Cancer Associated Macrophage-like Cells Are Prognostic for Highly Aggressive Prostate Cancer in Both the Non-Metastatic and Metastatic Settings.

Despite advancements in the early-stage detection and expansion of treatments for prostate cancer (PCa), patient mortality rates remain high in patients with aggressive disease and the overtreatment of indolent disease remains a major issue. Prostate-specific antigen (PSA), a standard PCa blood biomarker, is limited in its ability to differentiate disease subtypes resulting in the overtreatment of non-aggressive indolent disease. Here we assess engorged cancer-associated macrophage-like cells (CAMLs), a ≥50 µm, cancer-specific, polynucleated circulating cell type found in the blood of patients with PCa as a potential companion biomarker to PSA for patient risk stratification. We found that rising PSA is positively correlated with increasing CAML size (r = 0.307, p = 0.004) and number of CAMLs in circulation (r = 0.399, p < 0.001). Over a 2-year period, the presence of a single engorged CAML was associated with 20.9 times increased likelihood of progression (p = 0.016) in non-metastatic PCa, and 2.4 times likelihood of progression (p = 0.031) with 5.4 times likelihood of death (p < 0.001) in metastatic PCa. These preliminary data suggest that CAML cell monitoring, in combination with PSA, may aid in differentiating non-aggressive from aggressive PCas by adding biological information that complements traditional clinical biomarkers, thereby helping guide treatment strategies.

Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer.

Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m2/day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. Response was determined by imaging at weeks 4 and 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of veliparib with TMZ. Exploratory objectives included PARP-1 and SLFN11 immunohistochemical expression, MGMT promoter methylation, and circulating tumor cell quantification. Results No significant difference in 4-month PFS was noted between TMZ/veliparib (36%) and TMZ/placebo (27%; P = .19); median OS was also not improved significantly with TMZ/veliparib (8.2 months; 95% CI, 6.4 to 12.2 months; v 7.0 months; 95% CI, 5.3 to 9.5 months; P = .50). However, ORR was significantly higher in patients receiving TMZ/veliparib compared with TMZ/placebo (39% v 14%; P = .016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred with TMZ/veliparib: 50% versus 9% and 31% versus 7%, respectively. Significantly prolonged PFS (5.7 v 3.6 months; P = .009) and OS (12.2 v 7.5 months; P = .014) were observed in patients with SLFN11-positive tumors treated with TMZ/veliparib. Conclusion Four-month PFS and median OS did not differ between the two arms, whereas a significant improvement in ORR was observed with TMZ/veliparib. SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in SCLC.

Cerebrospinal fluid circulating tumor cells: a novel tool to diagnose leptomeningeal metastases from epithelial tumors.

BACKGROUND: Diagnosis of leptomeningeal metastasis (LM) remains challenging due to low sensitivity of CSF cytology and infrequent unequivocal MRI findings. In a previous pilot study, we showed that rare cell capture technology (RCCT) could be used to detect circulating tumor cells (CTC) in the CSF of patients with LM from epithelial tumors. To establish the diagnostic accuracy of CSF-CTC in the diagnosis of LM, we applied this technique in a distinct, larger cohort of patients. METHODS: In this institutional review board-approved prospective study, patients with epithelial tumors and clinical suspicion of LM underwent CSF-CTC evaluation and standard MRI and CSF cytology examination. CSF-CTC enumeration was performed through an FDA-approved epithelial cell adhesion molecule-based RCCT immunomagnetic platform. LM was defined by either positive CSF cytology or imaging positive for LM. ROC analysis was utilized to define an optimal cutoff for CSF-CTC enumeration. RESULTS: Ninety-five patients were enrolled (36 breast, 31 lung, 28 others). LM was diagnosed in 30 patients (32%) based on CSF cytology (n = 12), MRI findings (n = 2), or both (n = 16). CSF-CTC were detected in 43/95 samples (median 19.3 CSF-CTC/mL, range 0.3 to 66.7). Based on ROC analysis, 1 CSF-CTC/mL provided the best threshold to diagnose LM, achieving a sensitivity of 93%, specificity of 95%, positive predictive value 90%, and negative predictive value 97%. CONCLUSIONS: We defined ≥1 CSF-CTC/mL as the optimal cutoff for diagnosis of LM. CSF-CTC enumeration through RCCT is a robust tool to diagnose LM and should be considered in the routine LM workup in solid tumor patients.