Summary Eighteen patients with advanced cancer have been treated intravenously with human recombinant tumour necrosis factor (rhTNF). The drug produced febrile reactions at all doses although these were preventable by steroids and indomethacin. Doses at or above 9 x 105 units (400 pg)m-2 were associated with hypotension, abnormal liver enzymes, leucopenia and mild renal impairment in a substantial proportion of patients. RhTNF was cleared from plasma with a half life of -20 minutes but non-linear pharmacokinetics were seen with decreased clearance at higher doses. In 3 patients, all with lymphoma, improvements in their tumours were recorded.RhTNF was noted to produce rapid increases in serum C-reactive protein concentrations. Endogenous TNF levels were not found to be elevated in 72 cancer patients.TNF deserves further therapeutic evaluation and these observations support its biological importance as an endogenous pyrogen, mediator of acute phase protein responses, and a mediator of endotoxic shock.

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The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. Optimizing the selection and sequencing of endocrine and targeted therapies for hormone-sensitive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer is a rapidly evolving field owing in large part to an increasing pace of drug development coupled with a greater understanding of the genomic drivers of breast cancer. The recently published results from the MAINTAIN clinical trial begin to answer an important question in this patient population—can the well-established benefit with first-line cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors be stretched further by continuing this drug class beyond progression and selecting an alternate endocrine therapy partner? We present a case of a patient with hormone-sensitive HER2 low metastatic breast cancer who underwent circulating tumor DNA next-generation sequencing to better inform her treatment options after progression on first-line therapy with a CDK 4/6 inhibitor and aromatase inhibitor. Our clinical approach in this patient population prioritizes the identification of actionable mutations with high-quality evidence for efficacy on the basis of clinical trials post-CDK 4/6 inhibitors, while balancing comorbidities and patient priorities for care. Several recent clinical trials discussed herein present clinically meaningful results linking emerging targeted therapies to actionable alterations in PIK3CA, ESR1, AKT1, and PTEN. Continued drug development in this space delays time to treatment with chemotherapy, and hopefully contributes to maintaining a high quality of life for these patients on primarily oral-based therapy.

Background: The benefits of immune check point inhibition (ICI) are primarily seen in immunogenic cancer types. Unfortunately, most breast cancers are non-immunogenic, and therefore new approaches that target tumor immunogenicity are key to increasing the efficacy of ICI. Even within a single breast cancer subtype, patients with liver metastases are less responsive to ICI as compared to other metastatic sites. Therefore, the objective of this analysis is to investigate differences in prognostic and predictive ICI related biomarkers such as PD-L1 expression, tumor mutation burden (TMB), and immune-cell populations between primary tumors, liver metastases (LM) and non-liver metastatic (NLM) sites from breast cancer patients. Our goal is to provide an in-depth analysis of current and potential markers of immunogenicity within LM and NLM. Methods: Unpaired samples taken from primary and recurrent breast (BT), liver metastases (LM) and non-liver metastases (NLM) (all identified as breast cancer) were compared using Fisher-exact or Chi2 and corrected for multiple comparison. Tumors were classified as hormone receptor positive (HR+), HER2+ or triple negative breast cancer (TNBC). Breast cancer samples were tested using NextGen DNA sequencing (NextSeq, 592 gene panel) and whole transcriptome RNA sequencing (NovaSeq). PDL1 was scored on immune cells using VENTANA PD-L1 (SP142) assay. TMB was measured by counting somatic non- synonymous missense mutations on the 592 gene panel and ≥ 10 mutations/Megabase (mut/Mb) was considered high. MCP counter was used to evaluate relative cell abundance (in arbitrary units) in TME using transcriptome data. Results: Biopsies from 3166 tumors were queried, 1268 of which were from BT, 495 from LM, and 1403 from NLM, all are unpaired. All histologic subtypes are represented. HR+ breast cancer was the most prevalent among LM. Both metastatic groups (LM and NLM) were significantly more likely to have a high TMB as compared to BT (24.8 & 24.8 vs. 16.6%, p<0.0001). PD-L1 expression in immune cells however, was significantly decreased in LM as compared to BT (12 vs. 34%, p<0.0001) and NLM (12 vs. 28%, p<0.0001), a trend largely driven by HER2+ and TNBC subtypes. Comparison of immune cells within tumor biopsies of LM vs. BT demonstrated significantly fewer cytotoxic CD8+ T cells (1.38 vs. 0.69, p<0.001), B cells (234 vs. 98, p<0.001), and myeloid dendritic cells (DCs) (1.5 vs. 1.02, p<0.001). These observations were most predominant in TNBC and HR+ breast cancers. HR+ LM also had fewer natural killer cells (0.85 vs. 0.03, p<0.005). Cytotoxic T cells and DCs were not significantly altered in HER2+ LM. All immune cell types, except for the monocytic lineage, were significantly (p<0.001) higher within NLM as compared to LM. Investigation of molecular alterations revealed significant differences in LM vs. NLM vs. BT, e.g, LM from all subtypes were enriched for copy number alterations in genes such as CCND1 and FGF19/14, FGFR1. Significant (p<0.001) enrichment of mutations in ESR1 (2.8 vs. 27.1%), HER2 (1.9 vs.6.1%), and GATA3 (7.8 vs> 12.9%), were observed in LM vs. BT. Conclusions: In this patient cohort, immune cells within the TME of LM were less abundant and suggest the liver is a less immunogenic niche. However, LM had increased TMB as compared to breast tumors, suggesting that immunosuppressive cells (i.e. Tregs and MDSCs) or cytokines, may be preventing cytotoxic immune cell infiltration into the TME. Moreover, immune cell populations within LM had decreased PD-L1 expression when compared to breast tumors, suggesting another mechanism that could explain the lack of response to ICI in such patients. Further characterization of the genetic and molecular alterations of breast cancer LM and NLM will help identify additional biomarkers of response and determine their role in defining tumor immune response to ICI. Citation Format: Sofi Castanon, Daniel Flores, Joanne Xiu, Paula R. Pohlmann, Foluso Ademuyiwa, Elia Obeid, Jasgit Sachdev, Michael Simon, Elisa Krill Jackson, Lee Schwartzberg, Antoinette R Tan, Neelima Denduluri, W. Michael Korn, Evanthia T Roussos Torres. The immune microenvironment of liver metastasis as a guide for immunotherapeutic potential in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-02.

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