Publications by authors named "Angelo Di Leo"

186 Publications

Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update.

J Clin Oncol 2021 Jul 29:JCO2101374. Epub 2021 Jul 29.

UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC.

Purpose: This guideline updates recommendations of the ASCO guideline on chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) that is either endocrine-pretreated or hormone receptor (HR)-negative.

Methods: An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations.

Results: The Expert Panel reviewed abstracts from the literature review and retained 14 articles.

Recommendations: Patients with triple-negative, programmed cell death ligand-1-positive MBC may be offered the addition of immune checkpoint inhibitor to chemotherapy as first-line therapy. Patients with triple-negative, programmed cell death ligand-1-negative MBC should be offered single-agent chemotherapy rather than combination chemotherapy as first-line treatment, although combination regimens may be offered for life-threatening disease. Patients with triple-negative MBC who have received at least two prior therapies for MBC should be offered treatment with sacituzumab govitecan. Patients with triple-negative MBC with germline mutations previously treated with chemotherapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. Patients with HR-positive human epidermal growth factor receptor 2-negative MBC for whom chemotherapy is being considered should be offered single-agent chemotherapy rather than combination chemotherapy, although combination regimens may be offered for highly symptomatic or life-threatening disease. Patients with HR-positive MBC with disease progression on an endocrine agent may be offered treatment with either endocrine therapy with or without targeted therapy or single-agent chemotherapy. Patients with HR-positive MBC with germline mutations no longer benefiting from endocrine therapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. No recommendation regarding when a patient's care should be transitioned to hospice or best supportive care alone is possible.Additional information is available at www.asco.org/breast-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.21.01374DOI Listing
July 2021

The prognostic relevance of HER2-positivity gain in metastatic breast cancer in the ChangeHER trial.

Sci Rep 2021 07 2;11(1):13770. Epub 2021 Jul 2.

Department of Ematology and Oncology, Pugliese-Ciaccio Hospital, Catanzaro, Italy.

In metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2-positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p < 0.0001 and p = 0.006, respectively). HER2-discordant tumors were characterized also by a lower rate of brain metastases (p = 0.01) and a longer disease free interval (p < 0.0001). Median overall survival was longer, although not statistically significant, in the subgroup of patients with HER2-discordant cancer with respect to patients with HER2-concordant status (140 vs 78 months, p = 0.07). Our findings suggest that patients with HER2-positive mBC with discordant HER2 status in early BC may have different clinical, biological and prognostic behavior compared to HER2-concordant patients.
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http://dx.doi.org/10.1038/s41598-021-92774-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253801PMC
July 2021

A Serum Metabolomics Classifier Derived from Elderly Patients with Metastatic Colorectal Cancer Predicts Relapse in the Adjuvant Setting.

Cancers (Basel) 2021 Jun 2;13(11). Epub 2021 Jun 2.

Department of Medical Oncology, New Hospital of Prato S. Stefano, 59100 Prato, Italy.

Adjuvant treatment for patients with early stage colorectal cancer (eCRC) is currently based on suboptimal risk stratification, especially for elderly patients. Metabolomics may improve the identification of patients with residual micrometastases after surgery. In this retrospective study, we hypothesized that metabolomic fingerprinting could improve risk stratification in patients with eCRC. Serum samples obtained after surgery from 94 elderly patients with eCRC (65 relapse free and 29 relapsed, after 5-years median follow up), and from 75 elderly patients with metastatic colorectal cancer (mCRC) obtained before a new line of chemotherapy, were retrospectively analyzed via proton nuclear magnetic resonance spectroscopy. The prognostic role of metabolomics in patients with eCRC was assessed using Kaplan-Meier curves. PCA-CA-kNN could discriminate the metabolomic fingerprint of patients with relapse-free eCRC and mCRC (70.0% accuracy using NOESY spectra). This model was used to classify the samples of patients with relapsed eCRC: 69% of eCRC patients with relapse were predicted as metastatic. The metabolomic classification was strongly associated with prognosis (-value 0.0005, HR 3.64), independently of tumor stage. In conclusion, metabolomics could be an innovative tool to refine risk stratification in elderly patients with eCRC. Based on these results, a prospective trial aimed at improving risk stratification by metabolomic fingerprinting (LIBIMET) is ongoing.
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http://dx.doi.org/10.3390/cancers13112762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199587PMC
June 2021

Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative.

Cancer Discov 2021 Jun 28. Epub 2021 Jun 28.

Sahlgrenska University Hospital, Gothenburg, Sweden.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for and somatic mutations. Metastases were enriched in , and mutations; and amplifications; and deletions. An increase in clonality was observed in driver genes such as and . Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with and/or mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR/HER2 cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. SIGNIFICANCE: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1647DOI Listing
June 2021

Circulating Biomarkers of CDK4/6 Inhibitors Response in Hormone Receptor Positive and HER2 Negative Breast Cancer.

Cancers (Basel) 2021 May 27;13(11). Epub 2021 May 27.

"Sandro Pitigliani" Translational Research Unit, Hospital of Prato, Azienda USL Toscana Centro, 59100 Prato, Italy.

CDK4/6 inhibitors (CDK4/6i) and endocrine therapy are the standard treatment for patients with hormone receptor-positive and HER2 negative (HR+/HER2-) metastatic breast cancer. Patients might show intrinsic and acquired resistance, which leads to treatment failure and progression. Circulating biomarkers have the potential advantages of recognizing patients who might not respond to treatment, monitoring treatment effects and identifying markers of acquired resistance during tumor progression with a simple withdrawal of peripheral blood. Genomic alterations on circulating tumor DNA and serum thymidine kinase activity, but also circulating tumor cells, epigenetic or exosome markers are currently being tested as markers of CDK4/6i treatment response, even though none of these have been integrated into clinical practice. In this review, we discuss the recent advancements in the development of circulating biomarkers of CDK4/6i response in patients with HR+/HER2-breast cancer.
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http://dx.doi.org/10.3390/cancers13112640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199335PMC
May 2021

Heparanase: a potential marker of worse prognosis in estrogen receptor-positive breast cancer.

NPJ Breast Cancer 2021 May 28;7(1):67. Epub 2021 May 28.

Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Heparanase promotes tumor growth in breast tumors. We now evaluated heparanase protein and gene-expression status and investigated its impact on disease-free survival in order to gain better insight into the role of heparanase in ER-positive (ER+) breast cancer prognosis and to clarify its role in cell survival following chemotherapy. Using pooled analysis of gene-expression data, we found that heparanase was associated with a worse prognosis in estrogen receptor-positive (ER+) tumors (log-rank p < 10) and predictive to chemotherapy resistance (interaction p = 0.0001) but not hormonal therapy (Interaction p = 0.62). These results were confirmed by analysis of data from a phase III, prospective randomized trial which showed that heparanase protein expression is associated with increased risk of recurrence in ER+ breast tumors (log-rank p = 0.004). In vitro experiments showed that heparanase promoted tumor progression and increased cell viability via epithelial-mesenchymal transition, stemness, and anti-apoptosis pathways in luminal breast cancer. Taken together, our results demonstrated that heparanase is associated with worse outcomes and increased cell viability in ER+ BC.
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http://dx.doi.org/10.1038/s41523-021-00277-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163849PMC
May 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 cells and palbociclib treatment in patients with ER-positive, HER2-negative advanced breast cancer: results from a translational sub-study of the TREnd trial.

Breast Cancer Res 2021 03 24;23(1):38. Epub 2021 Mar 24.

"Sandro Pitigliani" Translational Research Unit, Hospital of Prato, Prato, Italy.

Background: Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation.

Methods: Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood samples were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. Samples with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR.

Results: All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 (n = 26) had a worse PFS than those with 0 CTCs (n = 16) (p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, (p = 0.004). Finally, patients with ≥ 5 CTCs at T2 (n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF (p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels.

Conclusions: CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied sample size.
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http://dx.doi.org/10.1186/s13058-021-01415-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992319PMC
March 2021

Meta-analyses of visceral versus non-visceral metastatic hormone receptor-positive breast cancer treated by endocrine monotherapies.

NPJ Breast Cancer 2021 Feb 12;7(1):11. Epub 2021 Feb 12.

Biostatistics, Frontier Science, Kincraig, Scotland, UK.

Endocrine therapy (ET) is recommended as first-line therapy for the majority of patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative advanced breast cancer (ABC); however, the efficacy of ET in patients with visceral metastases (VM) versus patients whose disease is limited to non-visceral metastases (non-VM) is debated. Meta-analyses including available data from randomised controlled trials of first- and second-line endocrine monotherapies for patients with HR+ ABC were performed to address this question. In one and two-stage meta-analyses, progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and duration of clinical benefit (DoCB) outcomes were analysed. In the first-line meta-analysis (seven trials; n = 1988) tamoxifen and fulvestrant significantly improved PFS, OS and CBR for patients with non-VM versus those whose disease included VM. The most substantial hazard ratios were observed for fulvestrant 500 mg; 0.56 (95% confidence interval [CI] 0.45-0.70) and 0.55 (95% CI 0.42-0.72) for PFS and OS, respectively. In the second-line meta-analysis (seven trials; n = 2324), all ET combined was more effective (in terms of PFS, OS and DoCB) for non-VM versus VM. In both meta-analyses, patients with non-liver VM had better clinical outcomes than patients with liver VM for all types of ET. Patients whose disease included non-VM sites had better clinical outcomes with endocrine monotherapy compared with patients whose disease included VM. These findings may facilitate better informed treatment decision-making.
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http://dx.doi.org/10.1038/s41523-021-00222-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881093PMC
February 2021

CDK4/6 inhibitors: A focus on biomarkers of response and post-treatment therapeutic strategies in hormone receptor-positive HER2-negative breast cancer.

Cancer Treat Rev 2021 Feb 7;93:102136. Epub 2020 Dec 7.

"Sandro Pitigliani" Translational Research Unit, Hospital of Prato, Azienda USL Toscana Centro, Prato, Italy; "Sandro Pitigliani" Department of Medical Oncology, Hospital of Prato, Azienda USL Toscana Centro, Prato, Italy.

CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy are the mainstay of treatment for patients with hormone receptor-positive, HER2 negative (HR+/HER2neg) metastatic breast cancer. However, resistance - either de novo or acquired - invariably occurs, leading to treatment failure and cancer progression. Genomic alterations, gene expression data and circulating biomarkers have been correlated to response to treatment, but to date no biomarker has been approved to stratify patients. Treatment strategies after progression on CDK4/6i are yet to be standardized. Current approaches include endocrine therapy alone or in combination with target therapy, or chemotherapy. New agents are in clinical development based on potential mechanisms of acquired resistance. Here we will review recent advancements in biomarkers of response to CDK4/6i, and in post- treatment therapeutic strategies.
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http://dx.doi.org/10.1016/j.ctrv.2020.102136DOI Listing
February 2021

Cell-Free DNA-Methylation-Based Methods and Applications in Oncology.

Biomolecules 2020 12 15;10(12). Epub 2020 Dec 15.

Bioinformatics Unit, Hospital of Prato, 59100 Prato, Italy.

Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm being more prevalent, pervasive, and cell- and tumor-type specific than genomics, for which established cfDNA assays already exist. Herein, we report on recent advances on experimental strategies for the analysis of DNAm in cfDNA samples. We describe the main steps of DNAm-based analysis workflows, including pre-analytics of cfDNA samples, DNA treatment, assays for DNAm evaluation, and methods for data analysis. We report on protocols, biomolecular techniques, and computational strategies enabling DNAm evaluation in the context of cfDNA analysis, along with practical considerations on input sample requirements and costs. We provide an overview on existing studies exploiting cell-free DNAm biomarkers for the detection and monitoring of cancer in early and advanced settings, for the evaluation of drug resistance, and for the identification of the cell-of-origin of tumors. Finally, we report on DNAm-based tests approved for clinical use and summarize their performance in the context of liquid biopsy.
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http://dx.doi.org/10.3390/biom10121677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765488PMC
December 2020

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

Clinical behavior of recurrent hormone receptor-positive breast cancer by adjuvant endocrine therapy within the Breast International Group 1-98 clinical trial.

Cancer 2021 03 8;127(5):700-708. Epub 2020 Dec 8.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Endocrine therapy resistance is a major cause of distant recurrence (DR) in hormone receptor-positive breast cancer. This study evaluated differences in survival after DR in patients treated with different adjuvant endocrine therapy regimens in the Breast International Group (BIG) 1-98 trial.

Methods: BIG 1-98 compared 5 years of adjuvant treatment among 4 arms: tamoxifen (T), letrozole (L), tamoxifen followed by letrozole (TL), and letrozole followed by tamoxifen (LT). After a median follow-up of 8.1 years, 911 of 8010 patients (T, 302; L, 285; TL, 170; and LT, 154) had DR as the site of first recurrence. Univariate and multivariate Cox analyses were performed to determine features associated with post-DR survival.

Results: The median follow-up time after DR was 59 months (interquartile range, 29-88 months). Among all patients with DR, 38.1% were 65 years old or older at enrollment, 61.9% had tumors larger than 2 cm, and 69.7% were node positive. Neoadjuvant or adjuvant chemotherapy was administered to 35.6% of the patients. There was no difference in post-DR survival by treatment arm (median survival, 20.8 months for T, 17.9 months for L, 17.3 months for TL, and 20.8 months for LT; P = .21). In multivariate analysis, older patients (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.15-1.59) and patients with tumors larger than 2 cm (HR, 1.19; 95% CI, 1.00-1.41), 4 or more positive nodes (HR, 1.31; 95% CI, 1.05-1.64), progesterone receptor (PR)-negative tumors (HR, 1.25; 95% CI, 1.02-1.52), or shorter disease-free survival (DFS) had significantly worse post-DR survival.

Conclusions: Treatment with adjuvant T, L, or their sequences was not associated with differences in survival after DR. Significant differences in survival were observed by age, primary tumor size, nodal and PR status, and DFS, and this suggests that traditional baseline high-risk features remain prognostic in the metastatic setting.
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http://dx.doi.org/10.1002/cncr.33318DOI Listing
March 2021

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

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

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

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

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

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

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

Catheterization laboratory activity before and during COVID-19 spread: A comparative analysis in Piedmont, Italy, by the Italian Society of Interventional Cardiology (GISE).

Int J Cardiol 2021 01 25;323:288-291. Epub 2020 Aug 25.

Division of Cardiology, Azienda Ospedaliera Ordine Mauriziano, Turin, Italy.

Background: COronaVIrus Disease 19 (COVID-19) led to the reorganization of Cardiology Units in terms of working spaces and healthcare personnel. In this scenario, both outpatient visits and elective interventional cardiology procedures were suspended and/or postponed. We aimed to report the impact of COVID-19 on interventional coronary and structural procedures in Piedmont, Italy.

Methods: The number of coronary angiographies (CAG), percutaneous coronary interventions (PCI), primary PCI (pPCI), transcatheter aortic valve replacements (TAVR) and Mitraclip performed in Piedmont between March 1st and April 20th, 2020 (CoV-time) were collected from each catheterization laboratory and compared to the number of procedures performed the year before in the same months (NoCoV-time).

Results: Procedural data from 18 catheterization laboratories were collected. Both coronary (5498 versus 2888: difference: -47.5%; mean 305.4 VS 160.4; p = 0.002) and structural (84 versus 17: difference: -79.8%; mean 4.7 Vs 0.9; p < 0.001) procedures decreased during CoV-time compared to NoCoV-time. In particular, coronary angiographies (1782 versus 3460), PCI (1074 versus 1983), p PCI (271 versus 410), TAVR (11 versus 72) and Mitraclip (6 versus 12) showed a reduction of 48.5%, 45.7%, 33.7%, 84.7% and 50.0%, respectively (all p for comparison <0.05).

Conclusions: Compared to the same time-period in 2019, both coronary and structural interventional procedures during COVID-19 epidemic suffered a dramatic decrease in Piedmont, Italy. Organizational change and structured clinical pathways should be created, together with awareness campaigns.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446645PMC
January 2021

Differential Benefit of Adjuvant Docetaxel-Based Chemotherapy in Patients With Early Breast Cancer According to Baseline Body Mass Index.

J Clin Oncol 2020 09 2;38(25):2883-2891. Epub 2020 Jul 2.

Unit of Medical Statistics, Biometry and Bioinformatics Giulio A. Maccacaro Department of Clinical Sciences and Community Health & DSRC, University of Milan, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Purpose: Lipophilic drugs, such as taxanes, have a high affinity for adipose tissue and a resulting higher volume of distribution. Here, we reanalyzed clinical trial data to investigate whether the efficacy of docetaxel-based chemotherapy differs from non-docetaxel-based chemotherapy in patients with breast cancer according to their baseline body mass index (BMI).

Patients And Methods: We retrospectively analyzed data from all of the patients in the adjuvant BIG 2-98 trial (ClinicalTrials.gov identifier: NCT00174655; N = 2,887) comparing non-docetaxel- to docetaxel-containing chemotherapy. BMI (kg/m) was categorized as follows: 18.5 to < 25, lean; 25 to < 30, overweight; and ≥ 30, obese. Disease-free survival (DFS) was the primary endpoint, and overall survival (OS) was the secondary endpoint. A second-order interaction was assessed among treatment, BMI, and estrogen receptor (ER) status.

Results: There was no difference in DFS or OS according to BMI in the non-docetaxel group, while reduced DFS and OS were observed with increasing BMI category in the docetaxel group. Adjusted hazard ratios for DFS and OS were, respectively, 1.12 (95% CI, 0.98 to 1.50; = .21) and 1.27 (95% CI, 1.01 to 1.60; = .04) for overweight versus lean groups and were 1.32 (95% CI, 1.08 to 1.62; = .007) and 1.63 (95% CI, 1.27 to 2.09; < .001), respectively, for obese versus lean groups. Similar results were obtained when considering ER-negative and ER-positive tumors separately and when considering only patients who received a relative dose intensity ≥ 85% for docetaxel. A joint modifying role of BMI and ER status on treatment effect was evident for DFS (adjusted = .06) and OS (adjusted = .04).

Conclusion: This retrospective analysis of a large adjuvant trial highlights a differential response to docetaxel according to BMI, which calls for a body composition-based re-evaluation of the risk-benefit ratio of the use of taxanes in breast cancer. These results now must be confirmed in additional series.
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http://dx.doi.org/10.1200/JCO.19.01771DOI Listing
September 2020

Real-World Experience With a Tapered Biodegradable Polymer-Coated Sirolimus-Eluting Stent in Patients With Long Coronary Artery Stenoses.

Cardiol Res 2020 Aug 3;11(4):219-225. Epub 2020 Jun 3.

Department of Cardiology, Ospedale Civile, Cirie, Italy.

Background: Treatment of long coronary stenoses (LCS) with long tapered drug-eluting stents (LT-DES) would offer clinical and economic benefits. However, the feasibility of an interventional strategy based upon the systematic LCS treatment with an LT-DES has not been evaluated so far.

Methods: We performed a multicenter prospective study including consecutive patients with: 1) An LCS > 25 mm at coronary angiography; 2) An attempt to fix the LCS with a single BioMime Morph™ stent, a novel LT-DES available from 30 to 60 mm long. The primary efficacy endpoint was procedural success. The secondary safety endpoints were post-procedural TIMI3 flow, stent detachment during delivery, acute stent thrombosis and in-hospital mortality.

Results: From February 2017 to March 2018, we recorded 272 patients with an LCS and an attempt to deploy an LT-DES during percutaneous coronary intervention (PCI) (69.3 ± 11.4 years, 75.7% males, 25.7% diabetic and 43.8% with acute coronary syndromes, mean LCS length 48.8 ± 9.5 mm). LT-DES deployment was successful in 262 patients (96.3%), and failure occurred without stent detachment or other complications. Final TIMI3 flow was present in 270 (99.3%) patients. In-hospital death occurred in five patients (1.8%), with no case of acute stent thrombosis, recurrent myocardial infarction or repeated revascularization.

Conclusion: In this real-world study, a strategy of fixing LCS with a single LT-DES was feasible and safe, with a high rate of procedural success and a low rate of in-hospital complications. More extensive randomized studies are warranted to assess the potential clinical and economic benefits of LT-DES.
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http://dx.doi.org/10.14740/cr1055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295557PMC
August 2020

Estimation of historical control rate for a single arm de-escalation study - Application to the POSITIVE trial.

Breast 2020 Oct 2;53:1-7. Epub 2020 Jun 2.

International Breast Cancer Study Group Statistical Center, Department of Data Sciences, Division of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA. Electronic address:

Background: Although randomized controlled clinical trials are optimal to evaluate the effect of an experimental therapy, single-arm trials are required whenever randomization is unethical or not feasible, such as de-escalation studies. We propose using prospectively identified historical controls to place results of single-arm, de-escalation trials into context.

Methods: POSITIVE is a prospective, single-arm study in young women with hormone-receptor-positive early breast cancer to determine if temporarily interrupting adjuvant endocrine therapy in order to become pregnant increases the risk of a breast cancer event. After 272 women enrolled in POSITIVE, we identified a cohort of 1499 SOFT/TEXT patients potentially eligible to enroll in POSITIVE who did not interrupt endocrine therapy. Method I used the SOFT/TEXT cohort to calculate annualized hazard rates by a piecewise exponential model. Method II used the SOFT/TEXT cohort to group-match SOFT/TEXT patients to POSITIVE patients; sample sets of SOFT/TEXT patients were randomly drawn 5000 times to obtain sets having patient, disease, and treatment characteristics more balanced with POSITIVE participants.

Results: Compared with SOFT/TEXT, POSITIVE participants were younger, less likely to be overweight/obese, had fewer positive nodes, and fewer received aromatase inhibitor or chemotherapy. The estimated 3-year breast cancer free interval event rates were 9.5% (95% CI: 7.9%,11.1%) for Method I and 9.4% (95% CI: 7.8%,10.9%) for Method II, compared with 5.8% initially assumed when POSITIVE was designed.

Conclusion: External control datasets should be identified before launching single-arm, de-escalation trials and methods applied during their conduct to provide context for interim monitoring and interpretation of the final analysis.
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http://dx.doi.org/10.1016/j.breast.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375555PMC
October 2020

Overall Survival of CDK4/6-Inhibitor-Based Treatments in Clinically Relevant Subgroups of Metastatic Breast Cancer: Systematic Review and Meta-Analysis.

J Natl Cancer Inst 2020 11;112(11):1089-1097

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

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors + endocrine therapy (ET) prolonged progression-free survival as first- or second-line therapy for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer prognosis. Given the recent publication of overall survival (OS) data for the 3 CDK4/6-inhibitors, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups.

Methods: We conducted a systematic literature search to select all available phase II or III randomized clinical trials of CDK4/6-inhibitors + ET reporting OS data in first- or second-line therapy of HR+/HER2-negative pre- or postmenopausal metastatic breast cancer. A random effect model was applied for the analyses. Heterogeneity was assessed with I2statistic. Subgroup analysis was performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP).

Results: Six studies were included in our analyses (3421 patients). A clear OS benefit was observed in patients without (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.54 to 0.85, I2 = 0.0%) and with visceral involvement (HR = 0.76, 95% CI = 0.65 to 0.89, I2 = 0.0%), with at least 3 metastatic sites (HR = 0.75, 95% CI = 0.60 to 0.94, I2 = 11.6%), in an endocrine-resistant (HR = 0.79, 95% CI = 0.67 to 0.93, I2 = 0.0%) and sensitive subset (HR = 0.73, 95% CI = 0.61 to 0.88, I2 = 0.0%), for younger than 65 years (HR = 0.80, 95% CI = 0.67 to 0.95, I2 = 0.0%) and 65 years or older (HR = 0.71, 95% CI = 0.53 to 0.95, I2 = 44.4%), in postmenopausal (HR = 0.76, 95% CI = 0.67 to 0.86, I2 = 0.0%) and pre- or perimenopausal setting (HR = 0.76, 95% CI = 0.60 to 0.96, I2 = 0.0%) as well as in chemotherapy-naïve patients (HR = 0.72, 95% CI = 0.55 to 0.93, I2 = 0.0%).

Conclusions: CDK4/6-inhibitors + ET combinations compared with ET alone improve OS independent of age, menopausal status, endocrine sensitiveness, and visceral involvement and should be preferred as upfront therapy instead of endocrine monotherapy.
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http://dx.doi.org/10.1093/jnci/djaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669227PMC
November 2020

Treatment-induced symptoms, depression and age as predictors of sexual problems in premenopausal women with early breast cancer receiving adjuvant endocrine therapy.

Breast Cancer Res Treat 2020 Jun 9;181(2):347-359. Epub 2020 Apr 9.

International Breast Cancer Study Group (IBCSG) Coordinating Center, Effingerstrasse 40, 3008, Bern, Switzerland.

Purpose: Sexual dysfunction is an important concern of premenopausal women with early breast cancer. We investigated predictors of sexual problems in two randomized controlled trials.

Methods: A subset of patients enrolled in TEXT and SOFT completed global and symptom-specific quality-of-life indicators, CES-Depression and MOS-Sexual Problems measures at baseline, six, 12 and 24 months. Mixed models tested the association of changes in treatment-induced symptoms (baseline to 6 months), depression at 6 months, and age at randomization with changes in sexual problems over 2 years.

Results: Sexual problems increased by 6 months and persisted at this level. Overall, patients with more severe worsening of vaginal dryness, sleep disturbances and bone or joint pain at 6 months reported a greater increase in sexual problems at all time-points. Depression scores were significantly associated with sexual problems in the short-term. All other symptoms had a smaller impact on sexual problems. Age was not associated with sexual problems at any time-point.

Conclusion: Among several key symptoms, vaginal dryness, sleep disturbance, and bone and joint pain significantly predicted sexual problems during the first 2 years. Early identification of these symptoms may contribute to timely and tailored interventions.
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http://dx.doi.org/10.1007/s10549-020-05622-5DOI Listing
June 2020

WorldwIde SurvEy on Clinical and Anatomical Factors Driving the Choice of Transcatheter Aortic Valve pRostheses.

Front Cardiovasc Med 2020 20;7:38. Epub 2020 Mar 20.

Division of Cardiac Surgery, Cardiocentro Ticino, Lugano, Switzerland.

Following the success of the first human transcatheter aortic valve replacement (TAVR) in 2002, multiple transcatheter heart valves (THVs) have become available. However, guidelines or expert consensus on how to optimize THV choice according to patients' anatomical and clinical characteristics is missing. This survey-based study aimed to identify patient-specific characteristics deemed important in the choice of THV type. A web-based survey including 39 questions was completed by 71 experienced TAVR operators from 23 countries with a median TAVR volume of 88 procedures in the year prior to survey completion (IQR 61-180). The survey covered five topics: access, aortic annulus/leaflets, aortic root, left ventricular function and clinical characteristics. Factors with the most impact on THV choice were reported to be a calcified sinotubular junction, valve-in-valve procedure, annular dimension >575 mm, femoral diameter ≤ 5.0 mm, low coronary ostia, calcification at the annular level and/or protruding into the left ventricular outflow tract, and need for post TAVR PCI. Also, in case of off-label use of THVs to treat bicuspid aortic valve disease and isolated aortic regurgitation, the choice of THV type was reported to be important. This survey-based study identifies key patient characteristics that impact THV selection. As such, we present a guide, based on current practice, of which THV types are best suited to these different patient-specific characteristics. A patient-tailored THV choice is likely to optimize TAVR outcomes.
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http://dx.doi.org/10.3389/fcvm.2020.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098951PMC
March 2020

Plasma Thymidine Kinase Activity as a Biomarker in Patients with Luminal Metastatic Breast Cancer Treated with Palbociclib within the TREnd Trial.

Clin Cancer Res 2020 05 14;26(9):2131-2139. Epub 2020 Jan 14.

"Sandro Pitigliani" Medical Oncology Department, Hospital of Prato, Azienda USL Toscana Centro, Prato, Italy.

Purpose: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both and in patients with ABC.

Experimental Design: Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor-positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the "To Reverse ENDocrine Resistance" (TREnd) trial ( = 46).

Results: Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients ( = 8) showing an increase-correlating with a worse outcome than those with decreased/stable TKa ( = 33; mPFS 3.0 vs 9.0 months; = 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months; = 0.05).

Conclusions: TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3271DOI Listing
May 2020

An RB-1 loss of function gene signature as a tool to predict response to neoadjuvant chemotherapy plus anti-HER2 agents: a substudy of the NeoALTTO trial (BIG 1-06).

Ther Adv Med Oncol 2019 11;11:1758835919891608. Epub 2019 Dec 11.

Sandro Pitigliani Medical Oncology Department, Hospital of Prato, Prato, Italy.

Background: Chemotherapy added to anti-HER2 agents (H) is the treatment of choice in patients with HER2+ early breast cancer. However, HER2+ tumours are clinically and biologically heterogeneous, and treatment response varies significantly by hormone receptor (HR) status and molecular subtype. Predictive biomarkers are needed in this context. This study assessed whether an RB-1 loss of function gene signature (RBsig) is predictive of response to neoadjuvant chemotherapy in combination with trastuzumab, lapatinib or both, within the NeoALTTO trial.

Methods: We collected RNA-sequencing data from pretreatment biopsies derived from the NeoALTTO trial. RBsig expression was computed retrospectively and correlated with pathological complete response (pCR) using receiver-operating characteristic (ROC) curves. The RBsig was dichotomised as High/Low in correspondence to the 25th percentile. Reported values resulted from Fisher's exact test.

Results: Of 455 NeoALTTO patients, 244 were eligible for this substudy (HR+  = 129; HR-  = 115). Overall, pCR rate was significantly higher in patients with RBsig High tumours than those with RBsig Low (35% 18% respectively;  = 0.01). The area under the ROC curve (AUC) was 0.60 (95% CI 0.52-0.67). A remarkably low pCR rate of 11% was seen in HR+/RBsig Low patients 28% in HR+/RBsig High.

Conclusions: These results indicate RBsig may add valuable information to HER2 and HR expression, which may in turn inform treatment choices. HR+/HER2+/RBsig Low breast cancers exhibited the poorest pathological response following chemotherapy plus H. Accordingly, in such patients, endocrine therapy in combination with H and, possibly, a CDK4/6 inhibitor, may potentially prove to be a more effective treatment.
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http://dx.doi.org/10.1177/1758835919891608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906346PMC
December 2019

Estimating the magnitude of clinical benefit from (neo)adjuvant chemotherapy in patients with ER-positive/HER2-negative breast cancer.

Breast 2019 Nov;48 Suppl 1:S81-S84

"Sandro Pitigliani" Department of Medical Oncology, Hospital of Prato, Prato, Italy. Electronic address:

Gene-expression assays were originally validated retrospectively as tools of prognostication, with evidence emerging from more recent prospectively-conducted studies such as MINDACT and TAILORx supporting their clinical validity and utility as biomarkers in identifying patients with luminal breast cancer who might be spared chemotherapy. However, these assays still do not have the ability to identify all patients who may safely avoid chemotherapy, and may over-estimate the risk of relapse in some cases. Future studies should aim to prospectively integrate contemporary approaches that assume a theoretical risk of relapse (based on pathological and/or genomic evaluation of the primary tumour), with new tools that can detect signals of active micro-metastatic disease. Until current methods of estimating prognosis and predicting benefit from adjuvant chemotherapy are significantly refined, estimating and improving the true magnitude of benefit derived from chemotherapy remains a challenge for clinicians.
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http://dx.doi.org/10.1016/S0960-9776(19)31130-0DOI Listing
November 2019

The Emerging Role of Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy.

Cancers (Basel) 2019 Nov 28;11(12). Epub 2019 Nov 28.

"Sandro Pitigliani" Medical Oncology Department, Hospital of Prato, 59100 Prato, Italy.

Mutations in the hotspot ligand-binding domain of the estrogen receptor (ER) gene have recently been recognized as mechanisms of endocrine resistance in endocrine receptor-positive metastatic breast cancer (MBC). Accumulating data suggest these mutations develop under the selective pressure of endocrine treatments, and are infrequent in untreated ER-positive breast cancers. In vitro studies show that these mutations confer ligand-independent activity, resistance to estrogen deprivation, and relative resistance to tamoxifen and fulvestrant. Post-hoc retrospective and prospective analyses of mutations in patients with MBC have consistently found that these mutations are markers of poor prognosis and predict resistance to aromatase inhibitors (AIs). These results warrant further investigation and prospective validation in dedicated studies. Moreover, studies are ongoing to clarify the activity of novel drugs in the context of metastatic endocrine resistant luminal breast cancer harboring mutations. In this review, we summarize the pre-clinical and clinical findings defining the characteristics of mutant breast cancer, and highlight the potential clinical developments in this field.
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http://dx.doi.org/10.3390/cancers11121894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966519PMC
November 2019

Absolute Improvements in Freedom From Distant Recurrence to Tailor Adjuvant Endocrine Therapies for Premenopausal Women: Results From TEXT and SOFT.

J Clin Oncol 2020 04 16;38(12):1293-1303. Epub 2019 Oct 16.

International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Purpose: The Tamoxifen and Exemestane Trial (TEXT)/Suppression of Ovarian Function Trial (SOFT) showed superior outcomes for premenopausal women with hormone receptor (HR)-positive breast cancer treated with adjuvant exemestane plus ovarian function suppression (OFS) or tamoxifen plus OFS versus tamoxifen alone. We previously reported the magnitude of absolute improvements in freedom from any recurrence across a continuous, composite measure of recurrence risk to tailor decision making. With longer follow-up, we now focus on distant recurrence.

Methods: The TEXT/SOFT HR-positive/human epidermal growth factor receptor 2 (HER2)-negative analysis population included 4,891 women stratified by predetermined chemotherapy use. Kaplan-Meier estimates of 8-year freedom from distant recurrence were analyzed using subpopulation treatment effect pattern plot (STEPP) methodology across subpopulations defined by the continuous composite measure of recurrence risk. For each patient, the composite risk value was obtained from a Cox model that incorporated age; nodal status; tumor size; grade; and estrogen receptor, progesterone receptor, and Ki-67 labeling index expression levels.

Results: The overall rate of 8-year freedom from distant recurrence was 91.1% and ranged from approximately 100% to 63% across lowest to highest composite risks. TEXT patients who received chemotherapy had an average absolute improvement with exemestane plus OFS versus tamoxifen plus OFS of 5.1%, and STEPP analysis showed improvements from less than 1% to more than 15% from lowest to highest composite risks. SOFT patients who remained premenopausal after chemotherapy had an average 5.2% absolute improvement with exemestane plus OFS versus tamoxifen and reached 10% across composite risks; for tamoxifen plus OFS versus tamoxifen, the maximum improvement was approximately 3.5%. Women who did not receive chemotherapy had a more than 97% rate of 8-year freedom from distant recurrence, and improvements with exemestane plus OFS ranged from 1% to 4%.

Conclusion: Premenopausal women with HR-positive/HER2-negative breast cancer and high recurrence risk, as defined by clinicopathologic characteristics, may experience a 10% to 15% absolute improvement in 8-year freedom from distant recurrence with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone. The potential benefit of escalating endocrine therapy versus tamoxifen alone is minimal for those at low recurrence risk.
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http://dx.doi.org/10.1200/JCO.18.01967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164485PMC
April 2020

Metabolomic analysis of serum may refine 21-gene expression assay risk recurrence stratification.

NPJ Breast Cancer 2019 29;5:26. Epub 2019 Aug 29.

"Sandro Pitigliani" Department of Medical Oncology, Prato Hospital, Via Suor Niccolina 20, Prato, Italy.

Despite recent refinements to the 21-gene g score, allowing a better identification of patients who may derive no benefit from the addition of adjuvant chemotherapy to that of endocrine therapy, patients with early breast cancer still stand to be over-treated in the setting of clinical and/or genomic uncertainty or discordance. Here we describe and demonstrate a potential approach of further refining the OncotypeDX risk score by metabolomic analysis of serum. In a clinical dataset ( = 87), the risk of recurrence was further sub-stratified by metabolomic signature, with an effective splitting of each Oncotype risk classification. A total of seven recurrences were recorded, with metabolomic analysis accurately predicting six of these. Contrastingly, the genomic risk score of the seven recurrences ranged across all three Oncotype classifications (one recurrence occurred in the "low"-risk group, three in the "intermediate" group and three in the "high"-risk group).
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http://dx.doi.org/10.1038/s41523-019-0123-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715716PMC
August 2019

Mechanisms of Resistance to CDK4/6 Inhibitors: Potential Implications and Biomarkers for Clinical Practice.

Front Oncol 2019 23;9:666. Epub 2019 Jul 23.

"Sandro Pitigliani" Department of Medical Oncology, Hospital of Prato, Prato, Italy.

The recent arrival of CDK4/6 inhibitor agents, with an approximate doubling of progression-free survival (PFS) associated with their use in hormone receptor-positive, HER2-negative advanced breast cancer (BC), has radically changed the approach to managing this disease. However, resistance to CDK4/6 inhibitors is considered a near-inevitability in most patients. Mechanisms of resistance to these agents are multifactorial, and research in this field is still evolving. Biomarkers with the ability to identify early resistance, or to predict the likelihood of successful treatment using CDK4/6 inhibitors are yet to be identified, and represent an area of unmet clinical need. Here we present selected mechanisms of resistance to CDK4/6 inhibitors, largely focussing on roles of Rb, cyclin E1, and the PIK3CA pathway, with discussion of associated biomarkers which have been investigated and applied in recent pre-clinical and clinical studies. These biological drivers may furthermore influence clinical treatment strategies adopted beyond CDK4/6 resistance.
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http://dx.doi.org/10.3389/fonc.2019.00666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664013PMC
July 2019

Cyclin-Dependent Kinase 4/6 Inhibitors in Neoadjuvant Endocrine Therapy of Hormone Receptor-Positive Breast Cancer.

Clin Breast Cancer 2019 12 11;19(6):392-398. Epub 2019 Jun 11.

"Sandro Pitigliani" Medical Oncology Department, Hospital of Prato, Prato, Italy.

The landscape of therapeutic options for the treatment of hormone receptor (HR)-positive (HR) HER2 breast cancer (BC) has been profoundly changed by the introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors into the metastatic setting. Currently all CDK4/6 inhibitors are approved only in the metastatic setting by Food and Drug Administration (FDA) and European Medicine Agency (EMA), whereas their role in the neoadjuvant setting is still at an investigational stage. Exploitation of novel agents such as CDK4/6 inhibitors to improve the efficacy of neoadjuvant endocrine therapy (ET) or to overcome de novo resistance to ET is an area of research under active evaluation. We present a review of the currently available data and ongoing clinical trials that are evaluating the role of CDK4/6 inhibitors in neoadjuvant therapy of HR HER2 early BC, and also illustrate translational aspects, such as the potential biomarkers of response to these new therapeutic agents.
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http://dx.doi.org/10.1016/j.clbc.2019.05.019DOI Listing
December 2019
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