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Background: Changes in the clinical subtype (CS) and intrinsic subtype (IS) between breast cancer (BC) metastases and corresponding primary tumours have been reported. However, their relationship with tumour genomic changes remains poorly characterised. Here, we analysed the association between genomic remodelling and subtype conversion in paired primary and metastatic BC samples., Methods: A total of 57 paired primary and metastatic tumours from GEICAM/2009-03 (ConvertHER, NCT01377363) study participants with centrally assessed CS (n = 57) and IS (n = 46) were analysed. Targeted capture and next-generation sequencing of 202 genes on formalin-fixed paraffin-embedded samples was performed. The cancer cell fraction (CCF) of mutations in primary and metastatic pairs was estimated as a surrogate of tumour clonal architecture. Changes in mutation CCF between matched primary and metastatic tumours were analysed in the presence or absence of subtype conversion., Findings: CS conversion occurred in 24.6% and IS conversion occurred in 36.9% of metastases. Primary tumours and metastases had a median of 11 (range, 3-29) and 9 (range, 1-38) mutations, respectively (P = 0.05). Overall, mutations in metastases showed a higher estimated CCF than in primary tumours (median CCF, 0.51 and 0.47, respectively; P = 0.042), consistent with increased clonal homogeneity. The increase in mutation CCF was significant in CS-converted (P = 0.04) but not in IS-converted (P = 0.48) metastases. Clonal remodelling was highest in metastases from hormone receptor-positive and human epidermal growth factor 2 (HER2)-positive tumours (P = 0.006)., Conclusions: Mutations in BC metastases showed significantly higher estimated CCF than primary tumours. CCF changes were more prominent in metastases with CS conversion. Our findings suggest that changes in BC subtypes are linked to clonal remodelling during BC evolution., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

HER2 mutations have been reported in approximately 2% of breast cancers. Regardless of HER2 overexpression or amplification status, breast cancer with HER2 mutations may respond to HER2-targeted therapy. As HER2 mutation is rare, the clinical and pathological features of HER2-mutated breast cancers, such as hormonal status, histological grade, and metastasis, remain poorly defined. Therefore, the identification of HER2-mutated breast cancer has clinical significance. We retrospectively screened patients with metastatic breast cancer in whom molecular profiling had been performed using next-generation sequencing from 2012 to 2015; we identified 18 patients with HER2 mutation. Mutations were found on next-generation sequencing-based panels, including Ion AmpliSeq Cancer Hotspot, Oncomine, FoundationOne, and Guardant360. HER2 mutations were identified in both the tyrosine kinase (n = 14) and extracellular (n = 4) domains. Of the 14 cases with tyrosine kinase domain mutations, 13 were estrogen receptor positive; the 4 cases with extracellular domain mutations were exclusively estrogen receptor negative. In addition, 11 of 14 patients with tyrosine kinase domain mutations had bone metastasis, whereas no patients with HER2 extracellular domain mutations had bone metastasis. Histologically, 13 patients had invasive ductal carcinoma, 1 had metaplastic carcinoma, and 4 had invasive lobular carcinoma (ILC). All 4 ILCs were high grade and pleomorphic, and not only had an HER2 mutation in the kinase domain but also had an HER2 mutation involving the L755 site. Specific mutation sites may be involved in the pathogenesis of nonclassic ILC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Fibroblast growth factor receptor (FGFR) 2 is overexpressed in several tumor types, including triple-negative breast cancer and gastric cancer, both of which have a high unmet medical need. Aprutumab ixadotin (BAY 1187982) is the first antibody-drug conjugate (ADC) to target FGFR2 and the first to use a novel auristatin-based payload., Objective: This first-in-human trial was conducted to determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin in patients with advanced solid tumors from cancer indications known to be FGFR2-positive., Patients and Methods: In this open-label, multicenter, phase I dose-escalation trial (NCT02368951), patients with advanced solid tumors received escalating doses of aprutumab ixadotin (starting at 0.1 mg/kg body weight), administered intravenously on day 1 of every 21-day cycle. Primary endpoints included safety, tolerability, and the MTD of aprutumab ixadotin; secondary endpoints were pharmacokinetic evaluation and tumor response to aprutumab ixadotin., Results: Twenty patients received aprutumab ixadotin across five cohorts, at doses of 0.1-1.3 mg/kg. The most common grade ≥ 3 drug-related adverse events were anemia, aspartate aminotransferase increase, proteinuria, and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia, proteinuria, and corneal epithelial microcysts, and were only seen in the two highest dosing cohorts. The MTD was determined to be 0.2 mg/kg due to lack of quantitative data following discontinuations at 0.4 and 0.8 mg/kg doses. One patient had stable disease; no responses were reported., Conclusions: Aprutumab ixadotin was poorly tolerated, with an MTD found to be below the therapeutic threshold estimated preclinically; therefore, the trial was terminated early. CLINICALTRIALS., Gov Identifier: NCT02368951.

Purpose: Cell-free DNA (cfDNA) next-generation sequencing is a noninvasive approach for genomic testing. We report the frequency of identifying alterations and their clinical actionability in patients with advanced/metastatic cancer., Patients and Methods: Prospectively consented patients had cfDNA testing performed. Alterations were assessed for therapeutic implications., Results: We enrolled 575 patients with 37 tumor types. Of these patients, 438 (76.2%) had at least one alteration detected, and 205 (35.7%) had one or more alterations of high potential for clinical action. In diseases with 10 or more patients enrolled, 50% or more had at least one alteration deemed of high potential for clinical action. Trials were identified in 80% of patients (286 of 357) with any alteration and in 92% of patients (188 of 205) with one or more alterations of high potential for clinical action of whom 57.6% (118 of 205) had 6 or more months of follow-up available. Of these patients, 10% (12 of 118) had received genomically matched therapy through enrollment in clinical trials (n = 8), off-label drug use (n = 3), or standard of care (n = 1). Although 88.6% of all patients had a performance status of 0 or 1 upon enrollment, the primary reason for not acting on alterations was poor performance status at next treatment change (28.1%; 27 of 96)., Conclusion: cfDNA testing represents a readily accessible method for genomic testing and allows for detection of genomic alterations in most patients with advanced disease. Utility may be higher in patients interested in investigational therapeutics with adequate performance status. Additional study is needed to determine whether utility is enhanced by testing earlier in the treatment course., Competing Interests: 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). Nora S. SánchezEmployment: Foundation Medicine Stock and Other Ownership Interests: RocheAnn Marie BaileyEmployment: QIAGEN Travel, Accommodations, Expenses: QIAGENKavitha BalajiEmployment: Lexicon Stock and Other Ownership Interests: Lexicon Travel, Accommodations, Expenses: LexiconDong YangEmployment: Molecular HealthMilind JavleConsulting or Advisory Role: QED Therapeutics, Oncosil Medical, Incyte, Mundipharma Other Relationship: Rafael Pharmaceuticals, Incyte, Pieris Pharmaceuticals, Merck, Merck Serono, Novartis, Seattle Genetics, BeiGene, QED Therapeutics, Bayer AGAhmed KasebStock and Other Ownership Interests: Gilead Sciences Honoraria: Merck, Exelixis, Bayer AG, Bristol-Myers Squibb Consulting or Advisory Role: Bayer AG, Bristol-Myers Squibb, Merck, Exelixis Research Funding: Bristol-Myers Squibb, Merck, Bayer AG, Onyx Pharmaceuticals, Genentech Travel, Accommodations, Expenses: Exelixis, Merck, Bayer AG, Onyx Pharmaceuticals, Bristol-Myers SquibbCathy EngHonoraria: Roche, Bayer AG Consulting or Advisory Role: Roche, Genentech, Bayer Schering Pharma, Taiho, Terumo Clinical Supply Travel, Accommodations, Expenses: Genentech, Roche, Bayer AG, Sirtex MedicalVivek SubbiahConsulting or Advisory Role: MedImmune Research Funding: Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech (Inst), Roche (Inst), Berg Pharma (Inst), Bayer AG (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Inst), Amgen (Inst), AbbVie (Inst), Multivir (Inst), Blueprint Medicines (Inst), Loxo Oncology (Inst), Vegenics (Inst), Takeda Pharmaceuticals (Inst), Alfasigma (Inst), Agensys (Inst), Idera (Inst), Boston Medical (Inst), Inhibrx (Inst), Exelixis (Inst) Travel, Accommodations, Expenses: PharmaMar, Bayer AGFilip JankuStock and Other Ownership Interests: Trovagene Consulting or Advisory Role: Deciphera, Trovagene, Novartis, Sequenom, Foundation Medicine, Guardant Health, Immunome, Synlogic, Valeant, Dendreon, IFM Therapeutics, Sotio, PureTech Research Funding: Novartis (Inst), BioMed Valley Discoveries (Inst), Roche (Inst), Agios (Inst), Astellas Pharma (Inst), Deciphera (Inst), Plexxikon (Inst), Piqur (Inst), Fujifilm (Inst), Symphogen (Inst), Bristol-Myers Squibb (Inst), Asana Biosciences (Inst), Astex Pharmaceuticals (Inst) Other Relationship: Bio-RadVictoria M. RaymondEmployment: Trovagene, Guardant Health Stock and Other Ownership Interests: Trovagene, Guardant HealthRichard B. LanmanEmployment: Guardant Health, Veracyte Leadership: Guardant Health, Biolase Stock and Other Ownership Interests: Guardant Health, Biolase, Forward Medical Consulting or Advisory Role: Forward Medical Research Funding: Guardant HealthKenna R. Mills ShawResearch Funding: Guardant Health (Inst), Tempus (Inst)Funda Meric-BernstamHonoraria: Sumitomo Group, Dialectica Consulting or Advisory Role: Genentech, Inflection Biosciences, Pieris Pharmaceuticals, Clearlight Diagnostics, Darwin Health, Samsung Bioepis, Spectrum Pharmaceuticals, Aduro Biotech, Origimed, Xencor, Debiopharm Group, Mersana, Seattle Genetics Research Funding: Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer AG, Aileron Therapeutics, Puma Biotechnology, CytomX Therapeutics, Jounce Therapeutics, Zymeworks, Curis, Pfizer, eFFECTOR Therapeutics, AbbVie, Boehringer Ingelheim (I), Guardant Health (Inst), Daiichi Sankyo, GlaxoSmithKline Speakers’ Bureau: Chugai Biopharmaceuticals No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

Background: Adrenocortical carcinoma (ACC) is a rare malignancy without good treatment options. There are limited data about the use of immunotherapy in ACC. We investigated the efficacy and safety of pembrolizumab in patients with metastatic ACC., Methods: This is a pre-specified cohort of a single-center, investigator-initiated, phase II clinical trial using pembrolizumab monotherapy in patients with rare malignancies. Patients must have had prior treatment fail in the past 6 months before study enrollment. Patients were enrolled from August 2016 to October 2018. Follow-up data were updated as of March 26, 2019. Patients received 200 mg pembrolizumab intravenously every 3 weeks without concomitant oncologic therapy. The primary endpoint was non-progression rate (NPR) at 27 weeks. Other endpoints included adverse events, tumor responses measured independently by objective radiologic criteria, and select immunological markers., Results: Sixteen patients with ACC (including eight women [50%]) were included in this cohort. Ten patients (63%) had evidence of hormonal overproduction (seven had cortisol-producing ACC). Non-progression rate at 27 weeks was evaluable in 14 patients, one patient was lost to follow-up, and one patient left the study because of an adverse event. Five of 14 patients were alive and progression-free at 27 weeks (non-progression rate at 27 weeks was 36, 95% confidence interval 13-65%). Of the 14 patients evaluable for imaging response by immune-related Response Evaluation Criteria in Solid Tumors, two had a partial response (including one with cortisol-producing ACC), seven had stable disease (including three with cortisol-producing ACC), and five had progressive disease, representing an objective response rate of 14% (95% confidence interval 2-43%). Of those who had stable disease, six had disease stabilization that lasted ≥4 months. Severe treatment-related adverse events (≥grade 3) were seen in 2 of 16 patients (13%) and resulted in one patient discontinuing study participation. All studied tumor specimens (14/14) were negative for programmed cell death ligand-1 expression. Thirteen of 14 tumor specimens (93%) were microsatellite-stable. Eight of 14 patients (57%) had a high tumor-infiltrating lymphocyte score on immunohistochemistry staining., Conclusions: Single-agent pembrolizumab has modest efficacy as a salvage therapy in ACC regardless of the tumor's hormonal function, microsatellite instability status, or programmed cell death ligand-1 status. Treatment was well tolerated in most study participants, with a low rate of severe adverse events., Trial Registration: ClinicalTrials.gov identifier: NCT02721732 , Registered March 29, 2016.

Genomic testing has become a part of routine oncology care and plays critical roles in diagnosis, prognostic assessment, and treatment selection. Thus, in parallel, the variety of genomic testing providers and sequencing platforms has grown exponentially. Selection of the best-fit panel for each case can be daunting, with many factors to consider. Among them is whether alteration interpretation and therapy/clinical trial matching are included and/or sufficient. In this article, we review some common commercially available sequencing platforms for the genes and types of alterations tested, samples needed, and reporting content provided. We review publicly available resources for a do-it-yourself approach to alteration interpretation when it is not provided or when supplemental research is needed, along with resources to identify genomically matched treatment options that are approved and/or investigational. However, with both commercially provided interpretation and publicly available resources, there are still caveats and limitations that can stem from insufficient or ambiguous nomenclature as well as from the presentation of information. Use cases in which clinical decision making was affected are discussed. After treatment options are identified, it is important to assess the level of evidence for use within the patient's tumor type and molecular profile. However, numerous level-of-evidence scales have been published in recent years, so we provide a publicly available tool to facilitate interoperability. The level of evidence, along with other factors, such as allelic frequency and copy number, can be used to prioritize treatment options when multiple are identified.

Background: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) negatively regulates the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Triple negative breast cancers (TNBC) are often PTEN-deficient, making mTOR a compelling target. We evaluated the efficacy of catalytic mTOR inhibitor TAK228 alone and in combination with eribulin in TNBC. Results: Five of eight triple negative breast cell lines were sensitive to TAK228, independent of PIK3CA/PTEN status. Western blotting demonstrated inhibition of mTORC1/2 signaling as demonstrated by decreased phospho-AKT, phospho-S6 and phospho-4EBP1. In vitro , TAK228 was synergistic with eribulin in all eight TNBC cell lines. The combination of TAK228 and eribulin did not enhance apoptosis but increased G2/M growth arrest. In vivo , TAK228 led to modest growth inhibition in TNBC patient-derived xenografts (PDXs) with no tumor regression observed. In two TNBC PDXs with PTEN loss, one with intrinsic eribulin sensitivity, another eribulin resistance, TAK228 in combination with eribulin did not enhance in vivo efficacy. In a third PTEN-negative TNBC model, eribulin alone achieved disease stabilization, but the combination of TAK228 and eribulin led to significantly smaller tumor volumes compared to eribulin alone ( p < 0.001). Methods: We tested in vitro efficacy of TAK228 in a panel of TNBC cell lines with cell proliferation assays. In vivo antitumor efficacy of TAK228 was evaluated alone and in combination with eribulin. Conclusion: TAK228 enhances the antitumor efficacy of eribulin in TNBC models in vitro , and enhanced in vivo activity in selected models. Further study is needed to determine the potential of this combination, and optimal patient selection strategies., Competing Interests: CONFLICTS OF INTEREST N. Owusu-brackett, K.W. Evans, A. Akcakanat, E. Yuca, C. Tapia, Y. Q. Rizvi, and E.I. Dumbrava have no potential conflicts of interest to disclose. F. Meric-Bernstam reports receiving commercial research grants from Novartis, AstraZeneca, Calithera, Aileron, Bayer, Jounce, CytoMx, eFFECTOR, Zymeworks, PUMA Biotechnology, Curis, Millennium, Daiichi Sankyo, Abbvie, Guardant Health, Takeda, Seattle Genetics, and GlaxoSmithKline as well as grants and travel related fees from Taiho, Genentech, Debiopharm Group, and Pfizer. She also served as a consultant to Pieris, Dialectica, Sumitomo Dainippon, Samsung Bioepis, Aduro, OrigiMed, Xencor, Jackson Laboratory, Zymeworks, Kolon Life Science, and Parexel International, and advisor to Inflection Biosciences, GRAIL, Darwin Health, Spectrum, Mersana, and Seattle Genetics. F. Janku reports grants from Novartis, FujiFilm Pharmaceuticals, Plexxikon, Deciphera Pharmaceuticals, Symphogen, Asana, BioMed Valley Discoveries, Bristol-Myers Squibb Genentech, Astellas Pharma, Agios, PIQUR Therapeutics AG, Bayer, Proximagen, and served as consultant to Novartis, Deciphera Pharmaceuticals, Synlogic, IFM Therapeutics, Illumina, GRAIL, Valeant, Sotio, PureTech Health, Guardant Health, Trovagene, and ImmunoMet. He also has ownership interest in Trovagene.

Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor-positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor-positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival., (© The Author(s) 2019. Published by Oxford University Press.)

Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies., (© The Author(s) 2019. Published by Oxford University Press.)

Next-generation sequencing is a novel method of DNA sequencing that has become a cornerstone of precision oncology. This sequencing method detects differences in specific DNA sequences between a sample and a reference genome or matched normal DNA. In addition to single-nucleotide variants, other insertions, deletions, copy number changes, and fusions may be drivers of cancer growth, and thus represent therapeutic opportunities. As a result, genomic characterization has been increasingly used to guide treatment decisions, especially in patients with advanced disease. This review discusses the basic technologies involved in next-generation sequencing, the applications of this method, and limitations in the clinical realm.

Background: The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation., Methods: The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed., Results: Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders., Conclusions: MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection., Trial Registration: ClinicalTrials.gov, NCT01277757 . Registered 13 January 2011.

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.

Purpose: Many targeted therapies are currently available only via clinical trials. Therefore, routine precision oncology using biomarker-based assignment to drug depends on matching patients to clinical trials. A comprehensive and up-to-date trial database is necessary for optimal patient-trial matching., Methods: We describe processes for establishing and maintaining a clinical trial database, focusing on genomically informed trials. Furthermore, we present OCTANE (Oncology Clinical Trial Annotation Engine), an informatics framework supporting these processes in a scalable fashion. To illustrate how the framework can be applied at an institution, we describe how we implemented an instance of OCTANE at a large cancer center. OCTANE consists of three modules. The data aggregation module automates retrieval, aggregation, and update of trial information. The annotation module establishes the database schema, implements data integration necessary for automation, and provides an annotation interface. The update module monitors trial change logs, identifies critical change events, and alerts the annotators when manual intervention may be needed., Results: Using OCTANE, we annotated 5,439 oncology clinical trials (4,438 genomically informed trials) that collectively were associated with 1,453 drugs, 779 genes, and 252 cancer types. To date, we have used the database to screen 4,220 patients for trial eligibility. We compared the update module with expert review, and the module achieved 98.5% accuracy, 0% false-negative rate, and 2.3% false-positive rate., Conclusion: OCTANE is a general informatics framework that can be helpful for establishing and maintaining a comprehensive database necessary for automating patient-trial matching, which facilitates the successful delivery of personalized cancer care on a routine basis. Several OCTANE components are publically available and may be useful to other precision oncology programs.

Purpose: The prognosis of metastatic osteosarcoma continues to be poor. We hypothesized that alpha-emitting, bone-targeting radium 223 dichloride ( 223 RaCl 2 ) can be safely administered to patients with osteosarcoma and that early signals of response or resistance can be assessed by quantitative and qualitative correlative imaging studies and biomarkers., Patients and Methods: A 3+3 phase I, dose-escalation trial of 223 RaCl 2 (50, 75, and 100 kBq/kg) was designed in patients with recurrent/metastatic osteosarcoma aged ≥15 years. Objective measurements included changes in standardized uptake values of positron emission tomography (PET; 18FDG and/or NaF-18) and single-photon emission CT/CT (99mTc-MDP) as well as alkaline phosphatase and bone turnover markers at baseline, midstudy, and the end of the study., Results: Among 18 patients enrolled (including 15 males) aged 15-71 years, tumor locations included spine ( n = 12, 67%), pelvis ( n = 10, 56%), ribs ( n = 9, 50%), extremity ( n = 7, 39%), and skull ( n = 2, 11%). Patients received 1-6 cycles of 223 RaCl 2 ; cumulative doses were 6.84-57.81 MBq. NaF PET revealed more sites of metastases than did FDG PET. One patient showed a metabolic response on FDG PET and NaF PET. Four patients had mixed responses, and one patient had a response in a brain metastasis. Bronchopulmonary hemorrhage from Grade 3 thrombocytopenia ( N = 1) was a DLT. The median overall survival time was 25 weeks., Conclusions: The first evaluation of the safety and efficacy of an alpha particle in high-risk osteosarcoma shows that the recommended phase II dose for 223 RaCl 2 in osteosarcoma is 100 kBq/kg monthly (twice the dose approved for prostate cancer), with minimal hematologic toxicity, setting the stage for combination therapies., (©2019 American Association for Cancer Research.)

Purpose: To study whether BRAF V600 mutations in non-small-cell lung cancer (NSCLC) may indicate sensitivity to the BRAF inhibitor vemurafenib, we included a cohort of patients with NSCLC in the vemurafenib basket (VE-BASKET) study. On the basis of observed early clinical activity, we expanded the cohort of patients with NSCLC. We present results from this cohort., Methods: This open-label, histology-independent, phase II study included six prespecified cohorts, including patients with NSCLC, and a seventh all-comers cohort. Patients received vemurafenib (960 mg two times per day) until disease progression or unacceptable toxicity. The primary end point of the final analysis was objective response rate (Response Evaluation Criteria in Solid Tumors, version 1.1). Secondary end points included progression-free survival, overall survival, and safety. Because the prespecified clinical benefit endpoint was met in the initial NSCLC cohort, the cohort was expanded., Results: Sixty-two patients with BRAF V600-mutant NSCLC were enrolled and treated: 13% (n = 8) had received no prior systemic therapy, and 87% (n = 54) had received prior therapies. The objective response rate was 37.1% (95% CI, 25.2% to 50.3%) overall, 37.5% (95% CI, 8.5% to 75.5%) in previously untreated patients, and 37.0% (24.3% to 51.3%) in previously treated patients. Median progression-free survival was 6.5 months (95% CI, 5.2 to 9.0 months), and median overall survival was 15.4 months (95% CI, 9.6 to 22.8 months). The most common all-grade adverse event was nausea (40%). The safety profile of vemurafenib was similar to that observed in melanoma studies., Conclusion: Vemurafenib showed promising activity in patients with NSCLC harboring BRAF V600 mutations. The safety profile of vemurafenib was similar to previous observations in patients with melanoma. Our results suggest a role for single-agent BRAF inhibition in patients with NSCLC and BRAF V600 mutations., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. 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. Vivek SubbiahConsulting or Advisory Role: MedImmune Research Funding: Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech (Inst), Berg Pharma (Inst), Bayer (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Inst), Amgen (Inst), AbbVie (Inst), Multivir (Inst), Blueprint Medicines (Inst), Loxo (Inst), Vegenics (Inst), Takeda (Inst), Alfasigma (Inst), Agensys (Inst), Idera (Inst), Boston Biomedical (Inst), Inhibrx (Inst), Exelixis (Inst) Travel, Accommodations, Expenses: PharmaMar Expenses: BayerGregory RielyResearch Funding: Novartis (Inst), Genentech (Inst), Millennium (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), Infinity Pharmaceuticals (Inst), Ariad (Inst), Mirati Therapeutics (Inst), Merck (Inst) Patents, Royalties, Other Intellectual Property: Patent application submitted covering pulsatile use of erlotinib to treat or prevent brain metastases (Inst) Travel, Accommodations, Expenses: Merck Sharp & Dohme Other Relationship: Pfizer, Genentech, TakedaAntoine HollebecqueHonoraria: Merck Serono Consulting or Advisory Role: Amgen, AstraZeneca/MedImmune (Inst), Gritstone Oncology, Incyte (Inst), Eli Lilly (Inst), Spectrum Pharmaceuticals (Inst) Travel, Accommodations, Expenses: Amgen, Servier, Eli Lilly, AstraZeneca/MedImmune Other Relationship: AbbVie, Agios, Amgen, Argenx, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharma, Clovis Oncology, Daiichi Sankyo, Debiopharm Group, Eisai, Exelixis, Forma Therapeutics, GamaMabs Pharma, Genentech, GlaxoSmithKline, H3 Biomedicine, Innate Pharma, Janssen-Cilag, Kyowa Hakko Kirin, Loxo, Lytix Biopharma, MedImmune, Menarini, Merck Sharp & Dohme, Merrimack, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar, Novartis, Octimet, Oncoethix, Onyx, Orion Pharma, Oryzon Genomics, Pfizer, Pierre Fabre, Genentech, Sanofi/Aventis, Taiho Pharmaceutical, Tesaro, Xencor, Roche, Servier, Eli LillyJean-Yves BlayLeadership: Innate Pharma Honoraria: Roche, Novartis Bayer, GlaxoSmithKline, Pharmamar, Eli Lilly Consulting or Advisory Role: Roche, Novartis, GlaxoSmithKline, Bayer, PharmaMar, Merck, GlaxoSmithKline (Inst), PharmaMar (Inst), Novartis (Inst), Bayer (Inst), Roche (Inst) Other Relationship: Innate PharmaEnriqueta FelipConsulting or Advisory Role: Pfizer, Roche, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Celgene, Guardant Health, Novartis, Takeda, AbbVie, Blueprint Medicines, Eli Lilly, Merck, Merck Sharp & Dohme Speakers' Bureau: AstraZeneca, Bristol-Myers Squibb, Novartis, Boehringer Ingelheim, Merck Sharp & Dohme, Roche, Pfizer, AbbVie, Eli Lilly, Merck, Takeda Research Funding: Fundación Merck Salud (Inst), EMD Serono (Inst)Martin SchulerHonoraria: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Eli Lilly, Celgene Consulting or Advisory Role: AstraZeneca Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Roche Research Funding: Bristol-Myers Squibb (Inst), Novartis (Inst), Boehringer Ingelheim (Inst), AstraZeneca (Inst) Patents, Royalties, Other Intellectual Property: Highly sensitive method for mutation detection by polymerase chain reaction (Inst)Anthony GonçalvesResearch Funding: MSD (Inst), Bristol-Myers Squibb (Inst), Novartis (Inst), Cascadian Therapeutics (Inst), Nektar (Inst), Boehringer Ingelheim (Inst), Eli Lilly (Inst), AbbVie (Inst), Genentech (Inst), AstraZeneca (Inst), Roche (Inst) Travel, Accommodations, Expenses: Pfizer, Novartis, Genentech, Celgene, Boehringer Ingelheim, MSD, AstraZenecaAntonio ItalianoHonoraria: Bayer, Daiichi Sankyo, Eli Lilly, Epizyme, Novartis, Roche Consulting or Advisory Role: Roche, Daiichi Sankyo, Immune Design, Epizyme, Bayer, Eli Lilly Research Funding: Roche, Bayer, AstraZeneca/MedImmune, PharmaMar, MSD Oncology, Merck Serono, Merck SeronoVicki KeedyConsulting or Advisory Role: Karyopharm Therapeutics Research Funding: Medpacto (Inst), Plexxikon (Inst), Roche (Inst), Daiichi Sankyo (Inst), Eli Lilly (Inst), BioMed Valley Discoveries (Inst), Immune Design (Inst), GlaxoSmithKline (Inst), Tracon Pharma (Inst), Advenchen Laboratories (Inst)Ian ChauHonoraria: Eli Lilly Consulting or Advisory Role: Eli Lilly, Bristol-Myers Squibb, MSD Oncology, Merck Serono, Genentech, Bayer, AstraZeneca, Oncologie International, Pierre Fabre Research Funding: Janssen-Cilag (Inst), Sanofi (Inst), Merck Serono (Inst), Eli Lilly (Inst) Travel, Accommodations, Expenses: MSD, Merck Serono, Eli Lilly, Bristol-Myers SquibbIgor PuzanovConsulting or Advisory Role: Amgen, Genentech, Bristol-Myers Squibb Travel, Accommodations, Expenses: Amgen, MerckNoopur S. RajeConsulting or Advisory Role: Amgen, Celgene, Takeda, Novartis, Bristol-Myers Squibb, Merck, Janssen Oncology Research Funding: AstraZeneca (Inst)Funda Meric-BernstamHonoraria: Sumitomo Group, Dialectica Consulting or Advisory Role: Genentech, Inflection Biosciences, Pieris Pharmaceuticals, Clearlight Diagnostics, Darwin Health, Samsung Bioepis, Spectrum Pharmaceuticals, Aduro Biotech, Origimed, Xencor, Debiopharm Group, Mersana Research Funding: Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, Puma Biotechnology, CytomX Therapeutics, Jounce Therapeutics, Zymeworks, Curis, Pfizer, Effector Therapeutics, AbbVie, Boehringer Ingelheim (I), Guardant Health (Inst), Daiichi Sankyo, GlaxoSmithKlineMartina MakrutzkiEmployment: RocheTodd RiehlEmployment: Genentech Stock and Other Ownership Interests: GenentechBethany PitcherEmployment: Hoffmann-La RocheJose BaselgaLeadership: Infinity Pharmaceuticals, Varian Medical Systems, Bristol-Myers Squibb, Foghorn Stock and Other Ownership Interests: PMV Pharma, Juno Therapeutics, Grail, Tango, Venthera, Northern Biologics, Apogen Biotechnologies, Aura Biosciences Consulting or Advisory Role: Novartis Patents, Royalties, Other Intellectual Property: Combination therapy using PDK1 and PI3K inhibitors, use of phosphoinositide 3-kinase inhibitors for treatment of vascular malformations, inhibition of KMT2D for the treatment of cancer Travel, Accommodations, Expenses: Roche, Daiichi SankyoDavid M. HymanConsulting or Advisory Role: Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Genentech Research Funding: AstraZeneca, Puma Biotechnology, Loxo, Bayer Travel, Accommodations, Expenses: Genentech, Chugai Pharma No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

Background: Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinical and molecular features to identify those features unique to early-onset CRC that differentiate these patients from patients 50 years old or older., Methods: Baseline characteristics were evaluated according to the CRC onset age with 3 independent cohorts. A fourth cohort was used to describe the impact of age on the consensus molecular subtype (CMS) prevalence., Results: This retrospective review of more than 36,000 patients with CRC showed that early-onset patients were more likely to have microsatellite instability (P = .038), synchronous metastatic disease (P = .009), primary tumors in the distal colon or rectum (P < .0001), and fewer BRAF V600 mutations (P < .001) in comparison with patients 50 years old or older. Patients aged 18 to 29 years had fewer adenomatous polyposis coli (APC) mutations (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.35-0.90; P = .015) and an increased prevalence of signet ring histology (OR, 4.89; 95% CI, 3.23-7.39; P < .0001) in comparison with other patients younger than 50 years. In patients younger than 40 years, CMS1 was the most common subtype, whereas CMS3 and CMS4 were uncommon (P = .003). CMS2 was relatively stable across age groups. Early-onset patients with inflammatory bowel disease were more likely to have mucinous or signet ring histology (OR, 5.54; 95% CI, 2.24-13.74; P = .0004) and less likely to have APC mutations (OR, 0.24; 95% CI, 0.07-0.75; P = .019) in comparison with early-onset patients without predisposing conditions., Conclusions: Early-onset CRC is not only distinct from traditional CRC: special consideration should be given to and further investigations should be performed for both very young patients with CRC (18-29 years) and those with predisposing conditions. The etiology of the high rate of CMS1 in patients younger than 40 years deserves further exploration., (© 2019 American Cancer Society.)

The BRAF V600E mutation and BRAF inhibitor responsiveness characterize ∼50% of patients with the non-Langerhans cell histiocytosis (non-LCH) Erdheim-Chester disease (ECD). We interrogated the non-LCH molecular landscape [ECD, n = 35; Rosai-Dorfman disease (RDD), n = 3; mixed ECD/RDD, n = 1] using BRAF V600E PCR and/or next-generation sequencing [tissue and cell-free DNA (cfDNA) of plasma and/or urine]. Of 34 evaluable patients, 17 (50%) had the BRAF V600E mutation. Of 31 patients evaluable for non- BRAF V600E alterations, 18 (58%) had ≥1 alteration and 12 putative non- BRAF V600E MAPK pathway alterations: atypical BRAF mutation; GNAS, MAP2K1, MAP2K2, NF1 , and RAS mutations; RAF1 or ERBB2 amplifications; LMNA-NTRK1 (TRK inhibitor-sensitive) and CAPZA2-BRAF fusions. Four patients had JAK2, MPL ASXL1, U2AF1 alterations, which can correlate with myeloid neoplasms, a known ECD predisposition, and one developed myelofibrosis 13 months after cfDNA testing. Therefore, our multimodal comprehensive genomics reveals clinically relevant alterations and suggests that MAPK activation is a hallmark of non-LCH., (©2019 American Association for Cancer Research.)

Profiling of both the genome and the transcriptome promises a comprehensive, functional readout of a tissue sample, yet analytical approaches are required to translate the increased data dimensionality, heterogeneity and complexity into patient benefits. We developed a statistical approach called Texomer ( https://github.com/KChen-lab/Texomer ) that performs allele-specific, tumor-deconvoluted transcriptome-exome integration of autologous bulk whole-exome and transcriptome sequencing data. Texomer results in substantially improved accuracy in sample categorization and functional variant prioritization.

Malignant gliomas are a group of intracranial cancers associated with disproportionately high mortality and morbidity. Here, we report ultradeep targeted sequencing of a prospective cohort of 237 tumors from 234 patients consisting of both glioblastoma (GBM) and lower-grade glioma (LGG) using our customized gene panels. We identified 2,485 somatic mutations, including single-nucleotide substitutions and small indels, using a validated in-house protocol. Sixty-one percent of the mutations were contributed by 12 hypermutators. The hypermutators were enriched for recurrent tumors and had comparable outcome, and most were associated with temozolomide exposure. TP53 was the most frequently mutated gene in our cohort, followed by IDH1 and EGFR We detected at least one EGFR mutation in 23% of LGGs, which was significantly higher than 6% seen in The Cancer Genome Atlas, a pattern that can be partially explained by the different patient composition and sequencing depth. IDH hotspot mutations were found with higher frequencies in LGG (83%) and secondary GBM (77%) than primary GBM (9%). Multivariate analyses controlling for age, histology, and tumor grade confirm the prognostic value of IDH mutation. We predicted 1p/19q status using the panel sequencing data and received only modest performance by benchmarking the prediction to FISH results of 50 tumors. Targeted therapy based on the sequencing data resulted in three responders out of 14 participants. In conclusion, our study suggests ultradeep targeted sequencing can recapitulate previous findings and can be a useful approach in the clinical setting., (©2019 American Association for Cancer Research.)

Purpose: To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor., Patients and Methods: This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks., Results: A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day., Conclusions: Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study., (©2019 American Association for Cancer Research.)

Background: The complexity of breast cancer at the clinical, morphological and genomic levels has been extensively studied in the western population. However, the mutational genomic profiles in Chinese breast cancer patients have not been explored in any detail., Methods: We performed targeted sequencing using a panel consisting of 33 breast cancer-related genes to investigate the genomic landscape of 304 consecutive treatment-naïve Chinese breast cancer patients at Guangdong Provincial People's Hospital (GDPH), and further compared the results to those in 453 of Caucasian breast cancer patients from The Cancer Genome Atlas (TCGA)., Results: The most frequently mutated gene was TP53 (45%), followed by PIK3CA (44%), GATA3 (18%), MAP3K1 (10%), whereas the copy-number amplifications were frequently observed in genes of ERBB2 (24%), MYC (23%), FGFR1 (13%) and CCND1 (10%). Among the 8 most frequently mutated or amplified genes, at least one driver was identifiable in 87.5% (n=267) of our GDPH cohort, revealing the significant contribution of these known driver genes in the development of Chinese breast cancer. Compared to TCGA data, the median age at diagnosis in our cohort was significantly younger (48 vs. 58 years; P<0.001), while the distribution of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) statuses were similar. The largest difference occurred in HR+/HER2- subtype, where 8 of the 10 driver genes compared had statistically significant differences in their frequency, while there were differences in 2 of 10 driver genes among the TNBC and HR+/HER2+ group, but none in the HR-/HER2+ patients in our cohort compared to the TCGA data. Collectively, the most significant genomic difference was a significantly higher prevalence for TP53 and AKT1 in Chinese patients. Additionally, more than half of TP53 -mutation HR+/HER2- Chinese patients (~60%) are likely to harbor more severe mutations in TP53 , such as nonsense, indels, and splicing mutations., Conclusions: We elucidated the mutational landscape of cancer genes in Chinese breast cancer and further identified significant genomic differences between Asian and Caucasian patients. These results should improve our understanding of pathogenesis and/or metastatic behavior of breast cancer across races/ethnicities, including a better selection of targeted therapies., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The introduction of HER2-targeted therapy for breast and gastric patients with ERBB2 ( HER2 ) amplification/overexpression has led to dramatic improvements in oncologic outcomes. In the past 20 years, five HER2-targeted therapies have been FDA approved, with four approved in the past 8 years. HER2-targeted therapy similarly was found to improve outcomes in HER2-positive gastric cancer. Over the past decade, with the introduction of next-generation sequencing into clinical practice, our understanding of HER2 biology has dramatically improved. We have recognized that HER2 amplification is not limited to breast and gastric cancer but is also found in a variety of tumor types such as colon cancer, bladder cancer, and biliary cancer. Furthermore, HER2-targeted therapy has signal of activity in several tumor types. In addition to HER2 amplification and overexpression, there is also increased recognition of activating HER2 mutations and their potential therapeutic relevance. Furthermore, there is a rapidly growing number of new therapeutics targeting HER2 including small-molecule inhibitors, antibody-drug conjugates, and bispecific antibodies. Taken together, an increasing number of patients are likely to benefit from approved and emerging HER2-targeted therapies., (©2018 American Association for Cancer Research.)

Background: Genomic profiling of colorectal cancer aims to identify actionable somatic mutations but can also discover incidental germline findings., Objective: The purpose of this study was to report the detection of pathogenic germline variants that confer heritable cancer predisposition., Design: This was a retrospective study., Settings: The study was conducted at a tertiary-referral institution., Patients: Between 2012 and 2015, 1000 patients with advanced cancer underwent targeted exome sequencing of a 202-gene panel. The subgroup of 151 patients with advanced colorectal cancer who underwent matched tumor-normal (blood) sequencing formed our study cohort., Interventions: Germline variants in 46 genes associated with hereditary cancer predisposition were classified according to a defined algorithm based on in silico predictions of pathogenicity. Patients with presumed pathogenic variants were examined for type of mutation, as well as clinical, pedigree, and clinical genetic testing data., Main Outcome Measures: We measured detection of pathogenic germline variants., Results: A total of 1910 distinct germline variants were observed in 151 patients. After filtering, 15 pathogenic germline variants (9.9%) were found in 15 patients, arising from 9 genes of varying penetrance for colorectal cancer (APC (n = 2; 13%), ATM (n = 1; 6%), BRCA1 (n = 2; 13%), CDH1 (n = 2; 13%), CHEK2 (n = 4; 27%), MSH2 (n = 1; 7%), MSH6 (n = 1; 7%), NF2 (n = 1; 7%), and TP53 (n = 1; 7%)). Patients with pathogenic variants were diagnosed at a younger age than those without (median, 45 vs 52 y; p = 0.03). Of the 15 patients, 7 patients (46.7%) with variants in low/moderate- penetrant genes for colorectal cancer would likely have not been tested based on clinical and pedigree criteria, where 2 harbored clinically actionable variants (CDH1 and NF2, 28.5% of 7)., Limitations: This study was limited by its small sample size and advanced-stage patients., Conclusions: Tumor-normal sequencing can incidentally discover clinically unsuspected germline variants that confer cancer predisposition in 9.9% of patients with advanced colorectal cancer. Precision medicine should integrate clinical cancer genetics to inform and interpret the actionability of germline variants and to provide follow-up care to mutation carriers. See Video Abstract at http://links.lww.com/DCR/A906.

Background: Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer., Methods: MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov, number NCT02091141., Findings: Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20-45). The most common treatment-emergent adverse events were diarrhoea (19 [33%] of 57 patients), fatigue (18 [32%] patients), and nausea (17 [30%] patients). Grade 3-4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three [5%] patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths., Interpretation: Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer., Funding: F Hoffmann-La Roche/Genentech., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The role of cancer-related internet use on the patient-physician relationship has not been adequately explored among patients who are cancer-related internet users (CIUs) in early-phase clinical trial clinics., Objective: We examined the association between cancer-related internet use and the patient-physician relationship and decision making among CIUs in an early drug development clinic., Methods: Of 291 Phase I clinic patients who completed a questionnaire on internet use, 179 were CIUs. Generations were defined by the year of patient's birth: "millennials" (after 1990) and "Generation X/Y" (1965-1990) grouped as "Millennials or Generation X/Y"; "Baby Boomers" (1946-1964); and "Greatest or Silent Generation" (1945 and earlier). Statistical analyses included the Wilcoxon matched-pairs signed-rank test and the Mann-Whitney U test., Results: CIUs were 52% (94/179) female, 44% (78/179) were older than 60 years, and 60% (108/179) had household incomes exceeding US $60,000. The sources of information on cancer and clinical trials included physicians (171/179, 96%), the internet (159/179, 89%), and other clinical trial personnel (121/179, 68%). For the overall sample and each generation, the median values for trust in referring and Phase I clinical trial physicians among early drug development clinic CIUs were 5 on a 0-5 scale, with 5 indicating "complete trust." CIUs' trust in their referring (5) and phase 1 (5) physicians was higher than CIUs' trust in Web-based cancer-related information (3; P<.001 for both). CIUs who reported visiting the National Cancer Institute (NCI) website, NCI.org, to learn about cancer reported higher levels of trust in Web-based cancer-related information than CIUs who did not use the NCI website (P=.02). Approximately half of CIUs discussed internet information with their doctor. Only 14% (23/165) of CIUs had asked their physician to recommend cancer-related websites, and 24% (35/144) of CIUs reported at least occasional conflict between their physician's advice and Web-based information., Conclusions: Despite the plethora of websites related to cancer and cancer clinical trials, patients in early-phase clinical trial settings trust their physicians more than Web-based information. Cancer-related organizations should provide regularly updated links to trustworthy websites with cancer and clinical trial information for patients and providers and educate providers on reliable cancer websites so that they can better direct their patients to appropriate internet content., (©Goldy C George, Eucharia C Iwuanyanwu, Adrianna S Buford, Sarina A Piha-Paul, Vivek Subbiah, Siqing Fu, Daniel D Karp, Shubham Pant, Christina O Hinojosa, Kenneth R Hess, Charles S Cleeland, Elmer V Bernstam, Funda Meric-Bernstam, David S Hong. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 14.03.2019.)

Purpose: Smaller hotspot-based next-generation sequencing (NGS) panels have emerged to support standard of care therapy for patients with cancer. When standard treatments fail, it is unknown whether additional testing using an expanded panel of genes provides any benefit. The purpose of this study was to determine if larger sequencing panels that capture additional actionable genes, coupled with decision support, translates into treatment with matched therapy after frontline therapy has failed., Patients and Methods: A prospective protocol accrued 521 patients with a wide variety of refractory cancers. NGS testing using a 46- or 50-gene hotspot assay, then a 409-gene whole-exome assay, was sequentially performed in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. A decision-support team annotated somatic alterations in clinically actionable genes for function and facilitated therapeutic matching. Survival and the impact of matched therapy use were determined by Kaplan-Meier estimate, log-rank test, and Cox proportional hazards regression., Results: The larger NGS panel identified at least one alteration in an actionable gene not previously identified in the smaller sequencing panel in 214 (41%) of 521 of enrolled patients. After the application of decision support, 41% of the alterations in actionable genes were considered to affect the function of the gene and were deemed actionable. Forty patients (40 of 214 [19%]) were subsequently treated with matched therapy. Treatment with matched therapy was associated with significantly improved overall survival compared with treatment with nonmatched therapy ( P = .017)., Conclusion: Combining decision support with larger NGS panels that incorporate genes beyond those recommended in current treatment guidelines helped to identify patients who were eligible for matched therapy while improving overall treatment selection and survival. This survival benefit was restricted to a small subset of patients., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. 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 po.ascopubs.org/site/ifc. Scott KopetzStock and Other Ownership Interests: MolecularMatch, Navire Consulting or Advisory Role: Roche, Genentech, EMD Serono, Merck, Karyopharm Therapeutics, Amal Therapeutics, Navire Pharma, Symphogen, Holy Stone, Biocartis, Amgen, Novartis Research Funding: Amgen (Inst), Sanofi (Inst), Biocartis (Inst), Guardant Health (Inst), Array BioPharma (Inst), Genentech (Inst), EMD Serono (Inst), MedImmune (Inst), Novartis (Inst)J. Jack LeeConsulting or Advisory Role: AbbVieBeate LitzenburgerEmployment: QiagenFunda Meric-BernstamHonoraria: Sumitomo Group, Dialectica Consulting or Advisory Role: Genentech, Inflection Biosciences, Pieris Pharmaceuticals, Clearlight Diagnostics, Darwin Health, Samsung Bioepis, Spectrum Pharmaceuticals, Aduro Biotech, Origimed, Xencor, Debiopharm Group Research Funding: Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, Puma Biotechnology, CytomX Therapeutics, Jounce Therapeutics, Zymeworks, Curis, Pfizer, eFFECTOR Therapeutics, AbbVie, Boehringer Ingelheim (I), Guardant Health (Inst) No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

Background: OncotypeDX recurrence score (RS) ® has been found to predict recurrence and disease-free survival in patients with node negative breast cancer. Whether RS is useful in guiding locoregional therapy decisions is unclear. We sought to evaluate the relationship between RS and lymph node burden., Methods: Patients with invasive breast cancer who underwent sentinel lymph node dissection from 2010 to 2015 were identified from a prospectively maintained database. Patients were excluded if they were clinically node positive or if they received neoadjuvant chemotherapy. RS was classified as low (< 18), intermediate (18-30), or high (> 30). The association between RS, lymph node burden, and disease recurrence was evaluated. Statistical analyses were performed in R version 3.4.0; p < 0.05 was considered significant., Results: A positive SLN was found in 168 (15%) of 1121 patients. Completion axillary lymph node dissection was performed in 84 (50%) of SLN-positive patients. The remaining 84 (50%) patients had one to two positive SLNs and did not undergo further axillary surgery. RS was low in 58.5%, intermediate in 32.6%, and high in 8.9%. RS was not associated with a positive SLN, number of positive nodes, maximum node metastasis size, or extranodal extension. The median follow-up was 23 months. High RS was not associated with locoregional recurrence (p = 0.07) but was significantly associated with distant recurrence (p = 0.0015)., Conclusions: OncotypeDX RS is not associated with nodal burden in women with clinically node-negative breast cancer, suggesting that RS is not useful to guide decisions regarding extent of axillary surgery for these patients.

Background: The genomic landscape of Hodgkin lymphoma (HL) has been difficult to characterize due to the paucity of neoplastic cells and an abundant microenvironment. Such characterization is needed in order to improve treatment strategies., Materials and Methods: We performed comprehensive genomic profiling (CGP) using targeted next-generation sequencing on archival formalin-fixed paraffin embedded tumor samples from 63 patients to analyze the landscape of HL., Results: CGP was successful for 49/63 archival specimens (78%), and revealed aberrations impacting genes including B2M , TP53 , and XPO1 (E571). Of the 34 patients for whom total mutation burden (TMB; mutations/megabase [Mb]) was assessed, 5 (15%) had high TMB (≥20 mutations/Mb), 18 (53%) had intermediate TMB (6-19 mutations/Mb), and 11 (32%) had low TMB (≤5 mutations/Mb). We next tested 13 patients' plasma cell-free DNA with droplet digital polymerase chain reaction for the presence of XPO1 E571 mutation, which was confirmed in the plasma of 31% of patients. In three patients with serially collected plasma samples, XPO1 E571K allelic frequency changes corresponded with changes in tumor size on conventional radiographic imaging., Conclusion: The study demonstrates that comprehensive genomic profiling of archival Hodgkin lymphoma tumor samples is feasible and leads to the identification of genes that are recurrently mutated and that Hodgkin lymphoma has increased mutation burden in the majority of samples analyzed. Furthermore, tracking of XPO1 E571 mutant allele frequency in a subset of patients may also represent a potential disease-monitoring strategy and warrants further investigation., Implications for Practice: This study provides the first evidence that comprehensive genomic profiling can be performed to map the genomic landscape of Hodgkin lymphoma and that a subpopulation of patients has mutations in TP53 , B2M , XPO1 , and other genes. It was found that 15% of patients have high mutation burden, which, in cancers such as melanoma, may indicate sensitivity to immune checkpoint inhibitors, and may thus be explored for Hodgkin lymphoma. Lastly, this work demonstrates that changes in the mutant allele frequency of XPO1 in serially collected plasma cell-free DNA samples correspond with treatment outcomes measured with conventional radiographic imaging., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

The 'Competing interests' statement of this Article has been updated; please see the accompanying Amendment. The original Article has not been corrected online.

Background: BRAF inhibitors are effective against selected BRAF V600 -mutated tumors. Preclinical data suggest that BRAF inhibition in conjunction with chemotherapy has increased therapeutic activity., Methods: Patients with advanced cancers and BRAF mutations were enrolled into a dose-escalation study (3+3 design) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs)., Results: Nineteen patients with advanced cancers and BRAF mutations were enrolled and received vemurafenib (480-720 mg orally twice a day), carboplatin (area under the curve [AUC] 5-6 intravenously every 3 weeks), and paclitaxel (100-135 mg/m 2 intravenously every 3 weeks). The MTD was not reached, and vemurafenib at 720 mg twice a day, carboplatin at AUC 5, and paclitaxel at 135 mg/m 2 were the last safe dose levels. DLTs included a persistent grade 2 creatinine elevation (n = 1), grade 3 transaminitis (n = 1), and grade 4 thrombocytopenia (n = 1). Non-dose-limiting toxicities that were grade 3 or higher and occurred in more than 2 patients included grade 3/4 neutropenia (n = 5), grade 3/4 thrombocytopenia (n = 5), grade 3 fatigue (n = 4), and grade 3 anemia (n = 3). Of the 19 patients, 5 (26%; all with melanoma) had a partial response (PR; n = 4) or complete response (CR; n = 1); these responses were mostly durable and lasted 3.1 to 54.1 months. Of the 13 patients previously treated with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, 4 (31%) had a CR (n = 1) or PR (n = 3). Patients not treated with prior platinum therapy had a higher response rate than those who did (45% vs 0%; P = .045)., Conclusions: The combination of vemurafenib, carboplatin, and paclitaxel is well tolerated and demonstrates encouraging activity, predominantly in patients with advanced melanoma and BRAF V600 mutations, regardless of prior treatment with BRAF and/or MEK inhibitors., (© 2018 American Cancer Society.)

Background: NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions., Patients and Methods: This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity., Results: Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose., Conclusions: Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients., Clincaltrials.gov Number: NCT02122913., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND DATA AVAILABILITY STATEMENT The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. 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/rwcor ascopubs.org/po/author-center.

Importance: Pathologic complete response rate (pCR), the primary end point of the ACOSOG (American College of Surgeons Oncology Group) Z1041 (Alliance) trial, and disease-free survival (DFS) and overall survival (OS) in women with operable HER2-positive breast cancer are similar between treatment regimens., Objective: To assess DFS and OS for patients treated with sequential vs concurrent anthracycline plus trastuzumab., Design, Setting, and Participants: Phase 3 randomized clinical trial conducted at 36 centers in the continental United States and Puerto Rico. Women 18 years or older with invasive operable HER2-positive breast cancer were enrolled from September 15, 2007, to December 15, 2011, and randomized to 1 of 2 treatment arms. The analysis data set was locked on October 15, 2017, and analysis was completed on December 15, 2017., Interventions: Patients randomized to arm 1 received 500 mg/m2 of fluorouracil, 75 mg/m2 of epirubicin, and 500 mg/m2 of cyclophosphamide (FEC) every 3 weeks for 12 weeks followed by the combination of 80 mg/m2 of paclitaxel and 2 mg/kg (except initial dose of 4 mg/kg) of trastuzumab weekly for 12 weeks. Patients randomized to arm 2 received the same combination of paclitaxel with trastuzumab weekly for 12 weeks followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks. Women with hormone receptor-positive disease received endocrine therapy, and radiotherapy was delivered at physician discretion., Main Outcomes and Measures: The primary outcomes were DFS and OS and pCR in the breast and nodes., Results: Two hundred eighty-two women with HER2-positive breast cancer were enrolled in the trial, and 2 withdrew consent before treatment. Among the remaining 280 women, the median age was 50 years (range, 28-76 years), 232 (82.9%) were white, 29 (10.3%) were black, 8 (2.9%) were Asian, 4 (1.4%) were American Indian or Alaskan Native, and 7 (2.5%) did not report race/ethnicity. There were 22 disease events in arm 1 and 27 in arm 2. Disease-free survival rates did not differ with respect to treatment arm (stratified log-rank P = .96; stratified hazard ratio [HR] [arm 2 to arm 1], 1.02; 95% CI, 0.56-1.83). Overall survival did not differ with respect to treatment arm (stratified log-rank P = .73; stratified HR [arm 2 to arm 1], 1.17; 95% CI, 0.48-2.88)., Conclusions and Relevance: Across a median follow-up of 5.1 years (range, 26 days to 6.2 years), pCR, DFS, and OS did not differ with respect to sequential or concurrent administration of FEC with trastuzumab., Trial Registration: ClinicalTrials.gov identifier: NCT00513292.

Background: Next-generation sequencing (NGS) for tumor molecular profiling can reveal secondary germline pathogenic and likely pathogenic variants (LPV/PV). The American College of Medical Genetics (ACMG) recommends return of secondary results for a subset of 59 genes, but other genes with evidence of clinical utility are emerging. We previously reported that 4.3% of patients who underwent NGS of a targeted panel of 201 genes had LPV/PV based on the ACMG list. Here we report the frequency of additional germline cancer-related gene variants and discuss their clinical utility., Patients and Methods: Matched tumor and germline DNA NGS of a targeted panel of 201 genes was performed in a research laboratory on samples from 1000 patients with advanced or metastatic solid tumors enrolled in a molecular testing protocol (NCT01772771). The frequency of germline LPV/PV in 54 cancer-related genes, beyond the genes in ACMG list, were analyzed., Results: Among 1000 patients who underwent tumor/normal DNA sequencing, 46 (4.6%) were found to have a germline LPV/PV in the following genes: AR -(5), ATM -(4), BAP1 -(1), CDH1 -(1), CDKN2A -(1), CHEK1 -(2), CHEK2 -(10), EGFR -(1), ERCC3 -(4), ERCC5 -(1), HNF1B -(1), HRAS -(1), MITF -(4), MLL3 -(1), NF1 -(3), PKHD1 -(4), PTCH1 -(1), and SMARCA4 -(1). Thus, a total 8.7% of patients had an LPV/PV with 2 patients having 2 concomitant germline LPV/PV. Five mutations in high-penetrance hereditary cancer predisposition genes were selected to be returned to patients or their representatives: BAP1, CDH1, CDKN2A, EGFR , and SMARCA4 ., Conclusions: Broader genomic testing is likely to identify additional secondary pathogenic germline alterations, some with potential clinical utility for return to patients and their relatives. The recommended genes for which germline results should be returned are continually changing, warranting continued study.

Abnormal FGFR1 alternative splicing is correlated with tumorigenicity and poor prognosis in several tumor types. We sought to determine the roles of FGFR1α and FGFR1β variants in breast cancer. TCGA samples and cell lines were analyzed for FGFR1α/FGFR1β expression. MCF-10A cells were used to overexpress these variants. Cell growth and transformation were assessed by SRB, colony formation, 3D-Matrigel, soft agar, cell motility assays. In TCGA, compared to FGFR1 non-amplified samples, FGFR1-amplified samples had significantly higher FGFR1α but not FGFR1β levels. FGFR1β expression levels and FGFR1β/FGFR1α ratio were higher in basal subtype samples than in ER-positive/luminal samples in both TCGA and breast cancer cell lines. Both FGFR1α and FGFR1β induced transformation of MCF-10A cells. However, only FGFR1β-expressing cells, not FGFR1α, enhanced cell growth and cell motility. Cells with higher FGFR1β levels and FGFR1β/FGFR1α ratio were more sensitive to FGFR inhibitor BGJ-398. Interestingly, in ER-negative cells, FGFR inhibitors decreased FGFR1β levels, likely by increasing expression of splicing repressor PTBP1. In ER-positive cells, estrogen treatment increased FGFR1β levels by decreasing PTBP1 expression, which was blocked by 4-OHT. Lastly, combination treatment with BGJ-398 and 4-OHT synergistically inhibited cell survival. These findings suggest that FGFR1 alternative FGFR1α/FGFR1β splicing plays an important role in breast cancer., Competing Interests: CONFLICTS OF INTEREST Drs. Ming Zhao, Ming-Lei Zhuo, Xiaofeng Zheng, and Xiaoping Su have nothing to disclose. Dr. Meric-Bernstam reports grants from Novartis, AstraZeneca, Calithera, Bayer, Jounce, CytoMx, eFFECTOR, Zymeworks, PUMA Biotechnology, Curis, Millennium, Daiichi Sankyo, Abbvie, Guardant Health, and Takeda; grants and travel related fees from Taiho, Genentech, Debiopharm Group, and Pfizer; and served as a consultant to Inflection Biosciences, Pieris, Darwin Health, GRAIL, Clearlight Diagnostics, Dialectica, Sumitomo Dainippon, Spectrum, Samsung Bioepis, Aduro, OrigiMed, Xencor, Jackson Laboratory, and Mersana.

Purpose: Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in patients with TNBC, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell-cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775., Experimental Design: Mono- and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient-derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E-mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cell lines., Results: Cyclin E overexpression (i) is enriched in TNBCs with high recurrence rates, (ii) sensitizes TNBC cell lines and PDX models to AZD1775, (iii) leads to CDK2-dependent activation of DNA replication stress pathways, and (iv) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E-low tumors) and result in DNA replicative stress. Such drug-mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy. Conclusions: Cyclin E is a potential biomarker of response (i) for AZD1775 as monotherapy in cyclin E-high TNBC tumors and (ii) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E-low TNBC tumors., (©2018 American Association for Cancer Research.)

Purpose: We examined patterns, correlates, and the impact of cancer-related Internet use among patients with advanced cancer in a phase I clinical trials clinic for molecularly targeted oncologic agents., Methods: An anonymous questionnaire on Internet use for cancer-related purposes that incorporated input from phase I clinical trial oncologists and patients was self-administered by patients age ≥ 18 years in a phase I clinic. Multivariable modeling was used. Data were analyzed for the overall sample and by generation, which was defined by year of birth., Results: Of 291 patients (52% women, 82% non-Hispanic white, 50% age ≤ 60 years), 62% were cancer-related Internet users (CIUs). Cancer-related Internet use was associated with an income of ≥ $60,000 (odds ratio, 2.42; P = .004). CIUs used the Internet to learn about their cancer (85%), treatment adverse effects (65%), clinical trials (52%), new alternative treatments (42%), and symptom management (41%). CIUs most frequently used the hospital Web site (70%) to learn about clinical trials, followed by ClinicalTrials.gov (42%) and search engines (41%). The emotional impact of Internet-derived cancer information on CIUs varied-56% felt empowered, 34% anxious, 29% relieved, and 17% confused. Cancer-related Internet information made 51% of patients from the Millennial (born after 1990) and Generation X/Y (born 1965 to 1990) CIU populations anxious compared with < 29% of CIUs from older generations (born 1964 and before). Most CIUs desired more online information about new experimental drugs (91%) and US Food and Drug Administration-approved drugs for cancer (72%)., Conclusion: As most phase I patients use the Internet for cancer-related purposes, the Internet overall and hospital Web sites should provide more extensive, pertinent, and helpful information on clinical trials and cancer treatment to phase I patients.

Background: Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC., Methods: We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided., Results: ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = .002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < .001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated with worse overall survival., Conclusions: MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3.

Purpose: FGFR genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with FGFR GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown., Patients and Methods: Patients with CCA with FGFR GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with FGFR wild-type counterparts. Data reviewed included demographic, treatment, overall survival (OS), and GA data. Fisher's exact test, Kaplan-Meier plots, and log-rank tests were used for statistical analysis., Results: Three hundred seventy-seven patients with CCA were identified, and 95 had FGFR GAs. FGFR2 GA was most common (n = 74, with 63 fusions) and seen in intrahepatic CCA. In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001), presented at an earlier stage (TNM stage I/II v III/IV: 35.8% v 22%, respectively; P = .001), and were associated with a longer OS compared with patients without FGFR GAs (37 v 20 months, respectively; P < .001). This difference remained significant after excluding 36 patients treated with FGFR inhibitors. There was no OS difference ( P = .60) between CCA with FGFR2 fusions (n = 63) versus other FGFR GAs (n = 29). Patients with FGFR GAs had a better OS with FGFR-targeted therapy compared with standard treatment ( P = .01). BAP1 mutation was the most common coexisting mutation without prognostic impact, whereas TP53 ( P = .04) and CDKN2A/B ( P = .04) were correlated with a shorter OS., Conclusion: CCA with FGFR GAs represents a unique subtype occurring in younger patients with an indolent disease course. FGFR-targeted therapy may have a positive impact on OS in this subgroup.

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease with subtypes having different "targetable" molecular aberrations. Metaplastic breast cancers (MpBCs) are typically TNBCs and commonly have alterations in the PI3K/Akt/mTOR pathway. We previously reported efficacy for an mTOR-based chemotherapy regimen in MpBC. To determine if tumor subtype influences prognosis, we compared treatment outcomes of patients with MpBC with those of patients with nonmetaplastic TNBC receiving an mTOR-based systemic therapy regimen., Patients and Methods: Patients with advanced MpBC and nonmetaplastic TNBC were treated at our institution from April 16, 2009, through November 4, 2014, using mTOR inhibition (temsirolimus or everolimus) with liposomal doxorubicin and bevacizumab (DAT/DAE). Median progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Cox regression analyses were used to evaluate associations between tumor histology and outcomes. Multivariable models were adjusted for all covariates., Results: Fourteen patients with nonmetaplastic TNBC and 59 patients with advanced MpBC were treated with DAT/DAE. MpBC patients were older ( p = .002) and less likely to have a history of bevacizumab use ( p = .023). Median PFS for the nonmetaplastic TNBC and MpBC patients was 2.5 months and 4.8 months, respectively. This difference in PFS was statistically significant on univariable ( p = .006) but not multivariable analysis ( p = .087). Median OS for the nonmetaplastic TNBC and MpBC patients was 3.7 months and 10.0 months, respectively ( p = .0003). MpBC remained significantly associated with improved OS on multivariable analysis ( p < .0001)., Conclusion: In our study, DAT/DAE appeared to be more effective in MpBC compared with nonmetaplastic TNBC. These data support patient selection for targeted therapy in TNBC., Implications for Practice: Metaplastic breast cancers (MpBCs) represent <1% of all breast cancers, demonstrate mesenchymal differentiation, and are typically resistant to chemotherapy. Patients with advanced MpBC treated with an mTOR-based systemic therapy regimen had better long-term outcomes compared with patients with nonmetaplastic triple-negative breast cancer treated with the same regimen, suggesting that metaplastic histology may predict benefit from agents targeting the PI3K/Akt/mTOR pathway., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Purpose: To determine the potential for detection of incidental germline cancer predisposition mutations through cell-free DNA (cfDNA) analyses in patients who underwent solid tumor somatic mutation evaluation., Patients and Methods: Data were evaluated from 10,888 unselected patients with advanced (stage III/IV) cancer who underwent Guardant360 testing between November 2015 and December 2016. The main outcome was prevalence of putative germline mutations identified among 16 actionable hereditary cancer predisposition genes., Results: More than 50 cancer types were studied, including lung (41%), breast (19%), colorectal (8%), prostate (6%), pancreatic (3%), and ovarian (2%). Average patient age was 63.5 years (range, 18 to 95 years); 43% were male. One hundred and fifty-six individuals (1.4%) had suspected hereditary cancer mutations in 11 genes. Putative germline mutations were more frequent in individuals younger than 50 years versus those 50 years and older (3.0% v 1.2%, respectively; P < .001). Highest yields of putative germline findings were in patients with ovarian (8.13%), prostate (3.46%), pancreatic (3.34%), and breast (2.2%) cancer. Putative germline mutation identification was consistent among 12 individuals with multiple samples. Patients with circulating tumor DNA copy number variation and/or reversion mutations suggestive of functional loss of the wild-type allele in the tumor DNA also are described., Conclusion: Detection of putative germline mutations from cfDNA is feasible across multiple genes and cancer types without prior mutation knowledge. Many mutations were found in cancers without clear guidelines for hereditary cancer genetic counseling/testing. Given the clinical significance of identifying hereditary cancer predisposition for patients and their families as well as targetable germline alterations such as in BRCA1 or BRCA2, research on the best way to validate and return potential germline results from cfDNA analysis to clinicians and patients is needed.

Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1-3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1-3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p  < 0.0001 and p  = 0.0070, respectively). Three patients had matched primary vs. LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) vs. controls (14%, p  = 0.0045). In summary, mutations in the MAPK pathway, specifically NF1 , were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence., Competing Interests: Gordon B. Mills serves as a Consultant and/or on the Scientific Advisory Board for the following companies Allostery, Inc., AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMet, Ionis, Medimmune, Nuevolution, Precision Medicine, Signalchem Lifesciences, Symphogen, Takeda/Millenium Pharmaceuticals, Tarveda. He has a financial interest in Catena Pharmaceuticals, ImmunoMet, PTV Ventures, Spindletop Ventures. He holds licensed technology in HRD assay to Myriad Genetics. He has sponsored research from AstraZeneca, Critical Outcome Technologies, Illumina, Ionis, Karus, Nanostring, Takeda/Millenium Pharmaceuticals. Funda Meric Bernstam has grant or research support from Novartis, AstraZeneca, Taiho, Genentech, Calithera, Debiopharma, Bayer, PUMA, Aileron, Jounce, CytoMx, eFFECTOR, Zymeworks, Curis, Pfizer. She is a paid consultant for Dialecta, Sumitomo Dainippon Pharma. She is on advisory committees/review panels/board membership for Inflection Biosciences, Clearlight Diagnostics, Pieris, Darwin Health, GRAIL. Hong Zhang is a consultant for Genentech/Roche. Nancy Klauber-Demore is the Chief Scientific Officer, Co-founder and shareholder for Enci Therapeutic INC. The remaining authors declare no competing interests.

Purpose: Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in BRAF -mutated advanced solid tumors., Patients and Methods: We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily., Results: Twenty patients with advanced cancers were enrolled. The median adult age was 64 years (range, 17 to 85 years); two pediatric patients were 10 and 13 years old. Patients were heavily pretreated with prior BRAF or MEK inhibitors (n = 11), phase I clinical trial therapy (n = 10), surgery (n = 18), radiation therapy (n = 11), and chemotherapy (n=13). One of the two pediatric patients initially experienced grade 3 rash, but after dermatologic intervention, the patient remains on trial with partial response and no dose reduction at time of analysis. Four dose-limiting toxicities (rash, n = 1; fatigue, n = 3) were observed at dose level 2. Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was the maximum-tolerated dose. Overall, four patients (22%) had a partial response and nine patients (50%) had stable disease as best response. One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles., Conclusion: The combination of vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily is safe and well tolerated and has activity across histologies, with partial responses noted in advanced non-small-cell lung cancer, melanoma, optic nerve glioma, and xanthroastrocytoma, including patients who previously experienced progression on BRAF and/or MEK inhibitor therapy. Further investigation in a larger cohort of molecularly matched patients is warranted., Competing Interests: The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the article; and the decision to submit the article for publication.The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. 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. Vivek SubbiahConsulting or Advisory Role: MedImmune Research Funding: Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech (Inst), Berg Pharma (Inst), Bayer (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Inst), Amgen (Inst), AbbVie (Inst), Multivir (Inst), Blueprint Medicines (Inst), Loxo (Inst), Vegenics (Inst), Takeda (Inst), Alfasigma (Inst), Agensys (Inst), Idera (Inst), Boston Biomedical (Inst) Travel, Accommodations, Expenses: PharmaMar, BayerShiraj SenNo relationship to discloseKenneth R. HessNo relationship to discloseFilip JankuStock and Other Ownership Interests: Trovagene Consulting or Advisory Role: Deciphera, Trovagene, Novartis, Sequenom, Foundation Medicine, Guardant Health, Immunome Research Funding: Novartis, BioMed Valley Discoveries, Roche, Agios, Astellas Pharma, Deciphera, Symphony Evolution, Plexxikon, Piqur, Fujifilm Other Relationship: Bio-RadDavid S. HongStock and Other Ownership Interests: MolecularMatch, Oncorena Honoraria: Adaptimmune, Baxter, Merrimack, Bayer Consulting or Advisory Role: Baxter, Bayer, Guidepoint Global, Janssen Speakers' Bureau: Genentech, Janssen Oncology Research Funding: Novartis, Genentech, Eisai, AstraZeneca, Pfizer, miRNA Therapeutics, Amgen, Daiichi Sankyo, Merck, Mirati Therapeutics, Eli Lilly, Adaptimmune, AbbVie, Bayer, Bristol-Myers Squibb, Genmab, Ignyta, Infinity Pharmaceuticals, Kite Pharma, Kyowa Hakko Kirin, Loxo, MedImmune, Molecular Templates, Takeda Travel, Accommodations, Expenses: Loxo, miRNA Therapeutics Other Relationship: Oncorena, EisaiSoumen KhatuaNo relationship to discloseDaniel D. KarpConsulting or Advisory Role: Black Beret Life Sciences Research Funding: Phosplatin Therapeutics Travel, Accommodations, Expenses: Phosplatin TherapeuticsJavier MunozConsulting or Advisory Role: Kite Pharma, Pfizer, Pharmacyclics, Bayer, Alexion Pharmaceuticals, Bristol-Myers Squibb, Janssen, Seattle Genetics, Gilead Sciences, Kyowa Hakko Kirin Speakers' Bureau: Kite PharmaGerald S. FalchookEmployment: Sarah Cannon Research Institute, HealthONE Research Funding: Millennium, EMD Serono, Celgene, MedImmune, Genmab, Vegenics, Novartis, AstraZeneca, Incyte, ARMO BioSciences, Kolltan Pharmaceuticals, 3-V Biosciences, AbbVie, Aileron Therapeutics, DelMar Pharmaceuticals, eFFECTOR Therapeutics, Strategia Therapeutics, Fujifilm, Hutchison MediPharma, Regeneron, Biothera, Curegenix, Curis, Eli Lilly, Jounce Therapeutics, OncoMed, Precision Oncology, Syndax, Taiho Pharmaceutical, Tesaro, Takeda, BeiGene, Ignyta, Merck, Rgenix, Tarveda Therapeutics, Tocagen Patents, Royalties, Other Intellectual Property: Handbook of Targeted Cancer Therapy Travel, Accommodations, Expenses: Millennium, Sarah Cannon Research Institute, EMD Serono, Bristol-Myers SquibbRoman GroisbergNo relationship to discloseApostolia M. TsimberidouConsulting or Advisory Role: Roche Research Funding: EMD Serono (Inst), Baxter (Inst), Foundation Medicine (Inst), Onyx (Inst), Bayer (Inst), Boston Biomedical (Inst), Placon (Inst), IMMATICS (Inst), Karus Therapeutics (Inst), Stem Cells (Inst), OBI Pharma (Inst)Steven I. ShermanHonoraria: Genzyme, Eisai Consulting or Advisory Role: Eisai, Exelixis, Veracyte, Novo Nordisk, Bristol-Myers Squibb, Loxo, Genzyme, Ignyta, Novartis Research Funding: Genzyme Travel, Accommodations, Expenses: Eisai, Veracyte, IgnytaPatrick HwuStock and Other Ownership Interests: Immatics Consulting or Advisory Role: Dragonfly Therapeutics, GlaxoSmithKline, Immatics, Sanofi Research Funding: Genentech (Inst)Funda Meric-BernstamHonoraria: Sumitomo Group, Dialectica Consulting or Advisory Role: Genentech, Inflection Biosciences, Pieris Pharmaceuticals, Clearlight Diagnostics, Darwin Health, Samsung Bioepis, Spectrum Pharmaceuticals Research Funding: Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, PUMA Biotechnology, CytomX Therapeutics, Jounce Therapeutics, Zymeworks, Curis, Pfizer, eFFECTOR Therapeutics, AbbVie, (© 2018 by American Society of Clinical Oncology.)

Background: Bone is the most common site of metastasis of breast cancer. Biological mechanisms of metastasis to bone may be different from mechanisms of metastasis to non-bone sites, and identification of distinct signaling pathways and somatic mutations may provide insights on biology and rational targets for treatment and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone-only versus non-bone sites of first metastasis. Methods: Primary tumor samples were collected before treatment from 389 patients with untreated primary breast cancer and distant metastasis at diagnosis. In each sample, 46 or 50 cancer-related genes were analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. Fisher's exact test was used to identify somatic mutations associated with bone-only first metastasis. Logistic regression models were used to identify differences in detected somatic mutations, clinicopathologic characteristics, and survival between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only ("other-only first metastasis"). Results: Among the 389 patients, 72 (18.5%) had bone-only first metastasis, 223 (57.3%) had other-only first metastasis, and 94 (24.2%) had first metastasis in both bone and non-bone sites. The most commonly mutated genes were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone-receptor-positive disease, non-triple-negative subtype, and lower grade (grade 1 or 2; Nottingham grading system) (all three comparisons, p <0.001); had a lower ratio of cases of invasive ductal carcinoma to cases of invasive lobular carcinoma ( p =0.002); and tended to have a higher 5-year overall survival (OS) rate (78.2% [95% confidence interval (CI), 68.6%-89.0%] vs 55.0% [95% CI, 48.1%-62.9%]; p =0.051). However, in the subgroup of patients with TP53 mutation and in the subgroup of patients with PIK3CA mutation, OS did not differ between patients with bone-only and other-only first metastasis ( p =0.49 and p =0.68, respectively). In univariate analysis, the rate of TP53 mutation tended to be lower in patients with bone-only first metastasis than in those with other-only first metastasis (15.3% vs 29.1%; p =0.051). In multivariate analysis, TP53 mutation was not significantly associated with site of first metastasis ( p =0.54) but was significantly associated with hormone-receptor-negative disease ( p <0.001). Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone-only first metastasis tend to have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

KRAS and TP53 mutations, which are the most common genetic drivers of tumorigenesis, are still considered undruggable targets. Therefore, we analyzed these genetic aberrations in metastatic non-small cell lung cancer (NSCLC) for the development of potential therapeutics. One hundred eighty-five consecutive patients with metastatic NSCLC in a phase 1 trial center were included. Their genomic aberrations, clinical characteristics, survivals, and phase 1 trial therapies were analyzed. About 10%, 18%, 36%, and 36% of the patients had metastatic KRAS +/ TP53 +, KRAS +/ TP53 -, KRAS -/ TP53 +, and KRAS -/ TP53 - NSCLC, respectively. The most common concurrent genetic aberrations beside KRAS and/or TP53 (>5%) were KIT, epidermal growth factor receptor, PIK3CA, c-MET, BRAF, STK11, ATM, CDKN2A, and APC. KRAS +/ TP53 + NSCLC did not respond well to the phase 1 trial therapy and was associated with markedly worse progression-free (PFS) and overall (OS) survivals than the other three groups together. KRAS hotspot mutations at locations other than codon G12 were associated with considerably worse OS than those at this codon. Gene aberration-matched therapy produced prolonged PFS and so was anti-angiogenesis in patients with TP53 mutations. Introduction of the evolutionary action score system of TP53 missense mutations enabled us to identify a subgroup of NSCLC patients with low-risk mutant p53 proteins having a median OS duration of 64.5 months after initial diagnosis of metastasis. These data suggested that patients with metastatic dual KRAS+/TP53+ hotspot-mutant NSCLC had poor clinical outcomes. Further analysis identified remarkably prolonged survival in patients with low-risk mutant p53 proteins, which warrants confirmatory studies., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed.