CANCER DISCOVERY · CANCER DISCOVERY CONTENTS ii | CANCER DISCOVERY September 2017 September 2017...
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CANCER DISCOVERY CONTENTS ii | CANCER DISCOVERY SEPTEMBER 2017 www.aacrjournals.org SEPTEMBER 2017 ≠ VOLUME 7 ≠ NUMBER 9 New Horizons for Precision Medicine in Biliary Tract Cancers 943 JW Valle, A Lamarca, L Goyal, J Barriuso, and AX Zhu A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid Tumors 963 A Drilon, R Nagasubramanian, JF Blake, N Ku, BB Tuch, K Ebata, S Smith, V Lauriault, GR Kolakowski, BJ Brandhuber, PD Larsen, KS Bouhana, SL Winski, R Hamor, W-I Wu, A Parker, TH Morales, FX Sullivan, WE DeWolf, LA Wollenberg, PR Gordon, DN Douglas-Lindsay, M Scaltriti, R Benayed, S Raj, B Hanusch, AM Schram, P Jonsson, MF Berger, JF Hechtman, BS Taylor, S Andrews, SM Rothenberg, and DM Hyman Précis: Parallel development of the first-generation TRK TKI larotrectinib with the next-generation TKI LOXO-195 allowed for rapid use of LOXO-195 to treat patients with acquired larotrectinib resistance See commentary, p. 934 Exome Sequencing of African-American Prostate Cancer Reveals Loss-of- Function ERF Mutations 973 FW Huang, JM Mosquera, A Garofalo, C Oh, M Baco, A Amin-Mansour, B Rabasha, S Bahl, SA Mullane, BD Robinson, S Aldubayan, F Khani, B Karir, E Kim, J Chimene-Weiss, M Hofree, A Romanel, JR Osborne, JW Kim, G Azabdaftari, A Woloszynska-Read, K Sfanos, AM De Marzo, F Demichelis, S Gabriel, EM Van Allen, J Mesirov, P Tamayo, MA Rubin, IJ Powell, and LA Garraway Précis: Sequencing of an African-American prostate cancer cohort identified ERF as a tumor suppressor in prostate cancer and shows that increasing ethnic diversity enhances the discovery of potential cancer drivers REVIEW RESEARCH BRIEFS Highlighted research articles 920 Important news stories affecting the community 924 Why First-Line Nivolumab Is No Better than Chemo 927 Taking the Guesswork Out of Stopping TKIs 928 Selected highlights of recent articles of exceptional significance from the cancer literature 929 For more News and Research Watch, visit Cancer Discovery online at http://cancerdiscoveryaacrjournalsorg/ content/early/by/section In The Spotlight Fast-TRKing Drug Development for Rare Molecular Targets 934 AR Parikh and RB Corcoran See article, p. 963 Reversion Mutations with Clinical Use of PARP Inhibitors: Many Genes, Many Versions 937 SM Domchek See article, p. 984 See article, p. 999 See article, p. 1006 Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap 940 A Lakshmanan and JC Byrd See article, p. 1018 IN THIS ISSUE NEWS IN BRIEF NEWS IN DEPTH RESEARCH WATCH ONLINE VIEWS Cancer Research. on August 12, 2020. © 2017 American Association for cancerdiscovery.aacrjournals.org Downloaded from
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CANCER DISCOVERY contents
ii | CANCER DISCOVERY September 2017 www.aacrjournals.org
September 2017 ≠ Volume 7 ≠ Number 9
New Horizons for Precision Medicine in Biliary Tract Cancers . . . . . . . . . . . . 943J .W . Valle, A . Lamarca, L . Goyal, J . Barriuso, and A .X . Zhu
A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid Tumors . . . 963A . Drilon, R . Nagasubramanian, J .F . Blake, N . Ku, B .B . Tuch, K . Ebata, S . Smith, V . Lauriault, G .R . Kolakowski, B .J . Brandhuber, P .D . Larsen, K .S . Bouhana, S .L . Winski, R . Hamor, W .-I Wu, A . Parker, T .H . Morales, F .X . Sullivan, W .E . DeWolf, L .A . Wollen berg, P .R . Gordon, D .N . Douglas-Lindsay, M . Scaltriti, R . Benayed, S . Raj, B . Hanusch, A .M . Schram, P . Jonsson, M .F . Berger, J .F . Hechtman, B .S . Taylor, S . Andrews, S .M . Rothenberg, and D .M . HymanPrécis: Parallel development of the first-generation TRK TKI larotrectinib with the next-generation TKI LOXO-195 allowed for rapid use of LOXO-195 to treat patients with acquired larotrectinib resistance . See commentary, p. 934
Exome Sequencing of African-American Prostate Cancer Reveals Loss-of- Function ERF Mutations . . . . . . . .973F .W . Huang, J .M . Mosquera, A . Garofalo, C . Oh, M . Baco, A . Amin-Mansour, B . Rabasha, S . Bahl, S .A . Mullane, B .D . Robinson, S . Aldubayan, F . Khani, B . Karir, E . Kim, J . Chimene-Weiss, M . Hofree, A . Romanel, J .R . Osborne, J .W . Kim, G . Azabdaftari, A . Woloszynska-Read, K . Sfanos, A .M . De Marzo, F . Demichelis, S . Gabriel, E .M . Van Allen, J . Mesirov, P . Tamayo, M .A . Rubin, I .J . Powell, and L .A . GarrawayPrécis: Sequencing of an African-American prostate cancer cohort identified ERF as a tumor suppressor in prostate cancer and shows that increasing ethnic diversity enhances the discovery of potential cancer drivers .
review
research Briefs
Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . 920
Important news stories affecting the community . . . . . . . . . 924
Why First-Line Nivolumab Is No Better than Chemo . . . . . . . 927Taking the Guesswork Out of Stopping TKIs . . . . . . . . . . . . . . . 928
Selected highlights of recent articles of exceptional significance from the cancer literature . . . . . . . . . . . . . 929
For more News and Research Watch, visit Cancer Discovery online at http://cancerdiscovery .aacrjournals .org/content/early/by/section .
in The spotlight
Fast-TRKing Drug Development for Rare Molecular Targets . . . . 934A .R . Parikh and R .B . Corcoran
See article, p. 963
Reversion Mutations with Clinical Use of PARP Inhibitors: Many Genes, Many Versions . . . . . . . . . 937S .M . Domchek
See article, p. 984See article, p. 999See article, p. 1006
Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap . . . . . . . . . . . . . 940A . Lakshmanan and J .C . Byrd
See article, p. 1018
in This issue
news in Brief
news in DePTh
research waTch
Online
views
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September 2017 CANCER DISCOVERY | iii
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Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma . . . . . . . 984O . Kondrashova, M . Nguyen, K . Shield-Artin, A .V . Tinker, N .N .H . Teng, M .I . Harrell, M .J . Kuiper, G .-Y . Ho, H . Barker, M . Jasin, R . Prakash, E .M . Kass, M .R . Sullivan, G .J . Brunette, K .A . Bernstein, R .L . Coleman, A . Floquet, M . Friedlander, G . Kichenadasse, D .M . O’Malley, A . Oza, J . Sun, L . Robillard, L . Maloney, D . Bowtell on behalf of the AOCS Study Group, H . Giordano, M .J . Wakefield, S .H . Kaufmann, A .D . Simmons, T .C . Harding, M . Raponi, I .A . McNeish, E .M . Swisher, K .K . Lin, and C .L . ScottPrécis: In patients with high-grade ovarian carcinoma treated with the PARP inhibitor rucaparib, secondary reversion mutations in HR genes restore the open reading frame and HR activity to confer resistance . See commentary, p. 937See article, p. 999See article, p. 1006
Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors . . . . . . . . 999D . Quigley, J .J . Alumkal, A .W . Wyatt, V . Kothari, A . Foye, P . Lloyd, R . Aggarwal, W . Kim, E . Lu, J . Schwartzman, K . Beja, M . Annala, R . Das, M . Diolaiti, C . Pritchard, G . Thomas, S . Tomlins, K . Knudsen, C .J . Lord, C . Ryan, J . Youngren, T .M . Beer, A . Ashworth, E .J . Small, and F .Y . FengPrécis: Multiclonal BRCA2 reversion mutations were detected in circulating cell-free DNA from two patients with metastatic prostate cancer after PARP inhibitor treatment, suggesting a mechanism of resistance . See commentary, p. 937See article, p. 984See article, p. 1006
Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition . . . . . . . . . . . . . . . . . . . . . . 1006J . Goodall, J . Mateo, W . Yuan, H . Mossop, N . Porta, S . Miranda, R . Perez-Lopez, D . Dolling, D .R . Robinson, S . Sandhu, G . Fowler, B . Ebbs, P . Flohr, G . Seed,
research arTicles
D . Nava Rodrigues, G . Boysen, C . Bertan, M . Atkin, M . Clarke, M . Crespo, I . Figueiredo, R . Riisnaes, S . Sumanasuriya, P . Rescigno, Z . Zafeiriou, A . Sharp, N . Tunariu, D . Bianchini, A . Gillman, C .J . Lord, E . Hall, A .M . Chinnaiyan, S . Carreira, and J .S . de Bono for the TOPARP-A investigatorsPrécis: Sequencing cfDNA from patients with olaparib-treated prostate cancer reveals that reduced cfDNA is a biomarker of response and can harbor resistance mutations that may guide treatment .See commentary, p. 937See article, p. 984See article, p. 999
Ibrutinib Unmasks Critical Role of Bruton Tyro sine Kinase in Primary CNS Lymphoma . . . . . . . . . . . . .1018C . Grommes, A . Pastore, N . Palaskas, S .S . Tang, C . Campos, D . Schartz, P . Codega, D . Nichol, O . Clark, W .-Y . Hsieh, D . Rohle, M . Rosenblum, A . Viale, V .S . Tabar, C .W . Brennan, I .T . Gavrilovic, T .J . Kaley, C .P . Nolan, A . Omuro, E . Pentsova, A .A . Thomas, E . Tsyvkin, A . Noy, M .L . Palomba, P . Hamlin, C .S . Sauter, C .H . Moskowitz, J . Wolfe, A . Dogan, M . Won, J . Glass, S . Peak, E .C . Lallana, V . Hatzoglou, A .S . Reiner, P .H . Gutin, J .T . Huse, K .S . Panageas, T .G . Graeber, N . Schultz, L .M . DeAngelis, and I .K . MellinghoffPrécis: The BTK inhibitor ibrutinib has activity in patients with relapsed or refractory B-cell lymphomas of the CNS, and dual treatment with PI3K/mTOR inhibitors may enhance ibrutinib efficacy in patients with CD79B-mutant tumors . See commentary, p. 940
Discovery and Optimization of HKT288, a Cadherin-6–Targeting ADC for the Treat ment of Ovarian and Renal Cancers . . . . . . . . . . . . . . . . . . . 1030C .U . Bialucha, S .D . Collins, X . Li, P . Saxena, X . Zhang, C . Dürr, B . Lafont, P . Prieur, Y . Shim, R . Mosher, D . Lee, L . Ostrom, T . Hu, S . Bilic, I .L . Rajlic, V . Capka, W . Jiang, J .P . Wagner, G . Elliott, A . Veloso, J .C . Piel, M .M . Flaherty, K .G . Mansfield, E .K . Meseck, T . Rubic-Schneider, A .S . London, W .R . Tschantz, M . Kurz, D . Nguyen, A . Bourret, M .J . Meyer, J .E . Faris, M .J . Janatpour, V .W . Chan, N .C . Yoder, K .C . Catcott, M .A . McShea, X . Sun, H . Gao, J . Williams, F . Hofmann, J .A . Engelman, S .A . Ettenberg, W .R . Sellers, and E . LeesPrécis: The CDH6-targeting antibody–drug conjugate HKT288 causes regression of patient-derived xenografts of CDH6-overexpressing ovarian and renal cancers .
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CANCerDISCoVerY CONTENTS
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PARP inhibitors (PARPi) have demonstrated activity in patients with mutations in homologous recombination (HR) genes such as BRCA1 and BRCA2 . Three related studies identified HR gene reversion mutations that confer resistance to PARPi . Kondrashova and colleagues discovered secondary reversion mutations in BRCA1, RAD51C, and RAD51D in patients with PARPi-resistant ovarian cancer . Similarly, Quigley, Alumkal, and colleagues identified BRCA2 reversion mutations associated with PARPi resistance in circulating cell-free DNA (cfDNA) from two patients with prostate cancer . Finally, Goodall, Mateo, and colleagues found secondary reversion mutations in BRCA2 and PALB2 in cfDNA from patients with PARPi-resistant met-astatic prostate cancer . Together, these studies demonstrate that HR gene rever-sion mutations can promote resistance to PARPi . For details, please see the article by Kondrashova and colleagues on page 984, the article by Quigley, Alumkal, and colleagues on page 999, and the article by Goodall, Mateo, and colleagues on page 1006 .
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