A B S T R A C T PurposeTo evaluate the risk of recurrence in women diagnosed with T1a and T1b, node-negative, human epidermal growth factor receptor 2 (HER2) -positive breast cancer. MethodsWe reviewed 965 T1a,bN0M0 breast cancers diagnosed at our institution between 1990 and 2002. Dedicated breast pathologists confirmed HER2 positivity if 3ϩ by immunohistochemistry or if it had a ratio of 2.0 or greater by fluorescence in situ hybridization (FISH). Patients who received adjuvant chemotherapy or trastuzumab were excluded. Kaplan-Meier product was used to calculate recurrence-free survival (RFS) and distant recurrence-free survival (DRFS). Cox proportional hazard models were fit to determine associations between HER2 status and survival after adjustment for patient and disease characteristics. Additionally, 350 breast cancers from two other institutions were used for validation. ResultsTen percent of patients had HER2-positive tumors. At a median follow-up of 74 months, there were 72 recurrences. The 5-year RFS rates were 77.1% and 93.7% in patients with HER2-positive and HER2-negative tumors, respectively (P Ͻ .001). The 5-year DRFS rates were 86.4% and 97.2% in patients with HER2-positive and HER2-negative tumors, respectively (P Ͻ .001). In multivariate analysis, patients with HER2-positive tumors had higher risks of recurrence (hazard ratio [HR], 2.68; 95% CI, 1.44 to 5.0; P ϭ .002) and distant recurrence (HR, 5.3; 95% CI, 2.23 to 12.62; P Ͻ .001) than those with HER2-negative tumors. Patients with HER2-positive tumors had 5.09 times (95% CI, 2.56 to 10.14; P Ͻ .0001) the rate of recurrences and 7.81 times (95% CI, 3.17 to 19.22; P Ͻ .0001) the rate of distant recurrences at 5 years compared with patients who had hormone receptor-positive tumors. ConclusionPatients with HER2-positive T1abN0M0 tumors have a significant risk of relapse and should be considered for systemic, anti-HER2, adjuvant therapy.

#701 Background: Controversy surrounds the prognosis of breast cancer patients with T1a,bN0M0 tumors following locoregional therapy and the need for adjuvant systemic therapy, especially for HER2+ disease. The purposes of the study were to determine the recurrence-free survival (RFS), and distant recurrence-free survival (DRFS) in small HER2+ tumors compared with hormone receptor ( HR)+ and triple receptor- (TN) tumors.
 Methods: Stage T1a,bN0M0 breast cancers diagnosed between 1973-2003 were reviewed by dedicated breast pathologists. HER2+ tumors were defined as 3+ by IHC or gene amplification. Patients were categorized into 3 groups:TN (ER-, PR-and HER2-), HER2+ (regardless of HR status) and HR+ (HER2-). RFS and DRFS were estimated by the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards models were fit to determine the association of each group with the risk of recurrence after adjustment for other characteristics.
 Results: Of the 1796 patients, 427 were excluded from the analysis due to being male (2), lack of receptor information (249), and adjuvant chemotherapy (176) leaving 1369 pts for analysis. Median age was 57 years,(range, 26-88). There were 381(28%) T1a and 988(72%) T1b tumors; HR+ 68%, TN 23%, HER2+ 9%. Patients who had HER2+ breast cancer tended to be younger,(p=0.001); have more T1a tumors, (p=0.001); and have higher nuclear grade,(p<0.001). At a median follow-up of 74 months(range 1-350), there were 160 recurrences and 77 distant metastases. Five and 10-year RFS and DRFS are summarized in the table. After adjustment for other characteristics, patients with HER2+ breast cancer had a significantly worse RFS (HR: 5.19, 95% CI: 3.21-8.39, p<0.0001) and DRFS (HR: 4.66, 95% CI: 2.47-8.80, p<0.0001) compared to patients with HR-positive breast cancer.
 Conclusions: Breast cancer patients with HER2+ T1a,bN0M0 tumors have a significant risk of relapse and should be considered candidates for adjuvant systemic therapy including anti-HER2 agents.
 
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 701.

Translocation (9;22)(q34;q11.2) resulting in BCR/ABL1 fusion at the molecular level is the hallmark of chronic myelogenous leukemia (CML). Variants of the Philadelphia translocation and complex translocations involving BCR have been reported in myeloproliferative disorders (MPD). A rare translocation, t(9;22)(p24;q11.2), resulting in a novel BCR-JAK2 fusion has been reported in a handful of cases of CML and acute myelogenous leukemia (AML). We present clinical-pathological and cytogenetic evaluation of a patient with Philadelphia-chromosome negative CML/MPD harboring a t(9;22)(p24;q11.2) resulting in BCR-JAK2 fusion. Fluorescence in situ hybridization and molecular characterization of the translocation confirmed a BCR-JAK2 fusion and helped delineate the breakpoints upstream of exon 1 of minor cluster region of BCR gene and likely intron 18 of the JAK2 gene, resulting in an in-frame transcript This case provides convincing support, along with two previous case-reports, for a role for activation of the Janus kinase 2 in evolution of myeloproliferative disease. The recurrent, albeit rare, nature of the breakpoints within BCR and JAK2 suggests a potential new diagnostic target that should be interrogated in Ph-negative CML/MPD patients.

Waldenstrom’s macroglobulinemia (WM) is an incurable malignancy characterized by malignant proliferation of lymphoplasmacytoid cells that produce a monoclonal IgM. Treatment of this disorder with nucleoside analogues like 2-CdA and fludarabine have resulted in excellent response rates and subsequent median survivals of approximately 8–9 years for previously untreated patients at our center. We, and others, have previously questioned the impact of initial treatment of Waldenstrom’s Macroglobulinemia on the risk of development of second malignancy and transformation (TR) to aggressive NHL (Non-Hodgkin’s Lymphoma). The objective of this analysis was to determine the incidence of transformation to large cell lymphoma and second malignancies in patients (pts) treated with 2-CdA either alone or in combination for induction therapy of patients with symptomatic WM. We performed a retrospective analysis of 111 consecutive, previously untreated patients with symptomatic WM who were treated with using 2 consecutive 4–6-week courses of either 2-CdA alone or in combination with other agents including prednisone (pred), cyclophosphamide (Cy), and rituximab (Rit) between January 1991 – July 2005. Patients received either 2-CdA 0.1 mg/kg by continuous infusion (CI) over 24 hours (hrs) × 7 days (n=16), an identical program with prednisone 60 mg/m2/d po for 7 days (n=22), 2-CdA 1.5 mg/m2 by subcutaneous injection (SC) q8 hrs × 7d + Cy 40 mg/m2 p.o. b.i.d. × 7d (n= 38), or identical 2-CdA (SC) + Cy + Rit 375 mg/m2 by intravenous infusion (IV) weekly × 4 weeks (n=35). Among 111 pts, 23 (21%) had either transformation to large cell lymphoma or development of a second malignancy within a median of 55 months. Ten patients (9%) had transformation to large cell lymphoma after treatment with 2-CdA alone (3 pts), 2-CdA/pred (1 pts), 2-CdA/Cy (3 pts) and 2CdA/Cy/Rit(3 pts). The median time to development of transformation to large cell lymphoma was 37 months (1mo – 110 mo) and 4 pts had transformation of disease within 13 months. An additional 13 pts (12%) developed other second malignancies including breast cancer (ca) (2pts), renal cell ca (2 pts), Basal cell ca of skin (2 pts), Hodgkin’s lymphomas (2 pts), cervical ca (1 pt), ovarian ca (1 pt), colorectal ca (1 pt), mesothelioma (1 pt), head/neck squamous cell ca (1 pt), vascular sarcoma (1 pt), bladder ca (1 pt) and prostate ca (1 pt), AML (1 pt) after treatment with 2-CdA (5 pts), 2-CdA/pred (1 pt), 2-CdA/Cy (4 pts), and 2CdA/Cy/Rit (3 pts). The median time to development of a second malignancy was 85.5 months and there did not appear to be any significant trend towards development of any particular secondary malignancy. While 2-CdA based induction regimens for WM provide excellent cause-specific survival for WM, this analysis suggests that the incidence of large cell transformation and second malignancies is pronounced among this group of patients with Waldenstrom’s Macroglobulinemia. Whether this rate of transformation/second malignancy is related to treatment with nucleoside analogues, or due to the natural progression of disease in patients with long survival after treatment with 2-CdA regimens remains unclear. We are currently extending the retrospective analysis to include a similar historic cohort of patients treated with alkylating agents and will provide updated data regarding both groups of patients at the time of presentation.