KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases.

BACKGROUND: Observational studies of patients with primary colorectal cancer have identified KRAS mutation as a marker of poor prognosis. To examine more directly whether KRAS mutations are associated with accelerated metastatic progression, we evaluated KRAS mutation as well as Ki-67 expression in patients with colorectal liver metastases not treated with cetuximab. METHODS: KRAS mutation status was assessed in a series of resected or sampled colorectal liver metastases. In a subset of these tumors, Ki-67 antigen expression was assessed by immunohistochemical stains. Median follow-up after liver resection or biopsy was 2.3 years. RESULTS: KRAS mutation in the liver metastasis was detected in 27% of the 188 patients. High Ki-67 expression in the liver metastasis was identified in 62% of 124 patients analyzed. Both markers were associated with multiple liver metastases and shorter time interval to their detection. KRAS mutation and high Ki-67 expression were independent predictors of poor survival after colon resection (hazard ratio [HR] 1.9 [95% confidence interval (95% CI), 1.1-3.4], HR 2.6 [95% CI, 1.4-4.8], respectively). Tumors with high Ki-67 expression were less likely to be selected for liver resection, and KRAS mutation was independently associated with poor survival after liver resection (HR 2.4 [95% CI, 1.4-4.0]). CONCLUSIONS: KRAS mutation is associated with more rapid and aggressive metastatic behavior of colorectal liver metastases. These data suggest an important role for KRAS activation in colorectal cancer progression and support continued efforts to develop KRAS pathway inhibitors for this disease.

KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer.

INTRODUCTION: We examined two genetic markers established early in colorectal tumor development, microsatellite instability (MSI) and mutation of the KRAS proto-oncogene, to see if these genetic changes influence metastatic disease progression and survival. PATIENTS AND METHODS: MSI and KRAS mutation status were assessed in 532 primary adenocarcinomas (stage I-IV) from patients treated by colon resection. Median follow-up was 4.1 years (range 0-13.3 years) overall, 5.4 years for survivors. RESULTS: MSI and KRAS mutation were detected in 12 and 36% of cases, respectively. MSI was more common in early-stage disease (I, 15%; II, 21%; III, 10%; IV, 2%; P = 0.0001). Prevalence of KRAS mutation did not vary with stage (I, 36%; II, 34%; III, 35%; IV, 40%; P = ns). Disease-specific survival was far superior for MSI tumors than for microsatellite stability (MSS) tumors (5-year survival 92 vs. 59%, P < 0.0001). KRAS mutation was a marker of poor survival (5-year survival 55 vs. 68%, P = 0.0002). Using Cox regression analysis MSI, KRAS mutation, and stage were strong independent predictors of survival in the entire patient population. A high-mortality group with MSS/KRAS-mutant tumors was identified within the stage I and II cohort. CONCLUSIONS: MSI and KRAS mutation provide fundamental genetic signatures influencing tumor behavior across patient subsets and stages of tumor development.

Endoluminal stent-graft stabilization for thoracic aortic dissection.

PURPOSE: To review our experience with thoracic endografting for type B aortic dissection using the TAG Endoprosthesis. METHODS: A retrospective analysis was performed of data collected prospectively from March 2000 to July 2004 under an investigational device exemption protocol for the TAG thoracic endograft. In this time period, 40 patients (29 women; mean age 67 years, range 39-91) were treated with this endograft for type B aortic dissection. RESULTS: Technical success was 95%. There was 1 (2.5%) perioperative death, and 1 (3%) endoleak was treated with an additional graft on postoperative day 2. Fifteen (38%) patients experienced postoperative complications, mainly renal or pulmonary, and 1 (3%) patient developed postoperative paraplegia that did not resolve. The 1-year survival was 85%. Follow-up computed tomography was available for 31 patients with an average 15-month follow-up. There was no significant change in size of the thoracic aorta in 22 patients; 8 aneurysmal segments were significantly reduced in size and 1 thoracic aortic aneurysm expanded. No thoracic aortic ruptures were seen in this series. CONCLUSIONS: These early results indicate type B thoracic aortic dissections can be treated with acceptable morbidity and mortality using endografts. Stent-graft repair of the thoracic aorta may decrease the incidence of thoracic aortic expansion and rupture.

Recent clinical trials summary.

The current standard of care for the treatment of anal cancer as demonstrated by all of the completed phase 3 clinical trials remains 5-FU and mitomycin C in combination with radiation therapy. The basic elements of the approach outlined by Nigro have not changed in the last 30 years. Future phase 3 trials will serve to further perfect this approach and outline the role of HPV and dysplasia in the development and progression of this disease.

Detection of HER-2/neu gene amplification in breast cancer using a novel polymerase chain reaction/ligase detection reaction technique.

BACKGROUND: Gene amplification is the primary mechanism of HER-2/neu overexpression in breast cancer and is a strong predictor of prognosis. Currently screening for HER-2/neu gene amplification in breast cancer is done by fluorescent in-situ hybridization (FISH), which is accurate but costly and labor intensive. We have evaluated a new PCR (polymerase chain reaction)-based assay for the detection of HER-2/neu gene amplification in human breast cancer. STUDY DESIGN: A total of 15 breast cancer cell lines and 14 breast cancer specimens were evaluated. HER-2/neu status of the tumors was evaluated by FISH and then assessed using a quantitative polymerase chain reaction/ligase detection reaction (PCR/LRD) technique. RESULTS: Amplification of the HER-2/neu gene was detected in seven cell lines previously reported to have amplification and no amplification was found in any of the six that had been reported not to have amplification. In the assessment of breast specimens the PCR/LDR and FISH assays were in complete agreement. All 10 tumors with amplification by FISH were also amplified by PCR/LDR. CONCLUSIONS: The PCR/LDR technique successfully detects HER-2/neu gene amplification in clinical breast cancer specimens and shows 100% concordance with FISH. This technique is an accurate and rapid alternative to FISH with the potential for automation and high throughput analysis of HER-2/neu status in breast cancer.

Evaluation of preoperative and postoperative radiotherapy on long-term functional results of straight coloanal anastomosis.

PURPOSE: Preoperative radiotherapy for rectal cancer avoids radiation to the reconstructed rectum and may circumvent the detrimental effects on bowel function associated with postoperative radiotherapy. We compared the long-term functional results of patients who received preoperative radiotherapy, postoperative radiotherapy, or no radiotherapy in conjunction with low anterior resection and coloanal anastomosis to assess the impact of pelvic radiation on anorectal function. METHODS: One hundred nine patients treated by low anterior resection and straight coloanal anastomosis for rectal cancer between 1986 and 1997 were assessed with a standardized questionnaire at two to eight years after resection. All radiotherapy was given to a total dose of 4,500 to 5,400 cGy with conventional doses and techniques. Most patients received concurrent 5-fluorouracil-based chemotherapy. RESULTS: There were 39 patients in the preoperative radiotherapy group, 11 patients in the postoperative radiotherapy group, and 59 patients in the no radiotherapy group. The postoperative radiotherapy group reported a significantly greater number of bowel movements per 24-hour period (P < 0.01) and significantly more episodes of clustered bowel movements (P < 0.02) than either the preoperative radiotherapy group or the no radiotherapy group. No significant difference in anal continence or satisfaction with bowel function was found among the three groups. CONCLUSION: In this study of straight (nonreservoir) coloanal anastomoses, postoperative pelvic radiotherapy had significant adverse effects on anorectal function, with higher rates of clustering and frequency of defecation than with preoperative radiotherapy. No differences in continence rates were demonstrated, perhaps because of the sample size of the compared groups. We attribute the adverse effects of postoperative radiotherapy to irradiation of the neorectum, which is spared when treatment is given preoperatively. The deleterious effects of adjuvant radiation on long-term anorectal function can be reduced by preoperative treatment.

HER 2/neu expression and gene amplification in colon cancer.

HER 2/neu is an important oncogene in breast cancer, but the prevalence and significance of HER 2/neu gene amplification in colon cancer have been poorly documented. We have evaluated HER 2/neu gene amplification and protein overexpression in a series of colon cancers to assess the frequency, concordance and clinical significance of these events. HER 2/neu gene copy number was measured in 154 primary colon tumors, 15 liver metastases and matched normal tissues using a quantitative PCR/ligase detection reaction (LDR) technique developed and validated in our laboratory. HER 2/neu copy number was confirmed by fluorescent in situ hybridization (FISH) in all tumors found to have gene amplification. In an independent and blinded fashion, HER 2/neu expression was assessed in paraffin sections from 139 of the tumor specimens using the HercepTest kit. HER 2/neu gene amplification was observed in 4 (2.4%) of the 169 tumor specimens and in none of the normal tissues. There was no apparent association with stage of disease, tumor grade or patient survival. Among 139 cases evaluated by immunohistochemistry (IHC), HER 2/neu overexpression was seen in 5 cases (3.6%). There was extremely high concordance (kappa = 0.852) between gene amplification and protein overexpression. The low prevalence of HER 2/neu gene amplification and protein overexpression suggests that this oncogene plays an infrequent role in the development and progression of colon cancer. These data indicate that the primary mechanism of dysregulated HER 2/neu expression in colon cancer, as in breast cancer, is gene amplification.

Radical resection of rectal cancer primary tumor provides effective local therapy in patients with stage IV disease.

BACKGROUND: The optimal use of radical surgery to palliate primary rectal cancers presenting with synchronous distant metastases is poorly defined. We have reviewed stage IV rectal cancer patients to evaluate the effectiveness of radical surgery without radiation as local therapy. METHODS: Eighty stage IV patients with resectable primary rectal tumors treated with radical rectal surgery without radiotherapy were identified. Sixty-one (76%) patients received chemotherapy; response information was available for 34 patients. RESULTS: Radical resection was accomplished by low anterior resection (n = 65), abdominoperineal resection (n = 11), and Hartmann's resection (n = 4). Surgical complications were seen in 12 patients (15%), with 1 death and 4 reoperations. The local recurrence rate was 6% (n = 5), with a median time to local recurrence of 14 months. Only one patient received pelvic radiotherapy as salvage treatment. One patient required subsequent diverting colostomy. Median survival was 25 months. On multivariate analysis, the extent of metastasis and response to chemotherapy were determinants of prolonged survival. CONCLUSIONS: For patients who present with distant metastases and resectable primary rectal cancers, radical surgery without radiotherapy can provide durable local control with acceptable morbidity. The extent of metastatic disease and the response to chemotherapy are the major determinants of survival. Effective systemic chemotherapy should be given high priority in the treatment of stage IV rectal cancer.

Long-term results of local excision for rectal cancer.

OBJECTIVE: To review the authors' experience with local excision of early rectal cancers to assess the effectiveness of initial treatment and of salvage surgery. SUMMARY BACKGROUND DATA: Local excision for rectal cancer is appealing for its low morbidity and excellent functional results. However, its use is limited by inability to assess regional lymph nodes and uncertainty of oncologic outcome. METHODS: Patients with T1 and T2 adenocarcinomas of the rectum treated by local excision as definitive surgery between 1969 to 1996 at the authors' institution were reviewed. Pathology slides were reviewed. Among 125 assessable patients, 74 were T1 and 51 were T2. Thirty-one patients (25%) were selected to receive adjuvant radiation therapy. Fifteen of these 31 patients received adjuvant radiation in combination with 5-fluorouracil chemotherapy. Median follow-up was 6.7 years. One hundred fifteen patients (92%) were followed until death or for greater than 5 years, and 69 patients (55%) were followed until death or for greater than 10 years. Recurrence was recorded as local, distant, and overall. Survival was disease-specific. RESULTS: Ten-year local recurrence and survival rates were 17% and 74% for T1 rectal cancers and 26% and 72% for T2 cancers. Median time to relapse was 1.4 years (range 0.4-7.0) for local recurrence and 2.5 years (0.8-7.5) for distant recurrence. In patients receiving radiotherapy, local recurrence was delayed (median 2.1 years vs. 1.1 years), but overall rates of local and overall recurrence and survival rates were similar to patients not receiving radiotherapy. Among 26 cancer deaths, 8 (28%) occurred more than 5 years after local excision. On multivariate analysis, no clinical or pathologic features were predictive of local recurrence. Intratumoral vascular invasion was the only significant predictor of survival. Among 34 patients who developed tumor recurrence, the pattern of first clinical recurrence was predominantly local: 50% local only, 18% local and distant, and 32% distant only. Among the 17 patients with isolated local recurrence, 14 underwent salvage resection. Actuarial survival among these surgically salvaged patients was 30% at 6 years after salvage. CONCLUSIONS The long-term risk of recurrence after local excision of T1 and T2 rectal cancers is substantial. Two thirds of patients with tumor recurrence have local failure, implicating inadequate resection in treatment failure. In this study, neither adjuvant radiotherapy nor salvage surgery was reliable in preventing or controlling local recurrence. The postoperative interval to cancer death is as long as 10 years, raising concern that cancer mortality may be higher than is generally appreciated. Additional treatment strategies are needed to improve the outcome of local excision.