Aspirin-induced nuclear translocation of NFκB and apoptosis in colorectal cancer is independent of p53 status and DNA mismatch repair proficiency

Substantial evidence indicates nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC). However, the molecular basis for this anti-tumour activity has not been fully elucidated. We previously reported that aspirin induces signal-specific IκBα degradation followed by NFκB nuclear translocation in CRC cells, and that this mechanism contributes substantially to aspirin-induced apoptosis. We have also reported the relative specificity of this aspirin-induced NFκB-dependent apoptotic effect for CRC cells, in comparison to other cancer cell types. It is now important to establish whether there is heterogeneity within CRC, with respect to the effects of aspirin on the NFκB pathway and apoptosis. p53 signalling and DNA mismatch repair (MMR) are known to be deranged in CRC and have been reported as potential molecular targets for the anti-tumour activity of NSAIDs. Furthermore, both p53 and MMR dysfunction have been shown to confer resistance to chemotherapeutic agents. Here, we set out to determine the p53 and hMLH1 dependency of the effects of aspirin on NFκB signalling and apoptosis in CRC. We specifically compared the effects of aspirin treatment on cell viability, apoptosis and NFκB signalling in an HCT-116 CRC cell line with the p53 gene homozygously disrupted (HCT-116p53−/−) and an HCT-116 cell line rendered MMR proficient by chromosomal transfer (HCT-116+ch3), to the parental HCT-116 CRC cell line. We found that aspirin treatment induced apoptosis following IκBα degradation, NFκB nuclear translocation and repression of NFκB-driven transcription, irrespective of p53 and DNA MMR status. These findings are relevant for design of both novel chemopreventative agents and chemoprevention trials in CRC

Treatment of infra-centimetric HER2-positive(+) invasive breast tumors. The Institut Curie experience.

Abstract Abstract #3152 Background: According to the adjuvant trastuzumab (T) trials, node-positive infracentimetric tumors stand for around 7% of all HER2+ breast carcinomas. The benefit of adjuvant T for women with node positive or supracentrimetric HER2+ breast tumors is established. There are no firm data establishing efficacy of T for infracentrimetric node-negative HER2+ tumors. We report our experience on infracentimetric tumors describing the received treatment, its efficacy and tolerance and the criteria that lead to therapeutic decision. Methods: We retrospectively reviewed electronic records of patients (pts) with invasive infra-centimetric HER2+ breast tumors treated in our institution from 2000 to 2008. Clinical, pathological, biological and therapeutic data were assessed. Tumors with a majority (≥80%) of ductal carcinoma in situ (DCIS) were excluded from this analysis. Results: 43 case records have been evaluated. Median age at diagnosis was 56 years (31-84). All tumors were treated by local surgery. 11 pts (26%) had node-positive tumors when including pN0i+ and pNmi+ tumors. 9 pts (82%) had local irradiation. A majority (n=8, 73%) were treated by chemotherapy and T except 1 with a pN0i+ tumor and 2 pts treated before T approval (2000-2001).32 pts (74%) had pN0 tumors. Ductal carcinomas accounted for 91% of tumors (n=29), and 14 (44%) were hormonal receptors-negative. Radiotherapy was given in 28 (88%) of them. 8 (29%) had nodal irradiation covering internal mammar chains, infra and supraclavicular regions. 21 of these pts (75%), had a 16 Gy breast tumor bed boost. Half the pts had chemotherapy (n=16). A sequential anthracycline/taxan (ATx)regimen was chosen for 10 pts (63%). Other regimen were A-based for 5 pts (31%) and Tx-based for 1 pt (6%). 1 pt developped myocardial infarction after her third anthracycline cycle. 22 pts (69%) have been treated with T. 13 of them have been treated by a chemotherapy/T (59%) combination. No significant correlation was found between decision of systemic treatment and age, hormone receptor status, grade, mitotic index or lymphovascu lar emboles. T treatment was complicated for 2 pts (13%) by left ventricular ejection fraction diminution under 50% after 5 and 6 months.With a median follow-up of 18 months, none of the 43 pts have developed recurrent invasive disease. In one pure micropapillary case, in situ local recurrence with micro-infiltration was seen at 5 years.Conclusion: In our experience, almost all pts were treated by local surgery and radiotherapy and around half pts received T since its approval with no significative clinical nor pathological factor leading to this decision. Usefulness of adjuvant chemotherapy and T for this tumors should be analyzed with data from prospective ongoing or closed trials. Systemic adjuvant treatment should be proposed for stage II tumors and discussed for smaller tumors taking into account age, grade, mitotic index, hormonal receptors status and presence of vascular invasion. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3152.</jats:p

Abstract P2-16-09: Wound Healing and Catheter Thrombosis after Implantable Venous Access Device Placement in 266 Metastatic Breast Cancer Patients Treated with Bevacizumab

Abstract OBJECTIVES: To determine in a population of metastatic breast cancer the incidence of wound dehiscence after placement of an implantable venous access device (VAD) in patients treated with bevacizumab, observe the optimum interval between placement and initiation of treatment and study the risk of catheter thrombosis. PATIENTS AND METHODS: Between 1/1/2007 and 31/12/2009, this study enrolled all VADs placed by 14 anesthetists: 273 VADs in patients treated by bevacizumab for metastatic breast cancer and 4196 VADs in patients not treated by bevacizumab. The medical charts of the 266 metastatic breast cancer patients treated with bevacizumab between 1/1/2007 and 31/12/2009 were reviewed up until 1/3/2010. A VAD was placed in all patients (goal standard in our institution). 7 patients in whom the VAD was inserted in another institution were excluded from this study. The VAD was removed and replaced in 14 patients with continuation of bevacizumab after replacement of the VAD RESULTS: 1 patient was lost to follow-up. Thirteen cases of wound dehiscence occurred in 12 patients requiring removal of the VAD (5,1 %). All cases of dehiscence occurred when bevacizumab was administered during the first 7 days after VAD placement. Bevacizumab therapy was initiated less than 7 days after VAD placement in 150 cases, requiring removal of the device in 12 patients (8.6%). The risk of dehiscence was the same from 0 to 7 days. In parallel, the VAD wound dehiscence rate in patients not receiving bevacizumab was 8/4,197 (0.19%) (Fisher's test significant, P&amp;lt;0.001). No risk factors were identified: anesthetists, learning curves, irradiated patients. In particular, 70 ports were placed by juniors with 6 dehiscences, 80 ports by seniors with 7 dehiscences. VAD thrombosis occurred in 4 patients (1,5 %) 3, 5, 7 and 22 months after VAD placement. In all these cases, VAD placement was at the time of initiation of bevacizumab therapy. In parallel, VAD thrombosis occurred in 51/4,197 (1.2%) patients not receiving bevacizumab (Fisher's test not significant; p=0.43). The other indications for VAD removal were end of treatment: 3 (0,91 %), mechanical problem other than thrombosis: 6 (1,8 %), local infection without wound dehiscence: 1 (0,31%). Bevacizumab was permanently discontinued in 5 patients related to wound dehiscence and in 1 patient due to extensive skin necrosis. Bevacizumab was continued in the other 7 patients. CONCLUSION: The risk of VAD thrombosis does not require any particular primary prevention. These data suggest the need to observe an interval of at least 7 days between VAD placement and initiation of bevacizumab therapy. Poor healing is a major complication of VAD, interfering with continuation of chemotherapy and the patient's subsequent management, resulting in a real risk of loss of chance. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-09.</jats:p

P2-18-03: Systemic Adjuvant Treatment of T1a and T1b N0M0 HER2+ Breast Carcinomas; an AERIO/UNICANCER Study.

Abstract Background: Trials have shown benefit of adjuvant trastuzumab (TZM) for node-positive (N+) or T1c+ HER2−positive breast carcinomas. Methods: Retrospective series in 6 french cancer centers from 2000 to 2010 of T1abN0M0 HER2 positive breast carcinomas. Multifocal tumors were excluded. Results: Two hundred five N- cases were retrieved. Median size was 8 mm (range, 2 to 10 mm), 51 were T1a (25%), 152 tumors were T1b; 120 tumors (59 %) exhibited significant hormonal receptors (HR) expression. All patients had surgery, 65 % (n= 133) had a local irradiation. Ninety percent of HR+ patients (108/120) received hormonotherapy: 77 received aromatase inhibitors (AI) upfront or sequential; 23 received tamoxifen (TAM) alone 13 received LHRH agonists alone or in combination with TAM or AI. Forty-nine percent (n= 101) had chemotherapy (CT) (Anthracycline alone for 41 cases, taxane alone for 31 cases, sequential A/T for 28 cases and concurrent for 1 case), associated with TZM in 90 cases. TZM was administered without chemotherapy in 3 cases. Decision of adjuvant CT and/or TZM was associated with (all p&amp;lt;0.05) HR-negative status, Elston-Ellis grade 2/3 and high mitotic index (MI) while patients with HR+/ low MI tumors were rarely treated (p&amp;lt;0.01). With a 41 months median follow-up, there was a statistically significant difference in invasive recurrences between TZM treated patients and others (log-rank test p=0.04). Twelve of the 112 patients treated without TZM (11%) had a recurrent invasive disease including 6 metastatic cases and 3 fatal events. There was one invasive recurrence in TZM group. There were as much recurrences in T1a as in T1b tumors. Three of the 12 recurrences (25%) in the group without TZM occurred in T1a cases. Conclusion: T1abN0M0 HER2 positive tumors have a significant risk of recurrence which could be avoided by adjuvant chemotherapy associated with TZM. Interestingly, there were no differences in the risk of recurrence between T1a and T1b. Adjuvant chemotherapy associated with TZM should not only be discussed in T1bN0 HER2−positive tumors but also in T1aN0 HER2−positive cases. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-18-03.</jats:p