Treatment Of Metastatic HER2 Research Articles

Abstract PO4-04-03: Empowering Oncologists to Develop Individualized Management Strategies for HER2+ Metastatic Breast Cancer: Findings from a Quality Improvement Initiative

Abstract Background: Rapidly evolving evidence in the treatment of metastatic HER2+ metastatic breast cancer (MBC) can present challenges in aligning practice with the latest clinical data and guideline recommendations. In this ongoing quality improvement initiative, we identify and address real-world challenges healthcare professionals (HCPs) face in individualizing treatment plans, adverse event management, and patient-centered care for HER2+ MBC. Methods: From 9/2022 to 12/2022, 22 HCPs who treat patients with breast cancer (BC) along with 52 patients with HER2+ MBC from 2 large US community oncology clinics completed tethered surveys assessing practice patterns, challenges, and attitudes related to individualized and patient-centered care for HER2+MBC. Patient charts (n=100) were audited to assess current practice patterns and to track changes over time. Inclusion criteria included a confirmed HER2+ MBC diagnosis, prescription for two or more lines of HER2+ breast cancer treatment, and ≥ 1 visit in the one-year chart abstraction period. HCPs participated in audit-feedback sessions to assess site-specific challenges and gaps and developed action plans for improvement. Follow-up chart audits and HCP surveys will evaluate changes in practice patterns 6 months after the educational intervention. Results: The most frequently reported HCP challenges included coordination of care (41%) and individualizing treatment plans (32%). The most frequently reported patient challenges included feeling confident in treatment plan (30%) and being unable to meet work or home responsibilities (22%). In tethered surveys, there were discordant findings between patient and HCP perceptions related to goals for treatment, patient education, and patient-centered care. For example, 82% of HCPs reported often or always asking patients about treatment preferences, but only 8% of patients reported their doctor asked. While HCPs overwhelmingly thought surviving as long as possible was their patients’ top goal (82%), patients reported their top goals for treatment were improving quality of life (57%) and controlling symptoms (41%). Additionally, while HCPs thought patients had the most difficulty managing nausea/vomiting (68%) and diarrhea (59%), patients reported they have the most difficulty managing fatigue (46%) and hair loss (44%). Baseline chart audits highlighted several areas for improvement in guideline-aligned care, including treatment selection, sequencing, and supportive care. Based on identified gaps, providers developed and implemented action plans, such as increasing use of patient navigators, referring patients for palliative care at time of diagnosis, improving multidisciplinary team-based approaches, and implementing tools and resources to stay up-to-date on clinical evidence and guidelines. Full findings from baseline surveys and chart audits will be presented, along with follow-up surveys and chart audits to measure impact. Conclusions: Through this QI initiative, we identified gaps in individualized, guideline-aligned, patient-centered care for patients with HER2+ MBC, and HCPs developed and are implementing action plans for improvement. The methods and findings from this initiative demonstrate key opportunities to improve outcomes for patients with HER2+ MBC in community oncology clinics. Citation Format: Reshma Mahtani, Erika Hamilton, Ilona Dewald, Chelsie Anderson, Jeffrey Carter, Cherilyn Heggen, Kelly McKinnon. Empowering Oncologists to Develop Individualized Management Strategies for HER2+ Metastatic Breast Cancer: Findings from a Quality Improvement Initiative [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 PO4-04-03.

A bibliometric analysis of HER2-positive breast cancer: 1987-2024.

The overamplification of human epidermal growth factor (HER2) in breast cancer (BC) has been the subject of numerous research publications since its discovery in 1987. This is the first bibliometric analysis (BA) conducted on HER2-positive (HER2+) BC. The purpose of this BA is to analyze the published research on HER2+ BC from 1987 to 2024, highlighting the most significant scientific literature, as well as the main contributing authors and journals, and evaluating the impact of clinical and lab-based publications on HER2+ BC research. The Web of Science Core Collection (WoSCC) was searched using the terms "Breast cancer" OR "Breast carcinoma" OR "Breast tumor" AND "HER2 positive" OR "HER2+". The search was limited by publication year (1987-2024) and only full English articles were included. WoS returned 7,469 relevant results, and from this dataset, a bibliometric analysis was conducted using the "analyze results" and "journal citation report" functions in WoS and the VOSviewer 1.6.16 software to generate bibliographic coupling and co-citation analysis of authors. The analysis encompassed a total of 7,469 publications, revealing a notable increase in the annual number of publications, particularly in recent years. The United States, China, Italy, Germany, and Spain were the top five most prolific countries. The top five significant institutions that published HER2+ research were the University of Texas System, Unicancer, UTMD Anderson Cancer Center, Harvard University, and University of California System. Breast Cancer Research and Treatment, Clinical Cancer Research, and Clinical Breast Cancer were the top three notable journals with the highest number of HER2+ BC publications. Dennis Slamon (Nc = 45,411, H-index = 51) and Jose Baselga (Nc = 32,592, H-index = 55) were the most prolific authors. Evolving research topics include anti-HER2 therapy in the neoadjuvant setting, treatment of metastatic HER2+ BC, and overcoming therapy resistance. This study provides an overview of HER2+ BC research published over the past three decades. It provides insight into the most cited papers and authors, and the core journals, and identifies new trends. These manuscripts have had the highest impact in the field and reflect the continued evolution of HER2 as a therapeutic target in BC.

Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo

Breast cancers (BrCas) that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2+ BrCa have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have investigated the role of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, in the response of HER2+ BrCa to HER2-targeting drugs. CDK8 was in the top 1% of all genes ranked by correlation with shorter relapse-free survival among treated HER2+ BrCa patients. Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel of HER2+ BrCa cell lines, overcoming and preventing resistance to HER2-targeting drugs. The synergistic effects were mediated in part through the PI3K/AKT/mTOR pathway and reduced by PI3K inhibition. Combination of HER2- and CDK8/19-targeting agents inhibited STAT1 and STAT3 phosphorylation at S727 and up-regulated tumor suppressor BTG2. The growth of xenograft tumors formed by lapatinib-sensitive or -resistant HER2+ breast cancer cells was partially inhibited by SNX631 alone and strongly suppressed by the combination of SNX631 and lapatinib, overcoming lapatinib resistance. These effects were associated with decreased tumor cell proliferation and altered recruitment of stromal components to the xenograft tumors. These results suggest potential clinical benefit of combining HER2- and CDK8/19-targeting drugs in the treatment of metastatic HER2+ BrCa.

Targeted therapy in the treatment of HER-2 positive breast cancer with brain metastases

Metastatic damage to the brain is a frequent manifestation in tumors of various localizations, including breast cancer. Until recently, systemic therapy of metastatic brain damage was of limited use; however, with the advent of targeted drugs that are better understood in terms of the specific molecular targets and biological characteristics of metastases, it is now possible to improve treatment results. In an analysis of the results of studies on the problem of metastasis of breast cancer in the brain, a comparison of the use of various targeted drugs in the treatment of metastatic HER2 + breast cancer is presented. The results of a comparison of the degrees of effectiveness of targeted drugs, both in monotherapy and in combination with chemotherapy, were obtained and analyzed.

New potential therapeutic-sequence strategies of TDM1 in the revolutionary era of metastatic HER2-positive breast cancer treatment: A monocentric retrospective experience.

e13014 Background: EMILIA study showed benefits in terms of both progression free survival (PFS) and overall survival (OS) administering Ado-trastuzumab emtansine (T-DM1) vs lapatinib-capecitabine in HER2+ mBC patients (pts) treated at least with a previous trastuzumab-taxane-based therapy. However a paucity of data is available on TDM1 efficacy after dual anti HER2 blockade with pertuzumab and trastuzumab (PT). Instead TH3RESA trial revealed the positive impact on OS of T-DM1 also in heavily pre-treated (at least 2 lines of T, lapatinib and taxanes regimens) pts. We conducted a retrospective analysis reporting innovative findings on the sequence of anti-HER2 treatments and how it could be potentially optimized. Methods: Between June 15, 2014 and January 31, 2020 we identified HER2+ (IHC: 3+ or 2+/FISH amplified) mBC pts treated with T-DM1, either as second-line after progression on dual blockade PT (Cohort PT) or after ≤ 3 anti her2-combined regimens (trastuzumab o lapatinib plus chemotherapy) (Cohort T). 74 pts received T-DM1: Cohort T n = 34 (all females, median age = 52,7), Cohort PT n = 40 (39 females, 1 male, median age = 52,2). Within Cohort T: 64,7 % of pts (n = 22) received T-DM1 after 1 previous anti her2-combined regimen, 20,6 % (n = 7) and 14,7 % (n = 5) in third and fourth lines, respectively. Instead, the whole Cohort PT received second line T-DM1 after pertuzumab/trastuzumab. Results: Median progression- free survival was 10,2 in Cohort T and 3,7 months in Cohort PT. As regards the best response rate, 8,8 % (n = 3/34) and 52,5 % (n = 21/40) of pts reported a progressive disease (PD) into the Cohorts T and PT, respectively: stable disease (SD) 38,2 % (n = 13/34) versus 15 % (n = 6/40); partial response (PR) 23,5 % (n = 8/34) vs 15 % (n = 6/40); complete response (CR) 23,5 % (n = 8/34) vs 12,5 % (n = 5/40). Almost 2/3 (n = 21/34) of Cohort T and half (n = 20/40) of Cohort PT pts had a 3+ IHC status. Conclusions: Our data suggest a lower efficacy of T-DM1 after progression on dual HER2-blockade PT. After all, EMILIA trial did not robustly evaluate the role of T-DM1 in this specific subset of pts. Obviously, larger prospective studies are necessary in order to optimize the best sequence strategy in the treatment of metastatic HER2+ BC, in light of the increasingly innovative anti-HER2 agents.

Abstract P5-03-15: Mechanism of activation of PPP1R1B drug-resistance gene in trastuzumab-resistant Her2+ breast cancer

Abstract Trastuzumab (Herceptin) resistance is a persistent challenge in the treatment of metastatic Her2+ breast cancer, with an average relapse time of 1 year after treatment. Human breast cancer cell-lines (SKBr3 and BT474) selected for trastuzumab resistance have a PPP1R1B gene (chr17:39,626,924-39,636,626) that is transcriptionally activated compared to their drug-sensitive counterparts. PPP1R1B codes for two related protein products, Darpp-32 (long) and t-Darpp (short), that are overexpressed in 50% of clinical breast cancer samples in comparison to normal breast tissue; reintroduction of t-Darpp into drug-sensitive cells confers drug resistance. The mechanism controlling overexpression of these transcripts is unknown. To gain insight into this mechanism we used ATAC-seq to map open chromatin areas in trastuzumab-resistant breast cancer cell lines and compared their open chromatin areas to those in the parental trastuzumab-sensitive counterparts. The PPP1R1B gene consists of 7 canonical exons. In each trastuzumab-resistant line there is two significantly increased open chromatin peaks, one within exon 2 and one within exon 3. We are performing deep sequencing (>200 million reads) to identify transcription factor footprints in these peaks. Furthermore, we performed RNA-seq analysis and identified genes that are similarly regulated in the resistant lines in comparison to their drug-sensitive counterparts. In summary, these results shed light on an area of high clinical importance and point to potential drug targets to be developed to overcome trastuzumab resistance in Her2+ breast cancer. Citation Format: Momand J, Murad R, Ma X, Geng S, Mortazavi A. Mechanism of activation of PPP1R1B drug-resistance gene in trastuzumab-resistant Her2+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-15.

Pre-clinical analysis of the CDK4/6 inhibitor palbociclib in HER2-positive breast cancer.

e12520 Background: There has been substantial progress in treatment of metastatic HER2+ breast cancer, unfortunately, treatment progression of the disease is universal. Palbociclib is an oral cyclin-dependent kinase (CDK) 4/6 inhibitor that is FDA approved in combination with endocrine therapy for treatment of patients with ER+ metastatic breast cancer. Here we present pre-clinical studies in HER2+ breast cancer cell lines investigating whether addition of palbociclib to the combination of trastuzumab and pertuzumab (TP) is an effective therapy, and whether we could identify predictive biomarkers for palbociclib in this setting. Methods: Crystal violet assays to measure growth of BT-474 (HER2+, ER+), SKBr3 (HER2+, ER-) and MDA-MB-361 (HER2+, ER+ but resistant to TP) were performed in the presence and absence of TP (5 µg/ml each) with increasing concentrations of palbociclib (25-500 µg/ml). Western blots were performed in the presence and absence of TP with and without palbociclib to demonstrate efficacy of TP (blocking phosphorylation of HER2), palbociclib (blocking phosphorylation of Rb), and expression of NIMA-related kinase 2 (NEK2), an established downstream target of CDK4 in HER2+ breast cancer cells. Results: We found growth inhibition in response to palbociclib as single agent in a dose-dependent manner in BT-474, SKBr3, and MDA-MB-361 cells (P < 0.05). Treatment with TP prevented growth in BT-474 and SKBr3 cells to such a great extent that an additive effect between TP and palbociclib was not detectable. However, treatment with palbociclib maintained a dose-dependent decrease in growth in the presence of TP in MDA-MB-361 cells (P < 0.05). Western blots showed decreased expression of pHER2 in response to TP in BT-474 and SKBr3, but not in MDA-MB-361. Treatment with palbociclib decreased pRB in BT474, SKBr3, and MDA-MB-361 with or without TP. NEK2 expression, however, was not affected in any of these cell lines. Conclusions: Palbociclib has an inhibitory effect in resistant and non-resistant HER2-positive cell lines suggesting palbociclib represents an alternate targeting pathway for growth inhibition. Our initial work did not show reliable biomarkers to predict palbociclib effects.

Abstract 642: Transcend, a protein vector for brain delivery, allows trastuzumab to reach the brain at effective concentration after incorporation to form BT2111

Abstract Trastuzumab, a monoclonal antibody against HER2, is an effective therapy for the treatment of peripheral HER2+ breast cancer. However a significant number of patients eventually succumb to metastases of the brain because the endothelial tight junctions of the blood-brain barrier prevent distribution of trastuzumab to the metastatic tumors. Improving distribution of trastuzumab to HER2+ brain tumors represents a major hurdle in the treatment of metastatic HER2+ breast cancer. Previous studies have shown that doxorubicin conjugated to melanotransferrin (MTf) increased significantly the survival of mice bearing intracranial tumors, while doxorubicin alone was not effective. In this study we examine the potential of MTf-trastuzumab conjugates (BT2111) to penetrate the blood-brain barrier. BT2111 and trastuzumab were labeled with fluorescent markers, either Cy5.5 or rhodamine. The cellular uptakes of these labeled proteins were studied with fluorescence microscopy in cultures of primary human brain endothelial cells (HBEC) and in HER2+ (A172, SKBR3, and BT474), and HER2- (MDA-MB-468) breast cancer cell lines. The fluorescent conjugates were also injected IV into mice and the distribution of BT2111 and trastuzumab to endothelial cells and brain parenchyma was compared with laser scanning confocal microscopy. To aid in the co-localization of BT2111 and trastuzumab to the brain vasculature, mice were injected with tomato lectin-FITC or anti CD31 IgG-FITC prior to sacrifice. The results showed that primary human brain endothelial cells (HBEC) took up BT2111 suggesting that BT2111 can interact with the MTf receptor and transport BT2111 into the intracellular compartment. In contrast, no specific staining associated with trastuzumab was observed, either on the surface or in the interior of HBECs. Uptake of both BT2111 and trastuzumab was observed on the surface of A172, SKBR3, and BT474 cells but not on MDA-MB-468 cells confirming that BT2111 retains HER2 binding activity. When BT2111 and trastruzumab were injected into mice, laser scanning confocal microscopy showed increased distribution of BT2111 in the brain parenchyma when compared to trastuzumab. 10 to 15 times more trastuzumab was delivered in the brain parenchyma when conjugated to MTf. Using a mice model characterized by the formation of brain metastasis after intracardiac administration of MDA-MB 231BR we show that BT2111 is homogenously distributed in normal brain and can reach therapeutical concentration in the brain using 10% of the predicted therapeutic IV dose when trastuzumab was administered as BT2111. These results indicate that BT2111 has the potential to become a new anti-cancer agent for treatment of HER2+brain metastases. Citation Format: Reinhard Gabathuler, Timothy Z. Vitalis, Mohamed I. Nounou, Chris E. Adkins, Paul R. Lockman, Wilfred A. Jefferies. Transcend, a protein vector for brain delivery, allows trastuzumab to reach the brain at effective concentration after incorporation to form BT2111. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 642. doi:10.1158/1538-7445.AM2014-642

Abstract 2653: Anti-cancer antibody trastuzumab-melanotransferrin conjugate (BT2111) for the treatment of metastatic HER2+ breast cancer tumors in the brain: An in vivo study

Abstract Background: Approximately 20% of patients with Her2+ metastatic breast cancer may be diagnosed with brain metastases. Trastuzumab, has been used successfully to treat peripheral Her2+ breast cancers, but has shown limited efficacy in brain metastases. Human melanotransferrin analog (MTf) is a vector to transport drugs across the blood brain barrier. In the current work, we investigated brain and brain metastases uptake of a MTf-trastuzumab conjugate (BT2111), and determined if the conjugate had efficacy in reducing the number and size of metastatic lesions in a preclinical model of brain metastases of breast cancer. Methods: Human metastatic brain seeking breast cancer cells (MDA-MB-231-Her2) were injected intracardially in 8 week old female NuNu mice (n=6-12 per group), allowed to circulate, and eventually develop experimental brain metastases. To examine drug uptake, radiolabeled conjugate (BT2111), trastuzumab and MTf was injected intravenously, and allowed to circulate for 30 min, 2 and 8 hours. Serial blood samples were drawn during circulation and terminal brain and blood samples were obtained. Drug uptake (Kin) was analyzed in relation to metastasis size and blood-tumor barrier permeability. To investigate in-vivo activity against brain metastases, we administered equimolar doses of the conjugate, and relevant controls in separate groups, biweekly starting 21 days after intracardiac injection of the metastatic cancer cells. Efficacy was assessed by determining both the number and size of metastases in brain at defined terminal endpoints. Results: Uptake of trastuzumab in “normal” brain (brain distant to tumor; BDT) was 0.17 + 0.004 x 10-6 mL/s/g and nearly 10 fold higher on average in metastatic lesions (1.1 + 0.04 x 10-6 mL/s/g). MTf uptake into BDT (18.4 + 0.5 x 10-6 mL/s/g) and brain metastases (53.0 + 3.1 x 10-6 mL/s/g) was significantly higher (p<0.01) than that of the antibody alone. BT2111 was nearly 30 fold higher (p<0.01) than that of the antibody alone in BDT (3.91 + 0.3 x 10-6 mL/s/g) and 10 fold higher (p<0.01) in metastases (10.7 + 0.43 x 10-6 mL/s/g). BT2111 reduced the number of preclinical human HER2+ breast cancer metastases in the brain of control animals (85 ± 6.3) by 68% (27.6 ± 3.9; P<0.001). Further, lesions in control animals were 54% larger (1.7 ± 0.7 µm2) than those in the BT2111 treated animals (0.78 ± 0.6 µm2; P<0.001). In contrast, trastuzumab alone had no effect on reducing the number of metastases (74 ± 5.0, P>0.05) and was associated with only a minimal (21%) reduction in metastasis size (1.34 ± 0.04 µm2). Conclusions: These results provide evidence that the MTf-trastuzumab conjugate, BT2111, has efficacy in treating brain metastasis in preclinical models and validates the role MTf has as a vector for the transport of antibodies across the BBB. Citation Format: Mohamed Nounou, Chris Adkins, Tori R. Terrell, Afroz Mohamed, Tim Vitalis, Reinhard Gabathuler, Paul R. Lockman. Anti-cancer antibody trastuzumab-melanotransferrin conjugate (BT2111) for the treatment of metastatic HER2+ breast cancer tumors in the brain: An in vivo study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2653. doi:10.1158/1538-7445.AM2014-2653

Abstract A247: BT2111, a new anticancer agent composed of trastuzumab and transcend a vector for brain delivery for the treatment of metastatic Her2+ breast cancer.

Abstract Background: The blood-brain barrier (BBB) is mainly formed by brain capillary endothelial cells, which are closely sealed by tight junctions and express high levels of active efflux transport proteins, including P-glycoprotein (Pgp). As a result, the overwhelming majority of small molecules, proteins such as antibodies do not cross the BBB. For example, a humanized monoclonal antibody, trastuzumab improves survival of patients with metastatic breast cancer that overexpress HER2. However, the breast cancer frequently progresses in the CNS probably a result from poor brain penetration of trastuzumab. BT2111 made by incorporating Transcend (Melanotransferrin, MTf, p97) a brain delivery vector to trastuzumab was manufactured to provide a non-invasive and flexible platform for transporting an active agent into the brain. Material and Methods: Brain distribution of Transcend, trastuzumab, and BT2111 was done by fluorescence confocal microscopy of brain slices after i.v. injection of rhodamine labeled molecules. Therapeutical efficacy was assessed in a mice model characterized by the formation of brain metastases after intracardiac administration of MDA-MB 231BR. A biweekly treatment was initiated on day 21 after the initial intracardiac injections. The efficacy of the different compounds was assessed by counting the number and size of metastases in brain at the termination of the experiment. Results: We demonstrate that an antibody, trastuzumab, labelled with rhodamine can be transported in the brain parenchyma after incorporation of MTf. By quantitative confocal fluorescence microscopy we determined that 10 to 15 times more antibodies were delivered in the brain parenchyma when conjugated to MTf. It was found that BT2111 reduces by 68% the number of human HER2+ breast cancer metastases in the brain when compared to control animals with the remaining tumors being 57% smaller than those in the control animals. In contrast, trastuzumab alone had no effect on reducing the number of metastases and was associated with only a slight reduction in metastasis size when compared to untreated control animals. Conclusion: Transcend (MTf, p97) a brain delivery vector can be used to transport large biologics such as mAbs, trastuzumab, at therapeutic concentration to the brain parenchyma for the treatment of brain cancers. BT2111 has the potential to become a new anticancer agent, BT2111, for treatment of brain metastases. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A247. Citation Format: Reinhard Gabathuler, Timothy Z. Vitalis, Mohamed I. Nounou, Umar Iqbal, Maria Moreno, Chris E. Adkins, Tori O. Torrell, Wilfred A. Jefferies, Paul R. Lockman. BT2111, a new anticancer agent composed of trastuzumab and transcend a vector for brain delivery for the treatment of metastatic Her2+ breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A247.

Abstract LB-481: MicroRNAs as novel therapeutic targets to treat drug-resistant breast cancers

Abstract Acquired drug resistance continues to be a major clinical impediment to the successful treatment of cancer. For example, resistance to agents such as paclitaxel and trastuzumab accounts for treatment failure in more than 90% of patients with metastatic breast cancers. Understanding the mechanisms underlying such resistance is therefore crucial for the development of new, efficacious drugs against cancer. Unfortunately in spite of extensive inquiry in this field, little is known about the key molecules and signaling pathways that regulate this phenomenon. Recently, we have discovered that microRNAs (miRNAs) may play critical roles in mediating drug sensitivity/resistance in breast cancers. We have identified miRNAs that are differentially expressed between chemo-resistant and sensitive HER2+ breast cancer cells. Specifically, through high-throughput miRNA inhibitor library screens, we have identified miRNAs that sensitize drug-resistant breast cancer cells to paclitaxel and trastuzumab, a drug combination commonly used for the treatment of metastatic HER2+ breast cancers. MiRNA/s that alter/s the cellular response to these drugs may target a common signaling pathway. For example, resistance to paclitaxel/trastuzumab in breast cancer has been proposed to be a consequence of loss of PTEN expression, leading to altered AKT signaling. Our findings suggest that certain miRNAs are selectively cytotoxic in a drug-specific manner and that these miRNAs may provide novel adjuvant therapeutic tools for the treatment of drug-resistant metastatic breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-481. doi:1538-7445.AM2012-LB-481

TRASTUZUMAB TREATMENT OF EARLY STAGE BREAST CANCER IS COST-EFFECTIVE FROM THE PERSPECTIVE OF THE BELGIAN HEALTH CARE AUTHORITIES

Trastuzumab (Herceptin®, Roche) is a recombinant, humanized monoclonal antibody directed against the neu-HER2 protein, since May 2002 reimbursed in Belgium for the treatment of metastatic HER2+ breast cancer and since June 2007 also in adjuvant therapy of HER2+ early stage breast cancer. The purpose of this study was to estimate the cost-effectiveness from the Belgian health care payer perspective of reimbursing trastuzumab in the latter indication.A Markov state transition model was designed to adequately capture the natural history and course of disease for early stage breast cancer patients, and to simulate cost and disease progression over a life time perspective. The model estimates differences in outcomes for patients treated with adjuvant trastuzumab during 1 year compared to current therapy, and captures cost consequences and health benefits of trastuzumab treatment. Health benefits were expressed in terms of quality-adjusted life years gained, and future benefits were discounted at 1.5%. Costs were calculated from the perspective of the Belgian authorities’ health care budget, and future costs were discounted at 3%. Where relevant, the costs per Markov state were obtained from the IMS Hospital Disease database. Additionally, an expert opinion analysis on resource use during the follow-up of treated early breast cancer patients provided the cost estimates for states with minor or without hospital costs.The incremental cost-effectiveness ratio based on a life time simulation was estimated at € 10,315 per quality-adjusted life year gained. It can be concluded that trastuzumab treatment of HER2+ early stage breast cancer patients is cost-effective from the perspective of the Belgian health care authorities.