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Purpose: Amplification of cyclin-dependent kinase 4 (CDK4) and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests that inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-Molecular Analysis for Therapy Choice trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors., Patients and Methods: Patients had a solid malignancy or lymphoma with progression on at least one systemic therapy for advanced disease or with no standard-of-care therapy available. Tumors with ≥7 copies of CDK4 or CDK6 were considered amplified and molecularly eligible. Enrolled patients were treated with palbociclib 125 mg daily on days 1 to 21 of a 28-day cycle. The primary endpoint was objective response rate., Results: Forty-three patients were enrolled on subprotocol Z1C, and 38 patients were deemed eligible, treated, and included in analyses; 25 patients were eligible, treated, and centrally confirmed to have CDK4 or CDK6 amplification and comprised the primary analysis cohort for objective response rate endpoint. Among the 25 patients in the primary cohort, one patient had a partial response, 4 patients had stable disease, and 16 patients had progressive disease as best response. Four patients were not evaluable due to lack of follow-up scans. Among the 38 evaluable patients, one patient had a partial response, 10 patients had stable disease, and 21 patients had progressive disease as best response. Partial response and stable disease were seen only in patients with CDK4 amplification. Median progression-free survival was 2.0 months, and median overall survival was 8.8 months., Conclusions: Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, although central nervous system tumors may be worthy of future investigation., (©2024 American Association for Cancer Research.)

Background: A prior pooled analysis of the MONALEESA-2, -3, and -7 trials identified baseline markers predictive of sensitivity or resistance to ribociclib plus endocrine therapy (ET). We report the results of an analysis of paired baseline and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples across the MONALEESA trials., Patients and Methods: Paired baseline and EOT ctDNA samples from MONALEESA-2, -3, and -7 were sequenced using a targeted next-generation sequencing panel. Genes with an EOT alteration prevalence of >5% were included. A McNemar test was carried out on paired samples and adjusted for multiple testing to control the false discovery rate. A Bayesian mixed-effects model was used to adjust for ctDNA fraction at both time points and for study differences., Results: The analysis included 523 paired samples. At EOT, 21 genes had a >5% alteration prevalence. A trend for higher ctDNA fraction at EOT versus baseline (P = 0.08) was observed. Prevalence of alterations was higher at EOT versus baseline in RB1, SPEN, TPR, PCDH15, and FGFR2 in the ribociclib arm; PBRM1 in the placebo arm; and ESR1 in both arms. The mixed-effects model demonstrated that the same trends for increased prevalence of these alterations at EOT were observed after adjusting for ctDNA fraction and that the increased rate of RB1 and SPEN alterations at EOT were specific to ribociclib plus ET. Analysis of ESR1 indicated a similar increase at EOT in both arms. The most common acquired ESR1 mutations at EOT included Y537C/N/S/D, D538G, E380Q, and L536H/R/P/LC. The prevalence of PIK3CA hotspot mutations at baseline and EOT was similar., Conclusions: This analysis identified acquired gene alterations in patients with hormone receptor-positive/human epidermal growth factor receptor-2 negative advanced breast cancer treated with ribociclib plus ET or placebo plus ET. These data may support further studies on acquired resistance mechanisms and inform future systemic interventions in the post-cyclin-dependent kinase 4/6 inhibitor setting., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The NCI-MATCH study is a tumor-agnostic platform trial enrolling patients to targeted therapies on the basis of genomic alterations. Subprotocol V investigated sunitinib in patients with tumors harboring c - KIT mutations., Methods: EAY131-V, is an open-label, single-arm, phase II study. Eligible patients had malignancies containing somatic c-KIT mutation on exons 9, 11, 13, or 14. Exclusions were mutations on exons 17 and 18, gastrointestinal stromal tumors, renal cell carcinoma, and pancreatic neuroendocrine tumors. Patients received sunitinib 50 mg orally once daily for 4 weeks with 2-week rest per cycle, until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points were progression-free survival (PFS) at 6 months, PFS, overall survival, and toxicities., Results: Between November 1, 2016, and May 21, 2020, 10 patients were enrolled and nine were eligible and started treatment. The median age was 62 years (range, 30-76), 77.8% received two previous lines of systemic therapy, and 22.2% received >3 lines. The most common histology was melanoma (44%) and then squamous cell carcinoma of the lung or thymus (33%). There were two partial responses with an ORR of 22.2% (90% CI, 4.1 to 55) and stable disease in 44%. All patients demonstrated tumor shrinkage of target lesions. The estimated 6-month PFS was 33.3% (90% CI, 15.4 to 72.4). Grade 3-4 toxicities occurred in five patients (55.6%). This arm was closed in 2022 on the basis of low accrual. Prevalence of eligible c-KIT mutations after screening 5,540 patients was 0.45%., Conclusion: Sunitinib for c-KIT mutations did not meet the primary end point, but in this small sample size, a potential signal cannot be ruled out. Rate of eligible c-KIT mutations was low, affecting accrual to this arm.

Purpose: The NCI-MATCH trial assigned patients with solid tumors, lymphomas, or multiple myeloma to targeted therapies on the basis of identified genetic alterations from tumor biopsies. In preclinical models, neurofibromatosis 2 ( NF2 )-inactivated tumors display sensitivity to focal adhesion kinase (FAK) inhibition. The EAY131-U subprotocol evaluated the efficacy of defactinib, a FAK inhibitor, in patients with NF2 -altered tumors., Methods: Patients whose tumors harbored an inactivating NF2 mutation on next-generation sequencing were assigned to subprotocol U. Defactinib 400 mg was given orally twice a day until progression or intolerable toxicity. The primary end point was objective response rate (ORR), secondary end points included toxicity, progression-free survival (PFS), and 6-month PFS., Results: Of 5,548 patients with sufficient tissue for genomic analysis, 57 patients were found to have NF2 alterations. Thirty-five patients ultimately enrolled and 33 were treated, with one not having central confirmation and two ineligible for outcome analysis. All patients had received previous treatment, with 52% having received three or more previous lines of therapy. The most common treatment-related toxicities were fatigue (36%), nausea (33%), and hyperbilirubinemia (27%), with 27% of patients having grade 3 toxicities. Median follow-up was 35.9 months with an ORR of 3% from one partial response in a patient with choroid meningioma. Among the 12 patients (40%) with a best response of stable disease, eight demonstrated some tumor shrinkage. Median PFS was 1.9 months, and six patients achieved a PFS >5.5 months. No correlation was identified between clinical outcomes and tumor histology or specific NF2 genotype., Conclusion: This protocol did not meet its prespecified primary end point. Defactinib monotherapy had limited clinical activity in this cohort of previously treated patients with solid tumors exhibiting NF2 loss.

Luminal Androgen Receptor (LAR) triple-negative breast cancers (TNBC) express androgen receptors (AR), exhibit high frequency of PIK3CA mutations and intact RB. Herein, we investigated combined blockade of the CDK4/6 and PI3K signaling with palbociclib, alpelisib, and capivasertib, which inhibit CDK4/6, PI3Kα, and AKT1-3, respectively. The combination of palbociclib/capivasertib, but not palbociclib/alpelisib, synergistically inhibited proliferation of MDA-MB-453 and MFM-223 LAR cells [synergy score 7.34 (p = 5.81x10 -11 ) and 4.78 (p = 0.012), respectively]. The AR antagonist enzalutamide was inactive against MDA-MB-453, MFM-223, and CAL148 cells and did not enhance the efficacy of either combination. Palbociclib/capivasertib inhibited growth of LAR patient-derived xenografts more potently than palbociclib/alpelisib. Treatment of LAR cells with palbociclib suppressed phosphorylated-RB and resulted in adaptive phosphorylation/activation of S473 pAKT and AKT substrates GSK3β, PRAS40, and FoxO3a. Capivasertib blocked palbociclib-induced phosphorylation of AKT substrates more potently than alpelisib. Treatment with PI3Kβ inhibitors did not block phosphorylation of AKT substrates, suggesting that PI3Kβ did not mediate the adaptive response to CDK4/6 inhibition. Phosphokinase arrays of MDA-MB-453 cells treated with palbociclib showed time-dependent upregulation of PDGFRβ, GSK3β, STAT3, and STAT6. RNA silencing of PDGFRβ in palbociclib-treated MDA-MB-453 and MFM-223 cells blocked the upregulation of S473 pAKT, suggesting that the adaptive response to CDK4/6 blockade involves PDGFRβ signaling. Finally, treatment with palbociclib and the PDGFR inhibitor CP637451 arrested growth of MDA-MB-453 and MFM-223 cells to the same degree as palbociclib/capivasertib. These findings support testing the combination of CDK4/6 and AKT inhibitors in patients with LAR TNBC, and further investigation of PDGFR antagonists in this breast cancer subtype., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ariella B. Hanker received or has received research grants from Takeda and Lilly and nonfinancial support from Puma Biotechnology, Daiichi Sankyo, and Tempus. Carlos L. Arteaga receives or has received research grants from Pfizer, Lilly, and Takeda; holds minor stock options in Provista; serves or has served in an advisory role to Novartis, Merck, Lilly, Daiichi Sankyo, Taiho Oncology, OrigiMed, Puma Biotechnology, Immunomedics, AstraZeneca, Arvinas, and Sanofi; and reports scientific advisory board remuneration from the Susan G. Komen Foundation., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently through the introduction of spatially resolved transcriptomics (SRT) technologies, especially those that achieve single-cell resolution. Nevertheless, substantial challenges remain to analyze such highly complex data properly. Here, we introduce a multiple-instance learning framework, Spacia, to detect CCCs from data generated by SRTs, by uniquely exploiting their spatial modality. We highlight Spacia's power to overcome fundamental limitations of popular analytical tools for inference of CCCs, including losing single-cell resolution, limited to ligand-receptor relationships and prior interaction databases, high false positive rates and, most importantly, the lack of consideration of the multiple-sender-to-one-receiver paradigm. We evaluated the fitness of Spacia for three commercialized single-cell resolution SRT technologies: MERSCOPE/Vizgen, CosMx/NanoString and Xenium/10x. Overall, Spacia represents a notable step in advancing quantitative theories of cellular communications., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the pre-clinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC., Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab., Conclusions: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time., Clinical Trial Information: NCT00520975., (© 2024. The Author(s).)

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR-targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Significance: This study reveals a bifurcated role of ZNF397, and a TET2-driven epigenetic mechanism regulating tumor lineage plasticity and therapy response in prostate cancer, enhances the understanding of drug resistance, and unveils a new therapeutic strategy for overcoming androgen receptor-targeted therapy resistance., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) was a multicohort phase 2 trial that assigned patients with advanced pretreated cancers to molecularly targeted therapies on the basis of tumor genomic testing. NCI-MATCH Arm A evaluated afatinib, an EGFR tyrosine kinase inhibitor (TKI) approved for advanced non-small cell lung cancer, in patients with tumors other than lung cancer harboring EGFR mutations., Methods: Patients with advanced pretreated cancers other than lung cancer found to have selected actionable EGFR mutations were offered participation in Arm A. Previous therapy with an EGFR TKI was not allowed. Patients received afatinib 40 mg once daily continuously until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival (OS)., Results: Seventeen patients received protocol therapy. Tumor types included glioblastoma multiforme (GBM) (13), gliosarcoma (1), adenocarcinoma not otherwise specified (NOS) (2), and adenosquamous carcinoma of the breast (1). Fifty-nine percent of patients received ≥2 lines of previous therapy. The ORR was 11.8% (90% CI, 2.1 to 32.6), with one complete response lasting 16.4 months (GBM harboring a rare exon 18 EGFR-SEPT14 fusion) and one partial response lasting 12.8 months (adenocarcinoma NOS with the classic EGFR mutation, p.Glu746_Ala750del). Three patients had stable disease. The 6-month PFS was 15% (90% CI, 0 to 30.7); the median OS was 9 months (90% CI, 4.6 to 14.0). Rash and diarrhea were the most common toxicities., Conclusion: Afatinib had modest activity in a cohort of patients with heavily pretreated cancer with advanced nonlung, EGFR- mutated tumors, but the trial's primary end point was not met. Further evaluation of afatinib in GBM with EGFR exon 18 fusions may be of interest.

Background: Patient-reported outcomes (PROs) are a better tool for evaluating the experiences of patients who have symptomatic, treatment-associated adverse events (AEs) compared with clinician-rated AEs. The authors present PROs assessing health-related quality of life (HRQoL) and treatment-related neurotoxicity for adjuvant capecitabine versus platinum on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) EA1131 trial (ClinicalTrials.gov identifier NCT02445391)., Methods: Participants completed the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI-16) and the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group neurotoxicity subscale (platinum arm only) at baseline, cycle 3 day 1 (C3D1), 6 months, and 15 months. Because of early termination, power was insufficient to test the hypothesis that HRQoL, as assessed by the NFBSI-16 treatment side-effect (TSE) subscale, would be better at 6 and 15 months in the capecitabine arm; all analyses were exploratory. Means were compared by using t-tests or the Wilcoxon rank-sum test, and proportions were compared by using the χ 2 test., Results: Two hundred ninety-six of 330 eligible patients provided PROs. The mean NFBSI-16 TSE subscale score was lower for the platinum arm at baseline (p = .02; absolute difference, 0.6 points) and for the capecitabine arm at C3D1 (p = .04; absolute difference, 0.5 points), but it did not differ at other times. The mean change in TSE subscale scores differed between the arms from baseline to C3D1 (platinum arm, 0.15; capecitabine arm, -0.72; p = .03), but not from baseline to later time points. The mean decline in Functional Assessment of Cancer Therapy-Gynecologic Oncology Group neurotoxicity subscale scores exceeded the minimal meaningful change (1.38 points) from baseline to each subsequent time point (all p < .05)., Conclusions: Despite the similar frequency of clinician-rated AEs, PROs identified greater on-treatment symptom burden with capecitabine and complemented clinician-rated AEs by characterizing patients' experiences during chemotherapy., (© 2024 American Cancer Society.)

Purpose: NCI-MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors., Patients and Methods: Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories. Patients with breast/gastroesophageal adenocarcinoma and those who received prior HER2-directed therapy were excluded. Enrollment of patients with colorectal cancer was capped at 4 based on emerging data. Patients received HP IV Q3 weeks until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS)., Results: Thirty-five patients were enrolled, with 25 included in the primary efficacy analysis (CN ≥7 confirmed by a central lab, median CN = 28). Median age was 66 (range, 31-80), and half of all patients had ≥3 prior therapies (range, 1-11). The confirmed ORR was 12% [3/25 partial responses (colorectal, cholangiocarcinoma, urothelial cancers), 90% confidence interval (CI) 3.4%-28.2%]. There was one additional partial response (urothelial cancer) in a patient with an unconfirmed ERBB2 copy number. Median PFS was 3.3 months (90% CI 2.0-4.1), and median OS 9.4 months (90% CI 5.0-18.9). Treatment-emergent adverse events were consistent with prior studies. There was no association between HER2 CN and response., Conclusions: HP was active in a selection of HER2-amplified tumors (non-breast/gastroesophageal) but did not meet the predefined efficacy benchmark. Additional strategies targeting HER2 and potential resistance pathways are warranted, especially in rare tumors., (©2024 American Association for Cancer Research.)

Purpose: Despite fibroblast growth factor receptor ( FGFR ) inhibitors being approved in tumor types with select FGFR rearrangements or gene mutations, amplifications of FGFR represent the most common FGFR alteration across malignancies. Subprotocol K1 (EAY131-K1) of the National Cancer Institute-MATCH platform trial was designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 amplification., Methods: EAY131-K1 was an open-label, single-arm, phase II study with central confirmation of presence of FGFR1-4 amplification in tumors. Patients with urothelial carcinoma were excluded. Enrolled patients received oral erdafitinib at a starting dose of 8 mg once daily continuously with escalation to 9 mg once daily continuously, on the basis of predefined time point assessments of phosphate levels, until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR), with key secondary end points being 6-month progression-free survival (PFS6), PFS, overall survival (OS), and safety., Results: Thirty-five patients were enrolled into this study with 18 included in the prespecified primary efficacy analysis. The median age of the 18 patients was 60 years, and 78% had received ≥3 previous lines of therapy. There were no confirmed responses to erdafitinib; however, five patients experienced stable disease (SD) as best response. One patient with an FGFR1 -amplified breast cancer had a prolonged PFS >168 days (5.5 months). The median PFS was 1.7 months (90% CI, 1.1 to 1.8 months) and the median OS was 4.2 months (90% CI, 2.3 to 9.3 months). The estimated PFS6 rate was 13.8% (90% CI, 3.3 to 31.6). The majority of toxicities were grade 1 to 2 in nature, although there was one grade 5 treatment-related adverse event., Conclusion: Erdafitinib did not meet its primary end point of efficacy as determined by ORR in treatment-refractory solid tumors harboring FGFR1-4 amplifications. Our findings support that rearrangements and gene mutations, but not amplifications, of FGFR remain the established FGFR alterations with approved indications for FGFR inhibition.

Purpose: The National Cancer Institute Molecular Analysis for Therapy Choice trial is a signal-finding genomically driven platform trial that assigns patients with any advanced refractory solid tumor, lymphoma, or myeloma to targeted therapies on the basis of next-generation sequencing results. Subprotocol E evaluated osimertinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with EGFR mutations., Methods: Eligible patients had EGFR mutations (T790M or rare activating) and received osimertinib 80 mg once daily. Patients with lung cancer with EGFR T790M were excluded. The primary end point was objective response rate (ORR), and the secondary end points were 6-month progression-free survival (PFS), overall survival, and toxicity., Results: A total of 19 patients were enrolled: 17 were evaluable for toxicity and 13 for efficacy. The median age of the 13 included in the efficacy analysis was 63 years, 62% had Eastern Cooperative Oncology Group performance status 1, and 31% received >three previous systemic therapies. The most common tumor type was brain cancers (54%). The ORR was 15.4% (n = 2 of 13; 90% CI, 2.8 to 41.0) and 6-month PFS was 16.7% (90% CI, 0 to 34.4). The two confirmed RECIST responses were observed in a patient with neuroendocrine carcinoma not otherwise specified ( EGFR exon 20 S768T and exon 18 G719C mutation) and a patient with low-grade epithelial carcinoma of the paranasal sinus ( EGFR D770&#95;N771insSVD). The most common (>20%) treatment-related adverse events were diarrhea, thrombocytopenia, and maculopapular rash., Conclusion: In this pretreated cohort, osimertinib did not meet the prespecified end point threshold for efficacy, but responses were seen in a neuroendocrine carcinoma with an EGFR exon 20 S768T and exon 18 G719C mutation and an epithelial carcinoma with an EGFR D770&#95;N771insSVD mutation. Osimertinib was well tolerated and had a safety profile consistent with previous studies.

Purpose: Subprotocol K2 (EAY131-K2) of the NCI-MATCH platform trial was an open-label, single-arm, phase II study designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 mutations or fusions., Methods: Central confirmation of tumor FGFR1-4 mutations or fusions was required for outcome analysis. Patients with urothelial carcinoma were excluded. Enrolled subjects received oral erdafitinib at a starting dose of 8 mg daily continuously until intolerable toxicity or disease progression. The primary end point was objective response rate (ORR) with key secondary end points of safety, progression-free survival (PFS), and overall survival (OS)., Results: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. The median age was 61 years, and 52% of subjects had received ≥3 previous lines of therapy. The confirmed ORR was 16% (4 of 25 [90% CI, 5.7 to 33.0], P = .034 against the null rate of 5%). An additional seven patients experienced stable disease as best-confirmed response. Four patients had a prolonged PFS including two with recurrent WHO grade IV, IDH1-/2-wildtype glioblastoma. The median PFS and OS were 3.6 months and 11.0 months, respectively. Erdafitinib was manageable with no new safety signals., Conclusion: This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner.

CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identify protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout breast cancer cells. Inhibition of PRMT5 blocks the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RB1-knockout cells. Proteomics analysis uncovers fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 results in dissociation of FUS from RNA polymerase II, leading to hyperphosphorylation of serine 2 in RNA polymerase II, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibits growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight dual ER and PRMT5 blockade as a potential therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer., (© 2024. The Author(s).)

Therapy resistance and metastatic progression are primary causes of cancer-related mortality. Disseminated tumor cells possess adaptive traits that enable them to reprogram their metabolism, maintain stemness, and resist cell death, facilitating their persistence to drive recurrence. The survival of disseminated tumor cells also depends on their ability to modulate replication stress in response to therapy while colonizing inhospitable microenvironments. In this study, we discovered that the nuclear translocation of AXL, a TAM receptor tyrosine kinase, and its interaction with WRNIP1, a DNA replication stress response factor, promotes the survival of HER2+ breast cancer cells that are resistant to HER2-targeted therapy and metastasize to the brain. In preclinical models, knocking down or pharmacologically inhibiting AXL or WRNIP1 attenuated protection of stalled replication forks. Furthermore, deficiency or inhibition of AXL and WRNIP1 also prolonged metastatic latency and delayed relapse. Together, these findings suggest that targeting the replication stress response, which is a shared adaptive mechanism in therapy-resistant and metastasis-initiating cells, could reduce metachronous metastasis and enhance the response to standard-of-care therapies., Significance: Nuclear AXL and WRNIP1 interact and mediate replication stress response, promote therapy resistance, and support metastatic progression, indicating that targeting the AXL/WRNIP1 axis is a potentially viable therapeutic strategy for breast cancer., (©2024 American Association for Cancer Research.)

BACKGROUNDHER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR).METHODSTo investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing and ERBB2 FISH of 285 pretreatment and posttreatment tumors from 129 patients in this T-DM1+P neoadjuvant trial. A subset of cases was also subject to NanoString spatial digital profiling.RESULTSPretreatment tumors from patients with pCR had the highest level of ERBB2 mRNA and ERBB signaling. HER2 heterogeneity was associated with no pCR, basal-like features, and low ERBB2 expression yet high ERBB signaling sustained by activation of downstream pathway components. Residual tumors showed decreased HER2 protein levels and ERBB2 copy number heterogeneity and increased PI3K pathway enrichment and luminal features. HET tumors showed minimal treatment-induced transcriptomic changes compared with non-HET tumors. Immune infiltration correlated with pCR and HER2-HET status.CONCLUSIONResistance mechanisms in HET and non-HET tumors are distinct. HER2-targeting antibodies have limited efficacy in HET tumors. Our results support the stratification of patients based on HET status and the use of agents that target downstream components of the ERBB signaling pathway in patients with HET tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT02326974.FUNDINGThis study was funded by Roche and the National Cancer Institute.

Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers Alliance will accelerate the pace of discovery by providing an ongoing mechanism for transferring new knowledge, sharing resources, developing national demonstration projects, and driving innovation that impacts cancer science, cancer care delivery, and science and health policy., (©2023 American Association for Cancer Research.)

Background: The phase III MONALEESA trials tested the efficacy and safety of the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib with different endocrine therapy partners as first- or second-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). Using the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date, we identified potential biomarkers of response to ribociclib., Patients and Methods: Baseline circulating tumour DNA from patients in the MONALEESA trials was assessed using next-generation sequencing. An analysis of correlation between gene alteration status and progression-free survival (PFS) was carried out to identify potential biomarkers of response to ribociclib., Results: Multiple frequently altered genes were identified. Alterations in ERBB2, FAT3, FRS2, MDM2, SFRP1, and ZNF217 were associated with a greater PFS benefit with ribociclib versus placebo. Patients with high tumour mutational burden (TMB) and with ANO1, CDKN2A/2B/2C, and RB1 alterations exhibited decreased sensitivity to ribociclib versus placebo., Conclusions: Although exploratory, these results provide insight into alterations associated with the improved response to ribociclib treatment and may inform treatment sequencing in patients with actionable alterations following progression on CDK4/6 inhibitors. Validation of potential biomarkers identified here and development of prospective trials testing their clinical utility are warranted., Gov Identifiers: NCT01958021, NCT02422615, NCT02278120., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T., Patients and Methods: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing., Results: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response., Conclusions: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy., Competing Interests: Disclosure KJ: Consultant/Advisory Board: Novartis, AstraZeneca, Pfizer, BMS, Jounce Therapeutics, Taiho Oncology, Genentech/Roche, Lilly Pharmaceuticals/Loxo Oncology, AbbVie, Eisai, Blueprint Medicines, Seattle Genetics, Daiichi Sankyo, Gilead, Olema Pharmaceuticals, Sun Pharma Advanced Research Company Ltd., Menarini/Stemline, and Scorpion Therapeutics. Research Funding: Novartis, Genentech/Roche, AstraZeneca, Debio Pharmaceuticals, Pfizer, Lilly Pharmaceuticals/Loxo Oncology, Zymeworks, Gilead, Puma Biotechnology, Merck Pharmaceuticals, and Scorpion Therapeutics. HW: His institution received financial compensation on his behalf for advisory boards, lecture fees and/or consultancy fees from Daiichi Sankyo, Gilead, Lilly, Augustine Therapeutics, AstraZeneca, Immutep Pty, MSD, and Roche. He received travel support from Gilead, Daiichi Sankyo, and Pfizer. SAH: Contracted research paid to institution +/- editorial support for authorship: Ambrx, Arvinas, AstraZeneca, Bayer, Celcuity, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, Greenwich Life Sciences Inc., GSK, Immunomedics, Eli Lilly, Loxo, Macrogenics, Novartis, OBI Pharma, Orinove, Orum, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Sanofi, Seattle Genetics/Seagen, and Zymeworks. Speaking: Daiichi Sankyo (2021). AG-Z: Advisory/Consultancy: AstraZeneca, Novartis, MSD, Pierre-Fabre, and Exact Science. Speaker Bureau/Expert testimony: Roche, AstraZeneca, Novartis, MSD, Pfizer, Lilly, and Pierre-Fabre. Research grant/Funding (institution): Pfizer. Travel/Accommodation/Expenses: Roche, Novartis, and Pfizer. NU: Consultant/Advisory Board: Novartis, Eli Lilly, BioTheranostics, Gilead. AB: Consultant: AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, Seagen, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma, Myriad, and Gilead; research support: Agendia and AstraZeneca. HP: Research grants to institution: Adlai Nortye USA, Ambrx, Aprea Therapeutics AB, Array BioPharma, AstraZeneca, BJ Bioscience, Bristol-Myers Squibb, Daiichi Pharmaceutical, Elicio Therapeutics, Exelixis, Fate Therapeutics, Genentech, GlaxoSmithKline, Gossamer Bio, Hutchison MediPharma, ImmuneOncia Therapeutics, ImmunoGen, Mabspace Biosciences, MacroGenics, Merck, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, PsiOxus Therapeutics, RePare Therapeutics, Seattle Genetics, Synermore Biologics, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, Xencor. ESY: Research funding: Puma Biotechnology; Advisory boards: Bayer, Clovis; Consultant: AstraZeneca. IS: Institutional Research Funding: Roche/Genentech, Puma Biotechnology, MSD, Merck, AstraZeneca, Incyte, Orion, Genmab, Bristol-Myers Squibb, Bayer/Loxo Oncology, Lilly Pharmaceuticals/Loxo Oncology, Novartis, Pfizer, Amgen, Repare Therapeutics. Honoraria: AstraZeneca. Support for travel and meeting attendance: Roche, Novartis, Merck/Pfizer, Incyte, and AstraZeneca. SR: Consultant/Advisory board: Novartis, AstraZeneca, Gilead, and Daiichi Sankyo. MBh: Consulting/Advisory Board: Daiichi Sankyo, Merck, Pfizer, and AstraZeneca. SV: Funding from Pfizer directly to institution for conducting clinical trial. MA: Consulting or advisory role: Pfizer, AstraZeneca, Menarini, Novartis, Daiichi Sankyo, and Gilead. Speaker’s bureau: Pfizer, Novartis, and Gilead. Research funding: AstraZeneca. F-CB: Consulting or advisory role: Pfizer; AstraZeneca; Lilly; Novartis; Menarini; Sanofi; GSK; Rain Oncology; Caris Life Sciences; GE Healthcare; Exact Sciences; Gilead. Speaker's bureau: Pfizer; Novartis; AstraZeneca; Roche; Lilly; Rain Oncology; Daiichi Sankyo; and Menarini-Stemline. Research Funding: Novartis; Pfizer; Menarini Silicon Biosystems; Prolynx; Merck KGaA; and GE Healthcare. SL: Receives research funding to her institution from Novartis, Bristol Myers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, and Seattle Genetics. She has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, Puma Biotechnology, Inc., Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, and Bristol Myers Squibb. JC: Has taken part in advisory boards for Puma Biotechnology. His unit is the recipient of a peer-reviewed grant from Science Foundation Ireland (an Irish government organization) which is part-funded by Puma Biotechnology Inc. Neither he nor his spouse own Puma Biotechnology stock. MEB: Medical advisory board of Strata Oncology; Research funding from AbbVie, Arcus, Apollomics, Elevation Oncology, Endeavor, Genetech, Puma, Loxo Oncology, and Seagen. SAP-P: Clinical trial research support/grant funding through the institution from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Epigenetix Inc., Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences, Inc., GlaxoSmithKline, Helix BioPharma Corp., Hengrui Pharmaceuticals, Co., Ltd., HiberCell, Inc., Immorna Biotherapeutics, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Ltd., Lytix Biopharma AS, Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Nectin Therapeutics, Ltd., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Replimune, Seattle Genetics, Silverback Therapeutics, Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, ZielBio, Inc., NCI/NIH, P30CA016672—Core Grant (CCSG Shared Resources); and consulting fees from CRC Oncology. JMS: Research grant support: AstraZeneca and Strata Oncology. SC: Advisory/Consultancy: Novartis, F. Hoffmann-La Roche, Pfizer, Eli Lilly, AstraZeneca, Amgen, Gilead, Merck, and Exact Sciences. Research funding to the institution: Novartis, F. Hoffmann-La Roche, Pfizer, Genomic Health/Exact Sciences, AstraZeneca, Genentech, Celgene, Amgen, BMS, Merck, Sanofi, Puma, and Gilead. CS: Consulting, advisory role or travel grants from: AstraZeneca, AX'Consulting, Byondis B.V, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd., Lilly, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre-Fabre, PintPharma, Puma Biotechnology, Seagen, and Zymeworks. JAG-S: Consulting or advisory role: Novartis Pharmaceuticals Corporation, AstraZeneca, Lilly, Seagen, Daiichi Sankyo, Gilead Sciences, Exact Sciences, and Stemline Menarini; speakers bureau: Novartis Pharmaceuticals Corporation, Lilly, AstraZeneca, and Stemline Menarini; travel, accommodations, expenses: Daiichi Sankyo, Gilead Sciences, and Exact Sciences. VG: Advisory Board: Boehringer. Research Funding: Bayer, Boehringer, Roche. Institutional Funding: Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Fibrogen, Amcure, Natera, Sierra Oncology, AstraZeneca, Medimmune, BMS, and MSD. ENG-Y: Honoraria from Novartis, Pfizer, Eli Lilly, MSD, and AstraZeneca. CM: Has received research grants from Puma Biotechnology and Pfizer. She received consulting fees from AstraZeneca, Olaris, Novartis, and Sanofi. ABH: Reports stock and other ownership interests in Pfizer (immediate family member) and research funding from Takeda. JWG: has received institutional research funding from Puma Biotechnology Inc. RB: Receives research grant from Puma; has performed consulting for Genentech. JSKB: Employee (and stockholder) of Tempus Labs. LDE, DD, AF, and AW: Employees and stockholders of Puma Biotechnology. CLA: Has received research grants from Pfizer, Lilly, and Takeda. He serves or has served as scientific advisor to Novartis, Lilly, AstraZeneca, Daiichi Sankyo, Merck, Immunomedics, OrigiMed, Sanofi, TAIHO Oncology, and Puma Biotechnology. DBS: Has served as a consultant for/received honorarium from Pfizer, Vividion Therapeutics, Scorpion Therapeutics, FORE Therapeutics, Fog Pharma, Elsie Biotechnologies, Fog Pharma, Rain Oncology, Function Oncology, and BridgeBio. All other authors have declared no conflicts of interest. Data Sharing The authors declare that the data supporting the findings of this study are available within the article. Qualified researchers and study participants may submit requests for other study documentation and clinical trial data to clinicaltrials@pumabiotechnology.com for consideration., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKI) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. It is unknown whether these secondary HER2 mutations, other than the HER2T798I gatekeeper mutation, are causal to neratinib resistance. Herein, we show that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling, which was blocked by combined inhibition of HER2 and MEK. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer., Significance: HER2-mutant breast cancers acquire secondary HER2 mutations that drive resistance to HER2 tyrosine kinase inhibitors, which can be overcome by combined inhibition of HER2 and MEK., (©2023 American Association for Cancer Research.)

CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer acquired resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Using a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/ RB1 -knockout (RBKO) breast cancer cells. PRMT5 inhibition blocked cell cycle G1-to-S transition independent of RB, thus arresting growth of RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Pharmacological inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), Ser2 Pol II hyperphosphorylation, and intron retention in genes that promote DNA synthesis. Treatment with the PRMT5i inhibitor pemrametostat and fulvestrant synergistically inhibited growth of ER+/RB-deficient patient-derived xenografts, suggesting dual ER and PRMT5 blockade as a novel therapeutic strategy to treat ER+/RB-deficient breast cancer.

Background: Although trastuzumab and other HER2-targeted therapies have significantly improved survival in patients with HER2 overexpressed or amplified (HER2+) breast cancer, a significant proportion of patients do not respond or eventually develop clinical resistance. Strategies to reverse trastuzumab resistance remain a high clinical priority. We were the first to report the role of CXCR4 in trastuzumab resistance. The present study aims to explore the therapeutic potential of targeting CXCR4 and better understand the associated mechanisms., Methods: Immunofluorescent staining, confocal microscopy analysis, and immunoblotting were used to analyze CXCR4 expression. BrdU incorporation assays and flow cytometry were used to analyze dynamic CXCR4 expression. Three-dimensional co-culture (tumor cells/breast cancer-associated fibroblasts/human peripheral blood mononuclear cells) or antibody-dependent cellular cytotoxicity assay was used to mimic human tumor microenvironment, which is necessary for testing therapeutic effects of CXCR4 inhibitor or trastuzumab. The FDA-approved CXCR4 antagonist AMD3100, trastuzumab, and docetaxel chemotherapy were used to evaluate therapeutic efficacy in vitro and in vivo. Reverse phase protein array and immunoblotting were used to discern the associated molecular mechanisms., Results: Using a panel of cell lines and patient breast cancer samples, we confirmed CXCR4 drives trastuzumab resistance in HER2+ breast cancer and further demonstrated the increased CXCR4 expression in trastuzumab-resistant cells is associated with cell cycle progression with a peak in the G2/M phases. Blocking CXCR4 with AMD3100 inhibits cell proliferation by downregulating mediators of G2-M transition, leading to G2/M arrest and abnormal mitosis. Using a panel of trastuzumab-resistant cell lines and an in vivo established trastuzumab-resistant xenograft mouse model, we demonstrated that targeting CXCR4 with AMD3100 suppresses tumor growth in vitro and in vivo, and synergizes with docetaxel., Conclusions: Our findings support CXCR4 as a novel therapeutic target and a predictive biomarker for trastuzumab resistance in HER2+ breast cancer., (© 2023. The Author(s).)

The NCI-MATCH (Molecular Analysis for Therapy Choice) trial ( NCT02465060 ) was launched in 2015 as a genomically driven, signal-seeking precision medicine platform trial-largely for patients with treatment-refractory, malignant solid tumors. Having completed in 2023, it remains one of the largest tumor-agnostic, precision oncology trials undertaken to date. Nearly 6,000 patients underwent screening and molecular testing, with a total of 1,593 patients (inclusive of continued accrual from standard next-generation sequencing) being assigned to one of 38 substudies. Each substudy was a phase 2 trial of a therapy matched to a genomic alteration, with a primary endpoint of objective tumor response by RECIST criteria. In this Perspective, we summarize the outcomes of the initial 27 substudies in NCI-MATCH, which met its signal-seeking objective with 7/27 positive substudies (25.9%). We discuss key aspects of the design and operational conduct of the trial, highlighting important lessons for future precision medicine studies., (© 2023. Springer Nature America, Inc.)

Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy. We explored the efficacy of palbociclib in patients with nonbreast solid tumors containing an amplification in CCND1, 2, or 3., Patients and Methods: Patients with tumors containing a CCND1, 2, or 3 amplification and expression of the retinoblastoma protein were assigned to subprotocol Z1B and received palbociclib 125 mg once daily for 21 days of a 28-day cycle. Tumor response was assessed every two cycles., Results: Forty patients were assigned to subprotocol Z1B; 4 patients had outside assays identifying the CCND1, 2, or 3 amplification and were not confirmed centrally; 3 were ineligible and 2 were not treated (1 untreated patient was also ineligible), leaving 32 evaluable patients for this analysis. There were no partial responses; 12 patients (37.5%) had stable disease as best response. There were seven deaths on study, all during cycle 1 and attributable to disease progression. Median progression-free survival was 1.8 months. The most common toxicities were leukopenia (n = 21, 55%) and neutropenia (n = 19, 50%); neutropenia was the most common grade 3/4 event (n = 12, 32%)., Conclusions: Palbociclib was not effective at treating nonbreast solid tumors with a CCND1, 2, or 3 amplification in this cohort. These data do not support further investigation of single-agent palbociclib in tumors with CCND1, 2, or 3 amplification., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 ( NF1 [S1] or GNA11/Q [S2]) altered tumors., Methods: Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss., Results: Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common., Conclusion: Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

Purpose: GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling., Methods: A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 -) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status., Results: Patients (N = 152) received GDC-0810 100-800 mg once daily (QD) or 300-400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%)., Conclusion: GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835 ., (© 2022. The Author(s).)

Purpose: Increased body mass index (BMI) and metabolic syndrome (MS) are associated with increased breast cancer recurrence risk. Whether this is due to intrinsic tumor biology or modifiable factors of the obese state remains incompletely understood., Methods: Oncotype DX Recurrence Scores of 751 patients were stratified by BMI to assess association with tumor-intrinsic recurrence risk. Cellular proliferation by Ki67 after 10-21 days of presurgical letrozole treatment was used to stratify endocrine therapy response (sensitive-ln(Ki67) < 1; intermediate-ln(Ki67)1-2; resistant-ln(Ki67) >  = 2). BMI at the time of surgery and MS variables were collected retrospectively for 143 patients to analyze association between therapy response and BMI/MS. Additionally, PI3K pathway signaling was evaluated by immunohistochemistry of phosphorylated Akt and S6., Results: There was no significant association between BMI and recurrence score (p = 0.99), and risk score distribution was similar across BMI groups. However, BMI was associated with short-term endocrine therapy resistance, with a significant enrichment of intermediate and resistant tumors in patients with obesity (55%, p = 0.0392). Similarly, the relative risk of an endocrine therapy-resistant tumor was 1.4-fold greater for patients with MS (p = 0.0197). In evaluating PI3K pathway mediators, we found patients with 3 or more MS criteria had more tumors with pAkt scores above the median (p = 0.0436). There were no significant differences in S6 activation., Conclusion: Our findings suggest the association between obesity/metabolic syndrome and breast cancer recurrence is better reflected by response to treatment than tumor-intrinsic properties, suggesting interventions to reverse obesity and/or MS may improve outcomes for breast cancer recurrence., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Clinical trials in patients with ER+ breast cancer with or without FGFR pathway somatic alterations have shown limited clinical benefit from treatment with FGFR tyrosine kinase inhibitors alone or in combination with endocrine therapy. This is likely because of an inadequate predictive biomarker to select appropriate patients. In this study, we evaluated 4 anti-FGFR1 antibodies in breast cancer cell lines and patient-derived xenografts with FGFR1 amplification. We correlated D8E4 expression in 209 tumors from postmenopausal patients with stage I-III operable ER+ breast cancer with FGFR1 amplification status as determined by fluorescence in situ hybridization. FGFR1 amplification was identified in 10% of tumors (21/209), 80% of which exhibited membranous FGFR1 expression; however, only 50% of amplified cases showed strong, complete membranous staining (3+) based on established criteria to score HER2 by immunohistochemistry. These findings suggest the combined evaluation of FGFR1 status by immunohistochemistry and fluorescence in situ hybridization may need to be incorporated into the selection of patients for trials with FGFR inhibitors., Competing Interests: C.L.A. receives or has received research grants from Pfizer, Lilly, and Takeda; holds minor stock options in Provista; serves or has served in a scientific advisory role to Novartis, Merck, Lilly, Daiichi Sankyo, Astra Zeneca, Immunomedics, Taiho Oncology, OrigiMed, Athenex, Arvinas, and Sanofi; and reports scientific advisory board remuneration from the Komen Foundation. The remaining authors declare no conflicts of interests., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: Deregulated signaling pathways are a hallmark feature of oncogenesis and driver of tumor progression. Dual specificity protein phosphatase 4 (DUSP4) is a critical negative regulator of the mitogen-activated protein kinase (MAPK) pathway and is often deleted or epigenetically silenced in tumors. DUSP4 alterations lead to hyperactivation of MAPK signaling in many cancers, including breast cancer, which often harbor mutations in cell cycle checkpoint genes, particularly in TP53., Methods: Using a genetically engineered mouse model, we generated mammary-specific Dusp4-deleted primary epithelial cells to investigate the necessary conditions in which DUSP4 loss may drive breast cancer oncogenesis., Results: We found that Dusp4 loss alone is insufficient in mediating tumorigenesis, but alternatively converges with loss in Trp53 and MYC amplification to induce tumorigenesis primarily through chromosome 5 amplification, which specifically upregulates Dbf4, a cell cycle gene that promotes cellular replication by mediating cell cycle checkpoint escape., Conclusions: This study identifies a novel mechanism for breast tumorigenesis implicating Dusp4 loss and p53 mutations in cellular acquisition of Dbf4 upregulation as a driver of cellular replication and cell cycle checkpoint escape., (© 2022. The Author(s).)

The MYC oncogene is frequently amplified in triple-negative breast cancer (TNBC). Here, we show that MYC suppression induces immune-related hallmark gene set expression and tumor-infiltrating T cells in MYC-hyperactivated TNBCs. Mechanistically, MYC repressed stimulator of interferon genes (STING) expression via direct binding to the STING1 enhancer region, resulting in downregulation of the T-cell chemokines CCL5, CXCL10, and CXCL11. In primary and metastatic TNBC cohorts, tumors with high MYC expression or activity exhibited low STING expression. Using a CRISPR-mediated enhancer perturbation approach, we demonstrated that MYC-driven immune evasion is mediated by STING repression. STING repression induced resistance to PD-L1 blockade in mouse models of TNBC. Finally, a small-molecule inhibitor of MYC combined with PD-L1 blockade elicited a durable response in immune-cold TNBC with high MYC expression, suggesting a strategy to restore PD-L1 inhibitor sensitivity in MYC-overexpressing TNBC., (©2022 American Association for Cancer Research.)

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death., (© 2022. The Author(s).)

Purpose: National Cancer Institute-Molecular Analysis for Therapy Choice is a multicohort trial that assigns patients with advanced cancers to targeted therapies on the basis of central tumor genomic testing. Arm B evaluated afatinib, an ErbB family tyrosine kinase inhibitor, in patients with ERBB2 -activating mutations., Methods: Eligible patients had selected ERBB2 single-nucleotide variants or insertions/deletions detected by the National Cancer Institute-Molecular Analysis for Therapy Choice next-generation sequencing assay. Patients had performance status ≤ 1, left ventricular ejection fraction > 50%, grade ≤ 1 diarrhea, and no prior human epidermal growth factor receptor 2 (HER2) therapy. Patients received afatinib 40 mg once daily in 28-day cycles. The primary end point was objective response rate (ORR). Secondary end points were 6-month progression-free survival, overall survival, toxicity, and molecular correlates., Results: A total of 59 patients were assigned and 40 were enrolled. The median age was 62 years, 78% were female, 68% had performance status = 1, and 58% had received > 3 prior therapies. The confirmed ORR was 2.7% (n = 1 of 37; 90% CI, 0.14 to 12.2), and 6-month progression-free survival was 12.0% (90% CI, 5.6 to 25.8). A confirmed partial response occurred in a patient with adenocarcinoma of extra-mammary Paget disease of skin who progressed after cycle 6. Two unconfirmed partial responses were observed (low-grade serous gynecological tract and estrogen receptor-positive/HER2-negative immunohistochemistry breast ductal carcinoma). Of 12 patients with breast cancer, 1 additional patient with lobular carcinoma (estrogen receptor-positive/HER2 fluorescent in situ hybridization) had a 51% reduction in target lesions but progressed because of a new lesion at cycle 6. The most common (> 20%) treatment-related adverse events were diarrhea (68%), mucositis (43%), fatigue (40%), acneiform rash (30%), dehydration (27%), vomiting (27%), nausea (27%), anemia (27%), and anorexia (22%). Four patients (11%) discontinued because of adverse events., Conclusion: Although afatinib did not meet the prespecified threshold for antitumor activity in this heavily pretreated cohort, the response in a rare tumor type is notable. The safety profile of afatinib was consistent with prior studies.

Purpose: Activating mutations in PIK3CA are observed across multiple tumor types. The NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolls patients to targeted therapies on the basis of matching genomic alterations. Arm Z1F evaluated copanlisib, an α and δ isoform-specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with PIK3CA mutations (with or without PTEN loss)., Patients and Methods: Patients received copanlisib (60 mg intravenous) once weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity. Patients with KRAS mutations, human epidermal growth factor receptor 2-positive breast cancers, and lymphomas were excluded. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival, 6-month progression-free survival, and overall survival., Results: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the Protocol. Multiple histologies were enrolled, with gynecologic (n = 6) and gastrointestinal (n = 6) being the most common. Sixty-eight percent of patients had ≥ 3 lines of prior therapy. The ORR was 16% (4 of 25, 90% CI, 6 to 33) with P = .0341 against a null rate of 5%. The most common reason for protocol discontinuation was disease progression (n = 17, 68%). Grade 3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Sixteen patients (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 12), diarrhea (n = 11), hypertension (n = 10), and nausea (n = 10)., Conclusion: The study met its primary end point with an ORR of 16% ( P = .0341) with copanlisib showing clinical activity in select tumors with PIK3CA mutation in the refractory setting., Competing Interests: Senthil DamodaranResearch Funding: EMD Serono (Inst), Guardant Health (Inst), Taiho Pharmaceutical (Inst), Novartis (Inst), Sermonix Pharmaceuticals (Inst) Fengmin ZhaoThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. Dustin A. DemingConsulting or Advisory Role: Bayer, Promega, Array BioPharma, Lilly, PfizerResearch Funding: Merck (Inst), Bristol Myers Squibb (Inst), Genentech (Inst), Revolution Medicines (Inst), Millennium (Inst), Bayer Edith P. MitchellLeadership: Corvus PharmaceuticalsHonoraria: Sanofi, ExelixisConsulting or Advisory Role: Genentech, Novartis, Merck, Bristol Myers SquibSpeakers' Bureau: IpsenResearch Funding: Genentech (Inst), sanofi (Inst) Robert J. GrayResearch Funding: Agios, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Genentech/Roche, Genomic Health, Genzyme, GlaxoSmithKline, Janssen-Ortho, Onyx, Pfizer, Sequenta, Syndax, Novartis, Takeda, AbbVie, Sanofi, Merck Sharp & Dohme Lisa M. McShaneThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. Larry V. RubinsteinThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. P. Mickey WilliamsResearch Funding: Illumina (Inst)Patents, Royalties, Other Intellectual Property: I was a coinventor of the DLBCL cell of origin patent recently filed by the NIH Stanley R. HamiltonResearch Funding: Minerva Biotechnologies, Intima Carlos L. ArteagaStock and Other Ownership Interests: Provista DiagnosticsConsulting or Advisory Role: Novartis, Lilly, Sanofi, Radius Health, Taiho Pharmaceutical, Puma Biotechnology, Merck, Origimed, Immunomedics, Daiichi Sankyo, Athenex, Astrazeneca, ArvinasResearch Funding: Pfizer, Lilly, TakedaOther Relationship: Susan G. Komen for the Cure Lyndsay N. HarrisPatents, Royalties, Other Intellectual Property: Philips Healthcare Peter J. O'DwyerConsulting or Advisory Role: GenentechResearch Funding: Bristol Myers Squibb (Inst), Pfizer (Inst), Novartis (Inst), Genentech (Inst), Mirati Therapeutics (Inst), Celgene (Inst), GlaxoSmithKline (Inst), BBI Healthcare (Inst), Pharmacyclics (Inst), Five Prime Therapeutics (Inst), Forty Seven (Inst), Amgen (Inst), H3 Biomedicine (Inst), Taiho Pharmaceutical (Inst), Array BioPharma (Inst), Lilly/ImClone (Inst), Syndax (Inst), Minneamrita Therapeutics (Inst)Expert Testimony: Lilly, Dai-ichi Sankyo Alice P. ChenUncompensated Relationships: Frontiers in Medicine Keith T. FlahertyStock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Shattuck Labs, Apricity Health, Oncoceutics, FOGPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley TherapeuticsConsulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, Boston Biomedical, Debiopharm Group, FOGPharmaNo other potential conflicts of interest were reported.

Background: In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known., Methods: Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings., Results: After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed., Conclusions: First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.)., (Copyright © 2022 Massachusetts Medical Society.)

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting., (© 2022. The Author(s).)

Purpose: PIK3CA mutations frequently contribute to oncogenesis in solid tumors. Taselisib, a potent and selective inhibitor of phosphoinositide 3-kinase, has demonstrated clinical activity in PIK3CA -mutant breast cancer. Whether PIK3CA mutations predict sensitivity to taselisib in other cancer types is unknown. National Cancer Institute-Molecular Analysis for Therapy Choice Arm EAY131-I is a single-arm, phase II study of the safety and efficacy of taselisib in patients with advanced cancers., Methods: Eligible patients had tumors with an activating PIK3CA mutation. Patients with breast or squamous cell lung carcinoma, or whose cancer had KRAS or PTEN mutations, were excluded. Patients received taselisib 4 mg, orally once daily continuously, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included progression-free survival (PFS), 6-month PFS, overall survival (OS), and identification of predictive biomarkers., Results: Seventy patients were enrolled, and 61 were eligible and initiated protocol therapy. Types of PIK3CA mutations included helical 41 of 61 (67%), kinase 11 of 61 (18%), and other 9 of 61 (15%). With a median follow-up of 35.7 months, there were no complete or partial responses. Six-month PFS was 19.9% (90% CI, 12.0 to 29.3) and median PFS was 3.1 months (90% CI, 1.8 to 3.7). Six-month OS was 60.7% (90% CI, 49.6 to 70.0) and median OS was 7.2 months (90% CI, 5.9 to 10.0). Individual comutations were too heterogeneous to correlate with clinical outcome. Fatigue, diarrhea, nausea, and hyperglycemia were the most common toxicities, and most were grade 1 and 2., Conclusion: In this study, taselisib monotherapy had very limited activity in a heterogeneous cohort of heavily pretreated cancer patients with PIK3CA -mutated tumors; the presence of a PIK3CA mutation alone does not appear to be a sufficient predictor of taselisib activity., Competing Interests: Ian E. KropEmployment: Freeline Therapeutics (I), PureTech (I), AMAG Pharmaceuticals (I)Leadership: AMAG Pharmaceuticals (I), Freeline Therapeutics (I), PureTech (I)Stock and Other Ownership Interests: AMAG Pharmaceuticals (I), Freeline Therapeutics (I), PureTech (I)Honoraria: Genentech/Roche, AstraZeneca, CelltrionConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Daiichi Sankyo, Macrogenics, Novartis, Merck, Bristol Myers Squibb, AstraZenecaResearch Funding: Genentech (Inst), Pfizer (Inst) Juneko E. Grilley-OlsonConsulting or Advisory Role: Bayer, Chimerix, Kura Oncology, SpringWorks TherapeuticsResearch Funding: NanoCarrier (Inst), Genentech (Inst), Seattle Genetics (Inst), Pfizer (Inst), Loxo (Inst), Astellas Pharma (Inst), Iovance Biotherapeutics (Inst) Josh D. LauringEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & JohnsonConsulting or Advisory Role: Galderma (I), Regeneron (I), Novartis (I)Speakers' Bureau: Galderma (I), AbbVie (I), Pfizer (I)Patents, Royalties, Other Intellectual Property: I intermittently receive royalty payments for cell lines created in my laboratory, which are licensed for commercial sale to Horizon Discovery, Ltd by Johns Hopkins UniversityTravel, Accommodations, Expenses: Galderma (I), AbbVie (I) Edith P. MitchellLeadership: Corvus PharmaceuticalsHonoraria: Sanofi, ExelixisConsulting or Advisory Role: Genentech, Novartis, Merck, Bristol Myers SquibSpeakers' Bureau: IpsenResearch Funding: Genentech (Inst), sanofi (Inst) Robert J. GrayResearch Funding: Agios, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Genentech/Roche, Genomic Health, Genzyme, GlaxoSmithKline, Janssen-Ortho, Onyx, Pfizer, Sequenta, Syndax, Novartis, Takeda, AbbVie, Sanofi, Merck Sharp & Dohme P. Mickey WilliamsResearch Funding: Illumina (Inst)Patents, Royalties, Other Intellectual Property: I was a coinventor of the DLBCL cell of origin patent recently filed by the NIH Stanley R. HamiltonResearch Funding: Minerva Biotechnologies, Intima James M. FordThis author is the Editor-in-Chief for JCO Precision Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Research Funding: Genentech (Inst), AstraZeneca (Inst), Puma Biotechnology (Inst), Pfizer (Inst), Merus (Inst), Bayer (Inst), Incyte (Inst) Agustin A. GarciaConsulting or Advisory Role: Biotheranostics, GlaxoSmithKlineResearch Funding: Advenchen Laboratories (Inst), Seattle Genetics (Inst), Merck (Inst), Iovance Pharm (Inst) Xingwei D. SuiConsulting or Advisory Role: Novartis Robert D. SiegelResearch Funding: Merck (Inst), Mirati Therapeutics (Inst), GRAIL (Inst), Altor BioScience (Inst), Galera Therapeutics (Inst), Apollomics (Inst), Strata Oncology (Inst), Arcus Biosciences (Inst), Bristol Myers Squibb (Inst), Cancer Insight (Inst), Puma Biotechnology (Inst), Conjupro Biotherapeutics (Inst), Razor Genomics (Inst), Sanofi (Inst), Seattle Genetics (Inst)Other Relationship: American Board of Internal Medicine (ABIM) Brian M. SlomovitzConsulting or Advisory Role: Clovis Oncology, AstraZeneca, Genentech, Incyte, Agenus, GlaxoSmithKline, GOG Foundation, Myriad Genetics, Merck, Eisai Carlos L. ArteagaStock and Other Ownership Interests: Provista DiagnosticsConsulting or Advisory Role: Novartis, Lilly, Sanofi, Radius Health, Taiho Pharmaceutical, Puma Biotechnology, Merck, Origimed, Immunomedics, Daiichi Sankyo, Athenex, Astrazeneca, ArvinasResearch Funding: Pfizer, Lilly, TakedaOther Relationship: Susan G. Komen for the Cure Lyndsay N. HarrisPatents, Royalties, Other Intellectual Property: Philips Healthcare Peter J. O'DwyerConsulting or Advisory Role: GenentechResearch Funding: Bristol Myers Squibb (Inst), Pfizer (Inst), Novartis (Inst), Genentech (Inst), Mirati Therapeutics (Inst), Celgene (Inst), GlaxoSmithKline (Inst), BBI Healthcare (Inst), Pharmacyclics (Inst), Five Prime Therapeutics (Inst), Forty Seven (Inst), Amgen (Inst), H3 Biomedicine (Inst), Taiho Pharmaceutical (Inst), Array BioPharma (Inst), Lilly/ImClone (Inst), Syndax (Inst), Syndax (Inst), Syndax (Inst), Syndax (Inst), syndax (Inst), Minneamrita Therapeutics (Inst)Expert Testimony: Lilly, Dai-ichi Sankyo Alice P. Chen(OPTIONAL) Uncompensated Relationships: Frontiers in Medicine Keith T. FlahertyStock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Shattuck Labs, Apricity Health, Oncoceutics, FOGPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley TherapeuticsConsulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, Boston Biomedical, Debiopharm Group, FOGPharmaNo other potential conflicts of interest were reported.

HER2+ breast cancer patients are presented with either synchronous (S-BM), latent (Lat), or metachronous (M-BM) brain metastases. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Here, employing brain metastatic models, we show that metabolic diversity and plasticity within brain-tropic cells determine metastatic fitness. Lactate secreted by aggressive metastatic cells or lactate supplementation to mice bearing Lat cells limits innate immunosurveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immunosurveillance, oxidize glutamine, and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched M-BM brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Inhibiting xCT function attenuates residual disease and recurrence in these preclinical models., Competing Interests: Declaration of interests A.B.H. has received research grant support from Takeda and travel support from Puma Biotechnology. C.L.A. receives or has received research grant support from Pfizer, Lilly, and Takeda; holds stock options in Provista and Y-TRAP; and serves or has served in an advisory role to Novartis, Lilly, TAIHO Oncology, Daiichi Sankyo, Merck, AstraZeneca, OrigiMed, Immunomedics, and Susan G. Komen Foundation. R.J.D. is a founder of Atavistik Biosciences and an advisor for Agios Pharmaceuticals, Nirogy Therapeutics, and Vida Ventures., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fibroblast growth factors (FGFs) and their receptors (FGFRs) have been extensively investigated in solid malignancies, representing an attractive therapeutic target. In breast cancer, especially in estrogen receptor positive (ER+) subtype, FGFR signaling aberrations have been reported to contribute to proliferation, dedifferentiation, metastasis and drug resistance. However, clinical trials evaluating the use of FGFR inhibitors in breast cancer have had disappointing results. The different biological properties of distinct FGFR alterations and lack of established patient selection criteria, in addition to the early use of non-selective inhibitors, are possible reasons of this failure. Herein, we review the current knowledge regarding the role of FGFR signaling in endocrine resistance in breast cancer. We will also summarize the results from the clinical development of FGFR inhibitors in breast cancer, discussing future challenges to identify the correct cohorts of patients to enroll in trials testing FGFR inhibitors., (Copyright © 2021. Published by Elsevier B.V.)