Yi, Joanne

Metastatic CUP is complex, especially NCUP. Precision oncology is crucial for rare, aggressive cancers. A 54-year-old had HER2+ neuroendocrine carcinoma of unknown origin. T-DXd treatment, response, re-challenge show importance of genomics and caution.

AbstractIntroductionPatients with small‐cell lung cancer (SCLC) have a very poor prognosis. However, a subset of SCLC achieves long‐term survival. The objective of this study was to investigate factors and pattern of long‐term survival in patients with limited‐stage small cell lung cancer (LS‐SCLC) who achieved a complete response (CR) after chemoradiotherapy.Patient and MethodsThis was a single‐center retrospective study. The analysis of hazard ratio (HR) and 95% confidence interval (CI) was performed using Cox proportional hazards model. For pattern analysis, the date of recurrence was used as the endpoint. The nominal categorical variables were analyzed by the χ2 test. Survival was estimated using the Kaplan–Meier model, and the results were reported as the median and interquartile range.ResultsWe identified 162 patients, median age was 64.7 (56.2–70.2) years, and 94 (58%) were females. Eighty‐one patients (50%) had recurrence during follow‐up. Gastroesophageal reflux disease (GERD) (HR, 0.65; 95% CI, 0.45–0.93; p = 0.016) and neurological paraneoplastic syndrome (PNS) (HR, 0.46; 95% CI, 0.29–0.72; p < 0.001) were independent factors associated with improved overall survival (OS). Patients with GERD had prolonged recurrence free survival (RFS) compared to patients without GERD (median, 29.1 months vs. 13.9 months, p < 0.001), whereas patients with neurological PNS had a reduced recurrence rate compared to those patients without neurological PNS (No. [%], 8 [20.5] vs. 73 [59.3], p < 0.001).ConclusionsPatients with LS‐SCLC achieving a CR after chemoradiotherapy, GERD, and neurological PNS were associated with improved OS. GERD and neurological PNS were associated with longer RFS and lower recurrence rate, respectively.

Abstract In lung adenocarcinoma, gene fusion involving the anaplastic lymphoma kinase (ALK) gene leads to overexpression of its tyrosine kinase domain, which serves as the oncogenic driver in lung tumors carrying such a molecular alteration. Similar fusions involving ROS1, RET and NTRK are also found in lung cancer and tumors with oncogenic fusions often respond well to targeted therapy. However, these tumors do develop resistance to the targeting drug and patients eventually relapse while on treatment. Although newer drugs have been developed, it remains a challenge to effectively control cancer recurrence after targeted therapy. In vivo tumor models carrying these fusions, particularly those that have progressed while on targeted treatment, will help to facilitate further drug evaluations prior to their administration to the patient as well as offer an opportunity to better understand the molecular mechanisms driving disease onset, progression, and drug resistance in tumors carrying the fusion of interest. Here, we describe the first patient-derived tumor xenograft (PDX) carrying an STRN-ALK fusion. The patient was diagnosed with stage IV lung adenocarcinoma in 2011. She was initially treated with crizotinib and remained stable until 2015. At the time of disease progression, a biopsy was taken with patient consent under CT guidance from a chest wall mass using an 18-gauge needle and then implanted into two SCID-beige mice subcutaneously and into the fat pad of the kidney. Palpable tumor was observed in both mice at about 28 weeks post implantation and passaged at 36 weeks. They have been passaged two successive times and viably frozen. Pathologic analysis of the PDX showed that both tumors have the same mucinous morphology as observed in the original biopsy sample. RNA-seq and matepair analysis revealed that the tumors carry a rare fusion involving the first three exons of STRN and exon 20 to 3’ end of the ALK gene. The patient has been on ceritinib since January 2016 and remains stable as of last follow up. Several unique features contributed to the success of this study. 1) The metastatic chest wall lesion used for the PDX developed was easily accessible on the chest wall using a relative large 18-gauge needle for CT-guided biopsies. 2) The slow growth of the tumor biopsy mirrors the clinical course of the disease observed in the patient. 3) The patient remains clinically stable and continues to respond to TKi. The availability of a viable PDX tumor model for this rare STRN-ALK fusion offers a unique opportunity to identify the most appropriate drug for the patient at the time of disease progression as well as the opportunity to examine the unique molecular features associated with this rare ALK fusion. This work was supported in part by the National Foundation for Cancer Research Hillsberg Lung Cancer Translational Research Grant and by the Biomarker Discovery Program at the Mayo Clinic Center for Individualized Medicine. Citation Format: HongZheng Res, XiaoNan Hou, Karlyn E. Pierson, Patric Eiken, Asha Nair, PingYang Yang, Joanne Eunhee Yi, Aaron S. Mansfield, Jin Jen. Establishment of a unique patient-derived tumor model positive for STRN-ALK fusion from a patient with stage IV lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A17.

Abstract Mutations in the EGFR gene or transcript fusion involving EML4-ALK result in oncogenic activation of these oncogenes driving lung adenocarcinoma growth in tumors carrying such an alteration. For lung adenocarcinoma with these genetic changes, small-molecule tyrosine kinase inhibitors have been highly effective at reducing tumor burden and improve the outcome of the patients. Unfortunately, drug resistance eventually develops in these tumors and challenges remain in controlling lung cancer recurrence after targeted therapy. To overcome recurrence, we initiated a prove-of-principle study to evaluate the feasibility of an integrated strategy utilizing genomic profiles of the tumor and patient-specific tumor xenografts derived (PDX) from biopsies for ex vivo evaluation of antitumor drugs to help guide personalized treatment of lung cancer in patients who have developed resistance to targeted therapy drugs. Our study has three main objectives. 1) Use tumor biopsies obtained at the time of recurrence for oncogene mutation and RNAseq analyses to identify molecular changes in oncogenes and gene pathways that can be potentially targeted. 2) Evaluate drug efficacy and optimize personalized therapy for each patient using PDX models. 3) Assess clinical feasibility and our experience using integrated approaches for lung cancer patients who failed targeted therapy. This study was approved by the Mayo Clinic Institutional Review Board (IRB) and utilizes both clinical and research biopsies. A dedicated nurse study coordinator reviews clinical patient list and history on weekly basis and informs the study team of each potential candidate patient. A total of 30 patients having ALK positive lung cancers have been identified and followed up from nearly 500 potentially ALK positive cases between April 2014 to Sept. 2015. Most patients were never smokers but six were former smokers and two were current smokers. Age at diagnoses ranged from 27-78 years (median = 61). Seven patients (23%) were 45 years or younger at the time of diagnosis. A total of 22 patients are currently being treated with crizotinib while eight are on ceritinib or alectinib. For each biopsy, tumor tissues are obtained using a 20 gauge needle, transferred on ice in preserving media and implanted within one hour into 6-8 week old NOD/SCID mice. Many patients have been on treatment for 2-3 years with stable disease so they do not require biopsy. Using a similar strategy, we also obtained biopsies from patients with EGFR gene mutations in their tumors and have progressed while on targeted therapy. A total of seven cases have been implanted. We will report our experiences in patient selection, clinical follow up, patient consent, PDX development, time from biopsy to tumor establishment, and the results of molecular analyses. Our study enabled us to gain new insights regarding the molecular changes associated with recurring tumors after they have failed targeted therapy as well as clinical experiences on how to utilize state-of-the art approaches and comprehensive genomic information to further improve cancer patient care upon disease progression. Acknowledgements: This work is supported in part by the Hillsberg Award from the National Foundation for Cancer Research and by the Biomarker Discovery Program at the Mayo Clinic Center for Individualized Medicine. Citation Format: Jin Jen, Aaron Mansfield, Patrick W. Eiken, Shawn Stoddard, Karlyn Pierson, Xiaonan Hou, Hong Zheng Ren, Julian Molina, Joanne Yi, Ping Yang. Integrated Approaches to Treating Lung Adenocarcinoma Resistant to Targeted Therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B34.

Abstract Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906–14. ©2016 AACR.

Abstract Lung cancer accounts for about 27% of the cancer related deaths in the USA annually. Pathologically, it is a very complex disease broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLCs are further classified into squamous cell carcinoma, large cell carcinoma and adenocarcinoma. Achaete-scute homolog 1 (ASCL1), an important transcription factor essential in the development of neuroendocrine cells (NE) in lungs is shown to be specifically expressed in lung NE cancers and 10-20% of adenocarcinomas (AD) with NE differentiation (NED), thus suggesting a role in the pathogenesis of these tumors. Our previous study showed that ASCL1 is a regulator of the RET oncogene in AD with NED. RET is a receptor tyrosine kinase with two isoforms in humans: RET9 (short) and RET51 (long). We performed survival analysis to study implications of RET isoforms in ASCL1+ tumors and found that elevated expression of the long RET mRNA was associated with poor survival. Subsequent in vitro experiments demonstrated that treatment with EGF robustly induced phosphorylation of RET in HCC1833 and H1755 cell lines which have high endogenous levels of ASCL1 and RET but not in VMRC-LCD cell line which has high level of ASCL1 but low level of RET. EGF induced phosphorylation of RET was diminished by gefitinib and by EGFR siRNA. Immunoprecipitation results indicated direct binding between EGFR and RET in presence of EGF. Furthermore, a high throughput drug screening found 8 EGFR inhibitors that were 10 - 250 fold more cytotoxic in ASCL1+ compared with ASCL1- AD cells. These results implicate EGFR as a key regulator of RET activation in ASCL1+ AD and suggest that EGFR inhibitors may be therapeutic for this population of patients. Citation Format: Kaustubh N. Bhinge, Yang Lin, Hamed Rahi, Marie Christine Aubry, Aaron Mansfield, Irina Kovtun, Stephen Murphy, Ping Yang, Dennis Wigle, Joanne (Eunhee) Yi, Aqsa Nasir, Simone Terra, Julian Molina, George Vasmatzis, Farhad Kosari. EGFR-mediated activation of RET in ASCL1+ lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1129.