Publications by authors named "Marcello Maugeri-Saccà"

77 Publications

Circulating HPV DNA in the Management of Oropharyngeal and Cervical Cancers: Current Knowledge and Future Perspectives.

J Clin Med 2021 Apr 6;10(7). Epub 2021 Apr 6.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

Human papillomaviruses (HPVs) are associated with invasive malignancies, including almost 100% of cervical cancers (CECs), and 35-70% of oropharyngeal cancers (OPCs). HPV infection leads to clinical implications in related tumors by determining better prognosis and predicting treatment response, especially in OPC. Currently, specific and minimally invasive tests allow for detecting HPV-related cancer at an early phase, informing more appropriately therapeutical decisions, and allowing for timely disease monitoring. A blood-based biomarker detectable in liquid biopsy represents an ideal candidate, and the use of circulating HPV DNA (ct-DNA) itself could offer the highest specificity for such a scope. Circulating HPV DNA is detectable in the greatest part of patients affected by HPV-related cancers, and studies have demonstrated its potential usefulness for CEC and OPC clinical management. Unfortunately, when using conventional polymerase chain reaction (PCR), the detection rate of serum HPV DNA is low. Innovative techniques such as droplet-based digital PCR and next generation sequencing are becoming increasingly available for the purpose of boosting HPV ct-DNA detection rate. We herein review and critically discuss the most recent and representative literature, concerning the role of HPV ctDNA in OPC and CEC in the light of new technologies that could improve the potential of this biomarker in fulfilling many of the unmet needs in the clinical management of OPC and CEC patients.
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http://dx.doi.org/10.3390/jcm10071525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038737PMC
April 2021

Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51.

Cell Death Differ 2021 Feb 2. Epub 2021 Feb 2.

IIGM - Italian Institute for Genomic Medicine, c/o IRCSS, Candiolo, Italy.

Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations.
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http://dx.doi.org/10.1038/s41418-020-00733-4DOI Listing
February 2021

Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study.

J Exp Clin Cancer Res 2020 Dec 10;39(1):279. Epub 2020 Dec 10.

Medical Oncology, Paolo Giaccone University Hospital, Palermo, Italy.

Background: HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.

Methods: The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.

Results: We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively).

Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.
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http://dx.doi.org/10.1186/s13046-020-01797-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731769PMC
December 2020

Efficacy of immunotherapy in lung cancer with co-occurring mutations in NOTCH and homologous repair genes.

J Immunother Cancer 2020 08;8(2)

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy

Background: Immune checkpoint inhibitors (ICIs) provide significant survival benefits in non-small cell lung cancer (NSCLC). Nevertheless, while some patients obtain a prolonged benefit, a non-negligible fraction of patients experiences an ultrarapid disease progression. Identifying specific molecular backgrounds predicting opposite outcomes is instrumental to optimize the use of these agents in clinical practice.

Methods: We carried out an observational study with prospective design envisioning targeted next-generation sequencing (NGS) with an approved assay in 55 patients with metastatic NSCLC (Rome cohort), of whom 35 were treated with ICIs. Data from three clinically comparable datasets were collected and combined into a metadataset containing 779 patients. The datasets were related to the Memorial Sloan Kettering Cancer Center (MSKCC) cohort (tissue-based NGS) and the randomized phase II and III POPLAR and OAK trials (blood-based NGS).

Results: In patients treated with ICIs in the Rome cohort, co-occurring mutations in NOTCH1-3 and homologous repair (HR) genes were associated with durable clinical benefit. Using the MSKCC/POPLAR/OAK metadaset, we confirmed the relationship between the NOTCH/HR signature and longer progression-free survival (PFS) in ICI-treated patients (multivariate Cox: HR 0.51, 95% CI 0.34 to 0.76, p=0.001). The NOTCH/HR genomic predictor was also associated with longer survival (log-rank p=0.008), despite patients whose tumors carried the NOTCH/HR signature had higher metastatic burden as compared with their negative counterpart. Finally, we observed that this genomic predictor was also associated with longer survival in patients with other tumor types treated with ICIs (n=1311, log-rank p=0.002).

Conclusions: Co-occurring mutations in the NOTCH and HR pathways are associated with increased efficacy of immunotherapy in advanced NSCLC. This genomic predictor deserves further investigation to fully assess its potential in informing therapeutic decisions.
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http://dx.doi.org/10.1136/jitc-2020-000946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409965PMC
August 2020

TRF2 and VEGF-A: an unknown relationship with prognostic impact on survival of colorectal cancer patients.

J Exp Clin Cancer Res 2020 Jun 15;39(1):111. Epub 2020 Jun 15.

Oncogenomic and Epigenetic Unit, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: Colorectal cancer is one of most common tumors in developed countries and, despite improvements in treatment and diagnosis, mortality rate of patients remains high, evidencing the urgent need of novel biomarkers to properly identify colorectal cancer high-risk patients that would benefit of specific treatments. Recent works have demonstrated that the telomeric protein TRF2 is over-expressed in colorectal cancer and it promotes tumor formation and progression through extra-telomeric functions. Moreover, we and other groups evidenced, both in vitro on established cell lines and in vivo on tumor bearing mice, that TRF2 regulates the vascularization mediated by VEGF-A. In the present paper, our data evidence a tight correlation between TRF2 and VEGF-A with prognostic relevance in colorectal cancer patients.

Methods: For this study we sampled 185 colorectal cancer patients surgically treated and diagnosed at the Regina Elena National Cancer Institute of Rome and investigated the association between the survival outcome and the levels of VEGF-A and TRF2.

Results: Tissue microarray immunohistochemical analyses revealed that TRF2 positively correlates with VEGF-A expression in our cohort of patients. Moreover, analysis of patients' survival, confirmed in a larger dataset of patients from TCGA, demonstrated that co-expression of TRF2 and VEGF-A correlate with a poor clinical outcome in stage I-III colorectal cancer patients, regardless the mutational state of driver oncogenes.

Conclusions: Our results permitted to identify the positive correlation between high levels of TRF2 and VEGF-A as a novel prognostic biomarker for identifying the subset of high-risk colorectal cancer patients that could benefit of specific therapeutic regimens.
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http://dx.doi.org/10.1186/s13046-020-01612-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294609PMC
June 2020

KEAP1-NFE2L2 Mutations in NSCLC: Increased Awareness Needed. Reply to "KEAP1-NFE2L2-Mutant NSCLC and Immune Checkpoint Inhibitors: A Large Database Analysis".

J Thorac Oncol 2020 06;15(6):e87-e88

Division of Medical Oncology 2, Istituto di Ricovero e Cura a Carattere Scientifico Regina Elena National Cancer Institute, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2020.03.024DOI Listing
June 2020

Prognostic relevance of DNA damage and repair biomarkers in elderly patients with hormone-receptor-positive breast cancer treated with neoadjuvant hormone therapy: evidence from the real-world setting.

Ther Adv Med Oncol 2019 18;11:1758835919853192. Epub 2019 Aug 18.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Background: The logic behind the outcome of endocrine therapy in breast cancer has long remained poorly understood. The prognostic role of DNA damage and repair biomarkers (DDR) was explored in postmenopausal, hormone-receptor-positive breast cancer patients treated with neoadjuvant hormone therapy (NAHT).

Methods: Data on 55 patients were included. The phosphorylated ataxia-teleangectasia and Rad3-related protein (pATR), phosphorylated ataxia-telangiectasia mutated (ATM) kinase, and phosphorylated H2A Histone Family Member X (γ-H2AX) were evaluated by immunohistochemistry in paired tissues collected at baseline and following NAHT. Biomarkers were considered both singularly and within signatures. Ki-67 percentage change was the primary biomarker endpoint. Classical endpoints were also considered.

Results: The most favorable Ki-67 outcome was associated with the γ-H2AX/pATM signature ( = 0.011). In models of Ki-67 reduction, 'luminal B' subtype, higher grade of anaplasia, and the γ-H2AX/pATM signature tested as significant ( < 0.05 for all). Results were confirmed in multivariate analysis. No association was observed with pathologic response. An increase of ∆γ-H2AX in paired breast tissues was associated with longer event-free survival ( = 0.027) and overall survival ( = 0.042). In Cox models, both survival outcomes were solely affected by grade of anaplasia, with less favorable prognosis in the highest grades ( < 0.05 for both).

Conclusions: We report novel evidence of the prognostic role of DDR biomarkers on important patient outcomes in postmenopausal hormone-receptor-positive breast cancer patients treated with NAHT. If confirmed in future and adequately sized trials, our results may help inform therapeutic decisions and clarify underlying biological mechanisms.
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http://dx.doi.org/10.1177/1758835919853192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700857PMC
August 2019

Mutations in the KEAP1-NFE2L2 Pathway Define a Molecular Subset of Rapidly Progressing Lung Adenocarcinoma.

J Thorac Oncol 2019 11 16;14(11):1924-1934. Epub 2019 Jul 16.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy. Electronic address:

Introduction: Molecular characterization studies revealed recurrent kelch like ECH associated protein 1 gene (KEAP1)/nuclear factor, erythroid 2 like 2 gene (NFE2L2) alterations in NSCLC. These genes encode two interacting proteins (a stress response pathway [SRP]) that mediate a cytoprotective response to oxidative stress and xenobiotics. Nevertheless, whether KEAP1/NFE2L2 mutations have an impact on clinical outcomes is unclear.

Methods: We performed amplicon-based next-generation sequencing to characterize the SRP in patients with metastatic NSCLC (Regina Elena National Cancer Institute cohort [n = 88]) treated with first-line chemotherapy. Mutations in the DNA damage response (tumor protein p53 gene [TP53], ATM serine/threonine kinase gene [ATM], and ATR serine/threonine kinase gene [ATR]) were concomitantly analyzed. In lung adenocarcinoma (LAC), we also determined the expression of phosphorylated ataxia telangiectasia mutated kinase and ataxia telangiectasia and Rad3-related protein. Two independent cohorts (the Memorial Sloan Kettering Cancer Center cohort and The Cancer Genome Atlas cohort) with data from approximately 1400 patients with advanced LAC were used to assess the reproducibility of the results.

Results: In the Regina Elena National Cancer Institute cohort, patients whose tumors carried mutations in the KEAP1/NFE2L2 pathway had significantly shorter progression-free survival and overall survival than their wild-type counterparts did (log-rank p = 0.006 and p = 0.018, respectively). This association was driven by LAC in which KEAP1/NFE2L2 mutations were overrepresented in fast progressors and associated with an increased risk of disease progression and death. LACs carrying KEAP1/NFE2L2 mutations were characterized by elevated expression of phosphorylated ataxia telangiectasia mutated (pATM) kinase and ataxia telangiectasia and Rad3-related (pATR) protein in association with a pattern of mutual exclusivity with TP53 alterations. The relationship between KEAP1/NFE2L2 mutations and shorter survival was validated in the Memorial Sloan Kettering Cancer Center cohort (n = 1256) (log-rank p < 0.001) and in The Cancer Genome Atlas cohort (n = 162) (log-rank p = 0.039).

Conclusion: These findings suggest that a mutant SRP represents a negative prognostic/predictive factor in metastatic LAC and that KEAP1/NFE2L2 mutations may define a molecular subtype of chemotherapy-resistant and rapidly progressing LAC.
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http://dx.doi.org/10.1016/j.jtho.2019.07.003DOI Listing
November 2019

Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma.

J Exp Clin Cancer Res 2018 Dec 17;37(1):318. Epub 2018 Dec 17.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161, Rome, Italy.

Background: Combination therapy with BRAF and MEK inhibitors significantly improves survival in BRAF mutated melanoma patients but is unable to prevent disease recurrence due to the emergence of drug resistance. Cancer stem cells (CSCs) have been involved in these long-term treatment failures. We previously reported in lung cancer that CSCs maintenance is due to altered lipid metabolism and dependent upon Stearoyl-CoA-desaturase (SCD1)-mediated upregulation of YAP and TAZ. On this ground, we investigated the role of SCD1 in melanoma CSCs.

Methods: SCD1 gene expression data of melanoma patients were downloaded from TCGA and correlated with disease progression by bioinformatics analysis and confirmed on patient's tissues by qRT-PCR and IHC analyses. The effects of combination of BRAF/MEKi and the SCD1 inhibitor MF-438 were monitored by spheroid-forming and proliferation assays on a panel of BRAF-mutated melanoma cell lines grown in 3D and 2D conditions, respectively. SCD1, YAP/TAZ and stemness markers were evaluated in melanoma cells and tissues by qRT-PCR, WB and Immunofluorescence.

Results: We first observed that SCD1 expression increases during melanoma progression. BRAF-mutated melanoma 3D cultures enriched for CSCs overexpressed SCD1 and were more resistant than 2D differentiated cultures to BRAF and MEK inhibitors. We next showed that exposure of BRAF-mutated melanoma cells to MAPK pathway inhibitors enhanced stemness features by upregulating the expression of YAP/TAZ and downstream genes but surprisingly not SCD1. However, SCD1 pharmacological inhibition was able to downregulate YAP/TAZ and to revert at the same time CSC enrichment and resistance to MAPK inhibitors.

Conclusions: Our data underscore the role of SCD1 as prognostic marker in melanoma and promote the use of SCD1 inhibitors in combination with MAPK inhibitors for the control of drug resistance.
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http://dx.doi.org/10.1186/s13046-018-0989-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298024PMC
December 2018

Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials.

J Clin Med 2018 Dec 12;7(12). Epub 2018 Dec 12.

Department of Medical, Oral and Biotechnological Sciences and CeSI-MeT, G. D'Annunzio University, 66100 Chieti, Italy.

Evidence has recently emerged on the influence of gender on the immune system. In this systematic review and meta-analysis of phase III randomized clinical trials (RCTs), we explored the impact of gender on survival in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). We performed a comprehensive search of the literature updated to April 2018, including the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We extracted data on study characteristics and risk of bias in duplicate. Of 423 unique citations, 21 RCTs were included, inherently to 12,635 patients. Both males and females showed reduced risk of death associated with ICIs use (HR 0.73, < 0.001 and HR 0.77, < 0.001, respectively). Subgroup analyses by specific ICI showed similar OS in both genders for anti-PD-1/PDL-1. Anti-CTLA-4 use was associated with longer OS in men only (HR 0.77, < 0.012), with the exception of melanoma (in women, HR 0.80, = 0.006). PFS was longer in men than in women (HR 0.67, < 0.001 and HR 0.77, = 0.100, respectively). Conclusively, ICIs use was associated with more favorable outcomes in men, particularly for anti-CTLA-4 agents. In melanoma, not gender-related factors may influence the anti-tumor immune response evoked by ICIs.
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http://dx.doi.org/10.3390/jcm7120542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306894PMC
December 2018

A multicenter REtrospective observational study of first-line treatment with PERtuzumab, trastuzumab and taxanes for advanced HER2 positive breast cancer patients. RePer Study.

Cancer Biol Ther 2019 7;20(2):192-200. Epub 2018 Nov 7.

r HPV Unit, Department of Gynaecologic Oncology , IRCCS Regina Elena National Cancer Institute , Rome , Italy.

We carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test. Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached. When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naïve patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06). The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively). In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p < 0.0001). An OS advantage was observed with lower PS (p < 0.0001), single metastatic site (p = 0.004), no prior exposure to trastuzumab (p = 0.004) and response to pertuzumab-based treatment (p = 0.003). Our results confirm that trastuzumab/pertuzumab/taxane is the standard of care as first-line treatment of patients with HER2-positive ABC even in the real-world setting. Moreover, the double-maintenance therapy (HER2 block and ET) is strongly recommended when feasible.
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http://dx.doi.org/10.1080/15384047.2018.1523095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343690PMC
April 2020

The clinical significance of PD-L1 in advanced gastric cancer is dependent on mutations and ATM expression.

Oncoimmunology 2018;7(8):e1457602. Epub 2018 Apr 24.

Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, Rome, Italy.

Whether PD-L1 expression is associated with survival outcomes in gastric cancer (GC) is controversial. The inhibition of the PD-1/PD-L1 pathway is effective against genomically unstable tumors. Hypothesizing that also the clinical significance of PD-L1 might be dependent on the activation of molecular circuits ensuring genomic stability, we evaluated PD-L1 expression in tissue samples from 72 advanced GC patients treated with first-line chemotherapy. Samples were already characterized for DNA damage repair (DDR) component expression (pATM, pChk1, pWee1, γ-H2AX and pRPA2) along with mutations in DDR-linked genes ( and ). Overall, PD-L1 expression was not associated with progression-free survival (PFS) and overall survival (OS), independently on whether we considered its expression in tumor cells (PD-L1-TCs) or in the immune infiltrate (PD-L1-TILs). In subgroup analysis, positive PD-L1-TC immunostaining was associated with better PFS in patients whose tumors did not carry DDR activation (multivariate Cox: HR 0.34, 95%CI: 0.15-0.76, p = 0.008). This subset (DDR) was characterized by negative pATM expression or the presence of mutations. Conversely, the relationship between PD-L1-TC expression and PFS was lost in a molecular scenario denoting DDR activation (DDR), as defined by concomitant pATM expression and wild-type form. Surprisingly, while PD-L1-TC expression was associated with better OS in the DDR subset (multivariate Cox: HR 0.41, 95% CI: 0.17-0.96, p = 0.039), in the DDR subgroup we observed an opposite impact on OS (multivariate Cox: HR 2.56, 95%CI: 1.06-6.16, p = 0.036). Thus, PD-L1-TC expression may impact survival outcomes in GC on the basis of the activation/inactivation of genome-safeguarding pathways.
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http://dx.doi.org/10.1080/2162402X.2018.1457602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136851PMC
April 2018

Coexisting YAP expression and TP53 missense mutations delineates a molecular scenario unexpectedly associated with better survival outcomes in advanced gastric cancer.

J Transl Med 2018 09 4;16(1):247. Epub 2018 Sep 4.

Division of Medical Oncology 2, IRCCS "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

We have previously reported that nuclear expression of the Hippo transducer TAZ in association with Wnt pathway mutations negatively impacts survival outcomes in advanced gastric cancer (GC) patients. Here, we extended these previous findings by investigating another oncogenic cooperation, namely, the interplay between YAP, the TAZ paralogue, and p53. The molecular output of the YAP-p53 cooperation is dependent on TP53 mutational status. In the absence of mutations, the YAP-p53 crosstalk elicits a pro-apoptotic response, whereas in the presence of TP53 mutations it activates a pro-proliferative transcriptional program. In order to study this phenomenon, we re-analyzed data from 83 advanced GC patients treated with chemotherapy whose tissue samples had been characterized for YAP expression (immunohistochemistry, IHC) and TP53 mutations (deep sequencing). In doing so, we generated a molecular model combining nuclear YAP expression in association with TP53 missense variants (YAP+/TP53). Surprisingly, this signature was associated with a decreased risk of disease progression (multivariate Cox for progression-free survival: HR 0.53, 95% CI 0.30-0.91, p = 0.022). The YAP+/TP53 model was also associated with better OS in the subgroup of patients who received chemotherapy beyond the first-line setting (multivariate Cox: HR 0.36, 95% CI 0.16-0.81, p = 0.013). Collectively, our findings suggest that the oncogenic cooperation between YAP and mutant p53 may translate into better survival outcomes. This apparent paradox can be explained by the pro-proliferative program triggered by YAP and mutant p53, that supposedly renders cancer cells more vulnerable to cytotoxic therapies.
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http://dx.doi.org/10.1186/s12967-018-1607-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122687PMC
September 2018

Deep sequencing and pathway-focused analysis revealed multigene oncodriver signatures predicting survival outcomes in advanced colorectal cancer.

Oncogenesis 2018 Jul 22;7(7):55. Epub 2018 Jul 22.

Division of Medical Oncology 2, IRCCS "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Genomic technologies are reshaping the molecular landscape of colorectal cancer (CRC), revealing that oncogenic driver mutations (APC and TP53) coexist with still underappreciated genetic events. We hypothesized that mutational analysis of CRC-linked genes may provide novel information on the connection between genetically-deregulated pathways and clinical outcomes. We performed next-generation sequencing (NGS) analysis of 16 recurrently mutated genes in CRC exploiting tissue specimens from 98 advanced CRC patients. Multiple correspondence analysis (MCA) was used to identify gene sets characterizing negative and positive outliers (patients in the lowest and highest quartile of progression-free survival, PFS). Variables potentially affecting PFS and overall survival (OS) were tested in univariate and multivariate Cox proportional hazard models. Sensitivity analyses and resampling were used to assess the robustness of genomic predictors. MCA revealed that APC and TP53 mutations were close to the negative outlier group, whereas mutations in other WNT pathway genes were in proximity of the positive outliers. Reasoning that genetic alterations interact epistatically, producing greater or weaker consequences in combination than when individually considered, we tested whether patients whose tumors carried a genetic background characterized by APC and TP53 mutations without coexisting mutations in other WNT genes (AMER1, FBXW7, TCF7L2, CTNNB1, SOX9) had adverse survival outcomes. With this approach, we identified two oncodriver signatures (ODS1 and ODS2) associated with shorter PFS (ODS1 multivariate Cox for PFS: HR 2.16, 95%CI: 1.28-3.64, p = 0.004; ODS2 multivariate Cox for PFS: HR 2.61, 95%CI: 1.49-4.58, p = 0.001). Clinically-focused and molecularly-focused sensitivity analyses, resampling, and reclassification of mutations confirmed the stability of ODS1/2. Moreover, ODS1/2 negatively impacted OS. Collectively, our results point to co-occurring driver mutations as an adverse molecular factor in advanced CRC. This relationship depends on a broader genetic context highlighting the importance of genetic interactions.
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http://dx.doi.org/10.1038/s41389-018-0066-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054833PMC
July 2018

Observational study of coagulation activation in early breast cancer: development of a prognostic model based on data from the real world setting.

J Transl Med 2018 05 16;16(1):129. Epub 2018 May 16.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: Cancer and coagulation activation are tightly related. The extent to which factors related to both these pathologic conditions concur to patient prognosis intensely animates the inherent research areas. The study herein presented aimed to the development of a tool for the assessment and stratification of risk of death and disease recurrence in early breast cancer.

Methods: Between 2008 and 2010, two hundreds thirty-five (N: 235) patients diagnosed with stage I-IIA breast cancer were included. Data on patient demographics and clinic-pathologic features were collected in course of face-to-face interviews or actively retrieved from clinical charts. Plasma levels of plasminogen activator inhibitor type 1 (PAI-1), fragment 1 + 2 (F1 + 2), thrombin antithrombin complex (TAT), factor VIII (FVIII), and D-dimer (DD) were measured at breast cancer diagnosis and prior to any therapeutic procedure, including breast surgery. The risk of death was computed in terms of overall survival (OS), which was the primary outcome. For a subset of patients (N = 62), disease free survival (DFS) was also assessed as a measure of risk of disease recurrence.

Results: Median follow up was 95 months (range 6-112 months). Mean age at diagnosis was 60.3 ± 13.4 years. Cancer cases were more commonly intraductal carcinomas (N: 204; 86.8%), pT1 (131; 55.7%), pN0 (141; 60%) and G2 (126; 53.6%). Elevated levels of PAI-1 (113; 48.1%) represented the most frequent coagulation abnormality, followed by higher levels of F1 + 2 (97; 41.3%), DD (63; 27.0%), TAT (34; 40%), and FVIII (29; 12.3%). In univariate models of OS, age, pT, DD, FVIII were prognostically relevant. In multivariate models of OS, age (p = 0.043), pT (p = 0.001), levels of DD (p = 0.029) and FVIII (p = 0.087) were confirmed. In the smaller subgroup of 62 patients, lymph node involvement, percent expression of estrogen receptors and levels of FVIII impacted DFS significantly.

Conclusions: We developed a risk assessment tool for OS including patient- and cancer-related features along with biomarkers of coagulation activation in a cohort of early BC patients. Further studies are warranted to validate our prognostic model in the early setting and eventually extend its application to risk evaluation in the advanced setting for breast and other cancers.
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http://dx.doi.org/10.1186/s12967-018-1511-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956941PMC
May 2018

Metabolic features of cancer stem cells: the emerging role of lipid metabolism.

Oncogene 2018 05 15;37(18):2367-2378. Epub 2018 Feb 15.

Scientific Direction, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, Rome, 00144, Italy.

Cancer stem cells (CSCs) are an uncommon subset of tumor cells capable of self-renewal, differentiating, and recreating the parental tumor when transplanted into the murine background. Over the past two decades, efforts toward understanding CSC biology culminated into identifying a set of signaling pathways sustaining "stemness". Nevertheless, while metabolic rewiring is nowadays considered a hallmark of cancer, no consensus has been reached on the metabolic features underlying the plastic nature of CSCs, which are capable of residing in a dormant state, and able to rapidly proliferate when the need to repopulate the tumor mass arises. An emerging concept in the field of CSC metabolism is that these cells are extremely reliant on the activity of enzymes involved in lipid metabolism, such as stearoyl-CoA desaturase 1 (SCD1) and 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR). Indeed, SCD1 and HMG-CoAR have been described as key factors for the correct function of a number of concatenated pathways involved in CSC fate decision, such as Hippo and Wnt. In the present review, we describe metabolic futures of CSCs with a special focus on lipid metabolism, which until now represents an underappreciated force in maintaining CSCs and an attractive therapeutic target.
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http://dx.doi.org/10.1038/s41388-018-0141-3DOI Listing
May 2018

Expression of the Hippo transducer TAZ in association with WNT pathway mutations impacts survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy.

J Transl Med 2018 02 5;16(1):22. Epub 2018 Feb 5.

Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: An extensive crosstalk co-regulates the Hippo and Wnt pathway. Preclinical studies revealed that the Hippo transducers YAP/TAZ mediate a number of oncogenic functions in gastric cancer (GC). Moreover, comprehensive characterization of GC demonstrated that the Wnt pathway is targeted by oncogenic mutations. On this ground, we hypothesized that YAP/TAZ- and Wnt-related biomarkers may predict clinical outcomes in GC patients treated with chemotherapy.

Methods: In the present study, we included 86 patients with advanced GC treated with first-line chemotherapy in prospective phase II trials or in routine clinical practice. Tissue samples were immunostained to evaluate the expression of YAP/TAZ. Mutational status of key Wnt pathway genes (CTNNB1, APC and FBXW7) was assessed by targeted DNA next-generation sequencing (NGS). Survival curves were estimated and compared by the Kaplan-Meier product-limit method and the log-rank test, respectively. Variables potentially affecting progression-free survival (PFS) were verified in univariate Cox proportional hazard models. The final multivariate Cox models were obtained with variables testing significant at the univariate analysis, and by adjusting for all plausible predictors of the outcome of interest (PFS).

Results: We observed a significant association between TAZ expression and Wnt mutations (Chi-squared p = 0.008). Combined TAZ expression and Wnt mutations (TAZ/WNT) was more frequently observed in patients with the shortest progression-free survival (negative outliers) (Fisher p = 0.021). Uni-and multivariate Cox regression analyses revealed that patients whose tumors harbored the TAZ/WNT signature had an increased risk of disease progression (univariate Cox: HR 2.27, 95% CI 1.27-4.05, p = 0.006; multivariate Cox: HR 2.73, 95% CI 1.41-5.29, p = 0.003). Finally, the TAZ/WNT signature negatively impacted overall survival.

Conclusions: Collectively, our findings indicate that the oncogenic YAP/TAZ-Wnt crosstalk may be active in GC, conferring chemoresistant traits that translate into adverse survival outcomes.
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http://dx.doi.org/10.1186/s12967-018-1385-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800016PMC
February 2018

Body mass index in HER2-negative metastatic breast cancer treated with first-line paclitaxel and bevacizumab.

Cancer Biol Ther 2018 04 16;19(4):328-334. Epub 2018 Feb 16.

a Division of Medical Oncology 2 , IRCCS Regina Elena National Cancer Institute , Rome , Italy.

The evidence emerged from the TOURANDOT trial encourages evaluating the role of anthropometric determinants on treatment outcomes in HER2-negative metastatic breast cancer patients treated with bevacizumab-including regimens. We thus analyzed data from a subgroup of these patients from a larger cohort previously assessed for treatment outcomes. Patients were included in the present analysis if body mass index values had been recorded at baseline. Clinical benefit rates, progression free survival and overall survival were assessed for the overall study population and subgroups defined upon molecular subtype. One hundred ninety six patients were included (N:196). Body mass index showed no impact on clinical benefit rates in the overall study sample and in the luminal cancer subset (p = 0.12 and p = 0.79, respectively), but did so in the triple negative subgroup, with higher rates in patients with body mass index ≥25 (p = 0.03). In the overall study sample, body mass index did no impact progression free or overall survival (p = 0.33 and p = 0.67, respectively). Conversely, in triple negative patients, progression free survival was significantly longer with body mass index ≥25 (6 vs 14 months, p = 0.04). In this subset, overall survival was more favorable (25 vs 19 months, p = 0.02). The impact of the molecular subtype was confirmed in multivariate models including the length of progression free survival, and number of metastatic sites (p < 0.0001). Further studies are warranted to confirm our findings in more adequately sized, ad hoc, prospective studies.
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http://dx.doi.org/10.1080/15384047.2017.1416938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902232PMC
April 2018

The Hippo pathway in normal development and cancer.

Pharmacol Ther 2018 06 3;186:60-72. Epub 2018 Jan 3.

Institute of General Pathology, Fondazione Policlinico Universitario A. Gemelli - Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168 Rome, Italy. Electronic address:

The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway. Over the past two decades, the Hippo pathway has increasingly been connected with developmental processes and tissue repair, being intimately tied to the function of tissue-specific progenitor cells. Pervasive activation of YAP/TAZ has been recognized in a multitude of human tumors and connected with the acquisition of malignant traits, including resistance to anticancer therapies, distant dissemination and maintenance of cancer stem cells. On this ground, Hippo-related biomarkers are increasingly investigated in translational studies striving to identify prognostic and predictive factors. In addition, the dependency of many tumors on YAP/TAZ may be exploited for therapeutic purposes. Albeit no direct inhibitors are currently available, drug repositioning approaches provided hints that YAP/TAZ inhibition can be achieved with old drugs, such as cholesterol-lowering agents or compounds blocking bone resorption.
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http://dx.doi.org/10.1016/j.pharmthera.2017.12.011DOI Listing
June 2018

Anthropometric, clinical and molecular determinants of treatment outcomes in postmenopausal, hormone receptor positive metastatic breast cancer patients treated with fulvestrant: Results from a real word setting.

Oncotarget 2017 Sep 9;8(40):69025-69037. Epub 2017 Apr 9.

Division of Medical Oncology 2, Regina Elena National Cancer Institute, Rome, Italy.

To characterize determinants of treatment outcome in a real world population of 161 post-menopausal hormone receptor-positive metastatic breast cancer patients treated with fulvestrant. Descriptive statistics for demographics, anthropometrics, clinical and molecular characteristic were compared across subgroups of sensitivity/resistance to prior endocrine therapy and tested in uni/multivariate models. Clinical benefit was more common in sensitive patients with higher estrogen receptor expression and when fulvestrant was given in first line (=0.02 and 0.046). In resistant patients, PFS was longer with lower BMI (=0.01). Among endocrine sensitive women, longer PFS was associated with fulvestrant in first-line, single metastasis and no visceral involvement (=0.01, 0.003 and 0.01). OS was shorter in resistant patients with HER2-positive disease and if fulvestrant was given in second and subsequent line (=0.03). In sensitive patients, we observed worse OS with multiple metastases (=0.008). Multivariate analyses confirmed longer PFS in resistant patients with lower BMI and older age (=0.002 and 0.007). OS in resistant patients was negatively influenced by HER2 positivity and fulvestrant in second and subsequent line (=0.04). In sensitive women, multiple metastases were associated with poorer survival (=0.002). This evidence encourages considering patient and disease characteristics in decision making and outcome interpretation for patients candidate to fulvestrant.
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http://dx.doi.org/10.18632/oncotarget.16982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620318PMC
September 2017

A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience.

Oncotarget 2017 08 25;8(34):56921-56931. Epub 2017 May 25.

Department of Medico-Surgical Sciences and Biotechnologies, "Sapienza" University of Rome, Oncology Unit, Istituto Chirurgico Ortopedico Traumatologico, Latina, Italy.

We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order.
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http://dx.doi.org/10.18632/oncotarget.18176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593613PMC
August 2017

Fasting glucose and body mass index as predictors of activity in breast cancer patients treated with everolimus-exemestane: The EverExt study.

Sci Rep 2017 09 6;7(1):10597. Epub 2017 Sep 6.

Division of Medical Oncology 2, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Evidence on everolimus in breast cancer has placed hyperglycemia among the most common high grade adverse events. Anthropometrics and biomarkers of glucose metabolism were investigated in a observational study of 102 postmenopausal, HR + HER2- metastatic breast cancer patients treated with everolimus-exemestane in first and subsequent lines. Best overall response (BR) and clinical benefit rate (CBR) were assessed across subgroups defined upon fasting glucose (FG) and body mass index (BMI). Survival was estimated by Kaplan-Meier method and log-rank test. Survival predictors were tested in Cox models. Median follow up was 12.4 months (1.0-41.0). The overall cohort showed increasing levels of FG and decreasing BMI (p < 0.001). Lower FG fasting glucose at BR was more commonly associated with C/PR or SD compared with PD (p < 0.001). We also observed a somewhat higher BMI associated with better response (p = 0.052). More patients in the lowest FG category achieved clinical benefit compared to the highest (p < 0.001), while no relevant differences emerged for BMI. Fasting glucose at re-assessment was also predictive of PFS (p = 0.037), as confirmed in models including BMI and line of therapy (p = 0.049). Treatment discontinuation was significantly associated with changes in FG (p = 0.014). Further research is warranted to corroborate these findings and clarify the underlying mechanisms.
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http://dx.doi.org/10.1038/s41598-017-10061-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587713PMC
September 2017

Analysis of the ATR-Chk1 and ATM-Chk2 pathways in male breast cancer revealed the prognostic significance of ATR expression.

Sci Rep 2017 08 14;7(1):8078. Epub 2017 Aug 14.

Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

The ATR-Chk1 and ATM-Chk2 pathways are central in DNA damage repair (DDR) and their over-activation may confer aggressive molecular features, being an adaptive response to endogenous DNA damage and oncogene-induced replication stress. Herein we investigated the ATR-Chk1 and ATM-Chk2 signalings in male breast cancer (MBC). The expression of DDR kinases (pATR, pATM, pChk1, pChk2, and pWee1) and DNA damage markers (pRPA32 and γ-H2AX) was evaluated by immunohistochemistry in 289 MBC samples to assess their association. Survival analyses were carried out in 112 patients. Survival curves were estimated with the Kaplan-Meier method and compared by log-rank test. Cox proportional regression models were generated to identify variables impacting survival outcomes. The expression of pATR conferred poorer survival outcomes (log rank p = 0.013, p = 0.007 and p = 0.010 for overall, 15- and 10-year survival, respectively). Multivariate Cox models of 10-year survival and overall indicated that pATR expression, alone or combined with pChk2, was an independent predictor of adverse outcomes (10-year survival: pATR: HR 2.74, 95% CI: 1.23-6.10; pATR/pChk2: HR 2.92, 95% CI: 1.35-6.33; overall survival: pATR: HR 2.58, 95% CI: 1.20-5.53; pATR/pChk2: HR 2.89, 95% CI: 1.37-6.12). Overall, the ATR/ATM-initiated molecular cascade seems to be active in a fraction of MBC patients and may represent a negative prognostic factor.
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http://dx.doi.org/10.1038/s41598-017-07366-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556084PMC
August 2017

Neoadjuvant chemotherapy in triple-negative breast cancer: A multicentric retrospective observational study in real-life setting.

J Cell Physiol 2018 Mar 27;233(3):2313-2323. Epub 2017 Sep 27.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

We aimed to assess the efficacy of neoadjuvant chemotherapy (NACT) in a cohort of 213 triple-negative breast cancer (TNBC) patients treated in real-world practice at eight Italian cancer centers. We computed descriptive statistics for all the variable of interest. Factors testing significant in univariate analysis were included in multivariate models. Survival data were compared by Kaplan-Meier curves and log-rank test. The median follow-up was 45 months. We observed 60 (28.2%) pathological complete response (pCR). The sequential anthracyclines-taxanes-based regimens produced the highest rate of pCR (42.6%), followed by concomitant anthracycline-taxane (24.2%), and other regimens (15.6%) (p = 0.008). When analyzing the role of baseline Ki-67, a 50% cut-off was the optimal threshold value for pCR prediction (p = 0.0005). The 5-year disease-free survival (DFS) was 57.3% and the 5-year overall survival (OS) was 70.8%. In patients not achieving pCR, the optimal Ki-67 variation between biopsy and surgical specimen with prognostic relevance on long-term outcomes was 13% (p = 0.04). Patients with a Ki-67 reduction (rKi-67)<13% had worse outcomes compared to those who experienced pCR or a rKi-67≥13%. The number of NACT cycles also affected long-term outcomes (5-year DFS 65.7% vs 51.6% in patients having received >6 cycles compared with their counterparts, p = 0.02). In multivariate analysis, node status, grading, and bio-pathological treatment response (including pCR and rKi-67) impacted DFS and OS. Our results confirmed the advantage conferred by more than 6 cycles of a sequential antracycline-taxane-based NACT. Higher baseline Ki-67 values shows greater predictive significance on pathogical response, while the rKi-67 plays a prognostic role on long-term outcomes.
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http://dx.doi.org/10.1002/jcp.26103DOI Listing
March 2018

GLUT 1 receptor expression and circulating levels of fasting glucose in high grade serous ovarian cancer.

J Cell Physiol 2018 Feb 14;233(2):1396-1401. Epub 2017 Jul 14.

Divisionof Medical Oncology 2, IRCCSRegina Elena National Cancer Institute, Rome, Italy.

In recent years, the poorly remarkable goals achieved in terms of patients' important outcomes for ovarian cancer have fueled our interest toward the study of its metabolic roots. Within this research pipeline, we assessed the association between the expression of the glucose transporter GLUT1, as expressed at the tumor tissue level, and circulating pre-surgical levels of fasting glucose in a case series including data from 40 patients with high FIGO stage serous ovarian cancer. Patients who provided data to the current analysis were randomly selected from a larger cohort. To our purposes, the procedures related to serum and tissue collection, storage and biomarker assessment were highly standardized and centralized at the institutional laboratories. The GLUT1 antibody SPM498 SPRING (REF. E13810) was used at a 1:500 dilution in 2 µm slides. Staining for GLUT1 was observed at the cell membrane level in all the cases assessed, but strong staining was described in 29 (72.5%) of them. The agreement between the two independent reviewers was 100%. Strong GLUT1 staining was inversely associated with circulating levels of fasting glucose, with a particularly striking difference for patients in the lowest fasting glucose tertile (p = 0.044). These results support the biological plausibility of the association of interest. If confirmed in larger studies, our findings may help clarify the potentials of biomarkers related to energy metabolism in terms of prognosis definition, treatment assignment, and outcome interpretation for patients with high FIGO stage serous ovarian cancer.
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http://dx.doi.org/10.1002/jcp.26023DOI Listing
February 2018

ESAS and FACT-B in eribulin-treated metastatic breast cancer patients: a multicenter, prospective and observational study.

Future Oncol 2017 Jul 21;13(17):1517-1525. Epub 2017 Apr 21.

Medical Oncology Unit, ASL Frosinone, Frosinone, Italy.

Aim: Quality of life (QoL) is a critical issue for women with metastatic breast cancer (MBC). Eribulin mesylate represents a novel and active drug for pretreated MBC. Regretfully, few data exploring health-related (HR) QoL are available in unselected populations.

Patients & Methods: A multicenter prospective observational study was conducted in 50 MBC patients treated with eribulin mesylate, in order to evaluate HRQoL and patients' well-being by using the Edmonton symptoms assessment scale (ESAS) and Functional Assessment of Cancer Therapy-Breast questionnaires.

Results: A significant ESAS score improvement was observed with a 10% median decrease. No differences were revealed for the QoL scores.

Conclusion: The analysis of ESAS and Functional Assessment of Cancer Therapy scores showed that eribulin mesylate contributes to preserve QoL in MBC patients.
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http://dx.doi.org/10.2217/fon-2017-0062DOI Listing
July 2017

CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells.

Gut 2018 05 7;67(5):903-917. Epub 2017 Apr 7.

Institute of General Pathology, Catholic University and A. Gemelli Polyclinic, Rome, Italy.

Objective: Cancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies.

Design: To discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein microarray (RPPA) and cytogenetic analyses, and validated by immunostainings. DNA replication stress (RS) was increased by employing DNA replication-perturbing or polyploidising agents.

Results: The drug-library screening led to the identification of LY2606368 as a potent anti-CSC agent acting in vitro and in vivo in tumour cells from a considerable number of patients (∼36%). By inhibiting checkpoint kinase (CHK)1, LY2606368 affected DNA replication in most CRC-SCs, including RAS-mutated ones, forcing them into premature, lethal mitoses. Parallel genomic, RPPA and cytogenetic analyses indicated that CRC-SCs sensitive to LY2606368 displayed signs of ongoing RS response, including the phosphorylation of RPA32 and ataxia telangiectasia mutated serine/threonine kinase (ATM). This was associated with mutation(s) in and hyperdiploidy, and made these CRC-SCs exquisitely dependent on CHK1 function. Accordingly, experimental increase of RS sensitised resistant CRC-SCs to LY2606368.

Conclusions: LY2606368 selectively eliminates replication-stressed, p53-deficient and hyperdiploid CRC-SCs independently of mutational status. These results provide a strong rationale for biomarker-driven clinical trials with LY2606368 in patients with CRC.
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http://dx.doi.org/10.1136/gutjnl-2016-312623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890648PMC
May 2018

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy.

Cancer Biol Ther 2017 05 7;18(5):339-346. Epub 2017 Apr 7.

c Division of Medical Oncology 2 , "Regina Elena" National Cancer Institute , Via Elio Chianesi, Rome , Italy.

The Hippo kinases MST1/2 and LATS1/2 inhibit the oncoproteins TAZ/YAP and regulate T cell function. Hippo kinases also cooperate with the ATR-Chk1 and ATM-Chk2 pathways, central orchestrators of the DNA damage response (DDR). We hypothesized that MST1/2 and LATS1/2 localization differently impacts the efficacy of neoadjuvant therapy (NAT) in breast cancer, being protective when expressed in the cytoplasm of tumor cells and in tumor-infiltrating lymphocytes, whereas representing molecular determinants of chemoresistance when present in the nucleus as a consequence of their cooperation with the DDR. Diagnostic biopsies from 57 HER2-positive and triple-negative breast cancer patients treated with NAT were immunostained for evaluating the expression of phosphorylated MST1/2 (pMST1/2) and LATS1/2 (pLATS1/2) in tumor-infiltrating lymphocytes (TILs) and in cancer cells. TAZ and Chk1 immunostaining was exploited for investigating subcellular compartment-dependent activity of Hippo kinases. Nuclear pMST1/2 (pMST1/2) expression was significantly associated with nuclear expression of Chk1 (p = 0.046), whereas cytoplasmic pMST1/2 (pMST1/2) expression was marginally associated with cytoplasmic TAZ staining (p = 0.053). Patients whose tumors expressed pMST1/2 were at increased risk of residual disease after NAT (pCR ypT0/is ypN0: OR 4.91, 95%CI: 1.57-15.30; pCR ypT0 ypN0: OR 3.59, 95%CI 1.14-11.34). Conversely, exclusive cytoplasmic localization of pMST1/2 (pMST1/2)seemed to be a protective factor (pCR ypT0/is ypN0: OR 0.34, 95%CI: 0.11-1.00; pCR ypT0 ypN0: OR 0.31, 95%CI 0.10-0.93). The subcellular localization-dependent significance of pMST1/2 expression suggests their involvement in different molecular networks with opposite impact on NAT efficacy. Larger studies are warranted to confirm these novel findings.
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http://dx.doi.org/10.1080/15384047.2017.1312230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499753PMC
May 2017

DNA damage repair and survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy.

Int J Cancer 2017 06 11;140(11):2587-2595. Epub 2017 Mar 11.

Division of Medical Oncology 2, "Regina Elena" National Cancer Institute, Rome, Italy.

The DNA damage response (DDR) network is exploited by cancer cells to withstand chemotherapy. Gastric cancer (GC) carries deregulation of the DDR and harbors genetic defects that fuel its activation. The ATM-Chk2 and ATR-Chk1-Wee1 axes are deputed to initiate DNA repair. Overactivation of these pathways in cancer cells may represent an adaptive response for compensating genetic defects deregulating G -S transition (e.g., TP53) and ATM/ATR-initiated DNA repair (e.g., ARID1A). We hypothesized that DDR-linked biomarkers may predict clinical outcomes in GC patients treated with chemotherapy. Immunohistochemical assessment of DDR kinases (pATM, pChk2, pChk1 and pWee1) and DNA damage markers (γ-H2AX and pRPA32) was performed in biological samples from 110 advanced GC patients treated with first-line chemotherapy, either in phase II trials or in routine clinical practice. In 90 patients, this characterization was integrated with targeted ultra-deep sequencing for evaluating the mutational status of TP53 and ARID1A. We recorded a positive association between the investigated biomarkers. The combination of two biomarkers (γ-H2AX /pATM ) was an adverse factor for both progression-free survival (multivariate Cox: HR 2.23, 95%CI: 1.47-3.40) and overall survival (multivariate Cox: HR: 2.07, 95%CI: 1.20-3.58). The relationship between the γ-H2AX /pATM model and progression-free survival was consistent across the different TP53 backgrounds and was maintained in the ARID1A wild-type setting. Conversely, this association was no longer observed in an ARID1A-mutated subgroup. The γ-H2AX /pATM model negatively impacted survival outcomes in GC patients treated with chemotherapy. The mutational status of ARID1A, but apparently not TP53 mutations, affects its predictive significance.
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http://dx.doi.org/10.1002/ijc.30668DOI Listing
June 2017