In this next section, we'll be discussing evidence for the existence of cancer dormancy. The main question here is, why do cancer patients relapse years after surgery? We know that surgical removal of the primary tumor is able to cure a proportion of patients. Yet, many patience continue to undergo cancer occurrence years to decades later. In fact, 62% of breast cancer deaths occur 5 years after surgery of the primary tumor. This phenomenon can be explained by clinical dormancy, which is the period when you cannot detect residual tumor cells even though they are still actually present. This figure does a nice job demonstrating the period of clinical dormancy. On the x-axis is time, and the y-axis is aggregate tumor burden. The first peak in purple is the growth of the primary tumor, and this creeps up and keeps growing until it crosses a threshold for clinical detection, which is a horizontal bar marked in orange. Treatment is initiated once this threshold is crossed and the tumor is detected. Then the tumor burden decreases dramatically from the treatment. Over time though, the tumor burden creeps back up and crosses the threshold for clinical detection. Again, it is detected once it is large enough, and this may not happen for years. Thus, clinical dormancy is a period between where the two peaks for tumor burden are detectable. As you can infer by now, the notion of cancer dormancy first evolved from clinical observations. In 1952, the pathologist Rupert Willis first coined the phrase, dormant cancer cell, as the only plausible explanation for his observations, which are listed in the table to the right. He noticed that for each of these primary tumors, the time to clinical relapse, which is when the patient presents with metastases, could be between 5 and 30 years. He thought that if even one cell started proliferating it would not take as long as 5 years for it to proliferate into a detectable mass. Then in 1954, a pathology professor named Geoffrey Hadfield agreed with this thought. Saying, when the interval is prolonged to six years or more it seems impossible to escape the conclusion that the cells of the dormant growth are in a state of temporary mitotic arrest, no matter how long the period may be. Another observation for the existence of clinical cancer dormancy unexpectedly comes from a transplantation case study. This study reported the unknowing transmission of a cancer to organ receivers. Patients who die from central nervous system tumors, or CNS tumors, are allowed to be organ donors because of the low metastatic rates of CNS tumors. The organs that were donated by these patients were seemingly disease free, but once they were transplanted to the receiving immunosuppressed patients, those patients rapidly developed cancer of CNS origin in those organs. The table below displays these observations where the cancer was transmitted in almost all of the organs transplanted from these patients, and that the onset of disease was only a matter of months post transplant. This indicated that there must have been residual cancer cells present in the transplanted organs that had disseminated from the CNS tumor. Yet, they were undetectable because they have been residual cancer cells. Once they were placed into a patient without a functioning immune system, the cancer cell were able to proliferate and grow out. This alludes to a type of cancer dormancy that we'll be discussing in the next section. More evidence for cancer dormancy comes from the fact that cancer cells disseminate early in primary tumor development. This has been proven through clinical observations, where disseminated tumor cells, or DTCs, have been found to be present in the bone marrow of breast and prostate cancer patients at the time of surgery, which is usually just after the tumor has been detected. We also know that even complete removal of early-stage breast and prostate cancer, when it is found early, does not always prevent relapse either, meaning cells had already disseminated. Additionally, early dissemination has been proven through genomic analysis where for example, one study found that bone marrow DTCs harbor fewer genomic aberrations compared to the primary tumor. This suggests that the primary tumor continued to evolve after the cells disseminated. To wrap up this section, we have introduced the concept of clinical dormancy and the observations that have sparked the investigation into what's really going on at the cellular level. This will be discussed in the following sections.
