Lindsay M. Jacks

BACKGROUND: Diagnosis of leptomeningeal metastasis (LM) has become increasingly frequent. The diagnostic gold standard has been CSF cytology, but MRI is now used routinely for diagnosis. Diagnosis and prognosis of LM has not been studied in the MRI era. METHODS: Patients with LM from 2002 through 2004 were identified through a neurology database, as well as by reviewing all abnormal CSF cytologies from a pathology database. Diagnosis was made by malignant cytology or imaging; suspicious cases treated as LM were also included. RESULTS: A total of 187 patients with LM were analyzed in this retrospective review. Of these, 150 had solid and 37 had hematopoietic malignancies. Median age was 56.4 years, and median Karnofsky performance status (KPS) was 70. The most common types of solid tumor were breast (65 patients), lung (47), gastrointestinal (11), and melanoma (9). Of the hematopoietic tumors, 21 were lymphoma and 15 were leukemia. Fifty-three percent of patients were diagnosed by imaging, 23% by cytology, and 24% by both. Treatment included radiation therapy in 55%, intrathecal chemotherapy in 29%, and systemic chemotherapy in 18%; 21% received supportive care alone. Median overall survival was 2.4 (95% confidence interval 1.9-3.1) months. Median survival for patients with hematopoietic tumors was 4.7 months and for solid tumors was 2.3 months (p = 0.0006). In multivariate analysis, initial KPS and tumor type (solid vs hematopoietic) were significant predictors of survival. CONCLUSIONS: Despite enhanced diagnosis with MRI, prognosis remains poor in leptomeningeal metastasis. Those with hematopoietic tumors continue to fare better than those with solid tumors.

PURPOSE: In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer. EXPERIMENTAL DESIGN: Archival formalin-fixed paraffin-embedded primary breast tumors, from 590 patients selected for known vital status with a median follow-up of 12.8 years and a tumor >1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast cancer-specific survival were examined using Kaplan-Meier or competing risk methodology. RESULTS: PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA mutated tumors have significant improvement in overall survival (P = 0.03) and breast cancer-specific survival (P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates with node negativity (P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis (P = 0.004). CONCLUSION: This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase-targeted therapy. Future work may define a population of older age breast cancer patients in whom therapy can be minimized.

OBJECTIVE: To compare disease-specific survival (DSS) between the US and Korea following R0 resection for gastric carcinoma (GC). SUMMARY BACKGROUND DATA: Many studies have described decreased 5-year survival after curative gastrectomy for GC in the West compared with the East. Although clinicopathological presentations of GC are known to vary widely between Eastern and Western countries, including histology, tumor location, and stage at presentation, it remains unclear whether these factors account for differences in survival. METHODS: All patients undergoing curative intent resections (R0) for GC (1995-2005) were evaluated in 2 independent, single-institution prospectively maintained databases from the US (711 patients) and Korea (1646 patients). Patients receiving neoadjuvant chemotherapy were excluded from this analysis. Patient, surgical and pathologic variables were compared. DSS was determined via multivariate analysis using prognostic variables from an internationally validated GC nomogram that estimates the probability of 5- and 9-year survival. RESULTS: Age and body mass index were significantly higher in US patients. Location of tumors was more often proximal in the United States (39% vs. 9%, P < 0.0001) and distal in Korea (54% vs. 33%, P < 0.0001). Korean patients had more early stage tumors (42% vs. 28% stage Ia, P < 0.0001) with a higher number of lymph nodes identified (97% vs. 79%, >or=15 lymph nodes, P < 0.0001). The 5-year DSS was higher in Korea than in the United States. After multivariate analysis, applying factors used in the nomogram, DSS of Korean GC patients remained significantly better than that of US patients (HR = 1.3, 95% CI; 1.0-1.6, P = 0.008). CONCLUSIONS: This study demonstrates better survival for GC patients in Korea compared with the US as determined by multivariate analysis with a validated gastric cancer nomogram. Multiple possibilities can explain this difference.

Purpose While the mortality associated with ductal carcinoma in situ (DCIS) is minimal, the risk of ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) is relatively high. Radiation therapy (RT) and antiestrogen agents reduce the risk of IBTR and are considered standard treatment options after BCS. However, they have never been proven to improve survival, and in themselves carry rare but serious risks. Individualized estimation of IBTR risk would assist in decision making regarding the various treatment options for women with DCIS. Patients and Methods From 1991 to 2006, 1,868 consecutive patients treated with BCS for DCIS were identified. A multivariate Cox proportional hazards model was constructed using the 1,681 in whom data were complete. Ten clinical, pathologic, and treatment variables were built into a nomogram estimating probability of IBTR at 5 and 10 years after BCS. The model was validated for discrimination and calibration using bootstrap resampling. Results The DCIS nomogram for prediction of 5- and 10-year IBTR probabilities demonstrated good calibration and discrimination, with a concordance index of 0.704 (bootstrap corrected, 0.688) and a concordance probability estimate of 0.686. Factors with the greatest influence on risk of IBTR in the model included adjuvant RT or endocrine therapy, age, margin status, number of excisions, and treatment time period. Conclusion The DCIS nomogram integrates 10 clinicopathologic variables to provide an individualized risk estimate of IBTR in a woman with DCIS treated with BCS. This tool may assist in individual decision making regarding various treatment options and help avoid over- and undertreatment of noninvasive breast cancer.