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1. Trifluridine/tipiracil regimen in combination with bevacizumab for metastatic colorectal cancer in the third line: an expert opinion

Author

Carmine Pinto, Sara Lonardi, Evaristo Maiello, Erika Martinelli, Michele Prisciandaro, Lisa Salvatore, Andrea Sartore-Bianchi, Mario Scartozzi, Giuseppe Aprile, Chiara Cremolini, and Alberto Sobrero

Subjects
trifluridine/tipiracil, bevacizumab, third line therapy, metastatic colorectal cancer, efficacy, safety, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

The prolongation of survival along with the preservation of quality of life, possibly avoiding harmful cumulative toxicities, is the primary therapeutic aim for patients with metastatic colorectal cancer (mCRC) in the third-line setting. Several therapeutic options are now available, although some differences across countries in drug approval and the optimal therapeutic sequencing associated with each peculiar patient subgroup represent a clinical challenge for oncologists. Among various options, the SUNLIGHT trial showed how the combination of trifluridine/tipiracil (FTD/TPI) with bevacizumab is effective with an easily manageable toxicity profile compared to FTD/TPI alone. Of note, the efficacy is confirmed independently from KRAS mutational status and also for patients who had breaks in anti-vascular endothelial growth factor (anti-VEGF) therapy. Herein, we describe the current state of the art in the landscape of treatments after the second progression in mCRC. Based on a critical review of the literature aimed to guide clinicians in their daily decision-making, we point out that the combination of FTD/TPI with bevacizumab produces a clinical benefit in unselected mCRC patients. Therefore, the FTD/TPI plus bevacizumab regimen can represent a new standard of care for the treatment of patients with refractory mCRC who have progressed after two lines of therapy.

Published
2025
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2. Early-onset cancers: Biological bases and clinical implications

Author

Gianluca Mauri, Giorgio Patelli, Andrea Sartore-Bianchi, Sergio Abrignani, Beatrice Bodega, Silvia Marsoni, Vincenzo Costanzo, Angela Bachi, Salvatore Siena, and Alberto Bardelli

Subjects
Medicine (General), R5-920
Abstract

Summary: Since the nineties, the incidence of sporadic early-onset (EO) cancers has been rising worldwide. The underlying reasons are still unknown. However, identifying them is vital for advancing both prevention and intervention. Here, we exploit available knowledge derived from clinical observations to formulate testable hypotheses aimed at defining the causal factors of this epidemic and discuss how to experimentally test them. We explore the potential impact of exposome changes from the millennials to contemporary young generations, considering both environmental exposures and enhanced susceptibilities to EO-cancer development. We emphasize how establishing the time required for an EO cancer to develop is relevant to defining future screening strategies. Finally, we discuss the importance of integrating multi-dimensional data from international collaborations to generate comprehensive knowledge and translate these findings back into clinical practice.

Published
2024
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3. Pelvic floor function after third and fourth degree perineal lacerations: a case-control study on quality of life

Author

Andrea Sartore, Maria Sole Scalia, Francesco Paolo Mangino, Giulia Savastano, Elena Magni, and Giuseppe Ricci

Subjects
Pelvic floor dysfunction, Quality of life, OASI, Perineal tears, Gynecology and obstetrics, RG1-991, Public aspects of medicine, RA1-1270
Abstract

Abstract Background The primary aim of this study was to compare the quality of life between women with obstetric anal sphincter injury (OASI) and women with intact perineum or minor vaginal tears following their first vaginal birth through a validated urogynaecological questionnaire. As a secondary aim, we wanted to identify the specific symptoms for pelvic floor dysfunction after a vaginal birth. Methods One hundred thirty-three cases (III- and IV-degree vaginal tears) and 133 controls (intact perineum or I- and II-degree vaginal tear) were asked to fill the PFDI-20 condition-specific and quality of life survey at three and 12 months after vaginal delivery. The survey evaluates pelvic floor dysfunction symptoms through three subsections: the Pelvic Organ Prolapse Distress Inventory (POPDI), the Colorectal-Anal Distress Inventory (CRADI), and Urinary Distress Inventory, (UDI). The scoring system ranges from 0 (no distress) to 100 (maximum distress) for each subsection, subsequently summed up to obtain the summary score (0 to 300). The patients recruited were asked to complete the survey at 3- and 12-months follow-up visit. Accordingly, data collection started. Categorical variables were subjected to Chi-square test or Fisher’s Exact test. Quantitative variables were compared through Student’s t-test or Mann-Whitney test. Results All surveys have shown statistically significant differences when comparing the cases to the control group. Consequently, PFDI-20 has shown a strong correlation between III- and IV-grade lacerations and pelvic floor dysfunction persistence at 12 months after delivery. Intestinal symptoms were the most reported disturbances among women with previous OASI. Conclusions Major vaginal tears have demonstrated to have a strong impact on women’s quality of life up to a follow-up of 12 months. The use of PFDI-20 questionnaire is a useful and valid tool in the diagnosis and follow-up of genital prolapse, fecal and urinary incontinence in primiparous women with a history of OASI. Thus, its application in clinical practice can help offering the most adequate rehabilitative treatment.

Published
2024
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4. A Comparative Study of Methyl-BEAMing and Droplet Digital PCR for MGMT Gene Promoter Hypermethylation Detection

Author

Marco Macagno, Valeria Pessei, Noemi Congiusta, Luca Lazzari, Sara Erika Bellomo, Fariha Idrees, Alessandro Cavaliere, Filippo Pietrantonio, Alessandra Raimondi, Eleonora Gusmaroli, Maria Giulia Zampino, Lorenzo Gervaso, Davide Ciardiello, Giuseppe Mondello, Armando Santoro, Nicola Personeni, Emanuela Bonoldi, Maria Costanza Aquilano, Emanuele Valtorta, Salvatore Siena, Andrea Sartore-Bianchi, Alessio Amatu, Erica Francesca Bonazzina, Katia Bruna Bencardino, Guido Serini, Silvia Marsoni, Ludovic Barault, Federica Di Nicolantonio, and Federica Maione

Subjects
MGMT, DNAmethylation, Methyl-BEAMing, digital PCR, metastatic colorectal cancer, Medicine (General), R5-920
Abstract

Background: O-6-methylguanine-DNA methyltransferase is responsible for the direct repair of O6-methylguanine lesions induced by alkylating agents, including temozolomide. O-6-methylguanine-DNA methyltransferase promoter hypermethylation is a well-established biomarker for temozolomide response in glioblastoma patients, also correlated with therapeutic response in colorectal cancer. Objectives: The ARETHUSA clinical trial aims to stratify colorectal cancer patients based on their mismatch repair status. Mismatch repair-deficient patients are eligible for treatment with immune checkpoint inhibitors (anti-PDL-1), whereas mismatch repair-proficient samples are screened for O-6-methylguanine-DNA methyltransferase promoter methylation to identify those suitable for temozolomide treatment. Methods: In this context, a subset of ARETHUSA metastatic colorectal cancer samples was used to compare two different techniques for assessing O-6-methylguanine-DNA methyltransferase hypermethylation: Methyl-BEAMing, a highly sensitive digital PCR approach that combines emulsion PCR and flow cytometry, and droplet digital PCR, a more automated procedure that enables the rapid, operator-independent analysis of a large number of samples. Results: Our study clearly demonstrates that the results obtained using Methyl-BEAMing and droplet digital PCR are comparable, with both techniques showing similar accuracy, sensitivity, and reproducibility. Conclusions: Digital droplet PCR proved to be an efficient method for detecting gene promoter methylation. However, the Methyl-BEAMing method has proved more sensitive for detecting low quantities of DNA.

Published
2024
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5. Multimodal treatment with curative intent in a germline BRCA2 mutant metastatic ampullary adenocarcinoma: a case report

Author

Gianluca Mauri, Viviana Gori, Giorgio Patelli, Laura Roazzi, Francesco Rizzetto, Luciano De Carlis, Anna Mariani, Ugo Cavallari, Elisabetta Prada, Tiziana Cipani, Maria Costanza Aquilano, Emanuela Bonoldi, Angelo Vanzulli, Salvatore Siena, and Andrea Sartore-Bianchi

Subjects
Case report, Surgical metastasectomy, BRCA, Ampullary cancer, Platinum toxicity and sensitivity, Surgery, RD1-811, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Cancers of the Vater ampulla (ampullary cancers, ACs) account for less than 1% of all gastrointestinal tumors. ACs are usually diagnosed at advanced stage, with poor prognosis and limited therapeutic options. BRCA2 mutations are identified in up to 14% of ACs and, differently from other tumor types, therapeutic implications remain to be defined. Here, we report a clinical case of a metastatic AC patient in which the identification of a BRCA2 germline mutation drove a personalized multimodal approach with curative-intent. Case presentation A 42-year-old woman diagnosed with stage IV BRCA2 germline mutant AC underwent platinum-based first line treatment achieving major tumor response but also life-threatening toxicity. Based on this, as well as on molecular findings and expected low impact of available systemic treatment options, the patient underwent radical complete surgical resection of both primary tumor and metastatic lesions. Following an isolated retroperitoneal nodal recurrence, given the expected enhanced sensitivity to radiotherapy in BRCA2 mutant cancers, the patient underwent imaging-guided radiotherapy leading to long-lasting complete tumor remission. After more than 2 years, the disease remains radiologically and biochemically undetectable. The patient accessed a dedicated screening program for BRCA2 germline mutation carriers and underwent prophylactic bilateral oophorectomy. Conclusions Even considering the intrinsic limitations of a single clinical report, we suggest that the finding of BRCA germline mutations in ACs should be taken into consideration, together with other clinical variables, given their potential association with remarkable response to cytotoxic chemotherapy that might be burdened with enhanced toxicity. Accordingly, BRCA1/2 mutations might offer the opportunity of personalizing treatment beyond PARP inhibitors up to the choice of a multimodal approach with curative-intent.

Published
2023
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6. Repotrectinib Overcomes F2004V Resistance Mutation in ROS1-Rearranged NSCLC: A Case Report

Author

Elio Gregory Pizzutilo, MD, Alberto Giuseppe Agostara, MD, Laura Roazzi, MD, Rebecca Romanò, MD, Valentina Motta, PhD, Calogero Lauricella, PhD, Giovanna Marrapese, PhD, Giulio Cerea, MD, Diego Signorelli, MD, PhD, Silvio Marco Veronese, PhD, Laura Giuseppina Giannetta, MD, Andrea Sartore-Bianchi, MD, and Salvatore Siena, MD

Subjects
Case report, Entrectinib, Repotrectinib, Resistance, ROS1 F2004V, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

ROS1 tyrosine kinase inhibitors (TKIs) were found to provide a substantial clinical benefit for patients with advanced ROS1-positive (ROS1+) NSCLC. Nevertheless, TKI resistance inevitably develops with different mechanisms, preventing prolonged responses. For this reason, next-generation compounds are under clinical development. ROS1 F2004 substitutions have been previously detected on circulating tumor DNA of patients progressing to entrectinib. Hereby, we report the case of a patient with ROS1+ NSCLC in which F2004V-acquired mutation was detected on a site of disease progression, after entrectinib and crizotinib failure. A subsequent treatment with next-generation TKI repotrectinib led to disease response, providing the first clinical evidence of activity of repotrectinib against F2004V resistance mutation.

Published
2023
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7. Corrigendum: Case report: MAP2K1 K57N mutation is associated with primary resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer

Author

Gianluca Mauri, Giorgio Patelli, Viviana Gori, Calogero Lauricella, Benedetta Mussolin, Alessio Amatu, Katia Bencardino, Federica Tosi, Erica Bonazzina, Emanuela Bonoldi, Alberto Bardelli, Salvatore Siena, and Andrea Sartore-Bianchi

Subjects
MAP2K1, MEK, panitumumab, resistance mechanisms, colorectal cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2023
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8. Case Report: MAP2K1 K57N mutation is associated with primary resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer

Author

Gianluca Mauri, Giorgio Patelli, Viviana Gori, Calogero Lauricella, Benedetta Mussolin, Alessio Amatu, Katia Bencardino, Federica Tosi, Erica Bonazzina, Emanuela Bonoldi, Alberto Bardelli, Salvatore Siena, and Andrea Sartore-Bianchi

Subjects
MAP2K1, MEK, panitumumab, resistance mechanisms, colorectal cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

BackgroundWe aim to identify the prevalence and the role of the MAP2K1 K57N mutation in predicting resistance to anti-EGFR agents in metastatic colorectal cancer (mCRC) patients.MethodsWe retrospectively reviewed tumor-based next generation sequencing (NGS) results from mCRC patients screened for enrollment in the GO40872/STARTRK-2 clinical trial between July 2019 and March 2021. Then, in patients harboring microsatellite stable (MSS) RAS and BRAF wild-type MAP2K1 mutant mCRC, we reviewed outcome to treatment with anti-EGFR monoclonal antibodies.ResultsA total of 246 mCRC patients were screened. Most of them, 215/220 (97.7%), were diagnosed with MSS mCRC and 112/215 (52.1%) with MSS, RAS and BRAF wild-type mCRC. Among the latter, 2/112 (1.8%) had MAP2K1 K57N mutant mCRC and both received anti-EGFR monotherapy as third line treatment. In both patients, MAP2K1 K57N mutant tumors proved primary resistant to anti-EGFR agent panitumumab monotherapy. Of interest, one of these patients was treated with anti-EGFR agents three times throughout his course of treatment, achieving some clinical benefit only when associated with other cytotoxic agents (FOLFOX or irinotecan).ConclusionWe verified in a clinical real-world setting that MAP2K1 K57N mutation is a resistance mechanism to anti-EGFR agents in mCRC. Thus, we suggest avoiding the administration of these drugs to MSS RAS and BRAF wild-type MAP2K1 N57K mutant mCRC.

Published
2022
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9. Characteristics of Submucous Myomas and the Risk of Anemia

Author

Giuseppe Ricci, Federica Scrimin, Andrea Sartore, Massimo Borelli, Gabriella Zito, Federico Romano, and Guglielmo Stabile

Subjects
myomas, anemia, metrorrhagia, myoma grade, hemoglobin, Medicine (General), R5-920
Abstract

Background and Objectives: Uterine fibroids still represent the most common indication for hysterectomy for benign pathologies. In the United States, more than 479,000 hysterectomies are performed annually, 46.6% for myomas and 47.7% in women aged from 18 to 44 years. By applying appropriateness criteria to this procedure, it has been estimated that overuse ranges from 16 to 70%. One of the main reasons that induce patients and gynecologists to consider hysterectomy is represented by severe anemia. Materials and Methods: This is a retrospective cohort study of 202 patients with uterine fibroids diagnosed by transvaginal ultrasound who underwent a hysteroscopic procedure. Myoma grade, size, location, and number were assessed by transvaginal scan and office hysteroscopy and correlated to the pre-treatment hemoglobin level. Results: Univariate analysis showed that anemia does not have a statistically significant association with myoma number and with age considered as a numerical predictor. In the patients with myoma type 0, there is a possibility of 81% having anemia regardless of menorrhagia. On the contrary, in patients with myoma type 1 or type 2, the possibility of having anemia varies according to the presence or absence of menorrhagia. If there is menorrhagia, the risk of moderate anemia is only present for myomas >60 mm. Conclusions: The results of this study may contribute to defining objective criteria for the management of submucous myomas and anemia. Our data suggest that submucosal myomas type 0 >10 mm should always be treated, putting patients at risk for anemia. Myomas type 2 and 3 should be treated for the risk of anemia in the presence of menorrhagia episodes or if > of 60 mm. Adequate management of anemia and myomas could reduce the rate of unnecessary hysterectomies.

Published
2022
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11. Application of histology-agnostic treatments in metastatic colorectal cancer

Author

Andrea Sartore-Bianchi, Alberto Giuseppe Agostara, Giorgio Patelli, Gianluca Mauri, Elio Gregory Pizzutilo, and Salvatore Siena

Subjects
Proto-Oncogene Proteins B-raf, Hepatology, Settore MED/06 - Oncologia Medica, Rectal Neoplasms, Gastroenterology, Colorectal cancer, Dostarlimab, Entrectinib, Larotrectinib, Metastasis, Pembrolizumab, Antibodies, Monoclonal, Humanized, Colonic Neoplasms, Biomarkers, Tumor, Humans, Microsatellite Instability, Colorectal Neoplasms
Abstract

Cancer treatment is increasingly focused on targeting molecular alterations identified across different tumor histologies. While some oncogenic drivers such as microsatellite instability (MSI) and NTRK fusions are actionable with the very same approach regardless of tumor type ("histology-agnostic"), others require histology-specific therapeutic adjustment ("histology-tuned") by means of adopting specific inhibitors and ad hoc combinations. Among histology-agnostic therapies, pembrolizumab or dostarlimab demonstrated comparable activity in MSI metastatic colorectal cancer (mCRC) as in other tumors with MSI status (ORR 38% vs 40% and 36% vs 39%, respectively), while entrectinib or larotrectinib proved effective in NTRK rearranged mCRC even though less dramatically than in the overall population (ORR 20% vs 57%, and 50% vs 78%, respectively). Histology-tuned approaches in mCRC are those targeting BRAF

Published
2022
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12. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial

Author

Andrea Sartore-Bianchi, Filippo Pietrantonio, Sara Lonardi, Benedetta Mussolin, Francesco Rua, Giovanni Crisafulli, Alice Bartolini, Elisabetta Fenocchio, Alessio Amatu, Paolo Manca, Francesca Bergamo, Federica Tosi, Gianluca Mauri, Margherita Ambrosini, Francesca Daniel, Valter Torri, Angelo Vanzulli, Daniele Regge, Giovanni Cappello, Caterina Marchiò, Enrico Berrino, Anna Sapino, Silvia Marsoni, Salvatore Siena, and Alberto Bardelli

Subjects
Proto-Oncogene Proteins B-raf, Rectal Neoplasms, Settore MED/06 - Oncologia Medica, Panitumumab, Antibodies, Monoclonal, Antineoplastic Agents, General Medicine, Antibodies, General Biochemistry, Genetics and Molecular Biology, Circulating Tumor DNA, Proto-Oncogene Proteins p21(ras), Antineoplastic Combined Chemotherapy Protocols, Humans, Mutation, Colonic Neoplasms, Colorectal Neoplasms, Monoclonal
Abstract

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.

Published
2022
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13. Early onset metastatic colorectal cancer in patients receiving panitumumab‐based upfront strategy: Overall and sex‐specific outcomes in the Valentino trial

Author

Alessandra Raimondi, Giovanni Randon, Michele Prisciandaro, Filippo Pagani, Sara Lonardi, Carlotta Antoniotti, Silvia Bozzarelli, Andrea Sartore‐Bianchi, Marco Tampellini, Laura Fanchini, Roberto Murialdo, Matteo Clavarezza, Alberto Zaniboni, Rosa Berenato, Margherita Ratti, Fausto Petrelli, Lorenzo Antonuzzo, Monica Giordano, Alessandro Rossi, Maria Di Bartolomeo, Massimo Di Maio, Filippo Pietrantonio, and Federica Morano

Subjects
Male, Proto-Oncogene Proteins B-raf, Cancer Research, Oncology, Panitumumab, Antineoplastic Combined Chemotherapy Protocols, Quality of Life, Humans, Female, Fluorouracil, Middle Aged, Colorectal Neoplasms, Prognosis
Abstract

Anti-EGFRs plus doublet chemotherapy is considered the optimal upfront option for RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC). Early-onset (EO) mCRC has an increasing incidence and its prognostic/predictive role and management is debatable. We performed a post hoc analysis of Valentino study, that randomized RAS wild-type mCRC patients to two panitumumab-based maintenance regimens after FOLFOX/panitumumab induction. We assessed the safety and efficacy outcomes in patients stratified for age (50/≥50 years old). We assessed progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of treatment-related and panitumumab-related adverse events (AEs) and quality of life (QoL). In 229 patients enrolled, 35 (15%) had EO mCRC, with a higher rate of female sex (P = .020) and lower rate of primary tumor resection (P = .001). Median PFS and OS were 10.9 vs 10.8 months (P = .593) and 28.1 vs 27.5 months (P = .865) in patients50 and ≥50 years old, respectively, with no significant impact of maintenance arm. ORR and disease control rate were 74% vs 65% (P = .337) and 97% vs 81% (P = .013) in patients50 or ≥50 years old. In younger patients, a trend for increased chemotherapy-related AEs (peculiarly anemia) was shown, while significantly decreased EGFR-related hypomagnesemia and increased skin rash were reported. No significant differences in treatment intensity or QoL were observed. In patients with EO mCRC and RAS wild-type status, we found no differences in terms of survival outcomes based on age when selecting maintenance strategies. Management of treatment-related AEs should consider the differential toxicity profile of age and sex.

Published
2022
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14. Benefit from upfront FOLFOXIRI and bevacizumab in BRAFV600E-mutated metastatic colorectal cancer patients: does primary tumour location matter?

Author

Roberto Moretto, Andrew Elliott, Daniele Rossini, Rossana Intini, Veronica Conca, Filippo Pietrantonio, Andrea Sartore-Bianchi, Carlotta Antoniotti, Cosimo Rasola, Mario Scartozzi, Massimiliano Salati, Nicoletta Pella, Maria Alessandra Calegari, Martina Carullo, Francesca Corti, Gianluca Mauri, Matteo Fassan, Gianluca Masi, Pavel Brodskiy, Heinz-Josef Lenz, Anthony Shields, Sara Lonardi, Michael Korn, and Chiara Cremolini

Subjects
Bevacizumab, Cancer Research, Organoplatinum Compounds, Oncology, Rectal Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Colonic Neoplasms, Leucovorin, Humans, Camptothecin, Fluorouracil, Colorectal Neoplasms, Article
Abstract

BACKGROUND: Recent data suggest that BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients with right-sided tumours and ECOG-PS = 0 may achieve benefit from the triplet regimen differently than those with left-sided tumours and ECOG-PS > 0. METHODS: The predictive impact of primary sidedness and ECOG-PS was evaluated in a large real-life dataset of 296 BRAFV600E-mutated mCRC patients treated with upfront triplet or doublet ± bevacizumab. Biological differences between right- and left-sided BRAFV600E-mutated CRCs were further investigated in an independent cohort of 1162 samples. RESULTS: A significant interaction effect between primary sidedness and treatment intensity was reported in terms of both PFS (p = 0.010) and OS (p = 0.003), with a beneficial effect of the triplet in the right-sided group and a possible detrimental effect in the left-sided. No interaction effect was observed between ECOG-PS and chemo-backbone. In the MSS/pMMR population, a consistent trend for a side-related subgroup effect was observed when FOLFOXIRI ± bevacizumab was compared to oxaliplatin-based doublets±bevacizumab (p = 0.097 and 0.16 for PFS and OS, respectively). Among MSS/pMMR tumours, the BM1 subtype was more prevalent in the right-sided group (p = 0.0019, q = 0.0139). No significant differences were observed according to sidedness in the MSI-H/dMMR population. CONCLUSIONS: Real-life data support the use of FOLFOXIRI ± bevacizumab only in BRAFV600E-mutated mCRC patients with right-sided tumours.

Published
2022
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15. Data from Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Author

Russo, Mariangela, primary, Misale, Sandra, primary, Wei, Ge, primary, Siravegna, Giulia, primary, Crisafulli, Giovanni, primary, Lazzari, Luca, primary, Corti, Giorgio, primary, Rospo, Giuseppe, primary, Novara, Luca, primary, Mussolin, Benedetta, primary, Bartolini, Alice, primary, Cam, Nicholas, primary, Patel, Roopal, primary, Yan, Shunqi, primary, Shoemaker, Robert, primary, Wild, Robert, primary, Di Nicolantonio, Federica, primary, Bianchi, Andrea Sartore, primary, Li, Gang, primary, Siena, Salvatore, primary, and Bardelli, Alberto, primary

Published
2023
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16. Supplementary Methods, Figure Legends, Table Legends, Figures S1 - S4, Tables S1 - S5 from Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Author

Russo, Mariangela, primary, Misale, Sandra, primary, Wei, Ge, primary, Siravegna, Giulia, primary, Crisafulli, Giovanni, primary, Lazzari, Luca, primary, Corti, Giorgio, primary, Rospo, Giuseppe, primary, Novara, Luca, primary, Mussolin, Benedetta, primary, Bartolini, Alice, primary, Cam, Nicholas, primary, Patel, Roopal, primary, Yan, Shunqi, primary, Shoemaker, Robert, primary, Wild, Robert, primary, Di Nicolantonio, Federica, primary, Bianchi, Andrea Sartore, primary, Li, Gang, primary, Siena, Salvatore, primary, and Bardelli, Alberto, primary

Published
2023
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17. Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients

Author

Giovanni Crisafulli, Andrea Sartore-Bianchi, Luca Lazzari, Filippo Pietrantonio, Alessio Amatu, Marco Macagno, Ludovic Barault, Andrea Cassingena, Alice Bartolini, Paolo Luraghi, Gianluca Mauri, Paolo Battuello, Nicola Personeni, Maria Giulia Zampino, Valeria Pessei, Pietro Paolo Vitiello, Federica Tosi, Laura Idotta, Federica Morano, Emanuele Valtorta, Emanuela Bonoldi, Giovanni Germano, Federica Di Nicolantonio, Silvia Marsoni, Salvatore Siena, and Alberto Bardelli

Subjects
Colorectal Cancer, Mutational Signature, Brain Neoplasms, Mismatch Repair, MSH6, Colorectal Cancer, Mismatch Repair, Temozolomide, Mutational Signature, MSH6, DNA Mismatch Repair, DNA-Binding Proteins, Dacarbazine, O(6)-Methylguanine-DNA Methyltransferase, Oncology, Cell Line, Tumor, Mutation, Temozolomide, Humans, Colorectal Neoplasms, Antineoplastic Agents, Alkylating
Abstract

The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond to immune-checkpoint blockade. We previously reported that the treatment of colorectal cancer preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB), and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)–deficient, MMR-proficient, RAS-mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes, and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A subset of patients whose tumors displayed the MSH6 mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment. Significance: MMR-proficient mCRCs are unresponsive to immunotherapy. We provide the proof of concept that inactivation of MMR genes can be achieved pharmacologically with TMZ and molecularly monitored in the tissue and blood of patients with mCRC. This strategy deserves additional evaluation in mCRC patients whose tumors are no longer responsive to standard-of-care treatments. See related commentary by Willis and Overman, p. 1612. This article is highlighted in the In This Issue feature, p. 1599

Published
2022
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18. Immune Checkpoint Inhibitors and the Exposome: Host-Extrinsic Factors Determine Response, Survival, and Toxicity

Author

Elio Gregory. Pizzutilo, Rebecca Romanò, Laura Roazzi, Alberto Giuseppe. Agostara, Sara Oresti, Annalisa Zeppellini, Laura Giannetta, Giulio Cerea, Diego Signorelli, Salvatore Siena, and Andrea Sartore-Bianchi

Subjects
Cancer Research, Oncology
Abstract

Cancer immunotherapy, largely represented by immune checkpoint inhibitors (ICIs), has led to substantial changes in preclinical cancer research and clinical oncology practice over the past decade. However, the efficacy and toxicity profiles of ICIs remain highly variable among patients, with only a fraction achieving a significant benefit. New combination therapeutic strategies are being investigated, and the search for novel predictive biomarkers is ongoing, mainly focusing on tumor- and host-intrinsic components. Less attention has been directed to all the external, potentially modifiable factors that compose the exposome, including diet and lifestyle, infections, vaccinations, and concomitant medications, which could affect the immune system response and its activity against cancer cells. We hereby provide a review of the available clinical evidence elucidating the impact of host-extrinsic factors on ICI response and toxicity.

Published
2023
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19. Figure S3 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

Familial history of cancers of the GEA patients carrying BRCA2 germline LOF mutations.

Published
2023
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20. Supplementary Table S2 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

Molecular, histological and pathological features of the 57 metastatic gastric cancer patients included in the retrospective analysis

Published
2023
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21. Supplementary Methods from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

Supplementary Methods

Published
2023
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22. BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Annalisa Petrelli, Sabrina Rizzolio, Filippo Pietrantonio, Sara E. Bellomo, Matteo Benelli, Loris De Cecco, Dario Romagnoli, Enrico Berrino, Claudia Orrù, Salvatore Ribisi, Daniel Moya-Rull, Cristina Migliore, Daniela Conticelli, Irene M. Maina, Elisabetta Puliga, Violeta Serra, Benedetta Pellegrino, Alba Llop-Guevara, Antonino Musolino, Salvatore Siena, Andrea Sartore-Bianchi, Michele Prisciandaro, Federica Morano, Maria Antista, Uberto Fumagalli, Giovanni De Manzoni, Maurizio Degiuli, Gian Luca Baiocchi, Marco F. Amisano, Alessandro Ferrero, Caterina Marchiò, Simona Corso, Silvia Giordano, Institut Català de la Salut, [Petrelli A, Rizzolio S] Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy. [Pietrantonio F] Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Bellomo SE] Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy. Department of Oncology, University of Torino, Candiolo, Italy. [Benelli M] Bioinformatics Unit, Oncology Department, Nuovo Ospedale-Santo Stefano, Prato, Italy. [De Cecco L] Molecular Mechanisms Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Serra V, Llop-Guevara A] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
fenómenos genéticos::variación genética::mutación::mutación de la línea germinal [FENÓMENOS Y PROCESOS], Cancer Research, neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias gástricas [ENFERMEDADES], Otros calificadores::/uso terapéutico [Otros calificadores], Medicaments antineoplàstics - Ús terapèutic, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Genetic Phenomena::Genetic Variation::Mutation::Germ-Line Mutation [PHENOMENA AND PROCESSES], Anomalies cromosòmiques, Estómac - Càncer - Tractament, Oncology, Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Stomach Neoplasms [DISEASES], Other subheadings::/therapeutic use [Other subheadings], Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], Estómac - Càncer - Aspectes genètics
Abstract

Mutations; Gastric cancers; PARP inhibitors Mutacions; Càncers gàstrics; Inhibidors de PARP Mutaciones; Cánceres gástricos; Inhibidores de PARP Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as “benign.” However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer. This work was funded by the Italian Association for Cancer Research (AIRC), IG 20210 and IG 27531 to S. Giordano; IG 23624 to F. Pietrantonio; IG 21770 to S. Corso. FPRC 5×1000 2015 Min. Salute “Strategy” to SG; Fondazione Piemontese per la Ricerca sul Cancro (FPRC) 5×1000 MS2017 PTCRC-intra 2020 to S. Giordano; Ricerca Locale Dept. Oncology 2021 to S. Corso; Italian Ministry of Health-Ricerca Corrente 2022–23. B. Pellegrino was supported by ESMO with a Clinical Translational Fellowship aid supported by Roche and received research grants from GOIRC. Fondazione CR Firenze to M. Benelli.

Published
2023

23. Data from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors

Author

Silvia Giordano, Simona Corso, Caterina Marchiò, Alessandro Ferrero, Marco F. Amisano, Gian Luca Baiocchi, Maurizio Degiuli, Giovanni De Manzoni, Uberto Fumagalli, Maria Antista, Federica Morano, Michele Prisciandaro, Andrea Sartore-Bianchi, Salvatore Siena, Antonino Musolino, Alba Llop-Guevara, Benedetta Pellegrino, Violeta Serra, Elisabetta Puliga, Irene M. Maina, Daniela Conticelli, Cristina Migliore, Daniel Moya-Rull, Salvatore Ribisi, Claudia Orrù, Enrico Berrino, Dario Romagnoli, Loris De Cecco, Matteo Benelli, Sara E. Bellomo, Filippo Pietrantonio, Sabrina Rizzolio, and Annalisa Petrelli

Abstract

Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as “benign.” However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer.Significance:PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.

Published
2023
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24. Supplementary Figure 2 from Combined Low Densities of FoxP3+ and CD3+ Tumor-Infiltrating Lymphocytes Identify Stage II Colorectal Cancer at High Risk of Progression

Author

Luigi Laghi, Alberto Malesci, Alberto Mantovani, Salvatore Siena, Lorenza Rimassa, Valter Torri, Luigi Ricciardiello, Andrea Sartore-Bianchi, Giovanni Brandi, Filippo Gustavo Dall'Olio, Mauro Truini, Gianluca Mauri, Emanuele Valtorta, Calogero Pitrone, Luana Greco, Paola Bossi, Fabio Grizzi, Giuseppe Celesti, Gianluca Basso, Paolo Bianchi, and Tommaso Cavalleri

Abstract

Kaplan-Meier curves for the duration of disease-free survival in joined cohorts with stage II CRC as to adjuvant treatment.

Published
2023
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25. Supplementary Table 4 from Combined Low Densities of FoxP3+ and CD3+ Tumor-Infiltrating Lymphocytes Identify Stage II Colorectal Cancer at High Risk of Progression

Author

Luigi Laghi, Alberto Malesci, Alberto Mantovani, Salvatore Siena, Lorenza Rimassa, Valter Torri, Luigi Ricciardiello, Andrea Sartore-Bianchi, Giovanni Brandi, Filippo Gustavo Dall'Olio, Mauro Truini, Gianluca Mauri, Emanuele Valtorta, Calogero Pitrone, Luana Greco, Paola Bossi, Fabio Grizzi, Giuseppe Celesti, Gianluca Basso, Paolo Bianchi, and Tommaso Cavalleri

Abstract

Low densities of FoxP3+ and CD3+ TILs, and their combination, to predict disease-free survival (DFS) in stage II MSS CRC Validation set.

Published
2023
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26. Data from Combined Low Densities of FoxP3+ and CD3+ Tumor-Infiltrating Lymphocytes Identify Stage II Colorectal Cancer at High Risk of Progression

Author

Luigi Laghi, Alberto Malesci, Alberto Mantovani, Salvatore Siena, Lorenza Rimassa, Valter Torri, Luigi Ricciardiello, Andrea Sartore-Bianchi, Giovanni Brandi, Filippo Gustavo Dall'Olio, Mauro Truini, Gianluca Mauri, Emanuele Valtorta, Calogero Pitrone, Luana Greco, Paola Bossi, Fabio Grizzi, Giuseppe Celesti, Gianluca Basso, Paolo Bianchi, and Tommaso Cavalleri

Abstract

The densities of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs), combined with tumor–node–metastasis (TNM) staging, have prognostic value for patients with nonmetastatic colorectal cancer. We compared the prognostic value of CD3+ and FoxP3+ TILs at the invasive front, TNM classifiers, and microsatellite (MS) status in a trial set of patients with stage II and III colorectal cancer (n = 413), by recursive partitioning with a classification and regression tree (CART). Significant prognostic factors and interactions were reassessed by logistic regression and Cox proportional-hazards modeling in the trial and a validation set (n = 215) of patients with stage II colorectal cancer. In the trial set, CART indicated that TIL numbers were of value only in predicting recurrence risk for stage II cancers, where low densities of FoxP3+ TILs ranked first and low densities of CD3+ TILs further stratifying risk. Multivariate analysis showed that TILs interacted with tumor stage (FoxP3+, P = 0.06; CD3+, P = 0.02) and MS instability (MSI; FoxP3+; P = 0.02). In stage II MS-stable cancers, concomitant low densities of both FoxP3+ and CD3+ TILs identified patients with the highest progression risk in the trial [HR 7.24; 95% confidence interval (CI), 3.41–15.4; P < 0.001] and the validation (HR 15.16; 95% CI, 3.43–66.9; P < 0.001) sets. FoxP3+ and CD3+ TIL load in colorectal cancer was more informative than other prognostic factors before the cancer progressed to lymph nodes. This prognostic information about TILs, including FoxP3+ cells, suggests that randomized controlled trials might be refined to include interactions between TNM status, molecular classifiers, and postsurgical treatments.

Published
2023
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27. Supplementary Table 3 from Combined Low Densities of FoxP3+ and CD3+ Tumor-Infiltrating Lymphocytes Identify Stage II Colorectal Cancer at High Risk of Progression

Author

Luigi Laghi, Alberto Malesci, Alberto Mantovani, Salvatore Siena, Lorenza Rimassa, Valter Torri, Luigi Ricciardiello, Andrea Sartore-Bianchi, Giovanni Brandi, Filippo Gustavo Dall'Olio, Mauro Truini, Gianluca Mauri, Emanuele Valtorta, Calogero Pitrone, Luana Greco, Paola Bossi, Fabio Grizzi, Giuseppe Celesti, Gianluca Basso, Paolo Bianchi, and Tommaso Cavalleri

Abstract

Densities of FoxP3+ and CD3+ TILs in validation set (161 stage II CRC), by clinical-pathological variables.

Published
2023
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28. Supplementary Table 1 from Combined Low Densities of FoxP3+ and CD3+ Tumor-Infiltrating Lymphocytes Identify Stage II Colorectal Cancer at High Risk of Progression

Author

Luigi Laghi, Alberto Malesci, Alberto Mantovani, Salvatore Siena, Lorenza Rimassa, Valter Torri, Luigi Ricciardiello, Andrea Sartore-Bianchi, Giovanni Brandi, Filippo Gustavo Dall'Olio, Mauro Truini, Gianluca Mauri, Emanuele Valtorta, Calogero Pitrone, Luana Greco, Paola Bossi, Fabio Grizzi, Giuseppe Celesti, Gianluca Basso, Paolo Bianchi, and Tommaso Cavalleri

Abstract

Densities of FoxP3+ and CD3+ TILs in 413 stage II-III CRC, by clinical-pathological variables.

Published
2023
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29. Supplementary Figure 1 from Combined Low Densities of FoxP3+ and CD3+ Tumor-Infiltrating Lymphocytes Identify Stage II Colorectal Cancer at High Risk of Progression

Author

Luigi Laghi, Alberto Malesci, Alberto Mantovani, Salvatore Siena, Lorenza Rimassa, Valter Torri, Luigi Ricciardiello, Andrea Sartore-Bianchi, Giovanni Brandi, Filippo Gustavo Dall'Olio, Mauro Truini, Gianluca Mauri, Emanuele Valtorta, Calogero Pitrone, Luana Greco, Paola Bossi, Fabio Grizzi, Giuseppe Celesti, Gianluca Basso, Paolo Bianchi, and Tommaso Cavalleri

Abstract

ROC curves for densities of FoxP3+ and CD3+ TILs as predictors of postsurgical recurrence in patients with stage II MSS CRC, validation set.

Published
2023
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30. Supplementary Table 2 from Combined Low Densities of FoxP3+ and CD3+ Tumor-Infiltrating Lymphocytes Identify Stage II Colorectal Cancer at High Risk of Progression

Author

Luigi Laghi, Alberto Malesci, Alberto Mantovani, Salvatore Siena, Lorenza Rimassa, Valter Torri, Luigi Ricciardiello, Andrea Sartore-Bianchi, Giovanni Brandi, Filippo Gustavo Dall'Olio, Mauro Truini, Gianluca Mauri, Emanuele Valtorta, Calogero Pitrone, Luana Greco, Paola Bossi, Fabio Grizzi, Giuseppe Celesti, Gianluca Basso, Paolo Bianchi, and Tommaso Cavalleri

Abstract

Predictors of post-surgical recurrence in 413 CRC patients with stage II/III CRC.

Published
2023
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31. Supplementary Figure from Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients

Author

Alberto Bardelli, Salvatore Siena, Silvia Marsoni, Federica Di Nicolantonio, Giovanni Germano, Emanuela Bonoldi, Emanuele Valtorta, Federica Morano, Laura Idotta, Federica Tosi, Pietro Paolo Vitiello, Valeria Pessei, Maria Giulia Zampino, Nicola Personeni, Paolo Battuello, Gianluca Mauri, Paolo Luraghi, Alice Bartolini, Andrea Cassingena, Ludovic Barault, Marco Macagno, Alessio Amatu, Filippo Pietrantonio, Luca Lazzari, Andrea Sartore-Bianchi, and Giovanni Crisafulli

Abstract

Supplementary Figure from Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients

Published
2023
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32. Supplementary Figure S5 from Amplification of the MET Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer

Author

Salvatore Siena, Silvia Giordano, Federica Di Nicolantonio, Livio Trusolino, Paolo Comoglio, Victor E. Velculescu, Mark Sausen, Luis A. Diaz, Marcello Gambacorta, Alessio Amatu, Giorgio Corti, Silvio Veronese, Timothy Perera, Carlo Zanon, Calogero Lauricella, Francesco Galimi, Giorgia Migliardi, Maria Apicella, Davide Zecchin, Andrea Cassingena, Elisa Scala, Andrea Sartore-Bianchi, Giulia Siravegna, Emanuele Valtorta, Sebastijan Hobor, Andrea Bertotti, Simona Corso, and Alberto Bardelli

Abstract

Supplementary Figure S5 - PDF file 777K, Schematic representation of the scoring system applied to assess MET protein expression by immunohistochemistry

Published
2023
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33. Cell Model Network-UK from Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy

Author

Mathew J. Garnett, Alberto Bardelli, Emile E. Voest, Sabrina Arena, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Fengtang Yang, Martin Michaelis, Jindrich Cinatl, Krijn K. Dijkstra, Daniele Oddo, Luuk J. Schipper, Ruby Banerjee, Carlotta Cancelliere, Iñigo Sánchez Rodríguez, Sara F. Vieira, Sarah Consonni, Giuseppe Rospo, Giovanni Crisafulli, Esmée J. van Vliet, Chiara M. Cattaneo, and Gabriele Picco

Abstract

The Cell Model Network-UK group author list

Published
2023
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34. Supplementary Table 1 from Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy

Author

Mathew J. Garnett, Alberto Bardelli, Emile E. Voest, Sabrina Arena, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Fengtang Yang, Martin Michaelis, Jindrich Cinatl, Krijn K. Dijkstra, Daniele Oddo, Luuk J. Schipper, Ruby Banerjee, Carlotta Cancelliere, Iñigo Sánchez Rodríguez, Sara F. Vieira, Sarah Consonni, Giuseppe Rospo, Giovanni Crisafulli, Esmée J. van Vliet, Chiara M. Cattaneo, and Gabriele Picco

Abstract

Supplementary Table 1

Published
2023
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35. Supplementary Table 3 from A Molecularly Annotated Platform of Patient-Derived Xenografts ('Xenopatients') Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer

Author

Livio Trusolino, Alberto Bardelli, Paolo M. Comoglio, Silvia Marsoni, Anna Sapino, Enzo Medico, Salvatore Siena, Marcello Gambacorta, Lorenzo Capussotti, Mauro Risio, Andrea Sartore-Bianchi, Emanuele Valtorta, Luca Molinaro, Alberto Pisacane, Paolo Massucco, Andrea Muratore, Nadia Russolillo, Dario Ribero, Consalvo Petti, Michela Buscarino, Federica Di Nicolantonio, Davide Corà, Claudio Isella, Davide Torti, Francesco Sassi, Francesco Galimi, Giorgia Migliardi, and Andrea Bertotti

Abstract

PDF file - 29K

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2023
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36. Supplementary Tables 1-6 from Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)

Author

Filippo G. De Braud, Alice T. Shaw, Pratik S. Multani, Zachary Hornby, Edna Chow-Maneval, David Luo, Rupal Patel, Ann D. Johnson, Karey Kowalski, Jason Christiansen, Gang Li, Elena Ardini, Matteo Duca, Silvia Damian, Sara Cresta, Angelo Vanzulli, Andrea Sartore-Bianchi, Laura Palmeri, Katia Bencardino, Alessio Amatu, Michele Schirru, Giovanna Marrapese, Giulio Cerea, Laura Giannetta, Robert Doebele, Stephen V. Liu, Jennifer J. Wheler, Anna F. Farago, Todd M. Bauer, Jeeyun Lee, Myung Ju Ahn, Manish Patel, Sai-Hong Ignatius Ou, Salvatore Siena, and Alexander Drilon

Abstract

DOC- 25K, Supplementary Tables 1-6

Published
2023
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37. Supplementary Figure 4 from Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy

Author

Mathew J. Garnett, Alberto Bardelli, Emile E. Voest, Sabrina Arena, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Fengtang Yang, Martin Michaelis, Jindrich Cinatl, Krijn K. Dijkstra, Daniele Oddo, Luuk J. Schipper, Ruby Banerjee, Carlotta Cancelliere, Iñigo Sánchez Rodríguez, Sara F. Vieira, Sarah Consonni, Giuseppe Rospo, Giovanni Crisafulli, Esmée J. van Vliet, Chiara M. Cattaneo, and Gabriele Picco

Abstract

Supplementary Figure 4

Published
2023
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38. Supplementary Figure 1 from A Molecularly Annotated Platform of Patient-Derived Xenografts ('Xenopatients') Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer

Author

Livio Trusolino, Alberto Bardelli, Paolo M. Comoglio, Silvia Marsoni, Anna Sapino, Enzo Medico, Salvatore Siena, Marcello Gambacorta, Lorenzo Capussotti, Mauro Risio, Andrea Sartore-Bianchi, Emanuele Valtorta, Luca Molinaro, Alberto Pisacane, Paolo Massucco, Andrea Muratore, Nadia Russolillo, Dario Ribero, Consalvo Petti, Michela Buscarino, Federica Di Nicolantonio, Davide Corà, Claudio Isella, Davide Torti, Francesco Sassi, Francesco Galimi, Giorgia Migliardi, and Andrea Bertotti

Abstract

PDF file - 431K

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2023
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39. Supplementary Figure 2 from Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy

Author

Mathew J. Garnett, Alberto Bardelli, Emile E. Voest, Sabrina Arena, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Fengtang Yang, Martin Michaelis, Jindrich Cinatl, Krijn K. Dijkstra, Daniele Oddo, Luuk J. Schipper, Ruby Banerjee, Carlotta Cancelliere, Iñigo Sánchez Rodríguez, Sara F. Vieira, Sarah Consonni, Giuseppe Rospo, Giovanni Crisafulli, Esmée J. van Vliet, Chiara M. Cattaneo, and Gabriele Picco

Abstract

Supplementary Figure 2

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2023
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40. Supplementary Figure 6 from A Molecularly Annotated Platform of Patient-Derived Xenografts ('Xenopatients') Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer

Author

Livio Trusolino, Alberto Bardelli, Paolo M. Comoglio, Silvia Marsoni, Anna Sapino, Enzo Medico, Salvatore Siena, Marcello Gambacorta, Lorenzo Capussotti, Mauro Risio, Andrea Sartore-Bianchi, Emanuele Valtorta, Luca Molinaro, Alberto Pisacane, Paolo Massucco, Andrea Muratore, Nadia Russolillo, Dario Ribero, Consalvo Petti, Michela Buscarino, Federica Di Nicolantonio, Davide Corà, Claudio Isella, Davide Torti, Francesco Sassi, Francesco Galimi, Giorgia Migliardi, and Andrea Bertotti

Abstract

PDF file - 3.8MB

Published
2023
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41. Supplementary Figure Legends from Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)

Author

Filippo G. De Braud, Alice T. Shaw, Pratik S. Multani, Zachary Hornby, Edna Chow-Maneval, David Luo, Rupal Patel, Ann D. Johnson, Karey Kowalski, Jason Christiansen, Gang Li, Elena Ardini, Matteo Duca, Silvia Damian, Sara Cresta, Angelo Vanzulli, Andrea Sartore-Bianchi, Laura Palmeri, Katia Bencardino, Alessio Amatu, Michele Schirru, Giovanna Marrapese, Giulio Cerea, Laura Giannetta, Robert Doebele, Stephen V. Liu, Jennifer J. Wheler, Anna F. Farago, Todd M. Bauer, Jeeyun Lee, Myung Ju Ahn, Manish Patel, Sai-Hong Ignatius Ou, Salvatore Siena, and Alexander Drilon

Abstract

Supplementary Figure Legends

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2023
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42. Supplementary Figure 3 from Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy

Author

Mathew J. Garnett, Alberto Bardelli, Emile E. Voest, Sabrina Arena, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Fengtang Yang, Martin Michaelis, Jindrich Cinatl, Krijn K. Dijkstra, Daniele Oddo, Luuk J. Schipper, Ruby Banerjee, Carlotta Cancelliere, Iñigo Sánchez Rodríguez, Sara F. Vieira, Sarah Consonni, Giuseppe Rospo, Giovanni Crisafulli, Esmée J. van Vliet, Chiara M. Cattaneo, and Gabriele Picco

Abstract

Supplementary Figure 3

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2023
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43. Supplementary Figure 5 from Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy

Author

Mathew J. Garnett, Alberto Bardelli, Emile E. Voest, Sabrina Arena, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Fengtang Yang, Martin Michaelis, Jindrich Cinatl, Krijn K. Dijkstra, Daniele Oddo, Luuk J. Schipper, Ruby Banerjee, Carlotta Cancelliere, Iñigo Sánchez Rodríguez, Sara F. Vieira, Sarah Consonni, Giuseppe Rospo, Giovanni Crisafulli, Esmée J. van Vliet, Chiara M. Cattaneo, and Gabriele Picco

Abstract

Supplementary Figure 5

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2023
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44. Supplementary Table 2 from A Molecularly Annotated Platform of Patient-Derived Xenografts ('Xenopatients') Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer

Author

Livio Trusolino, Alberto Bardelli, Paolo M. Comoglio, Silvia Marsoni, Anna Sapino, Enzo Medico, Salvatore Siena, Marcello Gambacorta, Lorenzo Capussotti, Mauro Risio, Andrea Sartore-Bianchi, Emanuele Valtorta, Luca Molinaro, Alberto Pisacane, Paolo Massucco, Andrea Muratore, Nadia Russolillo, Dario Ribero, Consalvo Petti, Michela Buscarino, Federica Di Nicolantonio, Davide Corà, Claudio Isella, Davide Torti, Francesco Sassi, Francesco Galimi, Giorgia Migliardi, and Andrea Bertotti

Abstract

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Published
2023
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45. Supplementary Methods, Figure Legends, Table Legends, Figures S1 - S4, Tables S1 - S5 from Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Author

Alberto Bardelli, Salvatore Siena, Gang Li, Andrea Sartore Bianchi, Federica Di Nicolantonio, Robert Wild, Robert Shoemaker, Shunqi Yan, Roopal Patel, Nicholas Cam, Alice Bartolini, Benedetta Mussolin, Luca Novara, Giuseppe Rospo, Giorgio Corti, Luca Lazzari, Giovanni Crisafulli, Giulia Siravegna, Ge Wei, Sandra Misale, and Mariangela Russo

Abstract

Supplementary Figure S1. LMNA-NTRK1 genetic rearrangement detected in patient's plasma and xeno. Supplementary Figure S2. Acquisition of mutations in the TRKA kinase domain drives secondary resistance to entrectinib in Ba/F3 TRKA WT cells. Supplementary Figure S3. NTRK1 mutations confer resistance to TRKA inhibition. Supplementary Figure S4. Homology alignment of NTRK1 p.G595 and p.G667 variants. Supplementary Table S1. NGS analysis of NTRK1 gene in patient's plasma and xeno. Supplementary Table S2. NGS analysis of patient's derived samples. Supplementary Table S3. Summary of serial ctDNA analyses. Supplementary Table S4. The p.G595R and p.G667C mutations confer resistance to multiple TRK inhibitors. Supplementary Table S5. NTRK1 p. G595R, p.G667C and LMNA-NTRK1 fusion probes for ddPCR.

Published
2023
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46. Supplementary Figures 1 - 2 from Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)

Author

Filippo G. De Braud, Alice T. Shaw, Pratik S. Multani, Zachary Hornby, Edna Chow-Maneval, David Luo, Rupal Patel, Ann D. Johnson, Karey Kowalski, Jason Christiansen, Gang Li, Elena Ardini, Matteo Duca, Silvia Damian, Sara Cresta, Angelo Vanzulli, Andrea Sartore-Bianchi, Laura Palmeri, Katia Bencardino, Alessio Amatu, Michele Schirru, Giovanna Marrapese, Giulio Cerea, Laura Giannetta, Robert Doebele, Stephen V. Liu, Jennifer J. Wheler, Anna F. Farago, Todd M. Bauer, Jeeyun Lee, Myung Ju Ahn, Manish Patel, Sai-Hong Ignatius Ou, Salvatore Siena, and Alexander Drilon

Abstract

Supplementary Figure 1. "Phase 2-Eligible" Population. Supplementary Figure 2. ALKA-372-001 and STARTRK-1 Dosing Regimens.

Published
2023
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47. Supplementary Figure 5 from A Molecularly Annotated Platform of Patient-Derived Xenografts ('Xenopatients') Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer

Author

Livio Trusolino, Alberto Bardelli, Paolo M. Comoglio, Silvia Marsoni, Anna Sapino, Enzo Medico, Salvatore Siena, Marcello Gambacorta, Lorenzo Capussotti, Mauro Risio, Andrea Sartore-Bianchi, Emanuele Valtorta, Luca Molinaro, Alberto Pisacane, Paolo Massucco, Andrea Muratore, Nadia Russolillo, Dario Ribero, Consalvo Petti, Michela Buscarino, Federica Di Nicolantonio, Davide Corà, Claudio Isella, Davide Torti, Francesco Sassi, Francesco Galimi, Giorgia Migliardi, and Andrea Bertotti

Abstract

PDF file - 186K

Published
2023
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48. Supplementary Table 1 from A Molecularly Annotated Platform of Patient-Derived Xenografts ('Xenopatients') Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer

Author

Livio Trusolino, Alberto Bardelli, Paolo M. Comoglio, Silvia Marsoni, Anna Sapino, Enzo Medico, Salvatore Siena, Marcello Gambacorta, Lorenzo Capussotti, Mauro Risio, Andrea Sartore-Bianchi, Emanuele Valtorta, Luca Molinaro, Alberto Pisacane, Paolo Massucco, Andrea Muratore, Nadia Russolillo, Dario Ribero, Consalvo Petti, Michela Buscarino, Federica Di Nicolantonio, Davide Corà, Claudio Isella, Davide Torti, Francesco Sassi, Francesco Galimi, Giorgia Migliardi, and Andrea Bertotti

Abstract

PDF file - 27K

Published
2023
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49. Data from Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy

Author

Mathew J. Garnett, Alberto Bardelli, Emile E. Voest, Sabrina Arena, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Fengtang Yang, Martin Michaelis, Jindrich Cinatl, Krijn K. Dijkstra, Daniele Oddo, Luuk J. Schipper, Ruby Banerjee, Carlotta Cancelliere, Iñigo Sánchez Rodríguez, Sara F. Vieira, Sarah Consonni, Giuseppe Rospo, Giovanni Crisafulli, Esmée J. van Vliet, Chiara M. Cattaneo, and Gabriele Picco

Abstract

Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of patients receiving immunotherapy have disease that is refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR colorectal cancer preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency. These data show the potential of therapeutically targeting WRN in patients with dMMR/MSI-H colorectal cancer and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies.Significance:We found that a large, diverse set of dMMR/MSI-H colorectal cancer preclinical models, including models of treatment-refractory disease, are WRN-dependent. Our results support WRN as a promising synthetic-lethal target in dMMR/MSI-H colorectal cancer tumors as a monotherapy or in combination with targeted agents, chemotherapy, or immunotherapy.This article is highlighted in the In This Issue feature, p. 1861

Published
2023
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50. Supplementary Figure 2 from A Molecularly Annotated Platform of Patient-Derived Xenografts ('Xenopatients') Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer

Author

Livio Trusolino, Alberto Bardelli, Paolo M. Comoglio, Silvia Marsoni, Anna Sapino, Enzo Medico, Salvatore Siena, Marcello Gambacorta, Lorenzo Capussotti, Mauro Risio, Andrea Sartore-Bianchi, Emanuele Valtorta, Luca Molinaro, Alberto Pisacane, Paolo Massucco, Andrea Muratore, Nadia Russolillo, Dario Ribero, Consalvo Petti, Michela Buscarino, Federica Di Nicolantonio, Davide Corà, Claudio Isella, Davide Torti, Francesco Sassi, Francesco Galimi, Giorgia Migliardi, and Andrea Bertotti

Abstract

PDF file - 158K

Published
2023
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