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3. Successful whole-exome sequencing from a prostate cancer bone metastasis biopsy.

Author

Van Allen, E, Foye, A, Wagle, N, Kim, W, Carter, S, McKenna, A, Garraway, L, Febbo, P, and Simko, Jeffry

Subjects
Biopsy, Bone Neoplasms, Exome, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Radiography
Abstract

BACKGROUND: Comprehensive molecular characterization of cancer that has metastasized to bone has proved challenging, which may limit the diagnostic and potential therapeutic opportunities for patients with bone-only metastatic disease. METHODS: We describe successful tissue acquisition, DNA extraction, and whole-exome sequencing from a bone metastasis of a patient with metastatic, castration-resistant prostate cancer (PCa). RESULTS: The resulting high-quality tumor sequencing identified plausibly actionable somatic genomic alterations that dysregulate the phosphoinostide 3-kinase pathway, as well as a theoretically actionable germline variant in the BRCA2 gene. CONCLUSIONS: We demonstrate the feasibility of diagnostic bone metastases profiling and analysis that will be required for the widespread application of prospective precision medicine to men with advanced PCa.

Published
2014

5. Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas

Author

Derks S, de Klerk L, Xu X, Fleitas T, Liu K, Liu Y, Dietlein F, Margolis C, Chiaravalli A, Da Silva A, Ogino S, Akarca F, Freeman G, Rodig S, Hornick J, van Allen E, Li B, Liu S, Thorsson V, and Bass A

Abstract

BACKGROUND: Gastroesophageal adenocarcinomas (GEA) are heterogeneous cancers where immune checkpoint inhibitors (ICI) have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr Virus (EBV) positive subtypes. ICI responses are markedly lower in diffuse/genome-stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies.; PATIENTS AND METHODS: Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (TCGA) (N=453 GEAs) and archival GEA resection specimen (N=63). TCGA RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristic within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses.; RESULTS: Our results confirmed substantial heterogeneity in TME between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+T cells, macrophages and B cells and, in 50% of cases, evidence for tertiary lymphoid structures (TLSs). In contrast, CIN cancers possessed CD8+T cells predominantly at the invasive margin while tumor associated macrophages (TAMs) showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1.; CONCLUSION: These results reveal the diversity of immune phenotypes of GEA. Half of GS GCs have TLSs and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities. Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Published
2020

6. Oncogenic signaling pathways in the Cancer Genome Atlas

Author

Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., Chakravarty, D., Daian, F., Gao, Q., Bailey, M. H., Liang, W. -W., Foltz, S. M., Shmulevich, I., Ding, L., Heins, Z., Ochoa, A., Gross, B., Gao, J., Zhang, H., Kundra, R., Kandoth, C., Bahceci, I., Dervishi, L., Doğrusöz, Uğur, Zhou, W., Shen, H., Laird, P. W., Way, G. P., Greene, C. S., Liang, H., Xiao, Y., Wang, C., Iavarone, A., Berger, A. H., Bivona, T. G., Lazar, A. J., Hammer, G. D., Giordano, T., Kwong, L. N., McArthur, G., Huang, C., Tward, A. D., Frederick, M. J., McCormick, F., Meyerson, M., Caesar-Johnson, S. J., Demchok, J. A., Felau, I., Kasapi, M., Ferguson, M. L., Hutter, C. M., Sofia, H. J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J. C., Zhang, J. J., Chudamani, S., Liu, J., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Cho, J., DeFreitas, T., Frazer, S., Gehlenborg, N., Getz, G., Heiman, D. I., Kim, J., Lawrence, M. S., Lin, P., Meier, S., Noble, M. S., Saksena, G., Voet, D., Bernard, B., Chambwe, N., Dhankani, V., Knijnenburg, T., Kramer, R., Leinonen, K., Liu, Y., Miller, M., Reynolds, S., Thorsson, V., Zhang, W., Akbani, R., Broom, B. M., Hegde, A. M., Ju, Z., Kanchi, R. S., Korkut, A., Li, J., Ling, S., Liu W., Lu, Y., Mills, G. B., Ng, K. -S., Rao, A., Ryan, M., Wang, J., Weinstein, J. N., Zhang, J., Abeshouse, A., de, Bruijn, I., Gross, B. E., Heins, Z. J., La, K., Ladanyi, M., Nissan, M. G., Phillips, S. M., Reznik, E., Sander, C., Schultz, N., Sheridan, R., Sumer, S. O., Sun, Y., Taylor, B. S., Anur, P., Peto, M., Spellman, P., Benz, C., Stuart, J. M., Wong, C. K., Yau, C., Hayes, D. N., Parker, J. S., Wilkerson, M. D., Ally, A., Balasundaram, M., Bowlby, R., Brooks, D., Carlsen, R., Chuah, E., Dhalla, N., Holt, R., Jones, S. J. M., Kasaian, K., Lee, D., Ma, Y., Marra, M. A., Mayo, M., Moore, R. A., Mungall, A. J., Mungall, K., Robertson, A. G., Sadeghi, S., Schein, J. E., Sipahimalani, P., Tam, A., Thiessen, N., Tse, K., Wong, T., Berger, A. C., Beroukhim, R., Cherniack, A. D., Cibulskis, C., Gabriel, S. B., Gao, G. F., Ha, G., Schumacher, S. E., Shih, J., Kucherlapati, M. H., Kucherlapati, R. S., Baylin, S., Cope, L., Danilova, L., Bootwalla, M. S., Lai, P. H., Maglinte, D. T., Van, Den, Berg, D. J., Weisenberger, D. J., Auman, J. T., Balu, S., Bodenheimer, T., Fan, C., Hoadley, K. A., Hoyle, A. P., Jefferys, S. R., Jones, C. D., Meng, S., Mieczkowski, P. A., Mose, L. E., Perou, A. H., Perou, C. M., Roach, J., Shi, Y., Simons, J. V., Skelly, T., Soloway, M. G., Tan, D., Veluvolu, U., Fan, H., Hinoue, T., Bellair, M., Chang, K., Covington, K., Creighton, C. J., Dinh, H., Doddapaneni, H., Donehower, L. A., Drummond, J., Gibbs, R. A., Glenn, R., Hale, W., Han, Y., Hu, J., Korchina, V., Lee, S., Lewis, L., Li, W., Liu, X., Morgan, M., Morton, D., Muzny, D., Santibanez, J., Sheth, M., Shinbrot, E., Wang, L., Wang, M., Wheeler, D. A., Xi, L., Zhao, F., Hess, J., Appelbaum, E. L., Bailey, M., Cordes, M. G., Fronick, C. C., Fulton, L. A., Fulton, R. S., Mardis, E. R., McLellan, M. D., Miller, C. A., Schmidt, H. K., Wilson, R. K., Crain, D., Curley, E., Gardner, J., Lau, K., Mallery, D., Morris, S., Paulauskis, J., Penny, R., Shelton, C., Shelton, T., Sherman, M., Thompson, E., Yena, P., Bowen, J., Gastier-Foster, J. M., Gerken, M., Leraas, K. M., Lichtenberg, T. M., Ramirez, N. C., Wise, L., Zmuda, E., Corcoran, N., Costello, T., Hovens, C., Carvalho, A. L., de, Carvalho, A. C., Fregnani, J. H., Longatto-Filho, A., Reis, R. M., Scapulatempo-Neto, C., Silveira, H. C. S., Vidal, D. O., Burnette, A., Eschbacher, J., Hermes, B., Noss, A., Singh, R., Anderson, M. L., Castro, P. D., Ittmann, M., Huntsman, D., Kohl, B., Le, X., Thorp, R., Andry, C., Duffy, E. R., Lyadov, V., Paklina, O., Setdikova, G., Shabunin, A., Tavobilov, M., McPherson, C., Warnick, R., Berkowitz, R., Cramer, D., Feltmate, C., Horowitz, N., Kibel, A., Muto, M., Raut, C. P., Malykh, A., Barnholtz-Sloan, J. S., Barrett, W., Devine, K., Fulop, J., Ostrom, Q. T., Shimmel, K., Wolinsky, Y., Sloan, A. E., De, Rose, A., Giuliante, F., Goodman, M., Karlan, B. Y., Hagedorn, C. H., Eckman, J., Harr, J., Myers, J., Tucker, K., Zach, L. A., Deyarmin, B., Hu, H., Kvecher, L., Larson, C., Mural, R. J., Somiari, S., Vicha, A., Zelinka, T., Bennett, J., Iacocca, M., Rabeno, B., Swanson, P., Latour, M., Lacombe, L., Têtu, B., Bergeron, A., McGraw, M., Staugaitis, S. M., Chabot, J., Hibshoosh, H., Sepulveda, A., Su, T., Wang, T., Potapova, O., Voronina, O., Desjardins, L., Mariani, O., Roman-Roman, S., Sastre, X., Stern, M. -H., Cheng, F., Signoretti, S., Berchuck, A., Bigner, D., Lipp, E., Marks, J., McCall, S., McLendon, R., Secord, A., Sharp, A., Behera, M., Brat, D. J., Chen, A., Delman, K., Force, S., Khuri, F., Magliocca, K., Maithel, S., Olson, J. J., Owonikoko, T., Pickens, A., Ramalingam, S., Shin, D. M., Sica, G., Van, Meir, E. G., Eijckenboom, W., Gillis, A., Korpershoek, E., Looijenga, L., Oosterhuis, W., Stoop, H., van, Kessel, K. E., Zwarthoff, E. C., Calatozzolo, C., Cuppini, L., Cuzzubbo, S., DiMeco, F., Finocchiaro, G., Mattei, L., Perin, A., Pollo, B., Chen, C., Houck, J., Lohavanichbutr, P., Hartmann, A., Stoehr, C., Stoehr, R., Taubert, H., Wach, S., Wullich, B., Kycler, W., Murawa, D., Wiznerowicz, M., Chung, K., Edenfield, W. J., Martin, J., Baudin, E., Bubley, G., Bueno, R., De, Rienzo, A., Richards, W. G., Kalkanis, S., Mikkelsen, T., Noushmehr, H., Scarpace, L., Girard, N., Aymerich, M., Campo, E., Giné, E., Guillermo, A. L., Van, Bang, N., Hanh, P. T., Phu, B. D., Tang, Y., Colman, H., Evason, K., Dottino, P. R., Martignetti, J. A., Gabra, H., Juhl, H., Akeredolu, T., Stepa, S., Hoon, D., Ahn, K., Kang, K. J., Beuschlein, F., Breggia, A., Birrer, M., Bell, D., Borad, M., Bryce, A. H., Castle, E., Chandan, V., Cheville, J., Copland, J. A., Farnell, M., Flotte, T., Giama, N., Ho, T., Kendrick, M., Kocher, J. -P., Kopp, K., Moser, C., Nagorney, D., O'Brien, D., O'Neill, B. P., Patel, T., Petersen, G., Que, F., Rivera, M., Roberts, L., Smallridge, R., Smyrk, T., Stanton, M., Thompson, R. H., Torbenson, M., Yang, J. D., Zhang, L., Brimo, F., Ajani, J. A., Gonzalez, A. M. A., Behrens, C., Bondaruk, J., Broaddus, R., Czerniak, B., Esmaeli, B., Fujimoto, J., Gershenwald, J., Guo, C., Logothetis, C., Meric-Bernstam, F., Moran, C., Ramondetta, L., Rice, D., Sood, A., Tamboli, P., Thompson, T., Troncoso, P., Tsao, A., Wistuba, I., Carter, C., Haydu, L., Hersey, P., Jakrot, V., Kakavand, H., Kefford, R., Lee, K., Long, G., Mann, G., Quinn, M., Saw, R., Scolyer, R., Shannon, K., Spillane, A., Stretch, J., Synott, M., Thompson, J., Wilmott, J., Al-Ahmadie, H., Chan, T. A., Ghossein, R., Gopalan, A., Levine, D. A., Reuter, V., Singer, S., Singh, B., Tien, N. V., Broudy, T., Mirsaidi, C., Nair, P., Drwiega, P., Miller, J., Smith, J., Zaren, H., Park, J. -W., Hung, N. P., Kebebew, E., Linehan, W. M., Metwalli, A. R., Pacak, K., Pinto, P. A., Schiffman, M., Schmidt, L. S., Vocke, C. D., Wentzensen, N., Worrell, R., Yang, H., Moncrieff, M., Goparaju, C., Melamed, J., Pass, H., Botnariuc, N., Caraman, I., Cernat, M., Chemencedji, I., Clipca, A., Doruc, S., Gorincioi, G., Mura, S., Pirtac, M., Stancul, I., Tcaciuc, D., Albert, M., Alexopoulou, I., Arnaout, A., Bartlett, J., Engel, J., Gilbert, S., Parfitt, J., Sekhon, H., Thomas, G., Rassl, D. M., Rintoul, R. C., Bifulco, C., Tamakawa, R., Urba, W., Hayward, N., Timmers, H., Antenucci, A., Facciolo, F., Grazi, G., Marino, M., Merola, R., de, Krijger, R., Gimenez-Roqueplo, A. -P., Piché, A., Chevalier, S., McKercher, G., Birsoy, K., Barnett, G., Brewer, C., Farver, C., Naska, T., Pennell, N. A., Raymond, D., Schilero, C., Smolenski, K., Williams, F., Morrison, C., Borgia, J. A., Liptay, M. J., Pool, M., Seder, C. W., Junker, K., Omberg, L., Dinkin, M., Manikhas, G., Alvaro, D., Bragazzi, M. C., Cardinale, V., Carpino, G., Gaudio, E., Chesla, D., Cottingham, S., Dubina, M., Moiseenko, F., Dhanasekaran, R., Becker, K. -F., Janssen, K. -P., Slotta-Huspenina, J., Abdel-Rahman, M. H., Aziz, D., Bell, S., Cebulla, C. M., Davis, A., Duell, R., Elder, J. B., Hilty, J., Kumar, B., Lang, J., Lehman, N. L., Mandt, R., Nguyen, P., Pilarski, R., Rai, K., Schoenfield, L., Senecal, K., Wakely, P., Hansen, P., Lechan, R., Powers, J., Tischler, A., Grizzle, W. E., Sexton, K. C., Kastl, A., Henderson, J., Porten, S., Waldmann, J., Fassnacht, M., Asa, S. L., Schadendorf, D., Couce, M., Graefen, M., Huland, H., Sauter, G., Schlomm, T., Simon, R., Tennstedt, P., Olabode, O., Nelson, M., Bathe, O., Carroll, P. R., Chan, J. M., Disaia, P., Glenn, P., Kelley, R. K., Landen, C. N., Phillips, J., Prados, M., Simko, J., Smith-McCune, K., VandenBerg, S., Roggin, K., Fehrenbach, A., Kendler, A., Sifri, S., Steele, R., Jimeno, A., Carey, F., Forgie, I., Mannelli, M., Carney, M., Hernandez, B., Campos, B., Herold-Mende, C., Jungk, C., Unterberg, A., von, Deimling, A., Bossler, A., Galbraith, J., Jacobus, L., Knudson, M., Knutson, T., Ma, D., Milhem, M., Sigmund, R., Godwin, A. K., Madan, R., Rosenthal, H. G., Adebamowo, C., Adebamowo, S. N., Boussioutas, A., Beer, D., Mes-Masson, A. -M., Saad, F., Bocklage, T., Landrum, L., Mannel, R., Moore, K., Moxley, K., Postier, R., Walker, J., Zuna, R., Feldman, M., Valdivieso, F., Dhir, R., Luketich, J., Pinero, E. M. M., Quintero-Aguilo, M., Carlotti, C. G., Jr., Dos, Santos, J. S., Kemp, R., Sankarankuty, A., Tirapelli, D., Catto, J., Agnew, K., Swisher, E., Creaney, J., Robinson, B., Shelley, C. S., Godwin, E. M., Kendall, S., Shipman, C., Bradford, C., Carey, T., Haddad, A., Moyer, J., Peterson, L., Prince, M., Rozek, L., Wolf, G., Bowman, R., Fong, K. M., Yang, I., Korst, R., Rathmell, W. K., Fantacone-Campbell, J. L., Hooke, J. A., Kovatich, A. J., Shriver, C. D., DiPersio, J., Drake, B., Govindan, R., Heath, S., Ley, T., Van, Tine, B., Westervelt, P., Rubin, M. A., Lee, J. I., Aredes, N. D., Mariamidze, A., Van, Allen, E. M., Ciriello, G., The, Cancer, Genome, Atlas, Research, Network.tif, Doğrusöz, Uğur, Cancer Genome Atlas Research Network, Caesar-Johnson, S.J., Demchok, J.A., Felau, I., Kasapi, M., Ferguson, M.L., Hutter, C.M., Sofia, H.J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J.C., Zhang, J.J., Chudamani, S., Liu, J., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Cho, J., DeFreitas, T., Frazer, S., Gehlenborg, N., Getz, G., Heiman, D.I., Kim, J., Lawrence, M.S., Lin, P., Meier, S., Noble, M.S., Saksena, G., Voet, D., Zhang, H., Bernard, B., Chambwe, N., Dhankani, V., Knijnenburg, T., Kramer, R., Leinonen, K., Liu, Y., Miller, M., Reynolds, S., Shmulevich, I., Thorsson, V., Zhang, W., Akbani, R., Broom, B.M., Hegde, A.M., Ju, Z., Kanchi, R.S., Korkut, A., Li, J., Liang, H., Ling, S., Liu, W., Lu, Y., Mills, G.B., Ng, K.S., Rao, A., Ryan, M., Wang, J., Weinstein, J.N., Zhang, J., Abeshouse, A., Armenia, J., Chakravarty, D., Chatila, W.K., de Bruijn, I., Gao, J., Gross, B.E., Heins, Z.J., Kundra, R., La, K., Ladanyi, M., Luna, A., Nissan, M.G., Ochoa, A., Phillips, S.M., Reznik, E., Sanchez-Vega, F., Sander, C., Schultz, N., Sheridan, R., Sumer, S.O., Sun, Y., Taylor, B.S., Anur, P., Peto, M., Spellman, P., Benz, C., Stuart, J.M., Wong, C.K., Yau, C., Hayes, D.N., Parker, J.S., Wilkerson, M.D., Ally, A., Balasundaram, M., Bowlby, R., Brooks, D., Carlsen, R., Chuah, E., Dhalla, N., Holt, R., Jones, SJM, Kasaian, K., Lee, D., Ma, Y., Marra, M.A., Mayo, M., Moore, R.A., Mungall, A.J., Mungall, K., Robertson, A.G., Sadeghi, S., Schein, J.E., Sipahimalani, P., Tam, A., Thiessen, N., Tse, K., Wong, T., Berger, A.C., Beroukhim, R., Cherniack, A.D., Cibulskis, C., Gabriel, S.B., Gao, G.F., Ha, G., Meyerson, M., Schumacher, S.E., Shih, J., Kucherlapati, M.H., Kucherlapati, R.S., Baylin, S., Cope, L., Danilova, L., Bootwalla, M.S., Lai, P.H., Maglinte, D.T., Van Den Berg, D.J., Weisenberger, D.J., Auman, J.T., Balu, S., Bodenheimer, T., Fan, C., Hoadley, K.A., Hoyle, A.P., Jefferys, S.R., Jones, C.D., Meng, S., Mieczkowski, P.A., Mose, L.E., Perou, A.H., Perou, C.M., Roach, J., Shi, Y., Simons, J.V., Skelly, T., Soloway, M.G., Tan, D., Veluvolu, U., Fan, H., Hinoue, T., Laird, P.W., Shen, H., Zhou, W., Bellair, M., Chang, K., Covington, K., Creighton, C.J., Dinh, H., Doddapaneni, H., Donehower, L.A., Drummond, J., Gibbs, R.A., Glenn, R., Hale, W., Han, Y., Hu, J., Korchina, V., Lee, S., Lewis, L., Li, W., Liu, X., Morgan, M., Morton, D., Muzny, D., Santibanez, J., Sheth, M., Shinbrot, E., Wang, L., Wang, M., Wheeler, D.A., Xi, L., Zhao, F., Hess, J., Appelbaum, E.L., Bailey, M., Cordes, M.G., Ding, L., Fronick, C.C., Fulton, L.A., Fulton, R.S., Kandoth, C., Mardis, E.R., McLellan, M.D., Miller, C.A., Schmidt, H.K., Wilson, R.K., Crain, D., Curley, E., Gardner, J., Lau, K., Mallery, D., Morris, S., Paulauskis, J., Penny, R., Shelton, C., Shelton, T., Sherman, M., Thompson, E., Yena, P., Bowen, J., Gastier-Foster, J.M., Gerken, M., Leraas, K.M., Lichtenberg, T.M., Ramirez, N.C., Wise, L., Zmuda, E., Corcoran, N., Costello, T., Hovens, C., Carvalho, A.L., de Carvalho, A.C., Fregnani, J.H., Longatto-Filho, A., Reis, R.M., Scapulatempo-Neto, C., Silveira, HCS, Vidal, D.O., Burnette, A., Eschbacher, J., Hermes, B., Noss, A., Singh, R., Anderson, M.L., Castro, P.D., Ittmann, M., Huntsman, D., Kohl, B., Le, X., Thorp, R., Andry, C., Duffy, E.R., Lyadov, V., Paklina, O., Setdikova, G., Shabunin, A., Tavobilov, M., McPherson, C., Warnick, R., Berkowitz, R., Cramer, D., Feltmate, C., Horowitz, N., Kibel, A., Muto, M., Raut, C.P., Malykh, A., Barnholtz-Sloan, J.S., Barrett, W., Devine, K., Fulop, J., Ostrom, Q.T., Shimmel, K., Wolinsky, Y., Sloan, A.E., De Rose, A., Giuliante, F., Goodman, M., Karlan, B.Y., Hagedorn, C.H., Eckman, J., Harr, J., Myers, J., Tucker, K., Zach, L.A., Deyarmin, B., Hu, H., Kvecher, L., Larson, C., Mural, R.J., Somiari, S., Vicha, A., Zelinka, T., Bennett, J., Iacocca, M., Rabeno, B., Swanson, P., Latour, M., Lacombe, L., Têtu, B., Bergeron, A., McGraw, M., Staugaitis, S.M., Chabot, J., Hibshoosh, H., Sepulveda, A., Su, T., Wang, T., Potapova, O., Voronina, O., Desjardins, L., Mariani, O., Roman-Roman, S., Sastre, X., Stern, M.H., Cheng, F., Signoretti, S., Berchuck, A., Bigner, D., Lipp, E., Marks, J., McCall, S., McLendon, R., Secord, A., Sharp, A., Behera, M., Brat, D.J., Chen, A., Delman, K., Force, S., Khuri, F., Magliocca, K., Maithel, S., Olson, J.J., Owonikoko, T., Pickens, A., Ramalingam, S., Shin, D.M., Sica, G., Van Meir, E.G., Eijckenboom, W., Gillis, A., Korpershoek, E., Looijenga, L., Oosterhuis, W., Stoop, H., van Kessel, K.E., Zwarthoff, E.C., Calatozzolo, C., Cuppini, L., Cuzzubbo, S., DiMeco, F., Finocchiaro, G., Mattei, L., Perin, A., Pollo, B., Chen, C., Houck, J., Lohavanichbutr, P., Hartmann, A., Stoehr, C., Stoehr, R., Taubert, H., Wach, S., Wullich, B., Kycler, W., Murawa, D., Wiznerowicz, M., Chung, K., Edenfield, W.J., Martin, J., Baudin, E., Bubley, G., Bueno, R., De Rienzo, A., Richards, W.G., Kalkanis, S., Mikkelsen, T., Noushmehr, H., Scarpace, L., Girard, N., Aymerich, M., Campo, E., Giné, E., Guillermo, A.L., Van Bang, N., Hanh, P.T., Phu, B.D., Tang, Y., Colman, H., Evason, K., Dottino, P.R., Martignetti, J.A., Gabra, H., Juhl, H., Akeredolu, T., Stepa, S., Hoon, D., Ahn, K., Kang, K.J., Beuschlein, F., Breggia, A., Birrer, M., Bell, D., Borad, M., Bryce, A.H., Castle, E., Chandan, V., Cheville, J., Copland, J.A., Farnell, M., Flotte, T., Giama, N., Ho, T., Kendrick, M., Kocher, J.P., Kopp, K., Moser, C., Nagorney, D., O'Brien, D., O'Neill, B.P., Patel, T., Petersen, G., Que, F., Rivera, M., Roberts, L., Smallridge, R., Smyrk, T., Stanton, M., Thompson, R.H., Torbenson, M., Yang, J.D., Zhang, L., Brimo, F., Ajani, J.A., Gonzalez, AMA, Behrens, C., Bondaruk, J., Broaddus, R., Czerniak, B., Esmaeli, B., Fujimoto, J., Gershenwald, J., Guo, C., Lazar, A.J., Logothetis, C., Meric-Bernstam, F., Moran, C., Ramondetta, L., Rice, D., Sood, A., 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Subjects
0301 basic medicine, cancer genome atlas, cancer genomics, combination therapy, pan-cancer, PanCanAtlas, precision oncology, signaling pathways, TCGA, therapeutics, whole exome sequencing, Signaling pathways, Somatic cell, Wnt Protein, Cancer Genome Atlas Research Network, Biochemistry, Medical and Health Sciences, Phosphatidylinositol 3-Kinases, Transforming Growth Factor beta, Neoplasms, Databases, Genetic, LS2_1, Cancer genomics, LS4_6, 610 Medicine & health, 11 Medical and Health Sciences, Cancer, biology, Wnt signaling pathway, cancer genomic, Precision oncology, Biological Sciences, Cell cycle, DNA methylation, Signal transduction, CICLO CELULAR, Life Sciences & Biomedicine, Genes, Neoplasm, Humans, Neoplasms/genetics, Neoplasms/pathology, Phosphatidylinositol 3-Kinases/genetics, Phosphatidylinositol 3-Kinases/metabolism, Signal Transduction/genetics, Transforming Growth Factor beta/genetics, Transforming Growth Factor beta/metabolism, Tumor Suppressor Protein p53/genetics, Tumor Suppressor Protein p53/metabolism, Wnt Proteins/genetics, Wnt Proteins/metabolism, Biotechnology, Human, Signal Transduction, signaling pathway, EXPRESSION, Biochemistry & Molecular Biology, GENES, Pan-cancer, Therapeutics, General Biochemistry, Genetics and Molecular Biology, NO, Databases, 03 medical and health sciences, Genetic, Genetics, Combination therapy, Protein kinase B, Gene, SIGNATURES, Cancer genome atlas, Science & Technology, LANDSCAPE, MUTATIONS, Biochemistry, Genetics and Molecular Biology(all), Human Genome, Whole exome sequencing, Cell Biology, Transforming growth factor beta, cancer genome atla, 06 Biological Sciences, COMPREHENSIVE MOLECULAR CHARACTERIZATION, Wnt Proteins, therapeutic, Good Health and Well Being, 030104 developmental biology, Genes, PanCanAtla, biology.protein, Cancer research, Neoplasm, Phosphatidylinositol 3-Kinase, Tumor Suppressor Protein p53, Digestive Diseases, Genetics and Molecular Biology(all), Developmental Biology
Abstract

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies. Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc. and a shareholder and advisory board member of Tempus, Inc. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae.

Published
2018

10. Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma

Author

Manier, S., primary, Park, J., additional, Capelletti, M., additional, Bustoros, M., additional, Freeman, S. S., additional, Ha, G., additional, Rhoades, J., additional, Liu, C. J., additional, Huynh, D., additional, Reed, S. C., additional, Gydush, G., additional, Salem, K. Z., additional, Rotem, D., additional, Freymond, C., additional, Yosef, A., additional, Perilla-Glen, A., additional, Garderet, L., additional, Van Allen, E. M., additional, Kumar, S., additional, Love, J. C., additional, Getz, G., additional, Adalsteinsson, V. A., additional, and Ghobrial, I. M., additional

Published
2018
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11. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

Author

Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Chemistry, Prakadan, Sanjay, Wadsworth, Marc Havens, Genshaft, Alex S., Hughes, Travis K., Ziegler, Carly, Kazer, Samuel Weisgurt, Gaillard de Saint Germain, Alethe, Kolb, Kellie Elizabeth, Johannessen, Cory M., Yoon, Clifford H., Shalek, Alexander K, Regev, Aviv, Garraway, Levi, Tirosh, I., Izar, B., Treacy, D., Trombetta, J. J., Rotem, A., Rodman, C., Lian, C., Murphy, G., Fallahi-Sichani, M., Dutton-Regester, K., Lin, J.-R., Cohen, O., Shah, P., Lu, D., Villani, A.-C., Andreev, A. Y., Van Allen, E. M., Bertagnolli, M., Sorger, P. K., Sullivan, R. J., Flaherty, K. T., Frederick, D. T., Jane-Valbuena, J., Rozenblatt-Rosen, O., Garraway, Levi A., Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Chemistry, Prakadan, Sanjay, Wadsworth, Marc Havens, Genshaft, Alex S., Hughes, Travis K., Ziegler, Carly, Kazer, Samuel Weisgurt, Gaillard de Saint Germain, Alethe, Kolb, Kellie Elizabeth, Johannessen, Cory M., Yoon, Clifford H., Shalek, Alexander K, Regev, Aviv, Garraway, Levi, Tirosh, I., Izar, B., Treacy, D., Trombetta, J. J., Rotem, A., Rodman, C., Lian, C., Murphy, G., Fallahi-Sichani, M., Dutton-Regester, K., Lin, J.-R., Cohen, O., Shah, P., Lu, D., Villani, A.-C., Andreev, A. Y., Van Allen, E. M., Bertagnolli, M., Sorger, P. K., Sullivan, R. J., Flaherty, K. T., Frederick, D. T., Jane-Valbuena, J., Rozenblatt-Rosen, O., and Garraway, Levi A.

Abstract

To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies., National Cancer Institute (U.S.) (1U24CA180922), National Cancer Institute (U.S.) (P30-CA14051)

Published
2017

12. Summary and Recommendations from the National Cancer Institute’s Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer

Author

Lerner, SP, Bajorin, DF, Dinney, CP, Efstathiou, JA, Groshen, S, Hahn, NM, Kwiatkowski, D, O'Donnell, M, Rosenberg, J, Svatek, R, Abrams, JS, Al-Ahmadie, H, Apolo, AB, Bellmunt, J, Callahan, M, Cha, EK, Drake, C, Jarrow, J, Kamat, A, Kim, W, Knowles, M, Mann, B, Marchioni, L, McConkey, D, McShane, L, Ramirez, N, Sharabi, A, Sharpe, AH, Solit, D, Tangen, CM, Amini, AT, Van Allen, E, West, PJ, Witjes, JA, and Quale, DZ

Abstract

The NCI Bladder Cancer Task Force convened a Clinical Trials Planning Meeting (CTPM) Workshop focused on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer (NMIBC). Meeting attendees included a broad and multi-disciplinary group of clinical and research stakeholders and included leaders from NCI, FDA, National Clinical Trials Network (NCTN), advocacy and the pharmaceutical and biotech industry. The meeting goals and objectives were to: 1) create a collaborative environment in which the greater bladder research community can pursue future optimally designed novel clinical trials focused on the theme of molecular targeted and immune-based therapies in NMIBC; 2) frame the clinical and translational questions that are of highest priority; and 3) develop two clinical trial designs focusing on immunotherapy and molecular targeted therapy. Despite successful development and implementation of large Phase II and Phase III trials in bladder and upper urinary tract cancers, there are no active and accruing trials in the NMIBC space within the NCTN. Disappointingly, there has been only one new FDA approved drug (Valrubicin) in any bladder cancer disease state since 1998. Although genomic-based data for bladder cancer are increasingly available, translating these discoveries into practice changing treatment is still to come. Recently, major efforts in defining the genomic characteristics of NMIBC have been achieved. Aligned with these data is the growing number of targeted therapy agents approved and/or in development in other organ site cancers and the multiple similarities of bladder cancer with molecular subtypes in these other cancers. Additionally, although bladder cancer is one of the more immunogenic tumors, some tumors have the ability to attenuate or eliminate host immune responses. Two trial concepts emerged from the meeting including a window of opportunity trial (Phase 0) testing an FGFR3 inhibitor and a second multi-arm multi-stage trial testing combinations of BCG or radiotherapy and immunomodulatory agents in patients who recur after induction BCG (BCG failure).

Published
2016

15. Transforming the Perioperative Treatment Paradigm in Non-Metastatic RCC—A Possible Path Forward

Author

Harshman, L.C., primary, Drake, C.G., additional, Haas, N.B., additional, Manola, J., additional, Puligandla, M., additional, Signoretti, S., additional, Cella, D., additional, Gupta, R.T., additional, Bhatt, R., additional, Van Allen, E., additional, Lara, P., additional, Choueiri, T.K., additional, Kapoor, A., additional, Heng, D.Y.C., additional, Shuch, B., additional, Jewett, M., additional, George, D., additional, Michaelson, D., additional, Carducci, M.A., additional, McDermott, D., additional, and Allaf, M., additional

Published
2017
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16. Abstract S3-03: Nuclear FGFR1 interaction with estrogen receptor (ER) α is associated with resistance to endocrine therapy in ER+/FGFR1-amplified breast cancer

Author

Formisano, L, primary, Young, CD, additional, Bhola, NE, additional, Bulen, B, additional, Estrada, VM, additional, Wagle, N, additional, Van Allen, E, additional, Red Brewer, ML, additional, Jansen, VM, additional, Guerrero, AL, additional, Giltnane, JM, additional, Strcker, T, additional, and Arteaga, CL, additional

Published
2016
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17. Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib

Author

Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Sabatini, David M., Lander, Eric S., Wagle, N., Grabiner, Brian C., Van Allen, E. M., Hodis, Eran, Jacobus, S., Supko, J. G., Stewart, M., Choueiri, T. K., Gandhi, L., Cleary, J. M., Elfiky, A. A., Taplin, M. E., Stack, E. C., Signoretti, S., Loda, Massimo, Shapiro, G. I., Gabriel, Stacey B., Kantoff, Philip W., Garraway, Levi A., Rosenberg, J. E., Sabatini, David, Lander, Eric Steven, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Sabatini, David M., Lander, Eric S., Wagle, N., Grabiner, Brian C., Van Allen, E. M., Hodis, Eran, Jacobus, S., Supko, J. G., Stewart, M., Choueiri, T. K., Gandhi, L., Cleary, J. M., Elfiky, A. A., Taplin, M. E., Stack, E. C., Signoretti, S., Loda, Massimo, Shapiro, G. I., Gabriel, Stacey B., Kantoff, Philip W., Garraway, Levi A., Rosenberg, J. E., Sabatini, David, and Lander, Eric Steven

Abstract

Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or “personalized”) medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR., National Human Genome Research Institute (U.S.) (5U54HG003067-11)

Published
2015

21. BM-07 * GENOMIC CHARACTERIZATION OF BRAIN METASTASES REVEALS BRANCHED EVOLUTION AND METASTASIS-SPECIFIC MUTATIONS

Author

Brastianos, P., primary, Carter, S., additional, Santagata, S., additional, Taylor-Weiner, A., additional, Jones, R., additional, Van Allen, E., additional, Horowitz, P., additional, Ligon, K., additional, Cahill, D., additional, Dunn, I., additional, Van Hummelen, P., additional, Lin, N., additional, Curry, W., additional, Stemmer-Rachamimov, A., additional, Beroukhim, R., additional, Batchelor, T., additional, Baselga, J., additional, Louis, D., additional, Getz, G., additional, and Hahn, W., additional

Published
2014
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22. Somatic ERCC2 Mutations Confer Cisplatin Sensitivity in Muscle-Invasive Urothelial Cancer

Author

Mouw, K., primary, Van Allen, E., additional, O’Connor, K., additional, Wagle, N., additional, Kim, P., additional, Al-Ahmadie, H., additional, Zhu, C., additional, Ostravnaya, I., additional, Iyer, G., additional, Signoretti, S., additional, Reuter, V., additional, Getz, G., additional, Kantoff, P.W., additional, Bochner, B., additional, Choueiri, T.K., additional, Bajorin, D.F., additional, Gabriel, S., additional, D’Andrea, A., additional, Garraway, L., additional, and Rosenberg, J.E., additional

Published
2014
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24. Characterizing genomic alterations in cancer by complementary functional associations

Author

Kim, J. W., Botvinnik, O. B., Abudayyeh, O., Birger, C., Rosenbluh, J., Shrestha, Y., Abazeed, M. E., Hammerman, P. S., DiCara, D., Konieczkowski, D. J., Johannessen, C. M., Liberzon, A., Alizad-Rahvar, A. R., Alexe, G., Aguirre, A., Ghandi, M., Greulich, H., Vazquez, F., Weir, B. A., Van Allen, E. M., Tsherniak, A., Shao, D. D., Zack, T. I., Noble, M., Getz, G., Beroukhim, R., Garraway, L. A., Ardakani, M., Romualdi, C., Sales, G., Barbie, D. A., Boehm, J. S., Hahn, W. C., Mesirov, J. P., and Tamayo, P.

Abstract

Systematic efforts to sequence the cancer genome have identified large numbers of relevant mutations and copy number alterations in human cancers; however, elucidating their functional consequences, and their interactions to drive or maintain oncogenic states, is still a significant challenge. Here we introduce REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene-dependency of oncogenic pathways or the sensitivity to a drug treatment. We use REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes.

Published
2016
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26. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study

Author

Dimitrios Farmakiotis, Susie Owenby, Arturo Loaiza-Bonilla, Mansi R. Shah, Matthew Puc, Vadim S. Koshkin, Ahmad Daher, Prakash Peddi, Cameron Rink, Heloisa P. Soares, Eneida R. Nemecek, Mehmet Asim Bilen, Sanjay Mishra, Lidia Schapira, Amit Verma, Ali Raza Khaki, Chih-Yuan Hsu, Sandy DiLullo, Mark Bonnen, Jeanna Knoble, Carla Casulo, Umit Topaloglu, Jorge A. Garcia, Geoffrey Shouse, Praveen Vikas, Clarke A. Low, Archana Ajmera, George D. Demetri, Leyre Zubiri, Grace Glace, Shannon K. McWeeney, Susan Yackzan, Pamela C Egan, Rachel P. Rosovsky, Salvatore Del Prete, Anthony P. Gulati, Lane R. Rosen, Andy Futreal, Merry Jennifer Markham, Sabitha Prabhakaran, Alicia K. Morgans, Sarah Nagle, Lisa Weissmann, Albert C. Yeh, Ziad Bakouny, Stephanie Berg, David Gill, Marcus Messmer, Ryan Nguyen, Terence Duane Rhodes, Vikram M. Narayan, Matthew D. Galsky, Arielle Elkrief, Lori J. Rosenstein, Roy S. Herbst, Justin Shaya, Thorvardur R. Halfdanarson, Douglas B. Johnson, Orestis A. Panagiotou, Sanjay G. Revankar, Toni K. Choueiri, Yu Shyr, Fiona Busser, Kaitlin M. Kelleher, Nicole M. Kuderer, Paul L. Weinstein, Anup Kasi, Grace Shaw, Adam J. Olszewski, Catherine Curran, Samuel M. Rubinstein, Angelo Cabal, Michael H. Bar, John F. Deeken, Vivek Subbiah, Abdul Hai Mansoor, Hina Khan, Rana R. McKay, Catherine Stratton, Saurabh Dahiya, Marc A. Rovito, John Philip, Sanjay Shete, Oscar K. Serrano, Julie Fu, Daniel W. Bowles, Candice Schwartz, Tian Zhang, Pier Vitale Nuzzo, Eric H. Bernicker, Wenxin Xu, Genevieve M. Boland, Sarah Wall, Babar Bashir, Solange Peters, Neeta K. Venepalli, Sandeep H. Mashru, William A. Wood, Anne H. Angevine, Mary F. Mulcahy, Gilberto Lopes, Justin F. Gainor, Jessica Hawley, Monika Joshi, Christopher R. Friese, Navid Hafez, Heather H. Nelson, Gregory J. Riely, Jordan Kharofa, Nilo Azad, Chintan Shah, Gerald Batist, Mary Salazar, Rosemary Zacks, Alice Zhou, Lawrence E. Feldman, Paul Fu, Gary H. Lyman, Nathaniel Bouganim, John A. Steinharter, Shilpa Gupta, Matthias Weiss, Peter Paul Yu, Susan Van Loon, Jamie Stratton, Karen Vega-Luna, Tyler Masters, Christopher Lemmon, Aakash Desai, Bryan A. Faller, Jessica M. Clement, Zhuoer Xie, Keith Stockerl-Goldstein, Corrie A. Painter, Gabrielle Bouchard, Rulla M. Tamimi, Daruka Mahadevan, Rimma Belenkaya, Jill S. Barnholtz-Sloan, Jarushka Naidoo, Amelie G. Ramirez, Philip E. Lammers, Elizabeth A. Griffiths, Michael J. Gurley, X. Li, Jonathan Riess, Syed A. Ahmad, Daniel Blake Flora, Salma K. Jabbour, Jared D. Acoba, Neeraj Agarwal, Ang Li, Sarah Mushtaq, Firas Wehbe, Tanios Bekaii-Saab, Donald C. Vinh, Emily Hsu, Ryan Monahan, Petros Grivas, Harry Menon, John M. Nakayama, Janice M. Mehnert, Elizabeth Marie Wulff-Burchfield, Sara Matar, Paul E. Oberstein, Mary M. Pasquinelli, Axel Grothey, Jack West, John C. Leighton, Dawn L. Hershman, Leslie A. Fecher, Aditya Bardia, Sumit A. Shah, Barbara Logan, Kerry L. Reynolds, Michael A. Thompson, Robert L. Rice, Erin Cook, Trisha Wise-Draper, Christine Bestvina, Daniel Castellano, Paolo Caimi, K. M.Steve Lo, Ruben A. Mesa, Maheen Z. Abidi, Alvaro G. Menendez, Daniel G. Stover, Colleen Lewis, Bertrand Routy, Deborah B. Doroshow, Carmen C. Solorzano, M. Wasif Saif, Rohit Bishnoi, Michael Glover, David D. Chism, Briana Barrow, Christopher McNair, Dimpy P. Shah, Erin A. Gillaspie, Andrea J. Zimmer, Andrew Schmidt, Jessica K. Altman, Michelle Marcum, Rawad Elias, Balazs Halmos, Karen Stauffer, Gayathri Nagaraj, Ardaman Shergill, Mark E. Dailey, Catherine Handy Marshall, Pramod K. Srivastava, Shuchi Gulati, Alokkumar Jha, Mateo Bover Larroya, Mark A. Lewis, Young Soo Rho, James L. Chen, Eli Van Allen, Julie Tsu Yu Wu, Antonio Giordano, Amit Kulkarni, Joerg Rathmann, Donna R. Rivera, Narjust Duma, Maryam B. Lustberg, Theresa M. Carducci, Jeremy L. Warner, Elizabeth Robilotti, Patricia LoRusso, Rohit Jain, Amit Sanyal, Nizar M. Tannir, Kent Hoskins, Nathan A. Pennell, Brian I. Rini, Suki Subbiah, COVID-19 and Cancer Consortium, Abidi, M., Acoba, J.D., Agarwal, N., Ahmad, S., Ajmera, A., Altman, J., Angevine, A.H., Azad, N., Bar, M.H., Bardia, A., Barnholtz-Sloan, J., Barrow, B., Bashir, B., Belenkaya, R., Berg, S., Bernicker, E.H., Bestvina, C., Bishnoi, R., Boland, G., Bonnen, M., Bouchard, G., Bowles, D.W., Busser, F., Cabal, A., Caimi, P., Carducci, T., Casulo, C., Chen, J.L., Clement, J.M., Chism, D., Cook, E., Curran, C., Daher, A., Dailey, M., Dahiya, S., Deeken, J., Demetri, G.D., DiLullo, S., Duma, N., Elias, R., Faller, B., Fecher, L.A., Feldman, L.E., Friese, C.R., Fu, P., Fu, J., Futreal, A., Gainor, J., Garcia, J., Gill, D.M., Gillaspie, E.A., Giordano, A., Glace, M.G., Grothey, A., Gulati, S., Gurley, M., Halmos, B., Herbst, R., Hershman, D., Hoskins, K., Jain, R.K., Jabbour, S., Jha, A., Johnson, D.B., Joshi, M., Kelleher, K., Kharofa, J., Khan, H., Knoble, J., Koshkin, V.S., Kulkarni, A.A., Lammers, P.E., Leighton, J.C., Lewis, M.A., Li, X., Li, A., Lo, KMS, Loaiza-Bonilla, A., LoRusso, P., Low, C.A., Lustberg, M.B., Mahadevan, D., Mansoor, A.H., Marcum, M., Markham, M.J., Handy Marshall, C., Mashru, S.H., Matar, S., McNair, C., McWeeney, S., Mehnert, J.M., Menendez, A., Menon, H., Messmer, M., Monahan, R., Mushtaq, S., Nagaraj, G., Nagle, S., Naidoo, J., Nakayama, J.M., Narayan, V., Nelson, H.H., Nemecek, E.R., Nguyen, R., Nuzzo, P.V., Oberstein, P.E., Olszewski, A.J., Owenby, S., Pasquinelli, M.M., Philip, J., Prabhakaran, S., Puc, M., Ramirez, A., Rathmann, J., Revankar, S.G., Rho, Y.S., Rhodes, T.D., Rice, R.L., Riely, G.J., Riess, J., Rink, C., Robilotti, E.V., Rosenstein, L., Routy, B., Rovito, M.A., Saif, M.W., Sanyal, A., Schapira, L., Schwartz, C., Serrano, O., Shah, M., Shah, C., Shaw, G., Shergill, A., Shouse, G., Soares, H.P., Solorzano, C.C., Srivastava, P.K., Stauffer, K., Stover, D.G., Stratton, J., Stratton, C., Subbiah, V., Tamimi, R., Tannir, N.M., Topaloglu, U., Van Allen, E., Van Loon, S., Vega-Luna, K., Venepalli, N., Verma, A.K., Vikas, P., Wall, S., Weinstein, P.L., Weiss, M., Wise-Draper, T., Wood, W.A., Xu, W.V., Yackzan, S., Zacks, R., Zhang, T., Zimmer, A.J., and West, J.

Subjects
Prognostic variable, medicine.medical_specialty, business.industry, Cancer, General Medicine, Odds ratio, Aged, Antiviral Agents/therapeutic use, Azithromycin/therapeutic use, Betacoronavirus, Cause of Death, Comorbidity, Coronavirus Infections/drug therapy, Coronavirus Infections/epidemiology, Coronavirus Infections/mortality, Databases, Factual, Female, Humans, Hydroxychloroquine/therapeutic use, Male, Middle Aged, Neoplasms/epidemiology, Neoplasms/mortality, Neoplasms/therapy, Pandemics, Pneumonia, Viral/drug therapy, Pneumonia, Viral/epidemiology, Pneumonia, Viral/mortality, Prognosis, Risk Factors, 030204 cardiovascular system & hematology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Cohort, Clinical endpoint, Medicine, 030212 general & internal medicine, business, Cause of death, Cohort study
Abstract

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Published
2020

27. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK.Cancer. 2015 Oct 1;121(19):3435-43. [Epub 2015 Jun 8]. doi: 10.1002/cncr.29503.

Author

Jay, Raman, McKay, R R, Werner, L, Atkins, M B, Van Allen, E M, Olivier, K M, Song, J, Signoretti, S, McDermott, D F, and Choueiri, T K

Abstract

Background: Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC.Methods: This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary end point was the objective response rate (ORR). Secondary end points included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives.Results: Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had>10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with≤10% sarcomatoid histology (P = 0.04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7).Conclusions: These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation. [ABSTRACT FROM AUTHOR]

Published
2017
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28. Dual Immune Checkpoint Inhibition in Patients With Aggressive Thyroid Carcinoma: A Phase 2 Nonrandomized Clinical Trial.

Author

Sehgal K, Pappa T, Shin KY, Schiantarelli J, Liu M, Ricker C, Besson NR, Jones SM, Welsh EL, Pfaff KL, Barletta JA, Park J, Reardon B, Doherty GM, Alexander EK, Rodig SJ, Barbie DA, O'Neill A, Van Allen E, Haddad RI, and Lorch JH

Abstract

Importance: Aggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition., Objective: To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma., Design, Setting, and Participants: This phase 2 nonrandomized clinical trial enrolled patients with RAIR DTC in a single center from October 2017 to May 2019, with exploratory cohorts in MTC and ATC. The data were analyzed between June 2021 and September 2023., Intervention: Intravenous nivolumab, 3 mg/kg, every 2 weeks and ipilimumab, 1 mg/kg, every 6 weeks until disease progression, intolerable adverse events, or a maximum duration of 2 years., Main Outcomes and Measures: The primary end point of the study was objective response rate (ORR) in RAIR DTC, which was scored according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1. Key secondary end points included safety, progression-free survival, overall survival, and biomarker analyses., Results: A total of 51 patients were registered, and 49 patients were evaluable for analysis. The median (range) age was 65 years (30-88 years), and 25 participants (51%) were female. ORR in the DTC cohort was 9.4% (3/32 [95% CI, 2.8%-28.5%]), with all partial responses in either oncocytic carcinoma (2/6 [33.0%]) or poorly differentiated thyroid carcinoma (1/5 [20.0%]). Clinical benefit rates were 62.5% (20/32) in the overall DTC cohort, including 83.3% (5/6) in oncocytic carcinoma and 40% (2/5) in poorly differentiated thyroid carcinoma. ORR in the exploratory ATC cohort was 30.0% (3/10 [95% CI, 6.7%-65.2%]), with a clinical benefit rates of 50.0% (5/10). No responses were observed in the exploratory MTC cohort. The safety profile was similar to prior reports with dual immune checkpoint inhibition (pruritus, rash, diarrhea, fatigue, and elevation of lipase and liver enzymes). The presence of NRAS tumor genetic sequence variations, but not BRAF V600E, was associated with worse outcomes., Conclusions and Relevance: This phase 2 nonrandomized clinical trial reported clinical activity of dual immune checkpoint inhibition in aggressive thyroid cancer. The study did not meet its end point in the primary population of RAIR DTC and does not support further investigation in non-biomarker-selected DTC. However, the signal observed in ATC may merit further evaluation., Trial Registration: ClinicalTrials.gov Identifier: NCT03246958.

Published
2024
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29. Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma.

Author

Yates J, Mathey-Andrews C, Park J, Garza A, Gagné A, Hoffman S, Bi K, Titchen B, Hennessey C, Remland J, Shannon E, Camp S, Balamurali S, Cavale SK, Li Z, Raghawan AK, Kraft A, Boland G, Aguirre AJ, Sethi NS, Boeva V, and Van Allen E

Abstract

Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We identified tumor microenvironmental features previously described to associate with therapy response. We identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response., Competing Interests: E.M.V.: Advisory/Consulting: Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Serinus Bio, TracerDx Research support: Novartis, BMS, Sanofi, NextPoint Equity: Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, Serinus Bio, Syapse, TracerDx Travel reimbursement: None Patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag Editorial Boards: Science Advances A.J.A. has consulted for Anji Pharmaceuticals, Affini-T Therapeutics, Arrakis Therapeutics, AstraZeneca, Boehringer Ingelheim, Kestrel Therapeutics, Merck & Co., Inc., Mirati Therapeutics, Nimbus Therapeutics, Oncorus, Inc., Plexium, Quanta Therapeutics, Revolution Medicines, Reactive Biosciences, Riva Therapeutics, Servier Pharmaceuticals, Syros Pharmaceuticals, T-knife Therapeutics, Third Rock Ventures, and Ventus Therapeutics. A.J.A. holds equity in Riva Therapeutics and Kestrel Therapeutics. A.J.A. has research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Deerfield, Inc., Eli Lilly, Mirati Therapeutics, Nimbus Therapeutics, Novartis, Novo Ventures, Revolution Medicines, and Syros Pharmaceuticals.

Published
2024
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30. Perspectives of Oncologists on the Ethical Implications of Using Artificial Intelligence for Cancer Care.

Author

Hantel A, Walsh TP, Marron JM, Kehl KL, Sharp R, Van Allen E, and Abel GA

Subjects
Humans, Male, Artificial Intelligence, Cross-Sectional Studies, Ambulatory Care Facilities, Neoplasms therapy, Oncologists
Abstract

Importance: Artificial intelligence (AI) tools are rapidly integrating into cancer care. Understanding stakeholder views on ethical issues associated with the implementation of AI in oncology is critical to optimal deployment., Objective: To evaluate oncologists' views on the ethical domains of the use of AI in clinical care, including familiarity, predictions, explainability (the ability to explain how a result was determined), bias, deference, and responsibilities., Design, Setting, and Participants: This cross-sectional, population-based survey study was conducted from November 15, 2022, to July 31, 2023, among 204 US-based oncologists identified using the National Plan & Provider Enumeration System., Main Outcomes and Measures: The primary outcome was response to a question asking whether participants agreed or disagreed that patients need to provide informed consent for AI model use during cancer treatment decisions., Results: Of 387 surveys, 204 were completed (response rate, 52.7%). Participants represented 37 states, 120 (63.7%) identified as male, 128 (62.7%) as non-Hispanic White, and 60 (29.4%) were from academic practices; 95 (46.6%) had received some education on AI use in health care, and 45.3% (92 of 203) reported familiarity with clinical decision models. Most participants (84.8% [173 of 204]) reported that AI-based clinical decision models needed to be explainable by oncologists to be used in the clinic; 23.0% (47 of 204) stated they also needed to be explainable by patients. Patient consent for AI model use during treatment decisions was supported by 81.4% of participants (166 of 204). When presented with a scenario in which an AI decision model selected a different treatment regimen than the oncologist planned to recommend, the most common response was to present both options and let the patient decide (36.8% [75 of 204]); respondents from academic settings were more likely than those from other settings to let the patient decide (OR, 2.56; 95% CI, 1.19-5.51). Most respondents (90.7% [185 of 204]) reported that AI developers were responsible for the medico-legal problems associated with AI use. Some agreed that this responsibility was shared by physicians (47.1% [96 of 204]) or hospitals (43.1% [88 of 204]). Finally, most respondents (76.5% [156 of 204]) agreed that oncologists should protect patients from biased AI tools, but only 27.9% (57 of 204) were confident in their ability to identify poorly representative AI models., Conclusions and Relevance: In this cross-sectional survey study, few oncologists reported that patients needed to understand AI models, but most agreed that patients should consent to their use, and many tasked patients with choosing between physician- and AI-recommended treatment regimens. These findings suggest that the implementation of AI in oncology must include rigorous assessments of its effect on care decisions as well as decisional responsibility when problems related to AI use arise.

Published
2024
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31. Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer.

Author

Kamran SC, Zhou Y, Otani K, Drumm M, Otani Y, Wu S, Wu CL, Feldman AS, Wszolek M, Lee RJ, Saylor PJ, Lennerz J, Van Allen E, Willers H, Hong TS, Liu Y, Davicioni E, Gibb EA, Shipley WU, Mouw KW, Efstathiou JA, and Miyamoto DT

Subjects
Humans, Neoplasm Invasiveness, Cisplatin therapeutic use, Cystectomy, Biomarkers, Tumor genetics, Biomarkers, Tumor therapeutic use, Genomics, Treatment Outcome, Xeroderma Pigmentosum Group D Protein genetics, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms therapy, Urinary Bladder Neoplasms pathology
Abstract

Purpose: There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood., Experimental Design: We characterized genomic and transcriptomic features correlated with long-term response in a single institution cohort of patients with MIBC homogeneously treated with TMT. Pretreatment tumors from 76 patients with MIBC underwent whole-exome sequencing; 67 underwent matched transcriptomic profiling. Molecular features were correlated with clinical outcomes including modified bladder-intact event-free survival (mBI-EFS), a composite endpoint that reflects long-term cancer control with bladder preservation., Results: With a median follow-up of 74.6 months in alive patients, 37 patients had favorable long-term response to TMT while 39 had unfavorable long-term response. Tumor mutational burden was not associated with outcomes after TMT. DNA damage response gene alterations were associated with improved locoregional control and mBI-EFS. Of these alterations, somatic ERCC2 mutations stood out as significantly associated with favorable long-term outcomes; patients with ERCC2 mutations had significantly improved mBI-EFS [HR, 0.15; 95% confidence interval (CI), 0.06-0.37; P = 0.030] and improved BI-EFS, an endpoint that includes all-cause mortality (HR, 0.33; 95% CI, 0.15-0.68; P = 0.044). ERCC2 mutant bladder cancer cell lines were significantly more sensitive to concurrent cisplatin and radiation treatment in vitro than isogenic ERCC2 wild-type cells., Conclusions: Our data identify ERCC2 mutation as a candidate biomarker associated with sensitivity and long-term response to chemoradiation in MIBC. These findings warrant validation in independent cohorts., (©2023 The Authors; Published by the American Association for Cancer Research.)

Published
2023
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33. Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma.

Author

Cotta BH, Choueiri TK, Cieslik M, Ghatalia P, Mehra R, Morgan TM, Palapattu GS, Shuch B, Vaishampayan U, Van Allen E, Ari Hakimi A, and Salami SS

Subjects
Humans, DNA Copy Number Variations, Genomics, Mutation, Biomarkers, Tumor genetics, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms pathology
Abstract

Context: Dramatic gains in our understanding of the molecular biology of clear cell renal cell carcinoma (ccRCC) have created a foundation for clinical translation to improve patient care., Objective: To review and contextualize clinically impactful data surrounding genomic biomarkers in ccRCC., Evidence Acquisition: A systematic literature search was conducted focusing on genomic-based biomarkers with an emphasis on studies assessing clinical outcomes., Evidence Synthesis: The advancement of tumor sequencing techniques has led to a rapid increase in the knowledge of the molecular underpinnings of ccRCC and with that the discovery of multiple candidate genomic biomarkers. These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1; copy number variations; transcriptomic multigene signatures; and specific immune cell populations. Many of these biomarkers have been assessed for their association with survival and a smaller number as potential predictors of a response to systemic therapy. In this scoping review, we discuss many of these biomarkers in detail. Further studies are needed to continue to refine and validate these molecular tools for risk stratification, with the ultimate goal of improving clinical decision-making and patient outcomes., Conclusions: While no tissue or blood-based biomarkers for ccRCC have been incorporated into routine clinical practice to date, the field continues to expand rapidly. There remains a critical need to develop and validate these tools in order to improve the care for patients with kidney cancer., Patient Summary: Genomic biomarkers have the potential to better predict outcome and select the most appropriate treatment for patients with kidney cancer; however, further research is needed before any of these currently developed biomarkers are adopted into clinical practice., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Published
2023
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34. Molecular markers of metastatic disease in KRAS-mutant lung adenocarcinoma.

Author

Boiarsky D, Lydon CA, Chambers ES, Sholl LM, Nishino M, Skoulidis F, Heymach JV, Luo J, Awad MM, Janne PA, Van Allen EM, Barbie DA, and Vokes NI

Subjects
Humans, Kelch-Like ECH-Associated Protein 1 genetics, Proto-Oncogene Proteins p21(ras) genetics, NF-E2-Related Factor 2 genetics, Prognosis, Protein Serine-Threonine Kinases genetics, Biomarkers, Tumor genetics, Mutation, DNA Helicases genetics, Nuclear Proteins genetics, Transcription Factors genetics, Lung Neoplasms pathology, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung pathology
Abstract

Background: Prior studies characterized the association of molecular alterations with treatment-specific outcomes in KRAS-mutant (KRAS MUT ) lung adenocarcinoma (LUAD). Less is known about the prognostic role of molecular alterations and their associations with metastatic disease., Patients and Methods: We analyzed clinicogenomic data from 1817 patients with KRAS MUT LUAD sequenced at the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC). Patients with metastatic (M1) and nonmetastatic (M0) disease were compared. Transcriptomic data from The Cancer Genome Atlas (TCGA) were investigated to characterize the biology of differential associations with clinical outcomes. Organ-specific metastasis was associated with overall survival (OS)., Results: KEAP1 (DFCI: OR = 2.3, q = 0.04; MSKCC: OR = 2.2, q = 0.00027) and SMARCA4 mutations (DFCI: OR = 2.5, q = 0.06; MSKCC: OR = 2.6, q = 0.0021) were enriched in M1 versus M0 tumors. On integrative modeling, NRF2 activation was the genomic feature most associated with OS. KEAP1 mutations were enriched in M1 versus M0 tumors independent of STK11 status (KEAP1 MUT /STK11 WT : DFCI OR = 3.0, P = 0.0064; MSKCC OR = 2.0, P = 0.041; KEAP1 MUT /STK11 MUT : DFCI OR = 2.3, P = 0.0063; MSKCC OR = 2.5, P = 3.6 × 10 -05 ); STK11 mutations without KEAP1 loss were not associated with stage (KEAP1 WT /STK11 MUT : DFCI OR = 0.97, P = 1.0; MSKCC OR = 1.2, P = 0.33) or outcome. KEAP1/KRAS-mutated tumors with and without STK11 mutations exhibited high functional STK11 loss. The negative effects of KEAP1 were compounded in the presence of bone (HR = 2.3, P = 4.4 × 10 -14 ) and negated in the presence of lymph node metastasis (HR = 1.0, P = 0.91)., Conclusions: Mutations in KEAP1 and SMARCA4, but not STK11, were associated with metastatic disease and poor OS. Functional STK11 loss, however, may contribute to poor outcomes in KEAP1 MUT tumors. Integrating molecular data with clinical and metastatic-site annotations can more accurately risk stratify patients., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2023
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35. Disparities in the Inclusion of Racial and Ethnic Minority Groups and Older Adults in Prostate Cancer Clinical Trials: A Meta-analysis.

Author

Riaz IB, Islam M, Ikram W, Naqvi SAA, Maqsood H, Saleem Y, Riaz A, Ravi P, Wang Z, Hussain SA, Warner JL, Odedina FT, Duma N, Singh P, Kehl KL, Kamran SC, Murad MH, Landman A, Van Allen E, and Bryce AH

Subjects
Male, Humans, Aged, Minority Groups, Ethnic and Racial Minorities, Hispanic or Latino, Ethnicity, Prostatic Neoplasms therapy
Abstract

Importance: Prostate cancer (PCa) is marked by disparities in clinical outcomes by race, ethnicity, and age. Equitable enrollment in clinical trials is fundamental to promoting health equity., Objective: To evaluate disparities in the inclusion of racial and ethnic minority groups and older adults across PCa clinical trials., Data Sources: MEDLINE, Embase, and ClinicalTrials.gov were searched to identify primary trial reports from each database's inception through February 2021. Global incidence in age subgroups and US population-based incidence in racial and ethnic subgroups were acquired from the Global Burden of Disease and Surveillance, Epidemiology, and End Results 21 incidence databases respectively., Study Selection: All phase 2/3 randomized PCa clinical trials were eligible for age disparity analyses. Trials recruiting exclusively from the US were eligible for primary racial and ethnic disparity analyses., Data Extraction and Synthesis: This study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Data were pooled using a random-effects model., Main Outcomes and Measures: Enrollment incidence ratios (EIRs), trial proportions (TPs) of participants 65 years or older or members of a racial and ethnic subgroup divided by global incidence in the corresponding age group, or US population-based incidence in the corresponding racial and ethnic subgroup, were calculated. Meta-regression was used to explore associations between trial characteristics and EIRs and trends in EIRs during the past 3 decades., Results: Of 9552 participants among trials reporting race, 954 (10.8%) were African American/Black, 80 (1.5%) were Asian/Pacific Islander, and 8518 (78.5) were White. Of 65 US trials, 45 (69.2%) reported race and only 9 (13.8%) reported data on all 5 US racial categories. Of 286 global trials, 75 (26.2%) reported the enrollment proportion of older adults. Outcomes by race and age were reported in 2 (3.1%) and 41 (15.0%) trials, respectively. Black (EIR, 0.70; 95% CI, 0.59-0.83) and Hispanic (EIR, 0.70; 95% CI, 0.59-0.83) patients were significantly underrepresented in US trials. There was no disparity in older adult representation (TP, 21 143 [71.1%]; EIR, 1.00; 95% CI, 0.95-1.05). The representation of Black patients was lower in larger trials (meta-regression coefficient, -0.06; 95% CI, -0.10 to -0.02; P = .002)., Conclusions and Relevance: The results of this meta-analysis suggest that Black and Hispanic men are underrepresented in trials compared with their share of PCa incidence. The representation of Black patients has consistently remained low during the past 2 decades.

Published
2023
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36. Racial and ethnic disparities in a real-world precision oncology data registry.

Author

Cheung ATM, Palapattu EL, Pompa IR, Aldrighetti CM, Niemierko A, Willers H, Huang F, Vapiwala N, Van Allen E, and Kamran SC

Abstract

Biorepositories enable precision oncology research by sharing clinically annotated genomic data, but it remains unknown whether these data registries reflect the true distribution of cancers in racial and ethnic minorities. Our analysis of Project Genomics Evidence Neoplasia Information Exchange (GENIE), a real-world cancer data registry designed to accelerate precision oncology discovery, indicates that minorities do not have sufficient representation, which may impact the validity of studies directly comparing mutational profiles between racial/ethnic groups and limit generalizability of biomarker discoveries to all populations., (© 2023. The Author(s).)

Published
2023
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37. Germline variants associated with toxicity to immune checkpoint blockade.

Author

Groha S, Alaiwi SA, Xu W, Naranbhai V, Nassar AH, Bakouny Z, El Zarif T, Saliby RM, Wan G, Rajeh A, Adib E, Nuzzo PV, Schmidt AL, Labaki C, Ricciuti B, Alessi JV, Braun DA, Shukla SA, Keenan TE, Van Allen E, Awad MM, Manos M, Rahma O, Zubiri L, Villani AC, Fairfax B, Hammer C, Khan Z, Reynolds K, Semenov Y, Schrag D, Kehl KL, Freedman ML, Choueiri TK, and Gusev A

Subjects
Interleukin-7, Cognition, Germ Cells, Retrospective Studies, Immune Checkpoint Inhibitors, Genome-Wide Association Study
Abstract

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10 -8 ) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10 -11 ; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10 -8 ; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10 -8 , HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2022
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38. Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer.

Author

Church AJ, Corson LB, Kao PC, Imamovic-Tuco A, Reidy D, Doan D, Kang W, Pinto N, Maese L, Laetsch TW, Kim A, Colace SI, Macy ME, Applebaum MA, Bagatell R, Sabnis AJ, Weiser DA, Glade-Bender JL, Homans AC, Hipps J, Harris H, Manning D, Al-Ibraheemi A, Li Y, Gupta H, Cherniack AD, Lo YC, Strand GR, Lee LA, Pinches RS, Lazo De La Vega L, Harden MV, Lennon NJ, Choi S, Comeau H, Harris MH, Forrest SJ, Clinton CM, Crompton BD, Kamihara J, MacConaill LE, Volchenboum SL, Lindeman NI, Van Allen E, DuBois SG, London WB, and Janeway KA

Subjects
Adolescent, Adult, Biomarkers, Tumor genetics, Child, Child, Preschool, Genomics, Humans, Infant, Infant, Newborn, Molecular Targeted Therapy methods, Prospective Studies, Young Adult, High-Throughput Nucleotide Sequencing methods, Neoplasms drug therapy, Neoplasms genetics, Neoplasms pathology
Abstract

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2022
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39. Autocrine Canonical Wnt Signaling Primes Noncanonical Signaling through ROR1 in Metastatic Castration-Resistant Prostate Cancer.

Author

Ma F, Arai S, Wang K, Calagua C, Yuan AR, Poluben L, Gu Z, Russo JW, Einstein DJ, Ye H, He MX, Liu Y, Van Allen E, Sowalsky AG, Bhasin MK, Yuan X, and Balk SP

Subjects
Autocrine Communication, Humans, Male, beta Catenin genetics, beta Catenin metabolism, Prostatic Neoplasms, Castration-Resistant drug therapy, Receptor Tyrosine Kinase-like Orphan Receptors genetics, Receptor Tyrosine Kinase-like Orphan Receptors metabolism, Wnt Signaling Pathway
Abstract

Wnt signaling driven by genomic alterations in genes including APC and CTNNB, which encodes β-catenin, have been implicated in prostate cancer development and progression to metastatic castration-resistant prostate cancer (mCRPC). However, nongenomic drivers and downstream effectors of Wnt signaling in prostate cancer and the therapeutic potential of targeting this pathway in prostate cancer have not been fully established. Here we analyzed Wnt/β-catenin signaling in prostate cancer and identified effectors distinct from those found in other tissues, including aryl hydrocarbon receptor and RUNX1, which are linked to stem cell maintenance, and ROR1, a noncanonical Wnt5a coreceptor. Wnt/β-catenin signaling-mediated increases in ROR1 enhanced noncanonical responses to Wnt5a. Regarding upstream drivers, APC genomic loss, but not its epigenetic downregulation commonly observed in prostate cancer, was strongly associated with Wnt/β-catenin pathway activation in clinical samples. Tumor cell upregulation of the Wnt transporter Wntless (WLS) was strongly associated with Wnt/β-catenin pathway activity in primary prostate cancer but also associated with both canonical and noncanonical Wnt signaling in mCRPC. IHC confirmed tumor cell WLS expression in primary prostate cancer and mCRPC, and patient-derived prostate cancer xenografts expressing WLS were responsive to treatment with Wnt synthesis inhibitor ETC-1922159. These findings reveal that Wnt/β-catenin signaling in prostate cancer drives stem cell maintenance and invasion and primes for noncanonical Wnt signaling through ROR1. They further show that autocrine Wnt production is a nongenomic driver of canonical and noncanonical Wnt signaling in prostate cancer, which can be targeted with Wnt synthesis inhibitors to suppress tumor growth., Significance: This work provides fundamental insights into Wnt signaling and prostate cancer cell biology and indicates that a subset of prostate cancer driven by autocrine Wnt signaling is sensitive to Wnt synthesis inhibitors., (©2022 American Association for Cancer Research.)

Published
2022
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40. Genomic attributes of homology-directed DNA repair deficiency in metastatic prostate cancer.

Author

De Sarkar N, Dasgupta S, Chatterjee P, Coleman I, Ha G, Ang LS, Kohlbrenner EA, Frank SB, Nunez TA, Salipante SJ, Corey E, Morrissey C, Van Allen E, Schweizer MT, Haffner MC, Patel R, Hanratty B, Lucas JM, Dumpit RF, Pritchard CC, Montgomery RB, and Nelson PS

Subjects
Animals, Disease Models, Animal, Humans, Male, Mice, Neoplasm Metastasis, DNA Repair-Deficiency Disorders genetics, Genomics methods, Prostatic Neoplasms genetics
Abstract

Cancers with homology-directed DNA repair (HRR) deficiency exhibit high response rates to poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy. Though mutations disrupting BRCA1 and BRCA2 associate with HRR deficiency (HRRd), patterns of genomic aberrations and mutation signatures may be more sensitive and specific indicators of compromised repair. Here, we evaluated whole-exome sequences from 418 metastatic prostate cancers (mPCs) and determined that one-fifth exhibited genomic characteristics of HRRd that included Catalogue Of Somatic Mutations In Cancer mutation signature 3. Notably, a substantial fraction of tumors with genomic features of HRRd lacked biallelic loss of a core HRR-associated gene, such as BRCA2. In this subset, HRRd associated with loss of chromodomain helicase DNA binding protein 1 but not with mutations in serine-protein kinase ATM, cyclin dependent kinase 12, or checkpoint kinase 2. HRRd genomic status was strongly correlated with responses to PARPi and platinum chemotherapy, a finding that supports evaluating biomarkers reflecting functional HRRd for treatment allocation.

Published
2021
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41. Racial and Ethnic Disparities Among Participants in Precision Oncology Clinical Studies.

Author

Aldrighetti CM, Niemierko A, Van Allen E, Willers H, and Kamran SC

Subjects
Cross-Sectional Studies, Cultural Diversity, Ethnicity, Female, Humans, Male, Medical Oncology, Middle Aged, Clinical Trials as Topic statistics & numerical data, Ethnic and Racial Minorities statistics & numerical data, Health Services Accessibility statistics & numerical data, Neoplasms ethnology, Neoplasms therapy, Precision Medicine statistics & numerical data
Abstract

Importance: Precision oncology is revolutionizing cancer care, allowing for personalized treatments to improve outcomes. Cancer research has benefitted from well-designed studies incorporating precision medicine objectives, but it is unclear if these studies are representative of the diverse cancer population., Objective: To evaluate racial and ethnic representation in breast, prostate, lung, and colorectal cancer studies incorporating precision oncology objectives in the Clinicaltrials.gov registry and compare with the incidence of these cancer types in racial and ethnic minority groups in the US population., Design, Setting, and Participants: This cross-sectional study identified US-based breast, prostate, lung, and colorectal cancer studies incorporating precision oncology objectives for reporting of race and ethnicity. The Surveillance, Epidemiology, and End Results and US Census databases were used to determine cancer incidence by race and ethnicity, linked with cancer type and median year of enrollment for each trial. Data were collected and analyzed between December 2020 and April 2021., Main Outcomes and Measures: The expected number of participants per study by each racial and ethnic group was calculated based on the corresponding US-based proportion. Under- and overrepresentation was defined as the ratio of the actual number of enrolled cases to the expected number of cases for each trial by cancer type. Ratios above 1 indicated overrepresentation while a ratio below 1 indicated underrepresentation. Random-effects meta-analysis of representation ratios of individual trials was performed to weigh each individual study., Results: Of 93 studies encompassing 5867 enrollees with race and ethnicity data; 4826 participants (82.3%) were non-Hispanic White, 587 (10.0%) were Black, and 238 (4.1%) were Asian. Per observed-to-expected ratios, White participants were overrepresented in all studies, with a ratio of 1.35 (95% CI, 1.30-1.37), as well as Asian participants, with a ratio of 1.46 (95% CI, 1.28-1.66), while Black participants (ratio, 0.49; 95% CI, 0.45-0.54), Hispanic participants (ratio, 0.24; 95% CI, 0.20-0.28), and American Indian and Alaskan Native participants (ratio, 0.43; 95% CI, 0.24-0.78) were underrepresented. By individual cancer site, White participants were consistently overrepresented in all studies, while Black and Hispanic participants were underrepresented., Conclusions and Relevance: This analysis found that precision oncology studies for breast, lung, prostate, and colorectal cancers vastly underrepresent racial and ethnic minority populations relative to their cancer incidence in the US population. It is imperative to increase diversity among enrollees so that all individuals may benefit from cancer research breakthroughs and personalized treatments.

Published
2021
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42. Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial.

Author

Hamid AA, Huang HC, Wang V, Chen YH, Feng F, Den R, Attard G, Van Allen EM, Tran PT, Spratt DE, Dittamore R, Davicioni E, Liu G, DiPaola R, Carducci MA, and Sweeney CJ

Subjects
Antineoplastic Combined Chemotherapy Protocols therapeutic use, Docetaxel therapeutic use, Hormones therapeutic use, Humans, Male, Androgen Antagonists therapeutic use, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics
Abstract

Background: The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined., Patients and Methods: Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC., Results: The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015)., Conclusion: This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC., Competing Interests: Disclosure A.A.H reports consulting fees from Merck Sharp & Dohme. H-C.H., R.D. and E.D. are employees of Decipher Biosciences. F.F. reports receiving fees for serving as a consultant from Janssen during the conduct of the study, Celgene, Blue Earth Diagnostics, Astellas, Myovant, Roivant, Genentech, and Bayer; being a co-founder having stock options in PFS Genomics; and having stock options and serving on the scientific advisory board of SerImmune Stock outside the submitted work. G.A. reports personal fees, research support and travel support from Janssen during the conduct of the study; personal fees and/or travel support from Astellas, Pfizer, Millennium Pharmaceuticals, Ipsen, Ventana, Veridex, Novartis, Abbott Laboratories, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Takeda and Sanofi-Aventis and research funding from AstraZeneca, Innocrin Pharma and Arno Therapeutics outside the submitted work; in addition, G.A.’s former employer, The Institute of Cancer Research (ICR), receives royalty income from abiraterone acetate and GA receives a share of this income through ICR’s Rewards to Discoverers scheme. E.M.V.A reports advisory/consulting role: Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support: Novartis, BMS; equity: Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; travel reimbursement: Roche/Genentech; patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation. P.T.T. reported receiving grants from RefleXion Medical, the Prostate Cancer Foundation, and Movember Foundation; personal fees from Noxopharm, Janssen-Taris Biomedical, Myovant, AstraZeneca, and RefleXion; grants from Astellas and Bayer Healthcare; and owning patent No. 9114158 (with royalties from Natsar Pharmaceuticals) outside the submitted work. D.E.S reports personal fees: Janssen, AstraZeneca, Bayer, Boston Scientific, and Blue Earth; funding: Janssen. G.L. is a co-founder and chief medical officer of AIQ Solutions (Madison, WI). M.A.A. reports past consultation for Pfizer, Astellas, and Exelixis, and current research funding from Arcus, Pfizer, and Merck. C.J.S. report consulting or advisory role: Sanofi, Janssen, Astellas Pharma, Bayer, Genentech, Pfizer, Lilly; research funding: Janssen Biotech (Inst), Astellas Pharma (Inst), Sanofi (Inst), Bayer (Inst), Sotio (Inst), Dendreon (Inst); patents, royalties, other intellectual property: Pathenolide (Indiana University): dimethylaminoparthenolide (Leuchemix); Exelixis: Abiraterone plus cabozantinib combination; stock or other ownership: Leuchemix., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2021
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43. Nivolumab in combination with cabozantinib for metastatic triple-negative breast cancer: a phase II and biomarker study.

Author

Barroso-Sousa R, Keenan TE, Li T, Tayob N, Trippa L, Pastorello RG, Richardson Iii ET, Dillon D, Amoozgar Z, Overmoyer B, Schnitt SJ, Winer EP, Mittendorf EA, Van Allen E, Duda DG, and Tolaney SM

Abstract

This single-arm phase II study investigated the efficacy and safety of cabozantinib combined with nivolumab in metastatic triple-negative breast cancer (mTNBC). The primary endpoint was objective response rate (ORR) by RECIST 1.1. Biopsies at baseline and after cycle 1 were analyzed for tumor-infiltrating lymphocytes (TILs), PD-L1, and whole-exome and transcriptome sequencing. Only 1/18 patients achieved a partial response (ORR 6%), and the trial was stopped early. Toxicity led to cabozantinib dose reduction in 50% of patients. One patient had a PD-L1-positive tumor, and three patients had TILs > 10%. The responding patient had a PD-L1-negative tumor with low tumor mutational burden but high TILs and enriched immune gene expression. High pretreatment levels of plasma immunosuppressive cytokines, chemokines, and immune checkpoint molecules were associated with rapid progression. Although this study did not meet its primary endpoint, immunostaining, genomic, and proteomic studies indicated a high degree of tumor immunosuppression in this mTNBC cohort., (© 2021. The Author(s).)

Published
2021
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44. Integrated Analysis of Germ Cell Tumors.

Author

Tewari A and Van Allen E

Subjects
Data Analysis, Databases, Genetic, Gene Dosage, Gene Expression Profiling, Gene Library, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Neoplasms, Germ Cell and Embryonal metabolism, Neoplasms, Germ Cell and Embryonal pathology, Quality Control, Sequence Analysis, DNA, Transcriptome, Disease Susceptibility, Genomics methods, Neoplasms, Germ Cell and Embryonal etiology
Abstract

Somatic analysis of the molecular features of human tumors through numerous efforts including The Cancer Genome Atlas consortium has led to unprecedented insight into the biological basis of cancer behavior. Numerous genomewide sequencing techniques have been utilized in these studies to understand DNA mutations, epigenomic alterations, and ultimately differences in protein expression profiles across various cancers. Due to the dropping costs of next-generation sequencing as well as growing power and ease of use of computational resources, researchers are able to apply these techniques to more specific cancer contexts and/or rarer tumor types. In this chapter, we describe the rationale for and details of methods used in our group for exome analysis of germ cell tumors. The methods described should also be readily applicable to genomic analysis of other tumors.

Published
2021
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45. Accelerating precision medicine in metastatic prostate cancer.

Author

Mateo J, McKay R, Abida W, Aggarwal R, Alumkal J, Alva A, Feng F, Gao X, Graff J, Hussain M, Karzai F, Montgomery B, Oh W, Patel V, Rathkopf D, Rettig M, Schultz N, Smith M, Solit D, Sternberg C, Van Allen E, VanderWeele D, Vinson J, Soule HR, Chinnaiyan A, Small E, Simons JW, Dahut W, Miyahira AK, and Beltran H

Subjects
Early Detection of Cancer, Humans, Male, Medical Oncology, Prostate-Specific Antigen, Precision Medicine, Prostatic Neoplasms diagnosis
Abstract

Despite advances in prostate cancer screening and treatment, available therapy options, particularly in later stages of the disease, remain limited and the treatment-resistant setting represents a serious unmet medical need. Moreover, disease heterogeneity and disparities in patient access to medical advances result in significant variability in outcomes across patients. Disease classification based on genomic sequencing is a promising approach to identify patients whose tumors exhibit actionable targets and make more informed treatment decisions. Here we discuss how we can accelerate precision oncology to inform broader genomically-driven clinical decisions for men with advanced prostate cancer, drug development and ultimately contribute to new treatment paradigms., Competing Interests: Competing Interests Statement. J.M. reports advisory board participation for Amgen, AstraZeneca, Roche, Janssen, MSD and Clovis Oncology; research funding from AstraZeneca and Pfizer Oncology; W.A. reports consulting /advisory for Clovis, Janssen, More Health, ORIC, Daiichi Sankyo; research funding from AstraZeneca, Zenith Epigenetics, Clovis, GlaxoSmithKline, ORIC, Epizyme; travel from GlaxoSmithKline, Clovis, ORIC; and honoraria from CARET. R.R.M. received research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for Bayer, Bristol Myers Squib, Exelixis, Janssen, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion. R.A. reports advisory board participation and research funding from Merck, AstraZeneca, and Janssen; B.M. reports research funding from AstraZeneca, Janssen, Clovis, Astellas, Beigene; M.R. reports consulting: Amgen, Ambryx, Constellation; educational writing and consulting: Plexus; speaking: Bayer, Janssen; funding and clinical research support: Novartis, Astellas, Medivation, Merck; D.B.S. has consulted for/received honoraria from Pfizer, Loxo Oncology, Lilly Oncology, BioBridge, Vivideon Therapeutics, and Illumina; E.V. reports advisory/consulting: Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; travel reimbursement: Roche/Genentech; institutional patents on chromatin mutations and immunotherapy response, and methods for clinical interpretation; D.V. reports honoraria from Clovis Oncology. H.B. reports advisory/consulting from Janssen, Amgen, Astra Zeneca, Pfizer, Astellas, Sanofi Genzyme and research funding from Janssen, Abbvie Stemcentryx, Eli Lilly, Millenium, Astellas. J.V. is employed by the Prostate Cancer Clinical Trials Consortium. H.R.S., J.W.S., and A.K.M. are employed by the Prostate Cancer Foundation.

Published
2020
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46. Germ Cell Tumor Molecular Heterogeneity Revealed Through Analysis of Primary and Metastasis Pairs.

Author

Cheng ML, Donoghue MTA, Audenet F, Wong NC, Pietzak EJ, Bielski CM, Isharwal S, Iyer G, Funt S, Bagrodia A, Bajorin DF, Reuter VE, Eng J, Joseph G, Bourque C, Bromberg M, Ling L, Selcuklu SD, Arcila ME, Tsui DWY, Zehir A, Viale A, Berger MF, Bosl GJ, Sheinfeld J, Van Allen E, Taylor BS, Al-Ahmadie H, Solit DB, and Feldman DR

Abstract

Purpose: Although primary germ cell tumors (GCTs) have been extensively characterized, molecular analysis of metastatic sites has been limited. We performed whole-exome sequencing and targeted next-generation sequencing on paired primary and metastatic GCT samples in a patient cohort enriched for cisplatin-resistant disease., Patients and Methods: Tissue sequencing was performed on 100 tumor specimens from 50 patients with metastatic GCT, and sequencing of plasma cell-free DNA was performed for a subset of patients., Results: The mutational landscape of primary and metastatic pairs from GCT patients was highly discordant (68% of all somatic mutations were discordant). Whereas genome duplication was common and highly concordant between primary and metastatic samples, only 25% of primary-metastasis pairs had ≥ 50% concordance at the level of DNA copy number alterations (CNAs). Evolutionary-based analyses revealed that most mutations arose after CNAs at the respective loci in both primary and metastatic samples, with oncogenic mutations enriched in the set of early-occurring mutations versus variants of unknown significance (VUSs). TP53 pathway alterations were identified in nine cisplatin-resistant patients and had the highest degree of concordance in primary and metastatic specimens, consistent with their association with this treatment-resistant phenotype., Conclusion: Analysis of paired primary and metastatic GCT specimens revealed significant molecular heterogeneity for both CNAs and somatic mutations. Among loci demonstrating serial genetic evolution, most somatic mutations arose after CNAs, but oncogenic mutations were enriched in the set of early-occurring mutations as compared with VUSs. Alterations in TP53 were clonal when present and shared among primary-metastasis pairs., Competing Interests: Conflicts of Interest Statement:The authors have declared that no competing interests exist.Conflicts of Interest Statement:Authors’ disclosures of potential conflicts of interest and contributions are found at the end of this article.The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Michael L. ChengHonoraria: The Lynx Group (supported by Bristol Myers Squibb), WebMD (supported by AstraZeneca), PCME (supported by Merck and Lilly) Consulting or Advisory Role: AstraZeneca, Inivata Travel, Accommodations, Expenses: Daiichi Sankyo, Allergan, Sanofi, Natera, AstraZeneca, Guardant Health, WebMD, PCMEFrançois AudenetHonoraria: Nucleix Travel, Accommodations, Expenses: Ferring, IpsenEugene J. PietzakHonoraria: UpToDate Consulting or Advisory Role: Merck, Chugai PharmaSumit IsharwalOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1232544Gopa IyerConsulting or Advisory Role: Bayer, Janssen, Mirati Therapeutics Research Funding: Mirati Therapeutics (Inst), Novartis (Inst), Debiopharm Group (Inst), Bayer (Inst)Samuel FuntStock and Other Ownership Interests: Kite Pharma, Urogen Pharma (I), Allogene Therapeutics, Neogene Therapeutics (I), Kronos Bio (I), Vida Ventures (I), Vaxigene Consulting or Advisory Role: AstraZeneca/MedImmune, Merck, Immunai Research Funding: Genentech (Inst), AstraZeneca (Inst), Decibel Therapeutics (Inst) Travel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca/MedImmuneDean F. BajorinHonoraria: Merck Sharp & Dohme Consulting or Advisory Role: Merck, Fidia Farmaceutici, Hoffman-La Roche, Dragonfly Therapeutics Research Funding: Novartis (Inst), Genentech (Inst), Merck (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Astellas Pharma (Inst), Seattle Genetics/Astellas (Inst) Travel, Accommodations, Expenses: Genentech, MerckVictor E. ReuterConsulting or Advisory Role: Cepheid Uncompensated Relationships: PaigeAIGabriella JosephStock and Other Ownership Interests: AmgenMaria E. ArcilaHonoraria: Invivoscribe, Biocartis Consulting or Advisory Role: AstraZeneca Travel, Accommodations, Expenses: AstraZeneca, Invivoscribe, Raindance TechnologiesDana W.Y. TsuiHonoraria: Cowen, BofA Merrill Lynch Patents, Royalties, Other Intellectual Property: I am a co-inventor on a provisional patent application filed by Memorial Sloan Kettering Cancer CenterAhmet ZehirHonoraria: IlluminaMichael F. BergerConsulting or Advisory Role: Roche Research Funding: Grail Patents, Royalties, Other Intellectual Property: Provisional patent pending for “Systems and Methods for Detecting Cancer via cfDNA Screening”Eliezer Van AllenStock and Other Ownership Interests: Syapse, Tango Therapeutics, Genome Medical, Microsoft, Ervaxx Consulting or Advisory Role: Syapse, Roche, Third Rock Ventures, Takeda, Novartis, Genome Medical, InVitae, Illumina, Tango Therapeutics, Ervaxx, Janssen Speakers' Bureau: Illumina Research Funding: Bristol Myers Squibb, Novartis Patents, Royalties, Other Intellectual Property: Patent on discovery of retained intron as source of cancer neoantigens (Inst); patent on discovery of chromatin regulators as biomarkers of response to cancer immunotherapy (Inst); patent on clinical interpretation algorithms using cancer molecular data (Inst) Travel, Accommodations, Expenses: GenentechBarry S. TaylorConsulting or Advisory Role: Boehringer Ingelheim, Loxo Oncology at Lilly Research Funding: GenentechHikmat Al-AhmadieConsulting or Advisory Role: Bristol Myers Squibb, EMD Serono, AstraZeneca/MedImmune, Janssen BiotechDavid B. SolitStock and Other Ownership Interests: Loxo Consulting or Advisory Role: Pfizer, Loxo, Illumina, Vivideon Therapeutics, Lilly Oncology, QED Therapeutics, BridgeBio PharmaDarren R. FeldmanResearch Funding: Novartis, Seattle Genetics, Decibel Therapeutics (Inst), Astellas Pharma Other Relationship: UpToDate No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Published
2020
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47. A phase 2 trial of buparlisib in patients with platinum-resistant metastatic urothelial carcinoma.

Author

McPherson V, Reardon B, Bhayankara A, Scott SN, Boyd ME, Garcia-Grossman IR, Regazzi AM, McCoy AS, Kim PH, Al-Ahmadie H, Ostrovnaya I, Roth AJ, Farooki A, Berger MF, Rosenberg JE, Solit DB, Van Allen E, Milowsky MI, Bajorin DF, and Iyer G

Subjects
Aged, Aged, 80 and over, Aminopyridines pharmacology, Cell Line, Tumor, Female, Humans, Male, Middle Aged, Morpholines pharmacology, Neoplasm Metastasis, Phosphatidylinositol 3-Kinase pharmacology, Aminopyridines therapeutic use, Morpholines therapeutic use, Phosphatidylinositol 3-Kinase therapeutic use, Urologic Neoplasms drug therapy
Abstract

Background: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the authors performed a phase 2 study evaluating the efficacy of the pan-isoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC., Methods: Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway-altered tumors. The primary endpoint was the 2-month progression-free survival rate. A rate of ≥80% was considered promising using a Simon 2-stage minimax design. Secondary endpoints included safety and correlation of markers of PI3K pathway activation with outcome., Results: Six of 13 evaluable patients within the initial cohort demonstrated stable disease and 1 demonstrated a partial response, which was below the cutoff of 9 patients required to proceed to stage 2. Three of the patients with stable disease and the patient with a partial response harbored somatic TSC1 alterations. Four patients subsequently were recruited onto an expansion cohort: 3 patients with TSC1 alterations and 1 patient with a PIK3CA-activating mutation. No patient achieved disease control at 8 weeks and accrual was halted. Of the 19 patients evaluable for toxicity, 17 demonstrated treatment-related toxicities, 2 of whom had to discontinue therapy., Conclusions: Buparlisib was found to demonstrate modest activity in patients with metastatic UC whose tumors harbored TSC1 loss of function alterations; however, this was not a robust predictor of response to buparlisib. The pattern of genetic coalterations likely influences drug sensitivity. Given the modest clinical activity and substantial toxicity of buparlisib, future trials of PI3K inhibitors in patients with UC should focus on isoform-selective PI3K inhibitors in genomically selected patients., Lay Summary: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway frequently is upregulated in patients with metastatic urothelial carcinoma (UC). This trial explored buparlisib, an inhibitor of the pathway, in patients with heavily pretreated metastatic UC. Although the drug was found to have modest efficacy, with 6 patients experiencing stable disease and 1 patient achieving a partial response at 8 weeks on therapy, significant side effects also were observed. Patients with specific genetic alterations responded to treatment. Further studies of PI3K pathway inhibition are warranted using newer agents that have superior toxicity profiles and are more selective inhibitors of the pathway., (© 2020 American Cancer Society.)

Published
2020
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48. Effect of Eribulin With or Without Pembrolizumab on Progression-Free Survival for Patients With Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: A Randomized Clinical Trial.

Author

Tolaney SM, Barroso-Sousa R, Keenan T, Li T, Trippa L, Vaz-Luis I, Wulf G, Spring L, Sinclair NF, Andrews C, Pittenger J, Richardson ET 3rd, Dillon D, Lin NU, Overmoyer B, Partridge AH, Van Allen E, Mittendorf EA, Winer EP, and Krop IE

Subjects
Adult, Aged, Antibodies, Monoclonal, Humanized adverse effects, B7-H1 Antigen analysis, Breast Neoplasms chemistry, Breast Neoplasms mortality, Cross-Over Studies, Female, Furans administration & dosage, Furans adverse effects, Humans, Ketones administration & dosage, Ketones adverse effects, Middle Aged, Receptor, ErbB-2 analysis, Receptors, Estrogen analysis, Receptors, Progesterone analysis, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms drug therapy, Furans therapeutic use, Ketones therapeutic use
Abstract

Importance: Prior studies have shown that only a small proportion of patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) experience benefit from programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors given as monotherapy. There are data suggesting that activity may be greater with combination strategies., Objective: To compare the efficacy of eribulin plus pembrolizumab vs eribulin alone in patients with HR-positive, ERBB2 (formerly HER2)-negative MBC., Design, Setting, and Participants: Multicenter phase 2 randomized clinical trial of patients with HR-positive, ERBB2-negative MBC who had received 2 or more lines of hormonal therapy and 0 to 2 lines of chemotherapy., Interventions: Patients were randomized 1:1 to eribulin, 1.4 mg/m2 intravenously, on days 1 and 8 plus pembrolizumab, 200 mg/m2 intravenously, on day 1 of a 21-day cycle or eribulin alone. At time of progression, patients in the eribulin monotherapy arm could cross over and receive pembrolizumab monotherapy., Main Outcomes and Measures: The primary end point was progression-free survival (PFS). Secondary end points were objective response rate (ORR) and overall survival (OS). Exploratory analyses assessed the association between PFS and PD-L1 status, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and genomic alterations., Results: Eighty-eight patients started protocol therapy; the median (range) age was 57 (30-76) years, median (range) number of prior lines of chemotherapy was 1 (0-2), and median (range) number of prior lines of hormonal therapy was 2 (0-5). Median follow-up was 10.5 (95% CI, 0.4-22.8) months. Median PFS and ORR were not different between the 2 groups (PFS, 4.1 vs 4.2 months; hazard ratio, 0.80; 95% CI, 0.50-1.26; P = .33; ORR, 27% vs 34%, respectively; P = .49). Fourteen patients started crossover treatment with pembrolizumab; 1 patient experienced stable disease. All-cause adverse events occurred in all patients (grade ≥3, 65%) including 2 treatment-related deaths in the combination group, both from immune-related colitis in the setting of sepsis, attributed to both drugs. The PD-L1 22C3 assay was performed on archival tumor samples in 65 patients: 24 (37%) had PD-L1-positive tumors. Analysis indicated that PD-L1 status, TILs, TMB, and genomic alterations were not associated with PFS., Conclusions and Relevance: In this randomized clinical trial of patients with HR-positive, ERBB2-negative MBC, the addition of pembrolizumab to eribulin did not improve PFS, ORR, or OS compared with eribulin alone in either the intention-to-treat or PD-L1-positive populations. Further efforts to explore the benefits of adding checkpoint inhibition to chemotherapy among less heavily pretreated patients are needed., Trial Registration: ClinicalTrials.gov Identifier: NCT03051659.

Published
2020
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49. Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression.

Author

Bustoros M, Sklavenitis-Pistofidis R, Park J, Redd R, Zhitomirsky B, Dunford AJ, Salem K, Tai YT, Anand S, Mouhieddine TH, Chavda SJ, Boehner C, Elagina L, Neuse CJ, Cha J, Rahmat M, Taylor-Weiner A, Van Allen E, Kumar S, Kastritis E, Leshchiner I, Morgan EA, Laubach J, Casneuf T, Richardson P, Munshi NC, Anderson KC, Trippa L, Aguet F, Stewart C, Dimopoulos MA, Yong K, Bergsagel PL, Manier S, Getz G, and Ghobrial IM

Subjects
Adult, Aged, Aged, 80 and over, Disease Progression, Female, Humans, Male, Middle Aged, Risk Factors, Genomics methods, High-Throughput Nucleotide Sequencing methods, Smoldering Multiple Myeloma genetics
Abstract

Purpose: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models., Methods: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors., Results: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53 , and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort., Conclusion: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.

Published
2020
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50. Cancer Moonshot Immuno-Oncology Translational Network (IOTN): accelerating the clinical translation of basic discoveries for improving immunotherapy and immunoprevention of cancer.

Author

Annapragada A, Sikora A, Bollard C, Conejo-Garcia J, Cruz CR, Demehri S, Demetriou M, Demirdjian L, Fong L, Horowitz M, Hutson A, Kadash-Edmondson K, Kufe D, Lipkin S, Liu S, McCarthy C, Morgan M, Morris Z, Pan Y, Pasquini M, Schoenberger S, Van Allen E, Vilar E, Xing Y, Zha W, and Odunsi A

Subjects
Humans, Immunotherapy methods, Medical Oncology organization & administration, Neoplasms drug therapy, Neoplasms immunology
Abstract

Despite regulatory approval of several immune-based treatments for cancer in the past decade, a number of barriers remain to be addressed in order to fully harness the therapeutic potential of the immune system and provide benefits for patients with cancer. As part of the Cancer Moonshot initiative, the Immuno-Oncology Translational Network (IOTN) was established to accelerate the translation of basic discoveries to improve immunotherapy outcomes across the spectrum of adult cancers and to develop immune-based approaches that prevent cancers before they occur. The IOTN currently consists of 32 academic institutions in the USA. By leveraging cutting-edge preclinical research in immunotherapy and immunoprevention, open data and resource sharing, and fostering highly collaborative team science across the immuno-oncology ecosystem, the IOTN is designed to accelerate the generation of novel mechanism-driven immune-based cancer prevention and therapies, and the development of safe and effective personalized immuno-oncology approaches., Competing Interests: Competing interests: AA is a board member and receives research grant from Alzeca. He is also a stockholder of Alzeca, Sensulin LLC., and Abbott Laboratories. AS receives grant funds from Tessa Therapeutics and Heat/Pelican Therapeutics, and serves on the data safety monitoring board of a Phase III clinical trial by Tessa Therapeutics. CB serves consulting or advisory role to Cellectis and Mana Therapeutics, and holds stock options or other ownership of Mana Therapeutics, Torque, Neximmune, and Cabaletta Bio. JC-G receives research supports, holds stock options and severs as member of the ethics advisory board to Compass Therapeutics and Anixa Biosciences. CRC is a cofounder of Mana Therapeutics, a biotechnology company developing T cell-based therapies for cancer. MD is an inventor on a patent that describes glycan-targeting bispecific proteins and CAR cells for cancer immunotherapy, and is a cofounder of GlyTR Therapeutics. LF receives research support from Abbvie, Bavarian Nordic, BMS, Dendreon, Janssen, Merck, and Roche/Genentech. DK has equity interests in Genus Oncology, Reata Pharmaceuticals, Hillstream BioPharma, Nanogen Therapeutics, and Victa BioTherapeutics. He also serves as a member of the board of directors of Nanogen and Victa, and is a paid consultant to Reata, CanBas and Victa. ZM receives research agreements/material support from BMS, AstraZeneca, Archeus Technologies, and Seneca Therapeutics, and is on the scientific advisory board to Archeus Technologies and Seneca Therapeutics. He also has patents filed in in situ Immune Modulated Cancer Vaccination, using targeted radiotherapy and bacterial membrane nanoparticles in immunotherapies, and multipurpose catheter for brachytherapy and intratumoral injection. EVA holds an advisory/consulting role to Tango Therapeutics, Genome Medical, Invitae, Illumina, and is an equity holder of Tango Therapeutics, Genome Medical, Syapse, Ervaxx, and Microsoft. He receives research support from Novartis and BMS, and travel reimbursement from Roche/Genentech. He also has institutional patents filed on ERCC2 mutations and chemotherapy response, chromatin mutations and immunotherapy response, and methods for clinical interpretation. EV has a consulting or advisory role with Janssen Research and Development and TFS Oncology. AO is a cofounder of Tactiva Therapeutics, a biotechnology company developing T cell-based therapies for cancer, receives research support from Astra Zeneca and Tessaro. YX is a scientific cofounder of Panorama Medicine., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Published
2020
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