The expression of TRMT2A, a novel cell cycle regulated protein, identifies a subset of breast cancer patients with HER2 over-expression that are at an increased risk of recurrence.

BACKGROUND: Over-expression of HER2 in a subset of breast cancers (HER2+) is associated with high histological grade and aggressive clinical course. Despite these distinctive features, the differences in response of HER2+ patients to both adjuvant cytotoxic chemotherapy and targeted therapy (e.g. trastuzumab) suggests that unrecognized biologic and clinical diversity is confounding treatment strategies. Furthermore, the small but established risk of cardiac morbidity with trastuzumab therapy compels efforts towards the identification of biomarkers that might help stratify patients. METHODS: A single institution tissue array cohort assembled at the Clearview Cancer Institute of Huntsville (CCIH) was screened by immunohistochemistry staining using a large number of novel and commercially available antibodies to identify those with a univariate association with clinical outcome in HER2+ patients. Staining with antibody directed at TRMT2A was found to be strongly associated with outcome in HER2+ patients. This association with outcome was tested in two independent validation cohorts; an existing staining dataset derived from tissue assembled at the Cleveland Clinic Foundation (CCF), and in a new retrospective study performed by staining archived paraffin blocks available at the Roswell Park Cancer Institute (RPCI). RESULTS: TRMT2A staining showed a strong correlation with likelihood of recurrence at five years in 67 HER2+ patients from the CCIH discovery cohort (HR 7.0; 95% CI 2.4 to 20.1, p < 0.0004). This association with outcome was confirmed using 75 HER2+ patients from the CCF cohort (HR 3.6; 95% CI 1.3 to 10.2, p < 0.02) and 64 patients from the RPCI cohort (HR 3.4; 95% CI 1.3-8.9, p < 0.02). In bivariable analysis the association with outcome was independent of grade, tumor size, nodal status and the administration of conventional adjuvant chemotherapy in the CCIH and RPCI cohorts. CONCLUSIONS: Studies from three independent single institution cohorts support TRMT2A protein expression as a biomarker of increased risk of recurrence in HER2+ breast cancer patients. These results suggest that TRMT2A expression should be further studied in the clinical trial setting to explore its predictive power for response to adjuvant cytotoxic chemotherapy in combination with HER2 targeted therapy.

Prognosis of occult breast carcinoma presenting as isolated axillary nodal metastasis.

Axillary metastasis from an occult breast carcinoma is an uncommon presentation and presents a therapeutic dilemma. The objective of this study is to describe the presenting clinical features, management approach and treatment outcomes for occult breast carcinoma. We conducted a retrospective review of patients who presented with axillary nodal metastases from an occult breast carcinoma between 1997 and 2004 at the Roswell Park Cancer Institute; 2,150 patients were diagnosed and treated for breast cancer during this period. After excluding stage I and IV patients, we identified 642 who had disease metastatic to lymph nodes, 10 of these had no primary tumor in the breast despite a thorough evaluation including bilateral mammography and breast ultrasound. Of these, 7 had undergone breast magnetic resonance imaging as well. All patients underwent axillary nodal dissection. The breast was managed with radiotherapy alone in 8 patients, wide local excision with radiation therapy in 1 patient and 1 patient underwent mastectomy. No patient had a recurrence with a median 57 months of follow-up. Breast conservation with radiation therapy alone can be considered as a management option for women with occult breast cancer presenting with axillary nodal metastasis.