bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from GRM1 is An Androgen-Regulated Gene and its Expression Correlates with Prostate Cancer Progression in Pre-Clinical Models
Authors: Shourideh Mojgan , Azabdaftari Gissou , Attwood Kristopher , DePriest Adam , Wadosky Kristine M , Gillard Bryan M , Karasik Ellen , Heemers Hannelore , Kyprianou Natasha , Gelman Irwin H. , Corey Eva , Vessella Robert L , Mohler James L. , Koochekpour Shahriar
Published: April 2023

Abstract
Purpose:We recently demonstrated that glutamate receptor GRM1 was expressed at high levels in castration-resistant prostate cancer (CR-PCa) tissues and cells. Herein, we determined the relationship between GRM1 and AR, PSA, and tumor growth, remission, and recurrence in preclinical PCa models. The effect of alterations in GRM1 expression was also investigated on PCa cell growth, migration and invasion. Experimental Design:We used quantitative gene expression and immunohistochemistry to define the temporal association between GRM1 expression and AR, PSA, and tumor growth during CR progression in CWR22 (n = 59) and LuCaP 35 (n = 12) PCa xenografts. The effect of alterations in GRM1 expression levels on growth, migration, and invasion was investigated in GRM1-overexpressed or -silenced PCa cell lines. The effect of DHT on GRM1 expression was determined in the presence or absence of the antiandrogen bicalutamide. Results:We found that GRM1 transcript and tissue expression directly correlated with growth and AR and PSA expression in hormone-sensitive (HS), castrated, and CR tumor xenografts. GRM1 overexpression or silencing directly correlated with PCa cell proliferation, migration, and invasion. DHT increased GRM1 expression via an AR-dependent manner in HS- and CR-PCa cell lines. Conclusions:This is a first report of GRM1 as an androgen and AR-target gene. GRM1 expression directly correlated with tumor growth, regression, and recurrence and may contribute to CR-progression of PCa in preclinical models. Further studies are needed to define the utility of GRM1 as a druggable target or biomarker for PCa.
Data from Antibody–Fc/FcR Interaction on Macrophages as a Mechanism for Hyperprogressive Disease in Non–small Cell Lung Cancer Subsequent to PD-1/PD-L1 Blockade
Authors: Lo Russo Giuseppe , Moro Massimo , Sommariva Michele , Cancila Valeria , Boeri Mattia , Centonze Giovanni , Ferro Simona , Ganzinelli Monica , Gasparini Patrizia , Huber Veronica , Milione Massimo , Porcu Luca , Proto Claudia , Pruneri Giancarlo , Signorelli Diego , Sangaletti Sabina , Sfondrini Lucia , Storti Chiara , Tassi Elena , Bardelli Alberto , Marsoni Silvia , Torri Valter , Tripodo Claudio , Colombo Mario Paolo , Anichini Andrea , Rivoltini Licia , Balsari Andrea , Sozzi Gabriella , Garassino Marina Chiara
Published: April 2023

AbstractPurpose:
Hyperprogression (HP), a paradoxical boost in tumor growth, was described in a subset of patients treated with immune checkpoint inhibitors (ICI). Neither clinicopathologic features nor biological mechanisms associated with HP have been identified.
Experimental Design:
Among 187 patients with non–small cell lung cancer (NSCLC) treated with ICI at our institute, cases with HP were identified according to clinical and radiologic criteria. Baseline histologic samples from patients treated with ICI were evaluated by IHC for myeloid and lymphoid markers. T-cell–deficient mice, injected with human lung cancer cells and patient-derived xenografts (PDX) belonging to specific mutational subsets, were assessed for tumor growth after treatment with antibodies against mouse and human programmed death receptor-1 (PD-1). The immune microenvironment was evaluated by flow cytometry and IHC.
Results:
Among 187 patients, 152 were evaluable for clinical response. We identified four categories: 32 cases were defined as responders (21%), 42 patients with stable disease (27.7%), 39 cases were defined as progressors (25.7%), and 39 patients with HP (25.7%). Pretreatment tissue samples from all patients with HP showed tumor infiltration by M2-like CD163+CD33+PD-L1+ clustered epithelioid macrophages. Enrichment by tumor-associated macrophages (TAM) was observed, even in tumor nodules from immunodeficient mice injected with human lung cancer cells and with PDXs. In these models, tumor growth was enhanced by treatment with anti–PD-1 but not anti–PD-1 F(ab)2 fragments.
Conclusions:
These results suggest a crucial role of TAM reprogramming, upon Fc receptor engagement by ICI, eventually inducing HP and provide clues on a distinctive immunophenotype potentially able to predict HP.

See related commentary by Knorr and Ravetch, p. 904
Data from HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2
Authors: Hanker Ariella B. , Garrett Joan T. , Estrada Mónica Valeria , Moore Preston D. , Ericsson Paula González , Koch James P. , Langley Emma , Singh Sharat , Kim Phillip S. , Frampton Garrett M. , Sanford Eric , Owens Philip , Becker Jennifer , Groseclose M. Reid , Castellino Stephen , Joensuu Heikki , Huober Jens , Brase Jan C. , Majjaj Samira , Brohée Sylvain , Venet David , Brown David , Baselga José , Piccart Martine , Sotiriou Christos , Arteaga Carlos L.
Published: April 2023

Abstract
Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2+) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.

Experimental Design: HER2+ BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples.

Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro. Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2+ early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathologic complete response in patients with HER2+ early breast cancer treated with neoadjuvant anti-HER2 therapy.

Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. Clin Cancer Res; 23(15); 4323–34. ©2017 AACR.
Data from Modeling the Cellular Response of Lung Cancer to Radiation Therapy for a Broad Range of Fractionation Schedules
Authors: Jeong Jeho , Oh Jung Hun , Sonke Jan-Jakob , Belderbos Jose , Bradley Jeffrey D. , Fontanella Andrew N. , Rao Shyam S. , Deasy Joseph O.
Published: April 2023

Abstract
Purpose: To demonstrate that a mathematical model can be used to quantitatively understand tumor cellular dynamics during a course of radiotherapy and to predict the likelihood of local control as a function of dose and treatment fractions.

Experimental Design: We model outcomes for early-stage, localized non–small cell lung cancer (NSCLC), by fitting a mechanistic, cellular dynamics-based tumor control probability that assumes a constant local supply of oxygen and glucose. In addition to standard radiobiological effects such as repair of sub-lethal damage and the impact of hypoxia, we also accounted for proliferation as well as radiosensitivity variability within the cell cycle. We applied the model to 36 published and two unpublished early-stage patient cohorts, totaling 2,701 patients.

Results: Precise likelihood best-fit values were derived for the radiobiological parameters: α [0.305 Gy−1; 95% confidence interval (CI), 0.120–0.365], the α/β ratio (2.80 Gy; 95% CI, 0.40–4.40), and the oxygen enhancement ratio (OER) value for intermediately hypoxic cells receiving glucose but not oxygen (1.70; 95% CI, 1.55–2.25). All fractionation groups are well fitted by a single dose–response curve with a high χ2 P value, indicating consistency with the fitted model. The analysis was further validated with an additional 23 patient cohorts (n = 1,628). The model indicates that hypofractionation regimens overcome hypoxia (and cell-cycle radiosensitivity variations) by the sheer impact of high doses per fraction, whereas lower dose-per-fraction regimens allow for reoxygenation and corresponding sensitization, but lose effectiveness for prolonged treatments due to proliferation.

Conclusions: This proposed mechanistic tumor-response model can accurately predict overtreatment or undertreatment for various treatment regimens. Clin Cancer Res; 23(18); 5469–79. ©2017 AACR.
Data from Prognostic Impact of Circulating Tumor Cells for Breast Cancer Patients Treated in the Neoadjuvant "Geparquattro" Trial
Authors: Riethdorf Sabine , Müller Volkmar , Loibl Sibylle , Nekljudova Valentina , Weber Karsten , Huober Jens , Fehm Tanja , Schrader Iris , Hilfrich Jörn , Holms Frank , Tesch Hans , Schem Christian , von Minckwitz Gunter , Untch Michael , Pantel Klaus
Published: April 2023

Abstract
Purpose: This study aimed to evaluate the prognostic impact of circulating tumor cells (CTC) detected in patients with operable or locally advanced breast cancer before and after neoadjuvant therapy (NT) within the clinical trial GeparQuattro.

Experimental Design: Data on CTCs enumerated with the CellSearch system were available for 213 and 207 patients before and after NT, respectively. Associations of CTCs with disease-free survival (DFS) and overall survival (OS) were analyzed by nonparametric Kaplan–Meier estimates and parametric Cox regression.

Results: After a median follow-up of 67.1 months, the detection of ≥1 CTC/7.5 mL and ≥2 CTCs/7.5 mL before NT was associated with reduced DFS (P = 0.031 and P < 0.0001, respectively) and OS (P = 0.0057 and P < 0.0001, respectively), whereas CTCs detected after NT did not correlate with DFS or OS. In parametric univariate and multivariate Cox models, ≥1 CTC/7.5 mL, ≥2 CTCs/7.5 mL, and absolute CTC numbers before NT revealed to be independent prognostic parameters of DFS and OS. CTC-negative patients with pathologic complete response (pCR) exhibited the best prognosis, whereas those with CTCs and less tumor response were at high risk of tumor relapse. In HER2 (ERBB2)-positive and triple-negative patients, ≥2 CTCs/7.5 mL detected before NT also were significantly associated with worse DFS and OS.

Conclusions: Detection of CTCs before NT is an independent prognostic factor of impaired clinical outcome, and combined with pCR, it could be helpful to stratify breast cancer patients for therapeutic interventions. Clin Cancer Res; 23(18); 5384–93. ©2017 AACR.
Data from EGFR Exon 20 Insertion Mutations Display Sensitivity to Hsp90 Inhibition in Preclinical Models and Lung Adenocarcinomas
Authors: Jorge Susan E. , Lucena-Araujo Antonio R. , Yasuda Hiroyuki , Piotrowska Zofia , Oxnard Geoffrey R. , Rangachari Deepa , Huberman Mark S. , Sequist Lecia V. , Kobayashi Susumu S. , Costa Daniel B.
Published: April 2023

AbstractPurpose:
EGFR exon 20 insertions account for up to 10% of all EGFR mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations remains elusive, without an approved inhibitor.
Experimental Design:
Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer.
Results:
We show that select first-, second-, and third-generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the Hsp90 chaperone system. We exploit this vulnerability to show that the nongeldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets, and induces apoptosis. In addition, a patient whose EGFR inhibitor–insensitive lung adenocarcinoma harbored an EGFR exon 20 insertion mutation had a confirmed radiographic response to luminespib.
Conclusions:
The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.
Data from In Vivo Validation of PAPSS1 (3′-phosphoadenosine 5′-phosphosulfate synthase 1) as a Cisplatin-sensitizing Therapeutic Target
Authors: Leung Ada W.Y. , Veinotte Chansey J. , Melong Nicole , Oh Min Hee , Chen Kent , Enfield Katey S.S. , Backstrom Ian , Warburton Corinna , Yapp Donald , Berman Jason N. , Bally Marcel B. , Lockwood William W.
Published: April 2023

Abstract
Purpose: Our previous screening efforts found that inhibition of PAPSS1 increases the potency of DNA-damaging agents in non–small cell lung cancer (NSCLC) cell lines. Here, we explored the clinical relevance of PAPSS1 and further investigated it as a therapeutic target in preclinical model systems.

Experimental Design: PAPSS1 expression and cisplatin IC50 values were assessed in 52 lung adenocarcinoma cell lines. Effects of PAPSS1 inhibition on A549 cisplatin sensitivity under hypoxic and starvation conditions, in 3D spheroids, as well as in zebrafish and mouse xenografts, were evaluated. Finally, the association between PAPSS1 expression levels and survival in patients treated with standard chemotherapy was assessed.

Results: Our results show a positive correlation between low PAPSS1 expression and increased cisplatin sensitivity in lung adenocarcinoma. In vitro, the potentiation effect was greatest when A549 cells were serum-starved under hypoxic conditions. When treated with low-dose cisplatin, PAPSS1-deficient A549 spheroids showed a 58% reduction in size compared with control cells. In vivo, PAPSS1 suppression and low-dose cisplatin treatment inhibited proliferation of lung tumor cells in zebrafish xenografts and significantly delayed development of subcutaneous tumors in mice. Clinical data suggest that NSCLC and ovarian cancer patients with low PAPSS1 expression survive longer following platinum-based chemotherapy.

Conclusions: These results suggest that PAPSS1 inhibition enhances cisplatin activity in multiple preclinical model systems and that low PAPSS1 expression may serve as a biomarker for platin sensitivity in cancer patients. Developing strategies to target PAPSS1 activity in conjunction with platinum-based chemotherapy may offer an approach to improving treatment outcomes. Clin Cancer Res; 23(21); 6555–66. ©2017 AACR.
Data from Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia
Authors: Mueller Karen Thudium , Waldron Edward , Grupp Stephan A. , Levine John E. , Laetsch Theodore W. , Pulsipher Michael A. , Boyer Michael W. , August Keith J. , Hamilton Jason , Awasthi Rakesh , Stein Andrew M. , Sickert Denise , Chakraborty Abhijit , Levine Bruce L. , June Carl H. , Tomassian Lori , Shah Sweta S. , Leung Mimi , Taran Tetiana , Wood Patricia A. , Maude Shannon L.
Published: April 2023

AbstractPurpose:
Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).
Patients and Methods:
We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).
Results:
Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders (N = 8; 74% and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence measurable beyond 2 years in responding patients. Cmax increased with occurrence and severity of cytokine release syndrome (CRS). Tisagenlecleucel continued to expand and persist following tocilizumab, used to manage CRS. Patients with B-cell recovery within 6 months had earlier loss of the transgene compared with patients with sustained clinical response. Clinical responses were seen across the entire dose range evaluated (patients ≤50 kg: 0.2 to 5.0 × 106/kg; patients >50 kg: 0.1 to 2.5 × 108 CAR-positive viable T cells) with no relationship between dose and safety. Neither preexisting nor treatment-induced antimurine CAR19 antibodies affected the persistence or clinical response.
Conclusions:
Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.
Data from ADAM17 is a Tumor Promoter and Therapeutic Target in Western Diet–associated Colon Cancer
Authors: Mustafi Reba , Dougherty Urszula , Mustafi Devkumar , Ayaloglu-Butun Fatma , Fletcher Michelle , Adhikari Sarbani , Sadiq Farhana , Meckel Katherine , Haider Haider I. , Khalil Abdurahman , Pekow Joel , Konda Vani , Joseph Loren , Hart John , Fichera Alessandro , Li Yan Chun , Bissonnette Marc
Published: April 2023

Abstract
Purpose: Epidermal growth factor receptors (EGFR) are required for tumor promotion by Western diet. The metalloprotease, ADAM17 activates EGFR by releasing pro-EGFR ligands. ADAM17 is regulated by G-protein–coupled receptors, including CXCR4. Here we investigated CXCR4–ADAM17 crosstalk and examined the role of ADAM17 in tumorigenesis.

Experimental Design: We used CXCR4 inhibitor, AMD3100 and ADAM17 inhibitor, BMS566394 to assess CXCR4–ADAM17 crosstalk in colon cancer cells. We compared the expression of CXCR4 ligand, CXCL2, and ADAM17 in mice fed Western diet versus standard diet. Separately, mice were treated with marimastat, a broad-spectrum ADAM17 inhibitor, or AMD3100 to assess EGFR activation by ADAM17 and CXCR4. Using Apc-mutant Min mice, we investigated the effects of ADAM17/10 inhibitor INCB3619 on tumorigenesis. To assess the effects of colonocyte ADAM17, mice with ADAM17 conditional deletion were treated with azoxymethane (AOM). ADAM17 expression was also compared in colonocytes from primary human colon cancers and adjacent mucosa.

Results: CXCL12 treatment activated colon cancer cell EGFR signals, and CXCR4 or ADAM17 blockade reduced this activation. In vivo, Western diet increased CXCL12 in stromal cells and TGFα in colonocytes. Marimastat or AMD3100 caused >50% reduction in EGFR signals (P < 0.05). In Min mice, INCB3619 reduced EGFR signals in adenomas and inhibited intestinal tumor multiplicity (P < 0.05). In the AOM model, colonocyte ADAM17 deletion reduced EGFR signals and colonic tumor development (P < 0.05). Finally, ADAM17 was upregulated >2.5-fold in human malignant colonocytes.

Conclusions: ADAM17 is a Western diet–inducible enzyme activated by CXCL12–CXCR4 signaling, suggesting the pathway: Western diet→CXCL12→CXCR4→ADAM17→TGFα→EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies. Clin Cancer Res; 23(2); 549–61. ©2016 AACR.
Data from XPO1 Inhibition using Selinexor Synergizes with Chemotherapy in Acute Myeloid Leukemia by Targeting DNA Repair and Restoring Topoisomerase IIα to the Nucleus
Authors: Ranganathan Parvathi , Kashyap Trinayan , Yu Xueyan , Meng Xiaomei , Lai Tzung-Huei , McNeil Betina , Bhatnagar Bhavana , Shacham Sharon , Kauffman Michael , Dorrance Adrienne M. , Blum William , Sampath Deepa , Landesman Yosef , Garzon Ramiro
Published: April 2023

Abstract
Purpose: Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore, we asked whether adding already established effective drugs such as topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML.

Experimental Design: The efficacy of combinatorial drug treatment using Topo II inhibitors (idarubicin, daunorubicin, mitoxantrone, etoposide) and selinexor was evaluated in established cellular and animal models of AML.

Results: Concomitant treatment with selinexor and Topo II inhibitors resulted in therapeutic synergy in AML cell lines and patient samples. Using a xenograft MV4-11 AML mouse model, we show that treatment with selinexor and idarubicin significantly prolongs survival of leukemic mice compared with each single therapy.

Conclusions: Aberrant nuclear export and cytoplasmic localization of Topo IIα has been identified as one of the mechanisms leading to drug resistance in cancer. Here, we show that in a subset of patients with AML that express cytoplasmic Topo IIα, selinexor treatment results in nuclear retention of Topo IIα protein, resulting in increased sensitivity to idarubicin. Selinexor treatment of AML cells resulted in a c-MYC–dependent reduction of DNA damage repair genes (Rad51 and Chk1) mRNA and protein expression and subsequent inhibition of homologous recombination repair and increased sensitivity to Topo II inhibitors. The preclinical data reported here support further clinical studies using selinexor and Topo II inhibitors in combination to treat AML. Clin Cancer Res; 22(24); 6142–52. ©2016 AACR.
Data from A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB)
Authors: Mayer Ingrid A. , Prat Aleix , Egle Daniel , Blau Sibel , Fidalgo J. Alejandro Pérez , Gnant Michael , Fasching Peter A. , Colleoni Marco , Wolff Antonio C. , Winer Eric P. , Singer Christian F. , Hurvitz Sara , Estévez Laura García , van Dam Peter A. , Kümmel Sherko , Mundhenke Christoph , Holmes Frankie , Babbar Naveen , Charbonnier Laure , Diaz-Padilla Ivan , Vogl Florian D. , Sellami Dalila , Arteaga Carlos L.
Published: April 2023

AbstractPurpose:
Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor–positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.

Patients and Methods: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts.
Results:
In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole.
Conclusions:
In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.
Data from Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis
Authors: Thomas Laura E. , Hurley Joanna J. , Meuser Elena , Jose Sian , Ashelford Kevin E. , Mort Matthew , Idziaszczyk Shelley , Maynard Julie , Brito Helena Leon , Harry Manon , Walters Angharad , Raja Meera , Walton Sarah-Jane , Dolwani Sunil , Williams Geraint T. , Morgan Meleri , Moorghen Morgan , Clark Susan K. , Sampson Julian R.
Published: April 2023

Abstract
Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.

Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing, and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared with each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.

Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006), and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2, and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P = 0.0017).

Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease. Clin Cancer Res; 23(21); 6721–32. ©2017 AACR.
Data from Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers
Authors: Offin Michael , Rizvi Hira , Tenet Megan , Ni Andy , Sanchez-Vega Francisco , Li Bob T. , Drilon Alexander , Kris Mark G. , Rudin Charles M. , Schultz Nikolaus , Arcila Maria E. , Ladanyi Marc , Riely Gregory J. , Yu Helena , Hellmann Matthew D.
Published: April 2023

AbstractPurpose:
Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored.
Experimental Design:
We identified all patients with metastatic EGFR exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type lung adenocarcinoma samples were used for comparison.
Results:
Among 153 patients with EGFR-mutant lung cancer, TMB was lower compared with EGFR wild-type (n = 1,849; median 3.77 vs. 6.12 mutations/Mb; P < 0.0001) with a broad range (0.82–17.9 mutations/Mb). Patients with EGFR-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; P = 0.0008) and OS (HR, 0.40; P = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, P = 0.006; OS, P = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, P = 0.01; HR = 0.50, P = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; P = 0.008).
Conclusions:
TMB is negatively associated with clinical outcomes in metastatic patients with EGFR-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.

See related commentary by Cheng and Oxnard, p. 899
Data from A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers
Authors: Paik Paul K. , Shen Ronglai , Berger Michael F. , Ferry David , Soria Jean-Charles , Mathewson Alastair , Rooney Claire , Smith Neil R. , Cullberg Marie , Kilgour Elaine , Landers Donal , Frewer Paul , Brooks Nigel , André Fabrice
Published: April 2023

Abstract
Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in FGFR1-amplified SQCLC cell lines and patient-derived xenografts.

Experimental Design: On the basis of these data, we performed a phase I study of AZD4547 in patients with previously treated stage IV FGFR1-amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses.

Results: Fifteen FGFR1-amplified patients were treated. The most common related adverse events (AE) were gastrointestinal and dermatologic. Grade ≥3–related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). Two of 15 patients (13.3%) were progression-free at 12 weeks, and the median overall survival was 4.9 months. Molecular tests, including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry, showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in 8p11 amplicon.

Conclusions: AZD4547 was tolerable at a dosage of 80 mg oral twice a day, with modest antitumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational covariates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease. Clin Cancer Res; 23(18); 5366–73. ©2017 AACR.
Data from Impact of Blood–Brain Barrier Integrity on Tumor Growth and Therapy Response in Brain Metastases
Authors: Osswald Matthias , Blaes Jonas , Liao Yunxiang , Solecki Gergely , Gömmel Miriam , Berghoff Anna S. , Salphati Laurent , Wallin Jeffrey J. , Phillips Heidi S. , Wick Wolfgang , Winkler Frank
Published: April 2023

Abstract
Purpose: The role of blood–brain barrier (BBB) integrity for brain tumor biology and therapy is a matter of debate.

Experimental Design: We developed a new experimental approach using in vivo two-photon imaging of mouse brain metastases originating from a melanoma cell line to investigate the growth kinetics of individual tumor cells in response to systemic delivery of two PI3K/mTOR inhibitors over time, and to study the impact of microregional vascular permeability. The two drugs are closely related but differ regarding a minor chemical modification that greatly increases brain penetration of one drug.

Results: Both inhibitors demonstrated a comparable inhibition of downstream targets and melanoma growth in vitro. In vivo, increased BBB permeability to sodium fluorescein was associated with accelerated growth of individual brain metastases. Melanoma metastases with permeable microvessels responded similarly to equivalent doses of both inhibitors. In contrast, metastases with an intact BBB showed an exclusive response to the brain-penetrating inhibitor. The latter was true for macro- and micrometastases, and even single dormant melanoma cells. Nuclear morphology changes and single-cell regression patterns implied that both inhibitors, if extravasated, target not only perivascular melanoma cells but also those distant to blood vessels.

Conclusions: Our study provides the first direct evidence that nonpermeable brain micro- and macrometastases can effectively be targeted by a drug designed to cross the BBB. Small-molecule inhibitors with these optimized properties are promising agents in preventing or treating brain metastases in patients. Clin Cancer Res; 22(24); 6078–87. ©2016 AACR.

See related commentary by Steeg et al., p. 5953
Data from FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation
Authors: Norsworthy Kelly J. , Luo Lola , Hsu Vicky , Gudi Ramadevi , Dorff Sarah E. , Przepiorka Donna , Deisseroth Albert , Shen Yuan-Li , Sheth Christopher M. , Charlab Rosane , Williams Gene M. , Goldberg Kirsten B. , Farrell Ann T. , Pazdur Richard
Published: April 2023

Abstract
The FDA approved ivosidenib (Tibsovo; Agios), a small-molecule inhibitor of isocitrate dehydrogenase (IDH)1 on July 20, 2018, for treatment of adults with relapsed or refractory acute myeloid leukemia (R/R AML) with susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of ivosidenib was established on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence (TD) to transfusion independence (TI) in Study AG120-C-001, a single-arm trial. With median follow-up of 8.3 months for 174 adults with IDH1-mutated R/R AML treated with 500 mg ivosidenib daily, the CR + CRh rate was 33% [95% confidence interval (CI), 26–40], median duration of response was 8.2 (95% CI, 5.6–12) months, and conversion from TD to TI occurred in 37% of patients. These endpoints reflect short-term benefit in patients with an unmet medical need; long-term efficacy outcomes were not assessed. Serious adverse reactions (AR) in ≥5% of patients were differentiation syndrome (10%), leukocytosis (10%), and QT interval prolongation (7%). Common (≥20%) ARs of any grade were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, QT interval prolongation, rash, pyrexia, cough, and constipation. Assessment of long-term safety of ivosidenib is a condition of this approval.
Data from Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma
Authors: Mohan Dipika R. , Lerario Antonio Marcondes , Else Tobias , Mukherjee Bhramar , Almeida Madson Q. , Vinco Michelle , Rege Juilee , Mariani Beatriz M. P. , Zerbini Maria Claudia N. , Mendonca Berenice B. , Latronico Ana Claudia , Marie Suely K. N. , Rainey William E. , Giordano Thomas J. , Fragoso Maria Candida B. V. , Hammer Gary D.
Published: April 2023

AbstractPurpose:
Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; however, patients with locoregional disease have variable outcomes. The Cancer Genome Atlas project on ACC (ACC-TCGA) identified that cancers of patients with homogeneously rapidly recurrent or fatal disease bear a unique CpG island hypermethylation phenotype, “CIMP-high.” We sought to identify a biomarker that faithfully captures this subgroup.

Experimental Design: We analyzed ACC-TCGA data to characterize differentially regulated biological processes, and identify a biomarker that is methylated and silenced exclusively in CIMP-high ACC. In an independent cohort of 114 adrenocortical tumors (80 treatment-naive primary ACC, 22 adrenocortical adenomas, and 12 non-naive/nonprimary ACC), we evaluated biomarker methylation by a restriction digest/qPCR-based approach, validated by targeted bisulfite sequencing. We evaluated expression of this biomarker and additional prognostic markers by qPCR.
Results:
We show that CIMP-high ACC is characterized by upregulation of cell cycle and DNA damage response programs, and identify that hypermethylation and silencing of G0S2 distinguishes this subgroup. We confirmed G0S2 hypermethylation and silencing is exclusive to 40% of ACC, and independently predicts shorter disease-free and overall survival (median 14 and 17 months, respectively). Finally, G0S2 methylation combined with validated molecular markers (BUB1B-PINK1) stratifies ACC into three groups, with uniformly favorable, intermediate, and uniformly dismal outcomes.
Conclusions:
G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal ACC, amenable to targeted assessment using routine molecular diagnostics. Assessing G0S2 methylation is straightforward, feasible for clinical decision-making, and will enable the direction of efficacious adjuvant therapies for patients with aggressive ACC.
Data from Telatinib Is an Effective Targeted Therapy for Pseudomyogenic Hemangioendothelioma
Authors: van IJzendoorn David G.P. , Sleijfer Stefan , Gelderblom Hans , Eskens Ferry A.L.M. , van Leenders Geert J.L.H. , Szuhai Karoly , Bovée Judith V.M.G.
Published: April 2023

Abstract
Purpose: Pseudomyogenic hemangioendothelioma (PHE) is an extremely rare locally aggressive neoplasm with endothelial differentiation, which often presents with multiple lesions. These tumors have characteristic SERPINE1–FOSB fusions. We report a 17 years old patient with advanced unresectable PHE with a durable complete remission to the multi-tyrosine kinase inhibitor telatinib. The aim of this study was to generate an in vitro model for PHE, to study the functional consequences of SERPINE1–FOSB in endothelial cells, and its interaction with telatinib, to biologically substantiate the complete response to telatinib.

Experimental Design: As the fusion results in overexpression of a truncated form of FOSB, we overexpressed truncated FOSB in normal endothelial cells.

Results: Truncated FOSB significantly affected tumor growth in three-dimensional (3D) on matrigel with increased and sustained sprouting. Moreover, truncated FOSB acted as an active transcription factor capable to regulate its own transcription, as well as to upregulate PDGFRA and FLT1 expression (four-fold). Telatinib decreased proliferation and tumor growth in 3D and induced apoptosis. As expected, telatinib blocked VEGF signaling as phosphorylation of ERK was abolished. Interestingly, in FOSB overexpressing cells, telatinib specifically affected PDGFRA, FLT1, and FLT4 signaling and downregulated SERPINE1, thereby affecting the self-regulation of the fusion gene.

Conclusions: We provide a biological substantiation of a complete clinical remission that was seen in a patient with PHE, showing that telatinib indirectly interferes with the self-regulated expression of the fusion product. Thus, telatinib or any other currently available VEGFR1-4/PDGFRA inhibitor could be a highly specific treatment option for patients with multifocal unresectable PHE. Clin Cancer Res; 24(11); 2678–87. ©2018 AACR.
Data from Circulating Tumor DNA in HER2-Amplified Breast Cancer: A Translational Research Substudy of the NeoALTTO Phase III Trial
Authors: Rothé Françoise , Silva Maria Joao , Venet David , Campbell Christine , Bradburry Ian , Rouas Ghizlane , de Azambuja Evandro , Maetens Marion , Fumagalli Debora , Rodrik-Outmezguine Vanessa , Di Cosimo Serena , Rosa Daniela , Chia Stephen , Wardley Andrew , Ueno Takayuki , Janni Wolfgang , Huober Jens , Baselga Jose , Piccart Martine , Loi Sherene , Sotiriou Christos , Dawson Sarah-Jane , Ignatiadis Michail
Published: April 2023

AbstractPurpose:
In the neoadjuvant treatment (NAT) setting, dual HER2-targeted therapy is associated with increased pathologic complete response (pCR) rates compared with each therapy alone. Biomarkers allowing to predict treatment response during NAT are needed. We aim to evaluate whether circulating tumor DNA (ctDNA) is associated with response to anti-HER2–targeted therapy.
Experimental Design:
Plasma DNA collected before NAT, at week 2, and before surgery from patients enrolled in the NeoALTTO trial was assessed using digital PCR for PIK3CA and TP53 mutation detection.
Results:
A total of 69 of 455 (15.2%) patients had a PIK3CA and/or TP53 mutation detected in the baseline tumor sample and evaluable ctDNA results from baseline samples. CtDNA was detected in 41%, 20%, and 5% patients before NAT, at week 2, and before surgery, respectively. ctDNA detection before NAT was significantly associated with older age and ER-negative status. ctDNA detection before NAT was associated with decreased odds of achieving pCR (OR = 0.15; 95% CI, 0.034–0.7; P = 0.0089), but not with event-free survival (EFS). Analyses for EFS were underpowered. Interestingly, the patients with HER2-enriched subtype tumors and undetectable ctDNA at baseline had the highest pCR rates. In contrast, patients with persistent ctDNA detection at baseline and week 2 had the lowest rate of pCR.
Conclusions:
ctDNA detection before neoadjuvant anti-HER2 therapies is associated with decreased pCR rates. Interestingly, patients with HER2-enriched tumors and undetectable ctDNA at baseline had the highest pCR rates, therefore appearing as the best candidates for treatment deescalation strategies.
Data from Molecular Lymph Node Status for Prognostic Stratification of Prostate Cancer Patients Undergoing Radical Prostatectomy with Extended Pelvic Lymph Node Dissection
Authors: Heck Matthias M. , Retz Margitta , Bandur Miriam , Souchay Marc , Vitzthum Elisabeth , Weirich Gregor , Schuster Tibor , Autenrieth Michael , Kübler Hubert , Maurer Tobias , Thalgott Mark , Herkommer Kathleen , Gschwend Jürgen E. , Nawroth Roman
Published: April 2023

Abstract
Purpose: Molecular lymph node (LN) analysis using quantitative polymerase chain reaction (qPCR) detects LN metastases with higher sensitivity than histopathology. However, the prognostic role of molecular LN status in prostate cancer patients treated with radical prostatectomy (RP) and extended pelvic LN dissection (ePLND) is unclear. To investigate the association of molecular compared with histopathologic LN status with biochemical recurrence.

Experimental Design: Patients with intermediate and high-risk prostate cancer were prospectively enrolled and underwent RP with ePLND, including the obturator, internal, external, and the common iliac region. LNs ≥3 mm were bisected and examined by standard histopathology and qPCR for Kallikrein3 (KLK3) expression. Biochemical recurrence was defined by confirmed postoperative PSA > 0.2 ng/mL.

Results: In 111 patients, 2,411 of 3,173 removed LNs were examined by both methods. Histopathology detected 68 LN metastases in 28 (25%) patients. Molecular analysis confirmed elevated KLK3 expression in 65 histopathologic LN metastases of all 28 pN1 patients (pN1/molN1) and additionally reclassified 224 histopathologic negative LNs and 32 (29%) pN0 patients as LN-positive (pN0/molN1).

At a median follow-up of 48 months, 52 (47%) patients developed biochemical recurrence. Median biochemical recurrence-free survival was 9 months [95% confidence interval (CI), 0.0–20.1] in pN1/molN1 patients, 24 months (95% CI, 1.7–46.3) in pN0/molN1 patients and was not reached in pN0/molN0 patients (P < 0.001). On multivariable Cox regression analysis, molecular LN status [HR 4.1 (95% CI, 1.9–8.8), P < 0.001] but not histopathologic LN status [HR 1.5 (95% CI, 0.8–3.0), P = 0.198] was confirmed as independent predictor of biochemical recurrence.

Conclusions: Molecular LN analysis identified pN0 patients with a high risk of biochemical recurrence and provided superior prognostic information in comparison with histopathology alone. Clin Cancer Res; 24(10); 2342–9. ©2018 AACR.
Data from Combinations of Bevacizumab and Erlotinib Show Activity in Colorectal Cancer Independent of RAS Status
Authors: Mésange Paul , Bouygues Anaïs , Ferrand Nathalie , Sabbah Michèle , Escargueil Alexandre E. , Savina Ariel , Chibaudel Benoist , Tournigand Christophe , André Thierry , de Gramont Aimery , Larsen Annette K.
Published: April 2023

Abstract
Purpose: There is extensive cross-talk between VEGF- and EGFR-pathway signaling in colorectal cancer. However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAb) show disappointing activity, in particular for patients with mutant RAS. Previous results show that tyrosine kinase inhibitors (TKI) can be active in colorectal cancer models resistant to mAbs. This prompted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib.

Experimental Design: The antitumor activity of bevacizumab, erlotinib, and their combination was determined in colorectal cancer models with different RAS status and bevacizumab sensitivity. EGFR/VEGF pathway activation was characterized by immunohistochemistry, Western blot, and ELISA assays. The influence of cetuximab and erlotinib on EGF-mediated migration and the EGFR–EGF ligand feedback loop was established in colorectal cancer cell lines with different RAS status.

Results: The addition of erlotinib increased bevacizumab activity in all models independent of RAS status. Bevacizumab exposure was accompanied by marked EGFR activation in tumor cells as well as in tumor-associated endothelial cells (TECs) and resulted in strong accumulation of intracellular EGFR, which could be attenuated by erlotinib. In cellular models, erlotinib was able to attenuate EGF-mediated functions in all cell lines independent of RAS status while cetuximab only showed activity in RAS wild-type cells.

Conclusions: These results should provide a molecular framework to better understand the increased activity of the bevacizumab–erlotinib combination, compared with bevacizumab alone, in the GERCOR DREAM phase III clinical trial. Differential activity of mAbs and TKIs targeting the same signaling pathway is likely applicable for other tumor types. Clin Cancer Res; 24(11); 2548–58. ©2018 AACR.