For women with ductal carcinoma in situ (DCIS) of the breast, the risk of developing an ipsilateral breast event (IBE; defined as local recurrence of DCIS or invasive carcinoma) after surgical ...excision without radiation is not well defined by clinical and pathologic characteristics.
The Oncotype DX breast cancer assay was performed for patients with DCIS treated with surgical excision without radiation in the Eastern Cooperative Oncology Group (ECOG) E5194 study. The association of the prospectively defined DCIS Score (calculated from seven cancer-related genes and five reference genes) with the risk of developing an IBE was analyzed using Cox regression. All statistical tests were two-sided.
There were 327 patients with adequate tissue for analysis. The continuous DCIS Score was statistically significantly associated with the risk of developing an IBE (hazard ratio HR = 2.31, 95% confidence interval CI = 1.15 to 4.49; P = .02) when adjusted for tamoxifen use (prespecified primary analysis) and with invasive IBE (unadjusted HR = 3.68, 95% CI = 1.34 to 9.62; P = .01). For the prespecified DCIS risk groups of low, intermediate, and high, the 10-year risks of developing an IBE were 10.6%, 26.7%, and 25.9%, respectively, and for an invasive IBE, 3.7%, 12.3%, and 19.2%, respectively (both log rank P ≤ .006). In multivariable analyses, factors associated with IBE risk were DCIS Score, tumor size, and menopausal status (all P ≤ .02).
The DCIS Score quantifies IBE risk and invasive IBE risk, complements traditional clinical and pathologic factors, and provides a new clinical tool to improve selecting individualized treatment for women with DCIS who meet the ECOG E5194 criteria.
We investigated the safety and pharmacokinetics of a recombinant human monoclonal antibody to vascular endothelial growth factor (rhuMAb VEGF) in patients with cancer.
Cohorts of patients with ...metastatic cancer having failed prior therapy entered a phase I trial of rhuMAb VEGF administered by a 90-minute intravenous infusion at doses from 0.1 to 10.0 mg/kg on days 0, 28, 35, and 42. Patients underwent pharmacokinetic sampling on day 0 and had serum samples obtained during the subsequent 28 days. Response assessment was carried out on days 49 and 72.
Twenty-five patients with a median Eastern Cooperative Oncology Group performance status of 0 were accrued. There were no grade III or IV adverse events definitely related to the antibody. There were three episodes of tumor-related bleeding. Infusions of rhuMAb VEGF were well tolerated without significant toxicity. Grades I and II adverse events possibly or probably related to study drug included asthenia, headache, and nausea. Pharmacokinetics revealed a linear profile with a half-life of 21 days. There were no objective responses, though 12 patients experienced stable disease over the duration of the study.
rhuMAb VEGF was safely administered without dose-limiting toxicity at doses ranging up to 10 mg/kg. Multiple doses of rhuMAb VEGF were well tolerated, and pharmacokinetic studies indicate that doses of > or = 0.3 mg/kg have a half-life similar to that of other humanized antibodies. Subsequent trials will explore rhuMAb VEGF alone and in combination chemotherapy.
Background: As screening central nervous system (CNS) imaging is not routinely performed, the incidence and clinical relevance of occult CNS metastases in advanced breast cancer is unknown. Patients ...and methods: All patients screened for participation in one of four clinical trials were included; each of the trials excluded patients with known CNS involvement and required screening CNS imaging. A cohort of breast cancer patients with symptomatic CNS metastases was identified from the IU Cancer Center Tumor Registry for comparison. Results: From November 1998 to August 2001, 155 screening imaging studies were performed. Twenty-three patients (14.8%) had occult CNS metastases. HER-2 overexpression (P = 0.02) and number of metastatic sites (P = 0.03) were predictive of CNS involvement by multivariate analysis. Median survival from time of metastasis (1.78 versus 2.76 years; P <0.0001) and from screening (4.67 versus 10.4 months; P = 0.0013) was shorter in patients with than without occult CNS metastasis. Survival among patients with occult CNS metastasis was similar to patients with symptomatic CNS disease. Conclusions: Patients with CNS involvement, whether occult or symptomatic, have an impaired survival. Occult CNS metastasis is relatively common, but impact on survival of treating occult CNS disease in patients with progressive systemic metastases is questionable.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Angiogenesis, or new blood vessel formation, is now known to play an important role in both growth and metastasis of many cancers. The central importance of angiogenesis and the understanding of how ...new blood vessels are formed, has led to novel therapies designed to interrupt this process. Though specific antiangiogenic compounds have only recently entered the clinic, they herald a new era, one in which biology is the basis for therapy. The intense interest in angiogenesis has also lead to a re-examination of the activity of many established cytotoxic agents. Claims of antiangiogenic activity abound, unfortunately, with no common criteria and often little evidence of clinical relevance. What are we to think? Have oncologists unknowingly been administering antiangiogenic therapy all these years? If chemotherapeutics are really antiangiogenics in disguise, why have they failed to cure most solid tumors? Might the hard-learned lessons of chemotherapy resistance pertain to the novel antiangiogenics as well? Though we can offer no certain answers to these important questions, we do offer a framework on which to order the rapidly burgeoning literature. We suggest criteria by which a cytotoxic agent might reasonably be considered to have meaningful antiangiogenic activity. Finally, we describe potential mechanisms of resistance to antiangiogenic chemotherapies-some of which may apply to the pure antiangiogenics currently in development.
Research needs in breast cancer Cardoso, F.; Harbeck, N.; Barrios, C.H. ...
Annals of oncology,
02/2017, Volume:
28, Issue:
2
Journal Article
Peer reviewed
Open access
New research questions emerge as medical needs continue to evolve and as we improve our understanding of cancer biology and treatment of malignancies. Although significant advances have been made in ...some areas of breast cancer research resulting in improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree and we continue to have many gaps in our knowledge. This article summarizes the 12 short and medium-term clinical research needs in breast cancer deemed as priorities in 2016 by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas: (i) de-escalate breast cancer therapies in early breast cancer without sacrificing outcomes; (ii) explore optimal adjuvant treatment durations; (iii) develop better tools and strategies to identify patients with genetic predisposition; (iv) improve care in young patients with breast cancer; (v) develop tools to speed up drug development in biomarker-defined populations; (vi) identify and validate targets that mediate resistance to chemotherapy, endocrine therapy and anti-HER2 therapies; (vii) evaluate the efficacy of local-regional treatments for metastatic disease; (viii) better define the optimal sequence of treatments in the metastatic setting; (ix) evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity); (x) better understand the biology and identify new targets in triple-negative breast cancer; (xi) better understand immune surveillance in breast cancer and further develop immunotherapies; and (xii) increase survivorship research efforts including supportive care and quality of life.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To determine indications for the use of postmastectomy radiotherapy (PMRT) for patients with invasive breast cancer with involved axillary lymph nodes or locally advanced disease who receive systemic ...therapy. These guidelines are intended for use in the care of patients outside of clinical trials.
The benefits and risks of PMRT in such patients, as well as subgroups of these patients, were considered. The details of the PMRT technique were also evaluated.
The outcomes considered included freedom from local-regional recurrence, survival (disease-free and overall), and long-term toxicity.
An expert multidisciplinary panel reviewed pertinent information from the published literature through July 2000; certain investigators were contacted for more recent and, in some cases, unpublished information. A computerized search was performed of MEDLINE data; directed searches based on the bibliographies of primary articles were also performed.
Levels of evidence and guideline grades were assigned by the Panel using standard criteria. A "recommendation" was made when level I or II evidence was available and there was consensus as to its meaning. A "suggestion" was made based on level III, IV, or V evidence and there was consensus as to its meaning. Areas of clinical importance were pointed out where guidelines could not be formulated due to insufficient evidence or lack of consensus.
The recommendations, suggestions, and expert opinions of the Panel are described in this article.
Seven outside reviewers, the American Society of Clinical Oncology (ASCO) Health Services Research Committee members, and the ASCO Board of Directors reviewed this document.
Numerous chemotherapeutic agents have been shown to have an inhibitory effect on endothelial cell proliferation and migration, and tubule formation. In this study, we examined the antiangiogenic ...activity of docetaxel. Docetaxel inhibited endothelial cell proliferation and tubule formation in vitro in a dose-dependent fashion. Docetaxel treatment also inhibited angiogenesis in an in vivo Matrigel plug assay. The endothelial stimulating factors, vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor are able to protect endothelial cells from the antiangiogenic properties of docetaxel. This protective effect can be overcome by a recombinant humanized monoclonal antibody directed against VEGF in both in vitro and in vivo models. Similarly, combination of docetaxel with the antiangiogenic agent 2-methoxyestradiol also overcomes the protective effect of VEGF in both in vitro and in vivo models. These data suggest that microenvironmental factors (e.g., local release of VEGF and basic fibroblast growth factor) could play a role in decreasing the antiangiogenic effects of docetaxel, whereas agents such as 2- methoxyestradiol and recombinant humanized monoclonal antibody directed against VEGF may reverse this protective effect.
Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension.
A genome-wide association study ...(GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100.
When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10(-8); OR=3.3) and in the cumulative dose model (P=4.7 × 10(-8); HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4).
A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•This ESO-ESMO ABC 5 Clinical Practice Guideline provides key recommendations for managing advanced breast cancer patients.•It provides updates on managing patients with all breast cancer subtypes, ...LABC, follow-up, palliative and supportive care.•Updated diagnostic and treatment algorithms are also provided.•All recommendations were compiled by a multidisciplinary group of international experts.•Recommendations are based on available clinical evidence and the collective expert opinion of the authors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
What separates a malignant from a normal cell? This question has occupied scientists for decades. Although a simple answer remains elusive, several hallmarks of malignancy have been identified. These ...critical features include uncontrolled proliferation, insensitivity to negative growth regulation, evasion of apoptosis, lack of senescence, invasion and metastasis, angiogenesis and genomic elasticity. Existing therapies predominantly target proliferation either with cytotoxic agents, ionising radiation or more targeted attacks on growth factor signalling pathways. Our most successful therapies to date inhibit proliferation via the oestrogen receptor (ER) and HER2 pathways. Further improvements in therapy must attack the other hallmarks of malignancy and will undoubtedly be accompanied by a better means of individual patient selection for such therapies. Indeed, each of these hallmarks presents a therapeutic opportunity. To believe otherwise would be to assume that a feature is both biologically crucial, yet therapeutically unimportant, an unlikely paradox. Here, we suggest the hallmarks of malignancy as a conceptual framework for understanding novel breast cancer therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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