Publications by authors named "F Schettini"

243 Publications

Poly (ADP-ribose) polymerase inhibitors in solid tumours: Systematic review and meta-analysis.

Eur J Cancer 2021 Apr 13;149:134-152. Epub 2021 Apr 13.

Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy; Breast Cancer Unit, Azienda Socio Sanitaria Territoriale di Cremona, Cremona, Italy.

Background: Poly (ADP-ribose) polymerase-inhibitors (PARPis) showed antitumour activity in BRCA1/2-mutated cancers, with more heterogeneous outcomes in tumours harbouring mutations that impair other genes involved in the DNA homologous recombination repair (HRR) or wild-type (wt).

Methods: We conducted a systematic review and meta-analysis to better assess the role of PARPis in the treatment of metastatic solid tumours, with and without BRCA1/2 mutations. The primary end-point was progression-free survival (PFS). The secondary end-points were overall response rate (ORR) and overall survival (OS). A random-effects model was applied.

Results: Twenty-nine studies (8,839 patients) were included. PFS was significantly improved (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.51-0.68, p < 0.001), without being affected by BRCA mutational status (p = 0.65). Significant subgroup differences were observed with regard to the tumour site (p = 0.001), line of therapy (p = 0.002), control arm (p < 0.001), type of PARPi (p < 0.001) and trials' phase (p = 0.006). PARPis were associated with ORR (relative risk: 1.35, 95% CI: 1.16-1.56, p < 0.001), with significant subgroup differences observed with regard to treatment line (p = 0.03), control arm (p = 0.04) and PARPis (p < 0.001) and independent of mutational status (p = 0.44), tumour site (p = 0.86) and trials' phase (p = 0.09). OS was significantly improved by PARPis (HR: 0.86, 95% CI: 0.80-0.92, p < 0.001), regardless of mutational status (p = 0.57), tumour site (p = 0.82), treatment line (p = 0.22), control arm (p = 0.21), PARPis (p = 0.30) and trials' phase (p = 0.26). Finally, an exploratory subgroup analysis showed a significant PFS improvement (HR: 0.51, 95% CI: 0.43-0.60, p < 0.001) with PARPis in BRCA-wt/HRR-deficient tumours.

Conclusion: Our results confirm the efficacy of already approved PARPi-based treatments in BRCA1/2-mutant solid tumours, support their role also in BRCA-independent HRR-deficient tumours and suggest a potentially broader efficacy in some wt tumours, perhaps with appropriate therapeutic partners. Prospective studies are warranted.
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http://dx.doi.org/10.1016/j.ejca.2021.02.035DOI Listing
April 2021

Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer.

ESMO Open 2021 Apr 7;6(3):100102. Epub 2021 Apr 7.

Department of Hematology, Hospital Clinic, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Electronic address:

Background: Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody-drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation.

Methods: We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets.

Results: We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database.

Conclusions: Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC.
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http://dx.doi.org/10.1016/j.esmoop.2021.100102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038941PMC
April 2021

T-DM1 versus pertuzumab, trastuzumab and a taxane as first-line therapy of early-relapsed HER2-positive metastatic breast cancer: an Italian multicenter observational study.

ESMO Open 2021 Apr 2;6(2):100099. Epub 2021 Apr 2.

Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genoa, Italy; U.O.S.D. Breast Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Background: The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting.

Patients And Methods: We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian 'real-world' setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant.

Results: Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095).

Conclusions: Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials.
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http://dx.doi.org/10.1016/j.esmoop.2021.100099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047485PMC
April 2021

Endocrine-Based Treatments in Clinically-Relevant Subgroups of Hormone Receptor-Positive/HER2-Negative Metastatic Breast Cancer: Systematic Review and Meta-Analysis.

Cancers (Basel) 2021 Mar 22;13(6). Epub 2021 Mar 22.

Department of Medical, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy.

A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted a systematic literature search to identify all first-/second-line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET ± TT. Then, we performed a meta-analysis to assess progression-free (PFS) and/or overall survival (OS) benefit in several clinically-relevant prespecified subgroups. Thirty-five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26-41% and 12-27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single-agent ET (PFS hazard ratio (HR) range for combinations: 0.60-0.65 vs. HR range for single agent ET: 0.59-1.37; OS HR range for combinations: 0.74-0.87 vs. HR range for single agent ET: 0.68-0.98), with CDK4/6-inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in non-visceral ( = 0.63) and endocrine sensitive disease ( = 0.79), while mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision-making.
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http://dx.doi.org/10.3390/cancers13061458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004645PMC
March 2021

Circulating tumor DNA dynamics in advanced breast cancer treated with CDK4/6 inhibition and endocrine therapy.

NPJ Breast Cancer 2021 Feb 3;7(1). Epub 2021 Feb 3.

SOLTI Cancer Research Group, Barcelona, Spain.

Circulating tumor DNA (ctDNA) levels may predict response to anticancer drugs, including CDK4/6 inhibitors and endocrine therapy combinations (CDK4/6i+ET); however, critical questions remain unanswered such as which assay or statistical method to use. Here, we obtained paired plasma samples at baseline and week 4 in 45 consecutive patients with advanced breast cancer treated with CDK4/6i+ET. ctDNA was detected in 96% of cases using the 74-gene Guardant360 assay. A variant allele fraction ratio (VAFR) was calculated for each of the 79 detected mutations between both timepoints. Mean of all VAFRs (mVAFR) was computed for each patient. In our dataset, mVAFR was significantly associated with progression-free survival (PFS). Baseline VAF, on-treatment VAF or absolute changes in VAF were not associated with PFS, nor were CA-15.3 levels at baseline, week 4 or the CA-15.3 ratio. These findings demonstrate that ctDNA dynamics using a standardized multi-gene panel and a unique methodological approach predicts treatment outcome. Clinical trials in patients with an unfavorable ctDNA response are needed.
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http://dx.doi.org/10.1038/s41523-021-00218-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859394PMC
February 2021