See article, p. 575

  • A patient with breast cancer harboring the HER2L869R mutation initially responded to neratinib.

  • HER2T798I acquisition promoted neratinib resistance, but cells remained sensitive to afatinib in vitro.

  • Patients with HER2L869R/T798I tumors may respond to afatinib even after neratinib resistance develops.


The receptor tyrosine kinase HER2 (also known as ERBB2) is subject to activating mutations in a subset of breast cancers. Irreversible EGFR/HER2 tyrosine kinase inhibitors including neratinib and afatinib have demonstrated preclinical activity against HER2-mutant tumors and clinical trials are ongoing. Hanker and colleagues identified a HER2 kinase domain mutation (HER2L869R) in a patient with estrogen receptor–positive, progesterone receptor–positive lobular breast carcinoma through targeted capture next-generation sequencing (NGS) of DNA from a skin metastasis. Structural modeling predicted that the HER2L869R mutation would destabilize the inactive kinase conformation to activate HER2. The patient also harbored an ERBB3E928G mutation, and the dimerization of HER2L869R and ERBB3E928G enhanced HER2 signaling. Consistent with these findings, HER2L869R expression transformed MCF10A breast epithelial cells, and neratinib blocked the activity of HER2L869R. Based on these findings, the patient was enrolled in a clinical trial to receive single-agent neratinib and exhibited an excellent clinical response. The patient eventually progressed on neratinib, and NGS detected an acquired HER2T798I mutation. Computational models predicted that this mutation would result in steric hindrance to reduce neratinib binding. Indeed, the T798I mutation reduced HER2 stability and rendered HER2L869R-transformed cells refractory to neratinib, suggesting that neratinib treatment selects for the HER2T798I mutation to promote neratinib resistance. HER2L869R/T798Icells that had developed resistance to neratinib showed sensitivity to afatinib. In addition to identifying HER2T798I as an acquired neratinib-resistant mutation, these results suggest that patients with this mutation may respond to afatinib.

See article, p. 586

  • Clinical outcomes were evaluated in patients with advanced solid tumors treated with matched therapies.

  • Matched therapy improved progression-free survival compared with previous therapy in 33% of patients.

  • Using genomics analyses to select targeted therapies may benefit patients with advanced cancer.


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

See article, p. 596

  • Mutational profiling discovers targetable alterations in patients with advanced lung carcinoma.

  • Genomic alteration–matched therapies produced clinical benefit in 78.1% of patients.

  • Early genomic testing identifies targeted therapies that may improve outcomes in patients with cancer.


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

See article, p. 610

  • Encorafenib plus cetuximab with or without alpelisib is tolerable in patients with colorectal cancer.

  • Dual RAF/EGFR and triple RAF/EGFR/PI3Kα targeting achieves responses in BRAF-mutant tumors.

  • Encorafenib and cetuximab combination therapies warrant further study in patients with BRAF-mutant tumors.


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

See article, p. 620

  • The PARP inhibitor talazoparib is active against BRCA-mutant tumors and some pancreatic and lung tumors.

  • Talazoparib induces sustained PARP inhibition in a phase I dose-escalation and dose-expansion trial.

  • Single-agent talazoparib may be effective in patients with BRCA-mutant breast or ovarian cancer.


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

See article, p. 630

  • Gastric cancers contain somatic promoter alterations that upregulate tumor-specific isoforms.

  • Alternative promoter use results in downregulation of immunogenic N-terminal peptides.

  • Tumor-specific alternative promoters may reduce tumor antigenicity to promote tumor immune evasion.


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

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