The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) share similar molecular characteristics in that they frequently harbor hotspot mutations in JAK2 , CALR or MPL , leading to activated JAK/STAT signaling. However, these MPN have distinct symptoms, morphology, and natural histories, including different tendencies to progress to fibrosis. Although the role of inflammation in tissue fibrosis is well recognized, inflammatory gene expression in bone marrows involved by MPN has been understudied. We analyzed the expression of inflammatory genes by directly measuring RNA transcript abundance in bone marrow biopsies of 108 MPN patients. Unsupervised analyses identified gene expression patterns that distinguish prefibrotic (grade 1–2) MPN from overtly fibrotic (grade 2–3) MPN with high sensitivity and specificity in two independent cohorts. Furthermore, prefibrotic and overtly fibrotic MPN are separable into subsets with different activities in biological pathways linked to inflammation, including cytokines, chemokines, interferon response, and toll-like receptor signaling. In conclusion, this study demonstrates that MPN with overt fibrosis is associated with significant inflammatory gene upregulation in the bone marrow, revealing potential roles for multiple pro-inflammatory signaling networks in the development of myelofibrosis and suggesting potential therapeutic mechanisms to alleviate this process in the bone marrow microenvironment.
Background: Previous data suggest that the immune microenvironment plays a critical role in human epidermal growth factor receptor 2 (HER2) -positive breast cancer; however, there is little known about the immune profiles of small HER2-positive tumors. In this study, we aimed to characterize the immune microenvironment of small HER2-positive breast cancers included in the Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer (APT) trial and to correlate the immune markers with pathological and molecular tumor characteristics.Patients and methods: The APT trial was a multicenter, single-arm, phase II study of paclitaxel and trastuzumab in patients with node-negative HER2-positive breast cancer. The study included 406 patients with HER2-positive, node-negative breast cancer, measuring up to 3 cm. Exploratory analysis of tumor infiltrating lymphocytes (TIL), programmed death-ligand 1 (PD-L1) expression (by immunohistochemistry), and immune gene signatures using data generated by nCounter PanCancer Pathways Panel (NanoString Technologies, Seattle, WA), and their association with pathological and molecular characteristics was carried out.Results: Of the 406 patients, 328 (81%) had at least one immune assay carried out: 284 cases were evaluated for TIL, 266 for PD-L1, and 213 for immune gene signatures. High TIL (60%) were seen with greater frequency in hormone-receptor (HR) negative, histological grades 2 and 3, as well in HER2-enriched and basal-like tumors. Lower stromal PD-L1 (1%) expression was seen with greater frequency in HR-positive, histological grade 1, and in luminal tumors. Both TIL and stromal PD-L1 were positively correlated with 10 immune cell signatures, including Th1 and B cell signatures. Luminal B tumors were negatively correlated with those signatures. Significant correlation was seen among these immune markers; however, the magnitude of correlation did not indicate a monotonic relationship between them. Conclusion:Immune profiles of small HER2-positive breast cancers differ according to HR status, histological grade, and molecular subtype. Further work is needed to explore the implication of these findings on disease outcome.Clinical trial registration: clinicaltrials.gov identifier: NCT00542451.
Background: APT is a single arm multicenter, phase II study of paclitaxel and trastuzumab. Patients with HER2+ breast cancer with negative nodes and tumor size < 3 cm were eligible. Disease-free survival at 7 years was 93.3% with only 4 distant recurrences. Characterizing intrinsic subtype and immune profiles of these smaller tumors may help us better understand if the biology of smaller HER2+ tumors is different than larger tumors that have been previously characterized. Methods: Intrinsic subtyping by PAM50 and immune signatures by PanCancer Immune Profiling Panel were performed on the nCounter Analysis system on archival tissue. Tissue was also tested by immunohistochemistry for PDL1 (tumoral and immune cells) and was assessed for tumor infiltrating lymphocytes (TILs) using guidelines from the International TILs Working Group. TILS were categorized as follows: low (≤10%), intermediate (10-60%), high (≥60%); PD-L1 was characterized as low (0-1%), intermediate (1-10%), and high (>10%). Results: PAM50 data were available for 209 of the 406 cases: 142 (68%) were HER2-Enriched (HER2E), 22 (11%) Luminal A, 25 (12%) Luminal B, and 20 (10%) Basal-like. Immune profile information was available for 162 cases, of which 138 also had intrinsic subtype data. 184 cases were evaluated for PD-L1, and 210 cases for TILs. There was a strong correlation between PD-L1 in the tumor and lymphoid compartments (McNemar's chi-squared, p= 6.5x10-12). High tumoral PD-L1 was seen with higher frequency in the HER2E subset, while high immune cell PD-L1 and high TILs were seen with higher frequency within both the HER2E and Basal-like subtypes (Table). Immune profile data demonstrates that the T-cell signature has the strongest association with TILs, and that luminal A tumors tend to have very similar immune profiles while there is more variable expression of immune cell types with the basal-like tumors. Further work is ongoing to complete PAM50 and intrinsic subtype profiling of remaining tumors, and additional relationships between immune profile and intrinsic subtype will be presented at the meeting. Conclusions: The majority of small HER2+ breast cancers are HER2E, and tumors of this intrinsic subtype have the highest prevalence of high expression of PDL1 and high TILs, suggesting that these tumors may be more immunogenic than the luminal A and B HER2+ tumors. Further work to explore immune profile data by intrinsic subtype is ongoing and may have implications for future trial design. HER2ELuminal ALuminal BBasal-LikePDL1 (tumoral) Low6712159Intermediate16124High8100PDL1 (immune cell) Low3712113Intermediate27154High26116TILs Low6415165Intermediate36308High7011 Citation Format: Tolaney SM, Barry W, Guo H, Dillon D, Tan YB, Fuhrman K, Osmani W, Getz A, Baltay M, Dang C, Yardley D, Moy B, Marcom K, Krop I, Winer E. Immune profile of small HER2+ tumors in the APT trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-01.
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