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The US National Cancer Institute is launching an 'exceptional responder' programme to see whether outliers from failed cancer trials can open up new drug development avenues.

// Vivek Subbiah 1,* , Robert E. Brown 2,* , Mary F. McGuire 2 , Jamie Buryanek 2 , Filip Janku 1 , Anas Younes 3 , David Hong 1 1 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 2 Department of Pathology & Laboratory Medicine, UT Health, University of Texas-Houston Medical School, Houston, Texas, 3 Memorial Sloan-Kettering Cancer Center, Memorial Hospital, New York, NY * Both authors contributed equally to the study. Correspondence: Vivek Subbiah, email: // Keywords : Hodgkin’s lymphoma, PI3K/AKT/mTOR, mTOR, HDAC, immune dysregulation, morphoproteomics, biomedical analytics, vorinostat, sirolimus , adolescent and young adult oncology, ,rapalog, targeted therapy, immunotherapy, unusual responder, exceptional responder, complete response, FDG-PET, brentuximab vedotin, CD8, CD30, T-cell regulatory cells Received : October 4, 2013 Accepted : November 19, 2013 Published : November 19, 2013 Abstract Although Hodgkin’s lymphoma (HL) was one of the first human cancers to be cured by chemotherapy, no new agents other than brentuximab vedotin ( Adcetris®, CD 30 directed antibody drug conjugate) have received US Food and Drug Administration (FDA) approval for HL since 1977. Subsets of young adult patients with HL continue to relapse, even after stem cell transplantation, warranting new approaches. Against this background, we report a dramatic response in a young patient with advanced HL refractory to the standard treatment who responded to the combination of a pan-histone deacetylase inhibitor (vorinostat, suberoylanilide hydroxamic acid, SAHA) and mammalian target of rapamycin (mTOR) inhibitor therapy (sirolimus,rapamume). In-depth immunohistochemical and morphoproteomic analyses of this exceptional responder to targeted therapy have yielded potential insights into the biology of advanced HL. The PI3K/AKT/mTOR pathway is a commonly activated pathway in multiple tumor types including HL. The patient was treated using therapy based on mechanistic in vitro data demonstrating that combined histone deacetylase (HDAC) and mTOR inhibition act together on this pathway, resulting in inhibition of reciprocal feedback networks, leading to better anti-proliferative activity. The in vivo response signature from this patient’s tissue sample sheds light on immune dysregulation in HL. We describe the response signature achieved from targeting immune dysregulation in addition to targeting the key oncogenic PI3K/AKT/mTOR pathway. We also expand on the role of rapamycin analogs in oncology. This study supports a role for an immune-type pathogenesis that is amenable to immune modulating targeted therapy in refractory HL. Significance: We report an exceptional responder to molecularly targeted and immune modulator therapy in advanced Hodgkin’s lymphoma. The morphoproteomic/morphometric findings in this “unusual responder” patient’s relapsed HL that correlate best, as a response signature with the subsequent clinical remission following rapamycin (sirolimus) and vorinostat (SAHA) therapies, center on an immune dysregulation involving an imbalance between effector and functional T regulatory cells in addition to targeting the mTOR pathway. This underscores the need for an approach illustrated in our study – namely of focusing on pathogenetic mechanisms and combinatorial therapies that target both the pathogenesis and adaptive responses to contemplated therapies.

We used next-generation sequencing to identify somatic alterations in multiple metastatic sites from an “exceptional responder” lung adenocarcinoma patient during his 7-yr course of ERBB2-directed therapies. The degree of heterogeneity was unprecedented, with ∼1% similarity between somatic alterations of the lung and lymph nodes. One novel translocation, PLAG1-ACTA2, present in both sites, up-regulated ACTA2 expression. ERBB2, the predominant driver oncogene, was amplified in both sites, more pronounced in the lung, and harbored an L869R mutation in the lymph node. Functional studies showed increased proliferation, migration, metastasis, and resistance to ERBB2-directed therapy because of L869R mutation and increased migration because of ACTA2 overexpression. Within the lung, a nonfunctional CDK12, due to a novel G879V mutation, correlated with down-regulation of DNA damage response genes, causing genomic instability, and sensitivity to chemotherapy. We propose a model whereby a subclone metastasized early from the primary site and evolved independently in lymph nodes.

Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low frequency mutations. We describe an evidence-based precision medicine program designed to bring whole exome sequencing (WES) into clinical practice and illustrate how this can be utilized to identify novel predictive biomarkers associated with exceptional systemic response. Metastatic and treatment-resistant cancer patients are prospectively enrolled for paired metastatic tumor and normal WES. Using a comprehensive computational pipeline, point mutations, indels and copy number alterations are detected. Mutations are categorized as Category I-III based on actionability and a report is generated and discussed in tumor board. Patients are followed prospectively for correlation of molecular information with clinical response and patient outcomes. A rapid response functional team follows on key findings to expand actionability based on the WES results. In the first year, 154 tumor-normal pairs from 97 patients were sequenced, with an average coverage of 95X of over 21,000 genes and 16 somatic alterations detected on average per patient. In total, 16 mutations were Category I, 98 were Category II, and 1474 were Category III. Tumor purity ranged from 14 to near 100%. Among unexpected findings, a prostate cancer exceptional responder was identified that harbored a somatic hemizygous deletion of the DNA repair gene FANCA and likely loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. The establishment of a clinical program for whole exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response. Citation Format: Mark A. Rubin. Towards the next clinical option: Experience from a precision cancer medicine trial. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA19.

Background: Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low frequency mutations. We describe an evidence-based precision medicine program designed to bring whole exome sequencing into clinical practice and illustrate how this can be utilized to identify novel predictive biomarkers associated with exceptional systemic response. Methods: Metastatic and treatment-resistant cancer patients are prospectively enrolled under an IRB approved protocol for paired metastatic tumor and normal WES through our Precision Medicine Clinic. Using a comprehensive computational pipeline, point mutations, indels and copy number alterations are detected. Mutations are categorized as Category I-III based on actionability and a report is generated and discussed in tumor board. Patients are followed prospectively for correlation of molecular information with clinical response and patient outcomes. A rapid response functional team follows on key findings to expand actionability based on the WES results. Results: In the first year, 154 tumor-normal pairs from 97 patients were sequenced, with an average coverage of 95X of over 21,000 genes and 16 somatic alterations detected on average per patient. In total, 16 mutations were Category I, 98 were Category II, and 1474 were Category III. Tumor purity ranged from 14 to near 100%. Among unexpected findings, a prostate cancer exceptional responder was identified that harbored a somatic hemizygous deletion of the DNA repair gene FANCA and likely loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. Conclusions: The establishment of a clinical program for whole exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response. Citation Format: Himisha Beltran, Kenneth Eng, Juan Miguel Mosquera, Alexandros Sigaras, Alessandro Romanel, Hanna Rennart, Myriam Kossai, Chantal Pauli, Bishoy Faltas, Jacqueline Fontugne, Brian Robinson, David M. Nanus, Scott T. Tagawa, Jenny Z. Xiang, Francesca Demichelis, David Rickman, Andrea Sboner, Olivier Elemento, Mark A. Rubin. Precision cancer medicine program for whole-exome sequencing of metastatic tumors reveals biomarkers of response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4745. doi:10.1158/1538-7445.AM2015-4745

Introduction: The molecular characterization of patients who exhibit a unique response to treatments that are not effective in most patients, so called “exceptional responders”, can shed light on the biological underpinnings of the response and provide rationale for selection of future patients for the same treatment. Here we present the genomic characterization of a 22-year-old female patient who presented with an unclassifiable kidney cancer and diffuse bilateral lung metastases. The primary tumour was resected and platinum plus gemcitabine therapy achieved a complete resolution of the lung metastases. Approximately 2 years later the patient again developed bilateral lung metastases and an additional course of platinum plus gemcitabine once again achieved a complete radiological response. To better understand the genomic contributors to this dramatic and recurrent response, we performed whole exome sequence analysis of the diagnostic formalin-fixed paraffin-embedded tumor tissue and a matched blood sample. Methods and Results: The patient provided informed consent and was profiled through the Princess Margaret Cancer Centre Genomic Investigation of Unusual and Spectacular responders (GENIUS) program. From tumour and matched blood specimens, we isolated coding and untranslated regions followed by deep sequencing (∼250X median coverage) on an Illumina HiSeq 2000. Copy-number analysis using VarScan2 revealed 23 somatic copy-number alterations (12 gains, 11 losses) including loss of 9p and gains of 3q and 8q, consistent with reports on clear cell renal cell carcinomas. Mutational analysis using muTect found 60 somatic, coding mutations, consistent with mutation rates seen in other kidney cancers. Of these variants, only one was a previously reported hotspot mutation, GNAS p.R201H (NM_000516, also known as p.R844H on transcript NM_080425). This mutation causes constitutive activation of the G-protein complex and activates adenylate cyclase to produce cyclic-AMP (cAMP) that can activate oncogenic pathways. However, excess cellular cAMP levels have also been found to promote apoptosis. Furthermore, a germline SNP in GNAS (rs7121), thought to increase GNAS transcript stability, is associated with improved response to gemcitabine plus platinum in non-small-cell lung cancer patients. The current patient was found to be heterozygous for the rs7121 SNP, which may compound the chemosensitivity phenotype observed. Conclusion: We have identified a p.R201H mutation in GNAS that may both drive tumour progression and confer exceptional chemo-sensitivity in a patient with an unclassified kidney cancer. Further analysis is underway in vitro to validate the hypothesis that this mutation confers sensitivity to chemotherapy. Confirmation of this hypothesis may suggest that chemotherapy could be considered for patients harbouring this mutation. Citation Format: Jeff P. Bruce, Arnavaz Danesh, Neil Winegarden, Patrick Yau, Carl Virtanen, Suzanne Kamel-Reid, Michael H. Roehrl, Anthony M. Joshua, Jennifer Knox, Trevor J. Pugh. Exome analysis of an exceptional responder uncovers an activating GNAS mutation that may confer sensitivity to cytotoxic chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3898. doi:10.1158/1538-7445.AM2015-3898

Aims Advanced biliary tract carcinomas (ABC) are malignancies with limited effective therapies for advanced disease. There is little published evidence of outcomes of ABC patients participating in phase I clinical trials. Materials and methods Patient characteristics, treatment details and outcomes of ABC patients treated at a dedicated phase I unit were captured and analysed from case and trial records. Results In total, 123 ABC patients were included in the study, of which 48 patients participated in 41 different phase I trials; 75 (61%) did not participate due to rapid disease progression or patient choice. Molecular characterisation of tumours using a targeted panel was conducted in 15 (31%), yielding several potentially actionable mutations, including BRCA , PIK3CA , FGFR , AKT and PTEN loss. Of the 39 evaluable patients there was one exceptional responder. Eighteen (46%) other patients achieved stable disease as their best response, with a clinical benefit rate at 4 months of 10%. Treatment was generally well tolerated with grade 3 or 4 adverse events only observed in eight patients (17 %), of which six were drug related and led to trial discontinuation in one (3%), with no toxicity-related deaths. Conclusion Carefully selected ABC patients have been found to tolerate experimental phase I clinical trials without excess toxicity. The aggressive nature of this disease warrants consideration of early referral to a phase I unit. Future work will require comprehensive molecular profiling in an attempt to understand the biology underlying the exceptional responders and to match patients in real-time to targeted therapies.