HER2 mutation as an emerging target in advanced breast cancer.

HER2 activating mutations have emerged as oncogenic drivers and therapeutic targets in a variety of human tumors. In breast cancer, these deregulations occur at low frequency, and are mostly detected in HER2-nonamplified, metastatic disease. Preclinical evidence has clarified the role of hotspot mutations in HER2 constitutive activation, defining them as an alternative mechanism to HER2 gene amplification. Furthermore, recent clinical studies have indicated the emergence of newly acquired HER2 deregulations in significant proportions of breast cancer patients who experience disease progression following both endocrine and HER2-targeted therapies. As the involvement of HER2 mutation in therapy resistance may profoundly impact patient outcomes on successive therapies, several clinical trials are currently investigating the efficacy of various HER2-targeted drugs in HER2-mutant breast cancer. In this review, we firstly summarize the structural organization of the HER2 oncogene and its historical impact on breast cancer prognosis and therapeutic advancement. Then, we provide an overview of the frequencies and functional relevance of clinically recurrent HER2 mutations in breast cancer with a special focus on their role in therapeutic resistance. Finally, we provide a collection of the clinical trials that are currently exploring novel therapeutic approaches for this patient subset and discuss the related perspectives and challenges.

Bcl-2 dependent modulation of Hippo pathway in cancer cells.

INTRODUCTION: Bcl-2 and Bcl-xL are the most studied anti-apoptotic members of Bcl-2 family proteins. We previously characterized both of them, not only for their role in regulating apoptosis and resistance to therapy in cancer cells, but also for their non-canonical functions, mainly including promotion of cancer progression, metastatization, angiogenesis, and involvement in the crosstalk among cancer cells and components of the tumor microenvironment. Our goal was to identify transcriptional signature and novel cellular pathways specifically modulated by Bcl-2. METHODS: We performed RNAseq analysis of siRNA-mediated transient knockdown of Bcl-2 or Bcl-xL in human melanoma cells and gene ontology analysis to identify a specific Bcl-2 transcriptional signature. Expression of genes modulated by Bcl-2 and associated to Hippo pathway were validated in human melanoma, breast adenocarcinoma and non-small cell lung cancer cell lines by qRT-PCR. Western blotting analysis were performed to analyse protein expression of upstream regulators of YAP and in relation to different level of Bcl-2 protein. The effects of YAP silencing in Bcl-2 overexpressing cancer cells were evaluated in migration and cell viability assays in relation to different stiffness conditions. In vitro wound healing assays and co-cultures were used to evaluate cancer-specific Bcl-2 ability to activate fibroblasts. RESULTS: We demonstrated the Bcl-2-dependent modulation of Hippo Pathway in cancer cell lines from different tumor types by acting on upstream YAP regulators. YAP inhibition abolished the ability of Bcl-2 to increase tumor cell migration and proliferation on high stiffness condition of culture, to stimulate in vitro fibroblasts migration and to induce fibroblasts activation. CONCLUSIONS: We discovered that Bcl-2 regulates the Hippo pathway in different tumor types, promoting cell migration, adaptation to higher stiffness culture condition and fibroblast activation. Our data indicate that Bcl-2 inhibitors should be further investigated to counteract cancer-promoting mechanisms.

Second-line Eribulin in Triple Negative Metastatic Breast Cancer patients. Multicentre Retrospective Study: The TETRIS Trial.

Introduction: Large and consistent evidence supports the use of eribulin mesylate in clinical practice in third or later line treatment of metastatic triple negative breast cancer (mTNBC). Conversely, there is paucity of data on eribulin efficacy in second line treatment. Methods: We investigated outcomes of 44 mTNBC patients treated from 2013 through 2019 with second line eribulin mesylate in a multicentre retrospective study involving 14 Italian oncologic centres. Results: Median age was 51 years, with 11.4% of these patients being metastatic at diagnosis. Median overall survival (OS) and progression free survival (PFS) from eribulin starting were 11.9 (95%CI: 8.4-15.5) and 3.5 months (95%CI: 1.7-5.3), respectively. We observed 8 (18.2%) partial responses and 10 (22.7%) patients had stable disease as best response. A longer PFS on previous first line treatment predicted a better OS (HR=0.87, 95%CI: 0.77-0.99, p= 0.038) and a longer PFS on eribulin treatment (HR=0.92, 95%CI: 0.85-0.98, p=0.018). Progression free survival to eribulin was also favorably influenced by prior adjuvant chemotherapy (HR=0.44, 95%CI: 0.22-0.88, p=0.02). Eribulin was generally well tolerated, with grade 3-4 adverse events being recorded in 15.9% of patients. Conclusions: The outcomes described for our cohort are consistent with those reported in the pivotal Study301 and subsequent observational studies. Further data from adequately-sized, ad hoc trials on eribulin use in second line for mTNBC are warranted to confirm our findings.

Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence.

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.

Neoadjuvant Endocrine Therapy in Breast Cancer: Current Knowledge and Future Perspectives.

In locally advanced (LA) breast cancer (BC), neoadjuvant treatments have led to major achievements, which hold particular relevance in HER2-positive and triple-negative BC. Conversely, their role in hormone receptor positive (HR+), hormone epidermal growth factor 2 negative (HER2-) BC is still under debate, mainly due to the generally low rates of pathological complete response (pCR) and lower accuracy of pCR as predictors of long-term outcomes in this patient subset. While administration of neoadjuvant chemotherapy (NCT) in LA, HR+, HER2- BC patients is widely used in clinical practice, neoadjuvant endocrine therapy (NET) still retains an unfulfilled potential in the management of these subgroups, particularly in elderly and unfit patients. In addition, NET has gained a central role as a platform to test new drugs and predictive biomarkers in previously untreated patients. We herein present historical data regarding Tamoxifen and/or Aromatase Inhibitors and a debate on recent evidence regarding agents such as CDK4/6 and PI3K/mTOR inhibitors in the neoadjuvant setting. We also discuss key issues concerning the optimal treatment length, appropriate comparisons with NCT efficacy and use of NET in premenopausal patients.

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

BACKGROUND: Cancer and coagulation activation are tightly related. The extent to which factors related to both these pathologic conditions concur to patient prognosis intensely animates the inherent research areas. The study herein presented aimed to the development of a tool for the assessment and stratification of risk of death and disease recurrence in early breast cancer. METHODS: Between 2008 and 2010, two hundreds thirty-five (N: 235) patients diagnosed with stage I-IIA breast cancer were included. Data on patient demographics and clinic-pathologic features were collected in course of face-to-face interviews or actively retrieved from clinical charts. Plasma levels of plasminogen activator inhibitor type 1 (PAI-1), fragment 1 + 2 (F1 + 2), thrombin antithrombin complex (TAT), factor VIII (FVIII), and D-dimer (DD) were measured at breast cancer diagnosis and prior to any therapeutic procedure, including breast surgery. The risk of death was computed in terms of overall survival (OS), which was the primary outcome. For a subset of patients (N = 62), disease free survival (DFS) was also assessed as a measure of risk of disease recurrence. RESULTS: Median follow up was 95 months (range 6-112 months). Mean age at diagnosis was 60.3 ± 13.4 years. Cancer cases were more commonly intraductal carcinomas (N: 204; 86.8%), pT1 (131; 55.7%), pN0 (141; 60%) and G2 (126; 53.6%). Elevated levels of PAI-1 (113; 48.1%) represented the most frequent coagulation abnormality, followed by higher levels of F1 + 2 (97; 41.3%), DD (63; 27.0%), TAT (34; 40%), and FVIII (29; 12.3%). In univariate models of OS, age, pT, DD, FVIII were prognostically relevant. In multivariate models of OS, age (p = 0.043), pT (p = 0.001), levels of DD (p = 0.029) and FVIII (p = 0.087) were confirmed. In the smaller subgroup of 62 patients, lymph node involvement, percent expression of estrogen receptors and levels of FVIII impacted DFS significantly. CONCLUSIONS: We developed a risk assessment tool for OS including patient- and cancer-related features along with biomarkers of coagulation activation in a cohort of early BC patients. Further studies are warranted to validate our prognostic model in the early setting and eventually extend its application to risk evaluation in the advanced setting for breast and other cancers.

Body mass index modifies the relationship between γ-H2AX, a DNA damage biomarker, and pathological complete response in triple-negative breast cancer.

BACKGROUND: Body mass index (BMI) is largely investigated as a prognostic and predictive factor in triple-negative breast cancer (TNBC). Overweight and obesity are linked to a variety of pathways regulating tumor-promoting functions, including the DNA damage response (DDR). The DDR physiologically safeguards genome integrity but, in a neoplastic background, it is aberrantly engaged and protects cancer cells from chemotherapy. We herein verified the role of BMI on a previously assessed association between DDR biomarkers and pathological complete response (pCR) in TNBC patients treated with neoadjuvant chemotherapy (NACT). METHODS: In this retrospective analysis 54 TNBC patients treated with NACT were included. The relationship between DDR biomarkers, namely phosphorylated H2A Histone Family Member X (γ-H2AX) and phosphorylated checkpoint kinase 1 (pChk1), and pCR was reconsidered in light of BMI data. The Pearson's Chi-squared test of independence (2-tailed) and the Fisher Exact test were employed to assess the relationship between clinical-molecular variables and pCR. Uni- and multivariate logistic regression models were used to identify variables impacting pCR. Internal validation was carried out. RESULTS: We observed a significant association between elevated levels of the two DDR biomarkers and pCR in patients with BMI < 25 (p = 0.009 and p = 0.022 for γ-H2AX and pChk1, respectively), but not in their heavier counterpart. Results regarding γ-H2AX were confirmed in uni- and multivariate models and, again, for leaner patients only (γ-H2AXhigh vs γ-H2AXlow: OR 10.83, 95% CI: 1.79-65.55, p = 0.009). The consistency of this finding was confirmed upon internal validation. CONCLUSIONS: The predictive significance of γ-H2AX varies according to BMI status. Indeed, elevated levels of γ-H2AX seemed associated with lower pCR rate only in leaner patients, whereas differences in pCR rate according to γ-H2AX levels were not appreciable in heavier patients. Larger investigations are warranted concerning the potential role of BMI as effect modifier of the relationship between DDR-related biomarkers and clinical outcomes in TNBC.

Neoadjuvant Sequential Docetaxel Followed by High-Dose Epirubicin in Combination With Cyclophosphamide Administered Concurrently With Trastuzumab. The DECT Trial.

To report the results of the DECT trial, a phase II study of locally advanced or operable HER2-positive breast cancer (BC) treated with taxanes and concurrent anthracyclines and trastuzumab. Eligible patients (stage IIA-IIIB HER2-positive BC, 18-75 years, normal organ functions, ECOG ≤1, and left ventricular ejection fraction (LVEF) ≥55%) received four cycles of neoadjuvant docetaxel, 100 mg/m(2) intravenously, plus trastuzumab 6 mg/kg (loading dose 8 mg/kg) every 3 weeks, followed by four 3-weekly cycles of epirubicin 120 mg/m(2) and cyclophosphamide, 600 mg/m(2) , plus trastuzumab. Primary objective was pathologic complete response (pCR) rate, defined as ypT0/is ypN0 at definitive surgery. We enrolled 45 consecutive patients. All but six patients (13.3%) completed chemotherapy and all underwent surgery. pCR was observed in 28 patients (62.2%) overall and in 6 (66.7%) from the inflammatory subgroup. The classification and regression tree analysis showed a 100% pCR rate in patients with BMI ≥25 and with hormone negative disease. The median follow up was 46 months (8-78). Four-year recurrence-free survival was 74.7% (95%CI, 58.2-91.2). Seven patients (15.6%) recurred and one died. Treatment was well tolerated, with limiting toxicity being neutropenia. No clinical cardiotoxicity was observed. Six patients (13.4%) showed a transient LVEF decrease (<10%). In one patient we observed a ≥10% asymptomatic LVEF decrease persisting after surgery. Notwithstanding their limited applicability due to the current guidelines, our findings support the efficacy of the regimen of interest in the neoadjuvant setting along with a fairly acceptable toxicity profile, including cardiotoxicity. Results on BMI may invite further assessment in future studies. J. Cell. Physiol. 231: 2541-2547, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

Anthropometric, metabolic and molecular determinants of human epidermal growth factor receptor 2 expression in luminal B breast cancer.

Genomic and trascriptomic profiling has recently contributed details to the characterization of luminal B breast cancer. We explored the contribution of anthropometric, metabolic, and molecular determinants to the multifaceted heterogeneity of this breast cancer subtype, with a specific focus on the association between body mass index (BMI), pre-treatment fasting glucose, hormone receptors, and expression of human epidermal growth factor receptor 2 (HER2). Extensively annotated specimens were obtained from 154 women with luminal B breast cancer diagnosed at two Italian comprehensive cancer centres. Participants' characteristics were descriptively analyzed overall and by HER2 status (positive vs. negative). BMI (<25 vs ≥25), pre-treatment fasting glucose (

Modeling the positioning of single needle electrodes for the treatment of breast cancer in a clinical case.

BACKGROUND: Breast cancer is the most common cancer in women worldwide and is the second most common cause of cancer death in women. Electrochemotherapy (ECT) used in early-phase clinical trials for the treatment of primary breast cancer resulted in a not complete tumor necrosis in most cases. The present study was undertaken to analyze the feasibility to use ECT to treat patients with histologically proven unifocal ductal breast cancer. In particular, results of ECT treatment in a clinical case are compared with the ones of a simplified 3D dosimetric model. METHODS: This clinical study was conducted with the pulse generator Cliniporator Vitae (IGEA, Carpi, Italy). ECT procedures were performed according to ESOPE standard operating procedures. Five single needle electrodes were used with one positioned in the center of the tumor, and the other four distributed around the nodule. Histological images of the resected tumor are compared with the maps of the electric field obtained with a simplified 3D model in Comsol Multiphysics v 4.3. RESULTS: The results of the clinical case demonstrated a reduced efficacy of the ECT treatment described. The proposed simple numerical model of the breast tumor located in a low conductive tissue suggests that this is due to the reduced electric field induced inside the tumor with such 5 electrodes placement. However, where the electric field is predicted higher than the reversible electroporation threshold (E>400 V/cm), also the histological images confirm the necrosis of the target with a good agreement between the modeled and clinical results. CONCLUSIONS: The results suggest the dependence of the effectiveness of the treatment on the careful placement of the electrodes. A detailed planned procedure for the tumor analysis after the treatment is also needed in order to better correlate the single electrode positions and the histological images. Simulation models could be used to identify better electrodes configuration in planning the experimental protocol for ECT treatment of breast tumors.

Regina Elena Institute (R.E.I.) Protocol for Breast Implant Salvage: Preliminary Results.

INTRODUCTION: implants are the most popular means of restoring the breast mound after mastectomy; the most feared complication is implant infection accounting for 4.8% to 35.4% of cases. Various antibiotic regimens or other surgical revisions to treat implant infections have been reported, but their failure rates are unacceptable. Implant removal is subsequently the most common recourse for managing prosthesis infections. we report preliminary results of infected breast implant salvage using our Regina Elena Institute (REI) protocol. METHODS: Since June 2021, a prospective single-centre study has been ongoing for patients burdened by implant infection or exposure. All qualifying participants underwent our REI protocol. They receive a temporary smooth implant and 1 week of implant's pocket irrigation with antibiotic solution along with systemic antibiotic and then a new permanent prosthesis positioning. RESULTS: Ten of whom completed at least 6 months of follow-up and were eligible for this preliminary analysis. Overall, the REI protocol was applied to 13 breasts. No infections relapsed during the 6-month minimum follow-up intervals; and no early capsular contraction was evident, resulting in good cosmetic outcomes for every treated breast. DISCUSSION: The smooth-surfaced implant's sizer helps maintain tissue expansion, preventing skin retraction; and the slightly smaller diameters used (compared with originals) facilitate antibiotic wash distribution. Combining a targeted systemic antibiotic and a topical agent is the best way to optimise infection resolution. This preliminary analysis has clear limitations. A larger population is warranted to increase the level of evidence. Longer follow-up is also advisable to monitor for delayed infection recurrence.

Comparison of Indocyanine Green with conventional tracers for sentinel lymph node biopsy in breast cancer: A multidisciplinary evaluation of clinical effectiveness, safety, organizational and economic impact.

BACKGROUND: Breast cancer is a global health problem, and sentinel lymph node biopsy (SLNB) is the standard procedure for early-stage breast cancer. Technetium-99 (TC-99), alone or combined with blue dye (BD) are conventional tracers for SLNB, but they have safety, availability, and cost limitations. Indocyanine green (ICG) is an alternative tracer that has been gaining acceptance among healthcare professionals. This study aimed at assessing the clinical and economic value of ICG in hospital settings, using the health technology assessment (HTA) framework. METHODS: We conducted a comprehensive evaluation of ICG for SLNB, based on literature sources and data collected from two Italian hospitals that switched from TC-99 to ICG. We analyzed ICG's technical attributes through technology documentation and relevant databases. We performed a systematic literature review of 36 studies to assess the clinical effectiveness and safety of ICG. We obtained organizational insights from clinicians and the clinical engineer involved in the study. We applied Time-Driven Activity-Based Costing (TDABC) and Budget Impact Analysis (BIA) to estimate the economic impact of ICG. The ethical, legal, and social implications of ICG were considered through clinicians' inputs and technology documentation. RESULTS: Our results showed that ICG had equivalent or superior clinical effectiveness compared to TC-99 and BD, with minimal adverse events. ICG simplified the surgical pathways, by streamlining procedures, reducing waiting times, and increasing flexibility in scheduling surgeries. Moreover, the TDABC analysis showed significant cost reductions by avoiding the need for pre-operative lymphoscintigraphy and hospitalization, with average savings per single care pathway of around 18% for ICG compared to TC-99. Finally, ICG improved patient experience, and proved regulatory compliance. CONCLUSIONS: This study provided strong evidence for ICG's clinical and economic value for SLNB in breast cancer. It ascertained ICG as a valuable alternative to conventional tracers, ensuring clinical effectiveness along with economic and organizational benefits.

Breast and cervical cancer in transgender men: literature review and a case report.

Transgender individuals exhibit a higher prevalence of cancer-related risk factors, such as substance abuse and sexually transmitted infections. These factors, coupled with suboptimal adherence to cancer screening recommendations, may lead to a higher incidence of cancers, such as breast and cervical cancer, and contribute to delayed diagnoses in transgender patients. Herein, we report a unique case of a transgender man with a history of alcohol and drug abuse, undergoing gender-affirming exogenous testosterone therapy, who developed synchronous locally advanced breast cancer and human papilloma virus (HPV)-related cervical cancer. He underwent concurrent chemoradiation for cervical cancer and surgery followed by endocrine therapy for breast cancer. The treatments were suboptimals due to patient's comorbidities, among them liver cirrhosis leading to an early death. Additionally, we have conducted a review of existing literature, including case reports, clinical studies, and review articles investigating the role of potential risk factors specifically related to breast and cervical tumors in transgender men. Gender-affirming testosterone therapy is common among transgender men to induce gender affirmation, but its link to breast cancer risk remains ambiguous, with studies being limited and sometimes contradictory. Conversely, HPV is a well-established cause of up to 99% of cervical cancers. Despite persistent risk for cervical cancer in transgender men who retain their cervix, several studies indicate notable disparities in screening adherence, due to personal and structural barriers. Moreover, alcohol and drug use disorders, commonly encountered in transgender population, may negatively influence the adherence to screening programs. Current cancer screening guidelines for this population are somewhat unclear, and specific programs based on more robust data are urgently required along with further tailored studies.

Breast and cervical cancer in transgender men: literature review and a case report Transgender individuals are persons whose gender identity does not conform to that typically associated with the sex to which they were assigned at birth. Transgender people may have more cancer-related risk factors, such as substance abuse and sexually transmitted infections. These factors, along with suboptimal adherence to cancer screening, may lead to a higher incidence of cancers, among them breast and cervical cancer, and may also contribute to delayed diagnoses. Herein we report the case of a transgender man, recorded as female at birth but identifying as male, with a history of alcohol and drug abuse. He underwent testosterone therapy in order to affirm his gender. Moreover, he refused cancer screening, due to personal and social barriers. During the transition, he developed simultaneously a locally advanced breast cancer and a cervical cancer, the latter related to an infection from Human Papillomavirus. The patient was treated with chemoradiation for cervical cancer, and with surgery followed by endocrine therapy for breast cancer. The treatments were suboptimals due to patient's comorbidities, partly related to his previous lifestyle. Additionally, we have conducted a review of existing literature on the topic. Trangender men usually undergo testosterone to induce gender-affirmation. The role of testosterone therapy in breast cancer development remains unclear, with studies being contradictory. Conversely, Human Papillomavirus is a well-established cause of cervical cancers. Transgender men who retain their cervix are at risk for cervical cancer. Despite the persistent risk, notable disparities in screening adherence, due to personal and structural barriers, are reported. Moreover, alcohol and drug use disorders, commonly encountered in transgender population, may contrtibute to the low adherence to screening programs. Furthermore, screening guidelines are somewhat unclear, and specific programs are urgently required.

DNA Damage Response in Early Breast Cancer: A Phase III Cohort in the Phobos Study.

We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D → EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical-pathological factors.

Exploiting Long Non-Coding RNAs and Circular RNAs as Pharmacological Targets in Triple-Negative Breast Cancer Treatment.

Breast cancer is one of the most frequent causes of cancer death among women worldwide. In particular, triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype because it is characterized by the absence of molecular targets, thus making it an orphan type of malignancy. The discovery of new molecular druggable targets is mandatory to improve treatment success. In that context, non-coding RNAs represent an opportunity for modulation of cancer. They are RNA molecules with apparently no protein coding potential, which have been already demonstrated to play pivotal roles within cells, being involved in different processes, such as proliferation, cell cycle regulation, apoptosis, migration, and diseases, including cancer. Accordingly, they could be used as targets for future TNBC personalized therapy. Moreover, the peculiar characteristics of non-coding RNAs make them reliable biomarkers to monitor cancer treatment, thus, to monitor recurrence or chemoresistance, which are the most challenging aspects in TNBC. In the present review, we focused on the oncogenic or oncosuppressor role of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) mostly involved in TNBC, highlighting their mode of action and depicting their potential role as a biomarker and/or as targets of new non-coding RNA-based therapeutics.

Sexual dysfunctions in breast cancer patients: evidence in context.

INTRODUCTION: In breast cancer patients, endocrine therapy may exert a negative impact on sexual functioning in both genders, with potentially relevant consequences concerning quality of life and treatment adherence. The availability of effective interventions to maintain and/or restore sexual health in breast cancer patients is a key issue to a research agenda. OBJECTIVES: To summarize and critically discuss the most updated and qualitatively relevant literature on the therapeutic approach to sexual impairment in breast cancer patients, with a focus on patients treated with endocrine therapy. METHODS: We searched PubMed from its inception to February 2022 for observational and intervention trials including participants with sexual dysfunctions. We were particularly interested in studies of breast cancer patients with sexual dysfunctions while undergoing endocrine therapy. We developed a search strategy with the aim of maximizing the number of articles considered for screening and potential inclusion. RESULTS: Forty-five studies were selected: 3 observational and 42 intervention studies. Thirty-five studies were exclusively focused on female breast cancer populations. We could not identify studies exclusively focused on or also including male breast cancer patients. Overall, in female patients, the available armamentarium encompasses vaginal lubricants, moisturizers, estrogens, dehydroepiandrosterone, CO2 laser, ospemifene, and counseling. None of these interventions has been demonstrated to completely solve sexual dysfunctions when singularly considered. More favorable outcomes have come from the combination of different therapies. CONCLUSION: In female breast cancer, future research is oriented toward the gain of evidence on combined therapies and long-term data on safety issues on the most promising interventions. The lack of evidence on sexual disturbances in male breast cancer patients remains a major concern.

How Dual-Energy Contrast-Enhanced Spectral Mammography Can Provide Useful Clinical Information About Prognostic Factors in Breast Cancer Patients: A Systematic Review of Literature.

Introduction: In the past decade, a new technique derived from full-field digital mammography has been developed, named contrast-enhanced spectral mammography (CESM). The aim of this study was to define the association between CESM findings and usual prognostic factors, such as estrogen receptors, progesterone receptors, HER2, and Ki67, in order to offer an updated overview of the state of the art for the early differential diagnosis of breast cancer and following personalized treatments. Materials and Methods: According to the PRISMA guidelines, two electronic databases (PubMed and Scopus) were investigated, using the following keywords: breast cancer AND (CESM OR contrast enhanced spectral mammography OR contrast enhanced dual energy mammography) AND (receptors OR prognostic factors OR HER2 OR progesterone OR estrogen OR Ki67). The search was concluded in August 2021. No restriction was applied to publication dates. Results: We obtained 28 articles from the research in PubMed and 114 articles from Scopus. After the removal of six replicas that were counted only once, out of 136 articles, 37 articles were reviews. Eight articles alone have tackled the relation between CESM imaging and ER, PR, HER2, and Ki67. When comparing radiological characterization of the lesions obtained by either CESM or contrast-enhanced MRI, they have a similar association with the proliferation of tumoral cells, as expressed by Ki-67. In CESM-enhanced lesions, the expression was found to be 100% for ER and 77.4% for PR, while moderate or high HER2 positivity was found in lesions with non-mass enhancement and with mass closely associated with a non-mass enhancement component. Conversely, the non-enhancing breast cancer lesions were not associated with any prognostic factor, such as ER, PR, HER2, and Ki67, which may be associated with the probability of showing enhancement. Radiomics on CESM images has the potential for non-invasive characterization of potentially heterogeneous tumors with different hormone receptor status. Conclusions: CESM enhancement is associated with the proliferation of tumoral cells, as well as to the expression of estrogen and progesterone receptors. As CESM is a relatively young imaging technique, a few related works were found; this may be due to the "off-label" modality. In the next few years, the role of CESM in breast cancer diagnostics will be more thoroughly investigated.

Reverse strategy to locally advanced breast implant-associated anaplastic large cell lymphoma: A case report.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T-cell lymphoma associated with textured breast implants. The most common presentation is a periprosthetic seroma that occurs at least 1 year after an aesthetic or reconstructive implantation, and in these cases, the surgical treatment seems to be successful. More rarely, BIA-ALCL presents with locally advanced mass-formed disease and a related regional lymph node involvement. In all these cases with worse prognosis, a multidisciplinary approach is required, including adjuvant chemotherapy, radiation therapy, and surgery. We present a clinical case of a 49-year-old woman who developed on the left side of the breast a mass-formed stage 3 BIA-ALCL 15 years after a bilateral breast augmentation with textured silicone implant. Our multidisciplinary team (MDT) scheduled the patient for a "reverse-strategy" sequential approach consisting of induction chemotherapy, hematopoietic stem cell mobilization, and harvest followed by autologous stem cell transplant (ASCT). After 100 days from the stem cell transplant, the patient showed a complete pathologic response and was a candidate for radical surgery. She underwent removal of both implants with total en bloc capsulectomy. On the left site, the periprosthetic mass was also en bloc removed. We did not perform any axillary dissection. Our surgical and hemato-oncological teams followed the patient every 3 months, and no local or systemic recurrences were observed 24 months after surgery. This case report has demonstrated the effectiveness of neoadjuvant chemotherapy as part of a "reverse strategy" in selected cases of advanced-stage BIA-ALCL in which it was not possible to perform an immediate radical surgery. Furthermore, in our case, the de-escalation strategy adopted permitted a less demolitic surgery with good functional and aesthetic results.

Breast cancer metastasis: Is it a matter of OMICS and proper ex-vivo models?

Genomics has greatly increased the understanding of the study of breast cancer (BC) and has shaped the concept of intra-tumor heterogeneity, currently recognized as a propelling force for cancer progression. In this context, knowledge and understanding of metastatic breast cancer (mBC) has somehow lagged behind that of primary breast cancer. This may be explained by the relative scarcity of matched mBC samples, however it is possible that the mutation spectrum obtained from primary BC does not capture the full complexity of the metastatic disease. Here, we provide a few examples supporting this possibility, from public databases. We evoke the need to perform an integrated multi-OMICS characterization of mBC, to obtain a broad understanding of this complex disease, whose evolution cannot be explained solely by genomics. Pertinent to this, we suggest that rather an infrequent use of Patient-Derived -Tumor-Organoids (PDTOs) may be influenced by assuming that the metastatic conditions of PDTOs growth (mPDTOs) should be similar to those of the tissue of origin. We challenge this view by suggesting that the use of "target-organ inspired" growth conditions for mPDTOs, may better fit the emerging knowledge of metastatic disease. Thus, the integrated use of multi-OMICS and of clinically relevant mPDTOs may allow a further understanding of such disease and foster therapeutically relevant advances. We believe that our points may be valid for other solid cancers.