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Circulating, cell-free microRNAs (miRNAs) are promising candidate biomarkers, but optimal conditions for processing blood specimens for miRNA measurement remain to be established. Our previous work showed that the majority of plasma miRNAs are likely blood cell-derived. In the course of profiling lung cancer cases versus healthy controls, we observed a broad increase in circulating miRNA levels in cases compared to controls and that higher miRNA expression correlated with higher platelet and particle counts. We therefore hypothesized that the quantity of residual platelets and microparticles remaining after plasma processing might impact miRNA measurements. To systematically investigate this, we subjected matched plasma from healthy individuals to stepwise processing with differential centrifugation and 0.22 µm filtration and performed miRNA profiling. We found a major effect on circulating miRNAs, with the majority (72%) of detectable miRNAs substantially affected by processing alone. Specifically, 10% of miRNAs showed 4-30x variation, 46% showed 30-1,000x variation, and 15% showed >1,000x variation in expression solely from processing. This was predominantly due to platelet contamination, which persisted despite using standard laboratory protocols. Importantly, we show that platelet contamination in archived samples could largely be eliminated by additional centrifugation, even in frozen samples stored for six years. To minimize confounding effects in microRNA biomarker studies, additional steps to limit platelet contamination for circulating miRNA biomarker studies are necessary. We provide specific practical recommendations to help minimize confounding variation attributable to plasma processing and platelet contamination.

BackgroundThere is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC.MethodsA retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/metastatic ACC.ResultsEight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21–49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2–9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression-free survival was 5.5 months (95% CI 1.8–not reached) and median duration of therapy was 8.5 months (range 2–22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events.ConclusionsIn our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response.

Background Anti‐PD1 checkpoint inhibitors (ICI) represent an established standard‐of‐care for patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC). Landmark studies excluded patients with ECOG performance status (PS) ≥2; the benefit of ICI in this population is therefore unknown. Methods We retrospectively reviewed RMHNSCC patients who received 1+ dose of ICI at our institution between 2013 and 2019. Demographic and clinical data were obtained; the latter included objective response (ORR), toxicity, and any unplanned hospitalization (UH). Associations were explored using uni‐ and multivariate analysis. Overall survival (OS) was estimated using a Cox proportional hazards model; ORR, toxicity, and UH were evaluated with logistic regression. Results Of the 152 patients, 29 (19%) had an ECOG PS ≥2. Sixty‐six (44%) experienced toxicity; 54 (36%) had a UH. A multivariate model for OS containing PS, smoking status, and HPV status demonstrated a strong association between ECOG ≥2 and shorter OS (p < 0.001; HR = 3.30, CI = 2.01–5.41). An association between OS and former (vs. never) smoking was also seen (p < 0.001; HR = 2.17, CI = 1.41–3.35); current smoking did not reach statistical significance. On univariate analysis, poor PS was associated with inferior ORR (p = 0.03; OR = 0.25, CI = 0.06–0.77) and increased UH (p = 0.04; OR = 2.43, CI = 1.05—5.71). There was no significant association between toxicity and any patient characteristic. Conclusions We observed inferior OS, ORR, and rates of UH among ICI‐treated RMHNSCC patients with ECOG 2/3. Our findings help frame discussion of therapeutic options in this poor‐risk population. Relative to those with a performance status of 0‐1, patients with an Eastern Cooperative Oncology Group performance status 2 who received immune checkpoint inhibitors for recurrent/metastatic head and neck cancer have poorer response rates and overall survival as well as increased rates of unplanned hospitalization; no significant difference in toxicity was seen.

Neuroendocrine transformation (NT) in cancers, typically observed under the selective pressure of targeted therapies, involves lineage plasticity where adenocarcinomas adopt neuroendocrine characteristics while retaining the molecular alterations of their original histology. This phenomenon, well-documented in prostate and lung cancers, has not been observed in gynecological malignancies until now. We present two pivotal cases involving primary ovarian and uterine cancers that developed neuroendocrine carcinomas post-treatment. Initially presumed to be independent primaries, comprehensive next-generation sequencing technologies, including UW-OncoPlex and BROCA panels, were used to establish a clonal relationship between the primary tumors and their respective neuroendocrine metastases. This report provides the first documented instances of NT in gynecological cancers, indicating that it may be a more widespread resistance mechanism than previously recognized. Routine re-biopsy and early integration of advanced molecular diagnostics into clinical practice will identify NT and provide insights into pathogenesis and eventual therapeutic options.

BackgroundNapsin A is normally expressed in human lung pneumocytes and is a highly expressed cancer antigen in lung adenocarcinoma. We examined whether T cells specific for Napsin A may play a role in immune checkpoint inhibitor (ICI)-mediated responses. We used bulk T-cell receptor (TCR) repertoire data to assess whether the presence of Napsin A-specific clonotypes in the peripheral blood was associated with improved clinical responses to ICI.MethodsPatients with metastatic non-small cell lung cancer (NSCLC) receiving anti-programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1) were enrolled at Fred Hutchinson Cancer Center and Stanford University Medical Center (n=62; histology of adenocarcinoma n=48, squamous n=9, NSCLC/other n=5). Peripheral blood mononuclear cells were collected for genomic DNA isolation at one pretreatment and one post-treatment time point (range 3 weeks to 3 months). TCRβ was bulk sequenced via the immunoSEQ platform (Adaptive Biotechnologies). Napsin A-specific TCRβ sequences were identified from publicly available data and their frequencies were quantified in each patient sample. We examined whether overall survival (OS) and progression-free survival (PFS) outcomes differed in patients with or without detectable Napsin A-specific TCRs (herein Napsin TCRs). We used Cox proportional hazards regression to assess the association between detectable Napsin TCRs and PFS or OS in univariable and multivariable analyses.ResultsNapsin TCRs were detectable in the blood in a large fraction of our cohort (n=25/62 (40%) pretreatment; n=21/42 (50%) post-treatment). Patients with detectable Napsin TCRs had a significant improvement in OS compared with patients without these TCRs (median OS 45.4 vs 14.8 months, p=0.0043 pretreatment; median OS 55.4 vs 18.9 months, p=0.0066 post-treatment). Among 27 HLA-A*02 carriers of 55 human leukocyte antigen-typed patients (49%), patients with detectable pretreatment Napsin TCRs had a significant improvement in OS (median 60.2 vs 16.5 months, p=0.0054) and PFS (median 21.5 vs 7.2 months, p=0.031) compared with patients without these TCRs. In univariate and multivariate analysis, the presence of Napsin TCRs pretreatment was associated with improved OS (p=0.0057, HR 0.40, 95% CI 0.21 to 0.76 univariate; p=0.033, HR 0.45, 95% CI 0.23 to 0.91 multivariate).ConclusionsNapsin TCRs are frequently detected in patients with NSCLC and are associated with improved OS in patients with NSCLC receiving ICI.

Background Neoadjuvant chemotherapy is effective in improving survival of resectable NSCLC. Based on findings in the adjuvant and metastatic setting, FDG positron emission tomography (PET) scans may offer early prognostic or predictive value after one cycle of induction chemotherapy. Methods In this phase II non-randomized trial, patients with AJCC version 6 stage IB to IIIB operable NSCLC were treated with 3 cycles of cisplatin and pemetrexed neoadjuvant chemotherapy. Patients underwent FDG-PET scanning prior to and 18 to 21 days after the first cycle of chemotherapy. Investigators caring for patients were blinded to results, unless the scans showed evidence of disease progression. FDG-PET response was defined prospectively as a ≥ 20% decrease in the SUV of the primary lesion. Results Between October 2005 and February 2010, 25 patients enrolled. Fifty two percent were female, 88% white, and median age was 62 years. Histology was divided into adenocarcinoma 66%, not otherwise specified (NOS) 16%, squamous cell 12%, and large cell 4%. Stage distribution was: 16% IB, 4% IIB, and 79% IIIA. Treatment was well tolerated and only one patient had a grade 4 toxicity. The median follow up was 95 months. The 5 year progression free survival (PFS) and overall survival (OS) for the entire population were 54 and 67%, respectively. Eighteen patients had a baseline FDG-PET scan and a repeat scan at day 18–21 available for comparison. Ten patients (56%) were considered metabolic responders on the day 18–21 FDG-PET scan. Responders had a 5 year PFS and OS of 60 and 70%, respectively, while the percentage for non-responders was 63 and 75% ( p  = 0.96 and 0.85). Conclusions This phase II trial did not demonstrate that a PET scan after one cycle of chemotherapy can predict survival outcomes of patients with NSCLC treated with neoadjuvant chemotherapy. Trial registration NCT00227539 registered September 28th, 2005.

Background Due to the increasing rates of oropharyngeal cancer, oral HPV infection is a significant concern. Methods for detecting oral HPVs is not standardized as there are different techniques available. We propose that use of oral rinse samples to detect for HPVs is a suitable technique within a clinic setting. Thus, our main objective is to study HPV detection in oral rinse samples. Methods In our study, we used oral rinse sample collection coupled with real-time PCR to detect for HPVs types 16 and 18, and preferentially amplified FAP PCR samples to detect for a broad range of HPVs, in oropharyngeal squamous cell carcinoma (OPSCC), non-OPSCC, and healthy patients. Results Thirty three percent of 100 cancer patients were positive for any type of HPV; of those 23 were positive for HPV16. Only 1 of 110 healthy controls was positive (this subject was positive for HPV18). Conclusion Our results indicate that HPV detection in oral rinse samples may be useful as a screening tool to detect HPV-associated oral cancers.

Background In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR). Methods This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes. Results Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail. Conclusions The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy. Trial Registration ClinicalTrials.gov NCT01011075

SummaryPurpose and Methods Trop-2 is a glycoprotein over-expressed in many solid tumors but at low levels in normal human tissue, providing a potential therapeutic target. We conducted a phase 1 dose-finding study of PF-06664178, an antibody-drug conjugate that targets Trop-2 for the selective delivery of the cytotoxic payload Aur0101. The primary objective was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included further characterization of the safety profile, pharmacokinetics and antitumor activity. Eligible patients were enrolled and received multiple escalating doses of PF-06664178 in an open-label and unblinded manner based on a modified continual reassessment method. Results Thirty-one patients with advanced or metastatic solid tumors were treated with escalating doses of PF-06664178 given intravenously every 21 days. Doses explored ranged from 0.15 mg/kg to 4.8 mg/kg. Seven patients experienced at least one dose limiting toxicity (DLT), either neutropenia or rash. Doses of 3.60 mg/kg, 4.2 mg/kg and 4.8 mg/kg were considered intolerable due to DLTs in skin rash, mucosa and neutropenia. Best overall response was stable disease in 11 patients (37.9%). None of the patients had a partial or complete response. Systemic exposure of PF-06664178 increased in a dose-related manner. Serum concentrations of free Aur0101 were substantially lower than those of PF-06664178 and total antibody. No correlation of Trop-2 expression and objective response was observed, although Trop-2 overexpression was not required for study entry. The intermediate dose of 2.4 mg/kg appeared to be the highest tolerated dose, but this was not fully explored as the study was terminated early due to excess toxicity. Conclusion PF-06664178 showed toxicity at high dose levels with modest antitumor activity. Neutropenia, skin rash and mucosal inflammation were dose limiting toxicities. Findings from this study may potentially aid in future antibody drug conjugate design and trials.

Central venous catheter (CVC) maintenance is critical in administering chemotherapy, transfusions, and high-frequency laboratory draws. Although normal saline (NS) flushes have been associated with similar incidences of irreversible port occlusions as heparin among adult patients with cancer and ports, additional research is needed regarding NS efficacy in other central line maintenance within large populations with cancer. The aim of this study was to analyze changes in reported CVC line patency via tissue plasminogen activator (tPA) administration rates in ports and other central lines because of an institutional switch from heparin to NS as preferred flushes in adult ambulatory patients with cancer. Retrospective data were collected from patients with ports (3,706 prepolicy, 3,402 postpolicy) and nonport CVCs (816 prepolicy, 694 postpolicy). Patients with nonport CVCs experienced similar tPA usage pre- versus postpolicy, versus an increased rate of tPA usage for ports. This policy resulted in institutional savings of $28,695.92. NS flushes are as effective as heparin for maintaining patency in ports and other CVCs for adult outpatients with cancer and address safety concerns with heparin-associated complications.