Edited Jame Abraham, MD

Ruxolitinib, a JAK 1/JAK 2 kinase inhibitor, was recently approved by the Food and Drug Administration for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. JAK kinases mediate signaling of cytokines and growth factors that are involved in hematopoiesis and immune function. JAK signaling involves the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, STAT activation, and localization of STATs to the nucleus, which results in the modulation of gene expression. Myelofibrosis is associated with aberrant JAK signaling. Ruxolitinib acts to attenuate downstream signaling by inhibiting JAK 1 and JAK 2 kinases, which results in reduced plasma cytokine levels and the induction of antiproliferative and proapoptotic effects...

*For a PDF of the full article and an accompanying Commentary, click on the links to the left of this introduction.

Ruxolitinib, a JAK 1/JAK 2 kinase inhibitor, was recently approved by the Food and Drug Administration for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. JAK kinases mediate signaling of cytokines and growth factors that are involved in hematopoiesis and immune function. JAK signaling involves the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, STAT activation, and localization of STATs to the nucleus, which results in the modulation of gene expression. Myelofibrosis is associated with aberrant JAK signaling. Ruxolitinib acts to attenuate downstream signaling by inhibiting JAK 1 and JAK 2 kinases, which results in reduced plasma cytokine levels and the induction of antiproliferative and proapoptotic effects...

*For a PDF of the full article and an accompanying Commentary, click on the links to the left of this introduction.

Ruxolitinib, a JAK 1/JAK 2 kinase inhibitor, was recently approved by the Food and Drug Administration for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. JAK kinases mediate signaling of cytokines and growth factors that are involved in hematopoiesis and immune function. JAK signaling involves the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, STAT activation, and localization of STATs to the nucleus, which results in the modulation of gene expression. Myelofibrosis is associated with aberrant JAK signaling. Ruxolitinib acts to attenuate downstream signaling by inhibiting JAK 1 and JAK 2 kinases, which results in reduced plasma cytokine levels and the induction of antiproliferative and proapoptotic effects...

*For a PDF of the full article and an accompanying Commentary, click on the links to the left of this introduction.

Vemurafenib, an oral inhibitor of some mutated forms of the BRAF serine threonine kinase, was recently approved for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA- approved test. It is not recommended for use in patients with wild-type BRAF melanoma. The clinical trial supporting approval of vemurafenib (PLX4032) was performed in treatment-naïve patients with the V600E mutation as detected by the Cobas 4800 BRAF V600 Mutation Test. About 40%-60% of cutaneous melanomas have BRAF mutations that result in constitutive activation of downstream signaling through the MAPK pathway; about 90% of those carry the V600E mutation.

*For a PDF of the full article, click on the link to the left of this introduction.

Vemurafenib, an oral inhibitor of some mutated forms of the BRAF serine threonine kinase, was recently approved for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA- approved test. It is not recommended for use in patients with wild-type BRAF melanoma. The clinical trial supporting approval of vemurafenib (PLX4032) was performed in treatment-naïve patients with the V600E mutation as detected by the Cobas 4800 BRAF V600 Mutation Test. About 40%-60% of cutaneous melanomas have BRAF mutations that result in constitutive activation of downstream signaling through the MAPK pathway; about 90% of those carry the V600E mutation.

*For a PDF of the full article, click on the link to the left of this introduction.

Vemurafenib, an oral inhibitor of some mutated forms of the BRAF serine threonine kinase, was recently approved for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA- approved test. It is not recommended for use in patients with wild-type BRAF melanoma. The clinical trial supporting approval of vemurafenib (PLX4032) was performed in treatment-naïve patients with the V600E mutation as detected by the Cobas 4800 BRAF V600 Mutation Test. About 40%-60% of cutaneous melanomas have BRAF mutations that result in constitutive activation of downstream signaling through the MAPK pathway; about 90% of those carry the V600E mutation.

*For a PDF of the full article, click on the link to the left of this introduction.

Whole-breast irradiation (WBI) plus regional nodal irradiation (RNI) significantly improved disease-free survival, but not overall survival, in a randomized, multicenter phase III trial of women with node-positive or high-risk node-negative disease who were treated with breast-conserving surgery and adjuvant therapy. An interim analysis of 1,832 women with breast cancer found that after a median follow-up of 62 months (between March 2000 and March 2007), WBI plus RNI significantly reduced the risk of locoregional recurrence from 5.5% to 3.2% (hazard ratio [HR], 0.58; P = 0.02) and distant recurrence from 13.0% to 7.6% (HR, 0.64; P = 0.002), according to the lead investigator, Dr. Timothy Whelan, head of radiation oncology at McMaster University and the Juravinski Cancer Centre, Hamilton, Ontario, Canada.

As a result, disease-free survival rate improved from 84.0% for WBI to 89.7% for WBI plus RNI (HR, 0.67; P = 0.003). Overall survival in the intergroup trial was 90.7% with WBI, compared with 92.3% with the combined radiation regimen, but the difference did not reach statistical significance (HR, 0.76; P = 0.07). In view of the positive findings from the National Cancer Institute of Canada Clinical Trials Group MA.20 study, the data safety monitoring committee recommended that the results be released. The data were presented by Dr. Whelan at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO).¹

Report prepared by Matt Stenger, MS

* For a PDF of the complete article, click on the link to the left of this introduction.

Whole-breast irradiation (WBI) plus regional nodal irradiation (RNI) significantly improved disease-free survival, but not overall survival, in a randomized, multicenter phase III trial of women with node-positive or high-risk node-negative disease who were treated with breast-conserving surgery and adjuvant therapy. An interim analysis of 1,832 women with breast cancer found that after a median follow-up of 62 months (between March 2000 and March 2007), WBI plus RNI significantly reduced the risk of locoregional recurrence from 5.5% to 3.2% (hazard ratio [HR], 0.58; P = 0.02) and distant recurrence from 13.0% to 7.6% (HR, 0.64; P = 0.002), according to the lead investigator, Dr. Timothy Whelan, head of radiation oncology at McMaster University and the Juravinski Cancer Centre, Hamilton, Ontario, Canada.

As a result, disease-free survival rate improved from 84.0% for WBI to 89.7% for WBI plus RNI (HR, 0.67; P = 0.003). Overall survival in the intergroup trial was 90.7% with WBI, compared with 92.3% with the combined radiation regimen, but the difference did not reach statistical significance (HR, 0.76; P = 0.07). In view of the positive findings from the National Cancer Institute of Canada Clinical Trials Group MA.20 study, the data safety monitoring committee recommended that the results be released. The data were presented by Dr. Whelan at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO).¹

Report prepared by Matt Stenger, MS

* For a PDF of the complete article, click on the link to the left of this introduction.

Whole-breast irradiation (WBI) plus regional nodal irradiation (RNI) significantly improved disease-free survival, but not overall survival, in a randomized, multicenter phase III trial of women with node-positive or high-risk node-negative disease who were treated with breast-conserving surgery and adjuvant therapy. An interim analysis of 1,832 women with breast cancer found that after a median follow-up of 62 months (between March 2000 and March 2007), WBI plus RNI significantly reduced the risk of locoregional recurrence from 5.5% to 3.2% (hazard ratio [HR], 0.58; P = 0.02) and distant recurrence from 13.0% to 7.6% (HR, 0.64; P = 0.002), according to the lead investigator, Dr. Timothy Whelan, head of radiation oncology at McMaster University and the Juravinski Cancer Centre, Hamilton, Ontario, Canada.

As a result, disease-free survival rate improved from 84.0% for WBI to 89.7% for WBI plus RNI (HR, 0.67; P = 0.003). Overall survival in the intergroup trial was 90.7% with WBI, compared with 92.3% with the combined radiation regimen, but the difference did not reach statistical significance (HR, 0.76; P = 0.07). In view of the positive findings from the National Cancer Institute of Canada Clinical Trials Group MA.20 study, the data safety monitoring committee recommended that the results be released. The data were presented by Dr. Whelan at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO).¹

Report prepared by Matt Stenger, MS

* For a PDF of the complete article, click on the link to the left of this introduction.

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

* For a PDF of the full article, click in the link to the left of this introduction.

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

* For a PDF of the full article, click in the link to the left of this introduction.

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

* For a PDF of the full article, click in the link to the left of this introduction.