Personalized medicine for brain metastases (BrMets) through patient-derived organoid (PDO) drug testing.

Abstract

11 Background: Therapeutic development for BrMets remains a critical need. Our previous work on functional precision medicine using patient-derived xenografts (PDXs) from BrMets suggested that drug sensitivity testing may help prioritize drug selection. However, the time needed to establish PDXs makes the PDX platform less desirable for translation into the clinic. Thus, we examined the feasibility of PDOs from BrMets to evaluate the drug sensitivities in a clinically meaningful time frame. Methods: BrMets were prospectively collected from clinically indicated neurosurgery. We collected DNA and RNA and cultured tumors as 3D organoids. Drugs were curated for each case based on clinical characteristics and molecular profiles when known a priori. The drugs included standard of care and investigational drugs. Rapid Nanostring PanCancer profiling was conducted to examine if contemporary source tumor profiling would inform additional drug selection. Results: 21 patients with breast cancer were consented to the biobanking program. 3 patients had no tissues collected. 17 PDOs were established from 20 cases: 3 without PDO were necrosis without viable tumors or primary brain tumors. 2 patients had multiple collections (recurrence and synchronous lesions). Clinical subtypes included HR+/- HER2+ (N=7), HR+HER2- (N=2), HR-HER2- (N=8). The median number of drugs tested was 19.5 (range:7-32). The median time for drug testing was 12.5 days (range: 9-32). Nanostring profiling was conducted at the time of drug testing in 12/17 PDOs, and pathway analysis indicated potential targeted drugs. The most common alteration was TP53 mutation with additional NGS. The potentially targetable alterations included mutation to PIK3CA, EGFR, FGFR, CDK2NA, and CDK4. The pair of initial and recurrent lesions was molecularly similar but demonstrated differential response to select chemotherapies following patient exposure to radiation. On the other hand, the pair of synchronous lesions showed discordance in PIK3CA status and discordant sensitivity to Pi3K inhibitors. Conclusions: Predictive drug testing with BrMet PDOs in a clinically meaningful time frame is feasible. The use of real-time PDO drug testing along with molecular profiling could be potentially leveraged to further personalize therapy and discover novel therapy options for patients with BrMets. We are currently conducting clinical correlations and working toward clinical validation of our proposed drug testing platform.