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Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a significant health issue. For most patients, there are no options for targeted therapy, and existing treatments are limited by toxicity. The HOPE trial (Harnessing Organoids for PErsonalized Therapy) was a pilot feasibility trial aiming to prospectively generate patient-derived organoids (PDO) from patients with PDAC and test their drug sensitivity and correlation with clinical outcomes. Experimental Design: PDOs were established from a heterogeneous population of patients with PDAC including both basal and classical PDAC subtypes. Results: A method for classifying PDOs as sensitive or resistant to chemotherapy regimens was developed to predict the clinical outcome of patients. Drug sensitivity testing on PDOs correlated with clinical responses to treatment in individual patients. Conclusions: These data support the investigation of PDOs to guide treatment in prospective interventional trials in PDAC.

Despite increasing appreciation for the medical needs of transgender individuals, the organization of transgender medical care remains suboptimal. Transgender individuals report difficulty in finding providers who have adequate expertise in caring for transgender patients, a lack of provider cultural competence, health system barriers, and discrimination in healthcare settings. At Boston Medical Center (BMC), we sought to address these gaps within an existing academic medical center. In February 2016, BMC established a Center for Transgender Medicine and Surgery (CTMS) to provide a single address for patients to obtain transgender-specific services across a spectrum of healthcare needs. With the establishment of a CTMS at BMC, we were able to leverage broad transgender medical coverage across multiple specialties within an existing academic medical framework. Furthermore, the development of the CTMS resulted in our identification of multiple gaps in transgender healthcare which we could target. Large gaps in care for our institution included genital surgery, perisurgical support, adolescent care, and care coordination. Notably, most of our interventions used existing resources. We propose that this is a replicable model that should be adopted by other academic medical institutions.

The HOPE trial (Harnessing Organoids for PErsonalized Therapy) was a pilot study to test the feasibility of generating patient derived organoids (PDOs) from patients with pancreatic cancer under real world conditions, test drug sensitivity against these PDOs, and correlate these findings with clinical outcomes. Biopsies were obtained primarily during routine clinical care from surgical specimens, ascites, fine needle biopsies (FNB) of primary tumors, and IR guided core biopsies of liver and lymph node metastases. PDOs were grown in WNT free media according to our previously published methods. PDO drug sensitivity testing was performed on a panel of drugs, AUC calculated, and sensitivity ranked. Patients were followed clinically and assessed for disease control. At data cutoff (January 2020), we enrolled a total of 76 subjects representing all stages of disease. Drug testing was performed successfully on PDOs generated from 12 of these subjects (16%). Factors contributing to success obtaining sufficient cells for PDO generation included modality, body part, and tumor cellularity. H&E and IHC corresponded in matched PDOs and donor tumors, as did DNA alterations. Transcriptomes of PDOs were classified as both ‘basal' and ‘classical' subtypes. When AUC values were annotated with clinical data, the Jenks break of 1.69 segregated matched PDO/AUC values into disease control and progressive disease. We estimated that a PDO AUC value 99% probability of disease control from a regimen that contains this drug, whereas if all drugs in a regimen had an AUC > 2.75 there is a > 80% probability of accurately predicting resistance. To illustrate the potential of PDO testing to tailor treatment for an individual patient, we described a case of a subject with stage IV PDAC with a KRAS mutation and ERBB2 amplification. The subject had disease control with FOLFIRINOX, which was held for toxicity. The PDO showed resistance to oxaliplatin and the patient subsequently had an extended period of disease control with regimens which did not include oxaliplatin, highlighting the potential of PDO drug sensitivity testing to exclude ineffective treatments from combination chemotherapy and limit toxicity. In conclusion, we have shown the feasibility of collecting material via real-world clinical practice sufficient to develop PDOs suitable for rapidly screening multiple drugs, and have shown a high degree of correlation between clinical outcomes in patients with PDAC and matched PDO drug sensitivity. We determined preliminary criteria based on the AUC of individual drugs in PDOs to predict drug sensitivity in subjects. These results highlight the potential of PDOs to personalize therapy and allow for the exclusion of ineffective drugs from combination regimens thereby reducing toxicity. We anticipate this approach will be used in future trials to prospectively inform treatment selection for patients with PDAC. Citation Format: Joseph Elan Grossman, Ling Huang, Lakshmi Muthuswamy, Sofia Perea, Dipikaa Akshinthala, Raul Gonzalez, Leo Tsai, Jonah Cohen, Mandeep Sawhney, Douglas Pleskow, Tyler M. Berzin, Bruno Bockorny, Andrea Bullock, Benjamin Schlechter, Mary Linton B. Peters, Catherine Conahan, Supraja Narasimhan, Christine Lim, Roger Davis, Robert Besaw, Martin Smith, Tara Kent, Mark Callery, Senthil K. Muthuswamy, Manuel Hidalgo. Organoid sensitivity in pancreatic cancer correlates with clinical response to treatment and reveals utility for reducing toxicity: Preliminary results from the HOPE trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT119.

This article provides an account of the current understanding of hormone therapy options for transgender men and emphasizes the importance of continued physician-supervised monitoring for long-term care.