Background:Breast cancer commonly metastasises to the brain, but little is known about changes in the molecular profile of the brain secondaries and impact on clinical outcomes.Methods:Patients with samples from brain metastases and matched breast cancers were included. Immunohistochemical analysis for oestrogen receptor, progesterone receptor, p27kip1, cyclin D1, epidermal growth factor receptor, insulin like growth factor 1, insulin like growth factor 1 receptor, vascular endothelial growth factor A, transforming growth factor-β and HER2 receptor was performed. Borderline HER2 results were analysed by fluorescent in situ hybridisation. Levels of expression were compared, with review of effect on clinical outcomes.Results:A total of 41 patients were included. Of the patients, 20% had a change in oestrogen receptor or HER2 in their brain metastasis that could affect therapeutic decisions. There were statistically significant rises in brain metastases for p27kip1 (P=0.023) and cyclin D1 (P=0.030) and a fall in vascular endothelial growth factor A (P=0.012). Overall survival from the time of metastasis increased significantly with oestrogen receptor-positive (P=0.005) and progesterone receptor-positive (P=0.013) brain lesions and with a longer duration from diagnosis of the breast primary (P<0.001).Conclusions:In this cohort there were phenotypic differences in metastatic brain tumours compared with matched primary breast tumours. These could be relevant for aetiology, and have an impact on prognostication, current and future therapies.

Thyroid cancer is the most common endocrine malignancy and incidences are rising rapidly, in both pediatric and adult populations. Many thyroid tumors are successfully treated which results in low mortality rates, but there is often a significant morbidity associated with thyroid cancer treatments. For patients with tumors that are not successfully treated with surgical resection or radioactive iodine treatment, prognosis is dramatically reduced. Patients diagnosed with anaplastic thyroid cancer face a very grim prognosis with a median survival of 6 months post-diagnosis. There is a critical need to identify patients who are at greatest risk of developing persistent disease and progressing to poorly differentiated or anaplastic disease. Furthermore, development of treatments associated with less morbidity would represent a significant improvement for thyroid cancer survivors. It is well established the stromal cells and components of the tumor microenvironment can drive tumor progression and resistance to therapy. Here we review the current state of what is known regarding the thyroid tumor microenvironment and how these factors may contribute to thyroid tumor pathogenesis. Study of the tumor microenvironment within thyroid cancer is a relatively new field, and more studies are needed to dissect the complex and dynamic crosstalk between thyroid tumor cells and its tumor niche.

Background Over 10% of patients with metastatic breast cancer develop symptomatic brain metastases. Limited treatment options can result in significant morbidity and a dismal prognosis. Little is known about the molecular profile of brain secondaries, differences compared with the patient's breast primary and whether any changes impact on prognosis. Methods Patients with resected or biopsied brain metastases from a breast cancer were identified from an electronic database, with clinical data collected from hospital notes for patients in the south west of the UK. Patients were included if tissue from the primary breast cancer and brain metastasis were available for testing. Immunohistochemical analysis was performed for oestrogen receptor (ER), progesterone receptor (PR), p27kip1, cyclin D1, epidermal growth factor receptor (EGFR), insulin like growth factor 1 (IGF1) and receptor (IGF1-R), vascular endothelial growth factor A (VEGF A), vascular endothelial growth factor receptor (VEGFR-2), transforming growth factor beta (TGFB) and Her 2 receptor on both the brain and breast samples. Borderline Her 2 results were analysed by fluorescent in situ hybridisation. Results 41 patients were identified. Median age of patients was 49, with a 26 month interval between breast cancer diagnosis and development of brain metastases. Median time from brain metastases to death was 15 months. 13 patients (32%) had a HER2 positive breast primary, 12 receiving HER2 directed therapy prior to development of brain metastases. 15 patients (37%) had an ER positive breast cancer at initial diagnosis. 11 patients had a biopsy of their brain secondary, 30 more extensive surgical resection. 28 patients received whole brain radiotherapy (WBRT), 1 patient stereotactic radiotherapy (SRT) alone, 6 patients both WBRT and SRT, 6 unknown. Changes in the molecular profile of the breast primary compared with the brain secondary are illustrated in Table 1. Number of patients with a change in molecular profile from breast primary to brain metastasis Breast positive to brain negativeBreast negative to brain positiveER03PR01Her214EGFR16IGF 1312IGF1-R34TGFB11p27 kip 1515cyclin D1312VEGF00VEGFR-211 There was a change in more than 10% of patients from a positive breast primary to a negative brain secondary for p27kip1 and from a negative breast cancer to a positive brain metastasis for EGFR, IGF1, cyclin D1 and p27kip1. These alterations did not have a significant impact on time from brain metastasis to death. However, there was a significant improvement in survival from brain metastasis diagnosis for secondary lesions that were ER positive (p=0.005) or PR positive (p=0.013). Survival from time of brain metastasis improved with a longer time to brain metastasis from initial diagnosis (p=0.001). Conclusions In this cohort there were demonstrable phenotypic differences in the expression levels of EGFR, IGF1, p27Kip1 and cyclin D1 in metastatic brain tumours compared with primary breast tumours of the same patient, although survival was not affected. 8 patients (20%) had a change in ER or Her 2 that could impact on current therapeutic decisions. Hormone receptor positive brain metastases had superior survival compared with negative lesions. Citation Format: Thomson AH, Purvis G, McGrane J, Palmer J, Jenkins R. Changing molecular profile of brain metastases compared with matched breast primaries and impact on clinical outcomes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-17-07.

Thyroid cancer is the most prevalent endocrine malignancy and is estimated to have affected 52,890 individuals in the United States in the year 2020. Papillary thyroid cancer (PTC) accounts for up to 80% of all thyroid cancer diagnoses. Within PTC, BRAFV600E is the most common mutation in adults and the second most common mutation in pediatrics. While there are several validated human thyroid cancer cell lines harboring BRAF mutations, no pediatric derived cell line has been established to date, limiting generalizations in pediatric disease. Patient-derived pre-clinical models are valuable tools but are limited due to their need to be studied in vitro or in an immunocompromised host. However, in vivo mouse models recapitulate the complex interactions between tumor cells, the immune system, and components of the microenvironment, allowing more comprehensive investigation of thyroid oncogenesis and response to therapy. In this study we describe a new subcutaneous mouse model that can be used to understand differences between pediatric onset and adult onset PTC. We have developed multiple independent, congenic murine cell lines from different stages of thyroid cancer progression. Two independent BRAFV600E-driven cell lines harboring the same genetic mutations were utilized in this study, one representing a well-differentiated tumor (WD) and one representing a poorly-differentiated tumor (PD). Despite coming from different stages of disease, both cell lines showed similar expression of the thyroid specific genes: Pax8, Ttf1, Tg, and Slc5a5, but expression of Pax8, Tg, and Slc5a5 was lower compared to WT thyrocytes. Activation of the Pi3Kinase pathway and the Akt Pathway were assessed via western blot analysis. The WD cell line had increased pERK activation compared to the PD cell line, and the PD cell line had increased pAKT compared to WD cell line. Both cell lines were injected subcutaneously into the hind flank of Wt SJV129 mice of pediatric age (4-5 weeks) and adult age (20-22 weeks). These animals were monitored for 10 weeks post injection. While the PD cell line developed tumors at approximately the same rate and penetrance in both age groups, tumors reached end point more rapidly in the adult cohort. Adult hosts injected with the WD cell line developed tumors more rapidly than in pediatric hosts, however, tumors receded in both cohorts. While adult and pediatric thyroid cancer share common driving mutations, there are distinct differences in disease pathogenesis between these patient populations. There are known differences in the immune system, metabolism, and other variables between pediatrics and adults. However, it is unknown what causes the difference in PTC pathogenesis between pediatric versus adult patients. We believe these new models provide a great opportunity to evaluate the role of age in PTC development and progression. Presentation: Saturday, June 11, 2022 12:15 p.m. - 12:30 p.m.

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