Metastasis, or the spread of cancer from its primary site to distant organs, is often painful and debilitating, and it is responsible for the vast majority of breast cancer-related deaths. At present, the best way to cure breast cancer is to treat the disease early before metastasis has occurred. For most patients, surgical removal and local radiation is sufficient to eradicate the tumor while it is still confined to the breast and regional lymph nodes. Occasionally, surgery and local radiation are not sufficient for cure because microscopic amounts of cancer have already spread to other organs. In this situation, chemotherapy can be given after surgery. However, even in women with only microscopic amounts of disseminated cancer, the likelihood of cure with chemotherapy is poor (about 30%-40%). Women with untreated or resistant microscopic disease can go on to develop gross metastasis (stage 4 disease) months or years later. Unfortunately, patients with stage 4 cancer are rarely cured because surgery is no longer an option and the metastases are nearly always resistant to chemotherapy. Thus, the window of opportunity to cure breast cancer rapidly closes once the disease has begun to spread, and it finally shuts when stage 4 metastasis and treatment resistance emerge. Attempts to re-open this window have failed time and time again, leading to the prevailing wisdom that stage 4 metastasis is incurable.

Although gross metastasis is considered incurable, clinical anecdotes suggest that not all stage 4 metastases are the same. The term oligometastases describes the concept that in some patients with only a few clinically apparent metastatic lesions, their cancer might be limited in its ability to further spread and colonize. Today with modern imaging, metastatic lesions are routinely detected when they are limited in size and number. Like primary breast cancer, might the early detection of metastases open a window of vulnerability whereby metastases can be treated before they are fully able to grow, spread further, and resist treatment? If so, the clinical implication would be that oligometastatic disease should be treated far more aggressively. Indeed, advances in surgery, radiation, and chemotherapy now provide tools that make aggressive treatment of limited metastatic disease possible. However, as yet, an oligometastatic state and its sensitivity to treatment remain hypotheses.

In support of the notion that an oligometastatic state exists, growing evidence suggests that neighboring cells that surround the tumor (the microenvironment) can interact with breast cancer and shape cancer behavior. Based on this idea, we hypothesize that these neighboring cells can progressively select for the ability of breast cancer to co-opt specific neighbor-to-cancer interactions that influence metastasis and treatment resistance. Therefore, there exists a state whereby effects of the microenvironment on metastatic behavior and treatment resistance are dynamic and reversible. The objective of this proposal is the discovery and clinical translation of genes and interactive pathways that mediate such microenvironmental effects on breast cancer metastasis and treatment resistance and to relate this to oligometastases.

Through discovery and mechanistic understanding, an important translational goal of this proposal is to incorporate our findings into a clinical trial for patients with apparent oligometastases. We will develop new, experimentally derived biomarkers to identify a subset of stage 4 patients with potential oligometastases, treat these patients for cure, and correlate the biomarkers to clinical outcome. The result will be novel assays that can predict which patients benefit from aggressive treatment of their oligometastatic disease. A second important goal will be to understand if and how interactions between breast cancer and different microenvironments might dynamically influence oligometastases and treatment resistance. Such efforts may identify potential therapeutic targets that can expand the number of stage 4 patients that benefit from aggressive oligometastases treatment. A clinical trial is currently in late-stage development; therefore, we anticipate that this proposal may lead to patient-related outcomes within 5 years.