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Abstract Background In Western countries, ovarian cancer (OC) still represents the leading cause of gynecological cancer-related deaths, despite the remarkable gains in therapeutical options. Novel biomarkers of early diagnosis, prognosis definition and prediction of treatment outcomes are of pivotal importance. Prior studies have shown the potentials of micro-ribonucleic acids (miRNAs) as biomarkers for OC and other cancers. Methods We focused on the prognostic and/or predictive potential of miRNAs in OC by conducting a comprehensive array profiling of miRNA expression levels in ovarian tissue samples from 17 non-neoplastic controls, and 60 tumor samples from OC patients treated at the Regina Elena National Cancer Institute (IRE). A set of 54 miRNAs with differential expression in tumor versus normal samples (T/N-deregulated) was identified in the IRE cohort and validated against data from the Cancer Genoma Atlas (TCGA) related to 563 OC patients and 8 non-neoplastic controls. The prognostic/predictive role of the selected 54 biomarkers was tested in reference to survival endpoints and platinum resistance (P-res). Results In the IRE cohort, downregulation of the 2 miRNA-signature including miR-99a-5p and miR-320a held a negative prognostic relevance, while upregulation of miR-224-5p was predictive of less favorable event free survival (EFS) and P-res. Data from the TCGA showed that downregulation of 5 miRNAs, i.e., miR-150, miR-30d, miR-342, miR-424, and miR-502, was associated with more favorable EFS and overall survival outcomes, while miR-200a upregulation was predictive of P-res. The 9 miRNAs globally identified were all included into a single biologic signature, which was tested in enrichment analysis using predicted/validated miRNA target genes, followed by network representation of the miRNA-mRNA interactions. Conclusions Specific dysregulated microRNA sets in tumor tissue showed predictive/prognostic value in OC, and resulted in a promising biological signature for this disease.

Abstract Breast cancer (BC) is a complex disease with primary or acquired incurability characteristics in a significant part of patients. Immunotherapeutical agents represent an emerging option for breast cancer treatment, including the human epidermal growth factor 2 positive (HER2+) subtype. The immune system holds the ability to spontaneously implement a defensive response against HER2+ BC cells through complex mechanisms which can be exploited to modulate this response for obtaining a clinical benefit. Initial immune system modulating strategies consisted mostly in vaccine therapies, which are still being investigated and improved. However, the entrance of trastuzumab into the scenery of HER2+ BC treatment was the real game changing event, which embodied a dominant immune-mediated mechanism. More recently, the advent of the immune checkpoint inhibitors has caused a new paradigm shift for immuno-oncology, with promising initial results also for HER2+ BC. Breast cancer has been traditionally considered poorly immunogenic, being characterized by relatively low tumor mutation burden (TMB). Nevertheless, recent evidence has revealed high tumor infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in a considerable proportion of HER2+ BC patients. This may translate into a higher potential to elicit anti-cancer response and, therefore, wider possibilities for the use and implementation of immunotherapy in this subset of BC patients. We are herein presenting and critically discussing the most representative evidence concerning immunotherapy in HER2+ BC cancer, both singularly and in combination with therapeutic agents acting throughout HER2-block, immune checkpoint inhibition and anti-cancer vaccines. The reader will be also provided with hints concerning potential future projection of the most promising immutherapeutic agents and approaches for the disease of interest.

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., Competing Interests: FSDL: Novartis, Gentili, Pfizer, Daiichi-Sankyo and Ipsen, outside the submitted manuscript. LF: Gilead, Daiichi-Sankyo, Gentili and Eisai, outside the submitted manuscript. LP: Pfizer and Novartis, outside the submitted manuscript. DS: MSD, outside the submitted work. PV: Pfizer, Novartis, Eisai, Daiichi Sankyo, Ipsen and Eli Lilly, outside the submitted work. AV, TA, BC, GS, EK, MB, FL, FR, CB, and GC declare no competing interests., (© The Author(s), 2024.)

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.

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., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The therapeutic scenario of Human Epidermal Growth Factor Receptor 2 positive advanced breast cancer (ABC) has been recently enriched by a number of innovative agents, which are reshaping treatment sequence. While randomized trials have documented an advantage in terms of efficacy, for the newly available agents we lack effectiveness and tolerability evidence from the real-world setting. Similarly, the identification of predictive biomarkers might improve clinical decision. We herein describe the outline of a prospective/retrospective study which aims to explore the optimal sequence of treatment in HER2+, pertuzumab pre-treated ABC patients treated in II line with anti-HER2 agents in clinical practice. As part of the pre-clinical tasks envisioned by the STEP study, in vitro cell models of resistance were exploited to investigate molecular features associated with reduced efficacy of HER2 targeting agents at the transcript level. The aggressive behavior of resistant cell populations was measured by growth assessment in mouse models. This approach led to the identification of DARPP-32 and t-DARPP proteins as possible predictive biomarkers of efficacy of anti-HER2 agents. Biomarkers validation and the clinical goals will be reached through patients' inclusion into two independent cohorts, i.e., the prospective and retrospective cohorts, whose setup is currently ongoing., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FSDL: Ipsen and Novartis, outside the submitted work. AB: Pfizer, Roche, Lilly, Novartis, Msd, Seagen, Gilead and Daiichi Sankyo, outside the submitted work. DS: Amgen, Astellas, Astrazeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, outside the submitted work. GDA: Novartis, Amgen, Eli Lilly, outside the submitted work. CM: Bayer, Roche, AstraZeneca and Daiichi-Sankyo, outside the submitted work. P.V.: Pfizer, Novartis, Eisai, Daiichi Sankyo and Eli Lilly, outside of the manuscript under consideration L.P.: Novartis and Pfizer, outside of the manuscript under consideration. No potential conflicts of interest were disclosed for other authors, (Copyright © 2023. Published by Elsevier Inc.)

Objective: The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy impressively improved the outcome of patients with hormone receptor-positive metastatic breast cancer. Despite their great efficacy, not all patients respond to treatment and many of them develop acquired resistance. The aim of this retrospective study was to assess the role of [18F]-FDG PET/CT in predicting PFS and OS in breast cancer patients treated with CDK4/6i., Methods: 114 patients who performed an [18F]-FDG PET/CT scan before (PET1) and 2-6 months (PET2) after starting treatment were retrospectively enrolled. Metabolic response was evaluated by EORTC, PERCIST and Deauville Score and correlated to PFS and OS., Results: In patients who did not progress at PET2 (n = 90), PFS rates were not significantly different between classes of response by EORTC and PERCIST. Conversely, patients showing a Deauville score ≤3 had a longer PFS (median PFS 42 vs 21.0 months; p = 0.008). A higher total metabolic tumor volume at PET1 (TMTV1) was also associated with a shorter PFS (median 18 vs 42 months; p = 0.0026). TMTV1 and Deauville score were the only independent prognostic factors for PFS at multivariate analysis and their combination stratified the population in four definite classes of relapse risk. Conversely, the above parameters did not affect OS which was only influenced by a progressive metabolic disease at PET2 (3-years survival rate 29.8 vs 84.9%; p<0.0001)., Conclusion: TMTV and metabolic response by Deauville score were significant prognostic factors for PFS in patients with breast cancer treated with CDK4/6i. Their determination could help physicians to select patients who may need a closer follow up., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Annovazzi, Rea, Maccora, Pizzuti, Ferretti, Vici, Cappuzzo and Sciuto.)

Purpose: Clinical trials have shown a significant increase in pathologic complete response (pCR) with the addition of pertuzumab to neoadjuvant chemotherapy for patients with early-stage HER-2 positive breast cancer. To date, limited studies have examined comparative outcomes of neoadjuvant pertuzumab in real-world setting. The Neopearl study aimed to assess comparative real-life efficacy and safety of neoadjuvant pertuzumab for these patients., Methods: We conducted a nationwide retrospective analysis involving 17 oncology facilities with a certified multidisciplinary breast cancer treatment committee. We identified patients with HER-2 positive stage II-III breast cancer treated with neoadjuvant chemotherapy based on trastuzumab and taxanes with or without pertuzumab. All patients underwent breast surgery and received a comprehensive cardiologic evaluation at baseline and after neoadjuvant treatment. Patients who received the combination of pertuzumab, trastuzumab, and chemotherapy constituted case cohort (PTCT), whereas those treated with trastuzumab and chemotherapy accounted for control cohort (TCT). The pCR rate and 5-year event free survival (EFS) were the primary outcomes. Secondary end-points were rates of conversion from planned modified radical mastectomy (MRM) to breast conservation surgery (BCS) and cardiotoxicities., Results: From March 2014 to April 2021, we included 271 patients, 134 (49%) and 137 (51%) in TCT and PTCT cohort, respectively. Positive axillary lymph nodes and stage III were more frequent in PTCT cohort. The pCR rate was significantly increased in patients who received pertuzumab (49% vs 62%; OR 1.74, 95%CI 1.04-2.89) and with HER-2 enriched subtypes (16% vs 85%; OR 2.94, 95%CI 1.60-5.41). After a median follow-up of 5 years, the 5-year EFS was significantly prolonged only in patients treated with pertuzumab (81% vs 93%; HR 2.22, 95%CI 1.03-4.79). The same analysis performed on propensity score matched population showed concordant results. On univariate analysis, only patients with positive lymph nodes were found to benefit from pertuzumab for both pCR and 5-year EFS. The rates of conversion from MRM to BCS and cardiologic toxicities did not differ between the cohorts., Conclusion: Our findings support previous data on improved outcomes with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy. This benefit seems to be more significant in patients with clinically positive lymph nodes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fabbri, Nelli, Botticelli, Giannarelli, Marrucci, Fiore, Virtuoso, Scagnoli, Pisegna, Alesini, Sini, Orlandi, Fabi, Piacentini, Moscetti, D’Auria, Gamucci, Mazzotta, Pizzuti, Vici, Cretella, Scavina, La Cesa, Persano, Atzori and Ruggeri.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available., Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years., Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles., Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research., Competing Interests: LP received speaker fees from Novartis, outside the submitted work. UDG: Pfizer, BMS, MSD, PharmaMAR, AStellas, Bayer, Ipsen, Novartis; Invited speaker Roche, BMS, SAnofi, AstraZeneca; received research grants from AstraZeneca, SAnofi, Roche, outside the submitted work. AF received honoraria as a speaker from Eli Lilly, Novartis, Pierre-Fabre, outside the submitted work. GT: advisory boards from Novartis, Pfizer, Eisai, Roche, and Eli Lilly, outside the submitted work. DS: advisory boards from Novartis, Pfizer, Eisai, Roche, and Eli Lilly, outside the submitted work. NLV: Roche, MSD, Eisai, Novartis, AstraZeneca, GSK, Pfizer, Gentili, Daiichi Sankyo, Dephaforum, outside the submitted work. OG: Eisai, MSD, Gilead, Seagen, Novartis, Eli Lilly, outside the submitted work. IM: advisory boards from Eli Lilly, Novartis, Gentili, Roche, Pfizer, Ipsen, and Pierre-Fabre, outside the submitted work. GD’A: Novartis, Amgen, Eli Lilly outside the submitted work. TG received travel grants from Eisai, Roche, Pfizer, and Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili, and Eli Lilly, outside the submitted work. MPi Consultant/advisory boards from Gilead, Eli Lilly, Pfizer, Novartis, Gentili, MSD, outside the submitted work. RB received research grant/advisory boards from AstraZeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli Lilly, Roche, Amgen, GSK, Eisai, outside the submitted work. FGi: advisory boards from Gilead, Daiichi Sankyo, Seagen, outside the submitted work. MEC consultant/advisory role for Pierre-Fabre, Roche, Novartis, Eli Lilly, Celgene, outside the submitted work. RT: AstraZeneca, Eisai, Pfizer, Eli Lilly, MSD, Exact Science, outside the submitted work. AB: MSD, BMS, Pfizer, Novartis, Roche outside the submitted work. AM received travel grants from Eisai, Celgene, and Novartis Ipsen; personal fees/advisory boards from Eisai, Novartis, AstraZeneca, Teva, Pfizer, and Celgene, outside the submitted work. IP received personal fees/advisory boards from Roche, Pfizer, Novartis, Italfarmaco, Gentili, and Pierre-Fabre. LG received congress travel accomodation from Roche, Daiichi Sankyo, AstraZeneca, Pfizer, Novartis; advisory role for Astra Zeneca outside the submitted work. MMin: Novartis, MSD, Eli Lilly, outside the submitted work. LM received personal fees/advisory board from Roche, Novartis, Eisai, and Pfizer, outside the submitted work. EC: Astellas, Roche, BMS, Jansen, MSD, Sirtex, Merck, Bayer, Servier, Novartis, outside the submitted work. PM has/had a consultant/advisory role for BMS, Roche, Genentech, MSD, Novartis, Amgen, Merck Serono, Pierre-Fabre and Incyte, outside the submitted work. PV received speaker fees/advisory boards from Roche, Pfizer, Novartis and Eli Lilly, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Di Lisa, Krasniqi, Pizzuti, Barba, Cannita, De Giorgi, Borella, Foglietta, Cariello, Ferro, Picardo, Mitidieri, Sini, Stani, Tonini, Santini, La Verde, Gambaro, Grassadonia, Tinari, Garrone, Sarobba, Livi, Meattini, D’Auria, Vergati, Gamucci, Pistelli, Berardi, Risi, Giotta, Lorusso, Rinaldi, Artale, Cazzaniga, Zustovich, Cappuzzo, Landi, Torrisi, Scagnoli, Botticelli, Michelotti, Fratini, Saltarelli, Paris, Muratore, Cassano, Gianni, Gaspari, Veltri, Zoratto, Fiorio, Fabbri, Mazzotta, Ruggeri, Pedersini, Valerio, Filomeno, Minelli, Scavina, Raffaele, Astone, De Vita, Pozzi, Riccardi, Greco, Moscetti, Giordano, Maugeri-Saccà, Zennaro, Botti, Pelle, Cappelli, Cavicchi, Vizza, Sanguineti, Tomao, Cortesi, Marchetti, Tomao, Speranza, Sperduti, Ciliberto and Vici.)

New evidence on the impact of dysregulation of the CDK4/6 pathway on breast cancer (BC) cell proliferation has led to the development of selective CDK4/6 inhibitors, which have radically changed the management of advanced BC. Despite the improved outcomes obtained by CDK4/6 inhibitors, approximately 10% of tumors show primary resistance, whereas acquired resistance appears to be an almost ubiquitous occurrence, leading to treatment failure. The identification of differentially expressed genes or genomic mutational signatures able to predict sensitivity or resistance to CDK4/6 inhibitors is critical for medical decision making and for avoiding or counteracting primary or acquired resistance against CDK4/6 inhibitors. In this review, we summarize the main mechanisms of resistance to CDK4/6 inhibitors, focusing on those associated with potentially relevant biomarkers that could predict patients' response/resistance to treatment. Recent advances in biomarker identification are discussed, including the potential use of liquid biopsy for BC management and the role of multiple microRNAs as molecular predictors of cancer cell sensitivity and resistance to CDK4/6 inhibitors.

The Hippo pathway and its two key effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are consistently altered in breast cancer. Pivotal regulators of cell metabolism such as the AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR) are relevant modulators of TAZ/YAP activity. In this prospective study, we measured the tumor expression of TAZ, YAP, AMPK, SCD1, and HMGCR by immunohistochemistry in 65 Her2+ breast cancer patients who underwent trastuzumab-based neoadjuvant treatment. The aim of the study was to assess the impact of the immunohistochemical expression of the Hippo pathway transducers and cell metabolism regulators on pathological complete response. Low expression of cytoplasmic TAZ, both alone and in the context of a composite signature identified by machine learning including also low nuclear levels of YAP and HMGCR and high cytoplasmic levels of SCD1, was a predictor of residual disease in the univariate logistic regression. This finding was not confirmed in the multivariate model including estrogen receptor > 70% and body mass index > 20. However, our findings were concordant with overall survival data from the TCGA cohort. Our results, possibly affected by the relatively small sample size of this study population, deserve further investigation in adequately sized, ad hoc prospective studies.

Purpose: Breast cancer (BC) patients' (pts) management was affected by a global reorganization after Coronavirus disease 2019 (COVID-19). Our multicenter study aimed to assess the impact of COVID-19 on access to diagnosis, staging and treatment for BC pts compared to pre-pandemic., Methods: Medical records of all consecutive newly diagnosed BC pts referred to 6 Italian Institutions between March and December 2020 were assessed. Monthly access rate and temporal intervals between date of symptoms onset, radiological, cytohistological diagnosis and treatment start were analyzed and compared with 2019., Results: A reduction (25%) in newly diagnosed BC was observed compared to 2019 (666 vs 890). New BC pts in 2020 were less likely to be diagnosed with early stage BC (77% vs 83%, p < 0.01), had a worse performance status according to the Eastern Cooperative Oncology Group (ECOG PS) (19.8% had PS > 0 in 2020 vs 16.5% in 2019, p < 0.01) and fewer pts were asymptomatic at diagnosis in 2020 (54% vs 71%,p < 0.01). COVID-19 did not negatively impact in terms of access to diagnosis, staging and treatment. Time intervals between symptom onset and radiological diagnosis, symptom onset and cytohistological diagnosis, cytohistological diagnosis and treatment start were maintained or improved. However, less cases were discussed in multidisciplinary tumor meetings during 2020 (60% vs 73%, p < 0.01)., Conclusions: Our data proved an alarming reduction of early stage BC associated with the COVID-19 crisis in 2020. Despite the upheaval generated by the pandemic, our study shed light on the effective performance delivered by Italian Oncology Departments to guarantee diagnostic-therapeutic pathways., Competing Interests: Declaration of competing interest Rita Chiari received fees for speaker's bureau and advisory boards participation in BMS, MSD, Roche, Pfizer, AZD, Takeda, Amgen, Boheringer, Novartis. Rossana Berardi is a consultant/advisory board member for Astra Zeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli-Lilly, Roche. Nicla La Verde declare the following financial interests/personal relationships which may be considered as potential competing interests: grants from EISAI; speaker bureau, travel expenses for conference from ROCHE, GENTILI; advisory role from NOVARTIS and CELGENE; advisor role, travel expenses for conference from PFIZER; advisory board from MSD. All other authors declare that there is no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy., (© 2022. The Author(s).)

The broad application of 1 H -indazoles has prompted the development of several approaches for the synthesis of such compounds, including metal-free, palladium-, or copper-promoted intramolecular N -arylation of in situ-generated or isolated o -haloarylhydrazones. Such methods mainly start from o -bromo derivatives due to the better yield observed when compared to those obtained from o -chloroarylhydrazones. However, the o -chloroarylaldehydes and o -chloroarylketones used to prepare the arylhydrazones are more commercially available and less expensive than brominated analogs. Seeking to cover a lack in the literature, this work reports a convenient protocol for the synthesis of N -phenyl- and N -thiazolyl-1 H -indazoles by copper-catalyzed intramolecular N -arylation of o -chlorinated arylhydrazones. Therefore, a series of seven N -phenyl derivatives and a series of six novel N -thiazolyl derivatives was obtained in 10-70% and 12-35% yield, respectively, after stirring the o -chlorinated arylhydrazones, CuI, KOH, and 1,10-phenantroline for 12-48 hours in DMF at 120 °C. The products were isolated by column chromatography on silica gel. All products were fully characterized by HRMS as well as 1 H and 13 C NMR spectroscopy. Thus, this approach is valuable for promoting the synthesis of N -phenyl-1 H -indazoles in a higher yield than that reported in the literature using copper catalysis and the same substrates. This study also prompted the first reported synthesis of pharmacologically interesting N -thiazolyl derivatives., (Copyright © 2022, Barbosa et al.)

The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors to endocrine therapy has remarkably improved the outcome of patients affected with hormone receptor positive (HR+), human epidermal grow factor receptor 2 negative (HER2 -) advanced breast cancer (ABC). Ribociclib showed to be effective across most subgroups, regardless of the number and the site of metastasis. Up to 10% of patients with ABC, reported an oligometastatic condition, recently defined as a slow-volume metastatic disease with limited number and size of metastatic lesions (up to 5 and not necessarily in the same organ), potentially amenable for local treatment, aimed at achieving a complete remission status. Despite the wide use of CDK4/6 inhibitors in HR+, HER2-, ABC treatment, data regarding both locally advanced, inoperable disease and oligometastatic conditions are still poor. We reported a review and case series of HR+, HER2-, ABC patients treated with ribociclib as first-line therapy, for a locally advanced and oligometastatic conditions, reporting an impressive response and good safety profile., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Botticelli, Fabbri, Roberto, Alesini, Cirillo, D’Auria, Krasniqi, Marrucci, Muratore, Pantano, Pizzuti, Portarena, Rossi, Scagnoli and Marchetti.)

Introduction: The connection between driver mutations and the efficacy of immune checkpoint inhibitors is the focus of intense investigations. In lung adenocarcinoma (LUAD), KEAP1/STK11 alterations have been tied to immunoresistance. Nevertheless, the heterogeneity characterizing immunotherapy efficacy suggests the contribution of still unappreciated events., Methods: Somatic interaction analysis of top-ranking mutant genes in LUAD was carried out in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) (N = 6208). Mutational processes, intratumor heterogeneity, evolutionary trajectories, immunologic features, and cancer-associated signatures were investigated, exploiting multiple data sets (AACR GENIE, The Cancer Genome Atlas [TCGA], TRAcking Cancer Evolution through therapy [Rx]). The impact of the proposed subtyping on survival outcomes was assessed in two independent cohorts of immune checkpoint inhibitor-treated patients: the tissue-based sequencing cohort (Rome/Memorial Sloan Kettering Cancer Center/Dana-Farber Cancer Institute, tissue-based next-generation sequencing [NGS] cohort, N = 343) and the blood-based sequencing cohort (OAK/POPLAR trials, blood-based NGS cohort, N = 304)., Results: Observing the neutral interaction between KEAP1 and TP53, KEAP1/TP53-based subtypes were dissected at the molecular and clinical levels. KEAP1 single-mutant (KEAP1 SM) and KEAP1/TP53 double-mutant (KEAP1/TP53 DM) LUAD share a transcriptomic profile characterized by the overexpression of AKR genes, which are under the control of a productive superenhancer with NEF2L2-binding signals. Nevertheless, KEAP1 SM and KEAP1/TP53 DM tumors differ by mutational repertoire, degree of intratumor heterogeneity, evolutionary trajectories, pathway-level signatures, and immune microenvironment composition. In both cohorts (blood-based NGS and tissue-based NGS), KEAP1 SM tumors had the shortest survival; the KEAP1/TP53 DM subgroup had an intermediate prognosis matching that of pure TP53 LUAD, whereas the longest survival was noticed in the double wild-type group., Conclusions: Our data provide a framework for genomically-informed immunotherapy, highlighting the importance of multimodal data integration to achieve a clinically exploitable taxonomy., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients., Methods: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS)., Results: Patients who received a first-line pertuzumab-based regimen showed better PFS ( p < 0.0001) and OS ( p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine ( p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine ( p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 ( p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era . No significant differences emerged when comparing patients treated with 'old' or 'new' drugs ( p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account., Conclusion: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EK, IS, MB, MM, MMaz, EMV, IM, RB, FSDL, MP, LI, ER, NDO, ST, CF, KC, FR, AC, MAF, GB, AB, GDA, AC, AR, BTS, GS, FG, RS, DM, DC, EMC, VS, LMe, GT, MR, LM, MMi, EMR, PS, NS, LL, NT, AG, AFS, RR, MRV, EL, SS, BF, MMS, MDT, AM, AO, VL, EC, GS, PP, FC, LL, CB, FT, SC, GB, FP, FCav, OB, EF, JF, SS, and GC declare no conflicts of interest. LP received travel grants from Eisai, Roche, Pfizer, and Novartis; speaker fees from Roche, Pfizer, Novartis, and Gentili. TG received travel grants from Eisai, Roche, Pfizer, and Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili, and Lilly. CN received travel grants/personal fees from Pfizer, Eisai, Novartis, Merck Sharp & Dohme, and AstraZeneca. EB is supported by the Italian Association for Cancer Research AIRC-IG 20583; he was supported by the International Association for Lung Cancer (IASLC), the LILT (Lega Italiana per la Lotta contro I Tumori), and Fondazione Cariverona; he received speakers’ and travels’ fee from MSD, AstraZeneca, Celgene, Pfizer, Helsinn, Eli Lilly, BMS, Novartis, and Roche; consultant’s fee from Roche, Pfizer; institutional research grants from AstraZeneca and Roche. AM received travel grants from Eisai, Celgene, and Novartis Ipsen; personal fees, advisory boards from Eisai, Novartis, AstraZeneca, Teva, Pfizer, and Celgene. IP received personal fees/advisory boards from Roche, Pfizer, Novartis, Italfarmaco, Gentili, and Pierre Fabre. LM received personal fees/advisory board from Roche, Novartis, Eisai, and Pfizer. GT and DS: advisory board Novartis, Pfizer, Eisai, Roche, and Eli Lilly. PM has/had a consultant/advisory role for BMS, Roche Genentech, MSD, Novartis, Amgen, Merck Serono, Pierre Fabre, and Incyte. PV received travel grants from Eisai, Roche, Pfizer, and Novartis; speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili, and Eli Lilly., (© The Author(s), 2021.)

Purpose: The most appropriate therapy for HR + /HER2-positive (HER2 +) advanced breast cancer (ABC) is a matter of debate. Co-targeting of both receptors represents an attractive strategy to overcome the cross-talk between them., Methods: The HERMIONE 9 is an observational retrospective multicentric study which aimed to describe the clinical outcome of patients with HR + /HER2 + ABC who received the combination of Fulvestrant (F) and Trastuzumab (T) as part of their routine treatment at 10 Italian Institutions., Results: Eighty-seven patients were included. Median age was 63 (range, 35-87) years. The median number of previous treatments was 3 (range, 0-10) and F and T were administered as ≥ 3rd line in 67 patients. Among the 86 evaluable patients, 6 (6.9%) achieved CR, 18 (20.7%) PR, and 44 (50.6%) had SD ≥ 24 weeks with an overall CBR of 78.2%. At a median follow-up of 33.6 months, mPFS of the entire cohort was 12.9 months (range, 2.47-128.67). No difference was observed in mPFS between patients treated after progression or as maintenance therapy (mPFS 12.9 and 13.9 months in 64 and 23 patients, respectively), neither considering the number of previous treatment lines (≤ 3 or < 3)., Conclusion: The combination of F and T was active in this cohort at poor prognosis and deserves further investigations possibly in combination with pertuzumab in patients with high ER expression., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The actual role of chemotherapy in vulvar cancer is undeniably a niche topic. The low incidence of the disease limits the feasibility of randomized trials. Decision making is thus oriented by clinical and pathological features, whose relevance is generally weighted against evidence from observational studies and clinical practice. The therapeutic management of vulvar cancer is increasingly codified and refined at an individual patient level. It is of note that the attitude towards evidence sharing and discussion within a multidisciplinary frame is progressively consolidating. Viable options included in the therapeutic armamentarium available for vulvar cancer patients are frequently an adaption from standards used for cervical or anal carcinoma. Chemotherapy is more frequently combined with radiotherapy as neo-/adjuvant or definitive treatment. Drugs commonly used are platinum derivative, 5-fluorouracil and mitomicin C, mostly in combination with radiotherapy for radiosensitization. Exclusive chemotherapy in the neo-/adjuvant setting comprises platinum-derivative, combined with bleomicin and methotrexate, 5-fluorouracil, ifosfamide or taxanes. In advanced disease, current regimens include cisplatin-based chemoradiation, with or without 5-fluorouracil, or doublets with platinum in combination with a taxane. Our work is also enriched by a concise excursus on the biologic pathways underlying vulvar cancer. Introductory hints are also provided on targeted agents, a rapidly evolving research field.

Background: In Western countries, ovarian cancer (OC) still represents the leading cause of gynecological cancer-related deaths, despite the remarkable gains in therapeutical options. Novel biomarkers of early diagnosis, prognosis definition and prediction of treatment outcomes are of pivotal importance. Prior studies have shown the potentials of micro-ribonucleic acids (miRNAs) as biomarkers for OC and other cancers., Methods: We focused on the prognostic and/or predictive potential of miRNAs in OC by conducting a comprehensive array profiling of miRNA expression levels in ovarian tissue samples from 17 non-neoplastic controls, and 60 tumor samples from OC patients treated at the Regina Elena National Cancer Institute (IRE). A set of 54 miRNAs with differential expression in tumor versus normal samples (T/N-deregulated) was identified in the IRE cohort and validated against data from the Cancer Genoma Atlas (TCGA) related to 563 OC patients and 8 non-neoplastic controls. The prognostic/predictive role of the selected 54 biomarkers was tested in reference to survival endpoints and platinum resistance (P-res)., Results: In the IRE cohort, downregulation of the 2 miRNA-signature including miR-99a-5p and miR-320a held a negative prognostic relevance, while upregulation of miR-224-5p was predictive of less favorable event free survival (EFS) and P-res. Data from the TCGA showed that downregulation of 5 miRNAs, i.e., miR-150, miR-30d, miR-342, miR-424, and miR-502, was associated with more favorable EFS and overall survival outcomes, while miR-200a upregulation was predictive of P-res. The 9 miRNAs globally identified were all included into a single biologic signature, which was tested in enrichment analysis using predicted/validated miRNA target genes, followed by network representation of the miRNA-mRNA interactions., Conclusions: Specific dysregulated microRNA sets in tumor tissue showed predictive/prognostic value in OC, and resulted in a promising biological signature for this disease., (© 2021. The Author(s).)