Timeline metastatic progression: in the wake of the « seed and soil » theory.

Little is known about the natural history of cancer and its evolution to metastasis. Paget was the first to postulate the important role played by microenvironment in metastasis progression. Since, the concept of his "seed and soil" theory has been supported and confirmed. Understanding the chronology and natural course that underlie metastasis is mandatory to deepen this concept and to progress in the development of novel therapeutic strategies. A total of 413 patients who underwent treatment for brain metastasis (2013-2016) were included. The identification of previous and newly diagnosed metastasis was made during the clinical and imaging follow-up. We identified 910 metastases in our series. The 2-, 5-, and 10-year survival estimates were 80% (SD 2), 59.1% (3), and 36% (4), respectively. The median time for first metastasis, referred as metastasis-free survival (MFS) was 15.2 months (SD 1.47). MFS were determined for each metastasis location and were as follows: 7.2 months (SD 8.0) for bone, adrenal 8.4 months (SD 9.4) for adrenal, 13.2 months (SD 1.7) for brain, 14.6 months (SD 5.4) for liver, 25.7 months (SD 11.7) for pleura, 27.7 months (SD 15.9) for peritoneum, 29.8 months (SD 7.2) for spine, 30.2 months (SD 5.2) for lungs, and 54.2 months (SD 12.4) for skin (p < 0.009 log rank). We identified a metastatic timeline process for breast cancer (p < 0.0001 log rank (Mantel-Cox)) and furthermore according to breast subtype cancer (p < 0.0001). We suggest that in addition to Paget's theory, a timeline and a natural history of metastasis exist in patients with cancer. We suppose that some, but not all, primary cancers follow chronological and scheduled metastatic processes to invade organs.