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Motivation: Despite increasing understanding of the molecular characteristics of cancer, chemotherapy success rates remain low for many cancer types. Studies have attempted to identify patient and tumor characteristics that predict sensitivity or resistance to different types of conventional chemotherapies, yet a concise model that predicts chemosensitivity based on gene expression profiles across cancer types remains to be formulated. We attempted to generate pan-cancer models predictive of chemosensitivity and chemoresistance. Such models may increase the likelihood of identifying the type of chemotherapy most likely to be effective for a given patient based on the overall gene expression of their tumor. Results: Gene expression and drug sensitivity data from solid tumor cell lines were used to build predictive models for 11 individual chemotherapy drugs. Models were validated using datasets from solid tumors from patients. For all drug models, accuracy ranged from 0.81 to 0.93 when applied to all relevant cancer types in the testing dataset. When considering how well the models predicted chemosensitivity or chemoresistance within individual cancer types in the testing dataset, accuracy was as high as 0.98. Cell line–derived pan-cancer models were able to statistically significantly predict sensitivity in human tumors in some instances; for example, a pan-cancer model predicting sensitivity in patients with bladder cancer treated with cisplatin was able to significantly segregate sensitive and resistant patients based on recurrence-free survival times ( P = .048) and in patients with pancreatic cancer treated with gemcitabine ( P = .038). These models can predict chemosensitivity and chemoresistance across cancer types with clinically useful levels of accuracy.

112 Background: Next-generation sequencing (NGS) is increasingly common in clinical practice, but its clinical utility may depend on the availability of sequencing-directed therapies (SDT). There were no FDA-approved SDTs in prostate cancer (PCa) until 2020, when PARP inhibitors olaparib and rucaparib were approved for tumors bearing alterations in certain homologous recombination repair (HRR) genes. We assessed the clinical utility of NGS in PCa before and after the approval of these agents in a single academic medical center. Methods: This was a retrospective single-center study including all PCa patients seen at Mount Sinai Hospital (New York, NY) between 2018–2021 who received NGS via the 161-gene Sema4 Signal Solid Tumor Panel. Clinical data were extracted from the Mount Sinai electronic medical record using a proprietary automated pipeline with limited manual curation (Sema4 PRODB). The primary outcome was clinical utility in metastatic PCa, defined as the proportion of metastatic PCa patients who received SDT. Secondary outcomes included time-to-next-treatment (TTNT, defined as time from SDT start to the start of next systemic therapy) and the proportion of patients with clinically actionable (as of 9/2021) alterations, defined as either Tier 1 (associated with FDA-approved treatments in prostate cancer) or Tier 2 (associated with either off-label or investigational agents). Results: The cohort consisted of 332 PCa patients; 51% (N = 170) were sequenced in 2020 or later. The median age at diagnosis was 65 (IQR 12). The most advanced stage documented was localized for 39% (N = 129) and metastatic for 61% (N = 203). Overall, 167 actionable alterations were identified in 125 patients (38% of cohort). Of the actionable alterations, 31% (N = 51) were Tier 1 and 69% (N = 116) were Tier 2. Of the 44 patients with Tier 1 alterations, 8 (18%) received SDT (all received olaparib). The proportion of metastatic patients receiving olaparib increased from 1% (2/145) before 2020 to 10% (6/58) during or after 2020 (p = 0.008). Of the 36 patients not receiving olaparib: 20 were sequenced before FDA approval and were treated with an alternative systemic therapy; 8 had localized disease and were not eligible; 8 had limited follow-up or unknown treatment status. For those who received olaparib, median TTNT was 5 months. Conclusions: In this single-center retrospective cohort, clinical utility of NGS was linked to treatment landscape. Increases in NGS test volume and olaparib use coincided with the approval of PARP inhibitors for patients with HRR-mutated prostate cancers. Notably, NGS was used to match patients to off-label/ investigational olaparib before its FDA approval.[Table: see text]