Abstract P5-01-01: Real-time imaging of lymph node metastasis in response to systemic ezrin inhibitor treatment in breast cancer
Bibliographic record
Abstract
Abstract Lymph node (LN) metastasis is a key driver of recurrence and survival in breast cancer (BC) patients. However, the mechanisms of metastatic dissemination of tumour cells from LNs to distant sites and their predictors of response to systemic therapy remain poorly understood, mainly due to a lack of non-invasive in vivo imaging models. We have recently described ezrin, a pro-metastatic crosslinker protein, as a regulator of tumour lymphangiogenesis and metastasis in BC (Breast Cancer Res. 2014; 16(5): 438). Furthermore, we demonstrated significant association of high ezrin expression with lymphovascular invasion in a cohort (n=63) of premenopausal patients with invasive BC (p =0.024). These findings prompted us to examine the role of ezrin in migration and invasion of metastatic tumour cells in LNs and their response to ezrin-targeted therapy. Using a locally accrued LN positive patient cohort (n=94), we demonstrated a significant association between high ezrin levels and reduced recurrence-free survival (univariate Log-rank test, p=0.033), suggesting that ezrin is a potential predictor of relapse in LN positive BC. To address the mechanistic role of ezrin in LN metastasis, we developed a novel intravital imaging model using a lymphatic reporter transgenic mouse (B6-prox1-mOrange2-pA-BAC) to examine the response of tumour-draining LN to anti-ezrin systemic therapy in real time. Next, we tested the effects of a small molecule ezrin inhibitor (NSC668394) in vitro and observed significant suppression of ezrin activation (p-T567) and cancer cell invasive phenotype. Intravital imaging of inguinal LN metastases, derived from subcutaneously implanted breast adenocarcinoma E0771-LMV (lung metastatic variant) cells, demonstrated significant reduction in mobility and invasiveness (Mann Whitney, p<0.0001) of metastatic cells following systemic treatment with NSC668394 (0.5 mg/kg at 24h and 8h prior to imaging). Interestingly, LN metastases engagement by host T cell (CD3+) was notably increased, whereas T cell mobility was not affected by ezrin inhibition. Our findings present a novel non-invasive imaging model to study the LN metastasis response to anti-cancer therapy in real time, and provide new insight into the role of ezrin as a potential anti-metastatic target in BC. (Supported by CRS, CIHR, CBCF, BCAK, Queen's SRC). Citation Format: Ghaffari A, Hoskin V, Mullins G, Greer P, Kiefer F, Madarnas Y, SenGupta S, Elliott B. Real-time imaging of lymph node metastasis in response to systemic ezrin inhibitor treatment in breast cancer. [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 P5-01-01.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".