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.

Real-World Outcomes and Treatments Patterns Prior and after the Introduction of First-Line Immunotherapy for the Treatment of Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: This study provides insights into the treatment use and outcomes of metastatic non-small cell lung cancer (NSCLC) patients in a real-world setting prior to and after the availability of immuno-oncology (IO) regimens in the first line (1L). METHODS: Metastatic NSCLC patients, who initiated systemic 1L anticancer treatment from 2014 to 2020, were identified from health records. Patients were grouped into Pre-1L IO and Post-1L IO, according to the availability of pembrolizumab 1L monotherapy at the date of initiating 1L systemic anticancer treatment. Patient characteristics, treatment patterns and outcomes were assessed by the cohort. Overall survival (OS) and real-world progression-free survival (rwPFS) were calculated using the Kaplan-Meier method. RESULTS: The most common 1L treatment was platinum-based chemotherapy regimens in both groups (≥46%), followed by single-agent chemotherapy (27.0%) in Pre-1L IO and pembrolizumab (26.0%) in Post-1L IO. Median OS was 6.2 (95% CI 5.5-7.4) in Pre- and 8.9 months (95% CI 7.5-10.6) in Post-1L IO, while rwPFS was 3.7 (95% CI 3.3-4.2) and 4.7 months (95% CI 3.9-5.7), respectively. CONCLUSIONS: Even if a small proportion of patients received a 1L IO, the data showed an improved survival outcomes in the Post-1L IO group.

How to discriminate non-small cell lung cancer (NSCLC) cases from an Italian administrative database? A retrospective, secondary data use study for evaluating a novel algorithm performance.

OBJECTIVES: To evaluate an algorithm developed for identifying non-small cell lung cancer (NSCLC) candidates among patients with lung cancer with a diagnosis International Classification of Diseases: ninth revision (ICD-9) 162.x code in administrative databases. Algorithm could then be applied for identifying the NSCLC population in order to assess the appropriateness and quality of care of the NSCLC care pathway. DESIGN: Algorithm discrimination capacity to select both NSCLC or non-NSCLC was carried out on a sample for which electronic health record (EHR) diagnosis was available. A bivariate frequency distribution and other measures were used to evaluate algorithm's performances. Associations between possible factors potentially affecting algorithm accuracy were investigated. SETTING: Administrative databases used in a specific geographical area of Emilia-Romagna region, Italy. PARTICIPANTS: Algorithm was carried out on patients aged >18 years, with a lung cancer diagnosis from January to December 2017 and resident in Emilia-Romagna region who have been hospitalised at IRST or in one of the hospitals placed in the Forlì-Cesena area and for which EHR diagnosis data were available. OUTCOME MEASURES: Overall accuracy, positive (PPV) and negative (NPV) predictive values, sensitivity and specificity, positive and negative likelihood ratios and diagnostic OR were calculated. RESULTS: A total of 430 patients were identified as lung cancer cases based on ICD-9 diagnosis. Focusing on the total incident cases (n=314), the algorithm had an overall accuracy of 82.8% with a sensitivity of 88.8%. The analysis confirmed a high level of PPV (90.2%), but lower specificity (53.7%) and NPV (50%). Higher length of stay seemed to be associated with a correct classification. Hospitalisation regimen and a supply of antiblastic therapy seemed to increase the level of PPV. CONCLUSION: The algorithm demonstrated a strong validity for identifying NSCLC among patients with lung cancer in hospital administrative databases and can be used to investigate the quality of cancer care for this population. TRIAL REGISTRATION NUMBER: NCT04676321.

Cell-Free DNA Variant Sequencing Using CTC-Depleted Blood for Comprehensive Liquid Biopsy Testing in Metastatic Breast Cancer.

Keup and colleagues provide liquid biopsy preliminary results by sequencing variants in circulating tumor cells (CTCs) and cell-free deoxyribonucleic acid (cfDNA) "all from one tube" format, in order to use the same blood sample under the same isolation conditions of both analytes to reach an unbiased comparability and consistency. We appreciated the attempt of the authors to improve technical procedures in liquid biopsy research area, but we wanted to raise several issues related to cfDNA detection, reporting our research experience. This is a feasibility study as the authors analyzed only one sample from a small case series at an advanced line of treatment. In the clinical practice to monitor the disease and predict the treatment response, the analysis should be done at multiple time points. We have previously demonstrated that the quantity and the integrity of the cfDNA are not useful to determine the evolution of early breast cancer (bc), maybe due to the fact that cfDNA is not strictly related to cancer but also to an inflammatory status. Given that a high content of cfDNA could reflect inflammatory processes, we decided to investigate the role of stimulator of interferon gene (STING), an important regulator of cancer cell growth and senescence, in bc tissue in relation to cfDNA. STING biomarker analyzed by immunohistochemistry on tumor tissue could reflect a circulating inflammatory status and needs to be further investigated, not only on CTCs but also on cfDNA. One of the major issues of cfDNA is to decide what to analyze on it, in terms of type of cells and genetic alterations. Considering that multiple tests could be done to study gene copy number alterations, mutations, and variant fusions, the proper molecular test should be chosen, on the basis of the clinical need, starting from the treatment choice to disease monitoring.

Can cyclin-dependent kinase 4/6 inhibitors convert inoperable breast cancer relapse to operability? A case report.

BACKGROUND: Pathological complete response (pCR) is rare in hormone receptor-positive (HR+) HER2-negative breast cancer (BC) treated with either endocrine therapy (ET) or chemotherapy. Radical resection of locoregional relapse, although potentially curative in some cases, is challenging when the tumor invades critical structures. The oral cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ET has obtained a significant increase in objective response rates and progression-free survival in patients with advanced BC and is now being evaluated in the neoadjuvant setting. We present a clinical case of a patient with an inoperable locoregional relapse of HR+ HER2-negative BC who experienced pCR after treatment with palbociclib. CASE SUMMARY: We report the clinical case of a 60-year-old patient who presented with an inoperable locoregional relapse of HR+, HER2-negative BC 10 years after the diagnosis of the primary tumor. During a routine follow-up visit, breast magnetic resonance imaging and positron emission tomography/computed tomography revealed a 4-cm lesion in the right subclavicular region, infiltrating the chest wall and extending to the subclavian vessels, but without bone or visceral involvement. Treatment was begun with palbociclib plus letrozole, converting the disease to operability over a period of 6 mo. Surgery was performed and a pCR achieved. Of note, during treatment the patient experienced a very uncommon toxicity characterized by burning tongue and glossodynia associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. A reduction in the dose of palbociclib did not provide relief and treatment with the inhibitor was thus discontinued, resolving the tongue symptoms. Laboratory exams were unremarkable. Given that this was a late relapse, the tumor was classified as endocrine-sensitive, a condition associated with high sensitivity to palbociclib. CONCLUSION: This case highlights the potential of the cyclin-dependent kinase 4/6 inhibitor plus ET combination to achieve pCR in locoregional relapse of BC, enabling surgical resection of a lesion initially considered inoperable.

Ki67 and PR in Patients Treated with CDK4/6 Inhibitors: A Real-World Experience.

CDK4/6 inhibitors (CDK4/6i) are recommended in patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer (ABC). Up to now, no prognostic biomarkers have been identified in this setting. We retrospectively analyzed the expression of progesterone receptor (PR) and Ki67, assessed by immunohistochemistry, in 71 ABC patients treated with CDK4/6i and analyzed the impact of these markers on progression-free survival (PFS). The majority of patients 63/71 (88.7%) received palbociclib, 4 (5.6%) received ribociclib, and 4 (5.6%) received abemaciclib. A higher median value of Ki67 was observed in cases undergoing second-line treatment (p = 0.047), whereas the luminal B subtype was more prevalent (p = 0.005). In the univariate analysis of the first-line setting, luminal A subtype showed a trend towards a correlation with a longer PFS (p = 0.053). A higher continuous Ki67 value led to a significantly shorter PFS. When the interaction between pathological characteristics and line of treatment was considered, luminal B subtype showed a significantly (p = 0.043) worse outcome (Hazard Ratio (HR) 2.84; 1.03-7.82 95% Confidence Interval (CI)). PFS in patients undergoing endocrine therapy plus CDK4/6i was inversely correlated with Ki67 expression but not with PR, suggesting that tumor proliferation has a greater impact on cell cycle inhibitors combined with endocrine therapy than PR expression.

Pregnancy after breast cancer: Are young patients willing to participate in clinical studies?

Young patients with breast cancer (BC) are often concerned about treatment-induced infertility and express maternity desire. Conception after BC does not seem to affect outcome, but information in estrogen-receptor positive (ER+) disease is not definitive. From September 2012-March 2013, 212 evaluable patients with ER+ early BC, <37 years at diagnosis, from 5 regions (Europe/US/Canada/Middle-East/Australia) answered a survey about fertility concerns, maternity desire and interest in a study of endocrine therapy (ET) interruption to allow pregnancy. Overall, 37% of respondents were interested in the study; younger patients (≤30 years) reported higher interest (57%). Motivation in younger patients treated >30 months was higher (83%) than in older women (14%), interest was independent of age in patients treated for ≤30 months. A prospective study in this patient population seems relevant and feasible. The International-Breast-Cancer-Study-Group (IBCSG), within the Breast-International-Group (BIG) - North-American-Breast-Cancer-Groups (NABCG) collaboration, is launching a study (POSITIVE) addressing ET interruption to allow pregnancy.

Adjuvant trastuzumab in elderly with HER-2 positive breast cancer: a systematic review of randomized controlled trials.

Trastuzumab, in combination with chemotherapy, is the gold standard in the adjuvant treatment of patients with HER2 positive breast cancer. Limited data are available on the role of adjuvant trastuzumab in the elderly population. We performed a systematic review of prospective randomized trials with available data on the use of adjuvant trastuzumab in patients older than 60years, focusing on both the efficacy and the cardiac safety. Data extrapolated from two prospective trials were included for efficacy and cardiac safety. A significant 47% relative risk reduction was observed in elderly patients receiving trastuzumab compared to chemotherapy alone (pooled Hazard Ratio: 0.53; 95% CI, 0.36-0.77). The pooled proportion of cardiac events in elderly patients treated with trastuzumab was 5% (95% CI, 4-7%). The use of trastuzumab should be considered as a standard of care in the adjuvant therapy of elderly patients with HER-2 positive breast cancer. Acute and chronic medical conditions, nutritional status and level of daily activities should be considered. Uncertainty about cardiac safety in the elderly is a major concern.