Publications by authors named "Caterina Fumagalli"

50 Publications

Hotspot ESR1 mutations are multimodal and contextual modulators of breast cancer metastasis.

Cancer Res 2022 Jan 25. Epub 2022 Jan 25.

University of Cambridge, Cancer Research UK Cambridge Institute.

Constitutively active estrogen receptor-α (ER/ESR1) mutations have been identified in approximately one third of ER+ metastatic breast cancers. Although these mutations are known mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1 mutant tumors, genome-edited ESR1 Y537S and D538G mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell-cell contacts while decreasing cell-extracellular matrix (ECM) adhesion. In vivo studies showed ESR1 mutant cells were associated with larger multi-cellular circulating tumor cell (CTC) clusters with increased compactness compared to ESR1 WT CTCs. These preclinical findings translated to clinical observations, where CTC clusters were enriched in patients with ESR1-mutated metastatic breast cancer. Conversely, context-dependent migratory phenotypes revealed co-targeting of Wnt and ER as a vulnerability in a D538G cell model. Mechanistically, mutant ESR1 exhibited non-canonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation-modulated metastasis and suggest future therapeutic strategies for targeting ESR1 mutant breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-2576DOI Listing
January 2022

Breast Cancer Heterogeneity.

Diagnostics (Basel) 2021 Aug 27;11(9). Epub 2021 Aug 27.

Division of Pathology, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy.

Breast tumor heterogeneity is a major challenge in the clinical management of breast cancer patients. Both inter-tumor and intra-tumor heterogeneity imply that each breast cancer (BC) could have different prognosis and would benefit from specific therapy. Breast cancer is a dynamic entity, changing during tumor progression and metastatization and this poses fundamental issues to the feasibility of a personalized medicine approach. The most effective therapeutic strategy for patients with recurrent disease should be assessed evaluating biopsies obtained from metastatic sites. Furthermore, the tumor progression and the treatment response should be strictly followed and radiogenomics and liquid biopsy might be valuable tools to assess BC heterogeneity in a non-invasive way.
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http://dx.doi.org/10.3390/diagnostics11091555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468623PMC
August 2021

Immunotherapy in Breast Cancer Patients: A Focus on the Use of the Currently Available Biomarkers in Oncology.

Anticancer Agents Med Chem 2021 Jul 6. Epub 2021 Jul 6.

Division of Pathology, IEO, European Institute of Oncology IRCCS, University of Milan, Via Giuseppe Ripamonti 435, 20141, Milan, Italy.

Immune checkpoint inhibitors (ICIs) have remarkably modified the way solid tumors are managed, including breast cancer. Unfortunately, only a relatively small number of breast cancer patients significantly respond to these treatments. To maximize the immunotherapy benefit in breast cancer, several efforts are currently being put forward for the identification of i) the best therapeutic strategy (i.e. ICI monotherapy or in association with chemotherapy, radiotherapy, or other drugs); ii) the optimal timing for administration (e.g. early/advanced stage of disease; adjuvant/neoadjuvant setting); iii) the most effective and reliable predictive biomarkers of response (e.g. tumor-infiltrating lymphocytes, programmed death-ligand 1, microsatellite instability associated with mismatch repair deficiency, and tumor mutational burden). This article reviews the impacts and gaps in the characterization of immune-related biomarkers raised by clinical and translational research studies with immunotherapy treatments. Particular emphasis has been put on the documented evidence of significant clinical benefits of ICI in different randomized clinical trials, along with preanalytical and analytical issues in predictive biomarkers pathological assessment.
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http://dx.doi.org/10.2174/1871520621666210706144112DOI Listing
July 2021

Biological and clinical features of triple negative Invasive Lobular Carcinomas of the breast. Clinical outcome and actionable molecular alterations.

Breast 2021 Oct 26;59:94-101. Epub 2021 Jun 26.

MultiMedica San Giuseppe Hospital, Milan, Italy.

Background: We report here for the first time, a comprehensive characterization of biological and clinical features of early-stage triple negative Invasive Lobular Carcinomas(TN-ILCs) METHODS: We analyzed all consecutive patients with early-stage TN-ILC operated at two reference cancer-centers between 1994 and 2012. Primary objective was to assess the invasive disease-free survival(iDFS). Co-primary objective was to assess biological features of TN-ILCs, including molecular intrinsic subtypes based on PAM-50 assay, expression of androgen receptor (AR) and mutational status of ERBB2-gene. Additionally, DNA mutational status of an independent cohort of 45 TN-ILCs from three databases were analyzed, to confirm mutations in ERBB2-gene and to identify other recurrently mutated genes.

Results: Among 4152 ILCs, 74(1.8%) were TN and were analyzed. The iDFS at 5 and 10 years of FUP were 50.4%(95%CI,38.0-61.6) and 37.2%(95%CI,25.5-48.8), respectively. The molecular subtype was defined through PAM50-classifier for 31 out of 74 TN-ILCs: 48% were Luminal-A(15/31), 3% luminal-B(1/31), 32% HER2-enriched (10/31), and only 16% basal-like(5/31). Luminal tumors expressed AR more frequently than non-luminal tumors (AR≥1% in 94% of luminal tumors versus 53% in non-luminal tumors; p-value = 0.001). 20% of TN-ILCs analyzed(7/35), harbored a pathogenetic and actionable mutation in the ERBB2-gene. Analysis of the independent cohort of 45 TN-ILCs from three different databases, confirmed similar percentage of pathogenetic and actionable mutations in ERBB2-gene(20%; 9/45). Among the top 10 molecular pathways significantly enriched for recurrently mutated genes in TN-ILCs(FDR<0.05), there were ErbB-signaling and DNA-damage-response pathways.

Conclusions: TN-ILCs are rare tumors with poor prognosis. Their specific biological features require newly defined targeted therapeutic strategies.
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http://dx.doi.org/10.1016/j.breast.2021.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261657PMC
October 2021

Diagnostic and Predictive Biomarkers in Lung Cancer.

Cancers (Basel) 2021 May 25;13(11). Epub 2021 May 25.

Division of Pathology, IEO, European Institute of Oncology, IRCCS, 20141 Milano, Italy.

Lung cancer is the most frequent cause of cancer-related mortality worldwide [...].
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http://dx.doi.org/10.3390/cancers13112577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197330PMC
May 2021

Genomic Characterization of Concurrent Alterations in Non-Small Cell Lung Cancer (NSCLC) Harboring Actionable Mutations.

Cancers (Basel) 2021 Apr 30;13(9). Epub 2021 Apr 30.

Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy.

An increasing number of driver genomic alterations with potential targeted treatments have been identified in non-small cell lung cancer (NSCLC). Much less is known about the incidence and different distribution of concurrent alterations, as identified by comprehensive genomic profiling in oncogene-addicted NSCLCs. Genomic data from advanced NSCLC consecutively analyzed using a broad next-generation sequencing panel were retrospectively collected. Tumors harboring at least one main actionable gene alteration were categorized according to the presence/absence of concurrent genomic aberrations, to evaluate different patterns among the main oncogene-addicted NSCLCs. Three-hundred-nine actionable gene alterations were identified in 284 advanced NSCLC patients during the study period. Twenty-five tumor samples (8%) displayed concurrent alterations in actionable genes. Co-occurrences involving any pathogenic variant or copy number variation (CNV) were identified in 82.8% of cases. Overall, statistically significant differences in the number of concurrent alterations, and the distribution of , , cyclines and receptor tyrosin kinase (RTK) aberrations were observed across the eight actionable gene groups. NGS analyses of oncogene-addicted NSCLCs showed a different distribution and pattern of co-alteration profiles. Further investigations are needed to evaluate the prognostic and treatment-related impact of these concurrent alterations, hooked to the main gene aberrations.
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http://dx.doi.org/10.3390/cancers13092172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124171PMC
April 2021

A systematic review and meta-analysis of the prognostic role of age in oral tongue cancer.

Cancer Med 2021 04 24;10(8):2566-2578. Epub 2021 Mar 24.

Division of Otolaryngology and Head and Neck Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy.

While evidence suggests an increasing incidence of tongue cancer in young adults, published findings regarding the prognostic role of age at diagnosis are inconsistent. We performed a meta-analysis of the literature to highlight key points that might help in understanding the association between age of oral tongue cancer patients at diagnosis and their prognosis. According to age at diagnosis, a systematic literature review of all published cohort studies assessing the recurrence risks and mortality associated with tongue cancer was conducted. We compared the risk estimates between patients aged >45 years and those aged <45 years at diagnosis. Random-effects models were used to calculate summary relative risk estimates (SRRs) according to different clinical outcomes and sources of between-study heterogeneity (I ) and bias. We included 31 independent cohort studies published between 1989 and 2019; these studies included a total of 28,288 patients. When risk estimations were not adjusted for confounders, no significant association was found between age at diagnosis and overall survival (OS). Conversely, after adjustment for confounders, older age at diagnosis was associated with a significantly increased risk of mortality. The difference between SRRs for adjusted and unadjusted estimates was significant (p < 0.01). Younger patients had a significantly higher risk of local recurrence. Younger patients with oral tongue cancer have better OS but a greater risk of recurrence than older patients. These findings should be validated in a large prospective cohort study which considers all confounders and prognostic factors.
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http://dx.doi.org/10.1002/cam4.3795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026930PMC
April 2021

Making the Most of Complexity to Create Opportunities: Comprehensive Genomic Profiling and Molecular Tumor Board for Patients with Non-Small Cell Lung Cancer (NSCLC).

Cancers (Basel) 2021 Feb 4;13(4). Epub 2021 Feb 4.

Division of Pathology, IEO, European Institute of Oncology, IRCCS, 20141 Milano, Italy.

Personalized cancer therapy matches the plan of treatment with specific molecular alterations [...].
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http://dx.doi.org/10.3390/cancers13040609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913872PMC
February 2021

Bowel-associated dermatosis-arthritis syndrome (BADAS).

Australas J Dermatol 2021 May 12;62(2):241-242. Epub 2020 Dec 12.

Department of Pathology, University Hospital Germans Trial i Pujol, Universitat Autònoma de Barcelona, Badalona, Badalona, Spain.

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http://dx.doi.org/10.1111/ajd.13516DOI Listing
May 2021

A role for the immune system in advanced laryngeal cancer.

Sci Rep 2020 10 27;10(1):18327. Epub 2020 Oct 27.

Division of Otolaryngology and Head and Neck Surgery, IEO, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141, Milan, Italy.

To investigate the role of the altered activation of the immune system in the prognosis of patients affected by laryngeal squamous cell carcinoma (LSCC). We analyzed 56 patients with advanced LSCC divided into two groups according to their prognosis: the first group relapsed within 24 months after treatment, the second group had no evidence of disease at 2 years. The presence of stromal tumor infiltrating lymphocytes (TILs) at the tumor-host border was investigated. In 43 patients we evaluated the expression of 395 genes related to immune system activation through a next generation sequencing panel. Priority-LASSO models and clustering analyses were integrated with multivariate Cox proportional hazard modeling to identify independent genes associated with relapse and estimate hazard ratios in relation to gene expression and TILs. TILs and the expression of genes related with immune system activation (FCGR1A, IFNA17, FCRLA, NCR3, KREMEN1, CD14, CD3G, CD19, CD20 and CD79A) were significantly associated with prognostic factors or disease specific survival. In patients with lymph node metastases and advanced T stage (pT4), the expression of other genes was altered. Low TILs count was highly associated with relapse within 2 years (p < 0.001). Low TILs and altered expression of specific genes associated with tumor-immune systems interactions emerged as independent risk factors, associated to poor prognosis and relapse within 2 years in advanced LSCC. Evaluation of patients' immune profile could be useful for prognosis and future therapeutic approaches towards personalized therapy.
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http://dx.doi.org/10.1038/s41598-020-73747-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591515PMC
October 2020

Genomic Aberrations and Late Recurrence in Postmenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the SOLE Trial.

Clin Cancer Res 2021 01 20;27(2):504-512. Epub 2020 Oct 20.

Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, Milan, International Breast Cancer Study Group Central Pathology Office and University of Milan, Department of Oncology and Hemato-Oncology, Milan, Italy.

Purpose: Women with hormone receptor-positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk.

Experimental Design: In a secondary analysis of Study of Letrozole Extension trial, a case-cohort-like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models.

Results: Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were mutations (42%) and CNGs of (15%), (10%), (8%), and (8%). mutations and CNGs were associated with lower ( = 0.03) and higher ( = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with , and CNGs ( = 0.01, < 0.001, and = 0.03, respectively). CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48-6.92; = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61-7.75; = 0.002) and in multivariable models adjusted for clinicopathologic factors.

Conclusions: Postmenopausal women with hormone receptor-positive early breast cancer harboring CNG had an increased risk of late recurrence despite extended therapy. CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0126DOI Listing
January 2021

Understanding EGFR heterogeneity in lung cancer.

ESMO Open 2020 10;5(5):e000919

Thoracic Oncology Department and Early Phase Clinical Trials Section, School of Medicine, University of Maryland, Baltimore, MD, United States.

The advances in understanding the inherited biological mechanisms of non-small cell lung cancer harbouring epidermal growth factor receptor (EGFR) mutations led to a significant improvement in the outcomes of patients treated with EGFR tyrosine kinase inhibitors. Despite these clinically impressive results, clinical results are not always uniform, suggesting the need for deepening the molecular heterogeneity of this molecularly defined subgroup of patients beyond the clinical and biological surface.The availability of tissue and blood-based tumour genotyping allows us to improve the understanding of molecular and genetic intratumor heterogeneity, driving the measurement of clonal evaluation in patients with lung cancer carrying EGFR mutations. Genetic diversification, clonal expansion and selection are highly variable patterns of genetic diversity, resulting in different biological entities, also a prerequisite for Darwinian selection and therapeutic failure.Such emerging pieces of evidence on the genetic diversity, including adaptive and immunomodulated aspects, provide further evidence for the role of the tumour microenvironment (TME) in drug-resistance and immune-mediated mechanisms. Matching in daily clinical practice, the detailed genomic profile of lung cancer disease and tracking the clonal evolution could be the way to individualise the further target treatments in EGFR-positive disease. Characterising the tumour and immune microenvironment during the time of the cancer evaluation could be the way forward for the qualitative leap needed from bench to bedside. Such a daring approach, aiming at personalising treatment selection in order to exploit the TME properties and weaken tumour adaptivity, should be integrated into clinical trial design to optimise patient outcome.
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http://dx.doi.org/10.1136/esmoopen-2020-000919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569934PMC
October 2020

Inter-tumor genomic heterogeneity of breast cancers: comprehensive genomic profile of primary early breast cancers and relapses.

Breast Cancer Res 2020 10 15;22(1):107. Epub 2020 Oct 15.

Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology, IRCCS, Milan, Italy.

Background: The breast cancer genome dynamically evolves during malignant progression and recurrence. We investigated the genomic profiles of primary early-stage breast cancers and matched relapses to elucidate the molecular underpinnings of the metastatic process, focusing on potentially actionable alterations in the recurrences.

Methods: A mono-institutional cohort of 128 patients with breast cancers (n = 68 luminal B HER2, n = 6 luminal B HER2+, n = 1 HER2+ non-luminal, n = 56 triple negative) and at least one recurrence in a timeframe of 17 years was evaluated. Next-generation sequencing comprehensive genomic profiling was performed on 289 formalin-fixed paraffin-embedded (FFPE) samples, including primary tumors and matched relapses. Correlations of genomic aberrations with clinicopathologic factors and time to breast cancer relapse were analyzed.

Results: Genomic data were available for 188 of 289 FFPE samples that achieved the sequencing quality parameters (failure rate 34.9%), including 106 primary tumors and 82 relapses. All primary and relapse samples harbored at least one genomic alteration, with a median number of six alterations per sample (range 1-16). The most frequent somatic genomic alterations were mutations of TP53 (primary tumors = 49%, relapses = 49%) and PIK3CA (primary tumors = 33%, relapses = 30%). Distinctive genomic alterations of primary tumors were significantly associated with molecular subtypes. TP53, PIK3R1, and NF1 somatic alterations were more frequently detected in triple negative tumors (p value < 0.05); CCND1, FGF3, and FGFR1 copy number gains were recurrently identified in luminal cases (p value < 0.05). Moreover, TP53 mutations and MYC amplification were significantly and independently associated with a shorter time to relapse (p value < 0.05). Molecular subtype changes between primary tumors and relapses were seen in 10 of 128 (7.8%) cases. Most driver genomic alterations (55.8%) were shared between primary tumors and matched recurrences. However, in 39 of 61 cases (63.9%), additional private alterations were detected in the relapse samples only, including 12 patients with potentially actionable aberrations.

Conclusions: Specific genomic aberrations of primary breast cancers were associated with time to relapse. Primary tumors and matched recurrences showed a core of shared driver genomic aberrations but private actionable alterations have been identified in the relapses.
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http://dx.doi.org/10.1186/s13058-020-01345-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566144PMC
October 2020

Reliability and reproducibility among different platforms for tumour BRCA testing in ovarian cancer: a study of the Italian NGS Network.

J Clin Pathol 2021 Oct 5;74(10):668-672. Epub 2020 Oct 5.

Laboratory of Diagnostic Molecular Oncology, Center for Advanced Studies and Technology (CAST), University of Chieti, Chieti, Italy.

Introduction: BRCA tumour testing is a crucial tool for personalised therapy of patients with ovarian cancer. Since different next-generation sequencing (NGS) platforms and BRCA panels are available, the NGS Italian Network proposed to assess the robustness of different technologies.

Methods: Six centres, using four different technologies, provided raw data of 284 cases, including 75 cases with pathogenic/likely pathogenic variants, for a revision blindly performed by an external bioinformatic platform.

Results: The third-party revision assessed that all the 284 raw data reached good quality parameters. The variant calling analysis confirmed all the 75 pathogenic/likely pathogenic variants, including challenging variants, achieving a concordance rate of 100% regardless of the panel, instrument and bioinformatic pipeline adopted. No additional variants were identified in the reanalysis of a subset of 41 cases.

Conclusions: BRCA tumour testing performed with different technologies in different centres, may achieve the realibility and reproducibility required for clinical diagnostic procedures.
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http://dx.doi.org/10.1136/jclinpath-2020-206800DOI Listing
October 2021

Temozolomide alone or in combination with capecitabine in patients with advanced neuroendocrine neoplasms: an Italian multicenter real-world analysis.

Endocrine 2021 04 22;72(1):268-278. Epub 2020 Jul 22.

Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy.

Purpose: Temozolomide (TEM) has been reported to be active alone or in combination with capecitabine (CAP) in patients with neuroendocrine neoplasms (NENs). We retrospectively evaluated activity and toxicity of TEM-based chemotherapy in patients with advanced NENs and explored the potential correlation with clinical/biological factors.

Methods: Patients received oral TEM alone or in combination with CAP. Objective response rate (ORR) [complete response + partial response (PR)], median progression-free survival (mPFS), and toxicity were calculated. The O-methylguanine-DNA-methyltransferase (MGMT) gene inactivation status in tumor tissue was evaluated by pyrosequencing.

Results: From September 2008 to April 2020, 170 patients (84% progressive on different therapies) were consecutively treated, 114 (67%) patients received TEM-CAP and 56 (33%) TEM alone. Primary tumor sites were: pancreas 98 (58%), gastrointestinal tract 21 (12%), lung 35 (21%), and unknown 16 (9%). The ORR was 28% for the whole population (33% for TEM-CAP and 18% for TEM as single agent). The median OS (mOS) and mPFS of the whole population were 35.6 months (32.6-48.7) and 14.7 months (10.1-18.3), respectively. There were 48% PR in the MGMT hypermethylated, mainly in pancreatic NENs. Vomiting and leukopenia were the most frequent grade 3/4 toxicity.

Conclusions: This large retrospective analysis suggested that a TEM-based chemotherapy is active in advanced, pretreated NEN patients. It generated solid hypotheses that warrant a future prospective study in a biological homogeneous NEN population and clinical setting.
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http://dx.doi.org/10.1007/s12020-020-02421-2DOI Listing
April 2021

SARS-CoV-2 detection in formalin-fixed paraffin-embedded tissue specimens from surgical resection of tongue squamous cell carcinoma.

J Clin Pathol 2020 Nov 4;73(11):754-757. Epub 2020 May 4.

Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology, IRCCS, Milano, Italy

In the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, pathologists can be exposed to infection handling surgical specimens. Guidelines related to safety procedures in the laboratory have been released. However, there is a lack of studies performed on biopsy and surgical resection specimens. Here we report the detection of SARS-CoV-2 in formalin-fixed paraffin-embedded samples from surgical resection of tongue squamous cell carcinoma of a patient who developed COVID-19 postsurgery. RNA of SARS-CoV-2 strain was detected in the tumour and the normal submandibular gland samples using real-time PCR-based assay. No viral RNA was found in metastatic and reactive lymph nodes. We demonstrated that SARS-CoV-2 RNA can be detected in routine histopathological samples even before COVID-19 disease development. These findings may give important information on the possible sites of infection or virus reservoir, and highlight the necessity of proper handling and fixation before sample processing.
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http://dx.doi.org/10.1136/jclinpath-2020-206635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431818PMC
November 2020

Broad-based genomic sequencing in advanced non-small cell lung cancer in the dock.

Transl Lung Cancer Res 2019 Dec;8(Suppl 4):S360-S363

Clinical Unit of Histopathology and Molecular Diagnostics, European Institute of Oncology, IRCCS, Milano, Italy.

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http://dx.doi.org/10.21037/tlcr.2019.04.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987345PMC
December 2019

A case of Warthin-like papillary thyroid carcinoma with diffuse sclerosing stroma and a novel RET mutation: a new entity or a combined tumour?

Ecancermedicalscience 2019 2;13:965. Epub 2019 Oct 2.

Department of Pathology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.

Activating mutations of the gene have been described for both papillary (chromosomal rearrangement) and medullary (missense mutations) thyroid carcinomas. Here, we describe a case of a Warthin-like variant of papillary thyroid carcinoma displaying some morphological aspects that mimic the diffuse sclerosing variant. The tumour harboured V600E mutation and a novel germline point mutation in the gene, with unknown clinical and pathological meaning.
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http://dx.doi.org/10.3332/ecancer.2019.965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834387PMC
October 2019

Efficacy of Anti-PD1/PD-L1 Therapy (IO) in KRAS Mutant Non-small Cell Lung Cancer Patients: A Retrospective Analysis.

Anticancer Res 2020 Jan;40(1):427-433

Division of Thoracic Oncology, European Institute of Oncology, IRCCS, Milan, Italy.

Background/aim: The role of anti-PD1/PD-L1 therapy (IO) in NSCLC harboring driver mutations is questionable. This study aimed to examine the efficacy of IO in patients with non-small cell lung cancer (NSCLC) with a KRAS mutation (KRAS).

Patients And Methods: We retrospectively identified NSCLC patients harboring KRAS mutation treated with IO in our Institution. We analyzed the results in comparison to non-KRAS patients.

Results: Among 328 consecutive KRAS NSCLC patients, 43 (13.1%) received IO in our Institution. In parallel 117 non-KRAS NSCLC patients treated with IO were selected for comparison. The baseline characteristics were similar between the two groups. No significant difference was observed between KRAS and non-KRAS patients in terms of mPFS (4.6 vs. 3.3 months, p=0.58) or OS (8.1 vs. 13.0 months, p=0.38).

Conclusion: KRAS mutations seem to be irrelevant for selecting patients for IO that could be therefore considered an effective therapy for NSCLC patients, independently of KRAS status.
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http://dx.doi.org/10.21873/anticanres.13970DOI Listing
January 2020

Tumor BRCA Test for Patients with Epithelial Ovarian Cancer: The Role of Molecular Pathology in the Era of PARP Inhibitor Therapy.

Cancers (Basel) 2019 Oct 24;11(11). Epub 2019 Oct 24.

Division of Pathology, European Institute of Oncology (IEO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy.

The PARP inhibitor olaparib has been approved in the maintenance setting of platinum-sensitive epithelial ovarian cancer patients with germline or somatic mutation. Therefore, the availability of a tumor BRCA test has become a clinical need. We report the results of the clinical implementation of a tumor BRCA test within the frame of an institutional workflow for the management of patients with nonmucinous and nonborderline epithelial ovarian cancer. In total, 223 patients with epithelial ovarian cancer were prospectively analyzed. status was evaluated on formalin-fixed, paraffin-embedded tumor specimens using next-generation sequencing technology. The tumor BRCA test had a success rate of 99.1% (221 of 223 successfully analyzed cases) and a median turnaround time of 17 calendar days. Among the 221 cases, or pathogenic/likely pathogenic mutations were found in 62 (28.1%) cases and variants of uncertain significance in 25 (11.3%) cases. The concordance rate between tumor BRCA test results and germline status was 87%, with five cases harboring pathogenic/likely pathogenic somatic-only mutations. The next-generation, sequencing-based tumor BRCA test showed a high success rate and a turnaround time compatible with clinical purposes. The tumor BRCA test could be implemented in a molecular diagnostic setting and it may guide the clinical management of patients with epithelial ovarian cancer.
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http://dx.doi.org/10.3390/cancers11111641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896171PMC
October 2019

Next-generation sequencing-based BRCA testing on cytological specimens from ovarian cancer ascites reveals high concordance with tumour tissue analysis.

J Clin Pathol 2020 Mar 19;73(3):168-171. Epub 2019 Sep 19.

Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.

Background: With the approval of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib for newly diagnosed, breast cancer gene mutated, ovarian cancer women, the assessment of tumour status will be shortly required at the time of diagnosis.

Aim: To investigate the feasibility of next-generation sequencing (NGS)-based BRCA tumour test on cytological specimens from ovarian cancer ascites.

Methods: We evaluated the status on neoplastic ascites and corresponding tumour tissue of 11 patients with ovarian cancer, using the NGS 'Oncomine BRCA Research Assay'.

Results: The NGS-based BRCA test on cytological samples had a success rate of 100%, with 11 of 11 concordant results between ascites and tumour tissues analyses, including two wild type samples and nine cases harbouring somatic or germline variants.

Conclusion: BRCA test may be performed on ovarian cancer ascites, reproducing tumour status and representing a useful tool for clinical decision-making.
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http://dx.doi.org/10.1136/jclinpath-2019-206127DOI Listing
March 2020

Molecular Profile of Advanced Non-Small Cell Lung Cancers in Octogenarians: The Door to Precision Medicine in Elderly Patients.

J Clin Med 2019 Jan 18;8(1). Epub 2019 Jan 18.

Unit of Histopathology and Molecular Diagnostics, Division of Pathology, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy.

Background: There is a pressing need to expand the evidence base in geriatric lung oncology. Most non-small cell lung cancers (NSCLCs) are diagnosed in the elderly, with approximately 15% of cases affecting octogenarians. Treatment-related decisions are challenging in this population, and the role of biologically driven therapies is still underrated.

Methods: A single-institution cohort of 76 NSCLCs from octogenarian patients was submitted to molecular analysis using a next-generation sequencing (NGS) multigene panel, fluorescence in situ hybridization (FISH) analyses, and immunohistochemistry for PD-L1 assessment. Treatment and clinical outcome data were available for 33 patients.

Results: Most cases ( = 66, 87%) harbored at least one genomic alteration. and mutations were detected in 18 (24%) and 20 (26%) patients, respectively. No alterations were found, but in two patients translocation was identified. Of 22 cases tested, 17 were positive for PD-L1 staining. Octogenarian patients who received tyrosine kinase inhibitors (TKIs) based on molecular analysis showed clinical benefits, with long progression-free survival as expected in TKI-treated younger cohorts.

Conclusions: This study highlights the utility of molecular profiling in all advanced-stage NSCLCs, regardless of the age at diagnosis, to drive personalized treatment. The prevalence of druggable alterations and the clinical benefits obtained by biologically-driven therapies in octogenarians were comparable to those of the younger NSCLC population.
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http://dx.doi.org/10.3390/jcm8010112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352111PMC
January 2019

Prognostic Value of the Burden of Cytomegalovirus Colonic Reactivation Evaluated by Immunohistochemical Staining in Patients with Active Ulcerative Colitis.

J Crohns Colitis 2019 Mar;13(3):385-388

Department of Gastroenterology, Hospital Germans Trias i Pujol, Badalona, Spain.

Background: Colonic cytomegalovirus [CMV] reactivation has been involved in steroid refractoriness in patients with active ulcerative colitis [UC]. The benefits of antiviral therapy in this clinical setting are still under debate, but the burden of viral reactivation has been associated with a poorer outcome in some studies. Our aim was to assess whether the burden of CMV reactivation measured by the number of viral inclusions by immunohistochemistry [IHC-CMV] is associated with a risk of colectomy.

Methods: Biopsy sets of UC patients with positive IHC-CMV were identified from the Pathology departments of three university hospitals. All biopsies were reviewed by expert pathologists, and the maximum number of IHC-CMV-positive cells in each biopsy set was re-assessed. Epidemiological and clinical features and clinical outcomes were recorded.

Results: Forty-six positive IHC-CMV cases with UC were included. At the time of CMV reactivation, 70% were receiving corticosteroids, 33% azathioprine, and 24% anti-tumour necrosis factor [TNF] agents. Thirty-two patients [70%] were treated with antiviral therapy. The median number of IHC-CMV-positive cells was 2 cells/biopsy [IQR 1-4]. Fourteen patients [30%] underwent colectomy, and 4 of them [29%] showed persistence of CMV in the surgical specimen. In the multivariate analysis, colectomy was only associated with >2 positive cells/biopsy [p = 0.048] and younger age [p = 0.023].

Conclusions: The burden of CMV colonic reactivation in patients with active UC, as measured by IHC, seems to be related to the risk of colectomy, and more data is needed to understand whether antiviral therapy guided by CMV burden will alter the clinical outcome.
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http://dx.doi.org/10.1093/ecco-jcc/jjy173DOI Listing
March 2019

The immune profile of EGFR-mutated non-small-cell lung cancer at disease onset and progression after tyrosine kinase inhibitors therapy.

Immunotherapy 2018 09;10(12):1041-1045

Division of Pathology & Laboratory Medicine, European Institute of Oncology, Via Ripamonti 451, 20141 Milan, Italy.

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http://dx.doi.org/10.2217/imt-2018-0027DOI Listing
September 2018

Letter to the Editor.

Clin Lung Cancer 2018 07 12;19(4):e439-e440. Epub 2018 Mar 12.

Division of Pathology and Laboratory Medicine, Istituto Europeo di Oncologia, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.

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http://dx.doi.org/10.1016/j.cllc.2018.03.001DOI Listing
July 2018

Mutational analysis of triple-negative breast cancers within the International Breast Cancer Study Group (IBCSG) Trial 22-00.

Breast Cancer Res Treat 2018 Jul 27;170(2):351-360. Epub 2018 Mar 27.

Division of Medical Senology, European Institute of Oncology, and International Breast Cancer Study Group, Milan, Italy.

Purpose: We investigated the occurrence and the prognostic and predictive relationship of a selected number of somatic mutations in triple-negative breast cancer (TNBC) patients having known clinical outcomes treated within the IBCSG Trial 22-00.

Methods: A matched case-control sampling selected patients enrolled in the IBCSG Trial 22-00 who had TNBC tumors, based on local assessment. Cases had invasive breast cancer recurrence (at local, regional, or distant site) according to the protocol definition. Matched controls had not recurred. Mutational analysis was performed with OncoCarta panel v1.0 using Mass Array System. The panel includes 19 genes belonging to different functional pathways as PI3K pathway, receptor tyrosine kinase, and cell cycle-metabolic group. Conditional logistic regression assessed the association of mutation status with breast cancer recurrence.

Results: Mutation assessment was successful for 135 patients (49 cases, 86 controls). A total of 37 (27.4%) of the 135 patients had at least one mutation in the selected genes. PIK3CA was the most common mutated gene (18/135; 13.3%), followed by BRAF, KIT and PDGFRA (each 4/135, 3.0%) and AKT1 (3/135; 2.2%). TNBC patients with at least one mutation had increased odds of recurrence compared with those with wild-type tumors (odds ratio (OR) 2.28; 95% CI 0.88-5.92), though this difference was not statistically significant (p = 0.09). We found no evidence that these mutations were predictive for the value of maintenance metronomic chemotherapy.

Conclusions: Mutations in the tested oncogenes were not associated with breast cancer recurrence in this TNBC subset of patients. The question of whether any of these mutated genes (e.g., PIK3CA) may represent a useful therapeutic target in TNBC may be answered by ongoing clinical trials and/or larger dataset analysis.
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http://dx.doi.org/10.1007/s10549-018-4767-1DOI Listing
July 2018

The long tail of molecular alterations in non-small cell lung cancer: a single-institution experience of next-generation sequencing in clinical molecular diagnostics.

J Clin Pathol 2018 Sep 13;71(9):767-773. Epub 2018 Mar 13.

Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy.

Background: Molecular profiling of advanced non-small cell lung cancers (NSCLC) is essential to identify patients who may benefit from targeted treatments. In the last years, the number of potentially actionable molecular alterations has rapidly increased. Next-generation sequencing allows for the analysis of multiple genes simultaneously.

Aims: To evaluate the feasibility and the throughput of next-generation sequencing in clinical molecular diagnostics of advanced NSCLC.

Methods: A single-institution cohort of 535 non-squamous NSCLC was profiled using a next-generation sequencing panel targeting 22 actionable and cancer-related genes.

Results: 441 non-squamous NSCLC (82.4%) harboured at least one gene alteration, including 340 cases (63.6%) with clinically relevant molecular aberrations. Mutations have been detected in all but one gene () of the panel. Recurrent alterations were observed in , , , and genes, whereas the remaining genes were mutated in <5% of the cases. Concurrent mutations were detected in 183 tumours (34.2%), mostly impairing or EGFR in association with alterations.

Conclusions: The study highlights the feasibility of targeted next-generation sequencing in clinical setting. The majority of NSCLC harboured mutations in clinically relevant genes, thus identifying patients who might benefit from different targeted therapies.
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http://dx.doi.org/10.1136/jclinpath-2018-205032DOI Listing
September 2018
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