Lindsay M. Jacks

PIK3CA mutation associates with improved outcome in breast cancer.

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. (Clin Cancer Res 2009;15(16):5049–59)

Comparison of gastric cancer survival following R0 resection in the United States and Korea using an internationally validated nomogram.

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%, ≥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.

Nomogram for Predicting the Risk of Local Recurrence After Breast-Conserving Surgery for Ductal Carcinoma In Situ

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.

Stage-Specific Outcomes of Patients With Uterine Leiomyosarcoma: A Comparison of the International Federation of Gynecology and Obstetrics and American Joint Committee on Cancer Staging Systems

PURPOSE Uterine leiomyosarcoma (LMS) is staged by the modified International Federation of Gynecology and Obstetrics (FIGO) staging system for uterine cancer. We aimed to determine whether the American Joint Committee on Cancer (AJCC) soft tissue sarcoma (STS) staging system is more accurate in predicting progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS Patients with uterine LMS who presented at our institution from 1982 to 2005 were staged retrospectively according to a modified FIGO staging system and the AJCC STS staging system. The predictive accuracy of the two staging systems was compared using concordance estimation. RESULTS Two hundred nineteen patients had sufficient clinical and pathologic information to be staged under both systems; 132 patients were upstaged using the AJCC staging system, whereas only four were downstaged. Stage-specific PFS and OS rates for stages I, II, and III differed substantially between the two staging systems. In both systems, there was prognostic overlap between stages II and III. Thus, despite the marked stage-specific differences in 5-year PFS and OS rates for stages I, II, and III, both systems had similar concordance indices. CONCLUSION Estimates of stage-specific PFS and OS for uterine LMS were altered substantially when using the AJCC versus FIGO staging system. Adjuvant treatment strategies should be tested in patients at substantial risk for disease progression and death. Neither the FIGO nor AJCC staging system is ideal for identifying such patients, suggesting a need for a uterine LMS-specific staging system to better target patients for trials of adjuvant therapies.

Comparative Effectiveness of Prostate Cancer Surgical Treatments: A Population Based Analysis of Postoperative Outcomes

PURPOSE Enthusiasm for laparoscopic surgical approaches to prostate cancer treatment has grown despite limited evidence of improved outcomes compared with open radical prostatectomy. We compared laparoscopic prostatectomy with or without robotic assistance vs open radical prostatectomy in terms of postoperative outcomes and subsequent cancer directed therapy. MATERIALS AND METHODS Using a population based cancer registry linked with Medicare claims we identified men 66 years old or older with localized prostate cancer who underwent radical prostatectomy from 2003 to 2005. Outcome measures were general medical/surgical complications and mortality within 90 days after surgery, genitourinary/bowel complications within 365 days, radiation therapy and/or androgen deprivation therapy within 365 days and length of hospital stay. RESULTS Of the 5,923 men 18% underwent laparoscopic radical prostatectomy. Adjusting for patient and tumor characteristics, there were no differences in the rate of general medical/surgical complications (OR 0.93 95% CI 0.77-1.14) or genitourinary/bowel complications (OR 0.96 95% CI 0.76-1.22), or in postoperative radiation and/or androgen deprivation (OR 0.80 95% CI 0.60-1.08). Laparoscopic prostatectomy was associated with a 35% shorter hospital stay (p <0.0001) and a lower bladder neck/urethral obstruction rate (OR 0.74, 95% CI 0.58-0.94). In laparoscopic cases surgeon volume was inversely associated with hospital stay and the odds of any genitourinary/bowel complication. CONCLUSIONS Laparoscopic prostatectomy and open radical prostatectomy have similar rates of postoperative morbidity and additional treatment. Men considering prostate cancer surgery should understand the expected benefits and risks of each technique to facilitate decision making and set realistic expectations.

Current Management of Pyogenic Liver Abscess: Surgery is Now Second-Line Treatment

BACKGROUND The objective of this study was to examine the current treatment for liver abscess and to assess the factors associated with failure of percutaneous drainage. STUDY DESIGN Records of 58 patients with pyogenic hepatic abscess, from 1998 to 2009, were examined. Clinicopathologic variables were analyzed as predictors of failure of percutaneous drainage using multivariable logistic regression. The results of surgical intervention after failure of percutaneous treatment were also examined. RESULTS Fifty-one patients (88%) had a history of malignancy including pancreas (36%), cholangiocarcinoma (17%), colon (12%), and gallbladder (10%). Recent hepatic artery embolization or radiofrequency ablation preceded development of abscess in 13 patients (22%). Fifteen patients (26%) had evidence of biliary tract communication, and 14 of 15 (93%) of these patients had concomitant biliary tract obstruction. Percutaneous drainage was successful in 38 patients (66%) with a median drain dwell time of 26 days (range 3 to 319 days). Five patients (9%) required operative intervention and 2 of these patients (3% overall) died postoperatively from septic complications. Fifteen patients (26%) died with percutaneous drains in place; 9 (60%) of these patients died of cancer progression without evidence of sepsis. Independent predictors of failure of percutaneous drainage included abscesses containing yeast (p = 0.003) and communication of the abscess cavity with the biliary tree (p = 0.02). CONCLUSIONS Pyogenic hepatic abscess was treated successfully in the majority of patients with advanced malignancy, although mortality remained high. The presence of yeast and communication with an untreated obstructed biliary tree were associated with failure of percutaneous drainage. The need for surgical salvage was associated with a high mortality.

Temporal trends and predictors of pelvic lymph node dissection in open or minimally invasive radical prostatectomy.

Pelvic lymph node dissection (PLND) is an important component of prostate cancer staging and treatment, especially for surgical patients who have high‐risk tumor features. It is not clear how the shift from open radical prostatectomy (ORP) to minimally invasive radical prostatectomy (MIRP) has affected the use of PLND. The objectives of this study were to identify predictors of PLND and to assess the impact of surgical technique in a contemporary, population‐based cohort.

Adjuvant trastuzumab with chemotherapy is effective in women with small, node‐negative, HER2‐positive breast cancer

Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node‐negative HER2‐positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single‐institution, sequential cohort study of women with small, node‐negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted.

A nomogram to predict postresection 5-year overall survival for patients with uterine leiomyosarcoma†

The clinical course of patients with uterine leiomyosarcoma (LMS) is difficult to predict with the currently available categorical staging systems of the American Joint Committee on Cancer (AJCC) and the International Federation of Gynecology and Obstetrics (FIGO). The objective of the current study was to develop and validate a novel, clinically relevant, individualized prognostic model for patients with uterine LMS.

Staging Laparoscopy in the Management of Gastric Cancer: A Population-Based Analysis

BACKGROUND Staging laparoscopy can detect radiographically occult peritoneal metastases and prevent futile laparotomy in patients with gastric adenocarcinoma. We sought to assess the use of staging laparoscopy for gastric adenocarcinoma in a cohort of older patients and to compare outcomes after laparoscopy alone with nontherapeutic laparotomy. STUDY DESIGN Using Surveillance, Epidemiology and End Results (SEER) population-based cancer registry data linked with Medicare claims, we identified patients aged 65 or older diagnosed with gastric adenocarcinoma between 1998 and 2005. We defined staging laparoscopy as a laparoscopic procedure from 1 month before the date of diagnosis until death and futile laparotomy as a laparotomy in the absence of a therapeutic intervention. We examined trends in the use of staging laparoscopy and compared outcomes between patients who underwent staging laparoscopy alone and those who had a futile laparotomy. RESULTS Of 11,759 patients with gastric adenocarcinoma, 6,388 (54.3%) had at least 1 surgical procedure. Staging laparoscopy was performed in 506 (7.9%) patients who had any surgery, and 151 (29.8%) of these patients did not have a subsequent therapeutic intervention. Patients who underwent staging laparoscopy alone had a significantly lower rate of in-hospital mortality (5.3% vs 13.1%, p < 0.001) and shorter length of hospitalization (2 vs 10 days, p < 0.001) than patients who had futile laparotomy. CONCLUSIONS Our findings in this large, population-based cohort suggest that staging laparoscopy is used infrequently in the management of older patients with gastric adenocarcinoma. Increased use of staging laparoscopy could reduce the substantial morbidity and mortality associated with nontherapeutic laparotomy.