The landscape of metastatic progression patterns across major human cancers

Abstract

The majority of patients with solid malignancies die from metastatic burden. However, our current understanding of the mechanisms and resulting patterns of dissemination is limited. Here, we analyzed patterns of metastatic progression across 16 major cancer types in a cohort of 1008 patients with metastatic cancer autopsied between 2000 and 2013 to assess cancer specific progression patterns of disease and related risk predictions. The frequency and location of metastases were evaluated in and across 1) 16 major cancers, 2) smoking- and non-smoking-related cancers and 3) adeno- and squamous cell carcinoma. Associations between primary and secondary sites were analyzed by the fractional and the relative risk methods. We detected significantly different cancer specific patterns of metastatic progression with specific relative risk profiles for secondary site involvement. Histology and smoking etiology influenced these patterns. Backward analysis showed that metastatic patterns help to predict unknown primary sites. Solid malignancies maintain a unique and recurrent organ tropism to specific secondary sites which does not appear to be strongly influenced by advances in cancer medicine as shown by comparison with previous data sets. The delineated landscape of metastatic progression patterns is a comprehensive data resource to both clinical and basic scientists which aids fostering new hypotheses for cancer research and cancer therapies.

Figure 1. CONSORT statement (flow diagram)

Out of 6597 patients autopsied in the years 2000-2013 at Charité hospital, 1008 patients were included in the study. Inclusion criterion was a diagnosed metastatic cancer disease with primary location at one of the 16 most common primary sites. Cancer diseases originating from more than one primary site were excluded from the study.

Figure 2. Frequency of metastases across 16 major cancer types

A) Number of metastasis sites (mean and sd) for each of the primary sites. The mean number of metastasis sites increased from 2.3 (liver cancer) via 4.0 (lung cancer) to 5.9 (melanoma). Different primary tumors had a significantly different number of metastasis sites (p=6.0E-14). B) Percentage of primary tumors that metastasized to 20 secondary sites. The frequency of metastatic hits strongly depends on the localization of the secondary site (p=2.5E-62).

Figure 3. Metastatic progression from 16 primary sites to 20 secondary sites

A) Percentage of primary tumors progressing to a secondary site. B) Percentage of metastases originating from a primary site. C Co-occurrence analysis of metastases. For each pair of secondary sites, the percentage of primaries with metastases at both sites relative to the number of primaries with metastases minimum at one of the two sites is shown.

Figure 4. Relative risk (RR) analysis of 16 primary and 20 secondary sites

A) RR for progression from a primary site to a secondary site. B) RR for co-occurrence of two secondary sites. Significantly enhanced RRs (red boxes) and significantly reduced RRs (green boxes) compared to the entire cohort.

Figure 5. Metastatic progression from 16 primary sites to 20 secondary sites

Circle size is proportional to the number of tumors or metastases. Orange circles refer to the number of metastases from a single primary site. Arrows width is proportional to the percentage of tumors that metastasize from a primary site to a secondary site. Colored arrows refer to significant enrichment (red arrows) or a significant depletion (green arrows) of a metastatic route. RR = relative risk.

Figure 6. Comparison of the metastatic progression in selected tumor subgroups

A) squamous cell cancer vs. adenocarcinoma, B) squamous cell lung cancer vs. adenocarcinoma of the lung, C) smoking-related vs. non-smoking-related cancer, D) node-positive vs. node-negative cancer. Circle size is proportional to the number of tumors or metastases. Orange circles refer to the number of metastases from a single primary site. Arrows width is proportional to the percentage of tumors that metastasize from a primary site to a secondary site. Colored arrows refer to significant enrichment (red arrows) or a significant depletion (green arrows) of a metastatic route. RR = relative risk, * = significant different metastasis frequency between subgroups.

Figure 7. Models for prediction of the primary cancer sites from secondary cancer sites (metastases)

For each primary site, multivariate logistic regression was executed to obtain odd ratios (ORs) associated with the secondary sites. Secondary sites associated with significantly higher probability for the primary site (red boxes) and secondary sites associated with significantly lower probability for the primary site (green boxes).

Figure 8. Multivariate analysis of lifetime using Cox proportional hazard modeling

Analysis of the influence of the primary tumor site and of secondary tumor sites on total lifetime. Different than in overall survival analysis (time of survival after the first cancer diagnosis) the total lifetime (patient age at death) is analyzed. Only cancer-related deaths are taken into consideration. HR = hazard ratio.