Antihormonal Therapy Research Articles

Admission to the ICU in the last 30 days of life and systemic anticancer therapy in the last two weeks of life at Lifespan Cancer Institute (LCI).

214 Background: The ASCO Quality Oncology Practice Initiative identifies ICU admission in the last 30 days and systemic anticancer therapy in the last 14 days of life as indicators of overly aggressive end-of-life care. We sought to delineate clinical factors associated with these indicators. Methods: An IRB approved retrospective chart review was conducted on patients with solid tumors at LCI who died in timepoints ending in January, July and November of 2016 and 2017. Patients were identified through our tumor registry. Patients’ medical records were reviewed for cancer stage, care received, palliative care contact, site of death, ICU admission in last 30 days, and receipt of systemic anticancer therapy (excluding antihormonal therapy) in last 6 months and 2 weeks of life. Results: A total of 250 patients were included in our analysis. 18.8% of LCI patients were admitted to the ICU in the last 30 days of life, 12.8% received systemic anticancer therapy in the last 2 weeks of life, and 19.2% experienced death in the hospital. Significant factors associated with an ICU admission in the last 30 days of life were a diagnosis of lymphoma compared to breast, gynecologic, gastrointestinal, lung, genitourinary, melanoma/carcinoma of unknown primary/head and neck cancer, or other (42.9% vs 20% vs 14.3% vs 9% vs 23.1% vs 25% vs 0% vs 26.3%; P = 0.01), systemic anticancer therapy in last 2 weeks of life (40.6% vs 16.1%; P < 0.005), and age ≤ 45 years at time of metastatic disease compared to age 46-65 or age ≥ 66 (50% vs 15.9% vs 18.1%; P < 0.05). A significant factor associated with systemic anticancer therapy in the last 2 weeks of life was age ≤ 45 years at time of metastatic disease compared to age 46-65 or age ≥ 66 (35.7% vs 16.9% vs 9.4%; P < 0.05). Lastly, a significant factor associated with death in the hospital was lack of palliative care team contact (28.9% vs 15%; P < 0.05). Conclusions: Understanding factors associated with intensive care at the end of life is critical to the provision of value-based cancer care. In this study, a diagnosis of lymphoma, systemic anticancer treatment in the last 2 weeks of life, and age ≤ 45 years at time of metastatic disease were associated with ICU stays in the last 30 days of life. Age ≤ 45 years at time of metastatic disease was associated with systemic anticancer treatment in the last 2 weeks of life, while lack of palliative care involvement was associated with greater chance of death in the hospital. Further understanding of the complex interplay that governs care and decision making at the end of life is required.

Risk of primary urological and genital cancers following incident breast cancer: a Danish population-based cohort study.

The prevalence of breast cancer survivors has increased due to dissemination of population-based mammographic screening and improved treatments. Recent changes in anti-hormonal therapies for breast cancer may have modified the risks of subsequent urological and genital cancers. We examine the risk of subsequent primary urological and genital cancers in patients with incident breast cancer compared with risks in the general population. Using population-based Danish medical registries, we identified a cohort of women with primary breast cancer (1990-2017). We followed them from one year after their breast cancer diagnosis until any subsequent urological or genital cancer diagnosis. We computed incidence rates and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) as the observed number of cancers relative to the expected number based on national incidence rates (by sex, age, and calendar year). Among 84,972 patients with breast cancer (median age 61years), we observed 623 urological cancers and 1397 genital cancers during a median follow-up of 7.4years. The incidence rate per 100,000 person-years was stable during follow-up (83 for urological cancers and 176 for genital cancers). The SIR was increased for ovarian cancer (1.37, 95% CI 1.23-1.52) and uterine cancer (1.37, 95% CI 1.25-1.50), but only during the pre-aromatase inhibitor era (before 2007). Moreover, the SIR of kidney cancer was increased (1.52, 95% CI 1.15-1.97), but only during 2007-2017. The SIR for urinary bladder cancer was marginally increased (1.15, 95% CI 1.04-1.28) with no temporal effects. No associations were observed for cervical cancer. Breast cancer survivors had higher risks of uterine and ovarian cancer than expected, but only before 2007, and of kidney cancer, but only after 2007. The risk of urinary bladder cancer was moderately increased without temporal effects, and we observed no association with cervical cancer.

Evidence for Enhanced Exosome Production in Aromatase Inhibitor-Resistant Breast Cancer Cells.

Aromatase inhibitors (AIs) represent the standard anti-hormonal therapy for post-menopausal estrogen receptor-positive breast cancer, but their efficacy is limited by the emergence of AI resistance (AIR). Exosomes act as vehicles to engender cancer progression and drug resistance. The goal of this work was to study exosome contribution in AIR mechanisms, using estrogen-dependent MCF-7 breast cancer cells as models and MCF-7 LTED (Long-Term Estrogen Deprived) subline, modeling AIR. We found that exosome secretion was significantly increased in MCF-7 LTED cells compared to MCF-7 cells. MCF-7 LTED cells also exhibited a higher amount of exosomal RNA and proteins than MCF-7 cells. Proteomic analysis revealed significant alterations in the cellular proteome. Indeed, we showed an enrichment of proteins frequently identified in exosomes in MCF-7 LTED cells. The most up-regulated proteins in MCF-7 LTED cells were represented by Rab GTPases, important vesicle transport-regulators in cancer, that are significantly mapped in “small GTPase-mediated signal transduction”, “protein transport” and “vesicle-mediated transport” Gene Ontology categories. Expression of selected Rab GTPases was validated by immunoblotting. Collectively, we evidence, for the first time, that AIR breast cancer cells display an increased capability to release exosomes, which may be associated with an enhanced Rab GTPase expression. These data provide the rationale for further studies directed at clarifying exosome’s role on endocrine therapy, with the aim to offer relevant markers and druggable therapeutic targets for the management of hormone-resistant breast cancers.

Abstract 5674: Discovery of AZD9833, an oral small molecule selective degrader of the estrogen receptor (SERD)

Abstract The estrogen receptor alpha (ERα) is expressed in >70% of breast cancers and is a clinically validated target in oncology. Anti-hormonal therapies that block ER function directly (e.g. tamoxifen) or therapies that block the production of estrogen itself (e.g., aromatase inhibitors) have proven to be effective treatments of the disease. Further advances in disease control have been made with the development of the Selective Estrogen Receptor Degrader (SERD) fulvestrant, which both antagonizes ERα-driven tumor cell growth and causes degradation of the ERα receptor. The first-generation oral SERDs, including AZD9496, showed full ER degradation in MCF-7 cells but incomplete ER degradation in other cell lines, and partial agonism. Building on that learning, extensive structure-enabled chemical optimization has resulted in the identification of a next generation oral SERD AZD9833, a potent degrader and antagonist of the ERα receptor (both EC50 <1 nM in MCF7 cells) with favorable physicochemical properties (logD7.4 <3). AZD9833 delivers maximal ERα degradation equivalent to fulvestrant in all ER+ cell lines tested, including MCF7, CAMA1, T47D and BT474. In addition, and in contrast to AZD9496, AZD9833 does not cause ER agonism in the endometrial carcinoma cell line Ishikawa in vitro and does not cause an increase in the thickness of the endometrium in juvenile rats. In several patient-derived and cell line xenograft models, including models with clinically relevant ESR1 mutations, AZD9833 completely suppresses tumor growth and gives equivalent pharmacodynamic activity to supra-clinical levels of fulvestrant. Furthermore, in an ESR1 wild-type and an ESR1 D538G PDX model, AZD9833 demonstrated combinatorial benefit with palbociclib. Based on this preclinical data AZD9833 has progressed into a multi-stage monotherapy and palbociclib combination First Time in Patient clinical trial, SERENA-1 (NCT03616587). Citation Format: James S. Scott, Thomas Moss, Steve Stokes, Willem M. Nissink, Christopher J. Morrow, Mandy Lawson, Natalie Cureton, Eric Gangl, Pablo Morentin Gutierrez, Richard Mather, Justin P. Lindemann, Andrew Sykes, David Fisher, Radoslaw Polanski, Danielle Carroll, Aisling Barton Twomey, Teresa Klinowska. Discovery of AZD9833, an oral small molecule selective degrader of the estrogen receptor (SERD) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5674.

Abstract 4120: ORIC-101 comprehensively inhibits glucocorticoid pathways to overcome therapeutic resistance in pan-cancer models

Abstract Preclinical studies have established a role for the Glucocorticoid Receptor (GR) in mediating resistance to both anti-hormonal therapies and conventional chemotherapies in epithelial cancers. Studies in breast cancer models have established that the chemoprotective effect afforded by GR activation is facilitated, at least partially, through upregulation of genes involved in anti-apoptosis, epithelial-to-mesenchymal transition (EMT), and metastasis - thus suggesting that GR inhibition may enhance therapeutic responses. A novel GR antagonist, ORIC-101, is in early clinical development in combination with nab-paclitaxel in advanced solid tumors (NCT03928314). We set out to understand the transcriptional consequences of activating GR in a panel of 9 triple negative breast cancer (TNBC), 12 non-small cell lung cancer (NSCLC) and 12 pancreatic ductal adenocarcinoma (PDAC) cell lines, covering three indications likely to be encountered in clinical trials. Cell lines were selected to capture the transcriptional variability across subtypes of each indication, and transcriptome profiling using RNA-sequencing was performed on these cell lines after treatment with the synthetic glucocorticoid dexamethasone (Dex) in the presence or absence of ORIC-101. We present a comprehensive evaluation of GR-mediated signaling across 3 key indications and 33 cancer cell lines. Overall, Dex resulted in transcriptional regulation of hundreds of genes. While there was a high degree of variation in the specific genes regulated by GR across TNBC, NSCLC, and PDAC models, a set of 11 genes emerged as consistently upregulated by GR, termed the “GR activation signature”. The addition of ORIC-101 completely reverted the expression of these 11 signature genes back to vehicle condition levels. We further validated a subset of signature genes as ORIC-101 pharmacodynamic biomarkers that may be used to inform target engagement status within a patient population in clinical trials. Despite the high degree of variability in the GR-driven transcriptional programs at the gene level, pathway enrichment analysis revealed biological convergence towards a common set of GR regulated pathways including EMT, apoptosis, stemness, hypoxia, inflammation/immune regulation, and extracellular matrix. These molecular processes associated with GR were observed across TNBC, NSCLC, and PDAC cell lines, suggesting a common drug resistance mechanism of GR across the cancer types. Importantly, ORIC-101 completely reversed these Dex-induced changes at both the gene and the pathway level. Our results not only elucidate the direct mechanism of GR-mediated chemotherapy resistance but also showcase the ability of ORIC-101 to revert all transcriptional changes caused by GR activation. Citation Format: Aleksandr Pankov, Haiying Zhou, Shravani Barkund, Ganapati Hegde, Padmini Narayanan, Omar Kabbarah, Lori S. Friedman, Anneleen Daemen. ORIC-101 comprehensively inhibits glucocorticoid pathways to overcome therapeutic resistance in pan-cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4120.

Triggering a switch from basal- to luminal-like breast cancer subtype by the small-molecule diptoindonesin G via induction of GABARAPL1

Breast cancer is a heterogeneous disease that includes different molecular subtypes. The basal-like subtype has a poor prognosis and a high recurrence rate, whereas the luminal-like subtype confers a more favorable patient prognosis partially due to anti-hormone therapy responsiveness. Here, we demonstrate that diptoindonesin G (Dip G), a natural product, exhibits robust differentiation-inducing activity in basal-like breast cancer cell lines and animal models. Specifically, Dip G treatment caused a partial transcriptome shift from basal to luminal gene expression signatures and prompted sensitization of basal-like breast tumors to tamoxifen therapy. Dip G upregulated the expression of both GABARAPL1 (GABAA receptor-associated protein-like 1) and ERβ. We revealed a previously unappreciated role of GABARAPL1 as a regulator in the specification of breast cancer subtypes that is dependent on ERβ levels. Our findings shed light on new therapeutic opportunities for basal-like breast cancer via a phenotype switch and indicate that Dip G may serve as a leading compound for the therapy of basal-like breast cancer.

Spontaneous Rib Fractures After Breast Cancer Treatment Based on Bone Scans: Comparison Of Conventional Versus Hypofractionated Radiotherapy

BackgroundSpontaneous rib fractures (SRFs) are defined as fractures without apparent blunt force trauma. This study evaluated the incidence and risk factors of SRFs after treatment of patients with breast cancer based on bone scans. In addition, we analyzed radiation-associated SRFs and identified radiotherapy (RT) factors related to SRF. Patients and MethodsWe retrospectively reviewed 1265 patients with breast cancer who underwent surgery in 2015 at our institution, and were followed-up with at least 3 bone scans. Bone scans were conducted approximately every 12 months after breast cancer treatment. The endpoint was SRF detected by bone scan. In this study, 754 (60%) patients were treated with chemotherapy, 867 (69%) with RT, and 946 (75%) with anti-hormone therapy. ResultsThe median follow-up duration was 37.5 months. A total of 209 (16.5%) patients experienced SRFs during follow-up. The incidence of SRFs increased sharply during the 3-year follow-up period after completion of treatment. In multivariate analyses, abnormal bone density, chemotherapy, and RT were significant risk factors for SRFs. In patients treated with RT (n = 867), 159 (18%) rib fractures occurred: 127 (80%) in the ipsilateral breast and 32 (20%) in the contralateral breast. Among the patients with ipsilateral SRFs who received tumor bed boost (n = 84), the SRF occurred inside the boost field in 80 (95%) cases. Multivariate analysis of RT subgroups showed that hypofractionated RT increased the rate of SRFs (P = .002). ConclusionsMost of the rib fractures that occurred after treatment were spontaneous. Hypofractionated RT increased the risk of ipsilateral rib fractures in RT-treated patients.

Expression Of Androgen Receptor, Estrogen Receptor And Progesterone Receptor In Endometrial Carcinoma (Immunohistochemical Study)

BACKGROUND Endometrial carcinoma is the most common pelvic genital malignancy and 4th most frequently diagnosed cancer in females with it’s incidence being 4.3/ 1 lac females. METHODS: Thirty histologically proven cases of endometrial carcinoma were taken up for the study in pathology department. Immunohistochemistry for expression of androgen receptor (AR), estrogen receptor (ER) and progesterone receptor (PR) was done using Biocare system kit. RESULTS: 80% of the cases were in 5th and 6th decade of life. Bleeding per vagina and post menopausal bleeding were the main complaints. Out of the total 22 abdominal hysterectomies the size of tumor varied from 1cm to >4cm. All were adenocarcinoma with 20 being moderately differentiated and only 2 being well differentiated. AR was positive in 8 cases with ER and PR being positive in 16 and 21 cases respectively with score being also the same. Receptor positivity decreased with increasing grade of the tumor. CONCLUSION: ER and PR status are important prognostic biomarkers which also predict response to antihormonal therapy in endometrial carcinoma. AR expression though associated with low grade tumors , but still is a driver for tumor growth and therefore a potential therapeautic target. Anti androgen therapy - enzalutamide may inhibit proliferation of AR positive primary endometrial cancer cells.

Retrospective chart review to characterize admission to the ICU in the last 30 days of life and use of systemic anticancer therapy in the last two weeks of life at the Lifespan Cancer Institute.

e19202 Background: Admission to the ICU in the last 30 days of life and use of systemic anticancer therapy in the last 2 weeks of life are indicators of overly aggressive end-of-life care and have been incorporated into the American Society of Clinical Oncology (ASCO) Quality Oncology Practice Initiative (QOPI) as benchmarks to assess care across cancer centers. We sought to better define the proportion of patients at our institution who met either of these endpoints and to delineate factors that might be associated with them. Methods: A retrospective chart review was conducted on patients with solid tumors, who underwent anticancer therapy at the LCI, and died in timepoints ending in January, July and November of 2017. After IRB approval, patients were identified through our tumor registry. Patients’ electronic medical records were reviewed for past history, cancer stage, type of care received, palliative care contact, site of death, ICU admission in last 30 days of life, receipt of immunotherapy and biologic (precision) therapy in last 6 months of life, and systemic anticancer therapy (excluding antihormonal therapy) in last 2 weeks of life. Results: A total of 134 patients died in this time period; 18 were excluded (leukemia/myeloma) leading to 116 patients for this analysis. Our review showed that 16.4% of LCI patients were admitted to the ICU in the last 30 days of life and 9.5% received systemic anticancer therapy in the last 2 weeks of life. Significant factors associated with an ICU admission in the last 30 days of life were receipt of biologic (precision) therapy in the last 6 months of life (41.7% vs. 13.9%; P<0.05) and never having been married (30.4% vs. 13.3%; P=0.05). Significant factors that were associated with death in the hospital were lack of palliative care team contact (34.3% vs. 13%; P<0.05) and male gender (24.1% vs. 9.1%; P<0.05). Conclusions: Understanding the factors associated with intensive care at the end of life is critical to the provision of value-based cancer care. In this study, the receipt of precision therapy in the last 6 months of life and never having been married were associated with ICU stays in the last 30 days of life, while lack of palliative care involvement and male gender were associated with greater chances of death in the hospital. Further understanding of the complex interplay that governs care and decision making in the end of life is required.

Utility of regional nodal irradiation in Japanese patients with breast cancer with 1-3 positive nodes after breast-conserving surgery and axillary lymph-node dissection.

The utility of regional nodal irradiation (RNI) is being considered in cases of 1-3 axillary node metastases after breast-conserving surgery (BCS) with axillary lymph-node dissection (ALND). Therefore, we examined the necessity of RNI by examining the sites of recurrences in cases at our institution. We retrospectively analyzed 5,164 cases of primary breast cancer between January 2000 and December 2014 at the Aichi Cancer Centre, identifying local and distant recurrences in 152 patients with primary breast cancer treated with BCS and ALND and who had 1-3 positive axillary nodes. All patients received whole-breast irradiation (WBI) and adjuvant systemic therapy with either chemotherapy or anti-endocrine therapy with or without anti-human epidermal growth factor receptor 2 therapy. The present study excluded patients with ipsilateral breast tumor recurrence, contralateral breast cancer, neoadjuvant chemotherapy, T4 tumors or N2-3 nodes and distant metastasis. From the database of our institution, we identified 152 cases that met the defined criteria. The median follow-up period was 71 months (1-176). Isolated locoregional recurrences were found in three patients (2.0%) and were recurrent only in the breast. Only one patient had local lymph node recurrence with distant recurrence. The 10-year rates of isolated regional disease-free survival (DFS), DFS, and overall survival were 95.41, 89.50 and 96.75%, respectively, which was better compared with previous studies. We conclude that the addition of RNI to WBI is not necessary for Japanese patients who have 1-3 positive axillary nodes and ALND.

Letrozole-Induced Acute Interstitial Nephritis

Background: Acute interstitial nephritis is often associated with drug therapy. It can be a common cause of acute kidney injury, traditional chemotherapy agents have been associated with various forms of renal damage, but this is not commonly seen with anti-hormone therapy. Here we report a case of aromatase inhibitor associated acute interstitial nephritis with the use of letrozole. Case Presentation: We present the case of an 84-year-old female commended on letrozole for the management of estrogen sensitive breast cancer. The patient developed oliguric acute kidney injury 3-weeks after initiation, with a creatinine rise to 1069µmol/L, from a previously normal baseline. She had no response to hydration and underwent a renal biopsy which demonstrated acute interstitial nephritis. She was commended on 4 weeks of oral prednisone starting at 20mg with a tapering dose. Renal function returned to baseline on discharge and her aromatase inhibitor was ceased. Conclusions: This is the first reported case of letrozole induced acute interstitial nephritis. It appears the disease was steroid responsive however it is unclear if this is a class effect of aromatase inhibitors or letrozole alone.

Stereotactic body radiotherapy (SBRT) for the treatment of bone metastases in oligometastasised prostate cancer

Local radiation therapy of metastases in prostate cancer patients has become increasingly important in recent years. In order to improve the evaluation of the outcome, we have studied oligometastatic prostate cancer patients who were treated with stereotactic radiation therapy. 24 patients with a total of 30 bone metastases were included in the study. We examined the response to SBRT (biochemical and imaging), as well as progression-free survival and time to start of antihormonal therapy (aHT). The mean follow-up interval after completion of SBRT was 32.7 months (1.4 - 84 months). The SBRT was well tolerated, without acute or late adverse effects. In 16 patients, the PSA value decreased from a mean of 4.58 ng/mL (0.05 - 50.25 ng/mL) before SBRT to 1.19 ng/mL (0.01 - 8.85 ng/mL) after completion of SBRT. The mean biochemical progression-free survival of these patients was 17.6 months (0.7 - 85.0 months). Six patients received aHT, either before or during SBRT. In ten patients, the aHT was initiated after a mean interval of 20.6 months (1.8 - 85.0 months) after completion of the SBRT. Another six patients were not given any aHT during the whole period of observation. In 18 of 30 metastases, there was a decrease in PSMA expression within the area of SBRT in the PSMA-PET - in accordance with a partial functional response. In five patients, PSMA hyperexpression was unchanged; in 7 patients there was no PSMA imaging for follow up. In 17 patients, distant metastasis progression was diagnosed by imaging after a mean of 16.2 months (1.6 - 40.6 months). Three patients had a local recurrence in the prostatic fossa. SBRT of bone metastases in oligometastatic prostate carcinoma patients is an effective and well tolerated therapy and can help to achieve high local control in the area of the metastases as well as delay the start or the escalation of systemic therapy. Nevertheless, the high rate of progression of distant metastases shows how important correct patient selection is and that combination with aHT may be necessary.

Usefulness of patient-reported outcomes to assess the effectiveness of topical hormonal therapy for gynecologic symptoms after antihormonal treatment for breast cancer

The aim of this retrospective study was to assess the efficacy of topical hormonal therapy (THT) to relieve vaginal symptoms resulting from antihormonal therapy in women with hormone receptor–positive breast cancer. A total of 74 breast cancer patients who received THT for vaginal complaints were retrospectively identified and statistically matched with 74 control breast cancer patients with vaginal complaints with no documented use of THT. Symptom scores were recorded from the center’s proprietary patient-reported outcomes database, Patient Care Monitor (ConcertoHealthAI, Boston). A baseline score was noted at the initiation of antihormonal therapy and was followed at 6 and 12 months. The median differences between baseline, 6-month, and 12-month scores were analyzed. Repeated measures analysis of variance assessed the impact of topical hormonal replacement. There was no statistically significant difference in score change between the two groups at 6 and 12 months. In the active THT group, there were no statistically significant differences in vaginal complaints or sexual problems over time: {F (2, 146) = 0.99, P = 0.369; and F (2, 146) = 1.56, P = 0.217}, respectively. In this study, the use of topical hormonal replacement was not effective in alleviating vaginal symptoms.

Breast cancer anti-hormonal therapy and rheumatic diseases: linking the clinical to molecular world

Anti-hormonal therapies are used in the treatment of hormone dependent breast cancer. Their use may be complicated with the onset of arthralgia and autoimmune diseases. Recently a clinical relationship between oestrogen, anti-oestrogen therapy and rheumatic diseases has been reported in the literature, but, until now, experimental supporting data about the interacting biochemical pathways involved are still very limited. The understanding of this molecular link may provide important information to elucidate the relationship between autoimmunity and cancer mechanism and treatment. This review is intended to highlight the relationship between known common molecular mechanisms which explain this association and that probably need to be investigated in future studies.

The Role of Pigment Epithelium‐Derived Factor’s Anti‐Angiogenic Properties on Tumor Suppression

Pigment epithelium‐derived factor (PEDF) is a multimodal secreted glycoprotein of roughly 50kDa size and 418 amino acids in length and is found in the interphotoreceptor matrix (ICM) that holds a variety of biological functions. It is a member of the non‐inhibitory serpin family and was first identified as a neurotrophic factor in retinal pigment epithelial cells, however, it has also been identified in several tissues throughout the body including the heart, lung, brain, and pancreas. PEDF is highly conserved throughout evolution and is known to possess neurotrophic, neuroprotective, anti‐tumorigenic, anti‐metastatic properties, and anti‐angiogenic properties. Indeed, PEDF is known as one of the most potent naturally occurring anti‐angiogenic agent. Angiogenesis plays a critical role in the development of cancer because it stimulates the formation of new blood vessels which carry blood to the tumor thereby providing it unlimited access to critical nutrients and oxygen needed for sustained growth and metastatic spread. Hence, the ability of PEDF to block angiogenesis highlights its potential as a novel anti‐cancer agent. Apart from inhibiting angiogenesis, PEDF also inhibits cancer cell proliferation and induces programmed cell death (apoptosis) through activation of FasR/FasL death signaling pathway. The importance of PEDF in cancer is validated by the fact that its expression is significantly reduced in several types of cancers and that loss of PEDF expression is associated with aggressive disease and poor overall survival. Indeed, PEDF expression has been shown to be markedly reduced in breast tumors compared with normal breast tissue and loss of PEDF is associated with resistance to anti‐endocrine therapy due to activation of two critical breast cancer proteins; the estrogen receptor (ER) and the Rearranged during Transfection (RET) proteins. The unique biology of the PEDF protein is directly related to its structure. PEDF is asymmetrically charged, one side being highly acidic the other highly basic, giving it a polar structure that has two functional epitopes. The acidic region contains a 34‐mer peptide that interacts with the PEDF‐RA receptor identified in endothelial cells. When this interaction occurs, apoptosis is initiated, epithelial cell migration is blocked, and corneal angiogenesis is induced. On the other hand, the basic region consists of a 44‐mer peptide that interacts with the PEDF‐RN receptor which has been identified on Y‐79 cells, cerebellar and motor neurons, and in the neural retina. When this epitope is activated, PEDF assists in conducting neural differentiation.Support or Funding InformationThe Olathe North MSOE Center for BioMolecular Modeling SMART Team used 3‐D modeling and printing technology to examine structure‐function of PEDF

Risk of breast cancer before and after rheumatoid arthritis, and the impact of hormonal factors

ObjectivesTo examine the risk of incident breast cancer in women with rheumatoid arthritis (RA), and the risk of RA in women with a history of breast cancer, taking antihormonal treatment...

Unmet information needs of men with breast cancer and health professionals.

ObjectiveMale breast cancer (MBC) is rare. Information about breast cancer is usually designed for female patients. However, in males this disease and some side effects differ from its female counterpart. Therefore, there is a need for male‐specific information. The aim was to assess unmet information needs of (a) MBC patients and (b) health professionals.MethodsDutch MBC patients (diagnosed between 2011 and 2016 in 21 hospitals), patient advocates and partners were invited to participate in focus groups and/or complete a paper‐based questionnaire on information needs. In addition, an online questionnaire on information needs was sent to health professionals involved in MBC patient care.ResultsIn three focus groups with MBC patients (N = 12) and partners (N = 2) the following unmet information themes were identified: patients' experiences/photographs, symptoms, (delay of) diagnosis, treatments, side effects, follow‐up, psychological impact/coping, genetics and family, research and raising awareness. 77 of 107 MBC patients (72%) completed the questionnaire: most patients lacked information about acute (65%) or late (56%) side effects, particularly sexual side effects. Among health professionals, 110 of 139 (79%) had searched for MBC‐related information, specifically: patient information, anti‐hormonal therapy, genetic testing, research, and psychosocial issues.ConclusionsUnmet information needs in MBC patients and health professionals were identified. Specific information on MBC should be developed to improve timely diagnosis, quality of life, treatment, and survival. A targeted website is an ideal tool to meet these needs. Therefore, we integrated these results into a user‐centered design to develop an informative website, www.mannenmetborstkanker.nl.

KEYNOTE-365 cohort B updated results: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).

103 Background: KEYNOTE-365 (NCT02861573) is a phase 1b/2 study to evaluate pembro in combination with other agents in mCRPC. Here we report updated results from cohort B (pembro + docetaxel and prednisone). Methods: Cohort B enrolled pts who failed or were intolerant to ≥4 wk of abi or enza in the prechemotherapy mCRPC state and whose disease progressed within 6 mo of screening as determined by PSA progression or radiologic bone/soft tissue progression. Pts received pembro 200 mg IV + docetaxel 75 mg/m2 IV Q3W and prednisone 5 mg orally twice daily. Primary end points were safety, PSA response rate (confirmed PSA decrease >50%), and ORR per blinded independent central review (BICR). Results: Of 104 treated pts, 72 discontinued, primarily due to progression (55%). Median age was 68 y (range 50-86), 24% were PD-L1+, 25% had visceral disease, and 50% had measurable disease. Median follow-up was 13 mo for all pts (n=104) and 19 mo for pts who had ≥27 wk of follow up (n=72). See table for efficacy outcomes. Treatment-related AEs occurred in 100 pts (96%); most frequent (≥30%) were alopecia, diarrhea, and fatigue (39% each). Grade 3-5 treatment-related AEs occurred in 42 pts (40%). Five pts died of AEs; 2 deaths were from treatment-related AEs (pneumonitis). Conclusions: With additional follow-up, pembro + docetaxel and prednisone continued to show activity in pts with mCRPC who failed previous antihormonal therapy. Safety of the combination was consistent with the known profiles of the individual agents and will be further evaluated in a phase 3 study (KEYNOTE-921). Clinical trial information: NCT02861573. [Table: see text]

Abstract P2-13-20: Conditional survival of female breast cancer patients by treatment patterns: Evidence from the Korean nationwide registry

Abstract Objective: With the development of breast cancer treatment, the prognosis of breast cancer patients is getting better over time. Breast cancer patients want to get accurate information about prognosis according to the treatment pattern. In this study, we investigated the 5-year Conditiona relative survival (CRS) of Korean female breast cancer patients. Materials and Methods: The data from this study was collected from the Korean Central Cancer Registry (KCCR) data, National Health Insurance Service (NHIS) data and Korean Statistical Information Service (KOSIS) data to certify relative survival and conditional relative survival for the female patients of breast cancer in the Korea. We identified 141,779 female breast cancer cases diagnosed between 2002 and 2013. The CRS was estimated for every year after diagnosis, according to age, stage at diagnosis, histologic type, year at diagnosis and treatment patterns within 1year after diagnosis. Results: The 5-year RS at diagnosis was 91.0% and the 10-year RS was 85.9%. The 5-year CRS was 91.1% and 94.3% at 1 year and 5 years after diagnosis, respectively. Very young and very old patients had worse 5-year CRS after 5 years of survival than those of other age groups (89.6% in the <40-year and 84.4% in the ≥70-year groups vs. 92.6% in 40-54-year, and 90.3% in 55-69-year groups). Patients who underwent surgery within one year after diagnosis of breast cancer showed better 5-year CRS than those who did not (94.0% vs 65.6%). The 5-year CRS was 91.8% and 89.9% according to whether systemic therapy (chemotherapy and targeted therapy) was performed after diagnosis of breast cancer. The 5-year CRS of the anti-hormone treatment group was 95.2%, which was higher than that of the non-hormone treatment group. In the group without antihormonal therapy, there was a different 5-year CRS according to the histological characteristics (89.8% in NST type, 83.5% in lobular type, 97.3% in mucinous type, 98.5% in medullary type and 86.3% in metaplastic type). Conclusions: This study shows that the improvement pattern of CRS may vary according to age group, treatment pattern, and histologic type. In the group without antihormone therapy, the histologic type seems to be a different aspect of CRS, which is useful information for clinicians and patients. Key words: conditional survival, breast cancer, histology, age, stage, treatment pattern Citation Format: Eun Jin Song, So-Youn Jung, Young Ae Kim, Sun-Young Kong, Eun Sook Lee, Eun-Gyeong Lee, Heein Jo, Jae Hong Han, Seeyoun Lee, Han-Sung Kang. Conditional survival of female breast cancer patients by treatment patterns: Evidence from the Korean nationwide registry [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 P2-13-20.

Abstract P3-08-50: Genome-wide association study predict prognosis of hormone receptor positive metastatic breast cancer in premenopausal women with endocrine therapy

Abstract Introduction: According to phase II clinical trial of endocrine treatment for hormone receptor positive (HR+) metastatic breast cancer(MBC) after tamoxifen treatment in premenopausal women, fulvestrant plus goserelin (F+G) has better clinical outcome than goserelin (G) alone in premenopausal women, in terms of time to progression (TTP). However, aromatase inhibitor (AI) with goserelin (A+G) is not superior to goserelin alone. Among three treatment arms, difference of overall survival (OS) was not observed. Accompanied with this clinical trial, we conducted further genotyping to identify alleles at some genomic loci associated with clinical outcome of endocrine treatments in premenopausal women with HR+ MBC. Methods: This prospective genotyping study included patients enrolled in a randomized phase II clinical trial of fulvestrant plus goserelin versus anastrozole plus goserelin versus goserelin alone for HR+, human epidermal growth factor receptor 2(HER2)-negative tamoxifen-pretreated premenopausal women with recurrent or metastatic breast cancer (KCSG BR10-04). To isolate genomic DNA from peripheral blood leukocytes, we used the Wizard Genomic DNA Purification Kit according to the manufacturer’s instructions (Promega, WI) and Axiom Precision Medicine Research Array (PMRA) (ThermoFisher, CA) was used to genotyping array. Survival analyses for time-to-progression (TTP) and overall survival (OS) were performed using the Kaplan-Meier method. To determine the association between clinical outcomes and single nucleotide polymorphisms (SNPs), we used an R package for genome-wide survival analysis (gwasurvivr). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for univariate and multivariate analyses. Finally, SNPs with adjusted p-value <0.05 were selected and used for survival analysis. Results: Of 138 participants, genomic DNA was collected and extracted from 127 participants. After quality control (QC), 103 genomic DNA were finally selected for genotyping (35 in F+G, 36 in A+G and 32 in G group). Patients with age under 40 were 34 (33%) and visceral metastases were observed in 50 patients (49%). Medial TTP was 16.3 months (95% confidence interval (CI): 13.3, 19.3) and median OS was 59.6 months (95% CI: 41.1, 78.1). Among 523,289 SNPs, 76 SNPs were associated with TTP (adjusted p-value <0.05, respectively). Of 76 SNPs, 47 were in coding lesions including ELF3, ARHGEF3, FOXP2, NTRK2, XPO5 and PI3KC2A. Other 29 were in non-coding lesions. In terms of OS, 13SNPs were associated and eleven were in coding lesions (ZMYM4, GRM7, ERC2, LEKR1, C3orf700, CEP135, ZNF827, LOC285692, DNAH11, FLJ42102 and LOC283440). Conclusions: Genetic polymorphisms influenced the clinical outcome of HR+ MBC patients treated with anti-hormonal therapy. Further studies on the functional mechanisms relating to these SNPs in these genes are warranted. Citation Format: Ji-Yeon Kim, Seock-Ah Im, Kyung Hae Jung, Keun Seok Lee, Joohyuk Sohn, Jee Hyun Kim, Hae Hyun Jung, Minjoo Lee, Young-Hyuck Im. Genome-wide association study predict prognosis of hormone receptor positive metastatic breast cancer in premenopausal women with endocrine 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 P3-08-50.