The Consistency and Quality of ChatGPT Responses Compared to Clinical Guidelines for Ovarian Cancer: A Delphi Approach.

INTRODUCTION: In recent years, generative Artificial Intelligence models, such as ChatGPT, have increasingly been utilized in healthcare. Despite acknowledging the high potential of AI models in terms of quick access to sources and formulating responses to a clinical question, the results obtained using these models still require validation through comparison with established clinical guidelines. This study compares the responses of the AI model to eight clinical questions with the Italian Association of Medical Oncology (AIOM) guidelines for ovarian cancer. MATERIALS AND METHODS: The authors used the Delphi method to evaluate responses from ChatGPT and the AIOM guidelines. An expert panel of healthcare professionals assessed responses based on clarity, consistency, comprehensiveness, usability, and quality using a five-point Likert scale. The GRADE methodology assessed the evidence quality and the recommendations' strength. RESULTS: A survey involving 14 physicians revealed that the AIOM guidelines consistently scored higher averages compared to the AI models, with a statistically significant difference. Post hoc tests showed that AIOM guidelines significantly differed from all AI models, with no significant difference among the AI models. CONCLUSIONS: While AI models can provide rapid responses, they must match established clinical guidelines regarding clarity, consistency, comprehensiveness, usability, and quality. These findings underscore the importance of relying on expert-developed guidelines in clinical decision-making and highlight potential areas for AI model improvement.

Abemaciclib pharmacology and interactions in the treatment of HR+/HER2- breast cancer: a critical review.

Abemaciclib (ABE) in combination with endocrine therapy represents the mainstay treatment for either endocrine-resistant metastatic or high-risk early-stage HR+/HER2- breast cancer patients. Hence, an adequate knowledge of this agent pharmacodynamic, pharmacokinetic, and of its drug-drug interactions (DDIs) is crucial for an optimal patients management. Additionally, ABE interference with food and complementary/alternative medicines should be taken into account in the clinical practice. Several online tools allow to freely check DDIs and can be easily consulted before prescribing ABE. According to one of this instruments, ABE display the lowest number of interactions among the available cyclin-dependent kinase 4/6 inhibitors. Still, clinicians should be aware that online tools cannot replace the technical datasheet of the drug as well as a comprehensive clinical assessment for each patient. Here we critically review the main pharmacological features of ABE, then focusing on its potential interactions with drugs, food, and alternative medicine, in order to provide a guide for its optimal use in the treatment of HR+/HER2- breast cancer patients.

Pharmacological features and drug interactions of abemaciclib Why was the review done? Abemaciclib, paired with hormone therapy, is a key treatment for breast cancer patients whose cancer cells respond to hormones but not to a protein called HER2. Understanding how this medication functions in the body, how it interacts with other drugs, and how the body processes it is crucial for providing optimal care. What did the authors do? The authors looked for published evidence about the way abemaciclib works into the body and about how it interacts with other drugs (including alternative medicines) or food. Then they summarized these findings. What did the authors find? Abemaciclib absorption, distribution, metabolism and excretion is well known and it is here described. What people eat and any alternative medications they take can affect how abemaciclib works. Online tools are available for doctors to check potential interactions between abemaciclib and other drugs a patient might be using. It's advisable for doctors to consult abemaciclib data sheet and use online tools before prescribing the drug. Notably, compared to similar treatments, abemaciclib has fewer interactions with other drugs. What does the review mean? This review delves into how abemaciclib works in the body and explore its potential interactions with other drugs, food, and alternative medicines. This information will aid doctors in using abemaciclib effectively for treating breast cancer patients.

Navigating the Nexus: HIV and Breast Cancer-A Critical Review.

Despite significant advances in the management of antiretroviral therapy (ART), leading to improved life expectancy for people living with HIV (PLWH), the incidence of non-AIDS-defining cancers, including breast cancer, has emerged as a critical concern. This review synthesizes current evidence on the epidemiology of breast cancer among HIV-infected individuals, highlighting the potential for an altered risk profile, earlier onset, and more advanced disease at diagnosis. It delves into the molecular considerations underpinning the relationship between HIV and breast cancer, including the role of immunosuppression, chronic inflammation, and gene expression alterations. Additionally, it examines the complexities of managing breast cancer in the context of HIV, particularly the challenges posed by ART and anticancer agents' cross-toxicities and drug-drug interactions. The review also addresses survival disparities, underscoring the need for improved cancer care in this population. By identifying gaps in knowledge and areas requiring further research, this review aims to illuminate the complexities of HIV-associated breast cancer, fostering a deeper understanding of its epidemiology, molecular basis, and clinical management challenges, thereby contributing to better outcomes for individuals at the intersection of these two conditions. This narrative review systematically explores the intersection of HIV infection and breast cancer, focusing on the impact of HIV on breast cancer risk, outcomes, and treatment challenges.

A review and metanalysis of metronomic oral single-agent cyclophosphamide for treating advanced ovarian carcinoma in the era of precision medicine.

OBJECTIVE: Oral metronomic cyclophosphamide has been used as a single agent or in combination with other drugs for several solid tumors with interesting results in disease palliation and mild to moderate toxicity, notably in patients with recurrent epithelial ovarian cancer (EOC) progressing after systemic chemotherapy. In this paper, we report a review and a metanalysis of heterogeneous data published up to date. DATA SOURCES: The literature search was restricted to single-agent MOC. The analysis was conducted through March 2023 by consulting PubMed, Embase, Google Scholar, and The Cochrane Library databases. Research string and Medical Subject Headings included "ovarian tumor," "ovarian carcinoma," or "ovarian cancer," "fallopian tube cancer," "primary peritoneal cancer," "oral chemotherapy," and "metronomic cyclophosphamide." All articles were assessed for quality by at least two investigators independently, and a < 18 patients sample size cutoff was chosen as a lower limit with a Cohen's kappa statistical coefficient for accuracy and reliability. Metanalysis of selected papers was carried out according to a fixed model. DATA SUMMARY: The percentage of agreement between investigators on literature study selection was very high, reaching 96.9% with a Cohen's k of 0.929. MOC pooled objective response rate (ORR) and disease control rate for recurrent or platinum-refractory ovarian cancer were 18.8% (range 4-44%) and 36.2% (range 16-58.8%), respectively. The mean progressive-free survival and overall survival were 3.16 months (range 1.9 to 5.0 months) and 8.7 months (range 8 to 13 months), respectively. The fixed model metanalysis of selected studies showed a 16% median ORR (12-20% CI, p < 0.001). CONCLUSIONS: Single-agent oral cyclophosphamide in EOC holds promise as a treatment option, even in the era of precision medicine. Genetic factors, such as DNA repair gene polymorphisms, may influence treatment response. Combining cyclophosphamide with biological agents such as PARP inhibitors or immunotherapy agents is an area of active investigation.

More Than Meets the Eye: A Case of Breast Cancer Switching from Being Luminal-Androgen-Receptor-Positive to Being Hormone-Receptor-Positive.

Triple-negative breast cancer (TNBC) represents about 15% of all breast cancers and is usually characterized by aggressive clinical behavior and a poor prognosis. Four TNBC subgroups have been previously defined with different molecular profiles: (i) luminal androgen receptor (LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS) and (iv) basal-like immune-activated (BLIA). Among these, LAR is characterized by the expression of the androgen receptor (AR), and exhibits genomic characteristics that resemble luminal breast cancers, with a still undefined prognosis and clinical behavior. Here, we report a case of a woman affected by recurring LAR TNBC, which underwent phenotypic changes throughout its natural history. After the initial diagnosis of LAR breast cancer, the patient experienced local recurrence with strong expression of the estrogen receptor. Due to this finding, she started treatment with a CDK4/6-inhibitor and an aromatase inhibitor, followed by oral vinorelbine, both with dismal outcomes. Then, she received everolimus and exemestane, which determined temporary disease stabilization. An extensive NGS analysis of tumor tissue showed PIK3CA and HER2 mutations. Our case is consistent with previous reports of LAR breast cancer and underlines the potential utility of re-biopsy and molecular testing in breast cancer (BC), especially in rare subtypes.

Single-Cell Analysis in the Omics Era: Technologies and Applications in Cancer.

Cancer molecular profiling obtained with conventional bulk sequencing describes average alterations obtained from the entire cellular population analyzed. In the era of precision medicine, this approach is unable to track tumor heterogeneity and cannot be exploited to unravel the biological processes behind clonal evolution. In the last few years, functional single-cell omics has improved our understanding of cancer heterogeneity. This approach requires isolation and identification of single cells starting from an entire population. A cell suspension obtained by tumor tissue dissociation or hematological material can be manipulated using different techniques to separate individual cells, employed for single-cell downstream analysis. Single-cell data can then be used to analyze cell-cell diversity, thus mapping evolving cancer biological processes. Despite its unquestionable advantages, single-cell analysis produces massive amounts of data with several potential biases, stemming from cell manipulation and pre-amplification steps. To overcome these limitations, several bioinformatic approaches have been developed and explored. In this work, we provide an overview of this entire process while discussing the most recent advances in the field of functional omics at single-cell resolution.

A retrospective, real-life analysis of metronomic oral single-agent cyclophosphamide for the treatment of platinum-pretreated advanced ovarian carcinoma in Italy.

INTRODUCTION: Metronomic oral cyclophosphamide (MOC) presents many potential advantages, such as significantly less severe side effects than standard regimens, ease of administration, and the delivery of a dose-dense but not necessarily dose-intense treatment. These observations prompted us to evaluate in a retrospective, multicenter study the efficacy and toxicity of MOC in a real-life series of pretreated cancer patients. METHODS: The study is a multicenter, retrospective analysis of the activity of single-agent MOC in patients with recurrent or residual epithelial ovarian, fallopian tube, or primary. Eligible patients were continuously treated with MOC at 50 mg/day until progression, toxicity, or death. Overall response rate (ORR), stable disease (SD), and disease control rate (DCR) were reported. RESULTS: The study included 62 patients. Three patients reached a complete response rate (5%), 11 had a partial response rate (18), and 15 had stabilization of disease (24) for an ORR of 23% and a DCR of 47%. Patients with low-grade indolent tumors showed an ORR and an SD rate higher than that observed in non-indolent ones (33% vs. 18% and 28% vs. 14%, respectively). Overall, progression-free survival was 3.5 months (range 1-9 months). CONCLUSION: Single-agent MOC is active and very well tolerated in a significant fraction of patients with refractory, recurrent, or residual epithelial ovarian, fallopian tube, or primary peritoneal cancer. In the vision of a practical approach, single-agent MOC may be a useful palliative treatment option for patients with poor tolerance to high-dose regimens or widely pretreated. Further studies are needed better to characterize the role of such an approach in clinical practice.

Glucose-dependent effect of insulin receptor isoforms on tamoxifen antitumor activity in estrogen receptor-positive breast cancer cells.

Introduction: Breast cancer is the most common malignancy in women, and it is linked to several risk factors including genetic alterations, obesity, estrogen signaling, insulin levels, and glucose metabolism deregulation. Insulin and Insulin-like growth factor signaling exert a mitogenic and pro-survival effect. Indeed, epidemiological and pre-clinical studies have shown its involvement in the development, progression, and therapy resistance of several cancer types including breast cancer. Insulin/Insulin-like growth factor signaling is triggered by two insulin receptor isoforms identified as IRA and IRB and by Insulin-like growth factor receptor I. Both classes of receptors show high homology and can initiate the intracellular signaling cascade alone or by hybrids formation. While the role of Insulin-like growth factor receptor I in breast cancer progression and therapy resistance is well established, the effects of insulin receptors in this context are complex and not completely elucidated. Methods: We used estrogen-dependent insulin-like growth factor receptor I deleted gene (MCF7IGFIRKO) breast cancer cell models, lentivirally transduced to over-express empty-vector (MCF7IGFIRKO/EV), IRA (MCF7IGFIRKO/IRA) or IRB (MCF7IGFIRKO/IRB), to investigate the role of insulin receptors on the antiproliferative activity of tamoxifen in presence of low and high glucose concentrations. The tamoxifen-dependent cytotoxic effects on cell proliferation were determined by MTT assay and clonogenic potential measurement. Cell cycle and apoptosis were assessed by FACS, while immunoblot was used for protein analysis. Gene expression profiling was investigated by a PCR array concerning genes involved in apoptotic process by RT-qPCR. Results: We found that glucose levels played a crucial role in tamoxifen response mediated by IRA and IRB. High glucose increased the IC50 value of tamoxifen for both insulin receptors and IRA-promoted cell cycle progression more than IRB, independently of glucose levels and insulin stimulation. IRB, in turn, showed anti-apoptotic properties, preserving cells' survival after prolonged tamoxifen exposure, and negatively modulated pro-apoptotic genes when compared to IRA. Discussion: Our findings suggest that glucose levels modify insulin receptors signaling and that this event can interfere with the tamoxifen therapeutic activity. The investigation of glucose metabolism and insulin receptor expression could have clinical implications in Estrogen Receptor positive breast cancer patients receiving endocrine treatments.

Potential Therapeutic Targets for Luminal Androgen Receptor Breast Cancer: What We Know so Far.

Luminal Androgen Receptor Breast Cancers (LAR BCs) are characterized by a triple negative phenotype and by the expression of Androgen Receptor (AR), coupled with luminal-like genomic features. This unique BC subtype, accounting for about 10% of all triple negative BC, has raised considerable interest given its ill-defined clinical behavior and the chance to exploit AR as a therapeutic target. The complexity of AR activity in BC cells, as revealed by decades of mechanistic studies, holds promise to offer additional therapeutic options beyond mere AR inhibition. Indeed, preclinical and translational evidence showed that several pathways and mediators, including PI3K/mToR, HER2, BRCA1, cell cycle and immune modulation, can be tackled in LAR BCs. Moving from bench to bedside, several clinical trials tested anti-androgen therapies in LAR BCs, but their results are inconsistent and often disappointing. More recently, studies exploring combinations of anti-androgen agents with other targeted therapies have been designed and are currently ongoing. While the results from these trials are awaited, a concerted effort will be needed to find the biological vulnerabilities of LAR BCs which may disclose new and effective therapeutic targets, eventually improving patients' outcomes.

Abemaciclib-associated Diarrhea: An Exploratory Analysis of Real-life Data.

BACKGROUND/AIM: Abemaciclib is a cyclin-dependent kinase 4/6 inhibitor approved in combination with endocrine therapy for treating hormone receptor-positive and human epidermal growth factor receptor 2-negative early and advanced breast cancer patients. The safety profile of abemaciclib is characterized by frequent gastrointestinal toxicity, especially diarrhea. Therefore, we performed an exploratory analysis of clinical factors that may be potentially associated with diarrhea in patients treated with abemaciclib plus endocrine therapy. PATIENTS AND METHODS: Factors potentially predisposing to diarrhea were selected, such as age ≥70 years, concomitant medications and diseases, diet, and use of laxatives. These variables were correlated with the onset of grade 2/3 diarrhea in a cohort of patients treated with abemaciclib from advanced breast cancer. Univariate and multivariate analysis was performed. Sensitivity and specificity were tested using the ROC curve. RESULTS: Eighty women with advanced breast cancer were included in the study. The univariate analysis found a statistically significant correlation between grade 2/3 diarrhea and age ≥70 years, polypharmacy, and concomitant gastrointestinal diseases (p<0.05). In the multivariate analysis, the number of risk factors significantly correlated with the outcome of interest (p<0.0001). ROC analysis showed our model's 82% sensitivity and 75% specificity. CONCLUSION: Taking into account specific pre-existing factors, it is possible to estimate the risk of diarrhea in hormone receptor-positive and human epidermal growth factor receptor 2-negative - advanced breast cancer patients, candidates for abemaciclib plus endocrine therapy. In these subjects, implementing proactive prevention and adopting a dose-escalation strategy may represent practical approaches to decrease the abemaciclib toxicity burden.

Giant Paratesticular Liposarcoma: Molecular Characterization and Management Principles with a Review of the Literature.

Paratesticular liposarcomas are extremely rare malignant tumors originating from fat tissues, with an often-challenging diagnosis. We present here the case of a 76-year-old man with a giant paratesticular liposarcoma, initially misdiagnosed as a scrotal hernia. After two years, the progressively enlarging mass underwent surgical resection, and a diagnosis of well-differentiated liposarcoma (lipoma-like subtype) was made. Post-operative treatments were not indicated, and the patient remains relapse free. Next generation sequencing performed on the neoplastic tissue showed co-amplification of MDM2 and CDK4. These alterations are molecular hallmarks of well-differentiated liposarcomas and corroborate the histological diagnosis. Clinical and molecular features of the presented case are in line with the majority of previously published experiences. In conclusion, the presence of a liposarcoma should be taken into account during the diagnostic workup of scrotal masses, in order to minimize the rate of misdiagnosis and improper management. Molecular analysis may support histological characterization of these rare entities and potentially disclose novel therapeutic targets.

Orbital metastasis from thyroid cancer: a case report and review of the literature.

BACKGROUND: Differentiated thyroid cancer (DTC) is generally associated with an excellent prognosis. However up to 20% of DTC patients have disease events during subsequent follow-up; rarely patients present an aggressive disease with distant metastases (DM), mainly in the lung and bone. Metastases at unusual sites may also occur, generally in patients with disseminated disease. Orbital localization is rare and only few cases have been described so far. CASE DESCRIPTION: A 36 years-old man, treated with chemo and radiotherapy during childhood for non-Hodgkin lymphoma, was referred for suspicious lymph node (LN) and multiple lung metastases. Total thyroidectomy and latero-cervical (LC) lymphadenectomy were performed: papillary thyroid cancer (PTC), 25 mm, 11/17 LN metastases; pT2N1bM1. Post-treatment total body scan with I-131 showed LN and lung uptake. Eighteen months from diagnosis he presented progressive diplopia, proptosis and right exophthalmos due to an 18 mm orbital metastasis. Hence, due to I-131 refractoriness for structural disease progression despite I-131 therapy, he started therapy with Lenvatinib for 6 months, with initial partial response followed by disease progression, and then with Cabozantinib, which he stopped after 6 months for adverse events and disease progression after therapy reduction. Currently, the patient is receiving Lenvatinib, rechallenge therapy, with disease stabilization and biochemical response. Molecular analysis, performed on both primary and relapsed tumor didn't show any significant pathogenic alteration. CONCLUSIONS: This case of DTC with an unusual metastasis in the orbit, may suggest that patient's exposure to chemo- and radiotherapy during pediatric age might have played a role in the subsequent development of this unusually aggressive tumor, reinforcing the recommendation of long-term and intensive follow-up of these patients.

Molecular Analysis of Luminal Androgen Receptor Reveals Activated Pathways and Potential Therapeutic Targets in Breast Cancer.

BACKGROUND/AIM: Triple-negative breast cancers represent 15% of all mammary malignancies and encompass several entities with different genomic characteristics. Among these, luminal androgen receptor (LAR) tumors express the androgen receptor (AR) and are characterized by a genomic profile which resembles luminal breast cancers. Moreover, LAR malignancies are usually enriched in PIK3CA, KMTC, CDH, NF1, and AKT1 alterations. Still, molecular features, clinical behavior and prognosis of this variant remain controversial, while identification of effective treatments represents an unmet medical need. Additionally, the predictive role of the AR is unclear. MATERIALS AND METHODS: We performed an extensive next generation sequencing analysis using a commercially available panel in a cohort of patients with LAR breast cancer followed at two local Institutions. We next employed bioinformatic tools to identify signaling pathways involved in LAR pathogenesis and looked for potentially targetable alterations. RESULTS: Eight patients were included in the study. In our cohort we found 26 known genetic alterations (KGAs) in 15 genes and 64 variants of unknown significance (VUS) in 59 genes. The most frequent KGAs were single nucleotide variants in PIK3CA, HER2, PTEN and TP53. Among VUS, CBFB, EP300, GRP124, MAP3K1, RANBP2 and TSC2 represented recurrently altered genes. We identified five signaling pathways (MAPK, PI3K/AKT, TP53, apoptosis and angiogenesis) involved in the pathogenesis of LAR breast cancer. Several alterations, including those in PIK3CA, ERBB2 and PI3K/AKT/mTOR signaling, were potentially targetable. CONCLUSION: Our findings confirm a role for PI3K/AKT/mTOR signaling in the pathogenesis of LAR breast cancers and indicate that targeting this pathway, along with ERBB2 mutations, may represent an additional therapeutic strategy which deserves further exploration in larger studies.

Mutational Analysis of BRCA1 and BRCA2 Genes in Breast Cancer Patients from Eastern Sicily.

Purpose: Germline mutations of BRCA1 and BRCA2 are associated with a defined lifetime risk of breast (BC), ovarian (OC) and other cancers. Testing BRCA genes is pivotal to assess individual risk, but also to pursue preventive approaches in healthy carriers and tailored treatments in tumor patients. The prevalence of BRCA1 and BRCA2 alterations varies broadly across different geographic regions and, despite data about BRCA pathogenic variants among Sicilian families exist, studies specifically addressing eastern Sicily population are lacking. The aim of our study was to investigate the incidence and distribution of BRCA pathogenic germline alterations in a cohort of BC patients from eastern Sicily and to evaluate their associations with specific BC features. Patients and Methods: Mutational status was assessed in a cohort of 389 BC patients, using next generation sequencing. The presence of alterations was correlated with tumor grading and proliferation index. Results: Overall, 35 patients (9%) harbored a BRCA pathogenic variant, 17 (49%) in BRCA1 and 18 (51%) in BRCA2. BRCA1 alterations were prevalent among triple negative BC patients, whereas BRCA2 mutations were more common in subjects with luminal B BC. Tumor grading and proliferation index were both significantly higher among subjects with BRCA1 variants compared to non-carriers. Conclusion: Our findings provide an overview about BRCA mutational status among BC patients from eastern Sicily and confirm the role of NGS analysis to identify hereditary BC patients. Overall, these data are consistent with previous evidences supporting BRCA screening to properly prevent and treat cancer among mutation carriers.

Next generation sequencing in a cohort of patients with rare sarcoma histotypes: A single institution experience.

Sarcomas are mesenchymal-derived cancers with overlapping clinical and pathologic features and a remarkable histological heterogeneity. While a precise diagnosis is often challenging to achieve, systemic treatment of sarcomas is still quite uniform. In this scenario, next generation sequencing (NGS) may be exploited to assist diagnosis and to identify specific targetable alterations. However, the precise role of genomic characterization in these diseases is still debated. In the present study, we analyzed 18 samples from 11 low-incidence sarcomas using NGS technology. We also used an in-silico prediction tool to reclassify variants of unknown significance and then looked for potentially druggable alterations to match with targeted therapies. Our cohort presented several predictable findings (e.g. MYC amplification in radio-induced angio-sarcoma, COL1A1-PDGFB rearrangements in dermatofibrosarcoma protuberans) along with unexpected results (e.g. the reciprocal WT1-EWSR1 fusion in a desmoplastic small round cell tumor). One third of patients (6/18) displayed at least one actionable molecular alterations. Our experience confirms the potential role of NGS in the management of rare sarcomas. This tool may support the diagnostic process, but also detect targets for personalized therapies.

Ribociclib efficacy in special populations and analysis of patient-reported outcomes in the MONALEESA trials.

INTRODUCTION: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors abemaciclib, palbociclib, and ribociclib radically modified the treatment of hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer. Ribociclib efficacy was proved in the phase III MONALEESA-2, -3, and -7 trials. In the first-line setting, ribociclib plus endocrine therapy determined statistically significant improvements in progression-free (PFS) and overall survival (OS) in pre-menopausal (MONALEESA-7) and post-menopausal (MONALEESA-2) women. Likewise, ribociclib and fulvestrant induced a significant PFS and OS benefit in post-menopausal women previously treated with endocrine therapy (MONALEESA-3). Additionally, ribociclib did not affect patients health-related quality of life in all the MONALEESA trials. AREAS COVERED: We reviewed the results of the available randomized phase III trials testing ribociclib and endocrine therapy in advanced breast cancer, focusing on different patient subgroups and then on health-related quality of life. EXPERT OPINION: The benefit of ribociclib is consistent across patient subgroups and is maintained in populations with unfavorable features, such as those with endocrine resistance or visceral metastases. Furthermore, the addition of ribociclib to endocrine therapy delays quality of life deterioration and improves pain scores. These results represent a pivotal improvement for the treatment of advanced breast cancer patients receiving CDK4/6 inhibitors.

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents.

Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.

A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors.

Human trophoblast cell-surface antigen-2 (Trop-2) is a membrane glycoprotein involved in cell proliferation and motility, frequently overexpressed in epithelial tumors. Thus, it represents an attractive target for anticancer therapies. Sacituzumab govitecan (SG) is a third-generation antibody-drug conjugate, consisting of an anti-Trop-2 monoclonal antibody (hRS7), a hydrolyzable linker, and a cytotoxin (SN38), which inhibits topoisomerase 1. Specific pharmacological features, such as the high antibody to payload ratio, the ultra-toxic nature of SN38, and the capacity to kill surrounding tumor cells (the bystander effect), make SG a very promising drug for cancer treatment. Indeed, unprecedented results have been observed with SG in patients with heavily pretreated advanced triple-negative breast cancer and urothelial carcinomas, and the drug has already received approval for these indications. These results are coupled with a manageable toxicity profile, with neutropenia and diarrhea as the most frequent adverse events, mainly of grades 1-2. While several trials are exploring SG activity in different tumor types and settings, potential biomarkers of response are under investigation. Among these, Trop-2 overexpression and the presence of BRCA1/2 mutations seem to be the most promising. We review the available literature concerning SG, with a focus on its toxicity spectrum and possible biomarkers of its response.

Targeting the DNA damage response: PARP inhibitors and new perspectives in the landscape of cancer treatment.

Cancer derives from alterations of pathways responsible for cell survival, differentiation and proliferation. Dysfunctions of mechanisms protecting genome integrity can promote oncogenesis but can also be exploited as therapeutic target. Poly-ADP-Ribose-Polymerase (PARP)-inhibitors, the first approved targeted agents able to tackle DNA damage response (DDR), have demonstrated antitumor activity, particularly when homologous recombination impairment is present. Despite the relevant results achieved, a large proportion of patients fail to obtain durable responses. The development of innovative treatments, able to overcome resistance and ensure long-lasting benefit for a wider population is still an unmet need. Moreover, improvement in biomarker assays is necessary to properly identify patients who can benefit from DDR targeting agents. Here we summarize the main DDR pathways, explain the current role of PARP inhibitors in cancer therapy and illustrate new therapeutic strategies targeting the DDR, focusing on the combinations of PARP inhibitors with other agents and on cell-cycle checkpoint inhibitors.