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Baselga J.,Harvard University | Campone M.,Institute Of Cancerologie Of Louest Rene Gauducheau | Piccart M.,Institute Jules Bordet | Burris III H.A.,Sarah Cannon Research Institute | And 17 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity. METHODS: In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone- receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed. RESULTS: Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001). CONCLUSIONS:Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.) Copyright © 2012 Massachusetts Medical Society. All rights reserved.

Martin L.-A.,Institute of Cancer Research | Andre F.,University Paris - Sud | Andre F.,Institute Gustave Roussy | Campone M.,Institute Of Cancerologie Of Louest Rene Gauducheau | And 2 more authors.
Cancer Treatment Reviews | Year: 2013

Current therapeutic approaches for advanced breast cancer frequently target receptors mediating cell survival and proliferation, such as the estrogen receptor and/or progesterone receptor and human epidermal growth factor receptor-2. Although these approaches are effective for many patients, treatment resistance is common. Therefore, new treatment approaches are needed for patients with advanced breast cancer. Mammalian target of rapamycin is a highly conserved serine-threonine kinase that acts as a major signaling hub that integrates and synergizes with cellular proliferation, survival, and/or motility signals mediated by estrogen receptor, human epidermal growth factor receptor-2, and other receptor tyrosine kinases. Dysregulation of mammalian target of rapamycin signaling occurs in various tumor types, including breast cancer, and has been associated with cancer pathogenesis, disease progression, and treatment resistance. Recent clinical trials show that combined inhibition of mammalian target of rapamycin and estrogen receptor represents an effective strategy for treating hormone receptor-positive advanced breast cancer progressing on nonsteroidal aromatase inhibitor therapy, and data from ongoing trials combining mammalian target of rapamycin inhibition with human epidermal growth factor receptor-2-targeted therapy are awaited. This review focuses on the molecular rationale underlying strategies to enhance sensitivity to treatment in hormone receptor-positive and human epidermal growth factor receptor-2-positive advanced breast cancer, the clinical efficacy of such approaches, and future perspectives. © 2013.

Gnant M.,Medical University of Vienna | Baselga J.,Sloan Kettering Cancer Center | Rugo H.S.,University of California at San Francisco | Noguchi S.,Osaka National Hospital | And 16 more authors.
Journal of the National Cancer Institute | Year: 2013

Background Breast Cancer Trials of Oral Everolimus 2 (BOLERO-2), a phase III study in postmenopausal women with estrogen receptor-positive breast cancer progressing despite nonsteroidal aromatase inhibitor therapy, showed statistically significant benefits with adding everolimus to exemestane. Moreover, in preclinical studies, mammalian target of rapamycin inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of everolimus on bone marker levels and progressive disease in bone. Methods Patients were treated with exemestane (25mg/day) and randomized (2:1) to everolimus (10mg/day; combination) or placebo (exemestane only). Exploratory endpoints included changes in bone turnover marker levels vs baseline and progressive disease in bone, defined as unequivocal progression of a preexisting bone lesion or the appearance of a new bone lesion. Results Baseline disease characteristics were well balanced between arms (N = 724); baseline bisphosphonate use was not (43.9% combination vs 54.0% exemestane only). At a median of 18 months of follow-up, median progression-free survival (primary endpoint) was statistically significantly longer with the combination vs exemestane only (Cox proportional hazard ratio = 0.45, 95% confidence interval = 0.38 to 0.54; log-rank, 1-sided P <. 0001). Bone marker levels at 6 and 12 weeks increased with exemestane only, as expected, but decreased with the combination. The cumulative incidence rate of progressive disease in bone was lower in the combination arm. Bone-related adverse events occurred with similar frequency in both arms (3.3% combination vs 4.2% exemestane only). Conclusion These exploratory analyses suggest that everolimus has beneficial effects on bone turnover and progressive disease in bone in patients receiving exemestane for hormone receptor-positive breast cancer progressing during/after nonsteroidal aromatase inhibitor therapy. © 2013 The Author.

Heinemann V.,Comprehensive Cancer Center der Krebszentrum Munich | Douillard J.Y.,Institute Of Cancerologie Of Louest Rene Gauducheau | Douillard J.Y.,Institute Of Cancerologie Louest Rene Gauducheau | Ducreux M.,Institute Gustave Roussy | And 2 more authors.
Cancer Treatment Reviews | Year: 2013

In metastatic colorectal cancer (mCRC), an improved understanding of the underlying pathology and molecular biology has successfully merged with advances in diagnostic techniques and local/systemic therapies as well as improvements in the functioning of multidisciplinary teams, to enable tailored treatment regimens and optimized outcomes. Indeed, as a result of these advancements, median survival for patients with mCRC is now in the range of 20-24. months, having approximately tripled in the last 20. years. The identification of KRAS as a negative predictive marker for activity of epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies (mAbs), such as panitumumab (Amgen, Thousand Oaks, USA) and cetuximab (ImClone, Branchburg, USA), has perhaps had the greatest impact on patient management. This meant that, for the first time, mCRC patients unlikely to respond to a targeted therapy could be defined ahead of treatment. Ongoing controversies such as whether patients with KRAS G13D- (or BRAF V600-) mutated tumours can still respond to EGFR-targeted mAbs and the potential impact of inter- and intra-tumour heterogeneity on tumour sampling show that the usefulness of KRAS as a biomarker has not yet been exhausted, and that other downstream biomarkers should be considered. Conversely, a predictive biomarker for anti-angiogenic agents such as bevacizumab (Genentech, San Francisco, USA) in the mCRC setting is still lacking. In this review we will discuss the discovery and ongoing investigation into predictive biomarkers for mCRC as well as how recent advances have impacted on clinical practice and ultimately the overall cost of treatment for these patients. © 2013 .

Romagnoli M.,Tufts University | Belguise K.,Toulouse 1 University Capitole | Belguise K.,French National Center for Scientific Research | Yu Z.,Tufts University | And 9 more authors.
Cancer Research | Year: 2012

Induction of epithelial-to-mesenchymal transition (EMT) by TGF-β1 requires Ras signaling. We recently identified the transcriptional repressor Blimp-1 (PRDM1) as a downstream effector of the NF-κB, RelB/Bcl-2/Ras-driven pathway that promotes breast cancer cell migration. As the RelB/Blimp-1 pathway similarly required Ras signaling activation, we tested whether Blimp-1 plays a role in TGF-β1-mediated EMT. Here, TGF-β1 treatment of untransformed NMuMG mammary epithelial and MDA-MB-231 breast cancer cells was shown to induce Blimp-1 expression, which promoted an EMT signature and cell migration. TGFB1 and BLIMP1 RNA levels were correlated in patient breast tumors. BLIMP1 gene transcription was activated by TGF-β1 via a c-Raf (RAF1) to AP-1 pathway. Blimp-1 induced expression of the EMT master regulator Snail (SNAI1) via repressing BMP-5, which inhibited Snail expression upon TGF-β1 treatment. Interestingly, a similar cascade was observed during postnatal mouse mammary gland development. RelB expression was detected early in pregnancy followed progressively by Blimp-1 and then Snail; whereas, BMP-5 levels were high in nulliparous and regressing glands. Finally, lower BMP5 RNA levels were detected in patient breast tumors versus normal tissues, and correlated with cancer recurrence. Thus, the Ras effector Blimp-1 plays an essential role in TGF-β1-induced EMT via repression of BMP-5 in breast cancer. ©2012 American Association for Cancer Research.

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