Despite improvements in early detection and treatment, cancer remains a major cause of mortality. Death from cancer is largely due to metastasis, which results in spreading of tumor cells to other parts of the body. The metastatic process is poorly understood, is often unpredictable, and usually results in incurable disease. There are no therapies specifically designed to target metastases or to block the metastatic process. Development and pre-clinical testing of new cancer therapies is limited by the scarcity of in vivo models that authentically reproduce human tumor growth and metastatic progression. Here, we report development of novel models for breast tumor growth and metastasis, which exist in the form of transplantable tumors derived directly from patients. These tumor grafts not only represent the diversity of human breast cancer, but also maintain essential features of the original patients’ tumors, including histopathology, clinical markers, hormone responsiveness, and metastasis to specific sites. Genomic features, such as gene expression profiles and DNA copy number variants, are also well maintained between the original specimens and the tumor grafts. We found that co-engraftment of primary human mesenchymal stem cells with tumor grafts helps to maintain the phenotypic stability of the tumors, and increases tumor growth by promoting angiogenesis and reducing necrosis. Remarkably, tumor engraftment is also a prognostic indicator of disease outcome: newly diagnosed women whose primary breast tumor successfully engrafted in mouse mammary glands had significantly reduced survival compared to patients whose tumors did not engraft. Thus, orthotopic breast tumor grafting marks a first step toward personalized medicine by replicating the diversity of human breast cancer through patient-centric models for tumor growth, metastasis, drug efficacy, and prognosis.

Background: Validation of a novel gene expression signature in independent data sets is a critical step in the development of a clinically useful test for cancer patient risk-stratification. However, validation is often unconvincing because the size of the test set is typically small. To overcome this problem we used publicly available breast cancer gene expression data sets and a novel approach

Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies. We report a bank of human patient-derived xenografts (PDXs) and matched organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers. We leverage matched PDXs and PDX-derived organoids (PDxO) for drug screening that is feasible and cost-effective with in vivo validation. Moreover, we demonstrate the feasibility of using these models for precision oncology in real time with clinical care in a case of triple-negative breast cancer (TNBC) with early metastatic recurrence. Our results uncovered a Food and Drug Administration (FDA)-approved drug with high efficacy against the models. Treatment with this therapy resulted in a complete response for the individual and a progression-free survival (PFS) period more than three times longer than their previous therapies. This work provides valuable methods and resources for functional precision medicine and drug development for human breast cancer.

IntroductionPredicting the clinical course of breast cancer is often difficult because it is a diverse disease comprised of many biological subtypes. Gene expression profiling by microarray analysis has identified breast cancer signatures that are important for prognosis and treatment. In the current article, we use microarray analysis and a real-time quantitative reverse-transcription (qRT)-PCR assay to risk-stratify breast cancers based on biological 'intrinsic' subtypes and proliferation.MethodsGene sets were selected from microarray data to assess proliferation and to classify breast cancers into four different molecular subtypes, designated Luminal, Normal-like, HER2+/ER-, and Basal-like. One-hundred and twenty-three breast samples (117 invasive carcinomas, one fibroadenoma and five normal tissues) and three breast cancer cell lines were prospectively analyzed using a microarray (Agilent) and a qRT-PCR assay comprised of 53 genes. Biological subtypes were assigned from the microarray and qRT-PCR data by hierarchical clustering. A proliferation signature was used as a single meta-gene (log2 average of 14 genes) to predict outcome within the context of estrogen receptor status and biological 'intrinsic' subtype.ResultsWe found that the qRT-PCR assay could determine the intrinsic subtype (93% concordance with microarray-based assignments) and that the intrinsic subtypes were predictive of outcome. The proliferation meta-gene provided additional prognostic information for patients with the Luminal subtype (P = 0.0012), and for patients with estrogen receptor-positive tumors (P = 3.4 × 10-6). High proliferation in the Luminal subtype conferred a 19-fold relative risk of relapse (confidence interval = 95%) compared with Luminal tumors with low proliferation.ConclusionA real-time qRT-PCR assay can recapitulate microarray classifications of breast cancer and can risk-stratify patients using the intrinsic subtype and proliferation. The proliferation meta-gene offers an objective and quantitative measurement for grade and adds significant prognostic information to the biological subtypes.

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The observations to be recorded in this Paper were commenced in March, 1905. They originated in an attempt to find a general method for rearing marine larval forms. Several investigators had previously succeeded in rearing Echinoderms, Molluscs, and Polychætes from artificially fertilized eggs under laboratory conditions, but the process was generally difficult and the results more or less uncertain. The most promising method seemed to be that adopted by Caswell Grave (26), who was able to rear his larvæ by feeding them on diatoms. Grave obtained his diatoms by placing sand, collected from the sea bottom, in aquaria and using such diatoms as developed from this material. All the methods, however, suffered from the uncertainty of not knowing what organisms were introduced into the aquaria in which the larvse were to be reared, either in the original sea-water or along with the food-supply.

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