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Purpose: The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor., Methods: As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m 2 /dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m 2 /dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS)., Results: Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF -altered CNS tumors achieved stable disease >6 months., Conclusion: Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m 2 /dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

Purpose: Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established., Methods: We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival., Results: A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors., Conclusion: This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population., Competing Interests: Benny JohnsonConsulting or Advisory Role: Gritstone Bio, Incyte, Taiho Oncology, InsmedResearch Funding: Bristol Myers Squibb (Inst), Syntrix Biosystems (Inst) Ibiayi Dagogo-JackHonoraria: American Academic Health System, Total Health Conferencing, DAVA Oncology, Creative Educational Concepts, Medscape, ASCO Post, OncLive/MJH Life SciencesConsulting or Advisory Role: Boehringer Ingelheim, AstraZeneca, Xcovery, Catalyst Pharmaceuticals, Pfizer, Syros Pharmaceuticals, Novocure, BostonGene, Bayer, Genentech, Sanofi, JanssenResearch Funding: Pfizer (Inst), Array BioPharma (Inst), Novartis (Inst), Genentech (Inst), Calithera Biosciences (Inst), Vivace Therapeutics (Inst)Travel, Accommodations, Expenses: Pfizer, Array BioPharma Nathaniel J. MyallHonoraria: Patient Power Georg RichtigTravel, Accommodations, Expenses: Ipsen Marco GerlingerStock and Other Ownership Interests: VertexResearch Funding: Bristol Myers Squibb, Merck KGaA, Roche/Genentech Eiji ShinozakiHonoraria: Yakult Honsha, Merck Serono, Chugai Pharma, Takeda, Sanofi, Lilly, Taiho Pharmaceutical, Daiichi Sankyo/UCB Japan Takayuki YoshinoHonoraria: Chugai Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical, MSD K.K.Research Funding: MSD (Inst), Daiichi Sankyo Company, Limited (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Amgen (Inst), Sanofi (Inst), Pfizer (Inst), Genomedia (Inst), Sysmex (Inst), Nippon Boehringer Ingelheim (Inst), Chugai Pharma (Inst) Daisuke KotaniHonoraria: Takeda, Chugai Pharma, Lilly Japan, Merck Serono, Sysmex, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD, Daiichi Sankyo/UCB JapanResearch Funding: Ono Pharmaceutical (Inst), MSD (Inst), Novartis (Inst), Janssen (Inst), IQvia (Inst), Syneos Health (Inst), CMIC (Inst) Jason R. FangusaroHonoraria: AstraZeneca, Pyramid BiosciencesConsulting or Advisory Role: Celgene, AstraZeneca Oliver GautschiConsulting or Advisory Role: Amgen (Inst), Lilly (Inst)Other Relationship: Bayer (Inst), Pfizer (Inst), Roche (Inst), Merck, Lilly Julien MazieresConsulting or Advisory Role: Novartis, Roche/Genentech, Pfizer, Bristol Myers Squibb, Lilly/ImClone, MSD, AstraZeneca, Pierre Fabre, Blueprint Medicines, Hengrui TherapeuticsResearch Funding: Roche (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Pierre Fabre (Inst)Travel, Accommodations, Expenses: Pfizer, Roche, Bristol Myers Squibb Jeffrey A. SosmanHonoraria: Jazz Pharmaceuticals, Apexian Pharmaceuticals, Iovance BiotherapeuticsConsulting or Advisory Role: Apexigen, Jazz Pharmaceuticals, Iovance Biotherapeutics Scott KopetzThis author is a member of the JCO Precision Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Stock and Other Ownership Interests: MolecularMatch, Lutris, Iylon, Frontier MedicinesConsulting or Advisory Role: Genentech, EMD Serono, Merck, Holy Stone Healthcare, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, AbbVie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotech, Bicara Therapeutics, Endeavor BioMedicines, Numab, Johnson & Johnson/Janssen, Genomic Health, Frontier Medicines, Replimune, Taiho PharmaceuticalResearch Funding: Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, Daiichi Sankyo Vivek SubbiahConsulting or Advisory Role: MedImmune, Helsinn Therapeutics, Loxo, R-Pharm, QED TherapeuticsResearch Funding: Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech/Roche (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), Turning Point Therapeutics (Inst)Travel, Accommodations, Expenses: PharmaMar, Bayer, Novartis, Helsinn TherapeuticsOther Relationship: Medscape Michael A. DaviesConsulting or Advisory Role: Genentech/Roche, Novartis, Bristol Myers Squibb, NanoString Technologies, Array BioPharma, Apexigen, Pfizer, Eisai, ABM, Iovance BiotherapeuticsResearch Funding: GlaxoSmithKline (Inst), Genentech/Roche (Inst), AstraZeneca (Inst), Merck (Inst), Oncothyreon (Inst), Myriad Genetics (Inst), Sanofi (Inst), Pfizer (Inst), ABM (Inst), LEAD (Inst) Anna L. GrooverEmployment: BioMed Valley Discoveries Ryan J. SullivanConsulting or Advisory Role: Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, Bristol Myers SquibbResearch Funding: Amgen (Inst), Lilly (Inst), BioMed Valley Discoveries (Inst), Merck (Inst), Deciphera (Inst), Roche/Genentech (Inst), Moderna Therapeutics (Inst), Sanofi (Inst), Aeglea Biotherapeutics (Inst), Asana Biosciences (Inst), Viralytics (Inst), Compugen (Inst), Neon Therapeutics (Inst), Pfizer (Inst), BeiGene (Inst), Rubius Therapeutics (Inst), Strategia (Inst) Keith T. FlahertyStock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Apricity Health, Oncoceutics, FOGPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley Therapeutics, Nextech InvestConsulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, Debiopharm Group, OmRx Douglas B. JohnsonConsulting or Advisory Role: Bristol Myers Squibb, Merck, Novartis, Iovance Biotherapeutics, Catalyst Pharmaceuticals, Oncosec, Pfizer, Mosaic ImmunoEngineering, Targovax, MallinckrodtResearch Funding: Incyte, Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Intellectual property and patents pending surrounding use of MHC-II and response to immune therapy David W. CesconConsulting or Advisory Role: Pfizer, AstraZeneca, Novartis, GlaxoSmithKline, Merck, Roche/Genentech, Exact Sciences, Gilead Sciences, EisaiResearch Funding: Merck (Inst), Roche/Genentech (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), Inivata (Inst), AstraZeneca (Inst), Gilead Sciences (Inst)Patents, Royalties, Other Intellectual Property: Patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore-associated complex subunit 3 (ska3) geneUncompensated Relationships: Inivata Anna SpreaficoHonoraria: Bristol Myers Squibb, Medison & ImmunocoreConsulting or Advisory Role: Novartis, Merck, Bristol Myers Squibb, Oncorus, Medison & ImmunocoreResearch Funding: Bristol Myers Squibb, Novartis, Merck, Symphogen, AstraZeneca/MedImmune, Bayer, Surface Oncology, Janssen Oncology, Northern Biologics, Replimune, Roche, Alkermes, Array BioPharma, GlaxoSmithKline, Treadwell Therapeutics (Inst), Amgen (Inst)Travel, Accommodations, Expenses: Merck, Bristol Myers Squibb, Idera, Bayer, Janssen Oncology, Roche George ZogopoulosPatents, Royalties, Other Intellectual Property: TC-PTP inhibitors as APC activators for immunotherapyTravel, Accommodations, Expenses: Baxalta April A.N. RoseEmployment: Merck (I)Stock and Other Ownership Interests: Merck (I)Consulting or Advisory Role: PfizerNo other potential conflicts of interest were reported.

Breast cancer (BC) is the most common cancer and the prevalent type of malignancy among women. Multiple risk factors, including genetic changes, biological age, dense breast tissue, and obesity are associated with BC. The mitogen-activated protein kinases (MAPK) signaling pathway has a pivotal role in regulating biological functions such as cell proliferation, differentiation, apoptosis, and survival. It has become evident that the MAPK pathway is associated with tumorigenesis and may promote breast cancer development. The MAPK/RAS/RAF cascade is closely associated with breast cancer. RAS signaling can enhance BC cell growth and progression. B-Raf is an important kinase and a potent RAF isoform involved in breast tumor initiation and differentiation. Depending on the reasons for cancer, there are different strategies for treatment of women with BC. Till now, several FDA-approved treatments have been investigated that inhibit the MAPK pathway and reduce metastatic progression in breast cancer. The most common breast cancer drugs that regulate or inhibit the MAPK pathway may include Farnesyltransferase inhibitors (FTIs), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, and Teriflunomide. In this review, we will discuss the roles of the MAPK/RAS/RAF/MEK/ERK pathway in BC and summarize the FDA-approved prescription drugs that target the MAPK signaling pathway in women with BC.

Introduction: MAPK genes are activated by a variety of factors related to growth factors, hormones, and environmental stress., Methods: We evaluated associations between 13 MAPK genes and survival among 1,187 nonHispanic White and 1,155 Hispanic/Native American (NA) women diagnosed with breast cancer. We assessed the influence of diet, lifestyle, and genetic ancestry on these associations. Percent NA ancestry was determined from 104 Ancestry Informative Markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance., Results: Associations were predominantly observed among women with lower NA ancestry. Specifically, the mitogen-activated protein kinases (MAPK) pathway was associated with all-cause mortality (P ARTP = 0.02), but not with breast cancer-specific mortality (P ARTP = 0.10). However, MAP2K1 and MAP3K9 were associated with both breast cancer-specific and all-cause mortality. MAPK12 (P ARTP = 0.05) was only associated with breast cancer-specific mortality, and MAP3K1 (P ARTP = 0.02) and MAPK1 (P ARTP = 0.05) were only associated with all-cause mortality. Among women with higher NA ancestry, MAP3K2 was significantly associated with all-cause mortality (P ARTP = 0.04). Several diet and lifestyle factors, including alcohol consumption, caloric intake, dietary folate, and cigarette smoking, significantly modified the associations with MAPK genes and all-cause mortality., Conclusions: Our study supports an association between MAPK genes and survival after diagnosis with breast cancer, especially among women with low NA ancestry. The interaction between genetic variation in the MAPK pathway with diet and lifestyle factors for all women supports the important role of these factors for breast cancer survivorship.