatic setting. MethodsFrom the local database of a French cancer center, we retrospectively identified 756 patients diagnosed with ER+/HER2-, or triple negative MBC, and treated between 2008 and 2021. Among them, 58 patients (7.8%) were rechallenged with taxanes. Clinical characteristics, response rates, and survival were retrospectively evaluated and compared to patients who received taxanes only once. ResultsCompared to non-rechallenged population, patients treated with taxane rechallenge were significantly younger, with better general status, and received more treatment. First taxane exposure led to better tumor response and was more frequently discontinued for reasons other than progression, compared to the non-rechallenged population. Taxane rechallenge led to an objective response rate of 27.6%, and a clinical benefit rate of 46.6%, with a median progression-free survival (PFS) of 5.7 months, and a median overall survival (OS) of 11.6 months. We also found a PFS2/PFS1 ratio >1.3 in 55.2% of the rechallenge population. ConclusionAlthough only a minority of MBC patients are concerned, taxane rechallenge appears to be a pragmatic option with an acceptable tolerance, and good efficacy, especially when these drugs have shown clinical activity earlier in the disease course, and/or have been stopped for reasons other than progression.

249P A retrospective analysis on capecitabine and vinorelbine combination in metastatic breast cancer: The MARCELLINO study

Capecitabine (cape) and vinorelbine (vino) are known effective drugs for metastatic breast cancer (mBC) and have been successfully used in combination in the past, especially in the pre-CDK4/6i era. No literature data are available comparing the combined regimen (concCV) with a sequential regimen (seqCV). We retrospectively analysed a cohort of 188 consecutive mBC patients (pts) treated with concCV or seqCV between January 2010 and December 2016 at IRCCS CRO of Aviano and ASUFC Academic Hospital of Udine. Only pts receiving the two drugs in direct sequence were considered for seqCV. For concCV, data on eventual maintenance therapy (MT) with either endocrine therapy (ET) or single-agent chemotherapy (CT) were collected. CV reintroduction at disease progression (PD) was considered only if immediately after MT. The association of CV regimen with survival outcomes was explored by the Kaplan-Meier method. PFS for concCV was compared to the sum of PFS for single drugs of seqCV. Median age at diagnosis was 51 years (yrs) [44;60], median age at metastatic disease was 57 yrs [49;66]. 20% of pts were classified as de novo metastatic. At diagnosis, 90% of pts were luminal-like, while 10% had a triple negative BC. Disease re-biopsy on a metastatic lesion was performed in 51% of pts (with a phenotype change in 18% of cases). Median number of treatment lines in the advanced setting was 5 [4;7], median line for CV regimen was 2 [2;3]. In total 138 pts (73%) received concCV, while 50 pts (27%) received seqCV (82% with cape as first drug). MT was offered in 67 pts (36%), with a median duration of 8 months (m) [6;14]. ET (mainly aromatase inhibitors, in 49% of cases) or cape/vino (in 12% and 10%, respectively) were used as MT. CV was reintroduced after MT at PD in 18 pts (27%). Overall, mPFS was 11 m [6;22] and mOS was 24.5 m [13.5;45.3] from CV start. In concCV pts, mPFS was 10 m [5;19] (mPFS2 was 18 m [9;31] with CV reintroduction) and mOS was 27.3 m [13.7;52.6]. In seqCV pts, total mPFS was 11 m [7;20] and mOS was 19.3 m [13.3;37.4]. According to our retrospective data, concCV and seqCV seem to be comparable in terms of survival outcomes, with the limits of a reduced sample size and unbalanced treatment arms.

Osthole inhibits the migration and invasion of highly metastatic breast cancer cells by suppressing ITGα3/ITGβ5 signaling.

Metastasis is the leading cause of death in breast cancer patients. Osthole, as an active compound detected in the traditional Chinese medicine Wenshen Zhuanggu Formula, has shown a promising anti-metastatic activity in human breast cancer cells, but the underlying mechanisms remain ambiguous. In this study we elucidated the anti-metastatic mechanisms of osthole in highly metastatic breast cancer cells and a zebrafish xenograft model. We showed that the expression of integrin α3 (ITGα3) and integrin β5 (ITGβ5) was upregulated in highly metastatic MDA-MB-231, MDA-MB-231BO breast cancer cell lines but was downregulated in poorly metastatic MCF-7 breast cancer cell line, which might be the key targets of osthole's anti-metastatic action. Furthermore, we showed that knockdown of ITGα3 and ITGβ5 attenuated breast cancer cell migration and invasion possibly via suppression of FAK/Src/Rac1 pathway, whereas overexpression of ITGα3 and ITGβ5 caused the opposite effects. Consistently, osthole significantly inhibited breast cancer metastasis by downregulating ITGα3/ITGβ5 signaling in vitro and in vivo. These results provide new evidence that osthole may be developed as a candidate therapeutic drug for metastatic breast cancer.

The impact of radiological assessment schedules on progression-free survival in metastatic breast cancer: A systemic review and meta-analysis.

1086 Background: The impact of the interval of radiological assessment on the magnitude of benefit observed in randomized trials (RCTs) in metastatic breast cancer is undefined. Methods: All RCTs investigating anti-neoplastic drugs for metastatic breast cancer published between 2006 and 2019 were identified. Intervals for restaging were categorized as short ( < 9 weeks) or long (≥9 weeks). Hazard ratios (HRs) and 95% confidence intervals for progression-free survival (PFS) and overall-survival (OS) were pooled in a meta-analysis and compared between trials employing short and long restaging intervals assessed as subgroup analyses. Analyses were repeated for pre-specified subgroups according to disease subtype, drug type, whether experimental therapy was added to or replaced standard treatment and whether HR for PFS was < 1 or ≥1. Results: Eighty-nine studies comprising 95 comparisons and 44,901 patients were included. The magnitude of PFS benefit was non-significantly larger in trials which employed short compared to long restaging intervals (HR 0.79 vs. 0.86, p = 0.15). Short restaging interval was associated with significantly higher magnitude of effect on PFS in pre-specified subgroups including non-first line studies (HR 0.78 vs. 0.92, p = 0.04), studies with drugs replacing standard treatment (HR 0.86 vs. 1.04, p = 0.02) and studies performed exclusively in human epidermal growth factor receptor 2 (HER2) positive disease (HR 0.72 vs. 0.90, p = 0.02). Restaging interval was not associated with OS for all included studies (HR 0.92 vs. 0.93, p = 0.66) or for any of the pre-specified subgroups. Conclusions: Shorter restaging intervals are associated with a higher magnitude of effect of PFS, but not OS. Awareness of the impact of the restaging interval on quantification of intermediate endpoints such as PFS is important for the design and interpretation of RCTs.

Everolimus in Advanced Breast Cancer: A Systematic Review and Meta-analysis.

Everolimus plus exemestane is approved forthe treatment of hormone receptor-positive metastatic breast cancer (MBC) after progression on nonsteroidal aromatase inhibitors. The role of everolimus is less well defined in other breast cancer phenotypes and in combinationwith other drugs. We conducted a systematic review and meta-analysis to assess the efficacy and safety of adding everolimus to standard of care (SoC) in MBC regardless of tumor phenotype and treatment type. The electronic databases PubMed and EMBASE were searched for eligible randomized trials. Pooled hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) and pooled risk ratios (RR) and odds ratios for objective response rates, disease control rate (DCR), and grade 3 or higher toxicity were meta-analyzed. Subgroup analyses compared survival outcomes by tumor phenotype. Data from 2826 patients from eight trials were analyzed. The addition of everolimus to SoC reduced the risk of disease progression by 29% (HR 0.71; 95% confidence interval [CI] 0.56-0.90). This did not translate into an OS benefit (HR 0.95; 95% CI 0.80-1.13). In addition, everolimus improved the DCR (RR 0.82; 95% CI 0.68-0.98), whereas it increased the risk of developing grade 3 or higher toxicity. The PFS benefit was more prominent for patients with hormone receptor-positive (+)/human epidermal growth factor receptor 2 (HER2)-negative (-) disease. For the HER2 (+) subgroup, the PFS benefit was restricted to patients with hormone receptor (-) disease. Everolimus reduces the risk of disease progression in hormone receptor (+) MBC. In patients with HER2 (+) disease, the benefit is limited for those with hormone receptor (-) disease. Given the approval and use of newer drugs in MBC, clinical trials and real-world data are needed to confirm the benefit of everolimus and define the best treatment sequence strategy to adopt in that setting.

Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer.

The addition of CDK4 and 6 inhibitors (abemaciclib, palbociclib or ribociclib) to endocrine therapy, as first-line treatment or following progression after initial endocrine therapy, significantly increased progression-free survival, objective response rates and in some trials overall survival, compared with endocrine therapy alone in HR+ andHER2-breastmetastatic breast cancer. These CDK4 and 6 inhibitors are now approved in this context and have become a new standard of care. A hypothesis-generating exploratory analysis suggested that the addition of abemaciclib to endocrine therapy showed the largest effects in subgroups of women with indicators of poor prognosis, although these data require confirmation. This review provides updated clinical trial data for all three drugs in metastatic breast cancer, focusing on abemaciclib, the most recently approved agent.

How shall we treat locally advanced triple negative breast cancer?

Triple negative breast cancer (TNBC) has been shown to respond to neoadjuvant chemotherapy (NACT). It has been established that achieving pathological complete response (pCR) for certain aggressive subtypes of breast cancer, including HER-2 (over-expressed) and TNBC, provides an important surrogate marker for predicting long-term clinical response and survival outcomes. How to increase the number of patients that achieve pCR remains challenging. Platinum-based NACT seems to be part of the solution and capecitabine, an active drug in metastatic breast cancer, but not a standard one in earlier stages may have found its place in the adjuvant setting. In the near future immunotherapy can play a role in early TNBC.

How shall we treat locally advanced triple negative breast cancer?

Triple negative breast cancer (TNBC) has been shown to respond to neoadjuvant chemotherapy (NACT). It has been established that achieving pathological complete response (pCR) for certain aggressive subtypes of breast cancer, including HER-2 (over-expressed) and TNBC, provides an important surrogate marker for predicting long-term clinical response and survival outcomes. How to increase the number of patients that achieve pCR remains challenging. Platinum-based NACT seems to be part of the solution and capecitabine, an active drug in metastatic breast cancer, but not a standard one in earlier stages may have found its place in the adjuvant setting. In the near future immunotherapy can play a role in early TNBC

How shall we treat locally advanced triple negative breast cancer?

Triple negative breast cancer (TNBC) has been shown to respond to neoadjuvant chemotherapy (NACT). It has been established that achieving pathological complete response (pCR) for certain aggressive subtypes of breast cancer, including HER-2 (over-expressed) and TNBC, provides an important surrogate marker for predicting long-term clinical response and survival outcomes. How to increase the number of patients that achieve pCR remains challenging. Platinum-based NACT seems to be part of the solution and capecitabine, an active drug in metastatic breast cancer, but not a standard one in earlier stages may have found its place in the adjuvant setting.

Abstract 1046: A breast cancer MET reporter cell line model for drug discovery and development

Abstract World-wide, cancer metastasis continues to be the leading cause of death in cancer (DIZON et al. 2016). Although epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) have been implicated in the incidence of cancer metastasis and drug resistance, their impact in cancer progression and patient survival is not fully understood (NIETO et al. 2016). This is partly due to the lack of suitable in vitro models. Thus, to facilitate the utility of the EMT concept in therapeutic development, we have utilized some of the basic biology of EMT/MET, to create a novel advanced in vitro model for use in both basic research and discovery of new anti-EMT drugs. In breast cancer, vimentin (VIM) intermediate filament (IF) proteins are generally upregulated during EMT and down-regulated during MET (GILLES et al. 1999; THIERY and SLEEMAN 2006; RICHARDSON et al. 2012; LAMOUILLE et al. 2014). Here we employed CRISPR/Cas9 gene editing to generate a VIM RFP (red fluorescent protein) reporter in the MDA-MB-231 breast adenocarcinoma cell line. The VIM RFP C-terminal fusion gene at the endogenous VIM locus, enables end-point or real-time tracking of the MET status as cells transition from epithelial to mesenchymal phenotype under distinct conditions. We have validated the cell line at the nucleic acid (genomic and mRNA) and protein levels as well as in cell-based assays. Bio-functional evaluation of the MDA-MB-231 VIM RFP cell line shows sensitivity to metastatic breast cancer drugs axitinib (tyrosine kinase inhibitor) and U0126 (MEK1/2 inhibitor) via the inhibition of the inherent signaling pathways which impact EMT. These effects provide the basis for the use of this cell line in high throughput screening (HTS) applications including the discovery of new anti-EMT drugs for metastatic breast cancer. Furthermore, the MDA-MB-231 VIM RFP reporter cell line is also a convenient and sensitive model for studying the mechanisms of metastasis and for basic translational science research. Citation Format: Metewo S. Enuameh, Weiguo Shu, Robert Newman, Sangeeta Kumari. A breast cancer MET reporter cell line model for drug discovery and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1046.

Abstract 1045: CRISPR/cas9 mediated generation of an EMT reporter cell line for metastatic breast cancer drug discovery and development

Abstract Among women, breast cancer continues to be the most common cancer, with metastasis being the leading cause of mortality in cancer patients around the world (DIZON et al. 2016). Epithelial to mesenchymal transition (EMT) - the process by which epithelial cells shift to the mesenchymal state, has been implicated in many aspects of breast cancer tumorigenesis, metastasis and drug resistance ). The accumulation of a large body of data on the association of EMT with cancer over the years has not resulted in EMT being an active target for therapeutic development. This is due in part to the lack of appropriate in vitro models. Here we have exploited some of the basic biology of EMT, to create an advanced in vitro metastatic breast cancer reporter cell line model for use in both basic research and discovery of new EMT inhibitors. During EMT, E-cadherin protein expression is down regulated in cancer cells in association with the loss of cell-to-cell adhesion, apico-basal polarity and a change to a spindle-shaped morphology. By installing an emerald green fluorescent protein (EmGFP) tag on the C-terminus of the e-cadherin (ECAD) gene in the epithelial BT-474 breast cancer cell line via CRISPR/Cas9 genome editing, end-point or real-time EMT status of cells can be tracked under defined conditions. The EMT reporter cell line was verified at the nucleic acid (genomic and mRNA) and protein levels as well as in cell-based assays. Bio-functional evaluation of the BT-474 ECAD EmGFP cell line, shows that it responds to EMT induction. The subsequent EMT status of cells can be monitored in real time by observing and measuring ECAD EmGFP expression, in addition, the resulting mesenchymal cells have increased invasive capacities. Furthermore, this EMT reporter cell line shows sensitivity to the MEK1/2 inhibitor U0126 - thereby providing the basis for the use of this cell line in high-throughput screening (HTS) applications including the identification of new anti-EMT drugs for metastatic breast cancer. The BT-474 ECAD EmGFP reporter cell line is also a convenient and sensitive model for basic science research on the mechanisms of metastasis. References DIZON, D. S., L. KRILOV, E. COHEN, T. GANGADHAR, P. A. GANZ et al., 2016 Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol 34: 987-1011. HAY, E. D., 1995 An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154: 8-20. Citation Format: Metewo S. Enuameh, Weiguo Shu, Robert Newman. CRISPR/cas9 mediated generation of an EMT reporter cell line for metastatic breast cancer drug discovery and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1045.

A Reassessment of Phosphatidylinositol Transfer Protein Alpha's Growth Factor Signaling Role

In mammals, the START‐like phosphatidylinositol transfer proteins (PITPs) remain an understudied group of proteins implicated in human health and disease. Phosphatidylinositol transfer protein alpha (PITPa) is linked to human epidermal growth factor receptor (HER2)‐positive metastatic breast cancer drug resistance, and muscular dystrophy, but its precise mechanism of action is unclear. Current dogma states that PITPa is essential for growth factor signaling through the epidermal growth factor (EGFR) and netrin signaling pathways, but little data has emerged supporting these claims. Data from our laboratory, from multiple experimental systems, strongly dispute PITPa requirement in these pathways. Strikingly, mouse and human cell lines lacking PITPa sense and chemotax towards EGF, and signaling responses downstream of EGFR‐stimulation are unimpaired, including phosphatidylinositol (3,4,5)P3 generation, and phosphorylation of protein kinase B (Akt). Surprisingly, lack of PITPa in human cells results in potentiation of Akt phosphorylation (threonine 308) following EGFR stimulation, indicating that contrary to current thinking, PITPa may actually repress this pathway. The dispensability of PITPa for EGF‐signaling explains the remarkable absence of EGF‐signaling associated phenotypes in PITPa nullizygous (Pitpa0/0) mice. We have previously reported that Pitpa0/0 animals exhibit a complex phenotype including spinocerebellar neurodegeneration characterized by gliosis and neuronal apoptosis of cerebellum, and hindbrain, and that neuronal specific eviction of embryonic PITPa and PITPb results in progeny born lacking a forebrain. Axon guidance and mouse forebrain development require netrin‐1 signaling through the netrin receptor (DCC), a process reported to require PITPa. We demonstrate that while compromise of netrin‐signaling results in structural brain derangements, these defects do not result from absence of PITPa. Furthermore, we fail to reproduce the previously reported physical interaction between the netrin receptor (DCC) and PITPa. In light of our findings the ‘essential’ role of PITPa in growth factor signaling must be reevaluated.Support or Funding InformationThis work was supported by the Robert A. Welch Foundation (BE0017), and a National Institutes of Health grant (GM44530) awarded to Vytas A. BankaitisThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract 2924: Preclinical analysis of synergistic antitumor effect of eribulin and HDAC inhibitor for triple-negative breast cancer cells

Abstract Eribulin (ERI), an inhibitor of microtubule dynamics, is a key drug for metastatic breast cancer. While HDAC inhibitors have been shown to presents antitumor effect for various malignancies. Among HDAC family, HDAC6 is known as a deacetylase of tubulin. To develop a novel therapeutic strategy for triple negative breast cancer (TNBC), we tested the combinational effect of ERI and HDAC inhibitor for TNBC cells in vitro. Two TNBC cell lines (MDA-MB-231, Hs578T) and their ERI-resistant cells (MDA-MB-231/E, Hs578T/E) established in our laboratory were used in the study. Vorinostat (VOR), a pan-HDAC inhibitor, and ricolinostat (RICO), a selective HDAC6 inhibitor were used. The sensitivity to VOR or RICO was not different between the parental and the ERI-resistant cells. In the protein expression analysis, HDAC6 expression was not altered between parental and ERI-resistant cells. Prior treatment with VOR or RICO increased the expression of acetylatedα-tubulin in both parental and ERI-resistant TNBC cell lines. When low concentration of VOR (0.5 μM) or RICO (0.5 μM) was added simultaneously with ERI, the sensitivity to ERI was enhanced significantly in both parental MDA-MB-231 and Hs578T cell lines. Furthermore, when both parental cell lines were treated with VOR (5 μM) or RICO (5 μM) for 48 hrs prior to addition of ERI, the sensitivity to ERI was significantly enhanced. The enhancement of sensitivity to ERI both by the simultaneous addition with low concentration of VOR or RICO and by the prior treatment with VOR or RICO was observed in the ERI-resistant cells as well. Moreover, inhibition of HDAC6 by small interfering RNA partially enhanced the sensitivity to ERI in the both parental cell lines. Our study demonstrated the possibility that the combination of ERI with HDAC inhibitor might enhance the antitumor effect of ERI and overcome ERI resistance through acetylation of α-tubulin by HDAC6 inhibition in TNBC cells. Citation Format: Takaaki Oba, Hiroto Izumi, Ken-ichi Ito. Preclinical analysis of synergistic antitumor effect of eribulin and HDAC inhibitor for triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2924.

Value Assessment in Oncology Drugs: Funding of Drugs for Metastatic Breast Cancer in Canada

Life expectancy for women with metastatic breast cancer has improved since the early 2000s, in part because of the introduction of novel therapies, including chemotherapy, hormonal therapy, and targeted agents. However, those treatments can come at a cost for the patient (short- and long-term toxicities from treatment) and at a financial cost for the health care system. Given the increase in the number of costly anticancer agents being introduced into the clinical setting, the American Society of Clinical Oncology (asco) and the European Society for Medical Oncology (esmo) have developed a system to quantify the value of new cancer treatments in terms of benefit, toxicities, and costs. In our value-assessment analysis, we included drugs that were funded in Canada between 2012 and 2017 for metastatic breast cancer. We reviewed the clinical benefit of those agents (survival, progression, quality of life), their costs, their value according to the asco and esmo value frameworks, and their assessments from the pan-Canadian Oncology Drug Review [pcodr (in Canada, except Quebec)] and the Institut national d'excellence en santé et en services sociaux [iness (in Quebec)]. Drugs funded in Canada showed variation in their asco net health benefit scores and esmo magnitude of clinical benefit scores, but all had a cost-effectiveness ratio greater than $100,000 per quality-adjusted life-year. The strength and magnitude of the clinical benefit (for example, overall survival benefit vs. progression-free survival benefit) was not necessarily associated with a higher value score. Although great progress has been made in developing value frameworks, use of those frameworks has to be refined to help patients and health care providers make informed decisions about the benefit of novel cancer therapies and to help policymakers make decisions about the societal benefit of funding those therapies.

Abstract P3-15-03: Clinical benefit, toxicity, and cost of metastatic breast cancer drug therapies: Visualizing randomized and non-randomized evidence

Abstract Background: Given the rapidly expanding size of the clinical trial literature for metastatic breast cancer (MBC) clinical trials, oncologists need tools that enable them to efficiently review the settings and results of previous studies. Methods: We searched the Cochrane Central Register of Controlled Trials and PubMed to identify clinical trials testing MBC drug therapies. Key eligibility criteria included >90% of patients enrolled in trial having MBC, therapeutic clinical trials, and Phase II or III studies with at least 10 patients at a dosage level. From each study, we extracted information about clinical benefit and toxicity of drug therapies, and we further estimated the costs of all drug therapies. We built a web-based visualization tool that presents the results of all studies testing a given drug combination, stratified based on patients' receptor statuses and prior exposure to therapy. The tool presents both aggregate and study-level results, and reports both unadjusted study results and standardized results based on key patient characteristics in the study populations. Results: We included 1,783 studies containing 2,549 treatment arms and 170,515 patients in the visualization tool. The tool reports information on 77 HER-2-directed therapies, 101 hormonal therapies, and 675 undirected therapies. The visualization tool has been made publicly accessible for patients and doctors to access at http://cancertrials.info. Discussion: We believe this tool will make literature reviews significantly more efficient for oncologists, enabling them to better leverage insights from the clinical trial literature when making treatment decisions. Citation Format: Silberholz J, Vahdat L, Bertsimas D. Clinical benefit, toxicity, and cost of metastatic breast cancer drug therapies: Visualizing randomized and non-randomized evidence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-15-03.

Epirubicin-Vinorelbine Intravenous Combination Followed by Oral Vinorelbine as First-Line Treatment in Metastatic Breast Cancer:

Epirubicin and vinorelbine are considered active drugs in metastatic breast cancer. The optimal duration of a chemotherapy regimen for metastatic breast cancer patients is still unknown. Nevertheless, epirubicin has a dose-limiting cardiotoxicity. Vinorelbine is also available as oral formulation. In a multicenter phase II study, we analyzed the feasibility and the efficacy of a maximum of six cycles of i.v. epirubicin plus vinorelbine, followed by oral vinorelbine. We enrolled 30 patients with metastatic breast cancer. Each patient received epirubicin (75 mg/m2 on day 1) and vinorelbine (25 mg/m2 on days 1-8), every 3 weeks, for three cycles or six cycles in case of objective response or stable disease. When a clinical benefit was obtained, patients received oral vinorelbine (60 mg/m2 on days 1-8 every 3 weeks for three cycles). The regimen demonstrated to be active and well tolerated in metastatic breast cancer, and 6-8 months represented the optimal treatment duration. Maintenance therapy with oral vinorelbine was feasible, effective, safe and well accepted by the patients.

A systematic review and pooled analysis of retrospective series of eribulin in metastatic breast cancer.

Eribulin is one of the newer chemotherapeutic agents approved for use in later line treatment of patients with metastatic breast cancer. Phase III studies have shown a useful clinical response rate for eribulin as well as equivalence to another commonly used drug in metastatic breast cancer, capecitabine. Nevertheless, whether this clinical value observed in trial patients is maintained in patients seen in clinical oncology practice, outside trials remains a question. Several series published over the last few years sought to answer this question. The current paper carries out a pooled analysis of these retrospective series to obtain efficacy and toxicity data for eribulin in metastatic breast cancer patients treated off trials. Thirteen series with a total of 1095 patients were identified. Pooled estimates of response rate and clinical benefit rate were 20.1% (95% confidence interval: 16.3-23.9%) and 46.3% (95% confidence interval: 39.4-53.2%) respectively. These were somewhat higher than the response rate and clinical benefit rate observed in a pooled analysis of two randomized phase III trials (14.9 and 30.9%, respectively, conducted in an intension-to-treat manner). In contrast overall survival was longer in the phase III trials (median 15.2 months) than in the retrospective studies (pooled estimate 9.8 months). All grades toxicities were similar in practice compared with trials with slightly higher grade 3 toxicities (46.1 vs. 38.7%) but lower grade 4 toxicities (17.2 vs. 27.7%) in patients off trials.