Clinton Yam

Targeting the Molecular Subtypes of Triple Negative Breast Cancer: Understanding the Diversity to Progress the Field

Triple negative breast cancers (TNBCs) represent 10%-20% of primary breast cancers, and despite having greater initial sensitivity to cytotoxic chemotherapy, patients with TNBCs have higher rates of distant metastasis and a poorer prognosis compared with patients with hormone receptor positive and/or human epidermal growth factor receptor 2 positive disease. TNBC has historically been treated as a single disease entity in targeted therapy trials, but advances in gene expression profiling and other molecular diagnostic techniques over the last decade have revealed considerable biologic heterogeneity within TNBCs, including subgroups with distinct, targetable aberrations. Such molecular heterogeneity explains, in part, the disappointing performance of targeted therapeutics in unselected TNBC. Here we discuss the history of gene expression profiling in breast cancer and its application in partitioning TNBCs into subtypes that may lead to more consistent therapeutic successes in this heterogeneous disease. IMPLICATIONS FOR PRACTICE Triple negative breast cancers (TNBCs) have historically been regarded as a single entity in clinical trial design. Over the last decade, molecular characterization has revealed much heterogeneity in TNBCs, explaining in part the lackluster performance of targeted therapeutics in TNBCs as a group. In this article, we review the history of the molecular classification of breast cancer based on gene expression profiling and discuss its role in TNBCs.

PET-CT in AML-related hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive immune activation syndrome characterized by widespread cytokine-mediated tissue destruction [1]. The rarity of this syndrome and variabilities in clinical presentation presents significant barriers toward marking an early diagnosis, a vital requisite for altering disease outcomes through prompt institution of HLH-directed therapy. Diagnosis is currently based upon a combination of clinical and laboratory markers, none of which are sufficiently specific or sensitive. Compounding the treatment dilemma is the lack of specificity of histological findings of hemophagocytosis to diagnosing HLH [2]. Therefore, there exists a need for more informative and accurate diagnostic markers/modalities to help facilitate an early and more accurate diagnosis of HLH. HLH pathophysiology derives from a profoundly dysregulated immune system repertoire involving T-cell-mediated macrophage activation with consequent multi-organ inflammatory damage. Toxic macrophage activation is not merely an epiphenomenon of systemic inflammation but likely plays a central role in the disease pathogenesis [3]. Metabolically activated macrophages and leukocytes express high concentrations of glucose transporters [4]. The diagnostic rationale behind PET-CT in HLH rests on the fact that higher glucose transporter expression on activated inflammatory cells would result in preferential uptake and accumulation of F-FDG radiopharmaceutical in involved tissues. A 77-year-old gentleman with an initial diagnosis of myelodysplastic syndrome was treated for 11 months with 5-azacytidine. Progressively worsening cytopenias while receiving 5-azacytidine led to the diagnosis of transformation to Fms-like tyrosine kinase-3 (FLT3)mutated acute myeloid leukemia (AML). His initial therapy for AML included decitabine and sorafenib, on which he achieved complete marrow remission. However, he relapsed, four months later, and then progressed to develop hepatosplenomegaly. During this time, his course was complicated by splenic infarctions requiring a splenectomy. Notably, the splenic specimen histology at that time revealed pathological findings consistent with hemophagocytosis (Figure 1, Panels A and B). Notably, a bone marrow performed at the time of splenectomy did not show any evidence of hemophagocytosis. Considering this may be related to sorafenib and the fact that he had progressed on therapy, his treatment was switched to cladribine and low-dose cytarabine. During his most recent visit, he presented in the midst of his second treatment cycle of cladribine and cytarabine, with a day of abdominal pain and fever. Labs on the current admission were remarkable for a WBC 0.2K/mL, hgb 9.3 gm/dL, platelet 7K/mL, mild transaminitis with AST 202 IU/L, ALT 102 IU/L, ALP 354 IU/L, and a total bilirubin 1.4mg/dL. Of note, lactate dehydrogenase (LDH), ferritin, and fibrinogen levels were normal at presentation. However, the patient’s condition began to deteriorate quickly over the following four days, with persistent fevers and cytopenias despite broad-spectrum antimicrobial coverage. Labs were remarkable for increasing trends in LDH and ferritin levels; the transaminitis had resolved but bilirubin worsened to 6.4mg/dL. Interim infectious disease workup was unrevealing. HLH was suspected based on fever, cytopenias, hepatomegaly, and corroborative findings of elevated ferritin, LDH, and low fibrinogen. A diagnostic bone marrow showed persistent AML but without hemophagocytosis. However, a PET-CT was performed as a part of the diagnostic workup and showed hepatomegaly with diffuse metabolic activity throughout the liver, axial, and appendicular skeleton (Figure 1, Panel C). Serologic tests and cultures for possible triggers of HLH, including viral and bacterial pathogens, were negative. The patient was treated with a dose of tocilizumab (4mg/kg), 5 doses of etoposide (100mg/m on day 1, 50mg/m on days 5, 8, 12, 19), and a prolonged dexamethasone taper. The patient had an impressive response to treatment with a steady resolution in laboratory parameters (Figure 1, Panel E). Meanwhile, baseline soluble IL-2 receptor levels returned high at 4390U/mL. A follow-up PET-CT on day 17 was done which showed marked metabolic response with resolution of marrow