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Papers by Sara Bravaccini

International Journal of Molecular Sciences, Dec 27, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Histopathology, Aug 27, 2018

AimsThe diagnosis of breast cancer (BC) is based on clinical examination in combination with imag... more AimsThe diagnosis of breast cancer (BC) is based on clinical examination in combination with imaging, and confirmed by pathological assessment of core needle biopsy or fine‐needle aspiration biopsy (FNAB). The biological profile of the lesion is needed to define the prognosis and establish therapy. Given the importance of an early and minimally invasive diagnosis, we aimed to verify whether the biological features detected in FNAB‐derived cytological material reflect the biological characteristics of surgical samples.Methods and resultsWe used immunohistochemistry and fluorescence in‐situ hybridisation to study a panel of conventional biomarkers [oestrogen receptor (ER), progesterone receptor (PgR), Ki67, and human epidermal growth factor receptor 2 (HER2)] in FNAB‐derived cytological samples included in cell blocks of 93 BC patients, and compared the results with those obtained from histological evaluation of the same parameters in surgical samples. Median immunopositive values of ER, PgR and Ki67 were similar in cell blocks and surgical samples. The concordance rates of ER and PgR between FNAB‐derived cell blocks and histological samples were 98% and 84%, respectively. The concordance rates of Ki67 and HER2 between the two sample types were 90% and 96%, respectively. Tumour subtype classification for triple‐negative and HER2‐positive BCs in FNAB‐derived cell blocks was always concordant with the subtype determined in surgical material.ConclusionsWe demonstrated that biological marker determination in FNAB‐derived cell blocks is feasible, and provides useful information and comparable results to those obtained with histological evaluation. Given the low cost of the procedure and its minimal impact on patients, we believe that cytological samples could be used as an alternative to tissue samples for early BC biomarker evaluation.

Journal of Clinical Pathology, Sep 1, 2005

To evaluate the potential use of the immunohistochemical expression of telomerase and the measure... more To evaluate the potential use of the immunohistochemical expression of telomerase and the measurement of its activity as diagnostic tools in the uterine cervix. Methods: The fluorescent telomeric repeat amplification protocol (TRAP) assay was used to evaluate telomerase activity in a series of 43 cervical scrapings. Twenty five cases were cytologically classified as inflammatory, and/or metaplastic, and/or acanthotic, and 18 cases presented cell alterations compatible with mild, moderate, or severe cervical intraepithelial neoplasia (CIN). Immunohistochemistry was performed on a retrospective series of 86 archival, paraffin wax embedded blocks using a recently developed anti-hTERT (human telomerase reverse transcriptase) monoclonal antibody. Results: Telomerase activity was expressed as arbitrary enzymatic units (AEU). Median values were 38.0 AEU for inflammatory non-dysplastic cell specimens, 33.5 AEU for CIN I, 41.0 AEU for CIN II, and 28.0 AEU for CIN III. The median percentage of immunoreactive dysplastic cells, as detected by immunohistochemistry, was significantly (p = 0.024) lower in CIN I (45%) than in more severe dysplastic (CIN II 70%, CIN III 80%) lesions. In contrast, no differences were seen in the enzymatic activity detected by the TRAP assay among the different dysplastic lesions. Conclusions: These data indicate that, using a molecular extra situ method, the telomerase activity of inflammatory and non-dysplastic elements masks the expected differences between mild and severe dysplasia. Conversely, an in situ approach permits the accurate identification of telomerase positive dysplastic cells.

Nature Communications, Sep 2, 2019

Resistant tumours are thought to arise from the action of Darwinian selection on genetically hete... more Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Here, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNAsequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare subpopulation of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.

Cellular oncology, Jun 27, 2013

The increasing use of breast-conserving surgery makes it essential to identify biofunctional prof... more The increasing use of breast-conserving surgery makes it essential to identify biofunctional profiles responsible for the progression of in situ to invasive carcinomas to facilitate the detection of lesions that are most likely to relapse or progress and, thus, to be able to offer patients tailored treatment options. Our objective was to analyse and compare biofunctional profiles in ductal carcinomas in situ (DCIS) and invasive ductal carcinomas (IDC). We also aimed to identify markers in tumor and normal surrounding tissues that may be predictive of locoregional recurrence in patients with DCIS. Biofunctional parameters including mitotic activity, estrogen receptor, progesterone receptor, microvessel density (MVD), c-kit and p27 expression were evaluated in 829 in situ and invasive carcinomas. The impact of the biomarker profiles of DCIS, IDC and normal surrounding tissues on loco-regional recurrence was analyzed. A progressive increase in cell proliferation and a concomitant decrease in steroid hormone receptor-positive lesions was observed during the transition from in situ to invasive carcinomas, as also within each subgroup as grade increased. Conversely, p27 expression and MVD dramatically decreased during the transition from in situ to invasive carcinomas. Finally, we found that a low c-kit expression was indicative of IDC relapse. Cell proliferation, hormonal and differentiation characteristics differed in DCIS with respect to IDC, and the main variation in the transition between the two histologic lesions was the decrease in p27 expression and MVD.

BioMed Research International, 2014

Background. Genomic studies have shown that gene expression profiles are similar in in situ (CIS)... more Background. Genomic studies have shown that gene expression profiles are similar in in situ (CIS) and invasive breast cancers, suggesting that several biofunctional modifications of the transformation process occur before or during the development of CIS lesion. Methods. We investigated 3 biomarkers in 44 patients with CIS: TG2 (transglutaminase 2), HJURP (Holliday junction recognition protein), and HIF-1 (hypoxia inducible factor-1 alpha). Results. TG2 was more highly expressed than the other two markers and significantly more so in stromal than in tumor cells. HIF-1 evaluation showed a higher expression in both tumor and stromal cells in patients with relapsed G3 tumors, indicating a potential role of this marker in CIS evolution. A greater than sevenfold higher risk of relapse (= 0.050) was observed in patients highly expressing HJURP in stroma and a tenfold higher recurrence risk (= 0.026) was seen in those with a higher stromal HIF-1 expression. An important increase in risk accuracy (AUC 0.80) was obtained when HIF-1 and HJURP were evaluated together. Conclusions. Despite the limited number of relapsed patients, we formulated some hypotheses on the factors responsible for malignant evolution and recurrence which are now being tested in a large case series with a longer follow-up.

Breast Cancer Research and Treatment

There are five BC gene-profiling tests commercially available namely Prosigna®(PAM50), Mammaprint... more There are five BC gene-profiling tests commercially available namely Prosigna®(PAM50), Mammaprint®, Oncotype DX®, Breast Cancer Index®, and Endopredict®. The use of these tests emerge to be different among the various countries because of the disparity in clinical criterion of genomic test recommendation (e.g., presence of axillary lymph nodes involvement or not), and test reimbursement. This implies that the country where a patient lives can be a discriminant for him to be eligible for the molecular test execution. Several time ago, the Italian Ministry of Health signed the approval for genomic test reimbursability for breast cancer patients who need the evaluation of gene profile in order to establish the risk of disease recurrence within 10 years. This means less toxicities for patients and to save money avoiding inappropriate treatments. In Italy, the diagnostic workflow requires that the clinicians ask to perform the molecular test to the reference laboratory. Unfortunately, not all laboratories are equipped to perform this type of test given that specific instruments are necessary as well as specialized personnel. The establishment of criteria used to perform molecular tests in BC patients needs to be standardized, and the tests should be performed in specialized laboratories. Test centralization and reimbursement are fundamental to be able to compare the outcome of patients treated or not with chemotherapy in addition to hormone therapy to verify data from clinical randomized studies in a real-world setting.

Cancer Research

The development of CDK4/6 inhibitors has changed the therapeutic management of hormone receptor p... more The development of CDK4/6 inhibitors has changed the therapeutic management of hormone receptor positive (HR+) metastatic breast cancer (mBC) by targeting the cell cycle machinery and overcoming endocrine resistance. However, a high proportion of patients will present disease progression due to the resistance of cancer cells to CDK4/6 inhibitors. Loss of retinoblastoma function, dysregulation of several signaling pathways and overexpression of CDK6, CDK7 and cyclin E have been described as main actors in the development of resistance to CDK4/6 inhibitors. Despite these findings on the role of new emerging biomarkers, we wondered if the clinicopathological characteristics could be useful to identify the patients that will respond to CDK4/6 inhibitors by the analysis of a retrospective case series of patients with HR+ mBC treated with hormone therapy plus CDK4/6 inhibitors (ribociclib, palbociclib, abemaciclib) at IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Ama...

Frontiers in Immunology

Tumors are complex and heterogeneous diseases characterized by an intricate milieu and dynamicall... more Tumors are complex and heterogeneous diseases characterized by an intricate milieu and dynamically in connection with surrounding and distant tissues. In the last decades, great efforts have been made to develop novel preclinical models able to recapitulate the original features of tumors. However, the development of an in vitro functional and realistic tumor organ is still utopic and represents one of the major challenges to reproduce the architecture of the tumor ecosystem. A strategy to decrypt the whole picture and predict its behavior could be started from the validation of simplified biomimetic systems and then proceed with their integration. Variables such as the cellular and acellular composition of tumor microenvironment (TME) and its spatio-temporal distribution have to be considered in order to respect the dynamic evolution of the oncologic disease. In this perspective, we aim to explore the currently available strategies to improve and integrate in vitro and in vivo mode...

Cancer Research

Toll like receptor-9 (TLR9) is an innate immunity DNA-receptor, which is widely expressed in vari... more Toll like receptor-9 (TLR9) is an innate immunity DNA-receptor, which is widely expressed in various cancers, including breast cancer. Low TLR9 expression in cancer cells was initially associated with poor prognosis among patients with triple negative breast cancer. We have now discovered a similar association also among among other breast cancer subtypes. The mechanism for TLR9-associated poor prognosis is not currently known, but our ongoing studies suggest that it may be due to poor chemotherapy responses. Regulation of TLR9 expression in breast cancer is poorly understood. It has been demonstrated that in cervical cancers, TLR9 expression is suppressed by human papillomavirus (HPV) infections. Although breast cancer is not typically considered HPV-associated, there are reports of HPV in breast cancer. The aim here was to test the hypothesis, that HPV-infections suppress TLR9 expression also in breast cancer. To study this, human breast cancer cells were infected with HPV16 E6-on...

European Journal of Cancer

Translational Oncology

Zhang et al. reported the impact of different risk factors and comorbidities in COVID-19 lethalit... more Zhang et al. reported the impact of different risk factors and comorbidities in COVID-19 lethality. The authors observed that the odds of dying by COVID-19 in cancer patients decrease with age and cancer becomes a non-significant factor above 80 years. We speculate on the possible causes for the different COVID-19 severity between elderly and young patients. Several factors that can have a different impact on young and elderly have to be taken into account such as inflammation, microbiota and anti-cancer therapies. Inflammaging is a complex process that characterizes elderly people and it is believed to contribute to the severity of COVID-19 associated with old age. Cancer and related therapies may alter the process of inflammaging both quantitatively and qualitatively and could impact on COVID-19 severity. Moreover, therapies used in elderly cancer patients are usually different from that used for young people where the presence of comorbidities and the mechanisms of action of the different drugs both on the susceptibility genes and on other factors have to be considered. Sex hormones and anti-estrogen therapies affect significantly gene expression in target cells thereby modulating the susceptibility of the tissues to SARS-CoV-2 infection and as a consequence the extent of the symptoms. The concentration of sex hormones varies with aging and among sexes. Interestingly, recent evidences, further corroborate the hypothesis that also sex hormones or anti-estrogen therapies impact the susceptibility to COVID-19 and its severity.

Frontiers in Endocrinology

Androgen receptor (AR) is expressed in 60-70% of breast cancers (BCs) and the availability of ant... more Androgen receptor (AR) is expressed in 60-70% of breast cancers (BCs) and the availability of anti-AR compounds, currently used for treating prostate cancer, paves the way to tackle specifically AR-positive BC patients. The prognostic and predictive role of AR in BC is a matter of debate, since the results from clinical trials are not striking, probably due to both technical and biological reasons. In this review, we aimed to highlight WHAT is AR, describing its structure and functions, WHAT to test and HOW to detect AR, WHERE AR should be tested (on primary tumor or metastasis) and WHY studying this fascinating hormone receptor, exploring and debating on its prognostic and predictive role. We considered AR and its ratio with other hormone receptors, analyzing also studies including patients with ductal carcinoma in situ and with early and advanced BC, as well. We also emphasized the effects that both other hormone receptors and the newly emerging androgen-inducible non coding RNAs ...

Expert Opinion on Therapeutic Targets

Cancer Research

Background: Immunohistochemistry (IHC) is conventionally used in clinical practice to define Brea... more Background: Immunohistochemistry (IHC) is conventionally used in clinical practice to define Breast Cancer (BC) subtypes, while PAM50 is useful in specific cases. The former is partly subjective and semi-quantitative, the latter is based on gene expression profile. We compared gene expression data obtained by NanoString BC 360™ panel with those obtained by RNAseq on 12 Formalin-Fixed Paraffin-Embedded (FFPE) BC samples. Methods: RNA was isolated from FFPE tumors and the quality was checked before performing NanoString BC 360™ assay and preparing RNAseq library (NEBNext Ultra II RNA Library Prep Kit, Illumina) following the manufacturers’ instructions. Libraries were sequenced on NextSeq500 (Illumina). Reads were aligned using Kallisto and raw read counts were normalized as Transcripts Per Million (TPM). PAM50 and Tumor Inflammation Signature (TIS) were determined on NanoString data. Two-sided t-test on TPM and on normalized NanoString counts was used to compare luminal and Triple Ne...

Cancer Research, 2022

Background Trastuzumab is the cornerstone of adjuvant therapy for HER2-positive breast cancer (BC... more Background Trastuzumab is the cornerstone of adjuvant therapy for HER2-positive breast cancer (BC), but due to de novo or primary resistance, >20% of early-stage patients become resistant. Thus, predicting the mechanisms of trastuzumab resistance would facilitate the planning of specific therapeutic strategies. We performed a case-control study of 26 HER2-positive BC patients who relapsed within 5 years of starting adjuvant treatment and 26 controls, no relapsed, analyzing an extensive gene expression profile. Methods Total RNA was isolated from formalin-fixed paraffin-embedded primary tumors with AllPrep DNA/RNA FFPE Kit (Qiagen) and quantified by Nanodrop, before performing Nanostring gene expression profiling. nCounter Breast Cancer 360 Panel (Nanostring Technologies) was used according to the manufacturer’s instructions to analyze the expression of 770 genes and important signatures for BC (e.g. PAM50). For the statistical analyses, genes were normalized using a ratio of the ...

Annals of Global Health, 2021

One of the major problems facing healthcare systems in countries with poor socio-economic conditi... more One of the major problems facing healthcare systems in countries with poor socio-economic conditions is the need to strengthen the system through the training of physicians, nurses and other healthcare operators. Partnering with more affluent countries is the key for hospitals in these areas, but such alliances are often based on limited educational exchanges. We present a retrospective study of our experience in building a collaborative relationship between our cancer institute in Italy and a Medical Center in sub-Saharan Africa (Tanzania). The main purpose is to see the changes in the clinical practice after educational interventions on health personnel in a Tanzanian cancer center.

Clinical Cancer Research, 2020

Narayan and colleagues summarized the results and FDA's review leading to the accelerated app... more Narayan and colleagues summarized the results and FDA's review leading to the accelerated approval of atezolizumab in combination with paclitaxel protein-bound for the treatment of patients with unresectable, locally advanced or metastatic triple-negative breast cancer (TNBC), whose tumors express

Journal of Clinical Oncology, 2015

e22227 Background: Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has not been i... more e22227 Background: Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has not been investigated as widely as invasive breast cancer. Thus, the search for biomarkers capable of identify...

Clinical Breast Cancer, 2020

whether the BMI is an independent prognostic factor or correlates with other known prognostic par... more whether the BMI is an independent prognostic factor or correlates with other known prognostic parameters such as ER À status, proliferative index, or HER2 status.

International Journal of Molecular Sciences, Dec 27, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Histopathology, Aug 27, 2018

AimsThe diagnosis of breast cancer (BC) is based on clinical examination in combination with imag... more AimsThe diagnosis of breast cancer (BC) is based on clinical examination in combination with imaging, and confirmed by pathological assessment of core needle biopsy or fine‐needle aspiration biopsy (FNAB). The biological profile of the lesion is needed to define the prognosis and establish therapy. Given the importance of an early and minimally invasive diagnosis, we aimed to verify whether the biological features detected in FNAB‐derived cytological material reflect the biological characteristics of surgical samples.Methods and resultsWe used immunohistochemistry and fluorescence in‐situ hybridisation to study a panel of conventional biomarkers [oestrogen receptor (ER), progesterone receptor (PgR), Ki67, and human epidermal growth factor receptor 2 (HER2)] in FNAB‐derived cytological samples included in cell blocks of 93 BC patients, and compared the results with those obtained from histological evaluation of the same parameters in surgical samples. Median immunopositive values of ER, PgR and Ki67 were similar in cell blocks and surgical samples. The concordance rates of ER and PgR between FNAB‐derived cell blocks and histological samples were 98% and 84%, respectively. The concordance rates of Ki67 and HER2 between the two sample types were 90% and 96%, respectively. Tumour subtype classification for triple‐negative and HER2‐positive BCs in FNAB‐derived cell blocks was always concordant with the subtype determined in surgical material.ConclusionsWe demonstrated that biological marker determination in FNAB‐derived cell blocks is feasible, and provides useful information and comparable results to those obtained with histological evaluation. Given the low cost of the procedure and its minimal impact on patients, we believe that cytological samples could be used as an alternative to tissue samples for early BC biomarker evaluation.

Journal of Clinical Pathology, Sep 1, 2005

To evaluate the potential use of the immunohistochemical expression of telomerase and the measure... more To evaluate the potential use of the immunohistochemical expression of telomerase and the measurement of its activity as diagnostic tools in the uterine cervix. Methods: The fluorescent telomeric repeat amplification protocol (TRAP) assay was used to evaluate telomerase activity in a series of 43 cervical scrapings. Twenty five cases were cytologically classified as inflammatory, and/or metaplastic, and/or acanthotic, and 18 cases presented cell alterations compatible with mild, moderate, or severe cervical intraepithelial neoplasia (CIN). Immunohistochemistry was performed on a retrospective series of 86 archival, paraffin wax embedded blocks using a recently developed anti-hTERT (human telomerase reverse transcriptase) monoclonal antibody. Results: Telomerase activity was expressed as arbitrary enzymatic units (AEU). Median values were 38.0 AEU for inflammatory non-dysplastic cell specimens, 33.5 AEU for CIN I, 41.0 AEU for CIN II, and 28.0 AEU for CIN III. The median percentage of immunoreactive dysplastic cells, as detected by immunohistochemistry, was significantly (p = 0.024) lower in CIN I (45%) than in more severe dysplastic (CIN II 70%, CIN III 80%) lesions. In contrast, no differences were seen in the enzymatic activity detected by the TRAP assay among the different dysplastic lesions. Conclusions: These data indicate that, using a molecular extra situ method, the telomerase activity of inflammatory and non-dysplastic elements masks the expected differences between mild and severe dysplasia. Conversely, an in situ approach permits the accurate identification of telomerase positive dysplastic cells.

Nature Communications, Sep 2, 2019

Resistant tumours are thought to arise from the action of Darwinian selection on genetically hete... more Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Here, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNAsequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare subpopulation of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.

Cellular oncology, Jun 27, 2013

The increasing use of breast-conserving surgery makes it essential to identify biofunctional prof... more The increasing use of breast-conserving surgery makes it essential to identify biofunctional profiles responsible for the progression of in situ to invasive carcinomas to facilitate the detection of lesions that are most likely to relapse or progress and, thus, to be able to offer patients tailored treatment options. Our objective was to analyse and compare biofunctional profiles in ductal carcinomas in situ (DCIS) and invasive ductal carcinomas (IDC). We also aimed to identify markers in tumor and normal surrounding tissues that may be predictive of locoregional recurrence in patients with DCIS. Biofunctional parameters including mitotic activity, estrogen receptor, progesterone receptor, microvessel density (MVD), c-kit and p27 expression were evaluated in 829 in situ and invasive carcinomas. The impact of the biomarker profiles of DCIS, IDC and normal surrounding tissues on loco-regional recurrence was analyzed. A progressive increase in cell proliferation and a concomitant decrease in steroid hormone receptor-positive lesions was observed during the transition from in situ to invasive carcinomas, as also within each subgroup as grade increased. Conversely, p27 expression and MVD dramatically decreased during the transition from in situ to invasive carcinomas. Finally, we found that a low c-kit expression was indicative of IDC relapse. Cell proliferation, hormonal and differentiation characteristics differed in DCIS with respect to IDC, and the main variation in the transition between the two histologic lesions was the decrease in p27 expression and MVD.

BioMed Research International, 2014

Background. Genomic studies have shown that gene expression profiles are similar in in situ (CIS)... more Background. Genomic studies have shown that gene expression profiles are similar in in situ (CIS) and invasive breast cancers, suggesting that several biofunctional modifications of the transformation process occur before or during the development of CIS lesion. Methods. We investigated 3 biomarkers in 44 patients with CIS: TG2 (transglutaminase 2), HJURP (Holliday junction recognition protein), and HIF-1 (hypoxia inducible factor-1 alpha). Results. TG2 was more highly expressed than the other two markers and significantly more so in stromal than in tumor cells. HIF-1 evaluation showed a higher expression in both tumor and stromal cells in patients with relapsed G3 tumors, indicating a potential role of this marker in CIS evolution. A greater than sevenfold higher risk of relapse (= 0.050) was observed in patients highly expressing HJURP in stroma and a tenfold higher recurrence risk (= 0.026) was seen in those with a higher stromal HIF-1 expression. An important increase in risk accuracy (AUC 0.80) was obtained when HIF-1 and HJURP were evaluated together. Conclusions. Despite the limited number of relapsed patients, we formulated some hypotheses on the factors responsible for malignant evolution and recurrence which are now being tested in a large case series with a longer follow-up.

Breast Cancer Research and Treatment

There are five BC gene-profiling tests commercially available namely Prosigna®(PAM50), Mammaprint... more There are five BC gene-profiling tests commercially available namely Prosigna®(PAM50), Mammaprint®, Oncotype DX®, Breast Cancer Index®, and Endopredict®. The use of these tests emerge to be different among the various countries because of the disparity in clinical criterion of genomic test recommendation (e.g., presence of axillary lymph nodes involvement or not), and test reimbursement. This implies that the country where a patient lives can be a discriminant for him to be eligible for the molecular test execution. Several time ago, the Italian Ministry of Health signed the approval for genomic test reimbursability for breast cancer patients who need the evaluation of gene profile in order to establish the risk of disease recurrence within 10 years. This means less toxicities for patients and to save money avoiding inappropriate treatments. In Italy, the diagnostic workflow requires that the clinicians ask to perform the molecular test to the reference laboratory. Unfortunately, not all laboratories are equipped to perform this type of test given that specific instruments are necessary as well as specialized personnel. The establishment of criteria used to perform molecular tests in BC patients needs to be standardized, and the tests should be performed in specialized laboratories. Test centralization and reimbursement are fundamental to be able to compare the outcome of patients treated or not with chemotherapy in addition to hormone therapy to verify data from clinical randomized studies in a real-world setting.

Cancer Research

The development of CDK4/6 inhibitors has changed the therapeutic management of hormone receptor p... more The development of CDK4/6 inhibitors has changed the therapeutic management of hormone receptor positive (HR+) metastatic breast cancer (mBC) by targeting the cell cycle machinery and overcoming endocrine resistance. However, a high proportion of patients will present disease progression due to the resistance of cancer cells to CDK4/6 inhibitors. Loss of retinoblastoma function, dysregulation of several signaling pathways and overexpression of CDK6, CDK7 and cyclin E have been described as main actors in the development of resistance to CDK4/6 inhibitors. Despite these findings on the role of new emerging biomarkers, we wondered if the clinicopathological characteristics could be useful to identify the patients that will respond to CDK4/6 inhibitors by the analysis of a retrospective case series of patients with HR+ mBC treated with hormone therapy plus CDK4/6 inhibitors (ribociclib, palbociclib, abemaciclib) at IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Ama...

Frontiers in Immunology

Tumors are complex and heterogeneous diseases characterized by an intricate milieu and dynamicall... more Tumors are complex and heterogeneous diseases characterized by an intricate milieu and dynamically in connection with surrounding and distant tissues. In the last decades, great efforts have been made to develop novel preclinical models able to recapitulate the original features of tumors. However, the development of an in vitro functional and realistic tumor organ is still utopic and represents one of the major challenges to reproduce the architecture of the tumor ecosystem. A strategy to decrypt the whole picture and predict its behavior could be started from the validation of simplified biomimetic systems and then proceed with their integration. Variables such as the cellular and acellular composition of tumor microenvironment (TME) and its spatio-temporal distribution have to be considered in order to respect the dynamic evolution of the oncologic disease. In this perspective, we aim to explore the currently available strategies to improve and integrate in vitro and in vivo mode...

Cancer Research

Toll like receptor-9 (TLR9) is an innate immunity DNA-receptor, which is widely expressed in vari... more Toll like receptor-9 (TLR9) is an innate immunity DNA-receptor, which is widely expressed in various cancers, including breast cancer. Low TLR9 expression in cancer cells was initially associated with poor prognosis among patients with triple negative breast cancer. We have now discovered a similar association also among among other breast cancer subtypes. The mechanism for TLR9-associated poor prognosis is not currently known, but our ongoing studies suggest that it may be due to poor chemotherapy responses. Regulation of TLR9 expression in breast cancer is poorly understood. It has been demonstrated that in cervical cancers, TLR9 expression is suppressed by human papillomavirus (HPV) infections. Although breast cancer is not typically considered HPV-associated, there are reports of HPV in breast cancer. The aim here was to test the hypothesis, that HPV-infections suppress TLR9 expression also in breast cancer. To study this, human breast cancer cells were infected with HPV16 E6-on...

European Journal of Cancer

Translational Oncology

Zhang et al. reported the impact of different risk factors and comorbidities in COVID-19 lethalit... more Zhang et al. reported the impact of different risk factors and comorbidities in COVID-19 lethality. The authors observed that the odds of dying by COVID-19 in cancer patients decrease with age and cancer becomes a non-significant factor above 80 years. We speculate on the possible causes for the different COVID-19 severity between elderly and young patients. Several factors that can have a different impact on young and elderly have to be taken into account such as inflammation, microbiota and anti-cancer therapies. Inflammaging is a complex process that characterizes elderly people and it is believed to contribute to the severity of COVID-19 associated with old age. Cancer and related therapies may alter the process of inflammaging both quantitatively and qualitatively and could impact on COVID-19 severity. Moreover, therapies used in elderly cancer patients are usually different from that used for young people where the presence of comorbidities and the mechanisms of action of the different drugs both on the susceptibility genes and on other factors have to be considered. Sex hormones and anti-estrogen therapies affect significantly gene expression in target cells thereby modulating the susceptibility of the tissues to SARS-CoV-2 infection and as a consequence the extent of the symptoms. The concentration of sex hormones varies with aging and among sexes. Interestingly, recent evidences, further corroborate the hypothesis that also sex hormones or anti-estrogen therapies impact the susceptibility to COVID-19 and its severity.

Frontiers in Endocrinology

Androgen receptor (AR) is expressed in 60-70% of breast cancers (BCs) and the availability of ant... more Androgen receptor (AR) is expressed in 60-70% of breast cancers (BCs) and the availability of anti-AR compounds, currently used for treating prostate cancer, paves the way to tackle specifically AR-positive BC patients. The prognostic and predictive role of AR in BC is a matter of debate, since the results from clinical trials are not striking, probably due to both technical and biological reasons. In this review, we aimed to highlight WHAT is AR, describing its structure and functions, WHAT to test and HOW to detect AR, WHERE AR should be tested (on primary tumor or metastasis) and WHY studying this fascinating hormone receptor, exploring and debating on its prognostic and predictive role. We considered AR and its ratio with other hormone receptors, analyzing also studies including patients with ductal carcinoma in situ and with early and advanced BC, as well. We also emphasized the effects that both other hormone receptors and the newly emerging androgen-inducible non coding RNAs ...

Expert Opinion on Therapeutic Targets

Cancer Research

Background: Immunohistochemistry (IHC) is conventionally used in clinical practice to define Brea... more Background: Immunohistochemistry (IHC) is conventionally used in clinical practice to define Breast Cancer (BC) subtypes, while PAM50 is useful in specific cases. The former is partly subjective and semi-quantitative, the latter is based on gene expression profile. We compared gene expression data obtained by NanoString BC 360™ panel with those obtained by RNAseq on 12 Formalin-Fixed Paraffin-Embedded (FFPE) BC samples. Methods: RNA was isolated from FFPE tumors and the quality was checked before performing NanoString BC 360™ assay and preparing RNAseq library (NEBNext Ultra II RNA Library Prep Kit, Illumina) following the manufacturers’ instructions. Libraries were sequenced on NextSeq500 (Illumina). Reads were aligned using Kallisto and raw read counts were normalized as Transcripts Per Million (TPM). PAM50 and Tumor Inflammation Signature (TIS) were determined on NanoString data. Two-sided t-test on TPM and on normalized NanoString counts was used to compare luminal and Triple Ne...

Cancer Research, 2022

Background Trastuzumab is the cornerstone of adjuvant therapy for HER2-positive breast cancer (BC... more Background Trastuzumab is the cornerstone of adjuvant therapy for HER2-positive breast cancer (BC), but due to de novo or primary resistance, >20% of early-stage patients become resistant. Thus, predicting the mechanisms of trastuzumab resistance would facilitate the planning of specific therapeutic strategies. We performed a case-control study of 26 HER2-positive BC patients who relapsed within 5 years of starting adjuvant treatment and 26 controls, no relapsed, analyzing an extensive gene expression profile. Methods Total RNA was isolated from formalin-fixed paraffin-embedded primary tumors with AllPrep DNA/RNA FFPE Kit (Qiagen) and quantified by Nanodrop, before performing Nanostring gene expression profiling. nCounter Breast Cancer 360 Panel (Nanostring Technologies) was used according to the manufacturer’s instructions to analyze the expression of 770 genes and important signatures for BC (e.g. PAM50). For the statistical analyses, genes were normalized using a ratio of the ...

Annals of Global Health, 2021

One of the major problems facing healthcare systems in countries with poor socio-economic conditi... more One of the major problems facing healthcare systems in countries with poor socio-economic conditions is the need to strengthen the system through the training of physicians, nurses and other healthcare operators. Partnering with more affluent countries is the key for hospitals in these areas, but such alliances are often based on limited educational exchanges. We present a retrospective study of our experience in building a collaborative relationship between our cancer institute in Italy and a Medical Center in sub-Saharan Africa (Tanzania). The main purpose is to see the changes in the clinical practice after educational interventions on health personnel in a Tanzanian cancer center.

Clinical Cancer Research, 2020

Narayan and colleagues summarized the results and FDA's review leading to the accelerated app... more Narayan and colleagues summarized the results and FDA's review leading to the accelerated approval of atezolizumab in combination with paclitaxel protein-bound for the treatment of patients with unresectable, locally advanced or metastatic triple-negative breast cancer (TNBC), whose tumors express

Journal of Clinical Oncology, 2015

e22227 Background: Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has not been i... more e22227 Background: Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has not been investigated as widely as invasive breast cancer. Thus, the search for biomarkers capable of identify...

Clinical Breast Cancer, 2020

whether the BMI is an independent prognostic factor or correlates with other known prognostic par... more whether the BMI is an independent prognostic factor or correlates with other known prognostic parameters such as ER À status, proliferative index, or HER2 status.