In the last decade, immune checkpoint inhibitors have revolutionized the treatment of metastatic nonsmall cell lung cancer without oncogenic addiction. Currently, programmed death ligand 1 (PD-L1) ...status, assessed in tissue biopsy samples, is the only test for guiding the prescription of these therapies in clinical practice. However, obtaining tumor tissue from patients with lung cancer is not always feasible and PD-L1 positivity is not a guarantee of immunotherapy efficacy. In this context, liquid biopsy, represented by several circulating biomarkers that reflect the tumor characteristics, is emerging as an interesting alternative approach.
We describe the main blood biomarkers evaluated in patients with metastatic nonsmall cell lung cancer before/during immune checkpoint inhibitor treatment, with a focus on circulating cell-free DNA, circulating tumor DNA (ctDNA), blood tumor mutational burden, and circulating tumor cells (CTCs).
Monitoring of ctDNA and CTCs during immunotherapy may be a promising tool to help clinicians in therapeutic decision-making.
Abstract
Background
In non-small cell lung cancer (NSCLC), analysis of programmed cell death ligand 1 (PD-L1) expression in circulating tumor cells (CTCs) is a potential alternative to overcome the ...problems linked to the tumor biopsy spatiotemporal heterogeneity. However, the prognostic significance of PD-L1-positive PD-L1(+) CTCs remains controversial.
Methods
We prospectively evaluated the correlation with clinicopathological variables and prognostic value of PD-L1(+) CTCs, detected with the FDA-cleared CellSearch® system, in 54 patients with advanced NSCLC.
Results
We detected CTCs and PD-L1(+) CTCs in 43.4% and 9.4% of patients with NSCLC. PD-L1 expression concordance between tumor tissue and CTCs was low (54%). The presence of PD-L1(+) CTC correlated with the absence of gene alterations in tumor tissue and with poor prognosis-related biological variables (anemia, hyponatremia, increased lactate dehydrogenase). In univariate analysis, absence of gene alterations, number of metastatic sites, prior systemic therapies, and presence of CTCs and PD-L1(+) CTCs were associated with worse overall survival, whereas PD-L1 expression in tumor tissue was not. In multivariate analysis, squamous cell carcinoma histology, number of prior systemic treatments, and the presence of CTC were significantly associated with overall survival. Survival was worse in patients with PD-L1(+) CTCs than in patients with PD-L1-negative CTC or without any CTC.
Conclusions
Our study suggests that the presence of PD-L1(+) CTCs is associated with poor prognosis in patients with advanced NSCLC. Studies with larger samples are needed to confirm our results and to determine how PD-L1(+) CTC detection could help to predict the response or resistance to anti-PD-1/PD-L1 therapies.
Clinical trial registration NCT02866149
In patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, leptomeningeal metastases (LM) are a rare but often a fatal clinical scenario. In this multicentric study, ...clinical and pathologic characteristics of patients with HER2+ breast cancer developing LM were described, as well as survival outcomes. Data were gathered retrospectively from medical records of 82 patients with advanced HER2+ breast cancer and LM treated between August 2005 and July 2020. Following LM diagnosis, 79 (96.3%) patients received at least one line of anti‐HER2 therapy, 25 (30.5%) patients received intrathecal therapy and 58 (70.7%) patients received radiotherapy. Overall survival (OS) was 8.3 months (95% confidence interval CI 5.7‐11), 1‐year OS was 42%, and 2‐year OS was 21%. At univariate analysis, patients who were treated after 2010, had better Karnofsky performance status, were free of neurological symptoms, had better prognostic, received chemotherapy (OS difference 9.4 months, P = .024), or monoclonal antibodies (trastuzumab ± pertuzumab; OS difference 6.1 months; P = .013) after LM diagnosis, had a statistically significantly longer OS. Presence of neurological symptoms (hazard ratio 3.32, 95% CI 1.26‐8.73; P = .015) and not having received radiotherapy (hazard ratio 2.02, 95% CI 1.09‐3.72; P = .024) were all associated with poorer OS at multivariate analysis. To summarize, not having neurological symptoms and receiving RT at LM diagnosis were associated with prolonged OS in our cohort. Survival seemed to be prolonged with multimodality treatment, which included targeted therapy, chemotherapy, and RT to the LM sites.
What's new?
Patients with human epidermal growth factor receptor 2‐positive (HER2+) breast cancer and leptomeningeal metastasis (LM) are likely to suffer neurological damage. The degree to which neurological symptoms are evident and their impact on survival remain uncertain. Here, investigation of pathological features and survival in a European cohort of HER2+ breast cancer patients with LM shows that preexisting brain metastases are common at LM diagnosis, affecting as many as two‐thirds of patients. Overall survival was longer among patients who lacked neurological symptoms and who received radiotherapy at LM diagnosis. Longer survival was further linked to the use of multimodality therapy.
Brain metastases (BM) are common among HER2+ breast cancer (BC) and prognostic stratification is crucial for optimal management. BC-GPA score and subsequent refinements (modified-GPA, updated-GPA) ...recapitulate prognostic factors. Since none of these indexes includes extracranial disease control, we evaluated its prognostic value in HER2+ BCBM.
Patients diagnosed with HER2+ BCBM at Istituto Oncologico Veneto-Padova (2002-2021) and Montpellier Cancer Institute (2001-2015) were included as exploratory and validation cohorts, respectively. Extracranial disease control at BM diagnosis (no disease/stable disease/response vs. progressive disease) was evaluated.
In the exploratory cohort of 113 patients (median OS 12.2 months), extracranial control (n = 65, 57.5%) was significantly associated with better OS at univariate (median OS 17.7 vs. 8.7 months, p = 0.005) and multivariate analysis after adjustment for BC-GPA (HR 0.61, 95% CI 0.39-0.94), modified-GPA (HR 0.64, 95% CI 0.42-0.98) and updated-GPA (HR 0.63, 95% CI 0.41-0.98). The prognostic impact of extracranial disease control (n = 66, 56.4%) was then confirmed in the validation cohort (n = 117) at univariate (median OS 20.2 vs. 9.1 months, p < 0.001) and multivariate analysis adjusting for BC-GPA (HR 0.41, 95% CI 0.27-0.61), modified-GPA (HR 0.44, 95% CI 0.29-0.67) and updated-GPA (HR 0.42, 95% CI 0.28-0.63).
Extracranial disease control provides independent prognostic information in HER2+ BCBM beyond commonly used prognostic scores.
Circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), and extracellular vesicles (EVs) are minimally invasive liquid biopsy biomarkers. This study investigated whether they predict ...prognosis, alone or in combination, in heterogenous unbiased non-small cell lung cancer (NSCLC) patients.
Plasma samples of 54 advanced NSCLC patients from a prospective clinical trial. CtDNA mutations were identified using the UltraSEEK™ Lung Panel (MassARRAY® technology). PD-L1 expression was assessed in small EVs (sEVs) using an enzyme-linked immunosorbent assay.
At least one ctDNA mutation was detected in 37% of patients. Mutations were not correlated with overall survival (OS) (HR = 1.1, 95% CI = 0.55; 1.83, P = 0.980) and progression-free survival (PFS) (HR = 1.00, 95% CI = 0.57-1.76, P = 0.991). High PD-L1
sEV concentration was correlated with OS (HR = 1.14, 95% CI = 1.03-1.26, P = 0.016), but not with PFS (HR = 1.08, 95% CI = 0.99-1.18, P = 0.095). The interaction analysis suggested that PD-L1
sEV correlation with PFS changed in function of CTC presence/absence (P interaction = 0.036). The combination analysis highlighted worse prognosis for patients with CTCs and high PD-L1
sEV concentration (HR = 7.65, 95% CI = 3.11-18.83, P < 0.001). The mutational statuses of ctDNA and tumour tissue were significantly correlated (P = 0.0001).
CTCs and high PD-L1
sEV concentration correlated with PFS and OS, but not ctDNA mutations. Their combined analysis may help to identify patients with worse OS.
NCT02866149, Registered 01 June 2015, https://clinicaltrials.gov/ct2/show/study/NCT02866149 .
We report the case of a patient with a complete metastatic adrenal response on Pembrolizumab for metastatic lung cancer. Treatment with a systemic corticosteroid‐induced a time‐dependent progression ...at his metastatic site. Surprisingly, after stopping the corticosteroid, we observed a new complete response in long‐term adrenal metastases.
The administration of systemic corticosteroid therapy for a prolonged period in patients undergoing treatment with immune checkpoint inhibitors for metastatic lung cancer can have a direct impact on the tumor response and may be reversible.
PDF
