Is There One Key Step in the Metastatic Cascade?

The majority of cancer-related deaths are the result of metastases (i.e., dissemination and establishment of tumor cells at distant sites from the origin), which develop through a multi-step process classically termed the metastatic cascade. The respective contributions of each step to the metastatic process are well described but are also currently not completely understood. Is there, for example, a critical phase that disproportionately affects the probability of the development of metastases in individual patients? Here, we address this question using a modified Drake equation, initially formulated by the astrophysicist Frank Drake to estimate the probability of the emergence of intelligent civilizations in the Milky Way. Using simulations based on realistic parameter values obtained from the literature for breast cancer, we examine, under the linear progression hypothesis, the contribution of each component of the metastatic cascade. Simulations demonstrate that the most critical parameter governing the formation of clinical metastases is the survival duration of circulating tumor cells (CTCs).

Treatment of patients with locally advanced Merkel cell carcinoma: A multicenter study.

e21566 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a high risk of recurrence and poor prognosis. The treatment of locally advanced disease includes surgery (SUR) and radiotherapy (RTH) to achieve high locoregional control rates. The sentinel lymph node biopsy (SLNB) is recommended procedure in cases without clinical nodal involvement. In selected cases, chemotherapy (CHT) may also be considered, but its role is not confirmed. This study aimed to analyze outcomes for locally advanced MCC pts treated in routine clinical practice. Methods: We conducted the retrospective analysis of data from 156 MCC pts treated with curative surgery in four oncological centers, diagnosed between 01/2010 and 12/2019, with data cut-off on 31/12/2020. The data collected included epidemiological and clinical information. Survival analyses were performed using the Kaplan-Meier method, log-rank test and multivariate Cox regression. Results: The median patient age at diagnosis was 72 years (30-94); 50.6% were male. The primary tumor (PT) locations were lower limbs (33.3%), upper limbs (30.1%), and head and neck (28.2%). MCC with no PT was diagnosed in 3.9%. In 62.0% the PT was located in the sun-exposed skin. The median tumor size was 25 mm (4-170). Lymph node (LN) involvement (clinical or positive SLNB or LND) at diagnosis was found in 26.9% (n = 42). The scar excision was done in 50.0% (positive in 16.6%), SLNB in 36.5% (positive in 10.5 %), 51.9% of pts received perioperative treatment, including RTH- 86.4%, CHT- 21%. The relapse rate was 38.3% (35.8% local-regional, 11.1% distant). With the median follow-up of 2.2-years, the median disease-free survival (DFS), local relapse-free survival (LRFS), and distant metastases-free survival (DMFS) were not reached. The 1-year DFS, LRFS and DMFS rates were 65%, 68%, and 90%. The negative independent risk factors for DFS were male gender (HR 1.42, 95%CI 1.06-3.01), metastases in LN at diagnosis (HR 5.41, 95%CI 2.39-12.26), no SLNB in pts with no clinical metastases in LN (HR 5.45, 95%CI 2.41-12.3), and no perioperative RTH (HR 2.19, 95%CI 1.29-3.76). The median overall survival (OS) was 6.9 years (95%CI 4.64-9.15). The negative independent risk factors for OS were male gender (HR 1.95, 95%CI 1.16-3.27), age above 70 (HR 2.0, 95%CI 1.15-3.48), metastases in LN at diagnosis (HR 3.15, 95%CI 1.49-6.68), and no SLNB in pts with no clinical metastases in LN (HR 2.30, 95%CI 1.10-4.82). PT location, UV-exposure, and perioperative CHT or RTH were not independent risk factors for OS. Conclusions: Our results confirm that the MCC treatment should be done in an experienced multidisciplinary team. Male gender, nodal involvement at diagnosis, and no SLNB in pts without clinical metastases in LN are associated with poor prognosis in DFS and OS. The perioperative RTH improves the treatment outcomes and reduces disease progression risk but does not impact OS. Perioperative CHT does not affect pts survival.

Creation of a tissue expression biomarker-augmented prognostic model for patients with metastatic renal cell carcinoma.

703 Background: Clinical and pathologic factors alone have limited prognostic ability in patients with metastatic clear cell renal cell carcinoma (ccRCC). We sought to determine if tissue biomarkers, along with our previously reported clinical metastases score, can be used to predict cancer specific survival (CSS) in patients with metastatic ccRCC. Methods: Patients with metastatic ccRCC who underwent nephrectomy between 1990-2004 were identified using the Mayo Clinic Nephrectomy Registry. Sections from paraffin-embedded primary tumor tissue blocks were used for immunohistochemistry staining for PD-1, B7-H1 (PD-L1), B7-H3, Bim (downstream pro-apoptotic signaling molecule in PD-1 pathway), CA-IX, IMP3, Ki67, and survivin. CSS was the primary outcome. Biomarkers that were significantly associated with CSS after adjusting for the metastases score were used to develop a biomarker-specific multivariable model using a bootstrap resampling approach and forward selection. Predictive ability was summarized using a bootstrap-corrected c-index. Results: The cohort included 602 patients, 192 (32%) with metastases at diagnosis and 410 (68%) who developed metastases after nephrectomy. Median follow-up among survivors was 9.6 years (IQR 4.2,12.8) and 504 patients died of RCC. Bim, IMP3, Ki67, and survivin expression were significantly associated with CSS after adjusting for the metastases score and were used to develop a biomarker-specific model. High Bim (HR 1.44; 95%CI 1.16-1.78; p < 0.001), high survivin (HR 1.35; 95%CI 1.08-1.68; p = 0.008), and the metastases score (HR 1.13 per one point; 95%CI 1.10-1.16; p < 0.001) were retained as independent predictors in the final multivariable model (c-index 0.69). Conclusions: We created a prognostic model combining the clinical metastases score and two primary tissue expression biomarkers, Bim and survivin, for patients with metastatic RCC who underwent nephrectomy. External validation will be required prior to clinical use.