Publications by authors named "Sara Lonardi"

240 Publications

HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target.

Authors:
Selma Ahcene Djaballah Francesca Daniel Anna Milani Gianmarco Ricagno Sara Lonardi

Am Soc Clin Oncol Educ Book 2022 Apr;42:1-14

Medical Oncology Unit 3, Veneto Institute of Oncology IRCCS, Padua, Italy.

Human epidermal growth factor receptor 2 () is a well-known oncogenic driver in different tumors and an approved therapeutic target in breast and gastroesophageal cancer. In metastatic colorectal cancer, only 3% to 5% of patients present with alterations: somatic mutations and amplifications. was first assessed as a biomarker of resistance to anti- therapy; however, in more recent years, its role as a potential actionable target has emerged. In this article, we discuss the predictive and prognostic value of in metastatic colorectal cancer, its emerging role as an actionable therapeutic target, and its possible future developments.
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http://dx.doi.org/10.1200/EDBK_351354DOI Listing
April 2022

Negative Ultraselection of Patients With / Wild-Type, Microsatellite-Stable Metastatic Colorectal Cancer Receiving Anti-EGFR-Based Therapy.

Authors:
Giovanni Randon Giulia Maddalena Marco Maria Germani Chiara Carlotta Pircher Paolo Manca Francesca Bergamo Mirella Giordano Caterina Sposetti Aldo Montagna Guglielmo Vetere Luca Zambelli Cosimo Rasola Alessandra Boccaccino Filippo Pagani Margherita Ambrosini Marco Massafra Gabriella Fontanini Massimo Milione Matteo Fassan Chiara Cremolini Sara Lonardi Filippo Pietrantonio

JCO Precis Oncol 2022 Apr;6:e2200037

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.

Purpose: Several uncommon genomic alterations beyond and BRAFV600E mutations drive primary resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC). Our PRESSING panel (including exon 20// mutations, / amplifications, gene fusions, and microsatellite instability-high status) represented a paradigm of negative hyperselection with more precise tailoring of EGFR blockade. However, a modest proportion of hyperselected mCRC has intrinsic resistance potentially driven by even rarer genomic alterations.

Materials And Methods: A prospective data set at three Italian Academic Hospitals included 650 patients with mCRC with comprehensive genomic profiling by FoundationOne CDx and treated with anti-EGFRs. PRESSING2 panel alterations were selected on the basis of previous clinico-biologic studies and included , , , //, pathogenic mutations; / loss; , , , , , and amplification; and rearrangements. These were collectively associated with outcomes in patients with hyperselected disease, ie, / wild-type, PRESSING-negative, and microsatellite stable.

Results: Among 162 hyperselected patients, 24 (15%) had PRESSING2 alterations, which were mutually exclusive except in two samples and were numerically higher in right-sided versus left-sided cancers (28% 13%; = .149). Independently of sidedness and other factors, patients with PRESSING2-positive status had significantly worse progression-free survival and overall survival compared with PRESSING2-negative ones (median progression-free survival 6.4 12.8 months, adjusted hazard ratio 4.19 [95% CI, 2.58 to 6.79]; median overall survival: 22.6 49.9 months, adjusted hazard ratio 2.98 [95% CI, 1.49 to 5.96]). The combined analysis of primary tumor sidedness and PRESSING2 status allowed us to better stratify outcomes.

Conclusion: Negative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with and wild-type, microsatellite stable mCRC.
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http://dx.doi.org/10.1200/PO.22.00037DOI Listing
April 2022

Encorafenib plus cetuximab treatment in BRAF V600E-mutated metastatic colorectal cancer patients pre-treated with an anti-EGFR: An AGEO-GONO case series.

Authors:
Emilie Hafliger Alessandra Boccaccino Alexandra Lapeyre-Prost Audrey Perret Claire Gallois Maria Antista Lorenzo Pilla Thierry Lecomte Mario Scartozzi Emilie Soularue Lisa Salvatore Vincent Bourgeois Massimiliano Salati David Tougeron Ludovic Evesque Jean-Nicolas Vaillant Reem El-Khoury Sara Lonardi Chiara Cremolini Julien Taieb

Eur J Cancer 2022 Jun 15;168:34-40. Epub 2022 Apr 15.

Department of Gastroenterology and Digestive Oncology, SIRIC CARPEM, Georges-Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP-Paris Centre), Université de Paris, Paris France. Electronic address:

Background: Encorafenib plus cetuximab is efficient in anti-EGFR-naïve patients with BRAF mutated (BRAFm) metastatic colorectal cancer (mCRC). No data are available concerning the efficacy of BRAF inhibitors associated with anti-EGFRs (B + E) in patients previously treated with an anti-EGFR agent.

Methods: We retrospectively collected a series of patients with BRAFm mCRC treated with B + E after previous anti-EGFR treatment, in 14 centers. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment, and we reported objective response and disease control rates (ORR, DCR; RECIST V1.1).

Results: Twenty-five BRAFm mCRC patients were enrolled. Prior to B + E treatment, 4/10/11 patients were treated with 1/2/> 2 previous treatment lines. Ten patients received previous panitumumab, 14 cetuximab, 1 both. Immediate progression with previous anti-EGFR was reported for 7 patients. Anti-BRAF was encorafenib for 21 patients, dabrafenib for 4 patients, with cetuximab for 24 patients and panitumumab for 1 patient. ORR was 40% (10 patients) and DCR was 80% (20 patients). Median PFS and OS were 4.8 months (95% CI, 4.01-7.95) and 10.1 months (95% CI, 7.75-NR). DCR amongst patients with previous primary resistance to anti-EGFR (N = 7) was 100%. Two patients discontinued B + E due to drug-related adverse event.

Conclusions: Though in a limited retrospective series of patients, these results show the efficacy of the combination of anti-BRAF and anti-EGFRs in BRAFm mCRC patients previously treated with an anti-EGFR. The use of this combination should thus not be ruled out in this population with limited therapeutic options.
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http://dx.doi.org/10.1016/j.ejca.2022.03.011DOI Listing
June 2022

Impact of Positive Radial Margin on Recurrence and Survival in Perihilar Cholangiocarcinoma.

Authors:
Francesco Enrico D'Amico Claudia Mescoli Silvia Caregari Alessio Pasquale Ilaria Billato Remo Alessandris Jacopo Lanari Domenico Bassi Riccardo Boetto Francesco D'Amico Alessandro Vitale Sara Lonardi Enrico Gringeri Umberto Cillo

Cancers (Basel) 2022 Mar 25;14(7). Epub 2022 Mar 25.

Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padova, 35128 Padua, Italy.

In resected perihilar cholangiocarcinoma (PHC), positive ductal margin (DM) is associated with poor survival. There is currently little knowledge about the impact of positive radial margin (RM) when DM is negative. The aim of this study was to evaluate the incidence and the role of positive RM. Patients who underwent surgery between 2005 and 2017 where retrospectively reviewed and stratified according to margin positivity: an isolated RM-positive group and DM ± RM group. Of the 75 patients identified; 34 (45.3%) had R1 resection and 17 had positive RM alone. Survival was poorer in patients with R1 resection compared to R0 ( = 0.019). After stratification according to margin positivity; R0 patients showed better survival than DM ± RM-positive patients ( = 0.004; MST 43.9 vs. 23.6 months), but comparable to RM-positive patients ( = 0.361; MST 43.9 vs. 39.5 months). Recurrence was higher in DM ± RM group compared to R0 ( = 0.0017; median disease-free survival (DFS) 15 vs. 30 months); but comparable between RM and R0 group ( = 0.39; DFS 20 vs. 30 months). In univariate and multivariate analysis, DM positivity resulted as a negative prognostic factor both for survival and recurrence. In conclusion, positive RM resections appear to have different recurrence patterns and survival rates than positive DM resections.
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http://dx.doi.org/10.3390/cancers14071680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996964PMC
March 2022

Clinical profile and mortality of Sars-Cov-2 infection in cancer patients across two pandemic time periods (Feb 2020-Sep 2020; Sep 2020-May 2021) in the Veneto Oncology Network: The ROVID study.

Authors:
Maria V Dieci Giuseppe Azzarello Vittorina Zagonel Franco Bassan Stefania Gori Giuseppe Aprile Vanna Chiarion-Sileni Sara Lonardi Cristina Oliani Marta Zaninelli Rita Chiari Adolfo Favaretto Alberto Pavan Elisabetta Di Liso Eleonora Mioranza Alessandra Baldoni Francesca Bergamo Marco Maruzzo Stamatia Ziampiri Alessandro Inno Filomena Graziani Giusy Sinigaglia Michele Celestino Pierfranco Conte Valentina Guarneri

Eur J Cancer 2022 May 18;167:81-91. Epub 2022 Mar 18.

Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy.

Introduction: We analyzed a cohort of patients with cancer and Sars-Cov-2 infection from the Veneto Oncology Network registry across two pandemic time periods.

Materials And Methods: 761 patients with cancer and SARS-CoV-2 infection were included.

Results: 198 patients were diagnosed during the first pandemic time period (TP1; February 2020 September 2020), 494 during TP2 before the vaccination campaign (TP2/pre-vaccination; September 2020-21 February 2021) and 69 in TP2/post-vaccination (22 February 2021-15 May 2021). TP2 vs TP1 patients were younger (p = 0.004), showed more frequently a good performance status (p < 0.001) and <2 comorbidities (p = 0.002), were more likely to be on active anticancer therapy (p = 0.006). Significantly fewer patients in TP2 (3-4%) vs TP1 (22%) had an in-hospital potential source of infection (p < 0.001). TP2 patients were more frequently asymptomatic (p = 0.003). Significantly fewer patients from TP2 were hospitalized (p < 0.001) or admitted to intensive care unit (p = 0.006). All-cause mortality decreased from 30.3% in TP1, to 8.9% and 8.7% in the two TP2 periods (p < 0.001), reflected by a significant reduction in Sars-Cov-2-related mortality (15.2%, 7.5% and 5.8% in the three consecutive time periods, p = 0.004).

Conclusions: Differences in clinical characteristics and features of Sars-Cov-2 infection between TP1 and TP2 reflect the effects of protective measures and increased testing capacity. The lower mortality in TP2 is in line with a less frail population. However, the vast majority of death events in TP2 were related to COVID-19, reinforcing the priority to protect cancer patients.
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http://dx.doi.org/10.1016/j.ejca.2022.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930432PMC
May 2022

Mismatch repair status and gastro-oesophageal dysplasia: need for a dedicated gastrointestinal pathologist?

Authors:
Valentina Angerilli Sara Lonardi Fabio Farinati Edoardo Savarino Francesca Bergamo Matteo Fassan

Histopathology 2022 Apr 5. Epub 2022 Apr 5.

Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy.

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http://dx.doi.org/10.1111/his.14647DOI Listing
April 2022

FOLFOXIRI and bevacizumab in patients with early-onset metastatic colorectal cancer. A pooled analysis of TRIBE and TRIBE2 studies.

Authors:
Carlotta Antoniotti Marco M Germani Daniele Rossini Sara Lonardi Filippo Pietrantonio Daniele Santini Federica Marmorino Giacomo Allegrini Francesca Daniel Alessandra Raimondi Beatrice Borelli Alberto Zaniboni Veronica Conca Jim Abraham David Spetzler Evaristo Maiello Alessandra Boccaccino Alessandro Passardi Mirella Giordano Emiliano Tamburini Michael W Korn Gianluca Masi Chiara Cremolini

Eur J Cancer 2022 05 30;167:23-31. Epub 2022 Mar 30.

Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy; Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. Electronic address:

Background: We performed a pooled analysis of TRIBE and TRIBE2 studies to assess the efficacy and safety of the intensification of upfront chemotherapy backbone - from doublets to the triplet FOLFOXIRI - in combination with bevacizumab (bev) in patients with early-onset metastatic colorectal cancer (EO-mCRC; aged <50 years) and to explore whether EO-mCRCs have a peculiar tumour genomic profiling.

Materials And Methods: Subgroup analyses according to age (<50 versus ≥50 years) and treatment (FOLFOXIRI/bev versus doublets/bev) were carried out for rates of any grade and grade ≥3 (≥G3) overall and singular adverse events, progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Tumour genomic profiling was obtained using a DNA-based next-generation sequencing platform.

Results: Of 1187 patients included, 194 (16%) patients were aged <50 years. Females were more frequently diagnosed with EO-mCRC (P = 0.04). Patients aged <50 years showed a lower risk of ≥G3 neutropenia (P = 0.07), diarrhoea (P = 0.04), asthenia (P = 0.008) and a higher risk of any grade nausea (P < 0.01) and vomiting (P < 0.01). Patients receiving FOLFOXIRI/bev more frequently experienced ≥G3 chemotherapy-related adverse events respect to doublets/bev, regardless of age (P = 0.60). FOLFOXIRI/bev was associated to a lower incidence of neutropenia (P = 0.04) and asthenia (P = 0.01) in patients <50 years old, than those aged ≥50 years. PFS, OS and ORR did not differ according to age (PFS P = 0.81, OS P = 0.44, ORR P = 0.50) and no interaction between age and the benefit from the intensification of upfront chemotherapy was observed (PFS P = 0.72, OS P = 0.54, ORR P = 0.65). Genomic profiling was assessed in 296 patients, showing an enrichment of FBXW7 and POLE mutations in EO-mCRC.

Conclusions: Upfront FOLFOXIRI/bev shows a favourable efficacy/safety balance in EO-mCRC.

Trial Registration: Clinicaltrials.gov Identifiers NCT00719797, NCT0233-9116.
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http://dx.doi.org/10.1016/j.ejca.2022.02.031DOI Listing
May 2022

Reinduction of an Anti-EGFR-based First-line Regimen in Patients with RAS Wild-type Metastatic Colorectal Cancer Enrolled in the Valentino Study.

Authors:
Giovanni Fucà Alessandra Raimondi Michele Prisciandaro Sara Lonardi Chiara Cremolini Margherita Ratti Matteo Clavarezza Roberto Murialdo Andrea Sartore-Bianchi Valeria Smiroldo Rosa Berenato Patrizia Racca Francesca Bergamo Salvatore Corallo Maria Di Bartolomeo Filippo de Braud Federica Morano Filippo Pietrantonio

Oncologist 2022 02;27(1):e29-e36

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: In patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC), growing evidence supports anti-epidermal growth factor receptor (EGFR) retreatment, whereas little is known on the outcomes of anti-EGFR-based reinduction therapy during the upfront strategy.

Methods: We included patients enrolled in the Valentino study who had disease progression and received at least one dose of post-progression therapy. The Kaplan-Meier method and Cox proportional hazards regression were used for the survival analysis. When comparing the outcomes of anti-EGFR-based reinduction versus any second line, a propensity score-based matching was used.

Results: Liver-limited/single site of disease (P < .001 and P = .002), left-sidedness (P = .029), surgery of metastases (P = .003), early tumor shrinkage, and deeper responses (P = .018 and P = .036) were associated with the use of anti-EGFR-based reinduction versus any other second line. All patients treated with reinduction had an anti-EGFR-free interval of at least 3 months. In the propensity score-matched population, progression-free survival (PFS) was similar in the 2 treatment groups, the overall survival (OS) was significantly longer for patients treated with reinduction (P = .029), and the response rate was higher in patients treated with reinduction (P = .033). An oxaliplatin-free interval ≥12 months, left-sidedness, and molecular hyperselection beyond RAS/BRAF were associated with significantly better outcomes after anti-EGFR-based reinduction.

Conclusions: Reinduction strategies with anti-EGFR-based regimens are commonly used in clinical practice. Our data highlight the importance of clinical-molecular selection for re-treatments and the need for prospective strategy trials in selected populations.
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http://dx.doi.org/10.1093/oncolo/oyab012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842305PMC
February 2022

Prognostic impact of FGFR2/3 alterations in patients with biliary tract cancers receiving systemic chemotherapy: the BITCOIN study.

Authors:
Mario Rizzato Stefano Brignola Giada Munari Maura Gatti Vincenzo Dadduzio Chiara Borga Francesca Bergamo Antonio Pellino Valentina Angerilli Claudia Mescoli Maria Guido Jessica Rearden Enrico Gringeri Umberto Cillo Angelo Paolo Dei Tos Vittorina Zagonel Fotios Loupakis Sara Lonardi Matteo Fassan

Eur J Cancer 2022 05 15;166:165-175. Epub 2022 Mar 15.

Department of Medicine (DIMED), University of Padua, Padua, Italy; Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. Electronic address:

Aim: FGFR2 rearrangements have been identified as a novel therapeutic target of biliary tract cancer (BTC). However, reliable prevalence estimates of this molecular alteration and its prognostic role have not been fully elucidated.

Methods: A retrospective mono-institutional series of 286 patients affected by locally advanced or metastatic BTC (183 intrahepatic cholangiocarcinomas, 67 extrahepatic cholangiocarcinomas, 36 gallbladder carcinomas) was profiled by means of targeted DNA/RNA next-generation sequencing, immunohistochemistry and fluorescence in situ hybridisation for FGFR2/3, ERBB2, NTRK alterations, IDH1/2 and BRAF mutations and DNA mismatch repair complex proteins alterations/microsatellite instability.

Results: FGFR2 rearrangements, amplifications and point mutations were detected in 15 (5.2%), 1 and 3 cases, respectively. FGFR3 alterations were observed in 5 (1.7%) cases. IDH1/2 were mutated in 35/223 cases (15.7%). A total of 9/258 (3.5%) and 6/260 (2.3%) BTCs had ERBB2 and BRAF gene alterations, respectively. Two cases (2/242; 0.8%) had NTRK1 amplifications but no rearrangement was found. A deficit of mismatch repair protein expression was identified in 9/237 cases (3.8%). At multivariate analysis, age, ECOG performance status, number of metastatic sites, tumour stage, FGFR2/3 alterations and IDH1/2 mutations were prognostic factors of overall survival.

Conclusions: These data provide a strong proof - challenged with a robust and detailed multivariate model - that FGFR2/3 aberrations (including FGFR2 rearrangements) and IDH1/2 mutations can be prognostic for better survival in patients with BTC . The recognition and the measurement of their prognostic impact could be of primary importance for the correct interpretation of currently available data and in the design of new therapeutic trials.
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http://dx.doi.org/10.1016/j.ejca.2022.02.013DOI Listing
May 2022

Interaction via Wnt/B-Catenin Is Associated with Patients' Survival in HER2-Positive Metastatic Gastric Adenocarcinoma.

Authors:
Valli De Re Lara Alessandrini Giulia Brisotto Laura Caggiari Mariangela De Zorzi Mariateresa Casarotto Gianmaria Miolo Fabio Puglisi Silvio Ken Garattini Sara Lonardi Renato Cannizzaro Vincenzo Canzonieri Matteo Fassan Agostino Steffan

Cancers (Basel) 2022 Feb 28;14(5). Epub 2022 Feb 28.

Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy.

Trastuzumab is a human epidermal growth factor receptor 2 (HER2) inhibitor used to treat HER2+ metastatic gastric cancer (mGC). The present study aims to investigate the relationship between mRNA expression and HER2-positivity in mGC using a multiplexed gene expression profile in two series of gastric cancer (GC): Series 1 ( = 38): HER2+ and HER2- mGC; Series 2 ( = 36) HER2- GC with and without metastasis. To confirm the results, the same expression profiles were analyzed in 354 GC from The Cancer Genome Atlas (TCGA) dataset. The difference in gene expression connected overexpression with canonical wingless-type (Wnt)/β-catenin pathway and immunohistochemical (IHC) expression loss of E-cadherin (E-CAD). mRNA expression was simultaneously associated with the rs16260-A variant and an increase in E-CAD expression. Differences in retinoic acid receptor alfa (), (coding for the 60S ribosomal L19 protein), catenin delta 1 (), and epidermal growth factor () mRNA levels-all included in the Wnt/β-catenin pathway-were found associated with overall survival (OS). , , and resulted in independent OS prognostic factors. was confirmed as an independent factor along with TNM stage in HER2-overpressed mGC from TCGA collection. Our study highlighted factors involved in the WNT/β-catenin pathway that interconnected E-CAD with overexpression and patient survival.
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http://dx.doi.org/10.3390/cancers14051266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909509PMC
February 2022

Temozolomide Followed by Combination With Low-Dose Ipilimumab and Nivolumab in Patients With Microsatellite-Stable, O-Methylguanine-DNA Methyltransferase-Silenced Metastatic Colorectal Cancer: The MAYA Trial.

Authors:
Federica Morano Alessandra Raimondi Filippo Pagani Sara Lonardi Lisa Salvatore Chiara Cremolini Sabina Murgioni Giovanni Randon Federica Palermo Lorenzo Antonuzzo Nicoletta Pella Patrizia Racca Michele Prisciandaro Monica Niger Francesca Corti Francesca Bergamo Alberto Zaniboni Margherita Ratti Michele Palazzo Celeste Cagnazzo Maria Alessandra Calegari Federica Marmorino Iolanda Capone Elena Conca Adele Busico Silvia Brich Elena Tamborini Federica Perrone Massimo Di Maio Massimo Milione

J Clin Oncol 2022 May 8;40(14):1562-1573. Epub 2022 Mar 8.

Department of the Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Purpose: This is a multicenter, single-arm phase II trial evaluating the efficacy and safety of an immune-sensitizing strategy with temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab in patients with microsatellite-stable (MSS) and O-methylguanine-DNA methyltransferase (MGMT)-silenced metastatic colorectal cancer (mCRC).

Patients And Methods: Patients with pretreated mCRC were centrally prescreened for MSS status and MGMT silencing (ie, lack of MGMT expression by immunohistochemistry plus methylation by pyrosequencing). Eligible patients received two priming cycles of oral temozolomide 150 mg/sqm once daily, days 1-5, once every 4 weeks (first treatment part) followed, in absence of progression, by its combination with ipilimumab 1 mg/kg once every 8 weeks and nivolumab 480 mg once every 4 weeks (second treatment part). The primary end point was the 8-month progression-free survival (PFS) rate calculated from enrollment in patients who started the second treatment part, with ≥ 4 out of 27 subjects progression-free by the 8-month time point as decision rule.

Results: Among 716 prescreened patients, 204 (29%) were molecularly eligible and 135 started the first treatment part. Among these, 102 (76%) were discontinued because of death or disease progression on temozolomide priming, whereas 33 patients (24%) who achieved disease control started the second treatment part and represented the final study population. After a median follow-up of 23.1 months (interquartile range, 14.9-24.6 months), 8-month PFS rate was 36%. Median PFS and overall survival were 7.0 and 18.4 months, respectively, and overall response rate was 45%. Grade 3-4 immune-related adverse events were skin rash (6%), colitis (3%), and hypophysitis (3%). No unexpected adverse events or treatment-related deaths were reported.

Conclusion: The MAYA study provided proof-of-concept that a sequence of temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab may induce durable clinical benefit in MSS and MGMT-silenced mCRC.
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http://dx.doi.org/10.1200/JCO.21.02583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9084437PMC
May 2022

BRAF-mutated colorectal adenocarcinomas: Pathological heterogeneity and clinical implications.

Authors:
Valentina Angerilli Giovanna Sabella Giovanni Centonze Sara Lonardi Francesca Bergamo Alessandro Mangogna Filippo Pietrantonio Matteo Fassan Massimo Milione

Crit Rev Oncol Hematol 2022 Apr 4;172:103647. Epub 2022 Mar 4.

Pathology Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. Electronic address:

Advances in molecular biology have markedly increased our understanding of the heterogeneous molecular landscape of colorectal cancer (CRC). Up to 15% of CRCs harbor the BRAF p.V600E somatic mutation (BRAFmt), a well-established negative prognostic marker in patients with metastatic CRC (mCRC). The BEACON CRC trial set a new standard of care in patients with progressive BRAFmt cancers, consisting of the combination of encorafenib and cetuximab. On these bases, BRAF mutational testing is now recommended in patients with mCRC. However, efforts are needed to further stratify patients carrying this mutation. Here, we discuss the heterogeneous pathologic and molecular landscape of BRAFmt CRCs, focusing on the promises and pitfalls of molecular diagnostics, on novel biomarkers to improve patients' stratification and on the current diagnostic scenario for CRC. We believe that a better stratification based on histopathological features and novel molecular biomarkers should be performed to optimize patient management and therapeutic decision-making.
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http://dx.doi.org/10.1016/j.critrevonc.2022.103647DOI Listing
April 2022

Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies.

Authors:
Anna Maria Rachiglio Laura Forgione Raffaella Pasquale Carlo Antonio Barone Evaristo Maiello Lorenzo Antonuzzo Antonino Cassata Giuseppe Tonini Roberto Bordonaro Gerardo Rosati Alberto Zaniboni Sara Lonardi Daris Ferrari Giovanni Luca Frassineti Stefano Tamberi Salvatore Pisconti Francesca Di Fabio Cristin Roma Armando Orlandi Tiziana Latiano Angela Damato Giampaolo Tortora Carmine Pinto Nicola Normanno

Cancers (Basel) 2022 Feb 18;14(4). Epub 2022 Feb 18.

Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, 80131 Naples, Italy.

Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline ( = 37), at 8 weeks of treatment ( = 32), progressive disease (PD; = 36) and 3 months after PD ( = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients ( = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.
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http://dx.doi.org/10.3390/cancers14041052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870112PMC
February 2022

Emetogenicity of Antibody-Drug Conjugates (ADCs) in Solid Tumors with a Focus on Trastuzumab Deruxtecan: Insights from an Italian Expert Panel.

Authors:
Giampaolo Bianchini Grazia Arpino Laura Biganzoli Sara Lonardi Fabio Puglisi Daniele Santini Matteo Lambertini Giovanni Pappagallo

Cancers (Basel) 2022 Feb 17;14(4). Epub 2022 Feb 17.

School of Clinical Methodology, IRCCS "Sacro Cuore-Don Calabria" Hospital, 37024 Negrar di Valpolicella, Italy.

In the past decade, nine antibody-drug conjugates (ADCs) have been approved for the treatment of various tumors, four of which specifically for solid malignancies. ADCs deliver the cytotoxic payload to the cancer site, thereby improving chemotherapy efficacy while reducing systemic drug exposure and toxicity. With their high selectivity, ADCs are associated with a manageable side-effect profile, with nausea and vomiting being among the most frequent toxicities, although this may vary according to the respective ADC and the associated payload. Information about the emetic risk of the new ADC compounds is limited. Three virtual focus groups of Italian oncologists were held to raise awareness on the importance of an antiemetic prophylaxis regimen to prevent and mitigate ADC-associated emesis and its sequelae. After reviewing published evidence and guidelines, the three expert panels shared their experience on the early use of ADCs gained through the participation in specific clinical trials and their clinical practice. The following issues were discussed: antiemetic therapy during trastuzumab deruxtecan treatment, with a protocol adopted at the San Raffaele Hospital (Milan, Italy); the use of steroids; the management of anticipatory nausea during trastuzumab deruxtecan therapy; nutritional counselling; and effective doctor-patient communication. The experts acknowledged that recommendations should be drug-specific, and formulated opinion-based advice intended to guide physicians in their daily practice until further evidence emerges.
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http://dx.doi.org/10.3390/cancers14041022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870408PMC
February 2022

An Unexpected Tumor Reduction: Treatment with Olaparib Monotherapy in Heavily Pretreated BRCA2 Mutated Metastatic Pancreatic Cancer.

Authors:
Alessandra Anna Prete Letizia Procaccio Francesca Bergamo Cosimo Rasola Floriana Nappo Vittorina Zagonel Sara Lonardi

Curr Oncol 2022 01 27;29(2):544-550. Epub 2022 Jan 27.

Oncology Unit 3, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy.

PARP inhibitors are largely recognized as active drugs in BRCA-mutated breast and ovarian malignancies. In pancreatic ductal adenocarcinoma, the PARP inhibitor olaparib has recently been approved as maintenance treatment in patients with germline BRCA mutations reaching disease control after a platinum-based first line chemotherapy, proving significant benefit on progression free survival. On the other hand, little evidence is available regarding olaparib as single agent after progression with standard treatment in BRCA-mutated pancreatic ductal adenocarcinoma. A 61-year-old female patient harboring germline BRCA2 mutation was treated at our institution for a pancreatic ductal adenocarcinoma with lung and liver metastases. The patient received three previous lines of treatment with standard therapies, as follows: after the third line treatment failure, we started a further line of treatment with olaparib in off-label prescription. After the first two cycles, a CT scan documented partial response, with complete regression of lung metastases. The response was maintained after four cycles, with further response and clinical benefit. The radiologic and clinical response was maintained for 6 months. This case highlights the potential of olaparib as single agent after progression with standard treatment in BRCA-mutated pancreatic cancer.
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http://dx.doi.org/10.3390/curroncol29020049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870641PMC
January 2022

Multimodal treatment of radiation-induced esophageal cancer: Results of a case-matched comparative study from a single center.

Authors:
Elisa Sefora Pierobon Giovanni Capovilla Lucia Moletta Anna Laura De Pasqual Caterina Fornasier Renato Salvador Gianpietro Zanchettin Sara Lonardi Sara Galuppo Edin Hadzijusufovic Peter P Grimminger Matteo Stocchero Mario Costantini Stefano Merigliano Michele Valmasoni

Int J Surg 2022 Mar 18;99:106268. Epub 2022 Feb 18.

Center for Esophageal Diseases - Department of Surgical, Oncological and Gastroenterological Sciences - University of Padova, Padova, Italy.

Purpose: Radiation-induced esophageal cancer (RIEC) is a rare but severe late consequence of radiotherapy. The literature regarding this topic is predominately limited in describing the risk of this disease. Tumor behavior, treatment strategies, and prognosis of this cancer remain poorly defined.

Patients And Methods: We collected data of patients who were referred to our unit between 2000 and 2020 for RIEC. After tumor board discussion, upfront surgery or neoadjuvant therapy and surgery were indicated as the main treatment. Preoperative characteristics, long-term and short-term postoperative outcomes of RIEC patients were compared with a 1:1 clustering-matched cohort of patients affected by primary esophageal cancer (PEC).

Results: At pre-matching, 54 RIEC and 936 PEC patients were enrolled. The median time between primary irradiation and diagnosis of RIEC was 13.5 years, and the median primary radiation dose was 60 Gy. Compared to the unmatched cohort of PECs, RIEC patients were more frequently female (p = 0.0007), had earlier detection of disease (p = 0.03) and presented more frequently with upper esophageal cancers (p < 0.0001). Neoadjuvant treatment was used less frequently in RIEC patients (p < 0.0001). After matching, the 51 RIEC and 50 PEC patients showed comparable results in terms of exposure to neoadjuvant treatment, surgical radicality and survival outcomes. RIEC patients had more severe postoperative complications (p = 0.04) and a higher proportion of pulmonary complications (p = 0.04).

Conclusions: Curative treatments are feasible for RIEC. Neoadjuvant chemotherapy or chemoradiation can be used in this subgroup, treatment response and long-term outcomes are comparable to those of PEC. The risk of postoperative complications is probably related to the detrimental effect of primary irradiation on lung function.
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http://dx.doi.org/10.1016/j.ijsu.2022.106268DOI Listing
March 2022

Cancer Patient-Reported Experience Measures (PREMs) Regarding the Policies Implemented to Contain the Spread of Sars-CoV-2 and Vaccination Campaign at Veneto Institute of Oncology.

Authors:
Mario Caccese Silvia Imbevaro Alessandra Feltrin Daniela Costardi Nadia Giordano Maristella Maran Rosalba Martino Ketti Ottolitri Malihe Shams Federica Vascon Anna Roma Antonella Galiano Marco Maruzzo Dario Marino Giuseppe Lombardi Sara Lonardi Antonella Brunello Vittorina Zagonel

Patient Prefer Adherence 2022 9;16:353-362. Epub 2022 Feb 9.

Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.

Purpose: The SARS-CoV-2 spread has impacted Healthcare systems. COVID-19 pandemic has had consequences for patients with cancer, being associated with delays in diagnosis, in treatment And follow-up care, increase in overall infection rates and higher mortality. A survey on COVID-19 and a vaccination-questionnaire were developed at different times of the outbreak, to evaluate cancer patient-reported experience measures (PREMs) on the policies implemented to reduce the infection from SARS-CoV-2 and on the timing and methods of COVID-19 vaccination.

Patients And Methods: The survey was distributed to all patients accessing the Institute during the "first-wave" Of the pandemic, evaluating patients' concerns about the pandemic, the pandemics' consequences on their cancer care, and their perception Of the measures adopted to limit the infection spread. The vaccination-questionnaire was proposed to 10% of the first 5297 cancer patients vaccinated with two doses of the Pfizer-BioNTechCOVID-19 vaccine. This questionnaire aimed at assessing the degree Of satisfaction with the Institutional vaccination campaign and vaccination-related adverse events.

Results: From May 18th 2020 to June 15th 2020 the survey was completed by 3238 patients. Most of the responders expressed concern on the pandemic yet acknowledging their oncological disease as a priority. Measures implemented were appreciated by patients. Telemedicine was positively evaluated and the absence of the caregiver during the visit did not determine discomfort for two thirds of patients. From March 6th 2021 to May 8th 2021 the vaccination-questionnaire was completed by 357 patients. The 98.8% were satisfied with the vaccination campaign. No serious vaccination-correlated adverse events were reported. No patient had to delay/discontinue chemotherapy due to vaccination.

Conclusion: PREMs during COVID-19 pandemic and related vaccination can provide important information to help reorganization of the health care systems for cancer care. Patients' feedback on the organizational changes implemented in the emergency period are essential for healthcare improvement and to help informed choices that are consistent with patients' needs.
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http://dx.doi.org/10.2147/PPA.S351771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841696PMC
February 2022

Could Total Neoadjuvant Therapy Followed by Surgical Resection Be the New Standard of Care in Pancreatic Cancer? A Systematic Review and Meta-Analysis.

Authors:
Ottavia De Simoni Marco Scarpa Caterina Soldà Francesca Bergamo Sara Lonardi Alberto Fantin Pierluigi Pilati Mario Gruppo

J Clin Med 2022 Feb 3;11(3). Epub 2022 Feb 3.

Unit of Surgical Oncology of Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy.

Background: Total neoadjuvant therapy (TNT), intended as induction chemotherapy (IC) followed by radio-chemotherapy (RCT), has been taking hold in the treatment of pancreatic ductal adenocarcinoma (PDAC). The aim of this review is to summarize the available evidence on the role of TNT followed by curative surgery.

Methods: Eligible studies were those reporting on patients with PDAC undergoing curative surgery after TNT. The primary endpoint was overall survival (OS).

Results: A total of 1080 patients with PDAC who had undergone TNT were analyzed. The most common IC regimen was Gemcitabine (N 620, 57%). Toxicity during IC varied from 14% to 51%. Disease progression during IC varied from 3% to 25%. 607 (62%) patients underwent curative surgery after IC + CRT. In meta-analysis, the available data on lymph node metastases radicality and 2 years OS had better results in favor of TNT groups (OR 1.77, 95% CI 1.20-2.60, = 0.004 and OR 2.03, 95% CI 1.19-3.47, = 0.01 and OR 1.64, CI 1.09-2.47, = 0.02, respectively).

Conclusions: Despite the heterogeneity of the studies, different selection criteria, and non-negligible drop-out rate, TNT demonstrated a potential superiority to NAT without CRT in oncological and pathological outcomes, even if the main differences seem to depend on the IC regimen.
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http://dx.doi.org/10.3390/jcm11030812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836959PMC
February 2022

Risk-adjusted analysis of survival variability among hospitals treating biliary malignancy.

Authors:
Margherita Rimini Andrea Casadei-Gardini Giovanni Brandi Francesco Leone Lorenzo Fornaro Nicoletta Pella Nicola Silvestris Francesco Montagnani Sara Lonardi Eleonora Lai Eva Galizia Daniele Santini Andrea Palloni Roberto Filippi Gianluca Masi Giuseppe Aprile Massimo Aglietta Giorgio Frega Elisabetta Fenocchio Caterina Vivaldi Maria Antonietta Satolli Francesca Salani Mario Scartozzi Luca Faloppi Antonio Pellino Elisa Sperti Valentina Burgio Francesca Ratti Luca Aldrighetti Stefano Cascinu

J Chemother 2022 Feb 14:1-7. Epub 2022 Feb 14.

Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.

Biliary tract cancer's (BTC) treatment main stone for advanced stages is constituted by chemotherapy. Surgical centralization and physicians' confidence in the use of new technologies and molecular analysis turned out to be of interest and potentially influencing survival. After applying a random-effect model, the relationship between each clinical variable on the main outcome was investigated through multilevel mixed-effects logistic regression. The risk-standardized outcomes were calculated for each centre involved. In the unadjusted cohort the median survival was 8.6 months (95%C.I.: 7.8-9.3) with a 9-month survival rate of 48.3% (95%C.I.: 45.0-51.5). A substantial heterogeneity across hospitals was found (I: 70.3%). In multilevel mixed effect logistic regression, male, being treated for gallbladder cancer, higher ECOG, increased NLR, CEA and Ca 19.9 and low value of haemoglobin showed to increase the odds for 9-month mortality. The model estimated that the residual variance observed in 9-month mortality was attributable for the 2.6% to the treating hospital. Through a multilevel mixed effect model, average risk-standardized mortality within 9 months was 50.1%. As noticeable, all hospital's risk-standardized mortality falls within 95%C.I., thus all participating centres provided similar outcomes when adjusted for patient case-mix. Heterogenicity between hospital did not affect the outcome in term of overall survival.
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http://dx.doi.org/10.1080/1120009X.2022.2036557DOI Listing
February 2022

MMR profile and microsatellite instability status in colorectal mucinous adenocarcinoma with synchronous metastasis: a new clue for the clinical practice.

Authors:
Paola Parente Umberto Malapelle Valentina Angerilli Mariangela Balistreri Sara Lonardi Salvatore Pucciarelli Caterina De Luca Francesco Pepe Gianluca Russo Elena Vigliar Angela Danza Fabio Scaramuzzi Giancarlo Troncone Paolo Graziano Matteo Fassan

J Clin Pathol 2022 Feb 10. Epub 2022 Feb 10.

Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua (PD), Italy

Aims: Mucinous adenocarcinoma (MA) is associated with a high frequency of microsatellite instability (MSI). In the metastatic setting, it is crucial to establish mismatch repair (MMR) and/or MSI status. However, genetic heterogeneity between primary tumour and synchronous metastasis and the diagnostic accuracy of the assay may hamper the MMR/MSI status evaluation.

Methods: In this study, we assessed the concordance rate of the MMR/MSI status between primary tumour and paired synchronous metastasis of 25 MAs. MMR status was evaluated by immunohistochemistry (IHC), while MSI status was evaluated by using three different molecular approaches: microfluidic electrophoresis of PCR products (TapeStation 4200 platform), full-closed RTqPCR system (Idylla system) and multiplex amplification with fluorescent primers and subsequent DNA fragment analysis on an automated sequencer (Titano MSI test).

Results: The concordance rate between primary MA and metastasis was 21/21 (100%), 23/25 (92.0%), 23/25 (92.0%) and 21/25 (84%) by using IHC, Idylla system, Titano MSI test and TapeStation 4200 system. All the four methods used in our study displayed high concordant rate, ranging from 91.0% (IHC vs Tapestation 4200 platform) to 98.0% (IHC vs Titano).

Conclusions: Several methodologies are frequently adopted in routine practice to successfully perform MMR/MSI status analysis. The most relevant issues related to MMR/MSI status analysis in MAs concern with low percentage of neoplastic cell and abundant mucine that may affect the molecular analysis. Thus, it might be useful to acquire both primary and metastatic sample to evaluate the MMR/MSI status by integrating IHC evaluation and molecular methodologies to successfully perform molecular profiling for MA patients.
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http://dx.doi.org/10.1136/jclinpath-2022-208143DOI Listing
February 2022

Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers.

Authors:
Giovanni Fucà Romain Cohen Sara Lonardi Kohei Shitara Maria Elena Elez Marwan Fakih Joseph Chao Samuel J Klempner Matthew Emmett Priya Jayachandran Francesca Bergamo Marc Díez García Giacomo Mazzoli Leonardo Provenzano Raphael Colle Magali Svrcek Margherita Ambrosini Giovanni Randon Aakash Tushar Shah Massimiliano Salati Elisabetta Fenocchio Lisa Salvatore Keigo Chida Akihito Kawazoe Veronica Conca Giuseppe Curigliano Francesca Corti Chiara Cremolini Michael Overman Thierry Andre

J Immunother Cancer 2022 02;10(2)

Sorbonne Université, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP and INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France.

Background: Despite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs.

Methods: We conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset.

Results: The mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement.

Conclusions: Patients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches.
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http://dx.doi.org/10.1136/jitc-2021-004001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8811606PMC
February 2022

Complete pathological response of colorectal peritoneal metastases in Lynch syndrome after immunotherapy case report: is a paradigm shift in cytoreductive surgery needed?

Authors:
Marco Tonello Floriana Nappo Loretta Vassallo Rosa Di Gaetano Carla Davoli Elisa Pizzolato Ottavia De Simoni Cristina Tassinari Antonio Scapinello Pierluigi Pilati Fotios Loupakis Sara Lonardi Antonio Sommariva

BMC Gastroenterol 2022 Jan 10;22(1):17. Epub 2022 Jan 10.

Surgical Oncology of the Esophagus and Digestive Tract Unit, Surgical Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128, Padua, Italy.

Background: We report the first case of a patient affected by peritoneal metastases from colon cancer, arising in the context of Lynch syndrome with pathological complete response. The patient was treated with immunotherapy and cytoreductive surgery. This paper discusses the implications of these novel therapies for the management of PM.

Case Presentation: A 50-year-old man affected by Lynch syndrome was referred to our institution for metachronous peritoneal recurrence of ascending colon adenocarcinoma. As a second-line treatment, he received Nivolumab therapy with stable disease. Patient underwent cytoreductive surgery with residual disease and a pathological complete response. Flow cytometry described a particular immune sub-population response. There was no evidence of disease progression after nine months.

Conclusion: This is the first report of a Lynch patient affected by peritoneal metastases of colorectal cancer, treated with cytoreductive surgery (CRS) and resulting in a pathological complete response after immune checkpoint inhibitors treatment (ICIs). This case report may suggest that patients with peculiar immunological features could benefit from a tailored approach, since "classical" CRS paradigms may not effectively predict the clinical outcome. Further large-scale studies are needed to determine the correct operative management of such patients (tailored or "standard" CRS), defining the correct surgical timing and eventual discontinuation of ICI therapy after surgery.
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http://dx.doi.org/10.1186/s12876-021-02084-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751316PMC
January 2022

Real-Life Clinical Data of Lenvatinib versus Sorafenib for Unresectable Hepatocellular Carcinoma in Italy.

Authors:
Valentina Burgio Massimo Iavarone Giovanni Giuseppe Di Costanzo Fabio Marra Sara Lonardi Emiliano Tamburini Fabio Piscaglia Gianluca Masi Ciro Celsa Francesco Giuseppe Foschi Marianna Silletta Daniela Caterina Amoruso Margherita Rimini Mariangela Bruccoleri Raffaella Tortora Claudia Campani Caterina Soldà Massimo Giuseppe Viola Antonella Forgione Fabio Conti Francesca Salani Silvia Catanese Carmelo Marco Giacchetto Claudia Fulgenzi Carmine Coppola Pietro Lampertico Antonio Pellino Gabriele Rancatore Giuseppe Cabibbo Francesca Ratti

Cancer Manag Res 2021 24;13:9379-9389. Epub 2021 Dec 24.

Hepatobiliary Surgery Division, Liver Center, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy.

Background: Lenvatinib has been approved in Italy since October 2019 as a first-line therapy for advanced hepatocellular carcinoma (HCC) and to date data on effectiveness and safety of lenvatinib are not available in our region. To fill this gap, we performed a multicentric analysis of the real-world treatment outcomes with the propensity score matching in a cohort of Italian patients with unresectable HCC who were treated with either sorafenib or lenvatinib.

Aims And Methods: To evaluate the effectiveness of sorafenib and lenvatinib as primary treatment of advanced HCC in clinical practice we performed a multicentric analysis of the treatment outcomes of 288 such patients recruited in 11 centers in Italy. A propensity score was used to mitigate confounding due to referral biases in the assessment of mortality and progression-free survival.

Results: Over a follow-up period of 11 months the Cox regression model showed 48% reduction of death risk for patients treated with lenvatinib (95% CI: 0.34-0.81; p = 0.0034), compared with those treated with sorafenib. The median PFS was 9.0 and 4.9 months for lenvatinib and sorafenib arm, respectively. Patients treated with lenvatinib showed a higher percentage of response rate (29.4% vs 2.8%; p < 0.00001) compared with patients treated with sorafenib. Sorafenib was shown to be correlated with more HFSR, diarrhea and fatigue, while lenvatinib with more hypertension and fatigue.

Conclusion: Our study highlighted for the first time the efficacy and safety of lenvatinib in an Italian cohort of patients.
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http://dx.doi.org/10.2147/CMAR.S330195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713715PMC
December 2021

Tumour mutational burden predicts resistance to EGFR/BRAF blockade in BRAF-mutated microsatellite stable metastatic colorectal cancer.

Authors:
Giovanni Randon Rossana Intini Chiara Cremolini Elena Elez Michael J Overman Jeeyun Lee Paolo Manca Francesca Bergamo Filippo Pagani Maria Antista Valentina Angerilli Francisco Javier Ros Montaña Daniele Lavacchi Alessandra Boccaccino Giovanni Fucà Silvia Brich Laura Cattaneo Matteo Fassan Filippo Pietrantonio Sara Lonardi

Eur J Cancer 2022 01 18;161:90-98. Epub 2021 Dec 18.

Department of Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy.

Aim: To unveil genomic and immunohistochemical expression profiles associated with primary resistance to EGFR/BRAF targeted therapy in patients with BRAF-mutated and microsatellite stable (MSS) metastatic colorectal cancer.

Experimental Design: In this multicenter case-control study on patients treated with EGFR/BRAF ± MEK blockade, we compared a primary resistance cohort (N = 20; RECISTv1.1 PD/SD, and progression-free survival [PFS] <16 weeks) versus a sensitive one (N = 19; RECISTv1.1 PR/CR, and PFS ≥16 weeks) in terms of clinical and genomic/expression data by means of comprehensive genomic profiling, tumour mutational burden (TMB), BRAF-mutant transcriptional subtypes (BM) classification and PTEN expression.

Results: Left-sided tumours (28% of the total) were enriched in the sensitive versus resistant cohort (53% versus 10%, P = 0.010). Genomic alterations in the PIK3CA/MTOR pathway, BM1 status and PTEN loss were similarly distributed among patients with resistant and sensitive tumours. Amplification of CCND1-3 genes were found only in patients with primary resistance (20% versus 0%, P = 0.106). TMB and prevalence of intermediate TMB (TMB-I 6-20 mutations/Mb) were higher in the resistant versus sensitive cohort (median TMB: 6 [IQR, 3-7.29] versus 3 [IQR, 1.26-3.5]; P = 0.013; TMB-I/H: 60% versus 11%; P = 0.001). Patients with TMB-I had shorter PFS (3.3 versus 5.9 months; HR = 2.19, 95%CI, 1.07-4.47, P = 0.031) and overall survival (6.3 versus 10.5 months; HR = 2.22, 95%CI, 1.02-4.81, P = 0.044).

Conclusion: Despite the small sample size, the association of a relatively higher TMB with limited benefit from EGFR/BRAF blockade in patients with MSS and BRAF-mutated mCRC deserves prospective validation.
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http://dx.doi.org/10.1016/j.ejca.2021.11.018DOI Listing
January 2022

The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer.

Authors:
Yelena Y Janjigian Akihito Kawazoe Patricio Yañez Ning Li Sara Lonardi Oleksii Kolesnik Olga Barajas Yuxian Bai Lin Shen Yong Tang Lucjan S Wyrwicz Jianming Xu Kohei Shitara Shukui Qin Eric Van Cutsem Josep Tabernero Lie Li Sukrut Shah Pooja Bhagia Hyun Cheol Chung

Nature 2021 12 15;600(7890):727-730. Epub 2021 Dec 15.

Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas. More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer, there are preclinical and clinical rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma ( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.
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http://dx.doi.org/10.1038/s41586-021-04161-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8959470PMC
December 2021

PD-L1 and Notch as novel biomarkers in pancreatic sarcomatoid carcinoma: a pilot study.

Authors:
Nicola Silvestris Antonella Argentiero Oronzo Brunetti Margherita Sonnessa Fulvia Colonna Sabina Delcuratolo Claudio Luchini Aldo Scarpa Sara Lonardi Floriana Nappo Matteo Fassan Antonio Giovanni Solimando Livia Fucci Concetta Saponaro

Expert Opin Ther Targets 2021 11 20;25(11):1007-1016. Epub 2021 Dec 20.

Functional Biomorphology Laboratory, Functional Biomorphology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo Ii" of Bari, Bari, Italy.

Background: The improved immunological understanding revealed the tumor microenvironment as an appealing driver to restore the immune response against cancer cells resulting in a paradigm shift in the oncology field. However, the complexity of the tumor milieu suggests the role of several pathways linking in immunomodulation mechanisms. Pancreatic cancer represents a model of the intricate relationship between malignant cells and their surrounding neighborhood.

Research Design And Methods: In this study, we analyzed, retrospectively, six cases of rare pancreatic sarcomatoid carcinoma (PSC) and evaluated the expression of PD-L1 and Notch, aiming to explore new attributes in immunophenotype.

Results: PD-L1 CPS ≥ 1was common in PSCs (83%) with half samples expressing PD-L1 CPS ≥ 50. Notch1 and Notch3 demonstrated a high range of expression. A direct significant correlation between PD-L1 and Notch3 overexpression (r = 0.7; p = 0.036) has been observed. Immunofluorescence studies revealed a co-localization of Notch3 and PD-L1 when both proteins were over-expressed within cytoplasmic or membranous compartments of the same cells.

Conclusions: Our data identify a unique biological characterization of this rare pancreatic histotype. These findings provide a rationale for future studies evaluating the potential crosstalk between PD-L1/PD-1 axis and Notch pathways and prompting the development of novel therapeutics strategy.
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http://dx.doi.org/10.1080/14728222.2021.2011859DOI Listing
November 2021

Association of CLDN18 Protein Expression with Clinicopathological Features and Prognosis in Advanced Gastric and Gastroesophageal Junction Adenocarcinomas.

Authors:
Antonio Pellino Stefano Brignola Erika Riello Monia Niero Sabina Murgioni Maria Guido Floriana Nappo Gianluca Businello Marta Sbaraglia Francesca Bergamo Gaya Spolverato Salvatore Pucciarelli Stefano Merigliano Pierluigi Pilati Francesco Cavallin Stefano Realdon Fabio Farinati Angelo Paolo Dei Tos Vittorina Zagonel Sara Lonardi Fotios Loupakis Matteo Fassan

J Pers Med 2021 Oct 26;11(11). Epub 2021 Oct 26.

Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35122 Padua, Italy.

The tight junction protein claudin-18 (CLDN18), is often expressed in various cancer types including gastric (GC) and gastroesophageal adenocarcinomas (GECs). In the last years, the isoform CLDN18.2 emerged as a potential drug target in metastatic GCs, leading to the development of monoclonal antibodies against this protein. CLDN18.2 is the dominant isoform of CLDN18 in normal gastric and gastric cancer tissues. In this work, we evaluated the immunohistochemical (IHC) profile of CLDN18 and its correlation with clinical and histopathological features including p53, E-cadherin, MSH2, MSH6, MLH1, PMS2, HER2, EBER and PD-L1 combined positive score, in a large real-world and mono-institutional series of advanced GCs ( = 280) and GECs ( = 70). The association of IHC results with survival outcomes was also investigated. High membranous CLDN18 expression (2+ and 3+ intensity ≥75%) was found in 117/350 (33.4%) samples analyzed. CLDN18 expression correlated with age <70 ( = 0.0035), positive EBV status ( = 0.002), high stage (III, IV) at diagnosis ( = 0.003), peritoneal involvement ( < 0.001) and lower incidence of liver metastases ( = 0.013). CLDN18 did not correlate with overall survival. The predictive value of response of CLDN18 to targeted agents is under investigation in several clinical trials and further studies will be needed to select patients who could benefit from these therapies.
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http://dx.doi.org/10.3390/jpm11111095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624955PMC
October 2021

Randomized phase II trial of avelumab alone or in combination with cetuximab for patients with previously treated, locally advanced, or metastatic squamous cell anal carcinoma: the CARACAS study.

Authors:
Sara Lonardi Alessandra Anna Prete Federica Morano Marco Messina Vincenzo Formica Domenico Cristiano Corsi Corrado Orciuolo Giovanni Luca Frassineti Maria Giulia Zampino Mariaelena Casagrande Gianluca Masi Monica Ronzoni Mario Scartozzi Angela Buonadonna Stefania Mosconi Margherita Ratti Andrea Sartore-Bianchi Emiliano Tamburini Michele Prisciandaro Francesca Bergamo Massimiliano Spada Salvatore Corallo Valentina Vettore Fotios Loupakis Matteo Fassan Paola Del Bianco Vittorina Zagonel Filippo Pietrantonio

J Immunother Cancer 2021 11;9(11)

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Background: No standard therapies beyond first line are established for advanced squamous cell anal carcinoma (aSCAC). Earlier preliminary data suggest activity of epidermal growth factor receptor (EGFR) inhibition and programmed cell death ligand (PD-(L))1 blockade in patients with previously treated disease. Aim of this study was to explore activity and safety of avelumab with/without cetuximab in patients with aSCAC.

Methods: In this open-label, non-comparative, 'pick the winner', multicenter randomized phase II trial (NCT03944252), patients with aSCAC progressing after one or more lines of treatment were randomized 1:1 to the anti-PD-L1 agent avelumab alone (arm A) or combined with cetuximab (arm B). Overall response rate (ORR) was the primary endpoint. With one-sided α error set at 0.05 and power of 80%, at least 4 responses out of 27 patients per arm had to be observed to declare the study positive. Secondary endpoints were progression free survival (PFS), overall survival (OS), and safety.

Results: Thirty patients per arm were enrolled. Three patients in arm A and five in arm B achieved partial response: primary endpoint was reached in combination arm. ORR was 10% (95% CI 2.1 to 26.5) and 17% (95% CI 5.6 to 34.7) in arms A and B; disease control rate was 50% (95% CI 31.3 to 68.7) in arm A and 57 (95% CI 37.4-74.5) in arm B. At a median follow-up of 26.7 months (IQR 26.5-26.9), median PFS was 2.0 months (95% CI 1.8 to 4.0) in arm A and 3.9 (95% CI 2.1 to 5.6) in arm B. Median OS was 13.9 months (95% CI 7.7 to 19.4) in arm A and 7.8 (95% CI 6.2 to 11.2) in arm B. Acceptable safety profile was observed in both arms.

Conclusions: CARACAS study met its primary endpoint in arm B, documenting promising activity of dual EGFR and PD-L1 blockade in aSCAC.
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http://dx.doi.org/10.1136/jitc-2021-002996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611452PMC
November 2021

Variant allele frequency in baseline circulating tumour DNA to measure tumour burden and to stratify outcomes in patients with RAS wild-type metastatic colorectal cancer: a translational objective of the Valentino study.

Authors:
Paolo Manca Salvatore Corallo Sara Lonardi Giovanni Fucà Adele Busico Alberto Giovanni Leone Francesca Corti Carlotta Antoniotti Letizia Procaccio Valeria Smiroldo Margherita Ratti Roberto Murialdo Patrizia Racca Filippo Pagani Giovanni Randon Antonia Martinetti Elisa Sottotetti Michele Prisciandaro Margherita Ambrosini Alessandra Raimondi Federica Morano Filippo Pietrantonio

Br J Cancer 2022 02 22;126(3):449-455. Epub 2021 Nov 22.

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Introduction: In patients with metastatic colorectal cancer (mCRC), baseline circulating tumour DNA (ctDNA) variant allele fraction (VAF) might serve as a surrogate of disease burden and should be evaluated in comparison with CEA and RECIST-defined sum of target lesions.

Methods: In this pre-planned analysis of the VALENTINO trial, we included patients with RAS wild-type mCRC receiving upfront FOLFOX/panitumumab with available baseline liquid biopsy. CtDNA was analysed by means of a 14-gene NGS panel. For each patient, the gene with the highest VAF in ctDNA was selected.

Results: The final cohort included 135 patients. The median VAF was 12.6% (IQR: 2.0-45.2%). Higher VAF was observed in patients with liver metastases and with synchronous metastases presentation. Patients with high VAF had poorer median OS compared to those with low VAF (21.8 vs 36.5 months; HR: 1.82, 95%CI: 1.20-2.76; p = 0.005). VAF outperformed baseline CEA and target lesion diameter in the prognostic stratification and remained significantly correlated with OS (p = 0.003) in a multivariate model. VAF was not significantly correlated with dimensional response and PFS.

Conclusion: CtDNA measured by VAF is prognostic in patients with RAS wild-type mCRC. Response and PFS after an anti-EGFR-based first-line strategy are independent from initial tumour burden.
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http://dx.doi.org/10.1038/s41416-021-01591-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810873PMC
February 2022

Early-Onset Colorectal Adenocarcinoma in the IDEA Database: Treatment Adherence, Toxicities, and Outcomes With 3 and 6 Months of Adjuvant Fluoropyrimidine and Oxaliplatin.

Authors:
Elisa Fontana Jeff Meyers Alberto Sobrero Timothy Iveson Anthony F Shields Julien Taieb Takayuki Yoshino Ioannis Souglakos Elizabeth C Smyth Florian Lordick Markus Moehler Anne Giraut Andrea Harkin Roberto Labianca Jeffrey Meyerhardt Thierry André Ioannis Boukovinas Sara Lonardi Mark Saunders Dewi Vernerey Eiji Oki Vassilis Georgoulias Irit Ben-Aharon Qian Shi

J Clin Oncol 2021 12 9;39(36):4009-4019. Epub 2021 Nov 9.

Department of Quantitative Health Science, Mayo Clinic, Rochester, MN.

Purpose: Early-onset (EO) colorectal cancer (CRC, age < 50 years) incidence is increasing. Decisions on optimal adjuvant therapy should consider treatment adherence, adverse events, and expected outcomes in a population with life expectancy longer than later-onset (LO) CRC (age ≥ 50 years).

Materials And Methods: Individual patient data from six trials in the International Duration Evaluation of Adjuvant Chemotherapy database were analyzed. Characteristics, treatment adherence, and adverse events in stage II or III EO-CRC and LO-CRC were compared. To reduce confounders of non-cancer-related deaths because of age or comorbidities, time to recurrence (3-year relapse-free rate) and cancer-specific survival (5-year cancer-specific mortality rate) were considered.

Results: Out of 16,349 patients, 1,564 (9.6%) had EO-CRC. Compared with LO-CRC, EO-CRC had better performance status (86% 80%, < .01), similar T stage (% T1-3/T4: 76/24 77/23, = .97), higher N2 disease rate (24% 22%, < .01), more likely to complete the planned treatment duration (83.2% 78.2%, < .01), and received a higher treatment dose intensity, especially with 6-month regimens. Gastrointestinal toxicity was more common in EO-CRC; hematologic toxicity was more frequent in LO-CRC. Compared with LO-CRC, significantly worse cancer-specific outcomes were demonstrated especially in high-risk stage III EO-CRC: lower 3-year relapse-free rate (54% 65%; hazard ratio [HR] 1.33; 95% CI, 1.14 to 1.55; value < .001) and higher 5-year cancer-specific mortality rate (24% 20%; HR 1.21; 95% CI, 1.00 to 1.47; value < .06). In this subgroup, no difference was observed with 3 or 6 months of therapy, with equally poor disease-free survival rates (57% 56%; HR 0.97; 95% CI, 0.73 to 1.29; value = .85).

Conclusion: Young age is negatively prognostic in high-risk stage III CRC and associated with significantly higher relapse rate; this is despite better treatment adherence and higher administered treatment intensity, suggesting more aggressive disease biology.
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http://dx.doi.org/10.1200/JCO.21.02008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677996PMC
December 2021
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