An estimated 231,840 new cases of invasive breast cancer are expected to be diagnosed among women in the US during 2015, making it the most frequently detected cancer in women in the United States, after cancers of the skin. Approximately 40,290 breast cancer deaths are expected in 2015, remaining the second most common cause of cancer deaths in women, behind lung cancer. The median survival of women with metastatic breast cancer remains low, around 18-24 months, 3 with a 5-year relative survival of 24%. Albeit these discouraging numbers, some women still live for many years after a diagnosis of metastatic disease and will undergo treatment with several lines of chemotherapy. In a single center study of 1,581 patients with metastatic disease between 1973 and 1982, 263 of patients (16.6%) achieved complete responses after treatment with consecutive doxorubicin and alkylating agent-containing front-line treatment protocols. Of those, 49 patients (3.1% of the total group) remained in complete remission for more than 5 years, and 26 patients (1.5%) were still in first complete remission at 16 years, with one patient alive with metastatic disease at 16 years.
Some common clinical features shared by these long-term survivors have been described in retrospective studies, these include low tumor burden, good performance status, soft tissue metastases, hormone receptor positivity, younger age and premenopausal status at diagnosis. Recent efforts in the oncology community are focusing on identifying driver mutations to select specific targeted therapies to treat metastatic disease, yet little data is known about the genetic profile of this subgroup of long-term survivors with metastatic disease. Yet, the long-term survival of these patients may represent more the indolent nature of the disease than the efficacy of treatment.
Identifying patients with indolent courses through unique genetic characteristics would be a critical advance as it may allow de-escalation of treatment and improved care. Additionally, the unique genetic characteristics of these patients could provide important insight into cancer biology. We hypothesize that there are valuable differences in tumor and/or somatic genetics of patients with indolent cancer.
Here, we test the hypothesis that long-term survivors with metastasis have unique genetic features of their tumor or, perhaps germline, that govern an indolent course of cancer outcomes. Importantly we focus on patients with incurable metastatic cancer as long survival is more likely representative of the characteristics of cancer behavior, in contrast to patients with early stage cancers that may be cured with surgery. Currently the field of cancer genomics seeks to identify actionable mutations, genetic alterations that indicate sensitivity to specific targeted therapies. Here, we conversely seek “inactionable” mutations, those that identify individuals whose personalized therapy plan may benefit from marked de-escalation of a conventional treatment plan.