Heterogeneity Of Metastatic Tumors Research Articles

Single-cell sequencing reveals the immune landscape of breast cancer patients with brain metastasis.

Breast cancer has the highest incidence rate of cancer worldwide, and brain metastases (BrM) are among the most malignant cases. While some patients have benefited from immune checkpoint inhibitors (ICIs), the complex anatomical structure of the brain and the heterogeneity of metastatic tumors have made it difficult to characterize the tumor immune microenvironment (TME) of metastatic tumors. To address this, we used single-cell RNA sequencing (scRNA-seq) to analyze immune cells in the cerebrospinal fluid (CSF) of BrM patients with breast cancer, thereby providing a comprehensive view of the immune microenvironment landscape of BrM. Based on canonical marker genes, we identified nine cell types, and further identified their subtypes through differential expression gene (DEG) analysis. We compared the changes in cells and functions in the immune microenvironment of patients with different prognoses. Our analysis revealed a series of genes that promote tumor immune function (CCR5, LYZ, IGKC, MS4A1, etc.) and inhibit tumor immune function (SCGB2A2, CD24, etc.). The scRNA-seq in CSF provides a noninvasive method to describe the TME of breast cancer patients and guide immunotherapy.

Genomic landscape of cell-free DNA in a diverse cohort of metastatic breast cancer patients.

e13066 Background: Breast cancer is the most prevalent cancer and the second leading cause of cancer deaths among women in the United States. Once the primary breast cancer has metastasized to other parts of the body, despite treatment, patients have an incurable disease. Compared to the primary tumor, often the metastasized tumor sites have different mutational profiles that are not represented in the initial biopsy. Liquid biopsy is becoming a more commonly accepted method in clinical practice to determine the heterogeneity of metastatic tumors by analyzing cell-free DNA (cfDNA). Several studies have demonstrated that cfDNA can be utilized as an effective prognostic tool and can reveal multiple clinically targetable alterations in metastatic breast cancer (mBC). Methods: We characterized the genomic landscape of cfDNA in a diverse patient population and across different subtypes of mBC. We performed a retrospective chart review in patients (n = 41) with metastatic breast cancer from a medical oncology clinic within the Hawaii Pacific Health system. Patients who had at least one cfDNA testing by Guardant360 were evaluated. Patient demographics, age at diagnosis, race, subtype and mutations were reviewed along with treatment information. Results: We found no statistically significant differences in genomic landscape according to race, however there were differences seen in tumor genomics according to age and subtype. Older patients were less likely to have detectable disease on liquid biopsy compared to younger patients (age 70+ and 60-69 vs 30-39; xp 0.02). Consistent with subtype, mutations in ESR1 (n = 12) and PIK3CA (n = 14) were more commonly seen in hormone positive (HR+) mBC where known tailored treatment options are available (ie. fulvestrant and alpelisib respectively). Postmenopausal patients were more likely to have ESR1 mutations than premenopausal patients (50-59 and 70+ vs 30-39 and 40-49, xp 0.009). About half (n = 20) had TP53 mutations, followed by PIK3CA (n = 14), ESR1 (n = 12), CCND1 (n = 7) and MYC (n = 6). Conclusions: We evaluated 41 unique cases of mBC and correlated them with their genomic profiles. We plan to further investigate genomic changes according to treatment with subsequent repeat liquid biopsies. We hope to utilize these findings to help prognosticate and guide future treatment options.

Systemic Targeting of Liposome-Encapsulated Immunomodulators to Macrophages for Treatment of Cancer Metastasis

and The therapy of cancer is, in reality, the design of therapeutic strategies for therapy of metastatic disease. Metastases consist of unique subpopulations of tumor cells that are derived from the primary tumor, colonize distant target organs, and are able to subvert host immune responses, establish necessary angiogenesis, and obtain a sufficient nutrient supply while evolving to become autonomous from homeostatic mechanisms that function within normal, differentiated tissues. Attempts at eradication of metastases by conventional therapies have generally been unsuccessful due to genetic instability and heterogeneity of metastatic tumors; these properties lead to the emergence of tumor cells that are resistant to most conventional treatments. It may be possible to circumvent this heterogeneity by the activation of tissue macrophages to the tumoricidal state. Activated macrophages are able to kill tumor normals while sparing normal tissues, and efficient activation can be achieved by encapsulation of synthetic muramyl tripeptide analogues into multilamellar vesicles composed of phospholipids. Systemic administration of these liposome-encapsulated compounds leads to tumoricidal activation of alveolar and peritoneal macrophages and eradication of established tumor metastasis in numerous animal tumor models, and this form of therapy is enhanced by combination with parenteral administration of cytokines. Phase III clinical trials of recurrent osteosarcoma are currently in progress. Modulation of the tumor microenvironment by activated macrophages may prove to be an additional modality in treatment strategies that combine the use of biological response modifiers with conventional therapies.