Citations

Abstract Rationale Usual interstitial pneumonia (UIP) is the histopathologic hallmark of idiopathic pulmonary fibrosis. Although UIP can be detected by high-resolution computed tomography of the chest, the results are frequently inconclusive, and pathology from transbronchial biopsy (TBB) has poor sensitivity. Surgical lung biopsy may be necessary for a definitive diagnosis. Objectives To develop a genomic classifier in tissue obtained by TBB that distinguishes UIP from non-UIP, trained against central pathology as the reference standard. Methods Exome enriched RNA sequencing was performed on 283 TBBs from 84 subjects. Machine learning was used to train an algorithm with high rule-in (specificity) performance using specimens from 53 subjects. Performance was evaluated by cross-validation and on an independent test set of specimens from 31 subjects. We explored the feasibility of a single molecular test per subject by combining multiple TBBs from upper and lower lobes. To address whether classifier accuracy depends upon adequate alveolar sampling, we tested for correlation between classifier accuracy and expression of alveolar-specific genes. Results The top-performing algorithm distinguishes UIP from non-UIP conditions in single TBB samples with an area under the receiver operator characteristic curve (AUC) of 0.86, with specificity of 86% (confidence interval = 71–95%) and sensitivity of 63% (confidence interval = 51–74%) (31 test subjects). Performance improves to an AUC of 0.92 when three to five TBB samples per subject are combined at the RNA level for testing. Although we observed a wide range of type I and II alveolar–specific gene expression in TBBs, expression of these transcripts did not correlate with classifier accuracy. Conclusions We demonstrate proof of principle that genomic analysis and machine learning improves the utility of TBB for the diagnosis of UIP, with greater sensitivity and specificity than pathology in TBB alone. Combining multiple individual subject samples results in increased test accuracy over single sample testing. This approach requires validation in an independent cohort of subjects before application in the clinic.

Abstract Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10−5 to 10−6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980–93. ©2017 AACR.

Abstract Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints. Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550). Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127–37. ©2017 AACR.

Abstract Background: While previous study showed that the enrichment of immune-related gene expression was associated with outcome in HER2+ patients receiving sequential or concurrent trastuzumab (H), stromal tumor infiltrating lymphocytes (sTIL) have not been consistently shown to associate with outcome in this group of patients. Given that TIL scoring may be subjective, we analyzed molecular signatures of different subsets of tumor infiltrating immune cell populations, using NanoStringTM gene expression data to assess molecular TIL (mTIL) signature enrichment and intrinsic subtype as a function of relapse-free survival (RFS). Methods: NanoStringTM technology was used to quantify mRNA in samples from 1,280 patients in N9831, 168 patients in FinHer, and 170 patients in FinXX. In N9831, patients in arm A were treated with chemotherapy alone (AC-T), arm B received chemotherapy followed by sequential H (AC-T-H), and arm C received H concurrently with chemotherapy (AC-TH). In the FinHer trial, H was given concurrently for 9 weeks and either 1 year or 9 weeks in FinXX trial. Cox proportional hazard ratio (HR) was used to determine the association of each gene signature with RFS. Different immune subset signatures, including CD45, B-cells, CD8 T-cells, cytotoxic-cells, and T-cells were analyzed using algorithms developed by NanoString. Results: In N9831, CD45, cytotoxic-cell, and T-cell signatures were significantly associated with improved RFS in patients receiving chemotherapy alone and AC-T-H. However, none of the mTIL signatures were significantly associated with outcome in patients receiving AC-TH. Patients lacking CD45 enrichment had better outcome when H was given concurrently with chemotherapy. The 10-year Kaplan-Meier estimates for RFS in arm B patients with CD45 enrichment or no enrichment were 81.3% and 72.6%, respectively (HR 0.63 [95% CI, 0.42-0.93]; p = 0.02), and in arm C were 83.6% and 79.8%, respectively (HR 0.79, 95%CI 0.49-1.28; p = 0.34). Among patients with HER2-enriched subtype, all of the mTIL signatures were associated with improved RFS in arm A (AC-T) and B (AC-T-H) but remained non-significant in arm C (AC-TH). In patients with luminal subtypes, mTIL signatures were not significantly associated with outcome in patients treated with chemotherapy alone. Similar findings were observed in the FinHer and FinXX trials, in which, none of mTIL signatures were significantly associated with outcome among patients who received H. Conclusion: This analysis sheds light on previous discrepancy between immune-related gene signature and sTIL findings. Our data also suggests that the poor prognosis associated with lack of infiltrating immune cells can be partly overcome by the concomitant administration of H with chemotherapy. mTIL signatures, specifically CD45, cytoxic, and T cells, were prognostically associated with improved outcome in patients receiving chemotherapy without concurrent trastuzumab. Understanding the role of the immune system in response to H will require a higher degree of granularity than can be achieved by histological quantification of TILs. Further studies are needed to validate the significance of mTIL signatures as predictive or prognostic biomarker in HER+ patients. Citation Format: Chumsri S, Serie DJ, Mashadi-Hossein A, Tenner KS, Lauttia SL, Moreno-Aspitia A, McLaughlin SA, Nassar A, Warren S, Danaher P, Colon-Otero G, Lindman H, Joensuu H, Perez EA, Thompson EA. Prognostic value of molecular tumor infiltrating lymphocyte (mTIL) signatures in HER2-positive breast cancer patients in N9831 and FinHer/FinXX trials [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD5-06.

Abstract Background:Anti-HER2 agents are associated with an increased risk of cardiotoxicity, occurring mostly during treatment and being generally reversible. To date, no cardiac biomarkers have been validated as predictive markers of cardiotoxicity in patients (pts) receiving anti-HER2 therapies. We evaluated high sensitivity (HS) troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in pts treated with neoadjuvant anti-HER2 therapies to evaluate if early elevation of cardiac biomarkers predicts early or late cardiac events. Material and Methods: 455 pts were randomized to receive either lapatinib (154 pts), trastuzumab weekly (149 pts), or lapatinib with trastuzumab for a total of 6 weeks (152 pts). After this biological window, pts continued on the same targeted therapy plus 12-weekly paclitaxel until definitive surgery. After surgery, patients received adjuvant FEC (3x) followed by the same HER2 therapy as in the neoadjuvant phase for further 34 weeks (to complete 52 weeks in total). Eligible pts had an LVEF ≥50%. Cardiac biomarkers were centrally tested in plasma samples collected at baseline, week 2 (W2) and at surgery. Elevated biomarker was defined as either TNT >0.015 μg/L or NT-proBNP >125 pg/mL. The small number of pts and rarity of marker elevations allowed only descriptive analyses. Results: At a median follow-up of 3.8 years, 280 pts had cardiac biomarkers tested at baseline (61.5%) and NT-proBNP was elevated in 39 pts (13.9%) while TNT was elevated in only 1 pt (0.35%). From those 39 pts with NT-proBNP elevated at baseline, only 1 pt experienced a cardiac event. Also, hypertension was presented in 14 pts (24.5%) with elevated NT-proBNP. Serial measurements were available in 173 pts (61.7%) and NT-proBNP was elevated in 25, 10 and 21 pts at baseline, W2 and at surgery, respectively, while among 171 pts (61%) TNT was elevated in 1, 1 and 5 pts, respectively. There were 13 cardiac events in 11 pts in the entire trial. Five of these pts had a measurement of cardiac biomarkers at baseline (non-elevated NT-prBNP and TNT were observed in 4 and 5 pts), 9 of them had a measurement at week 2 (non-elevated NT-prBNP and TNT were observed in 8 and 9 pts) and 3 of them at surgery (non-elevated NT-prBNP and TNT were observed in 3 and 3 pts), respectively. The following table show the low specificity of the cardiac biomarkers. Patients without cardiac event (N)Patients with cardiac event (N)Patients with elevated markerElevated NT-proBNP Baseline38139Week 229130Surgery40040Elevated TNT Baseline101Week 2101Surgery606 During adjuvant phase, 13 pts experienced LVEF drop to <50% and none had either NT-proBNP elevated or TNT at surgery. Conclusions: Despite the small sample size, we demonstrated that cardiac biomarkers are rarely elevated in pts receiving anti-HER2 therapies, which is probably due to the absence of myocyte necrosis with respect to TNT, and the lack of chamber dilation in the case of NT-proBNP after exposure to these drugs. In addition, few cardiac events were present in this population not previously exposed to anthracycline-based chemotherapy; therefore the use of cardiac biomarkers in this population may be unnecessary. Citation Format: de Azambuja E, Bradbury I, Ewer M, Campbell C, Zardavas D, Ameels H, Baselga J, Huober J, Izquierdo M, Bozovic-Spasojevic I, Maetens M, Harbeck N, Pusztai L, Piccart M, Rodeheffer R, Sutter T. Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2 positive early breast cancer (BIG 1-06) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-09.