Hormone Receptor-Positive/HER2-Positive Breast Cancer: Hormone Therapy and Anti-HER2 Treatment: An Update on Treatment Strategies.

Hormone receptor (HR)-positive/HER2-positive breast cancer represents a distinct subtype expressing estrogen and progesterone receptors with an overexpression of HER2. Approximately 14% of female breast cancer cases are HER2-positive, with the majority being HR-positive. These tumors show a cross-talk between the hormonal and HER2 pathways; the interaction has implications for the treatment options for the disease. In this review, we analyze the biology of HR-positive/HER2-positive breast cancer and summarize the evidence concerning the standard of care options both in neoadjuvant/adjuvant settings and in advanced disease. Additionally, we focus on new trials and drugs for HR-positive/HER2-positive breast cancer and the new entity: HER2-low breast cancer.

Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging.

Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes.

Malignant Pleural Mesothelioma: Staging and Radiological Response Criteria in Patients Treated with Immune Checkpoint Inhibitors.

Malignant pleural mesothelioma (MPM) is a rare and challenging cancer associated with asbestos fiber exposure, which offers limited treatment options. Historically, platinum-based chemotherapy has been the primary approach, but recent developments have introduced immunotherapy as a promising alternative for the treatment of this disease. Nevertheless, the unique growth patterns and occasionally ambiguous progressive characteristics of MPM make the interpretation of radiological assessments complex. Immunotherapy further complicates matters by introducing unconventional treatment response patterns such as hyperprogression and pseudoprogression. Consequently, there is a growing imperative to integrate the standard RECIST criteria with the mesothelioma-specific mRECIST criteria (version 1.1), as outlined in iRECIST. This comprehensive review is driven by the intent to provide a valuable resource for radiologists and clinicians engaged in the diagnosis, treatment, and monitoring of MPM in the era of immunotherapy. Specifically, the current imaging methods employed for staging and follow-up will be exposed and discussed, with a focus on the technical specificities and the mRECIST 1.1 methodology. Furthermore, we will provide a discussion about major clinical trials related to the use of immunotherapy in MPM patients. Finally, the latest advancements in radiomics, the applications of artificial intelligence in MPM, and their potential impact on clinical practice for prognosis and therapy, are discussed.

CDK4/6 inhibition in hormone receptor-positive/HER2-negative breast cancer: Biological and clinical aspects.

A dysregulated cell division, one of the key hallmarks of cancer, results in uncontrolled cellular proliferation. This aberrant process, mediated by a dysregulated cell-cycle machinery and overactivation of cyclin-dependent kinase (CDK) 4 and 6, can potentially promote tumorigenesis. The clinical application of CDK 4/6 inhibitors, developed to inhibit cell-cycle progression, in the treatment regimens of breast cancer (BC) patients is expanding. Currently, three agents, ribociclib, palbociclib, and abemaciclib, are approved for treating patients with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic BC. In addition, abemaciclib is FDA and EMA-approved for patients with hormone receptor-positive HER2-negative, node-positive, early BC at high risk of recurrence. Emerging data suggest potential anti-tumor effects beyond cell cycle arrest, providing novel insights into the agent's mechanisms of action. As a result, a broader application of the CDK4/6 inhibitors in patients with cancer is achieved, contributing to enhanced optimized treatment in the adjuvant and neoadjuvant settings. Herein, the immunomodulatory activities of CDK4/6 inhibitors, their impact on the cell's metabolic state, and the effect on the decision of the cell to undergo quiescence or senescence are discussed. Moreover, this review provides an update on clinical trial outcomes and the differences in the underlying mechanisms between the distinct CDK4/6 inhibitors.

The impact of COVID-19 on cancer patients.

The COVID-19 pandemic poses a significant challenge for individuals with compromised immune systems, such as patients with cancer, as they face a heightened susceptibility to severe infections compared to the general population. Such severe infections substantially increase the risk of morbidity and mortality among these patients. Notable risk factors for mortality include advanced age (> 70 years), current or past smoking history, advanced disease stage, the use of cytotoxic chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) score of 2 or higher. Multiple types of vaccines have been developed and implemented, demonstrating remarkable efficacy in preventing infections. However, there have been observable reductions in their ability to elicit an immune response, particularly among individuals with hematological malignancies. The situation becomes more challenging due to the emergence of viral variants of concern (VOCs). Despite the increase in neutralizing antibody levels after vaccination, they remain lower in response to these evolving variants. The need for booster vaccinations has become apparent, particularly for this vulnerable population, due to the suboptimal immune response and waning of immunity post-vaccination. Examining and comprehending how the immune system reacts to various vaccination regimens for SARS-CoV-2 and its VOCs in cancer patients is crucial for designing clinical and public health strategies. This review aims to provide an updated overview of the effectiveness of COVID-19 vaccines in cancer patients, including those undergoing treatments such as hematopoietic stem cell transplantation (HCT) or chimeric antigen receptor (CAR) T cell therapy, by exploring the extent of both humoral and cellular immune responses to COVID-19 vaccination. Furthermore, it outlines risk factors and potential biomarkers that are associated with severe SARS-CoV-2 infection and vaccine responses, and offers suggestions for improving SARS-CoV-2 protection in cancer patients.

COVID-19: From emerging variants to vaccination.

The vigorous spread of SARS-CoV-2 resulted in the rapid infection of millions of people worldwide and devastation of not only public healthcare, but also social, educational, and economic infrastructures. The evolution of SARS-CoV-2 over time is due to the mutations that occurred in the genome during each replication. These mutated forms of SARS-CoV-2, otherwise known as variants, were categorized as variants of interest (VOI) or variants of concern (VOC) based on the increased risk of transmissibility, disease severity, immune escape, decreased effectiveness of current social measures, and available vaccines and therapeutics. The swift development of COVID-19 vaccines has been a great success for biomedical research, and billions of vaccine doses, including boosters, have been administered worldwide. BNT162b2 vaccine (Pfizer-BioNTech), mRNA-1273 (Moderna), ChAdOx1 nCoV-19 (AstraZeneca), and Janssen (Johnson & Johnson) are the four major COVID-19 vaccines that received early regulatory authorization based on their efficacy. However, some SARS-CoV-2 variants resulted in higher resistance to available vaccines or treatments. It has been four years since the first reported infection of SARS-CoV-2, yet the Omicron variant and its subvariants are still infecting people worldwide. Despite this, COVID-19 vaccines are still expected to be effective at preventing severe disease, hospitalization, and death from COVID. In this review, we provide a comprehensive overview of the COVID-19 pandemic focused on evolution of VOC and vaccination strategies against them.

Primary adrenal insufficiency induced by immune checkpoint inhibitors: biological, clinical, and radiological aspects.

Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies, designed to enhance immune responses, have revealed a spectrum of immune-related adverse events (irAEs). While many irAEs exhibit favorable responses to corticosteroid or immunosuppressive therapy, most ICI-related endocrinopathies necessitate lifelong replacement therapy and pose significant clinical challenges. Adrenal insufficiency (AI), a noteworthy endocrine irAE, can manifest as primary AI (PAI) or secondary AI (SAI), resulting from adrenal or pituitary gland dysfunction, respectively. ICI-induced AI, albeit relatively infrequent, occurs in 1-2% of patients receiving single-agent anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) or Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) therapies and in a higher range of 4-9% when ICIs are used in combinations. Recognizing and addressing ICI-induced PAI is crucial, as it often presents with acute and potentially life-threatening symptoms, especially considering the expanding use of ICI therapy. This review provides an updated overview of ICI-induced PAI, exploring its clinical, diagnostic, and radiological aspects.

A Multidisciplinary Approach to Patients with Psoriasis and a History of Malignancies or On-Treatment for Solid Tumors: A Narrative Literature Review.

Psoriasis is a chronic immune-mediated disease that is linked to an increased risk of cancer. Although numerous studies have explored whether neoplasms are concurrent conditions or are induced by psoriasis, a definitive definition remains elusive. In this study, we conducted a comprehensive narrative literature review to offer practical guidance to oncologists and dermatologists regarding the initiation and discontinuation of biologics for psoriasis. The findings indicate that a customized approach is recommended for each patient, and that a history of malignancies does not constitute an absolute contraindication for biologics. Growing evidence supports the treatment of selected patients, emphasizing a nuanced assessment of benefits and risks. There is a lack of data specifying a safe timeframe to initiate biologics following a neoplasm diagnosis due to influences from cancer-related and patient-specific characteristics impacting prognosis. Some patients may continue anti-psoriasis therapy during cancer treatments. Enhanced comprehension of the biological mechanisms in cancer progression and the immune microenvironment of psoriasis holds promise for refining therapeutic strategies. In conclusion, a personalized treatment approach necessitates collaboration between oncologists and dermatologists, considering factors such as cancer prognosis, psoriasis clinical manifestations, patient characteristics, and preferences when making treatment decisions.

Mismatch Repair system protein deficiency as a resistance factor for locally advanced rectal adenocarcinoma patients receiving neoadjuvant chemo-radiotherapy.

BACKGROUND: Available data on Mismatch Repair system (MMR) deficiency are conflicting and derived from small studies. Our study aimed to evaluate the therapeutic implications of MMR status in patients with locally advanced rectal cancer (LARC). METHODS: We retrospectively collected data from 318 patients affected by LARC treated in Italy at the Medical Oncology Units of the University Hospital of Cagliari, Istituto Nazionale dei Tumori Milan, and AOU Ospedali Riuniti Ancona. All patients underwent neoadjuvant chemoradiotherapy. The primary objective was major TRG while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). RESULTS: One hundred sixty patients (148 pMMR and 12 dMMR) were included in the exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in the validation cohort. A major TRG has been shown in 42.6% and 43.1% patients with pMMR in exploratory and validation cohort, respectively; while no major TRG have been shown in dMMR patients in both cohorts. Exploratory and validation cohorts showed a statistically significant higher mDFS in pMMR patients compared to dMMR: NR vs. 14 months and NR vs. 17 months, respectively. CONCLUSION: Our results indicated an association between dMMR and poor response to preoperative chemoradiotherapy and they represent a hypothesis-generating data for new neoadjuvant strategies.

Cemiplimab in Ultra-Octogenarian Patients with Cutaneous Squamous Cell Carcinoma: The Real-Life Experience of a Tertiary Referral Center.

BACKGROUND: The incidence of cutaneous squamous cell carcinoma (cSCC) is rapidly increasing, paralleling the aging of the population. cSCC predominantly affects chronically sun-exposed areas, such as the head and neck region. At our tertiary center, a multidisciplinary approach to non-melanoma skin cancer is provided for locally advanced cSCC. METHODS: We retrospectively revised all patients with locally advanced/metastatic cSCC treated with anti-PD1 antibody (Cemiplimab) at our Institution from January 2020 to March 2023 (minimum follow-up of 4 months on treatment). RESULTS: Overall, we consecutively treated 20 ultra-octogenarian patients, of whom 15 were males and 5 were females (median age: 86.9 years). Despite age, a median number of concomitant drugs, and comorbidities, efficacy, and safety were superimposable with the available literature. No patients reported treatment-related adverse events of grade 3 or higher. Grade 2 adverse events were reported in 25% of patients. Overall, the response rate was 65%, with 50% partial responses and 20% long-lasting stable disease. The median duration of response was 14 months. The G8 elderly score was assessed in all patients, and the median score was 12 (range 9-14). CONCLUSIONS: Among ultra-octogenarian patients, a clinical benefit from Cemiplimab was obtained in most, including tumor shrinkage and pain relief. Cemiplimab confirmed its effectiveness in elderly patients in a real-life setting, with no new safety concerns.

Fibroblast growth factor receptors as targets for anticancer therapy in cholangiocarcinomas and urothelial carcinomas.

Cholangiocarcinomas and urothelial carcinomas are lethal tumors worldwide and only a minority of patients are eligible for surgery at diagnosis. Moreover, patients are poorly responsive to current therapeutic strategies, including chemotherapy, radiotherapy, immunotherapy, and multimodality treatments. Recently, several advances have been made in precision medicine and these results are modifying the treatment paradigm for patients diagnosed with cholangiocarcinomas and urothelial carcinoma. These histotypes exhibit a high rate of multiple fibroblast growth factor receptor (FGFR) genetic alterations and numerous preclinical and clinical studies support FGFR as a highly attractive novel therapeutic target. Moreover, identifying specific genetic alterations may predict the tumor's response to conventional and novel FGFR-targeted drugs. Recent clinical studies showed promising data for FGFR-targeted therapy in reducing tumor volume and led to the United States Food and Drug Administration (FDA) approval of, e.g., pemigatinib, infigratinib, futibatinib, and erdafitinib. Moreover, FGFR inhibitors show promising results in the first-line setting of cholangiocarcinomas and urothelial carcinomas. Pemigatinib (FIGHT-302) and futibatinib (FOENIX-CAA3) are being evaluated in phase III trials that compare these agents to current first-line gemcitabine and cisplatin in FGFR2-rearranged cholangiocarcinoma. However, complexity in targeting the FGFR signaling pathway is observed. Herein, we describe the characteristics of the FDA-approved and other investigational FGFR-targeted therapeutics, evaluate the most recent preclinical and clinical studies focusing on targeting FGFR genomic alterations in the treatment of cholangiocarcinomas and urothelial cancer, and provide insight into factors involved in response and (acquired) resistance to FGFR inhibition.

The Tumor Microenvironment and the Estrogen Loop in Thyroid Cancer.

Thyroid cancer (TC) cells employ multiple signaling pathways, such as PI3K/AKT/mTOR and RAS/Raf/MAPK, fostering cell proliferation, survival and metastasis. Through a complex interplay with immune cells, inflammatory mediators and stroma, TC cells support an immunosuppressive, inflamed, pro-carcinogenic TME. Moreover, the participation of estrogens in TC pathogenesis has previously been hypothesized, in view of the higher TC incidence observed among females. In this respect, the interactions between estrogens and the TME in TC could represent a relevant, unexplored area of research. We thereby collectively reviewed the available evidence concerning the potential carcinogenic role of estrogens in TC, specifically focusing on their crosstalk with the TME.

Treatments for relapsed, BRCA-wild type, platinum-sensitive ovarian cancer: A systematic review and network meta-analysis.

INTRODUCTION: Although platinum-based chemotherapy (CT) is considered the standard treatment for relapsed platinum-sensitive ovarian cancer, there is currently no standard treatment for these patients. We compared the effectiveness of modern and older therapies in relapsed platinum-sensitive, BRCA-wild type, and ovarian cancers using a network meta-analysis (NMA). METHODS: A systematic search of PubMed, EMBASE, and Cochrane Library was performed up to October 31, 2022. Randomized controlled trials (RCT) that compared different second-line approaches were included. The primary endpoint was overall survival (OS) and the secondary endpoint was progression-free survival (PFS). RESULTS: In total, 17 RCTs (n = 9405) comparing various strategies were included. The risk of death was significantly decreased with carboplatin + pegylated liposomal doxorubicin + bevacizumab compared to platinum-based doublet CT (hazard ratio [HR] = 0.59, 95%CI 0.35, 1). Various strategies, including secondary cytoreduction followed by platinum-based CT, carboplatin + pegylated liposomal doxorubicin + bevacizumab, and platinum-based CT with bevacizumab or cediranib, were better than platinum-based doublets alone for PFS. CONCLUSIONS: This NMA showed that carboplatin + pegylated liposomal doxorubicin + bevacizumab seems to increase the efficacy of standard second-line CT. These strategies can be considered when treating patients with relapsed platinum-sensitive ovarian cancer without BRCA mutations. This study provides systematic comparative evidence for the efficacy of different second-line therapies for relapsed ovarian cancer.

Infections in lung cancer patients undergoing immunotherapy and targeted therapy: An overview on the current scenario.

Patients with a diagnosis of lung cancer are often vulnerable to infection, and the risk is increased by tumor-associated immunosuppression and the effects of the treatments. Historically, links between the risk of infection and cytotoxic chemotherapy due to neutropenia and respiratory syndromes are well established. The advent of tyrosine kinase inhibitors (TKIs) and immune-checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1)/programmed cell death- ligand 1 (PD-L1) axis and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have changed the treatment paradigm for lung cancer patients. Our understanding of the risk of infections while administrating these drugs is evolving, as are the biological mechanisms that are responsible. In this overview, we focus on the risk of infection with the use of targeted therapies and ICIs, summarizing current evidence from preclinical and clinical studies and discussing their clinical implications.

The oligometastatic setting in HNSCC: A critical review by the Rete Oncologica Piemonte e Valle d'Aosta multidisciplinary team.

INTRODUCTION: The oligometastatic disease is a low burden metastatic disease that might still benefit from curable treatment. Squamous cell carcinoma of the head and neck (HNSCC) is a complex group of malignancies, with high rates of loco-regional recurrences. Distant metastases are less frequent, and a single or few deposits are often observed (oligometastatic disease). The optimal management of oligometastatic HNSCC remains to be defined. MATERIALS AND METHODS: Key references were derived from a PubMed query. Hand searching and clinicaltrials.gov were also used. RESULTS: This paper contains a narrative report and a critical discussion of the available evidence on the management of oligometastatic HNSCC patients, with a focus on metastasis-directed therapy (MDT), particularly stereotactic ablative radiotherapy (SABR). CONCLUSIONS: in line with literature data, the multidisciplinary evaluation emerged as the key element in the management of oligometastatic HNSCC patients.

Breast MRI: Clinical Indications, Recommendations, and Future Applications in Breast Cancer Diagnosis.

PURPOSE OF REVIEW: This article aims to provide an updated overview of the indications for diagnostic breast magnetic resonance imaging (MRI), discusses the available and novel imaging exams proposed for breast cancer detection, and discusses considerations when performing breast MRI in the clinical setting. RECENT FINDINGS: Breast MRI is superior in identifying lesions in women with a very high risk of breast cancer or average risk with dense breasts. Moreover, the application of breast MRI has benefits in numerous other clinical cases as well; e.g., the assessment of the extent of disease, evaluation of response to neoadjuvant therapy (NAT), evaluation of lymph nodes and primary occult tumor, evaluation of lesions suspicious of Paget's disease, and suspicious discharge and breast implants. Breast cancer is the most frequently detected tumor among women around the globe and is often diagnosed as a result of abnormal findings on mammography. Although effective multimodal therapies significantly decline mortality rates, breast cancer remains one of the leading causes of cancer death. A proactive approach to identifying suspicious breast lesions at early stages can enhance the efficacy of anti-cancer treatments, improve patient recovery, and significantly improve long-term survival. However, the currently applied mammography to detect breast cancer has its limitations. High false-positive and false-negative rates are observed in women with dense breasts. Since approximately half of the screening population comprises women with dense breasts, mammography is often incorrectly used. The application of breast MRI should significantly impact the correct cases of breast abnormality detection in women. Radiomics provides valuable data obtained from breast MRI, further improving breast cancer diagnosis. Introducing these constantly evolving algorithms in clinical practice will lead to the right breast detection tool, optimized surveillance program, and individualized breast cancer treatment.

Approaches to Fertility Preservation for Young Women With Breast Cancer.

In patients with early breast cancer, the combination of different systemic treatment strategies, including chemotherapy, endocrine therapy, targeted therapy, and more recently also immunotherapy has demonstrated to significantly improve their survival outcomes. However, this gain is often obtained at the cost of higher toxicity calling for the need of increased attention toward survivorship-related issues, including fertility preservation in young women. According to available guidelines, health care providers should offer oncofertility counseling to all patients with cancer diagnosed at reproductive age. Counselling should focus on the risk of gonadotoxicity of anticancer treatments and on the access to fertility preservation techniques. However, several surveys have demonstrated suboptimal implementation of these recommendations. This review aims at summarizing the available evidence on oncofertility to guide health care providers involved in the management of young women with breast cancer. Available and effective options for fertility preservation include oocyte/embryo cryopreservation or ovarian tissue cryopreservation. Patient, disease, and treatment characteristics should be carefully considered when offering these strategies. Ovarian function preservation with gonadotrophin-releasing hormone agonists during chemotherapy should be discussed and offered to every premenopausal woman concerned about developing premature ovarian insufficiency and independently of her wish to preserve fertility. Current available data confirm that pregnancy occurring after proper treatment for breast cancer is safe, both in terms of long-term clinical outcomes and for the babies. Fertility preservation and pregnancy desire should be pivotal components of the multimodal management of breast cancer in young women, and require a multidisciplinary approach based on close collaborations between oncologists and fertility specialists.

Adjuvant chemotherapy for resected triple negative breast cancer patients: A network meta-analysis.

The current standard of care for resected early-stage triple negative breast cancer (TNBC) patients who did not receive systemic preoperative therapy is adjuvant anthracycline- and taxane-based chemotherapy (CT). A network meta-analysis (NMA) of randomized controlled trials (phase III) enrolling patients with resected stage I-III TNBC comparing adjuvant regimens was performed. Overall survival (OS) and disease-free survival (DFS) data were extracted. A total of 27 phase III clinical trials were selected including 15,242 TNBC patients. This NMA showed an OS benefit from the incorporation of capecitabine into classic anthracycline/taxane-based combinations compared to anthracyclines with or without taxanes alone.

CDK4/6 inhibitors in the treatment of metastatic breast cancer: Focus on toxicity and safety.

The development of oral cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, including palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for patients with hormone-receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC). When combined with an aromatase inhibitor or fulvestrant, these agents have been approved as first-line therapy in the metastatic setting. Abemaciclib has also gained FDA approval for patients with HR-positive, HER2-negative, node-positive, early BC at high risk of recurrence. Moreover, ribociclib has recently improved disease-free survival in patients with stage II or III HR+/HER2-negative early BC. CDK4/6 inhibitors have favorable safety profiles. However, the available agents have different toxicity profiles that must be clearly discussed with the patients for optimal clinical decisions. This manuscript aims to review CDK4/6 inhibitor-related treatment-associated adverse events, identify risk factors for intolerable adverse events, and assess their safety in special patient populations such as the elderly and those with renal insufficiency. Enhanced knowledge and understanding of CDK4/6 inhibitor-related toxicities can improve treatment strategies and ultimately enhance patient care.