Patient attendance at molecular tumor board: A new means of shared decision making?

Patient engagement in medical decision-making improves patient related outcomes through compliance and patient satisfaction. The Inova Schar Cancer Institute has a weekly molecular tumor board (MTB) to match comprehensive genomic sequencing results with targeted therapies for patients. Primary oncologists extended MTB invitations to their patients. Ultimately, 20 of the 139 patients attended and completed pre- and post MTB surveys. There was a statistically significant change from the pre- to post- survey for the question "I am satisfied with how well informed I am about targeted therapy" with P = 0.016. Patients who attended MTB reported higher levels of satisfaction with their knowledge of targeted therapy after MTB as compared to before. A more holistic method of studying this practice would include sampling a larger patient population and a formal evaluation of the physicians' experience with patients attending.

Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines.

Pancreatic ductal adenocarcinoma (PDAC) cell lines, MIA PaCa-2, and UK Pan-1, were used to investigate the role of ErbB2 in PDAC oncogenesis. Both these cell lines exhibit exogenous growth factor-independent proliferation that was attributed to the production of autocrine growth factors and/or overexpression of growth factor receptors. The exogenous growth factor-independent phenotype displayed by these PDAC cell lines was dependent on ErbB2 kinase activity since treatment of cells with tyrphostin AG879 prevented serum-free media (SFM) induction of cell proliferation. We determined that ErbB2 kinase contributed to aberrant cell cycle regulation in PDAC through the induction of cyclin D1 levels and the suppression of p21(Cip1) and p27(Kip1). Inhibition of ErbB2 kinase led to cell cycle arrest marked by an increased association of p27(Kip1) with cdk2 and reduced levels of phosphorylated pRb. We further observed constitutive STAT3 activation in the PDAC cell lines and an increase in STAT3 activation upon stimulating quiescent cells with SFM. Inhibitors of ErbB2 kinase blocked STAT3 activation, whereas inhibition of EGFR kinase led to a slight reduction of STAT3 activation. STAT3 was coimmunoprecipitated with ErbB2. SFM stimulation caused an increase in the association of ErbB2 and STAT3, which was blocked by inhibition of ErbB2 kinase. Expression of a STAT3 dominant negative prevented SFM-stimulated cell proliferation of MIA PaCa-2 cells, suggesting that activation of STAT3 by ErbB2 is required for a growth factor-independent phenotype of these cells. Consistent with this observation in PDAC cell lines, we found that most PDAC tumor specimens (10 of 11) showed constitutive activation of STAT3 and that ErbB2 was readily detected in most of these tumors (nine of 11). We believe that these findings indicate a novel mechanism of oncogenesis in PDAC and may suggest future therapeutic strategies in the treatment of PDAC.

Overexpression of the nuclear receptor coactivator AIB1 (SRC-3) during progression of pancreatic adenocarcinoma.

PURPOSE: The nuclear receptor coactivator amplified in breast cancer 1 (AIB1) was found to be amplified and overexpressed in breast and some other epithelial tumors. We have reported that expression of AIB1 is rate limiting for growth factor, as well as hormone signaling. Here, we assess the involvement of AIB1 in the development of pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: We investigated expression levels of AIB1 protein and mRNA in pancreatic cancer cell lines and in a series of archival pancreatic adenocarcinoma (n=78), pancreatic intraepithelial neoplasia (n=93), pancreatitis (n=28), and normal pancreas tissues (n=52). We also determined AIB1 gene copy numbers by fluorescence in situ hybridization in a subset of cases. RESULTS: In normal pancreas ducts, we rarely found detectable levels of AIB1 mRNA or protein (<6% of the samples). In pancreatitis and low-grade intraepithelial neoplasia, we found an increased frequency of AIB1 expression (>14 and >23%, respectively) relative to normal tissues (P < 0.01). Adenocarcinoma, as well as high-grade intraepithelial neoplasia, showed increased levels as well as the highest frequency of AIB1 expression with >65% of samples positive for mRNA and protein (P < 0.0001 relative to the other groups). An increased copy number of the AIB1 gene, observed in 37% of cancers, may account for a portion of the increase in expression. CONCLUSIONS: AIB1 overexpression is frequent in pancreatic adenocarcinoma and its precursor lesions. On the basis of its rate-limiting role for the modulation of growth factor signals, we propose a major role of AIB1 in the multistage progression of pancreatic cancer.

Revised TN categorization for colon cancer based on national survival outcomes data.

PURPOSE: The sixth edition of American Joint Committee on Cancer (AJCC) Cancer Staging Manual for colon cancer subdivided stage II into IIA (T3N0) and IIB (T4N0) and stage III into IIIA (T1-2N1M0), IIIB (T3-4N1M0), and IIIC (anyTN2M0). Subsequent analyses supported revised substaging of stage III because of improved survival for T1-2N2 versus T3-4N2 and T4N1 survival was more similar to T3-4N2 than to T3N1. The AJCC Hindgut Taskforce sought population-based validation that depth of invasion and nodal status interact to affect survival. PATIENTS AND METHODS: Surveillance, Epidemiology, and End Results (SEER) population-based data from January 1992 to December 2004 for 109,953 colon cancer patients were compared with National Cancer Data Base (NCDB) data on 134,206 patients. T4N0 cancers were stratified by tumors that perforate visceral peritoneum (T4a) versus tumors that invade or are adherent to adjacent organs or structures (T4b). N1 and N2 were stratified by number of involved positive lymph nodes (N+): N1a/N1b (1 v 2-3), N2a/N2b (4 to 6 v > or = 7). Five-year observed and relative survival data were obtained for each TN category. RESULTS: SEER rectal cancer analyses confirm that T1-2N2 cancers have better prognosis than T3-4N2,T4bN1 have similar prognosis to T4N2, T1-2N1 have similar prognosis to T2N0/T3N0, and T1-2N2ahave similar prognosis to T2N0/T3N0 (T1N2a) or T4aN0 (T2N2a). Prognosis for T4a lesions is betterthan T4b by N category. The number of positive nodes affects prognosis. CONCLUSION: This SEER population-based colon cancer analysis is highly consistent with rectal cancer pooled analysis and SEER rectal cancer analyses, supporting the shift of T1-2N2 lesions from IIIC to IIIA/IIIB, shifting T4bN1 from IIIB to IIIC, subdividing T4/N1/N2, and revising substaging of stages II/III. Survival outcomes by TN category for colon and rectal cancer are strikingly similar.

Revised tumor and node categorization for rectal cancer based on surveillance, epidemiology, and end results and rectal pooled analysis outcomes.

PURPOSE: The sixth edition of the American Joint Committee on Cancer (AJCC) rectal cancer staging subdivided stage II into IIA (T3N0) and IIB (T4N0) and stage III into IIIA (T1-2N1M0), IIIB (T3-4N1M0), and IIIC (anyTN2M0). Subsequent analyses supported revised substaging of stage III as a result of improved survival with T1-2N2 versus T3-4N2 and survival of T4N1 more similar to T3-4N2 than T3N1. The AJCC Hindgut Taskforce sought population-based validation that depth of invasion interacts with nodal status to affect survival. METHODS: Surveillance, Epidemiology, and End Results (SEER) population-based data from January 1992 to December 2004 for 35,829 patients with rectal cancer were compared with rectal pooled analysis data (3,791 patients). T4N0 cancers were stratified by tumors that perforate visceral peritoneum (T4a) versus tumors that invade or are adherent to adjacent organs or structures (T4b). N1 and N2 were stratified by number of positive nodes as follows: N1a/N1b (one v two to three nodes) and N2a/N2b (four to six v > or = seven nodes). Five-year observed and relative survival rates were obtained for each TN category. RESULTS: SEER rectal cancer analyses confirm that T1-2N2 cancers have better prognosis than T3-4N2, T4bN1 have similar prognosis to T4N2, T1-2N1 have similar prognosis to T2N0/T3N0, and T1-2N2a have similar prognosis to T2N0/T3N0 (T1N2a) or T4aN0 (T2N2a). Prognosis for T4a lesions is better than T4b by N category. The number of positive nodes affects prognosis. CONCLUSION: This SEER population-based rectal cancer analysis validates the rectal pooled analyses and supports the shift of T1-2N2 lesions from IIIC to IIIA or IIIB and T4bN1 from IIIB to IIIC. SEER outcomes support subdividing T4, N1, and N2 and revised substaging of stages II and III. Survival by TN category suggests a complex biologic interaction between depth of invasion and nodal status.

Carcinoembryonic antigen induction of IL-10 and IL-6 inhibits hepatic ischemic/reperfusion injury to colorectal carcinoma cells.

Tumor cells cause ischemia/reperfusion (I/R) injury as they arrest within the hepatic microvasculature with the production of nitric oxide (NO) and reactive oxygen species (ROS) that kill both host liver and implanting tumor cells. Carcinoembryonic antigen (CEA) both facilitates the survival of experimental metastasis to nude mouse liver by weakly metastatic human colorectal carcinomas (CRCs) and induces the release of the proinflammatory cytokine IL-6. We hypothesized that CEA also stimulates the release of the antiinflammatory cytokine IL-10 causing inhibition of the toxicity of hepatic I/R injury and indirect stimulation of tumor cell colonization of the liver. Intravenous injection of CEA produced more than 1 ng/ml of IL-10 in the systemic circulation within 1 hr which subsided by 8 hr. The IL-10 response is specific to CEA since the pentapeptide sequence in CEA that binds to the CEA receptor stimulated isolated Kupffer cells to produce IL-10. IL-10, but not IL-6, increased the survival of weakly metastatic CRC cocultured with ischemic-reoxygenated liver fragments but did not affect the survival of CRC exposed to oxidative stress in the absence of any host cells. CEA, IL-6 and IL-10 pretreatment reduced expression of iNOS but only CEA and IL-10 strongly inhibited NO and total reactive species production by ischemic-rexoygenated liver. IL-6 was toxic to CRC exposed to oxidative stress while IL-10 did not have a direct effect on CRC. Thus, CEA stimulates production of IL-10 that may enhance metastasis by promoting the ability of circulating CRC cells to survive the I/R injury of implantation.