Primary ER Research Articles

Abstract PD6-10: 18F-fluoroestradiol (fes) and 18f-fluorodeoxyglucose (fdg) pet imaging in metastatic lobular breast cancer

Abstract Background: The histology and pattern of spread in lobular breast cancer has presented challenges in estimating extent of disease by traditional imaging methods. 18F-FES is an estrogen analogue PET imaging tracer which measures tumor ER expression at multiple tumor sites simultaneously. It is FDA approved in the US and will be available in 2021, pressing clinicians to define the role of FES in patients with breast cancer before use in practice. We compared quantitative FES-PET and clinical FDG-PET SUV uptake between patients with metastatic lobular carcinoma. Methods: Metastatic lesions in patients with primary ER+ lobular breast cancer were retrospectively evaluated with FES- and FDG-PET. SUV uptake was calculated in 38 patients enrolled in various studies at our institution. Up to ten matched lesions in each patient were assessed for a total of 192 lesions. Pairwise t-tests were performed to measure the difference between paired FES and FDG lesions. Results: Among metastatic breast cancer patients with lobular histology, 87% of patients had a positive FES scan. The majority of positive scans demonstrated uptake in all sites, with only a small percentage (6%) lacking FES uptake in at least one lesion. Uptake was noted in various metastatic tumor sites including bone (78%), soft tissue/lymph node (17%), breast (8%) and lung (1%). Mean (range) SUVmax in FES and FDG respectively was 3.38 (0.88, 9.08) and 4.14 (1.25, 9.49). Paired lesion analysis showed concordance between the two imaging modalities in lesions with low SUV uptake. FES and FDG uptake, however, could be discordant in both directions (FES > FDG, and FDG > FES) when there is higher level of uptake in at least one of the tracers. This was specifically seen in the 150 bone lesions, possibly indicating differences in lesion phenotype or response to therapy. Conclusions: FES and FDG scans demonstrate similar average SUV uptake in metastatic lobular breast cancer, suggesting that both scans have utility in detecting lobular histology. Our data suggests that at higher SUV values, FES may provide additional information to FDG. Discordance between FES and FDG SUV uptake in the same lesions, especially in bone, has important implications for staging and assessing response to therapy. Large prospective trials are needed to define the clinical utility of FES-PET in metastatic lobular breast cancer. Research Support: P01CA42045, R01CA72064, U01CA148131, DOD W81XWH-04-01-0675 Citation Format: Poorni Manohar, Lanell Peterson, Vicky Wu, Isaac Jenkins, Mark Muzi, Jennifer Specht, Delphine Chen, Jeanne Link, Kenneth Krohn, Paul Kinahan, David Mankoff, Hannah Linden. 18F-fluoroestradiol (fes) and 18f-fluorodeoxyglucose (fdg) pet imaging in metastatic lobular breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD6-10.

Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer.

Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor-positive (ER+)/HER2- breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes. Parental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes. Parental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an "IFN-related palbociclib-resistance Signature" (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis. Aberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.

Trefoil factor-1 upregulation in estrogen-receptor positive breast cancer correlates with an increased risk of bone metastasis.

Bone is one of the most preferred sites of metastatic spread from different cancer types, including breast cancer. However, different breast cancer subtypes exhibit distinct metastatic behavior in terms of kinetics and anatomic sites of relapse. Despite advances in the diagnosis, the identification of patients at high-risk of bone recurrence is still an unmet clinical need. We conducted a retrospective analysis, by gene expression and immunohistochemical assays, on 90 surgically resected breast cancer samples collected from patients who experienced no evidence of distant metastasis, bone or visceral metastasis in order to identify a primary tumor-derived marker of bone recurrence. We identified trefoil factor-1 (pS2 or TFF1) as strictly correlated to bone metastasis from ER+ breast cancer. In silico analysis was carried out to confirm this observation, linking gene expression data with clinical characteristics available from public clinical datasets. Then, we investigated TFF1 function in ER+ breast cancer tumorigenesis and bone metastasis through xenograft in vivo models of MCF 7 breast cancer with gain and loss of function of TFF1. As a response to microenvironmental features in primary tumors, TFF1 expression could modulate ER+ breast cancer growth, leading to a less proliferative phenotype. Our results showed it may not play a role in late stages of bone metastasis, however further studies are warranted to understand whether it could contribute in the early-stages of the metastatic cascade. In conclusion, TFF1 upregulation in primary ER+ breast cancer could be useful to identify patients at high-risk of bone metastasis. This could help clinicians in the identification of patients who likely can develop bone metastasis and who could benefit from personalized treatments and follow-up strategies to prevent metastatic disease.

Metformin partially reverses the inhibitory effect of co-culture with ER-/PR-/HER2+ breast cancer cells on biomarkers of monocyte antitumor activity.

BackgroundImmune activities of monocytes (MOs) can be altered within the microenvironment of solid malignancies, including breast cancer. Metformin (1,1-dimethylbiguanide hydrochloride, MET), has been shown to decrease tumor cell proliferation, but its effects have yet to be explored with respect to MOs (monocytes) activity during their crosstalk with breast cancer cells. Here, we investigated the effects of MET on overall phenotypic functional activities, including cellular immunometabolism and protective redox signaling based-biomarkers, intracellular free calcium ions (ifCa2+), phagocytosis and co-operative cytokines (IFN-γ and IL-10) of autologous MOs before and during their interplay with primary ER-/PR-/HER2+ breast cancer cells.MethodsHuman primary breast cancer cells were either cultured alone or co-cultured with autologous MOs before treatment with MET.ResultsMET downregulated breast cancer cell proliferation and phagocytosis, while having no significant effect on the ratio of phosphorylated Akt (p-Akt) to total Akt. Additionally, we observed that, in the absence of MET treatment, the levels of lactate dehydrogenase (LDH)-based cytotoxicity, catalase, ifCa2+, IL-10 and arginase activity were significantly reduced in co-cultures compared to levels in MOs cultured alone whereas levels of inducible nitric oxide synthase (iNOS) activity were significantly increased. In contrast, MET treatment reduced the effects measured in co-culture on the levels of LDH-based cytotoxicity, arginase activity, catalase, ifCa2+, and IFN-γ. MET also induced upregulation of both iNOS and arginase in MO cells, although the increase did not reach significant difference for iNOS activity. Moreover, MET induced a robust increase of superoxide dismutase (SOD) activity in MOs, but not in MOs co-cultured with breast cancer cells. Furthermore, MET markedly upregulated the levels of IFN-γ production and downregulated those of IL-10 in isolated MOs, while inducing a slight opposing up-regulation of IL-10 production in co-cultures.ConclusionsOur results show that the biomarkers of phenotypic functional activities of MOs are modified after co-culturing with primary human breast cancer cells. Treatment of co-cultures with MET resulted in increased release of antitumor cytokine IFN-γ and ifCa2+, and increased cell necrosis during breast cancer cells-MOs crosstalk.

Successful Implementation of the Exercise First Approach for Intermittent Claudication in the Netherlands is Associated with Few Lower Limb Revascularisations

A stepped care model, in which patients are primarily treated with supervised exercise therapy (SET), is recommended as the optimal strategy for intermittent claudication (IC). The aim of this study was to determine the primary treatment (SET, endovascular revascularisation [ER], or open surgery) in relation to secondary lower limb revascularisation and survival in patients with IC. This study was a nationwide retrospective data analysis of health insurance claims of patients newly diagnosed with IC between January 2013 and December 2017. Exclusion criteria were the presence of diagnostic codes for critical limb ischaemia or for a diabetic foot. Study outcomes were distribution of primary treatment modalities, freedom from secondary lower limb revascularisation, and overall five year survival. Analysis included Kaplan-Meier method and Cox proportional hazards regression models with adjustment for multiple confounders (age, gender, socioeconomic status, use of diabetes medication, statins, platelet aggregation inhibitors or anticoagulants, presence of cardiac disease, chronic obstructive pulmonary disease, and pre-dialysis). The five year cohort included 54504 patients with IC (primary SET n=39476, primary ER n=11769, and primary open surgery n=3 259). SET as primary treatment increased from 63% in 2013 to 87% in 2017. Patients who underwent ER or open surgery as a primary treatment had a higher risk of secondary revascularisations (hazard ratio [HR] 1.44; 95% confidence interval [CI] 1.37-1.51; p<.001 and HR 1.45; 95% CI 1.34-1.57; p<.001, respectively) and a higher mortality risk compared with SET as a primary treatment (HR 1.38; 95% CI 1.29-1.48; p<.001 and HR 1.49; 95% CI 1.34-1.65; p<.001, respectively). Guideline adherence improved to 87% in Dutch patients with IC. Patients receiving primary SET had fewer lower limb revascularisations and demonstrated better survival than patients undergoing primary ER or open surgery.

The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ

BackgroundOestrogen receptor (ER) in invasive breast cancer (BC) predicts response to endocrine therapy (ET) and provides prognostic value. In this study, we investigated the value of ER expression in ductal carcinoma in situ (DCIS) in terms of outcome and the impact on ET decision.MethodsIn total, 643 pure DCIS, diagnosed at Nottingham University Hospitals, were assessed for ER. Clinicopathological data were correlated against ER status, together with assessment of recurrence rate.ResultsER positivity was observed in 74% (475/643) of cases. ER positivity was associated with clinicopathological variables of good prognosis; however, outcome analysis revealed that ER status was not associated with local recurrence. In the intermediate- and high-grade ER-positive DCIS, 58% (11/19) and 63% (15/24) of the recurrences were invasive, respectively, comprising 7% and 6% of all ER-positive DCIS, respectively. Invasive recurrence in low-grade DCIS was infrequent (2%), and none of these patients died of BC. The ER status of the recurrent invasive tumours matched the primary DCIS ER status (94% in ipsilateral and 90% of contralateral recurrence).ConclusionThe strong correlation between DCIS and invasive recurrence ER status and the clinical impact of ET justify discussion of the use of ET in ER-positive DCIS treated by breast-conserving surgery. The excellent outcome of low-grade DCIS, which was almost always ER-positive, does not, in the opinion of authors, justify the use of risk-reducing ET. Therefore, the decision on ET for DCIS should be personalised and consider grade, ER status and other characteristics.

Primary 21-Gene Recurrence Score and Disease Outcome in Loco-Regional and Distant Recurrent Breast Cancer Patients.

Background: The 21-gene recurrence score (RS) assay has been proven prognostic and predictive for hormone receptor-positive/HER2-negative, node-negative early breast cancer patients. However, whether primary 21-gene RS can predict prognosis in recurrent breast cancer patients remained unknown.Patients and Methods: Consecutive breast cancer patients operated in Comprehensive Breast Health Center, Shanghai Ruijin Hospital between January 2009 and December 2018 were retrospectively analyzed. Patients with available 21-gene RS result for the primary tumor and reporting disease recurrence during follow-up were included. Association of 21-gene RS and overall survival (OS), post-recurrence overall survival (PR-OS), post-recurrence progression-free survival (PR-PFS), and first-line systemic treatment after recurrence were compared among different groups.Results: A total of 74 recurrent patients were included, with 10, 27, 37 patients in the RS <18, 18–30, and ≥ 31 groups, respectively. Recurrent patients with RS ≥ 31 were more likely to receive chemotherapy as their first-line treatment compared to those with RS <31 (P = 0.025). Compared to those with RS <31, patients with RS ≥ 31 had significantly worse OS (P = 0.025), worse PR-OS (P = 0.026), and a trend of inferior PR-PFS (P = 0.106). Multivariate analysis demonstrated that primary ER expression level (OS: P = 0.009; PR-OS: P = 0.017) and histological grade (OS: P = 0.003; PR-OS: P = 0.009), but not primary 21-gene RS (OS: P = 0.706; PR-OS: P = 0.120), were independently associated with worse OS and PR-OS.Conclusions: High primary 21-gene RS tended to be associated with worse disease outcome in loco-regional and distant recurrent breast cancer patients, which could influence the first-line systemic treatment after relapse, warranting further clinical evaluation.

Candidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancer

BackgroundEstrogen receptor (ER) positive breast cancer is often effectively treated with drugs that inhibit ER signaling, i.e., tamoxifen (TAM) and aromatase inhibitors (AIs). However, 30% of ER+ breast cancer patients develop resistance to therapy leading to tumour recurrence. Changes in the methylation profile have been implicated as one of the mechanisms through which therapy resistance develops. Therefore, we aimed to identify methylation loci associated with endocrine therapy resistance.MethodsWe used genome-wide DNA methylation profiles of primary ER+/HER2- tumours from The Cancer Genome Atlas in combination with curated data on survival and treatment to predict development of endocrine resistance. Association of individual DNA methylation markers with survival was assessed using Cox proportional hazards models in a cohort of ER+/HER2- tumours (N = 552) and two sub-cohorts corresponding to the endocrine treatment (AI or TAM) that patients received (N = 210 and N = 172, respectively). We also identified multivariable methylation signatures associated with survival using Cox proportional hazards models with elastic net regularization. Individual markers and multivariable signatures were compared with DNA methylation profiles generated in a time course experiment using the T47D ER+ breast cancer cell line treated with tamoxifen or deprived from estrogen.ResultsWe identified 134, 5 and 1 CpGs for which DNA methylation is significantly associated with survival in the ER+/HER2-, TAM and AI cohorts respectively. Multi-locus signatures consisted of 203, 36 and 178 CpGs and showed a large overlap with the corresponding single-locus signatures. The methylation signatures were associated with survival independently of tumour stage, age, AI treatment, and luminal status. The single-locus signature for the TAM cohort was conserved among the loci that were differentially methylated in endocrine-resistant T47D cells. Similarly, multi-locus signatures for the ER+/HER2- and AI cohorts were conserved in endocrine-resistant T47D cells. Also at the gene set level, several sets related to endocrine therapy and resistance were enriched in both survival and T47D signatures.ConclusionsWe identified individual and multivariable DNA methylation markers associated with therapy resistance independently of luminal status. Our results suggest that these markers identified from primary tumours prior to endocrine treatment are associated with development of endocrine resistance.

Evidence-based guidelines for managing patients with primary ER+ HER2\u2212 breast cancer deferred from surgery due to the COVID-19 pandemic

Many patients with ER+ HER2− primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER <6 or ER 6 and PgR <6) (ii) a biopsy for Ki67 analysis (on-treatment Ki67) could be considered after 2–4 weeks of NeoET (a: ER 7 or 8 and PgR <6 or b: ER 6 or 7 and PgR ≥6) or (iii) NeoET is an acceptable course of action (ER 8 and PgR ≥6). Cut-offs for percentage of cells positive are also given. For group (ii), a high early on-treatment level of Ki67 (>10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2− breast cancer during and in the aftermath of the COVID-19 crisis.

Acquired RB1 mutations in estrogen receptor-positive (ER+) clinically advanced and metastatic breast cancer (MBC).

1053 Background: Prior to use of cell cycle inhibitor drugs such as palbociclib, mutations in the retinoblastoma cell cycle inhibitory gene ( RB1) were extremely uncommon. To assess recent descriptions of RB1 mutations in MBC as treatment related, we compared primary untreated ER+ breast cancer samples from patients who developed MBC with ER+ MBC metastasis biopsies in post-primary treatment patients. Methods: Extracted DNA from 15 untreated primary breast tumors (PBx) and 36 treated metastatic MBC tumors (MBx) were sequenced by hybrid capture genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. PD-L1 expression was determined by IHC (Dako 22C3). Results: The age distribution, GA per tumor, CDH1 and ERBB2 GA frequencies were similar in PBx and MBx. GA in ESR1 (P &lt; 0.0008), classically associated with acquired hormonal therapy resistance, and PIK3CA (p &lt; 0.11) were increased in the MBx vs the PBx samples. RB1 GA were more frequent in the MBx samples (11%) than the pre-treatment PBx samples (0%, P &lt; 0.31). GA not associated with targeted therapy programs were similar in both groups. In addition to low frequencies of ERBB2 amplification in the ER+ tumors, the most frequent potentially targetable GA identified in both PBx and MBx included GA in FGFR1 and NF1. BRCA1 GA were identified in the MBx group only. Biomarkers of potential immunotherapy benefit including MSI status, TMB levels and PD-L1 IHC staining were at similarly low levels in both groups. Additional cases are being identified to expand the cohort sizes for final presentation. Conclusions: In addition to the well-known acquisition of hormonal therapy resistance mutations in ESR1 and PIK3CA in ER+ MBC, this study also supports the acquisition of RB1 mutations when post-treatment metastasis biopsies are sequenced rather than pre-treatment primary tumors. This increase in RB1 mutation identification is associated with exposure of the tumors to anti-cell cycle drugs such as palbociclib in the treated but not the untreated cohort. [Table: see text]

46P Tumour infiltrating lymphocytes in breast cancer: High levels of CD3, CD8 cells and Immunoscore® are associated with pathological CR in patients receiving neo-adjuvant chemotherapy

The presence of high levels of tumor infiltrating lymphocytes (TILs) has been associated with better prognosis in early triple-negative breast cancer (TNBC). The Immunoscore® (IS) is a prognostic tool, which categorizes the densities of spatially positioned CD3 and CD8 cells in both invasive margins (IM) and the center of the tumor (CT), yielding a five-tiered classification (0–4). High IS values have been reported to predict improved outcomes in colorectal cancer patients (pts). We performed the IS in 103 breast cancer (BC) pts who previously received neo-adjuvant anthracycline and taxane +/- trastuzumab based chemotherapy TNBC=53, Luminal=32, HER2+=18. Pre-treatment tumor samples were immune-stained for CD3 and CD8 T-cell markers. Quantitative analysis of the immune cells was carried out using a computer-assisted image analysis in different tumor locations. The pathological complete response (pCR) rate of the entire cohort was 44%. On univariate analysis, factors associated with higher pCR included primary tumor size (p<0.005), nodal status (p<0.069), ER (p<0.000), PR (p<0.000), molecular subtype (TNBC=62%, HER2+=50% and Luminal A+B=9%, p<0.000), Ki67 (>40=56% vs 15-39=40% vs <15=0%, p<0.000) and Stage (p<0.028). A high density of CD3 (> than 800mm2) and CD8 (> than 400mm2) positive T-cells in the CT was associated with higher pCR (CD3 CT: 60% vs 25%, p=0.000 and CD8 CT: 64% vs 27%, p=0.000). Analysis of CD3 (> than 1400mm2) (CD3 IM: 63% vs 19%, p=0.00) and CD8 in the IM (> than 500mm2) was also significant for an association with pCR (CD8 IM:63% vs 15%, p=0.000). High IS (3+4= 63%) vs intermediate (2=35%) vs low (0+1=24%) was significantly associated with pCR (p=0.006). In a logistic regression model Ki-67 (p<0.005) and IS (p<0.021) and molecular subtype (p<0.010) retained significance. DFS: At 3 years 94% of IS high pts did not relapse compared to 80% IS intermediate or low pts (p<0.07). This study shows a significant prognostic and potentially predictive role for the IS in BC pts, particularly in TNBC. This study shows a significant prognostic and potentially predictive role for the IS in BC pts, particularly in TNBC.

ER and PI3K Pathway Activity in Primary ER Positive Breast Cancer Is Associated with Progression-Free Survival of Metastatic Patients under First-Line Tamoxifen.

Estrogen receptor positive (ER+) breast cancer patients are eligible for hormonal treatment, but only around half respond. A test with higher specificity for prediction of endocrine therapy response is needed to avoid hormonal overtreatment and to enable selection of alternative treatments. A novel testing method was reported before that enables measurement of functional signal transduction pathway activity in individual cancer tissue samples, using mRNA levels of target genes of the respective pathway-specific transcription factor. Using this method, 130 primary breast cancer samples were analyzed from non-metastatic ER+ patients, treated with surgery without adjuvant hormonal therapy, who subsequently developed metastatic disease that was treated with first-line tamoxifen. Quantitative activity levels were measured of androgen and estrogen receptor (AR and ER), PI3K-FOXO, Hedgehog (HH), NFκB, TGFβ, and Wnt pathways. Based on samples with known pathway activity, thresholds were set to distinguish low from high activity. Subsequently, pathway activity levels were correlated with the tamoxifen treatment response and progression-free survival. High ER pathway activity was measured in 41% of the primary tumors and was associated with longer time to progression (PFS) of metastases during first-line tamoxifen treatment. In contrast, high PI3K, HH, and androgen receptor pathway activity was associated with shorter PFS, and high PI3K and TGFβ pathway activity with worse treatment response. Potential clinical utility of assessment of ER pathway activity lies in predicting response to hormonal therapy, while activity of PI3K, HH, TGFβ, and AR pathways may indicate failure to respond, but also opens new avenues for alternative or complementary targeted treatments.

Abstract P6-04-08: Mismatch repair defects induce metastasis of ER+ breast cancer

Abstract Estrogen receptor (ER) positive breast cancer is a leading cause of cancer-related death among women globally. Metastasis and endocrine treatment resistance are the two principal causes of death from ER+ breast cancer. There are few available targeted therapeutics for metastatic, endocrine treatment resistant disease other than CDK4/6 inhibitors. However, CDK4/6 inhibitors only work in a subset of patients and markers that can identify these patients have not yet been discovered. Considering cost and toxicity associated with chronic use of these inhibitors, it is critical to identify (a) biomarkers of response (b) combinatorial approaches to enhance efficacy. To achieve these goals, we need to understand the biology underlying endocrine treatment resistance and CDK4/6 inhibitor response. We recently identified loss of the MutL complex of mismatch repair (MLH1 and PMS2), as a cause of endocrine treatment resistance in 5-10% of women with primary (non-metastasized) ER+ breast cancer. We also demonstrated that primary ER+ breast cancer cells defective in these genes lacked ATM/Chk2 activation and were, therefore, sensitized to CDK4/6 inhibitors. Here, we present data demonstrating that MutL loss induces metastasis of ER+ breast cancer cells, which can be prevented/treated using ATM/Chk2 activators in combination with CDK4/6 inhibitors. We observed increased migration and invasion in three independent cell line models of MutL loss when treated with endocrine therapies in vitro, and increased lung colonization in vivo. We observe a similar phenotype in a PDX model of MutL defective ER+ disease. We also demonstrate significant inhibition of metastatic phenotypes upon administration of a combination of CDK4/6 inhibitors and ATM/Chk2 activators. Alternative targeted therapies that are effective against metastatic ER+ breast cancer remain elusive, and lethality associated with this diagnosis remains high. Current standard care comprises of endocrine treatment administered with CDK4/6 inhibitors. Even when effective, this combination is costly and associated with side effects as it requires chronic administration to maintain stable disease. The results of this study suggest that (a) MutL loss can be a predictor of increased risk for metastatic disease (b) MutL defective ER+ breast cancer has increased sensitivity to CDK4/6 inhibitors (c) combinatorial use of ATM/Chk2 activators with CDK4/6 inhibitors could significantly benefit ER+ breast cancer patients with defective MutL. These potential outcomes could greatly improve quality of life and decrease cancer-related death in thousands of women every year. Citation Format: Sujita Khanal, Athena Jimenez, Svasti Haricharan. Mismatch repair defects induce metastasis of ER+ breast cancer [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 P6-04-08.

Abstract GS2-01: High levels of interferon-response gene signatures are associated with de novo and acquired resistance to CDK4/6 inhibitors in ER+ breast cancer

Abstract Background: The CDK4/6 inhibitors (i) palbociclib (Palbo), ribociclib, and abemaciclib remarkably improved the outcome of patients with metastatic ER+/HER2- breast cancer (BC) and are now under clinical investigation in early BC. Despite high efficacy, de novo and acquired resistance to CDK4/6i is common. Elucidating the molecular basis for sensitivity and resistance to CDK4/6i is crucial to identify predictive biomarkers and novel therapeutic targets to improve patient outcome. Materials and Methods: MCF7, T47D and ZR75-1 parental (P) BC cells and their derivatives made resistant to tamoxifen, estrogen deprivation (EDR), or fulvestrant were used. The P and EDR models of MCF7 and T47D cells were chronically exposed to increasing concentrations of Palbo to generate derivatives with acquired resistance to Palbo (PalboR). The transcriptomic profiles of P, endocrine-resistant (EndoR) and PalboR models were determined by RNA-seq. IC50s were determined by exposing MCF7, T47D, and ZR75-1 P and EndoR lines (n=12) to increasing concentrations of Palbo. Cell growth was assessed by methylene blue staining, and changes in the mRNA and protein levels of key cell cycle molecules were assessed by RT-PCR and Western blot, respectively. Gene expression data from the Cancer Dependency Map (DepMap), baseline tumors from the NeoPalAna (NCT01723774) and neoMONARCH (NCT02441946) neoadjuvant trials, as well as the TCGA and METABRIC datasets were interrogated for correlations of gene signatures and patient outcome (by KMPlot). Results: Palbo treatment resulted in a dose-dependent inhibition of the growth of P and EndoR BC cell lines, with varying degree of sensitivity among the models. GSEA analysis comparing the least sensitive (IC50&amp;gt;350nM) vs. the most sensitive (IC50&amp;lt;100) cell lines identified the ‘interferon gamma response’ (IFNg) and ‘interferon alpha response’ (IFNa) as the top-ranked hallmark enriched signatures. Likewise, DepMap analysis of ER+/HER2- BC cell lines (n=11) revealed that cells with low CDK4 dependency scores displayed high IFN-signaling. We derived a 35-gene signature (termed ‘IFN-Related Palbociclib-Resistance Signature’, IRPS) comprised of genes belonging to the INFg and INFa gene sets that positively correlated with the Palbo IC50 values of our collection of P and EndoR lines. To extend these findings to primary ER+ BC, we interrogated transcriptomic data from the NeoPalAna and neoMONARCH trials that evaluated neoadjuvant CDK4/6i with endocrine therapy. In both trials, the IFNg, IFNa, and IRPS gene signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. We next investigated the underlying molecular changes and their association with IFN-signaling in our acquired resistant PalboR cell lines. Compared to the untreated cells, the PalboR models commonly displayed alterations in several components of the cyclin D-CDK4/6-Rb axis, including elevated expression of cyclin-D1, -E1, and CDK6, and reduced levels of Rb. Notably, the PalboR derivatives commonly displayed a dramatic activation of IFN/STAT1-signaling compared to their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB vs. lumA subtype and correlated with increased gene expression of immune checkpoints (PD-1, PD-L1, CTLA-4), endocrine-resistance, and poor prognosis. Conclusion: Aberrant IFN-signaling predicts resistance to CDK4/6i in both ER+/HER2- BC cell lines and in primary BCs from neoadjuvant clinical trials. Experimentally, acquired resistance to Palbo is associated with activation of the IFN-pathway suggesting its involvement in resistance to CDK4/6i. Future studies are warranted to provide mechanistic insights into the association of IFN-signaling with response to CDK4/6i. Citation Format: Carmine De Angelis, Xiaoyong Fu, Maria Letizia Cataldo, Agostina Nardone, Valerie M. Jansen, Jamunarani Veeraraghavan, Sarmistha Nanda, Lanfang Qin, Vidyalakshmi Sethunath, Resel Pereira, Matteo Benelli, Ilenia Migliaccio, Luca Malorni, Joshua Donaldson, Pier Selenica, David N. Brown, Britta Weigelt, Jorge S. Reis-Filho, Ben H. Park, Sara A. Hurvitz, Dennis J. Slamon, Mothaffar F. Rimawi, Rinath Jeselsohn, Kent Osborne, Rachel Schiff. High levels of interferon-response gene signatures are associated with de novo and acquired resistance to CDK4/6 inhibitors in ER+ breast cancer [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 GS2-01.

Abstract P4-10-18: Changes in tumour infiltrating lymphocytes during neoadjuvant endocrine therapy and possible clinical implications for guiding therapy

Abstract Background: Stromal Tumour Infiltrating Lymphocytes (sTILs) has been established as a predictive biomarker for response to neoadjuvant chemotherapy irrespective of subtype. While increased sTIL levels is associated with prolonged survival among patients with triple-negative and HER2 positive breast cancer increased sTILs has in Estrogen Receptor positive (ER+) breast cancer been suggested to be an adverse prognostic factor. It has been hypothesised that differences in the cellular composition of immune cells may explain the dissimilarity in prognostic impact according to breast cancer subtype. Here, we report data from a neoadjuvant phase II study, treating postmenopausal patients with primary ER+, HER2 negative, operable breast cancer with letrozole for four months by the Danish Breast Cancer Group (DBCG). We analysed the association of sTILs, and changes in sTILs during neoadjuvant endocrine treatment (NET), with pathological response and correlation with other clinicopathological variables such as Ki67, as potential biomarkers for risk-stratification of patients following NET. Method: 113 postmenopausal patients with ER+, HER2 negative breast cancer were treated with NET for four months. Endpoint was pathological response assessed by a modified Miller Payne scale and the Residual Cancer Burden (RCB) score. Pretherapeutic core biopsies and post therapeutic surgical specimens were assessed centrally for the percentage of sTILs on HE sections according to the International TILs working group guidelines. sTILs association to pathological response were assessed with univariate logistic regression. Odds Ratio (OR) was estimated with a 95 % confidence interval. Correlation of sTILs and Ki67 were tested with Pearson´s correlation coefficient. Changes in sTILs with a paired t-test. Level of significance was set to 5 %. Results: sTILs concentration increased with mean 6.8 % (p &amp;lt;.0001) during treatment in the assessable patients (range -39 % - 60 %). Forty-four percent had no pathological response as assessed by the modified Miller Payne scale and 11 % had RCB-Class III after NET. Increase in sTILs was significantly associated with poorer pathological response with OR=1.38 (95 % CI: 1.05 - 1.82; p = 0.03) per 10 % increase for no pathological response, and correspondingly OR=1.78 (95 % CI: 1.27 - 2.50; p &amp;lt;.0001) for higher level RCB-class per 10 % increase. The correlation between pre-therapeutic sTILs and Ki67 was moderate (Pearson 0.4; p = 0.0004), however the association grew stronger post treatment (Pearson 0.5; p &amp;lt;.0001). Conclusion: Increased sTILs activity during NET was associated with poor treatment response. An increase in sTILs during NET could be considered indictive for potential immunogenic tumours, suggesting that patients with increasing sTIL in residual disease after NET might derive benefit from the addition of immunotherapy. We found a significant correlation between sTILs and Ki67 levels. Ki67 has been established as a window of opportunity biomarker for antiproliferative response. Combining biomarkers of antiproliferative response such as Ki67 with biomarkers of immunogenetic significance might be important to determine optimal combination of adjuvant therapy. A window of opportunity study with an aromatase inhibitor could show if it is feasible to detect a rise in sTILs early enough to guide adjuvant treatment in the perioperative setting. Citation Format: Signe Korsgaard Skriver, Maj-Britt Jensen, Ann Soegaard Knoop, Bent Ejlertsen, Anne-Vibeke Laenkholm. Changes in tumour infiltrating lymphocytes during neoadjuvant endocrine therapy and possible clinical implications for guiding therapy [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 P4-10-18.

Abstract P3-01-27: Ectonucleotidase ATP hydrolysis facilitates breast cancer bone metastasis

Abstract Bone is the most common site for breast cancer metastasis. Osteocytes are the most abundant bone cell and can signal nearby cells by releasing ATP through connexin 43 hemichannels. We previously found that this signaling pathway hindered breast cancer growth in bone. In this study, we investigated the role of purinergic signaling on breast cancer bone metastasis in patient samples. Surprisingly, no ATP receptors were differentially expressed in bone metastases compared to other sites. However, enzymes that degrade ATP into adenosine (CD39/ENTPD1 and CD73/NT5E) were upregulated, as was the ADORA3 adenosine receptor (Limma, p=0.037, 0.016, 0.0019, respectively). We next investigated whether this expression signature in primary tumors predicts bone metastasis. In primary ER+ breast cancer, which predominately metastasizes to bone, high expression of these genes is correlated with lower distant metastasis-free survival (HR = 1.97, 1.49, 2.03, logrank p=0.0017, 0.0004, 0.0012). Moreover, this expression pattern is correlated with a bone metastasis signature (Spearman R=0.28, p=1.2 × 10−20). In a pharmacologic screen of 750 cancer cell lines, breast cancer lines and especially ER+ ones, are uniquely sensitive to a pan-adenosine receptor inhibitor (Limma, p=2.9 × 10−5) and ADORA3/2B inhibitor (p=5.4 × 10−5). Our findings suggest that an expression program to convert ATP to adenosine facilitates bone metastasis and begins in the primary tumor. ADORA3 inhibition is proposed as a pharmacologic strategy for preventing or treating bone metastasis. Furthermore, bone metastases should be analyzed in anti-CD39 and CD73 clinical trials. Citation Format: Daniel B Shropshire, Jaime Benavides, Jean X Jiang. Ectonucleotidase ATP hydrolysis facilitates breast cancer bone metastasis [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 P3-01-27.

Abstract P3-07-05: Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study

Abstract Background: Oncotype DX Recurrence Score (RS), Prosigna PAM50 ROR score, the EndoPredict score (EP, EPclin) and the Breast Cancer Index (BCI) all provide substantial molecular prognostic information and are used in clinical practice for guiding the treatment for large numbers of patients with primary ER+/HER2- breast cancer. Despite this, there is incomplete information on the concordance between these scores and very little understanding of the molecular features that drive the individual scores. Here we report from a unique database (i) the correlation between all 4 scores when measured by the respective manufacturers in the TransATAC set of samples and (ii) the degree to which each of the scores is driven by proliferation, oestrogen signalling, HER2 signalling and invasive properties insomuch as these are reflected by each component module of the RS test (PM, EM, HM and IM, respectively). Methods: The TransATAC tumour sample set was collected from patients in the tamoxifen or anastrozole arms from the ATAC clinical trial of 5 years of endocrine therapy in postmenopausal patients with primary hormone receptor positive breast cancer. Cases were included if HER2- and all 4 scores were available. None of the patients received adjuvant chemotherapy. EP and ROR both include some clinical features in their final score but components were excluded for the purposes of this study. The RS module scores were provided by the manufacturer. The genes that contribute to the module scores are as follows: PM: Ki67, STK15, Survivin, CCNB1, MYBL2; EM: ER, PGR, BCL2, SCUBE2; HM: GRB7, HER2; IM: MMP11, CTSL2). Spearman rank correlation was used to study the association between molecular components. Results: Data was available for all four molecular scores for 785 TransATAC patients. Correlations were moderate to strong for RS vs EP (r=0.63), ROR vs EP (r=0.68), ROR vs BCI (r=0.74) and EP vs BCI (r=0.67) but were weak for RS vs ROR (r=0.32) and RS vs BCI (r=0.35). The correlation between each score with the RS module scores are shown in the Table. Molecular scoreRS moduleRSROREPBCIPM0.360.860.710.74EM-0.790.00-0.38-0.10HM-0.04-0.14-0.15-0.18IM0.260.380.340.32 The RS had a strong negative correlation with its EM (r= -0.79) and a weak positive correlation with its PM (r= 0.36) although the latter was stronger when the PM was thresholded; 78% of the cases had a PM score below the threshold of 6.5 and were assigned a value of 6.5 in the RS with no correlation between RS and PM in these samples (r=-0.03). ROR showed a very strong correlation with the PM (r=0.86), but none with the EM (r: 0.00). EP and BCI both showed strong correlation with the PM (r= 0.71 and 0.74, respectively) and with low or near absent correlation with EM (r= -0.38 and -0.10, respectively). There was little correlation between the HM with each of the scores while the IM correlation was similar for each score varying from 0.26 to 0.38. Of the two module components of BCI, MGI was strongly associated with the PM (r= 0.84) and not at all with the EM while H/I moderately correlated with PM (r=0.51) and weakly correlated with EM (r= -0.31). Conclusion: EP scores are moderately correlated with each of the other 3 scores while RS scores are dissimilar to those from the ROR and BCI. In contrast to common thinking the RS is driven only weakly by proliferative features and more by those related to ER/PR pathways. The EP, BCI and particularly ROR are dominated by proliferative features. These relationships provide and explanation for the differences that we and others have reported in the prognostic performance of the tests for both early and late recurrence. Citation Format: Richard Buus, Ivana Sestak, Mitch Dowsett, Ralf Kronenwett, Sean Ferree, Catherine Schnabel, Frederick L Baehner, Jack Cuzick. Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study [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 P3-07-05.

Abstract P3-07-14: Multigene signatures based risk estimates in early ER+/HER2- breast cancer: The predictive value of inexpensive statistical models and changes in adjuvant chemotherapy use

Abstract Background Multigene signatures (MGS) select women with estrogen receptor positive human epidermal growth factor receptor 2 negative (ER+/HER2-) breast cancers where adjuvant chemotherapy (aCT) can be avoided. However, MGS are expensive and not always reimbursed. We investigated the predictive value of six inexpensive statistical models in tumors with low or high risk of relapse based on MGS and investigated the change in decision to add chemotherapy following MGS results. Patients and Methods In this retrospective study, we evaluated patients diagnosed with primary operable ER+/HER2- lymph node negative or positive breast cancer diagnosed at University Hospitals Leuven between 2013 and 2018. Tumor tissue of the patients was analyzed by MammaPrint® (MP) (n=25), OncotypeDX® (ODX) (n=44) or Prosigna® (n=57) as there was uncertainty about benefit of aCT during multidisciplinary meeting (MDM). Magee equations (ME), Memorial Sloan Kettering simplified score (MSK), Breast Cancer Recurrence Score Estimator (BCRSE), OncotypeDXCalculator (ODXC), new Adjuvant! Online (nAOL) and PREDICT v2.0 were computed. TAILORx cut-offs were used for ODX. A 85% cut-off was used for the probability of a low (0-25) or high risk (26-100) ODX recurrence score for ODXC and a 5% cut-off was used for 10-year survival benefit with aCT for nAOL and PREDICT. Results All ME- and BCRSE-high cases were classified by MGS as high or intermediate and not as MGS-low risk (Table 1). None of the low risk classifications by ME and nAOL resulted in MGS-high risk with ODX. High risk classification with nAOL showed strong concordance with all MGS-high risk results. A switch in chemotherapy recommendation based on MDM decisions, was observed in 46% (58/126) of patients after MGS results. Following MGS testing, aCT was given to 57 patients which resulted in 17% relative and 10% absolute reduction. Conclusion Inexpensive statistical models based on clinico-pathological parameters can be useful in selecting patients that may need MGS testing. The use of MGS resulted in a substantial decisional switch and reduction in aCT-use. Table 1 Predictive value of inexpensive statistical models in MGS tested tumors.MGS high risk (n=53)MGS low risk (n=52)ODX (n=17)MP (n=11)Prosigna (n=25)ODX (n=27)MP (n=14)Prosigna (n=11)MSK high (n=32)1038150ME high (n=7)411000BCRSE high (n=6)311000ODXC high (n=4)110010nAOL high (n=105)1772423123PREDICT high (n=47)7512850MSK low (n=37)3361145ME low (n=9)012202BCRSE low (n=50)3310967ODXC low (n=67)35131469nAOL low (n=21)041428PREDICT low (n=79)1061319911 Citation Format: Laurence Slembrouck, Isabelle Vanden Bempt, Hans Wildiers, Ann Smeets, Erik Van Limbergen, Philippe Moerman, Caroline Weltens, Kevin Punie, Griet Hoste, Els Van Nieuwenhuysen, Sileny Han, Ines Nevelsteen, Lynn Jongen, Patrick Neven, Giuseppe Floris. Multigene signatures based risk estimates in early ER+/HER2- breast cancer: The predictive value of inexpensive statistical models and changes in adjuvant chemotherapy use [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 P3-07-14.

Abstract P3-03-09: Dual targeting of BCL2 and MDM2 as a novel therapeutic strategy in ER+ breast cancer model

Abstract Background: Apoptosis is the therapeutic goal following the administration of anti-cancer drugs. BCL2 and p53 are two critical nodes in the apoptosis signaling pathway. BCL2 is overexpressed in approximately 80% of primary ER+ breast cancer (BC) patients (Merino D et al. Oncogene 2016). Venetoclax is a BCL2 selective inhibitor found to be active in clinical trials for solid tumors, including ER+ BC breast cancer (Lok SW et al. Cancer Discovery 2019). MDM2/MDM4 is a proliferating protein involved in tumorigenesis via degradation of p53. In our ER+ BC breast cancer cohort (Avera Cancer Institute, Sioux Falls, South Dakota), we observed TP53 and MDM2/4 alterations in 25% and 14% of patients respectively. Aim: Here, we hypothesize that concomitant p53 activation (by an MDM2 inhibitor, e.g., AMG232) and BCL2 inhibition (by venetoclax) induce maximum apoptosis and markedly reduce tumor cell proliferation in ER+/TP53 WT BC cells. Methods: We analyzed the expression pattern of 129 ER+ BC breast cancer patients whose tumors were subjected to comprehensive genomic profiling [FoundationOne]. We tested the anti-proliferative and apoptotic activity of venetoclax alone, AMG 232 alone, and a combination of venetoclax plus AMG 232 along with fulvestrant in ER+ BC breast cancer cells (MCF7, Zr-75-1, &amp; MDA-MB415). Results: 1) AMG 232 binds the MDM2 protein, blocks MDM2-p53 interaction, and induces p53 expression and activity, 2) p53 effector molecule p21 is robustly induced following the treatment of AMG 232, 3) the anti-proliferative activity of venetoclax or AMG232 was observed by 3D-ON-TOP clonogenic assay and real-time monitoring in an IncuCyte Zoom, 4) ER+ /TP53 wild-type (WT) cell lines exhibited an increase in annexin V positivity (initiation of apoptotic activity) following venetoclax or AMG 232 treatment, 5) importantly, a combination of venetoclax plus AMG232 robustly induced the apoptotic markers e.g. cleaved-CASPASE3/7 and cleaved PARP1 protein expression in all ER+ BC cell lines, 6) high mitochondrial depolarization was also observed following the combination of treatment, and 7) similar to protein expression data, mRNA data also showed that pro-apoptotic/cell cycle inhibitor transcripts such as p21 and PUMA mRNA expression were significantly increased and pro-survival transcripts such as survivin and stathmin mRNA expression were significantly decreased following the combination treatment. Conclusion: Our data reveal the potential of simultaneously targeting these two apoptosis regulators and provides a rational basis for clinical testing of this therapeutic approach for ER+ BC breast cancer patients that retain WT-TP53. Citation Format: Pradip De, Jennifer Carlson Aske, Poulin Pocha, Michael Sulaiman, Ethan Thompson, Nandini Dey. Dual targeting of BCL2 and MDM2 as a novel therapeutic strategy in ER+ breast cancer model [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 P3-03-09.

Abstract GS2-03: The androgen receptor is a tumour suppressor in estrogen receptor positive breast cancer

Abstract The Androgen receptor (AR) is expressed in up to 90% of primary ER-positive (ER+) breast cancer and high expression of AR is an independent prognostic factor associated with good outcome. Its role in the context of ER+ breast cancer is very controversial and has constrained clinical implementation of new drugs that influence AR activity for treatment of women with this disease, resulting in concurrent clinical trials of opposite AR agonist and antagonist strategies. Herein, using RNA-seq and Chip-seq approaches, we demonstrate that therapeutic activation of AR for treatment of breast cancer leverages a natural regulatory mechanism that inhibits estrogen-stimulated proliferation and induction of cell cycle genes in patient-derived explants (PDE) of primary ER+ breast cancers, and in contemporary in vivo patient-derived xenograft (PDX) and cell line xenograft models of ER+ breast cancer resistant to standard-of-care ER targeting agents, including those harbouring genomic aberrations of ESR1. AR-mediated growth inhibition mechanistically involved loss of ER or co-activator p300 recruitment to chromatin at key cell cycle genes, leading to transcriptional down-regulation. A signature of AR activity derived from the xenograft models positively predicted disease survival in multiple large clinical cohorts of ER+ breast cancer, outperforming other breast cancer-specific prognostic signatures. Finally, the combination strategy of a new class of non virilising Selective Androgen Receptor Modulator (SARM) in combination with CDK4/6 inhibitors demonstrated additive effects in our preclinical models. Collectively, these findings provide compelling evidence that AR has a tumour suppressor role in ER+ breast cancer and advocate an AR agonist strategy for treatment, even in the context of therapy-resistant, ESR1 mutant disease, and should dispel widespread confusion over the role of AR in ER-driven breast cancer, an issue that currently hinders progress in leveraging modern AR-targeted therapies, including available SARMs that lack the undesirable side-effects of androgens, for clinical benefit. Citation Format: Elgene Lim, Theresa A Hickey, Luke A Selth, Kee Ming Chia, Heloisa H Milioli, Daniel Roden, Geraldine Laven-Law, Shalini Jindal, Mun Hui, Esmaeil Ebrahimie, Stephen N Birrell, Suzan Stelloo, C. Elizabeth Caldon, Jessica Finlay-Schultz, Tarek M Abdel-Fatah, Ian O Ellis, Willbert Zwart, Carlo Palmieri, Carol A Sartorius, Alex Swarbrick, Jason S Carroll, Wayne D Tilley. The androgen receptor is a tumour suppressor in estrogen receptor positive breast cancer [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 GS2-03.