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.

PurposeBeing diagnosed with cancer causes major psychological distress; however, a majority of patients lack psychological support during this critical period. Internet interventions help patients overcome many barriers to seeking face-to-face support and may thus close this gap. We assessed feasibility and efficacy of Web-based stress management (STREAM [Stress-Aktiv-Mindern]) for newly diagnosed patients with cancer.Patients and MethodsIn a randomized controlled trial, patients with cancer who had started first-line treatment within the previous 12 weeks were randomly assigned to a therapist-guided Web-based intervention or a wait-list (control), stratified according to distress level (≥ 5 v < 5 on scale of 0 to 10). Primary efficacy end point was quality of life after the intervention (Functional Assessment of Chronic Illness Therapy–Fatigue). Secondary end points included distress (Distress Thermometer) and anxiety or depression (Hospital Anxiety and Depression Scale). Treatment effect was assessed with analyses of covariance, adjusted for baseline distress.ResultsA total of 222 of 229 screened patients applied online for participation. Between September 2014 and November 2016, 129 newly diagnosed patients with cancer, including 92 women treated for breast cancer, were randomly assigned to the intervention (n = 65) or control (n = 64) group. Adherence was good, with 80.0% of patients using ≥ six of eight modules. Psychologists spent 13.3 minutes per week (interquartile range, 9.5-17.9 minutes per week) per patient for online guidance. After the intervention, quality of life was significantly higher (Functional Assessment of Chronic Illness Therapy–Fatigue: mean, 8.59 points; 95% CI, 2.45 to 14.73 points; P = .007) and distress significantly lower (Distress Thermometer: mean, −0.85; 95% CI, −1.60 to −0.10; P = .03) in the intervention group as compared with the control. Changes in anxiety or depression were not significant in the intention-to-treat population (Hospital Anxiety and Depression Scale: mean, −1.28; 95% CI, −3.02 to 0.45; P = .15). Quality of life increased in the control group with the delayed intervention.ConclusionThe Web-based stress management program STREAM is feasible and effective in improving quality of life.

Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.