Abstract P3-04-05: Outliers—extreme long-term survivors with metastatic breast cancer
Authors: Ejebe IH , Denu RA , Longhurst C , Bauman JD , MacGregor S , Lee K , Burkard ME 
Published: February 2018

Breast cancer has an extremely heterogeneous clinical course, but the specific causes for this diversity are largely unknown. Understanding the basis for extreme long-term survival with incurable cancer can be of value for prognosis or possible interventions if they arise from modifiable factors.

Methods: We identified patients at our institution with persistent and distant metastases who are alive greater than 5 years from initial diagnosis, and evaluated the clinical characteristics of this population. Additionally we evaluated the published METABRIC cohort of patients who died of cancer to compare patients with greater than median survival (late) to those who died with less than median survival (early). In doing so, we evaluated the non-exclusive alternative hypotheses that long-survival is dictated by cancer genomes versus by host immunity. To do this, we grouped somatic mutations into 11 common pathways and compared the likelihood of being present in the tumors causing early versus late death, when stratified for hormone receptor [HR] status. To evaluate the effect of immune infiltration, we used gene expression profiles using the CIBERSORT algorithm (Nat Methods 12:453, 2015).

Results: We identified 53 individuals who are alive with metastatic breast cancer greater than 5 years from the original diagnosis. The four longest-term survivors were diagnosed with breast cancer in 1978, 1978, 1979, and 1980 and developed metastasis in 1982, 2007, 1996, and 2000 respectively. The median time to metastasis was 4.5 years. Of these, 80% had ER and/or PR-positive breast cancer, 9% triple negative and 18% had HER2+ disease. The longest-term survivors tend to have well-differentiated histology. Analysis of the METABRIC data, demonstrated, as expected, that long survival correlates with hormone-receptor-positive disease. Among 647 subjects who died of cancer, 192 were HR-negative (median survival 36 mo.) and 455 were HR-positive (median survival 76 mo.). Among HR-positive there were no statistical differences in genome profiles between long-versus-short survivors. By contrast, among HR-negative tumors, mutations PI3K-pathway genes and microenvironment maintenance were associated with longer survival (p=0.041 and p=0.047, respectively). CIBERSORT was used to provide quantitative estimates of infiltrating tumor cells, allowing patient groups to be divided by quartiles. However, no significant differences were found in survival among quartiles in T-cell infiltration, in T-cell subsets (activated CD4 memory, CD8, and Tregs) or in monocyte/macrophage subsets.

Conclusions: Some patients live for extended periods of time with metastatic breast cancer. Long-term survival of breast cancer can be explained, in part, by the cell-autonomous features of the tumor, including HR status and genes involved in PI3K signaling and microenvironment maintenance, but no major differences were found in immune infiltrates. Although these data are representative of longer-than-median survivors, extreme long-term survivors may have additional unique features in genomic and immune characteristics.

Citation Format: Ejebe IH, Denu RA, Longhurst C, Bauman JD, MacGregor S, Lee K, Burkard ME. Outliers—extreme long-term survivors with metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-05.