%0 Journal Article %J J Natl Cancer Inst %D 2021 %T The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study. %A Conley, Barbara A %A Staudt, Lou %A Takebe, Naoko %A David A Wheeler %A Wang, Linghua %A Cardenas, Maria F %A Korchina, Viktoriya %A Zenklusen, Jean Claude %A McShane, Lisa M %A Tricoli, James V %A Williams, Paul M %A Lubensky, Irina %A O'Sullivan-Coyne, Geraldine %A Kohn, Elise %A Little, Richard F %A White, Jeffrey %A Malik, Shakun %A Harris, Lyndsay N %A Mann, Bhupinder %A Weil, Carol %A Tarnuzzer, Roy %A Karlovich, Chris %A Rodgers, Brian %A Shankar, Lalitha %A Jacobs, Paula M %A Nolan, Tracy %A Berryman, Sean M %A Gastier-Foster, Julie %A Bowen, Jay %A Leraas, Kristen %A Shen, Hui %A Laird, Peter W %A Esteller, Manel %A Miller, Vincent %A Johnson, Adrienne %A Edmondson, Elijah F %A Giordano, Thomas J %A Kim, Benjamin %A Ivy, S Percy %K Adult %K Aged %K Aged, 80 and over %K Exome Sequencing %K Feasibility Studies %K Female %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Middle Aged %K Mutation %K National Cancer Institute (U.S.) %K Neoplasms %K Pilot Projects %K Precision Medicine %K Retrospective Studies %K Sequence Analysis, RNA %K Transcriptome %K United States %X

BACKGROUND: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.

METHODS: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease.

RESULTS: Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations.

CONCLUSION: Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.

%B J Natl Cancer Inst %V 113 %P 27-37 %8 2021 Jan 04 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32339229?dopt=Abstract %R 10.1093/jnci/djaa061 %0 Journal Article %J Cancer Cell %D 2021 %T Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment. %A David A Wheeler %A Takebe, Naoko %A Hinoue, Toshinori %A Hoadley, Katherine A %A Cardenas, Maria F %A Hamilton, Alina M %A Laird, Peter W %A Wang, Linghua %A Johnson, Adrienne %A Dewal, Ninad %A Miller, Vincent %A PiƱeyro, David %A Castro de Moura, Manuel %A Esteller, Manel %A Shen, Hui %A Zenklusen, Jean Claude %A Tarnuzzer, Roy %A McShane, Lisa M %A Tricoli, James V %A Williams, Paul M %A Lubensky, Irina %A O'Sullivan-Coyne, Geraldine %A Kohn, Elise C %A Little, Richard F %A White, Jeffrey %A Malik, Shakun %A Harris, Lyndsay %A Weil, Carol %A Chen, Alice P %A Karlovich, Chris %A Rodgers, Brian %A Shankar, Lalitha %A Jacobs, Paula %A Nolan, Tracy %A Jianhong Hu %A Donna M Muzny %A Harshavardhan Doddapaneni %A Korchina, Viktoriya %A Gastier-Foster, Julie %A Bowen, Jay %A Leraas, Kristen %A Edmondson, Elijah F %A Doroshow, James H %A Conley, Barbara A %A Ivy, S Percy %A Staudt, Louis M %K Antineoplastic Agents %K Biopsy %K Epigenesis, Genetic %K Female %K Gene Regulatory Networks %K Genetic Variation %K Genomics %K Humans %K Male %K Neoplasms %K Prognosis %K Survival Analysis %K Treatment Outcome %K Tumor Microenvironment %X

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.

%B Cancer Cell %V 39 %P 38-53.e7 %8 2021 Jan 11 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33217343?dopt=Abstract %R 10.1016/j.ccell.2020.10.015