According to current diagnostic criteria, mantle cell lymphoma (MCL) encompasses the usual, aggressive variants and rare, nonnodal cases with monoclonal asymptomatic lymphocytosis, cyclin D1-positive (MALD1). We aimed to understand the biology behind this clinical heterogeneity and to identify markers for adequate identification of MALD1 cases.We compared 17 typical MCL cases with a homogeneous group of 13 untreated MALD1 cases (median follow-up, 71 months). We conducted gene expression profiling with functional analysis in five MCL and five MALD1. Results were validated in 12 MCL and 8 MALD1 additional cases by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in 24 MCL and 13 MALD1 cases by flow cytometry. Classification and regression trees strategy was used to generate an algorithm based on CD38 and CD200 expression by flow cytometry.We found 171 differentially expressed genes with enrichment of neoplastic behavior and cell proliferation signatures in MCL. Conversely, MALD1 was enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 were differentially expressed between MCL and MALD1 and confirmed by flow cytometry (median CD38, 89% vs. 14%; median CD200, 0% vs. 24%, respectively). Assessment of both proteins allowed classifying 85% (11 of 13) of MALD1 cases whereas 15% remained unclassified. SOX11 expression by qRT-PCR was significantly different between MCL and MALD1 groups but did not improve the classification.We show for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. Assessment of CD38/CD200 by flow cytometry is useful to distinguish most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment.

Lymphocytosis

Immunophenotyping

10.1158/1078-0432.ccr-13-1077

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Supplementary Figure S3 from Palbociclib Rechallenge for Hormone Receptor–Positive/HER-Negative Advanced Breast Cancer: Findings from the Phase II BioPER Trial

Joan Albanell José Manuel Pérez-García Miguel Gil‐Gil Giuseppe Curigliano Manuel Ruíz-Borrego

The level of mutant and wild-type circulating DNA in baseline plasma samples by patient.

Palbociclib

10.1158/1078-0432.22489437

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Supplementary Tables 1-6 from Distinction between Asymptomatic Monoclonal B-cell Lymphocytosis with Cyclin D1 Overexpression and Mantle Cell Lymphoma: From Molecular Profiling to Flow Cytometry

Blanca Espinet Ana Ferrer Beatríz Bellosillo Lara Nonell Antonio Salar

PDF file 233K, SupplementaryTable S1. Detailed clinical and pathological features of all the cases included in the study; S2. Detailed flow cytometric, cytogenetic and molecular findings of all the cases included in the study; S3. Sequence analysis of the MTC PCR products encompassing the IGH/CCND1 junction; S4. List of differentially expressed genes between MCL and MALD1 with order of appearance in Figure 4C; S5. Summary of the main pathways differentially enriched in MALD1 and MCL lymphocytes; S6. Table of all samplesused to generatethe CART. Classification column presents the assigned group after applying the CART

Lymphocytosis

10.1158/1078-0432.22448786

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Supplementary Figure S1 from Distinction between Asymptomatic Monoclonal B-cell Lymphocytosis with Cyclin D1 Overexpression and Mantle Cell Lymphoma: From Molecular Profiling to Flow Cytometry

Blanca Espinet Ana Ferrer Beatríz Bellosillo Lara Nonell Antonio Salar

PDF file 122K, Absolute lymphocyte counts in peripheral blood from MALD1 individuals over time

Lymphocytosis

Profiling (computer programming)

10.1158/1078-0432.22448795.v1

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Supplementary Figure S2 from Emergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer

Sabrina Arena Beatríz Bellosillo Giulia Siravegna Alejandro Martínez Israel Cañadas

Supplementary Figure S2. Comparison of parental and cetuximab resistant cell lines.

10.1158/1078-0432.22459851.v1

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Supplementary Table S1 from Emergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer

Sabrina Arena Beatríz Bellosillo Giulia Siravegna Alejandro Martínez Israel Cañadas

Supplementary Table S1. Clinical characteristics of patients.

Table (database)

10.1158/1078-0432.22459842.v1

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588P Genomic landscape of acquired resistance to first-line (1L) anti-EGFR treatment in metastatic colorectal cancer (mCRC) beyond the classical EGFR pathway: Findings from the PLATFORM-B study

Annals of Oncology (2024)

V. Martelli J. Vidal Barrull Caridad Fernández Rodríguez Rodrigo de Almeida Toledo Joan Gibert

Acquired resistance

EGFR Inhibitors

10.1016/j.annonc.2024.08.657

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Data from HER-Family Ligands Promote Acquired Resistance to Trastuzumab in Gastric Cancer

Aïda Sampera Francisco Javier Sánchez-Martín Oriol Arpí Laura Visa Mar Iglesias

<div>AbstractDespite the clinical benefit of trastuzumab, eventually all HER2-amplified gastric cancer tumors develop drug resistance. We aimed to identify molecular mechanisms of acquired resistance to trastuzumab in gastric cancer by using well-established cell line–based preclinical models, as well as samples from patients with HER2-positive gastric cancer treated with trastuzumab. We studied trastuzumab resistance in NCI-N87 and OE19, two gastric cancer cell lines that overexpress HER2 receptor and are trastuzumab sensitive. Differences at protein, DNA, and RNA levels between the parental and resistant cells were characterized and functional studies were performed. Paired pre- and post-trastuzumab blood and tissue samples from patients with gastric cancer treated with trastuzumab were analyzed. We found that resistant cells were associated with increased activation of MAPK/ERK and PI3K/mTOR pathways driven by SRC activation. Upstream, resistant cells showed increased coexpression of multiple HER-family ligands that allowed for compensatory activation of alternative HER receptors upon HER2 blockade. Simultaneous inhibition of EGFR, HER2, and HER3 by the novel antibody mixture, Pan-HER, effectively reverted trastuzumab resistance in vitro and in vivo. Similarly, an increase in HER-family ligands was observed in serum and tumor from patients with gastric cancer after trastuzumab therapy. We propose that trastuzumab resistance in gastric cancer is mediated by HER-family ligand upregulation that allows a compensatory activation of HER receptors and maintains downstream signaling activation despite trastuzumab therapy. Resistance is reverted by simultaneous inhibition of EGFR, HER2, and HER3, thereby revealing a potential therapeutic strategy to overcome trastuzumab resistance in patients with gastric cancer.</div>

10.1158/1535-7163.c.6542220

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Data from Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies

Daniel Azuara Cristina Santos Adriana López‐Doriga Julieta Grasselli Marga Nadal

<div>AbstractThe clinical significance of low-frequent RAS pathway–mutated alleles and the optimal sensitivity cutoff value in the prediction of response to anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients remains controversial. We aimed to evaluate the added value of genotyping an extended RAS panel using a robust nanofluidic digital PCR (dPCR) approach. A panel of 34 hotspots, including RAS (KRAS and NRAS exons 2/3/4) and BRAF (V600E), was analyzed in tumor FFPE samples from 102 mCRC patients treated with anti-EGFR therapy. dPCR was compared with conventional quantitative PCR (qPCR). Response rates, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutated allele fraction. Tumor response evaluations were not available in 9 patients and were excluded for response rate analysis. Twenty-two percent of patients were positive for one mutation with qPCR (mutated alleles ranged from 2.1% to 66.6%). Analysis by dPCR increased the number of positive patients to 47%. Mutated alleles for patients only detected by dPCR ranged from 0.04% to 10.8%. An inverse correlation between the fraction of mutated alleles and radiologic response was observed. ROC analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value for all combinations of RAS and BRAF analysis. In addition, this threshold also optimized prediction both PFS and OS. We conclude that mutation testing using an extended gene panel, including RAS and BRAF with a threshold of 1% improved prediction of response to anti-EGFR therapy. Mol Cancer Ther; 15(5); 1106–12. ©2016 AACR.</div>

10.1158/1535-7163.c.6538722.v1

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