Adjuvant therapy decisions in breast cancer: comparison of a multi disciplinary team's decisions with the recommendations of web-based computer programme “Adjuvant Online”.
TL;DR: There are differences between the adjuvant therapy decisions by the MDT and the “best treatment” recommended by an evidence-based online computer programme “Adjuvant Online” (AO), and in the majority of cases the differences are due to either local or national guidelines that are in force in the United Kingdom.
Abstract: #2117 Introduction: Adjuvant therapy decisions in breast cancer impact on survival, recurrence and quality of life. We compared the hormonal and chemotherapy recommendations of a multi-disciplinary team (MDT) with the “best treatment” recommended by an evidence-based online computer programme “Adjuvant Online” (AO). Materials and Methods: We prospectively monitored a breast cancer MDT for a period of one year. Among 218 breast cancer patients discussed, patients who had DCIS, neoadjuvant therapy, primary hormonal therapy, multifocal disease and micrometastases only in the axillary lymph nodes and recurrent disease were excluded leaving 122 suitable for input into AO. The MDT recommendation and actual treatment received were recorded. Ten-year cancer-related death and relapse rates were calculated using AO and estimates of proportional risk reduction with MDT recommended therapy and AO “best treatment” were made. Results: Median age was 61 years (range 28-86). MDT recommended endocrine therapy (ET) to all patients with ER/PR positive cancers (n=103). Among 30 women aged 55 years or less with ER/PR positive cancers, 25 had tamoxifen, 4 had an aromatase inhibitor (AI) and one switched from tamoxifen to an AI. AO suggested AI or tamoxifen-AI switch as the best treatment for post-menopausal women. Among 73 women aged over 55 years with ER/PR positive cancers, 46% (n=34) received tamoxifen as per local cancer-network guidelines, which recommended tamoxifen for low-risk (T1 N0 M0) post-menopausal breast cancer. Others received an AI (n=38) except one patient who declined ET. There were 54 patients with >10% risk of cancer-related death in 10 years. Among these 36 were offered and 29 received chemotherapy. Chemotherapy was not offered to 17 patients due to age and/or comorbidity. Only 1 suitable patient with >10% risk was not offered chemotherapy by the MDT. Among those who had chemotherapy, only 31% had 3rd generation chemotherapy as recommended by AO, the main reason being national guidelines in the United Kingdom limiting the use of this regimen. Discussion: There are differences between the adjuvant therapy decisions by the MDT and the “best treatment” recommended by Adjuvant Online. This study shows that in the majority of these cases the differences are due to either local or national guidelines that are in force in the United Kingdom. Cancer MDTs in the UK National Health Service are expected to adhere to these guidelines. However, calculation of the risk of death and recurrence rates using AO may be useful to facilitate decision making of the MDT by giving quantitative prognostic estimates and this could be a useful adjunct to help patients make informed decisions. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2117.
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TL;DR: Daily administration of free sulforaphane shows promise in managing biochemical recurrences in prostate cancer after radical prostatectomy.
Abstract: Increases in serum levels of prostate-specific antigen (PSA) occur commonly in prostate cancer after radical prostatectomy and are designated "biochemical recurrence." Because the phytochemical sulforaphane has been studied extensively as an anticancer agent, we performed a double-blinded, randomized, placebo-controlled multicenter trial with sulforaphane in 78 patients (mean age, 69 ± 6 years) with increasing PSA levels after radical prostatectomy. Treatment comprised daily oral administration of 60 mg of a stabilized free sulforaphane for 6 months (M0-M6) followed by 2 months without treatment (M6-M8). The study was designed to detect a 0.012 log (ng/mL)/month decrease in the log PSA slope in the sulforaphane group from M0 to M6. The primary endpoint was not reached. For secondary endpoints, median log PSA slopes were consistently lower in sulforaphane-treated men. Mean changes in PSA levels between M6 and M0 were significantly lower in the sulforaphane group (+0.099 ± 0.341 ng/mL) than in placebo (+0.620 ± 1.417 ng/mL; P = 0.0433). PSA doubling time was 86% longer in the sulforaphane than in the placebo group (28.9 and 15.5 months, respectively). PSA increases >20% at M6 were significantly greater in the placebo group (71.8%) than in the sulforaphane group (44.4%); P = 0.0163. Compliance and tolerance were very good. Sulforaphane effects were prominent after 3 months of intervention (M3-M6). After treatment, PSA slopes from M6 to M8 remained the same in the 2 arms. Daily administration of free sulforaphane shows promise in managing biochemical recurrences in prostate cancer after radical prostatectomy.
89 citations
TL;DR: Data show for the first time that TLR3 and TLR5 stimulation of human prostate cancer cells triggers the production of chemokines, which, in turn, favor the attraction of immune effectors, thereby representing a tool to enhance the efficacy of conventional therapies by stimulating anticancer immune responses.
Abstract: TLRs boost antimicrobial response mechanisms by epithelial cells and represent the first line of defense at mucosal sites. In view of these immunomodulatory properties, TLR stimulation may represent a novel means to activate anticancer immune responses. In the present study, the ability of TLR ligands to affect the recruitment of different immune cell populations by human prostate cancer cell lines and the underlying mechanisms were investigated. We showed that LNCaP and DU-145 cells express functionally active TLR3 and TLR5. Treatment with their respective agonists, polyinosinic:polycytidylic acid and flagellin, rapidly triggered NF-kappaB-dependent upregulation of different inflammatory molecules, as assayed by microarray and ELISA. Furthermore, we demonstrated that conditioned media from polyinosinic:polycytidylic acid- and flagellin-treated LNCaP and DU-145 cells induced the recruitment of different leukocyte subpopulations, suggesting that TLR stimulation is able to activate the earliest step of immune response mediated by soluble factors. Interestingly, the more aggressive cancer cell line PC3 expressed TLR3 and TLR5 but failed to respond to TLR agonists in terms of NF-kappaB activation and the ability to attract immune effectors. Overall, these data show for the first time that TLR3 and TLR5 stimulation of human prostate cancer cells triggers the production of chemokines, which, in turn, favor the attraction of immune effectors, thereby representing a tool to enhance the efficacy of conventional therapies by stimulating anticancer immune responses.
70 citations
TL;DR: The concept of epithelial-mesenchymal plasticity, which describes the dynamic flux within the spectrum of phenotypic states that invasive carcinoma cells may reside, is being increasingly recognised for its role in cancer progression and therapy resistance as mentioned in this paper.
Abstract: The concept of epithelial-mesenchymal plasticity (EMP), which describes the dynamic flux within the spectrum of phenotypic states that invasive carcinoma cells may reside, is being increasingly recognised for its role in cancer progression and therapy resistance. The myriad of events that are able to induce EMP, as well as the more recently characterised control loops, results in dynamic transitions of cancerous epithelial cells to more mesenchymal-like phenotypes through an epithelial-mesenchymal transition (EMT), as well as the reverse transition from mesenchymal phenotypes to an epithelial one. The significance of EMP, in its ability to drive local invasion, generate cancer stem cells and facilitate metastasis by the dissemination of circulating tumour cells (CTCs), highlights its importance as a targetable programme to combat cancer morbidity and mortality. The focus of this review is to consolidate the existing knowledge on the strategies currently in development to combat cancer progression via inhibition of specific facets of EMP. The prevalence of relapse due to therapy resistance and metastatic propensity that EMP endows should be considered when designing therapy regimes, and such therapies should synergise with existing chemotherapeutics to benefit efficacy. To further improve upon EMP-targeted therapies, it is imperative to devise monitoring strategies to assess the impact of such treatments on EMP-related phenomenon such as CTC burden, chemosensitivity/-resistance and micrometastasis in patients.
64 citations
TL;DR: Mechanistic studies showed that prevention of prostate cancer and metastasis by the SFN + CQ combination was associated with decreased cell proliferation, increased apoptosis, alterations in protein levels of autophagy regulators Atg5 and phospho-mTOR, and suppression of biochemical features of epithelial-mesenchymal transition.
Abstract: There is a preclinical evidence that the oral administration of d,l-sulforaphane (SFN) can decrease the incidence or burden of early-stage prostate cancer [prostatic intraepithelial neoplasia (PIN)] and well-differentiated cancer (WDC) but not late-stage poorly differentiated cancer (PDC). Because SFN treatment induces cytoprotective autophagy in cultured human prostate cancer cells, the present study tested the hypothesis that chemopreventive efficacy of SFN could be augmented by the pharmacologic inhibition of autophagy using chloroquine (CQ). Incidence of PDC characterized by prostate weight of more than 1 g was significantly lower in the SFN + CQ group than in control (P = 0.004), CQ group (P = 0.026), or SFN group (P = 0.002 by Fisher exact test). Average size of the metastatic lymph node was lower by about 42% in the SFN + CQ group than in control (P = 0.043 by Wilcoxon test). On the other hand, the SFN + CQ combination was not superior to SFN alone with respect to inhibition of incidence or burden of microscopic PIN or WDC. SFN treatment caused in vivo autophagy as evidenced by transmission electron microscopy. Mechanistic studies showed that prevention of prostate cancer and metastasis by the SFN + CQ combination was associated with decreased cell proliferation, increased apoptosis, alterations in protein levels of autophagy regulators Atg5 and phospho-mTOR, and suppression of biochemical features of epithelial–mesenchymal transition. Plasma proteomics identified protein expression signature that may serve as biomarker of SFN + CQ exposure/response. This study offers a novel combination regimen for future clinical investigations for prevention of prostate cancer in humans. Cancer Res; 73(19); 5985–95. ©2013 AACR.
46 citations
TL;DR: Oral BSE-SFN is well tolerated at daily doses up to 200 μmol and achieves dose-dependent levels in plasma and skin and a larger efficacy evaluation of 200μmol daily for longer intervals is now reasonable to better characterize clinical and biological effects of BSE -SFN as chemoprevention for melanoma.
Abstract: Broccoli sprout extract containing sulforaphane (BSE-SFN) has been shown to inhibit ultraviolet radiation-induced damage and tumor progression in skin. This study evaluated the toxicity and potential effects of oral BSE-SFN at three dosages. Seventeen patients who each had at least 2 atypical nevi and a prior history of melanoma were randomly allocated to 50, 100, or 200 μmol oral BSE-SFN daily for 28 days. Atypical nevi were photographed on days 1 and 28, and plasma and nevus samples were taken on days 1, 2, and 28. Endpoints assessed were safety, plasma and skin sulforaphane levels, gross and histologic changes, IHC for phospho-STAT3(Y705), Ki-67, Bcl-2, HMOX1, and TUNEL, plasma cytokine levels, and tissue proteomics. All 17 patients completed 28 days with no dose-limiting toxicities. Plasma sulforaphane levels pooled for days 1, 2, and 28 showed median postadministration increases of 120 ng/mL for 50 μmol, 206 ng/mL for 100 μmol, and 655 ng/mL for 200 μmol. Median skin sulforaphane levels on day 28 were 0.0, 3.1, and 34.1 ng/g for 50, 100, and 200 μmol, respectively. Plasma levels of proinflammatory cytokines decreased from day 1 to 28. The tumor suppressor decorin was increased from day 1 to 28. Oral BSE-SFN is well tolerated at daily doses up to 200 μmol and achieves dose-dependent levels in plasma and skin. A larger efficacy evaluation of 200 μmol daily for longer intervals is now reasonable to better characterize clinical and biological effects of BSE-SFN as chemoprevention for melanoma. Cancer Prev Res; 11(7); 429-38. ©2018 AACR.
43 citations