Functional Tissue-based Therapy Response Prediction for Breast Cancer Patients

Breast cancer is a heterogeneous disease that can be classified into several subtypes. Triple-negative breast cancers (TNBC) lack estrogen and progesterone receptors and do not harbor HER2 amplification. TNBC accounts for 10-15% of all breast cancer cases and show great overlap with BRCA1/2 mutated breast cancers. BRCA1/2 mutations occur in 3% of breast cancer cases and cause defects in the homologous recombination (HR) pathway, leading to ineffective repair of double strand DNA breaks. Targeted therapy with Poly ADP Ribose Polymerase (PARP) inhibitors can specifically kill cells with impaired HR activity. The RECAP (homologous recombination REpair CAPacity) test, is a functional ex vivo assay that assesses whether the HR pathway is functioning, using RAD51 foci as a read-out. In a first cohort of primary breast cancer tumors, approximately 15% showed HR deficiency (HRD). The RECAP test is now also feasible on core needle biopsies from metastatic breast cancer, where 35% of the tumors showed HRD. Selection of patients for PARP inhibitor therapy using the functional RECAP test, as opposed to selection based on germline BRCA1/2 mutation, could enhance the number of patients benefiting from this therapy. Predictive value of the RECAP test for in vivo response to PARP inhibition requires validation, for which clinical trials are ongoing

Down-staging (<pT2) of urothelial cancer at cystectomy after the diagnosis of detrusor muscle invasion (pT2) at diagnostic transurethral resection (TUR): Is prediction possible?

Urothelial cell carcinoma (UCC) with musculus detrusor (MD) invasion is treated by cystectomy. Subsequent pathologic evaluation of cystectomies does not reveal MD invasion (<pT2) in a subgroup of patients. Our objective was to identify features at diagnostic transurethral resection (TUR) predicting down-staging (<pT2) at cystectomy. Patients with pathologically confirmed MD invasion at TUR followed by cystectomy for UCC without (neo-) adjuvant therapy were included (N=106). Slides of both TUR and cystectomy specimens were reviewed, and survival analyses were performed. In total, 27/106 (26 %) tumors were down-staged at cystectomy, of which 13 (12 %) had no residual tumor (pT0). There was no significant difference in age, gender, time interval between TUR and operation, number of slides sampled, and presence of TUR scar between down-staged (<pT2) and pT2 UCC. At review of TUR specimens (N=52) with UCC initially diagnosed as pT2, MD invasion was not confirmed in eight cases (15 %). One case showed extensive histiocytic reaction misinterpreted as UCC; in four cases, muscularis mucosae had been considered MD, and in three cases, desmoplastic reaction mimicked MD. No histologic parameter at TUR was significantly associated with down-staging at cystectomy. Overall and disease-specific survival was not statistically different in down-staged and pT2 UCC. In conclusion, down-staging of UCC (<pT2) at cystectomy occurred in 26 %. At review of diagnostic TURs, MD invasion was not confirmed in 15 %. No clinical or pathologic parameter was predictive for down-staging at cystectomy. There was no difference in survival between down-staged and pT2-staged UCC

Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response

Background: In vitro models of prostate cancer (PCa) are not always reliable to evaluate anticancer treatment efficacy. This limitation may be overcome by using viable tumor slice material. Here we report on the establishment of an optimize