Theranostic biomarkers and PARP-inhibitors effectiveness in patients with non-BRCA associated homologous recombination deficient tumors: Still looking through a dirty glass window?

Breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) deleterious variants were the first and, still today, the main biomarkers of poly(ADP)ribose polymerase (PARP)-inhibitors (PARPis) benefit. The recent, increased, numbers of individuals referred for counseling and multigene panel testing, and the remarkable expansion of approved PARPis, not restricted to BRCA1/BRCA2-Pathogenic Variants (PVs), produced a strong clinical need for non-BRCA biomarkers. Significant limitations of the current testing and assays exist. The different approaches that identify the causes of Homologous Recombination Deficiency (HRD), such as the germline and somatic Homologous Recombination Repair (HRR) gene PVs, the testing showing its consequences, such as the genomic scars, or the novel functional assays such as the RAD51 foci testing, are not interchangeable, and should not be considered as substitutes for each other in clinical practice for guiding use of PARPi in non-BRCA, HRD-associated tumors. Today, the deeper knowledge on the significant relationship among all proteins involved in the HRR, not limited to BRCA, expands the possibility of a successful non-BRCA, HRD-PARPi synthetic lethality and, at the same time, reinforces the need for enhanced definition of HRD biomarkers predicting the magnitude of PARPi benefit.

The significance of tissue-agnostic biomarkers in solid tumors: the more the merrier?

INTRODUCTION: To date, several emerging biomarkers have gained considerable interest in the field of predictive molecular oncology. The advent of precision medicine has led to the development of innovative drugs targeting rare molecular pathways independently from histology, defined as tissue-agnostic drugs. AREAS COVERED: Although there is a lot of promise for this new tissue-agnostic model in the oncological scenario, crucial issues from both the diagnostic and therapeutic standpoint are emerging. This review aims to critically examine the role of tissue-agnostic biomarkers in different solid tumors, focusing on the prevalence and methods of detection of agnostic biomarkers together with drug approvals to guide clinicians in this evolving landscape. EXPERT OPINION: To strengthen the framework for tissue-agnostic approvals, the dialogue between regulatory, industrial, and academic parties should be intensified. Critical questions include the development of an efficient network system that can overcome the heterogeneity of patients' inclusion criteria along with the increasingly difficult interpretation of next-generation sequencing (NGS) profiling technologies. Cost-effectiveness and risk-benefit studies are needed in the national context considering the modalities of access to diagnostic tests and reimbursement of treatments.

Body mass index and baseline platelet count as predictive factors in Merkel cell carcinoma patients treated with avelumab.

Background: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer, associated with a worse prognosis. The Immune Checkpoint Inhibitors (ICIs) avelumab and pembrolizumab have been recently approved as first-line treatment in metastatic MCC (mMCC). The clinical observation of improved outcomes in obese patients following treatment with ICIs, known as the "obesity paradox", has been studied across many types of tumors. Probably due to the rarity of this tumor, data on mMMC patients are lacking. Patients and methods: This is an observational, hospital-based, study to investigate the role of Body Mass Index (BMI) as predictive biomarker of ICI response in mMCC patients treated with avelumab as first-line treatment. The study population included the patients treated from February 2019 to October 2022 in an Italian referral center for rare tumors. Clinico-pathological characteristics, BMI, laboratory parameters (NLR and platelet count), and response to avelumab were analyzed from a MCC System database prospectively collected. Results: Thirty-two (32) patients were included. Notably, the presence of pre-treatment BMI ≥ 30 was significantly associated with longer PFS [BMI < 30 Group: median PFS, 4 months (95% CI: 2.5-5.4); BMI ≥ 30 Group: median PFS, not reached; p<0.001)[. Additionally, the median PFS was significantly higher in patients with higher PLT (median PFS: 10 months in the "low PLT" Group (95% CI: 4.9, 16.1) vs 33 months (95% CI: 24.3, 43.2) in the "high PLT" Group (p=0.006). The multivariable Cox regression model confirmed these results. Conclusion: To our knowledge, this is the first study that investigates the predictive role of BMI in MCC patients. Our data were consistent with the clinical observation of improved outcomes in obese patients across other tumor types. Thus, advanced age, a weakened immune system, and the obesity-associated "inflammaging", are key factors that could impact the cancer immune responses of mMCC patients.

Navigating the liquid biopsy Minimal Residual Disease (MRD) in non-small cell lung cancer: Making the invisible visible.

Liquid biopsy has gained increasing interest in the growing era of precision medicine as minimally invasive technique. Recent findings demonstrated that detecting minimal or molecular residual disease (MRD) in NSCLC is a challenging matter of debate that need multidisciplinary competencies, avoiding the overtreatment risk along with achieving a significant survival improvement. This review aims to provide practical consideration for solving data interpretation questions about MRD in NSCLC thanks to the close cooperation between biologists and oncology clinicians. We discussed with a translational approach the critical point of view from benchside, bedside and bunchside to facilitate the future applicability of liquid biopsy in this setting. Herein, we defined the clinical significance of MRD, focusing on relevant practical consideration about advantages and disadvantages, speculating on future clinical trial design and standardization of MRD technology.

Immunological Aspects of Von Hippel-Lindau Disease: A Focus on Neuro-Oncology and Myasthenia Gravis.

Von Hippel-Lindau (VHL) disease is an autosomal dominant condition that predisposes affected individuals to a variety of malignant and benign neoplasms. The pathogenetic turning point of this illness is the accumulation of hypoxia-inducible factor (HIF)-1α, a transcription factor of several genes involved in oncogenesis, angiogenesis, tissue regeneration, metabolic regulation, hematopoiesis, and inflammatory responses. From an oncological perspective, increased awareness of the molecular pathways underlying this disease is bringing us closer to the development of specific and targeted therapies. Meanwhile, on the surgical side, improved understanding can help to better identify the patients to be treated and the surgical timing. Overall, pathogenesis research is crucial for developing patient-tailored therapies. One of the actual key topics of interest is the link between the VHL/HIF axis and inflammation. The present study aims to outline the fundamental mechanisms that link VHL disease and immune disorders, as well as to explore the details of the overlap between VHL disease and myasthenia gravis (MG) pathogenetic pathways. As a result, MG becomes a paradigm for autoimmune disorders that might be related with VHL disease.

The Evolving Scenario in the Assessment of Radiological Response for Hepatocellular Carcinoma in the Era of Immunotherapy: Strengths and Weaknesses of Surrogate Endpoints.

Hepatocellular carcinoma (HCC) is a challenging malignancy characterised by clinical and biological heterogeneity, independent of the stage. Despite the application of surveillance programs, a substantial proportion of patients are diagnosed at advanced stages when curative treatments are no longer available. The landscape of systemic therapies has been rapidly growing over the last decade, and the advent of immune-checkpoint inhibitors (ICIs) has changed the paradigm of systemic treatments. The coexistence of the tumour with underlying cirrhosis exposes patients with HCC to competing events related to tumour progression and/or hepatic decompensation. Therefore, it is relevant to adopt proper clinical endpoints to assess the extent of treatment benefit. While overall survival (OS) is the most accepted endpoint for phase III randomised controlled trials (RCTs) and drug approval, it is affected by many limitations. To overcome these limits, several clinical and radiological outcomes have been used. For instance, progression-free survival (PFS) is a useful endpoint to evaluate the benefit of sequential treatments, since it is not influenced by post-progression treatments, unlike OS. Moreover, radiological endpoints such as time to progression (TTP) and objective response rate (ORR) are frequently adopted. Nevertheless, the surrogacy between these endpoints and OS in the setting of unresectable HCC (uHCC) remains uncertain. Since most of the surrogate endpoints are radiology-based (e.g., PFS, TTP, ORR), the use of standardised tools is crucial for the evaluation of radiological response. The optimal way to assess the radiological response has been widely debated, and many criteria have been proposed over the years. Furthermore, none of the criteria have been validated for immunotherapy in advanced HCC. The coexistence of the underlying chronic liver disease and the access to several lines of treatments highlight the urgent need to capture early clinical benefit and the need for standardised radiological criteria to assess cancer response when using ICIs in mono- or combination therapies. Here, we review the most commonly used clinical and radiological endpoints for trial design, as well as their surrogacy with OS. We also review the criteria for radiological response to treatments for HCC, analysing the major issues and the potential future perspectives.

The predictive and prognostic role of metabolic and volume-based parameters of positron emission tomography/computed tomography as non-invasive dynamic biological markers in early breast cancer treated with preoperative systemic therapy.

Introduction: The role of fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in early breast cancer treated with preoperative systemic therapy (PST) is not yet established in clinical practice. PET parameters have aroused great interest in the recent years, as non-invasive dynamic biological markers for predicting response to PST. Methods: In this retrospective study, we included 141 patients with stage II-III breast cancer who underwent surgery after PST. Using ROC analysis, we set optimal cutoff of FDG-PET/CT parameters predictive for pathological complete response (pCR). We investigated the correlation between FDG-PET/CT parameters and pCR, median disease-free survival (DFS), and median overall survival (mOS). Results: At multivariable analysis, baseline SUVmax (high vs low: OR 9.00, CI 1.85 - 61.9, p=0.012) and Delta SUVmax (high vs low: OR 9.64, CI 1.84, 69.2, p=0.012) were significantly associated with pCR rates. Interestingly, we found that a combined analysis of the metabolic parameter Delta SUVmax with the volume-based parameter Delta MTV, may help to identify patients with pCR, especially in the subgroup of hormone receptor positive breast cancer. Delta SUVmax was also an independent predictive marker for both mDFS (high vs low: HR 0.17, 95%CI 0.05-0.58, p=0.004) and mOS (high vs. low: HR 0.19, 95%CI 0.04-0.95, p=0.029). Discussion: Our results suggest that Delta SUVmax may predict survival of early BC patients treated with PST.

Exploring the Dynamic Crosstalk between the Immune System and Genetics in Gastrointestinal Stromal Tumors.

Gastrointestinal Stromal Tumors (GISTs) represent a paradigmatic model of oncogene addiction. Despite the well-known impact of the mutational status on clinical outcomes, we need to expand our knowledge to other factors that influence behavior heterogeneity in GIST patients. A growing body of studies has revealed that the tumor microenvironment (TME), mostly populated by tumor-associated macrophages (TAMs) and lymphocytes (TILs), and stromal differentiation (SD) have a significant impact on prognosis and response to treatment. Interestingly, even though the current knowledge of the role of immune response in this setting is still limited, recent pre-clinical and clinical data have highlighted the relevance of the TME in GISTs, with possible implications for clinical practice in the near future. Moreover, the expression of immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and their relationship to the clinical phenotype in GIST are emerging as potential prognostic biomarkers. Looking forward, these variables related to the underlying tumoral microenvironment in GIST, though limited to still-ongoing trials, might lead to the potential use of immunotherapy, alone or in combination with targeted therapy, in advanced TKI-refractory GISTs. This review aims to deepen understanding of the potential link between mutational status and the immune microenvironment in GIST.

Analysis of systemic inflammatory biomarkers in neuroendocrine carcinomas of the lung: prognostic and predictive significance of NLR, LDH, ALI, and LIPI score.

BACKGROUND: Lung neuroendocrine carcinoma (NEC) is characterized by aggressive clinical behavior and lack of treatment advances. We evaluate the prognostic and the predictive roles of systemic inflammatory biomarkers in patient circulating blood: neutrophil-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), advanced lung cancer inflammation index (ALI), and the Lung Immune Prognostic Index (LIPI) score. METHODS: A total of 120 patients with small-cell lung cancer (SCLC) (n = 110) and large cell neuroendocrine carcinoma (LCNEC) (n = 10) were enrolled. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS while χ2 test was used for categorical data. RESULTS: NLR cutoff value was 1.93. NLR was measured before and after first-line chemotherapy; 25 (21%) patients had higher NLR (delta NLR >1), whereas NLR was lower in 37 (31%). At the univariate analysis, median OS was 12 months: OS for SCLC and LCNEC were 11 months and 14 months, respectively. OS had a prognostic positive value in patients with pre-treatment NLR <1.93 (p = 0.0002), LDH <600 U/L (p = 0,03) and ALI ⩾34 (p = 0,0065). At the multivariate analysis, Eastern Cooperative Oncology Group performance status, LDH levels and response after first-line chemotherapy were independently associated with OS. Median OS for good, intermediate, and poor LIPI was 15 months, 11 months, and 9 months, respectively(p = 0.091). Patients with higher NLR (>1.93) had an increased probability of tumor progression (p = 0.045, χ2 test). CONCLUSION: This study demonstrated that systemic inflammatory biomarkers could facilitate the understanding of survival differences in the clinical management of lung NEC patients, underlying the need for prospective biomarker-driven studies in the immune checkpoint inhibitors setting.

Clinical Evaluation of Everolimus in the Treatment of Neuroendocrine Tumors of the Lung: Patient Selection and Special Considerations. A Systematic and Critical Review of the Literature.

Neuroendocrine tumors (NETs) of the lung are well-differentiated neuroendocrine neoplasms (NENs) with a heterogeneous clinical behaviour. Unlike gastroenteropancreatic NENs where therapeutic armamentarium clearly increased over the last decade, everolimus represented the only clinical practical innovation for lung NET patients over the last years. Therefore, for lung NETs, a multidisciplinary discussion within a dedicated team remains critical for an adequate decision-making. Although the main regulatory authorities considered the everolimus-related evidence is enough to approve the drug in advanced lung NETs, several clinical features deserve to be discussed. In this review, we systemically and critically analysed the main clinical studies including patients with advanced lung NETs receiving everolimus. Furthermore, we reported the biological and clinical background of everolimus in lung NET setting. The purpose of this review is to help clinical community to contextualize evidence and experience for a personalised use of this drug in clinical practice in the context of advanced lung NET patients.

Atypical radiological presentation of multiple cystic brain metastases from lung cancer simulating neurocysticercosis.

Brain metastases (BMs) are usually characterised by vasogenic oedema and mass effect, but cystic appearance can rarely occur, mimicking parasitosis, such as neurocysticercosis (NCC). A woman in her mid-50s was admitted for dizziness and upper left extremity paresis. Neuroimaging showed multiple cystic lesions consistent with multiple stages of NCC evolution, and empiric albendazole was started, without any clinical improvement. A whole-body CT revealed a pulmonary lesion in the right superior lobe. Pathological analysis from brain specimen demonstrated a clear cell lung carcinoma. The patient gradually worsened and died 4 months after the diagnosis. In conclusion, multiple cystic BMs are an atypical presentation on neuroimaging; in these cases, a meticulous diagnostic workup should be performed, looking for the possible site of malignancy. Even when it is not possible to perform a biopsy from the primitive lesion, as reported in this case, a brain biopsy should be considered.

A Case of Stage I Vulvar Squamous Cell Carcinoma with Early Relapse and Rapid Disease Progression.

Squamous cell carcinoma (SCC) is the most common subtype of vulvar cancer. Locoregional surgery is often curative when the tumor is diagnosed at an early stage. However, the disease can unexpectedly evolve with a dismal prognosis even after an early diagnosis. We report a case of a woman who experienced a rapid, chemorefractory tumor progression after surgery for stage IB vulvar SCC.

Combination of peripheral neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio is predictive of pathological complete response after neoadjuvant chemotherapy in breast cancer patients.

The immune system seems to play a fundamental role in breast cancer responsiveness to chemotherapy. We investigated two peripheral indicators of immunity/inflammation, i.e. neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), in order to reveal a possible relationship with pathological complete response (pCR) in patients with early or locally advanced breast cancer treated with neoadjuvant chemotherapy (NACT). We retrospectively analyzed 373 consecutive patients affected by breast cancer and candidates to NACT. The complete blood cell count before starting NACT was evaluated to calculate NLR and PLR. ROC curve analysis determined threshold values of 2.42 and 104.47 as best cut-off values for NLR and PLR, respectively. The relationships between NLR/PLR and pCR, along with other clinical-pathological characteristics, were evaluated by Pearson's χ 2 or Fisher's exact test as appropriate. Univariate and multivariate analyses were performed using a logistic regression model. NLR and PLR were not significantly associated with pCR if analyzed separately. However, when combining NLR and PLR, patients with a NLRlow/PLRlow profile achieved a significantly higher rate of pCR compared to those with NLRhigh and/or PLRhigh (OR 2.29, 95% CI 1.22-4.27, p 0.009). Importantly, the predictive value of NLRlow/PLRlow was independent from common prognostic factors such as grading, Ki67, and molecular subtypes. The combination of NLR and PLR may reflect patients' immunogenic phenotype. Low levels of both NLR and PLR may thus indicate a status of immune system activation that may predict pCR in breast cancer patients treated with NACT.

Pancoast's syndrome caused by lymph node metastasis from breast cancer.

Pancoast's syndrome may be the result of neoplastic, inflammatory or infectious disease. We report an unusual case of Pancoast's syndrome in a patient with metastatic breast cancer. A 54-year-old woman, affected by metastatic breast cancer, presented for severe shoulder pain, paraesthesia and numbness in the right arm. Despite further multiple lines of systemic chemotherapy, she developed a progressive enlargement of retropectoral, supraclavicular and infraclavicular lymph node metastases, which involved brachial plexus, apex of lung and anterior mediastinum. Physical examination revealed severe weakness of proximal muscles of the right arm. Neuropathic pain was managed with pharmacological treatment. Lastly, the patient has been treated with intrathecal analgesia with morphine and ziconotide with a good control of pain. The patient died after 3 months.

A single-institution retrospective analysis of metachronous and synchronous metastatic bronchial neuroendocrine tumors.

BACKGROUND: Broncho-pulmonary neuroendocrine tumors (bpNETs) are rare malignancies and there is no consensus on therapeutical management of metastatic disease and follow-up after radical resection. METHODS: Clinical records of patients with a cytological or histological diagnosis of bpNETs and distant metastases (metachronous or synchronous), evaluated at the European Institute of Oncology between 1997 and 2014, were retrospectively analyzed. Data on patient demographics, pathology, imaging exams, surgical and non-surgical treatments were collected. P value descriptive data, uni- and multi-variate survival analysis were generated for all variables. RESULTS: With a median follow-up of 53 [9-215] months, 61 patients with metachronous and 47 with synchronous metastases were analysed. The most common tool of first recurrence detection was computed tomography. Liver (67%), lymph node (25%), bone (22%) and lung (16%) were the most common sites of relapse. Median time to recurrence was 5 years. Median overall survival (OS) was 72 months for the whole population, with no significant difference between patients with synchronous and metachronous metastases. Age, bone metastases, liver metastases and Ki-67 as a continuous variable all significantly correlated with prognosis at the multivariate analysis. CONCLUSIONS: This is one of the largest, single-centre, series of metastatic bpNETs. Among patients with metachronous metastases the pattern of recurrences was heterogeneous as were the follow-up exams used to detect them. The results of our analysis may represent solid bases for designing prospective clinical trials in homogeneous settings of bpNETs.