Oral SERDs alone or in combination with CDK 4/6 inhibitors in breast cancer: Current perspectives and clinical trials.

Over the past few decades, first-line therapy for treating advanced and metastatic HR+/HER2-breast cancer has transformed due to the introduction of adjuvant endocrine therapy with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). However, there is an unmet need for novel classes of endocrine therapy with superior efficacy to improve treatment outcomes and overcome CDK4/6i resistance. New generation selective estrogen receptor degraders (SERDs), orally administered and with higher bioavailability, could potentially be the novel compounds to meet this emerging need. In this paper, we review accredited clinical studies on the combining effects of CDK4/6 inhibitors and oral SERDs, report efficacy of treatment data when available, and provide a framework for future research focusing on these promising agents.

Emerging Therapies in Kirsten Rat Sarcoma Virus (+) Non-Small-Cell Lung Cancer.

Kirsten rat sarcoma virus (KRAS) is the most frequently found oncogene in human cancers, including non-small-cell lung cancer (NSCLC). For many years, KRAS was considered "undruggable" due to its structure and difficult targeting. However, the discovery of the switch II region in the KRAS-G12C-mutated protein has changed the therapeutic landscape with the design and development of novel direct KRAS-G12C inhibitors. Sotorasib and adagrasib are FDA-approved targeted agents for pre-treated patients with KRAS-G12C-mutated NSCLC. Despite promising results, the efficacy of these novel inhibitors is limited by mechanisms of resistance. Ongoing studies are evaluating combination strategies for overcoming resistance. In this review, we summarize the biology of the KRAS protein and the characteristics of KRAS mutations. We then present current and emerging therapeutic approaches for targeting KRAS mutation subtypes intending to provide individualized treatment for lung cancer harboring this challenging driver mutation.

Efficacy of NSCLC Rechallenge with Immune Checkpoint Inhibitors following Disease Progression or Relapse.

Immune checkpoint inhibitors (ICIs) are at the forefront of advanced non-small-cell lung cancer (NSCLC) treatment. Still, only 27-46% of patients respond to initial therapy with ICIs, and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post hoc analyses of several clinical trials. Future research on ICI rechallenge for NSCLC should focus on better patient stratification to reflect the underlying biology of immunotherapy resistance more accurately. In this review, we summarize evidence regarding rechallenge immunotherapy efficacy following NSCLC disease progression or relapse, as well as ongoing trials on immunotherapy rechallenge.

Artificial Intelligence-Based Treatment Decisions: A New Era for NSCLC.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality among women and men, in developed countries, despite the public health interventions including tobacco-free campaigns, screening and early detection methods, recent therapeutic advances, and ongoing intense research on novel antineoplastic modalities. Targeting oncogenic driver mutations and immune checkpoint inhibition has indeed revolutionized NSCLC treatment, yet there still remains the unmet need for robust and standardized predictive biomarkers to accurately inform clinical decisions. Artificial intelligence (AI) represents the computer-based science concerned with large datasets for complex problem-solving. Its concept has brought a paradigm shift in oncology considering its immense potential for improved diagnosis, treatment guidance, and prognosis. In this review, we present the current state of AI-driven applications on NSCLC management, with a particular focus on radiomics and pathomics, and critically discuss both the existing limitations and future directions in this field. The thoracic oncology community should not be discouraged by the likely long road of AI implementation into daily clinical practice, as its transformative impact on personalized treatment approaches is undeniable.

Cardiovascular complications of ribociclib in breast cancer patients.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have unprecedentedly advanced hormone-dependent breast cancer treatment paradigm. In the metastatic setting, ribociclib has consistently demonstrated survival benefit in pre-, peri-, and postmenopausal patients, conjugating efficacy with health-related quality of life preservation. Accordingly, the emergence of cardiac and/or vascular adverse events related to this novel targeted agent is gaining significant interest. This narrative review provides an overview of the incidence and spectrum of cardiovascular toxicity, in both clinical trial framework and real-world evidence. The potential pathogenetic mechanism, along with the available diagnostic parameters including biomarkers, and proper management, are also summarized.

What to expect from paraneoplastic syndromes of the nervous system in uterine cancer: A review of the literature.

Neurological paraneoplastic syndromes are a rare subgroup of diseases commonly related to neuroendocrine tumors. However, they have been associated with uterine malignancies (sarcomas, endometrial carcinomas, and neuroendocrine cancers). Their presentation often correlates with a cancer diagnosis or cancer recurrence underlining their clinical significance. The most common neurological paraneoplastic syndrome in uterine cancer is cerebral degeneration with a comprehensive clinical presentation of pancerebral dysfunction. However, other neurological syndromes present with various symptoms leading to delayed diagnosis. Less common paraneoplastic neurological syndromes associated with uterine cancer are encephalitis, encephalomyelitis, subacute sensory neuropathy, sensory-motor neuropathy, dermatomyositis, cancer-associated retinopathy, opsoclonus, Guillain-Barre syndrome, necrotizing myopathy, and stiff-person syndrome. Herein, we reviewed published cases of neurological paraneoplastic syndromes in uterine cancer in order to raise awareness of these rare syndromes. We recorded patients' clinical presentation, antibodies detected, treatment, and clinical outcomes.

Subarachnoid hemorrhage in a postpartum mother: A rare manifestation of an uncommon disease.

Subarachnoid hemorrhage, a potentially lethal medical emergency, represents an atypical clinical manifestation of gestational choriocarcinoma. We present the uncommon case of a 31-year-old primigravid female who presented with cerebral oncotic aneurysmal rupture, five weeks after vaginal delivery. Albeit the absence of neurological deficits after endovascular embolization, the patient was soon readmitted, complaining of fever, abdominal pain, and fetid lochia, all suggestive of puerperal endometritis. Upon a comprehensive diagnostic work-up, she was subsequently diagnosed with metastatic choriocarcinoma. Early initiation of multiagent chemotherapy, despite being in septic shock associated with Escherichia coli bacteremia, resulted in favorable prognosis.

Machine learning applications in gynecological cancer: A critical review.

Machine Learning (ML) represents a computer science capable of generating predictive models, by exposure to raw, training data, without being rigidly programmed. Over the last few years, ML has gained attention within the field of oncology, with considerable strides in both diagnostic, predictive, and prognostic spectrum of malignancies, but also as a catalyst of cancer research. In this review, we discuss the state of ML applications on gynecologic oncology and systematically address major technical and ethical concerns, with respect to their real-world medical practice translation. Undoubtedly, advances in ML will enable the analysis of large, rather complex, datasets for improved, cost-effective, and efficient clinical decisions.

Assessment of Postvaccination Neutralizing Antibodies Response against SARS-CoV-2 in Cancer Patients under Treatment with Targeted Agents.

The administration of a third dose of a vaccine against SARS-CoV-2 has increased protection against disease transmission and severity. However, the kinetics of neutralizing antibodies against the virus has been poorly studied in cancer patients under targeted therapies. Baseline characteristics and levels of neutralizing antibodies at specific timepoints after vaccination were compared between patients suffering from breast, ovarian or prostate cancer and healthy individuals. Breast cancer patients were treated with cyclin D kinase 4/6 inhibitors and hormonal therapy, ovarian cancer patients were treated with poly (ADP-ribose) polymerase inhibitors and prostate cancer patients were treated with an androgen receptor targeted agent. Levels of neutralizing antibodies were significantly lower in cancer patients compared to healthy individuals at all timepoints. Antibodies' titers declined over time in both groups but remained above protective levels (>50%) at 6 months after the administration of the second dose. The administration of a third dose increased neutralizing antibodies' levels in both groups. The titers of protective against SARS-CoV-2 antibodies wane over time and increase after a third dose in cancer patients under treatment.

Advances in Gynecological Cancers.

The burden of gynecological cancer constitutes a major focus of public health efforts, as it continues to represent a significant cause of cancer mortality, exerting not only physical and emotional distress but also serious financial strain upon individuals, caregivers, and communities [...].

SARS-CoV-2 Neutralizing Antibodies Kinetics Postvaccination in Cancer Patients under Treatment with Immune Checkpoint Inhibition.

Considering that COVID-19 could adversely affect cancer patients, several countries have prioritized this highly susceptible population for vaccination. Thus, rapidly generating evidence on the efficacy of SARS-CoV-2 vaccination in the subset of patients with cancer under active therapy is of paramount importance. From this perspective, we launched the present prospective observational study to comprehensively address the longitudinal dynamics of immunogenicity of both messenger RNA (mRNA) and viral vector-based vaccines in 85 patients treated with immune checkpoint inhibitors (ICIs) for a broad range of solid tumors. Despite the relatively poor humoral responses following the priming vaccine inoculum, the seroconversion rates significantly increased after the second dose. Waning vaccine-based immunity was observed over the following six months, yet the administration of a third booster dose remarkably optimized antibody responses. Larger cohort studies providing real-world data with regard to vaccines effectiveness and durability of their protection among cancer patients receiving immunotherapy are an increasing priority.

Treatment with abiraterone or enzalutamide does not impair immunological response to COVID-19 vaccination in prostate cancer patients.

Data regarding the safety and efficacy of COVID-10 vaccines among cancer patients are lacking. Factors such as age, underlying disease and antineoplastic treatment confer negatively to the immune response due to vaccination. The degree of immunosuppression though may be lessen by targeted treatments like the androgen receptor-targeted agents (ARTA) that are commonly used in patients with metastatic prostate cancer. Herein, we report our data on 25 patients with prostate cancer under treatment with ARTA who were vaccinated for COVID-19. Our data suggest that these patients develop neutralizing antibodies against SARS-CoV-2 similarly to healthy volunteers. No safety issues were noted.

BRCA1/2 Mutation Types Do Not Affect Prognosis in Ovarian Cancer Patients.

BACKGROUND: High grade serous ovarian carcinoma (HGSOC) is the most lethal type of epithelial ovarian cancer, with a prevalence of germline BRCA1/2 mutations as high as 20%. Our objective is to determine whether the location of mutations in the different domains of the BRCA1/2 genes affects the clinical outcome of HGSOC patients. METHODS: A total of 51 women with BRCA1 or BRCA2 mutated ovarian cancer were identified. Progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: In our study cohort, 35 patients were carriers of germline mutations in BRCA1 and 16 in BRCA2. The median PFS time following completion of the primary therapy was 23.8 months (95% CI 20.1-27.5) and the median OS was 92.9 months (95% CI 69.8-116.1) in all BRCA carriers. After multivariate analysis, no significant association among the location or type of BRCA1/2 mutation with PFS or OS was identified. Notably, significant differences in PFS between carriers of identical mutations in the same BRCA gene were detected. CONCLUSIONS: Among HGSOC patients, BRCA1/2 carriers with mutations in different locations of the genes show no significant difference in survival outcomes, in terms of PFS and OS, suggesting the potential effect of other genetic abnormalities and co-contributing risk factors.

What Has Changed in the Management of Uterine Serous Carcinomas? Two Decades of Experience.

Uterine serous carcinoma accounts for 3-10% of endometrial cancers, but it is the most lethal histopathological subtype. The molecular characterization of endometrial carcinomas has allowed novel therapeutic approaches for these patients. We undertook a retrospective analysis of patients with uterine serous carcinomas treated in our hospital within the last two decades to identify possible changes in their management. The patients and their characteristics were evenly distributed across the two decades. Treatment modalities did not change significantly throughout this period. After adjuvant treatment, patients' median disease-free survival was 42.07 months (95% CI: 20.28-63.85), and it did not differ significantly between the two decades (p = 0.059). The median overall survival was 47.51 months (95% Cl: 32.18-62.83), and it significantly favored the first decade's patients (p = 0.024). In patients with de novo metastatic or recurrent disease, median progression-free survival was 7.8 months (95% Cl: 5.81-9.93), whereas both the median progression-free survival and the median overall survival of these patients did not show any significant improvement during the examined time period. Overall, the results of our study explore the minor changes in respect of uterine serous carcinoma's treatment over the last two decades, which are reflected in the survival outcomes of these patients and consequently underline the critical need for therapeutic advances in the near future.

Pembrolizumab in endometrial cancer: Where we stand now.

Recently, immunotherapy has shown promising results in solid tumors. To the best of our knowledge, this is the first systematic review of published literature synthesizing all the available data and evaluating both the efficacy and safety of pembrolizumab in endometrial cancer. The present study was performed in accordance with the PRISMA guidelines. Eligible articles were identified by searching the MEDLINE and ClinicalTrials.gov databases, using a predefined combination of the terms 'endometrial cancer' and 'pembrolizumab'. Overall, nine articles incorporating data from 712 patients were eligible. Pembrolizumab was demonstrated to be an effective and safe therapeutic option for the management of advanced/metastatic endometrial cancer. Results of ongoing trials evaluating either pembrolizumab alone or in combination with other antineoplastic regimens are expected to confirm its efficacy in this setting of patients. Pembrolizumab appears to be both durable and robust in endometrial cancer. However, there is an emerging need for novel predictive biomarkers to guide clinical practice.

Immunological Response to COVID-19 Vaccination in Ovarian Cancer Patients Receiving PARP Inhibitors.

OBJECTIVE: Vaccination for SARS-CoV-2 provides significant protection against the infection in the general population. However, limited data exist for cancer patients under systemic therapy. METHODS: In this cohort, we prospectively enrolled cancer patients treated with PARPi as well as healthy volunteers in order to study the kinetics of anti-SARS-CoV-2 antibodies (NAbs) after COVID-19 vaccination. Baseline demographics, co-morbidities, and NAb levels were compared between the two groups. RESULTS: The results of the cohort of 36 patients receiving PARP inhibitors are presented here. Despite no new safety issues being noticed, their levels of SARS-CoV-2 neutralizing antibodies were significantly lower in comparison to matched healthy volunteers up to day 30 after the second dose. CONCLUSIONS: These results suggest that maintaining precautions against COVID-19 is essential for cancer patients and should be taken into consideration for the patients under treatment, while further exploration is needed to reduce the uncertainty of SARS-CoV-2 immunity among cancer patients under treatment.

Occupational Exposure and Multiple Myeloma Risk: An Updated Review of Meta-Analyses.

The precise etiology of multiple myeloma remains elusive, but both genetic and environmental factors have been suggested to contribute to disease risk. Several occupational categories and toxic agents have been implicated as potentially causative, yet findings from the literature are inconsistent. The aim of this review was to summarize and critically comment on the accumulated epidemiological evidence, across published meta-analyses, about the association between occupational exposure and risk of multiple myeloma. Overall, results from eleven meta-epidemiological studies underscore a significantly increased risk for firefighters, hairdressers, and employees exposed to engine exhaust, whereas farming and methylene chloride exposure have been non-significantly correlated with the disease. Further epidemiological studies are of utmost importance whilst emphasis should be placed on occupational hazard surveillance, as such studies will obtain a more accurate picture of disease occurrence in working populations, and will enable both the implementation of preventive actions and the evaluation of their effectiveness.

SARS-CoV-2 neutralizing antibodies after first vaccination dose in breast cancer patients receiving CDK4/6 inhibitors.

Undoubtedly, the development of COVID-19 vaccines displays a critical step towards ending this devastating pandemic, considering their protective benefits in the general population. Yet, data regarding their efficacy and safety in cancer patients are limited. Herein we provide the initial analysis of immune responses after the first dose of vaccination in 21 breast cancer patients receiving cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. The levels of neutralizing antibodies post vaccination were similar to the matched healthy controls, whereas no safety issues have been raised. Further exploration is needed to reduce the uncertainty of SARS-CoV-2 immunity among cancer patients under treatment.

CDK4/6 Inhibitors and Arthralgia: A Single Institution Experience.

BACKGROUND: Aromatase inhibitors (AIs) are associated with musculoskeletal pain in one third (20-47%) of breast cancer patients. Recently, CDK4/6 inhibitors have emerged as a new therapeutic approach in hormone receptor (HR)-positive breast cancer. While hematological and gastrointestinal toxicities are frequently reported during treatment with CDK4/6 inhibitors, musculoskeletal symptoms are less commonly encountered. METHODS: Herein, we present a retrospective study of 47 breast cancer patients who received CDK4/6 inhibitors along with endocrine therapy in our department between 01/01/2018 and 01/09/2020. RESULTS: Median age at diagnosis was 58 years (29-81). Median duration of treatment was 8.76 months (SD: 7.68; 0.47-30.13 months). Median PFS was 24.33 months (95% CI; 1.71-46.96). Overall, toxicity was reported in 61.7% of the cases (29/47). Arthralgia was reported in 6.4% (3/47) of the patients. Hematological toxicity was reported in 51.1% (24/47) of the patients. Neutropenia was the main hematological toxicity observed (86.8%; 22/47) along with anemia (4.3%; 2/47), thrombocytopenia (2.1%; 1/47), and leukopenia (4.2%; 1/24). CONCLUSIONS: Though our data reflect a small sample size, we report a reduced arthralgia rate (6.4%) during treatment with CDK4/6 inhibitors compared with that reported in studies of AIs (20-47%).

Paraneoplastic cerebellar degeneration in platinum-responsive endometrial cancer: A case report and review of literature.

Paraneoplastic cerebellar ataxia is a rare immune-induced, non-metastatic neurologic syndrome, most frequently associated with gynecological cancers, which carries an abysmal prognosis. We report the case of a patient with advanced-stage uterine cancer, who developed severe pancerebellar ataxia, while in partial remission, after the completion of 3 cycles of neoadjuvant platinum-based chemotherapy. Swift initiation of immunosuppressive therapy with corticosteroids combined with plasmapheresis did not result in significant clinical benefit. Early recognition of this debilitating condition and standardization of its treatment strategy are prerequisites for both improved survival outcomes and quality of life in these patients. Further studies are warranted to clarify the immune-stimulating impact of effective cytotoxic chemotherapy and the occurence of autoimmune paraneoplastic neurological syndromes.