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The HER2T798I Mutation Promotes Acquired Resistance to Neratinib

• A patient with breast cancer • HER2 T798I acquisition promoted • Patients with HER2L869R/T798I tumors harboring the HER2L869R mutation neratinib resistance, but cells remained may respond to afatinib even after initially responded to neratinib. sensitive to afatinib in vitro. neratinib resistance develops.

The receptor tyrosine kinase Consistent with these findings, HER2L869R expression trans- HER2 (also known as ERBB2) is formed MCF10A breast epithelial cells, and neratinib blocked subject to activating mutations the activity of HER2L869R. Based on these findings, the patient in a subset of breast cancers. was enrolled in a clinical trial to receive single-agent neratinib Irreversible EGFR/HER2 tyros- and exhibited an excellent clinical response. The patient even- ine kinase inhibitors includ- tually progressed on neratinib, and NGS detected an acquired ing neratinib and afatinib have HER2T798I mutation. Computational models predicted that demonstrated preclinical activity this mutation would result in steric hindrance to reduce ner- against HER2-mutant tumors atinib binding. Indeed, the T798I mutation reduced HER2 and clinical trials are ongoing. stability and rendered HER2L869R-transformed cells refrac- Hanker and colleagues identified aHER2 kinase domain tory to neratinib, suggesting that neratinib treatment selects mutation (HER2L869R) in a patient with estrogen receptor– for the HER2T798I mutation to promote neratinib resistance. positive, progesterone receptor–positive lobular breast carci- HER2L869R/T798I cells that had developed resistance to ner- noma through targeted capture next-generation sequencing atinib showed sensitivity to afatinib. In addition to identify- (NGS) of DNA from a skin metastasis. Structural modeling ing HER2T798I as an acquired neratinib-resistant mutation, predicted that the HER2L869R mutation would destabilize the these results suggest that patients with this mutation may inactive kinase conformation to activate HER2. The patient respond to afatinib. n also harbored an ERBB3E928G mutation, and the dimerization of HER2L869R and ERBB3E928G enhanced HER2 signaling. See article, p. 575.

High-Throughput Genomics Identifies Actionable Therapeutic Targets

• Clinical outcomes were evaluated in • Matched therapy improved progres- • Using genomics analyses to select patients with advanced solid tumors sion-free survival compared with targeted therapies may benefit treated with matched therapies. previous therapy in 33% of patients. patients with advanced cancer.

Targeted therapies such as in 411 (49%) patients, and 199 patients were treated with a ALK and EGFR inhibitors have genomic alteration–matched therapy. The primary objective had clinical success in a small was to evaluate the clinical benefit, assessed by a greater than subset of patients with solid 1.3-fold increase in progression-free survival on matched metastatic tumors, but action- therapy (PFS2) compared with PFS on prior therapy (PFS1). able mutations are uncommon. The PFS2/PFS1 ratio was greater than 1.3 in 63 of 193 (33%) To determine if high-throughput evaluable patients, indicating that matched therapy was ben- genomic analyses could identify eficial in some patients. Objective responses were observed targetable alterations to improve in 22 of 194 patients (11%). A complete response occurred outcomes in patients with “hard- in a patient with FBXW7-mutant breast cancer treated with to-treat” advanced cancers, Massard and colleagues per- a NOTCH inhibitor and in a patient with HER+ biliary formed a single-arm prospective clinical trial evaluating the cancer treated with trastuzumab and chemotherapy, and 20 clinical benefit of testing a large panel of genes. In total, 1,035 patients achieved partial responses. These findings suggest patients with locally advanced or metastatic solid tumors that high-throughput genomics might identify targetable were enrolled, a successful tumor biopsy was obtained from alterations to improve outcomes in patients with hard-to- 948 patients, and a molecular portrait was obtained from treat cancers. n 843 patients by targeted sequencing and/or array compara- tive genomic hybridization. Actionable targets were found See article, p. 586.

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Molecular Profiling of Lung Tumors Identifies Actionable Alterations

• Mutational profiling discovers tar- • Genomic alteration–matched thera- • Early genomic testing identifies targetable alterations in patients with pies produced clinical benefit in geted therapies that may improve advanced lung carcinoma. 78.1% of patients. outcomes in patients with cancer.

In patients with advanced lung (e.g., EGFR mutations), biomarkers FDA-approved for other adenocarcinoma, tumor genetic cancer indications (e.g., ERBB2 amplification), and altera- testing can identify actionable tions with compelling clinical or preclinical evidence sup- alterations, but the proportion of porting use as a biomarker. Overall, 249 patients (78.1%) patients who benefit is not clear. derived clinical benefit from matched therapy, and, of the Jordan and colleagues developed patients receiving non–standard-of-care therapies, 36 of 69 a hybridization capture–based patients (52%) derived clinical benefit, suggesting that the next-generation sequencing plat- use of matched therapies may be limited by lack of access form, termed the Memorial Sloan to FDA-approved drugs. In 103 patients no potentially Kettering-Integrated Mutation actionable alterations were identified. However, mutations Profiling of Actionable Cancer Targets (MSK-IMPACT), to in several genes including STK11 and KEAP1 occurred more comprehensively profile somatic alterations in more than frequently than in tumors with alterations in known onco- 300 cancer-associated genes in matched normal and tumor genic drivers, indicating that STK11 and KEAP1 may be DNA. Of 860 patients with recurrent or metastatic lung targetable mitogenic drivers. Collectively, these findings adenocarcinoma analyzed with MSK-IMPACT, potentially support the use of early genomic testing to identify targeted actionable somatic mutations were identified in 747 (86.9%) therapies that may improve clinical outcomes in patients patients, and 319 (37.1%) patients were treated with matched with cancer. n therapy. Actionable mutations included FDA-approved or standard-of-care biomarkers in patients with lung cancer See article, p. 596.

Encorafenib Plus Cetuximab Is Active in BRAF-Mutant Colorectal Cancer

• Encor afenib plus cetuximab with or • Dual RAF/EGFR and triple RAF/ • Encor afenib and cetuximab combina- without alpelisib is tolerable in EGFR/PI3Kα targeting achieves tion therapies warrant further study in patients with colorectal cancer. responses in BRAF-mutant tumors. patients with BRAF-mutant tumors.

In patients with colorectal the maximum tolerated or recommended phase II dose. The cancer BRAF mutations includ- maximum tolerated dose was not reached; dual- and triple- ing BRAFV600E are associated with combination therapy was tolerable at the recommended a poor prognosis and limited phase II dose, and similar adverse events were observed in the responses to the BRAF inhibitors dual- and triple-combination groups. The overall response vemurafenib and dabrafenib. rate was 19% in the dual-combination group, with 1 complete However, preclinical studies and 4 partial responses, and 18% in the triple-combination have demonstrated that selective group, with 5 partial responses. The median response dura- BRAFV600E inhibitors promote tion was 46 weeks in the dual-combination group and 12 EGFR-mediated reactivation of weeks in the triple-combination group. Median progression- MAPK signaling; thus, combined inhibition of EGFR and free survival was 3.7 months for dual-combination therapy BRAF may be more effective. Van Geel, Tabernero, and col- and 4.2 months for triple-combination therapy. Altogether, leagues performed a phase Ib dose-escalation study of the these findings suggest that dual-combination (encorafenib RAF inhibitor encorafenib in dual combination therapy with plus cetuximab) and triple-combination (encorafenib plus the EGFR inhibitor cetuximab and in triple combination cetuximab plus alpelisib) therapy is tolerable and has antitu- therapy with the PI3Kα inhibitor alpelisib. A total of 54 mor activity in patients with BRAF-mutant colorectal cancer, patients with BRAF-mutant colorectal cancer were enrolled; supporting further clinical investigation. n 26 received dual-combination therapy and 28 received triple- combination therapy. The primary objective was to determine See article, p. 610.

540 | CANCER DISCOVERY JUNE 2017 www.aacrjournals.org

Talazoparib Is Well Tolerated and Has Single-Agent Antitumor Activity

• The PARP inhibitor talazoparib is • Talazoparib induces sustained PARP • Single-agent talazoparib may be active against BRCA-mutant tumors inhibition in a phase I dose-escala- effective in patients with BRCA- and some pancreatic and lung tumors. tion and dose-expansion trial. mutant breast or ovarian cancer.

The poly(ADP-ribose) poly- dose-expansion study treating 110 patients with advanced solid merase enzymes (PARP1/2) are tumors. Talazoparib was well tolerated at the determined rec- involved in DNA single-strand ommended phase II dose, although 45% of patients experi- break repair through the base enced grade 3 or 4 adverse events. Sustained PARP inhibition excision repair pathway. PARP occurred, and objective responses were observed in 12 of 26 deficiency leads to double strand (46%) patients with breast or ovarian cancer, all of whom had breaks that can usually be repaired germline BRCA1/2 mutations, including 2 complete and 10 by homologous recombination partial responses. Objective responses were also achieved in 2 repair (HRR); however, BRCA1/2 of 23 (8.7%) patients with small cell lung cancer (SCLC) and 2 mutations compromise HRR, of 10 (20%) patients with pancreatic cancer, but no responses resulting in synthetic lethality. The PARP inhibitor olaparib has were observed in patients with Ewing sarcoma. Collectively, been approved for the treatment of advanced ovarian cancer, these findings demonstrate that talazoparib is safe and exhibits and a next-generation PARP inhibitor, talazoparib, selectively single-agent antitumor activity in patients with BRCA-mutant and potently inhibits PARP1 and PARP2 at lower concentrations breast and ovarian cancer as well as pancreatic cancer and SCLC, than earlier PARP inhibitors, supporting its clinical investiga- supporting its further investigation in ongoing clinical trials. n tion. De Bono and colleagues evaluated the safety and activity of talazoparib in an open-label phase I dose-escalation and See article, p. 620.

Alternative Promoters May Promote Immune Evasion in Gastric Cancer

• Gastric cancers contain somatic • Alternativ e promoter use results in • Tumor-specific alternative promot- promoter alterations that upregu- downregulation of immunogenic ers may reduce tumor antigenicity late tumor-specific isoforms. N-terminal peptides. to promote tumor immune evasion.

Alternative gene promoters suggested that these promoters may be deregulated in other can produce oncogenic variant solid epithelial tumors. Of the gastric cancer somatic pro- isoforms in cancer. However, moters, 18% represented alternative promoters, and RNA global promoter diversity has sequencing confirmed the overexpression of corresponding not been well studied in gastric alternative transcript isoforms in gastric cancer. These alter- cancer, prompting Qamra and native promoters gave rise to a number of proteins with colleagues to investigate global altered N-terminal protein sequences, and thus may promote promoter alterations. Analysis of proteomic diversity in gastric cancer. Alternative somatic pro- 17 gastric tumors and matched moter usage was associated with reduced tumor immunity, normal gastric mucosae, as well and N-terminal peptides downregulated by somatic promot- as 13 gastric cancer cell lines, identified unaltered promoters ers in gastric cancer exhibited immune responses, suggesting (e.g., RHOA), somatic tumor-specific promoters gained in that the tumor-specific promoters may reduce tumor immu- tumors (e.g., CEACAM6), or normal-specific promoters lost in nogenicity. These promoters were also enriched for EZH2 tumors (e.g., ATP4A), and the epigenomic promoter profiles and sensitive to EZH2 inhibition. The characterization of the distinguished normal gastric epithelia from gastric tumors. promoter landscape in gastric cancer reveals tumor-specific The gained and lost somatic promoters were associated with alternative promoters that may generate tumor-specific iso- increased and decreased gene expression, respectively. Fur- forms to promote tumor immune evasion. n ther, analysis of data from The Cancer Genome Atlas (TCGA) validated the somatic promoters in gastric cancer, and also See article, p. 630.

In This Issue is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details.

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Cancer Discov 2017;7:539-541.

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