Breast Cancer

Patients with a history of contact allergies may be less likely to develop nonmelanoma skin cancer, brain cancer, and breast cancer, a study has shown.

In research published online July 11 in BMJ Open (doi:10.1136/bmjopen-2011-000084), investigators conversely found diagnoses of bladder cancer more likely in people with a history of contact allergies.

Any protective effects could possibly be explained by the stimulation of natural killer T (NKT) cells through contact allergic reactions, the observational study’s lead author, Kaare Engkilde, Ph.D., of the national allergy research center at Copenhagen University Hospital, said in an interview. "You would probably think that [contact allergy] could lead to skin cancer, but that is not what we found," Dr. Engkilde said.

Contact allergic reactions are delayed reactions caused by chemicals small enough to penetrate the skin – triggers can include perfumes, hair dyes, cobalt, nickel, and formaldehyde. Animal studies have shown that contact allergens have the ability to increase the number of NKT cells, at least temporarily, Dr. Engkilde said.

For their research, Dr. Engkilde and his colleagues used a database of 16,922 Danish patients patch tested for type IV allergies between 1984 and 2008. Of these, 6,065 (35.8%) had at least one positive reaction (26.1% of men, 41.4% of women). Linkage with the Danish Cancer Registry showed 3,200, or 18.9%, of dermatitis patients had a benign tumor, a malignant cancer diagnosis, or both, and 1,207 (37.7%) of these patients had had a positive patch test reaction.

Dr. Engkilde and his colleagues looked specifically at 15 types of cancers, all of which affected at least 40 people in the study population.

The investigators found an inverse association between diagnosed contact allergy and nonmelanoma skin cancer (OR, 0.82) along with breast cancer (OR, 0.80) among both men and women. Dr. Engkilde and his colleagues also noted an inverse trend for brain cancer among women with contact allergies, though the P value was above.05 (OR, 0.36).

The findings related to nonmelanoma skin cancers were on some level expected, Dr. Engkilde said; however, the researchers said they were surprised not to see any protective effect against melanomas.

Dr. Engkilde said his group had no hypothesis for the inverse breast cancer finding, but noted that an earlier study had found that self-reported perfume allergy, a type IV allergy, was related inversely to brain cancer incidence (Am. J. Epidemiol. 2007;166:941-50).

The positive association between contact allergy and bladder cancer (OR, 1.44) was more likely related to accumulations of chemical metabolites of type IV allergens in the bladder than to an effect on NKT cells or another immune response, the investigators said.

They cautioned that the relationships between type IV reactions and cancers were "uncertain and not necessarily the result of causality," and that future analyses would have to adjust for social class and smoking, as the latter can increase the risk of developing nickel contact allergies and several types of cancer.

Also, they wrote, "studies focusing on specific chemical exposures are required to further our understanding of the role of contact allergies in the development of cancer." However, if the relationships are in fact etiologic, the findings have "implications for understanding how contact allergy can affect cancer development and vice versa," they said.

Dr. Engkilde and his coauthors received research support from Aage Bang’s Foundation and the Capital Region’s Research Foundation, and disclosed no competing interests.

Patients with a history of contact allergies may be less likely to develop nonmelanoma skin cancer, brain cancer, and breast cancer, a study has shown.

In research published online July 11 in BMJ Open (doi:10.1136/bmjopen-2011-000084), investigators conversely found diagnoses of bladder cancer more likely in people with a history of contact allergies.

Any protective effects could possibly be explained by the stimulation of natural killer T (NKT) cells through contact allergic reactions, the observational study’s lead author, Kaare Engkilde, Ph.D., of the national allergy research center at Copenhagen University Hospital, said in an interview. "You would probably think that [contact allergy] could lead to skin cancer, but that is not what we found," Dr. Engkilde said.

Contact allergic reactions are delayed reactions caused by chemicals small enough to penetrate the skin – triggers can include perfumes, hair dyes, cobalt, nickel, and formaldehyde. Animal studies have shown that contact allergens have the ability to increase the number of NKT cells, at least temporarily, Dr. Engkilde said.

For their research, Dr. Engkilde and his colleagues used a database of 16,922 Danish patients patch tested for type IV allergies between 1984 and 2008. Of these, 6,065 (35.8%) had at least one positive reaction (26.1% of men, 41.4% of women). Linkage with the Danish Cancer Registry showed 3,200, or 18.9%, of dermatitis patients had a benign tumor, a malignant cancer diagnosis, or both, and 1,207 (37.7%) of these patients had had a positive patch test reaction.

Dr. Engkilde and his colleagues looked specifically at 15 types of cancers, all of which affected at least 40 people in the study population.

The investigators found an inverse association between diagnosed contact allergy and nonmelanoma skin cancer (OR, 0.82) along with breast cancer (OR, 0.80) among both men and women. Dr. Engkilde and his colleagues also noted an inverse trend for brain cancer among women with contact allergies, though the P value was above.05 (OR, 0.36).

The findings related to nonmelanoma skin cancers were on some level expected, Dr. Engkilde said; however, the researchers said they were surprised not to see any protective effect against melanomas.

Dr. Engkilde said his group had no hypothesis for the inverse breast cancer finding, but noted that an earlier study had found that self-reported perfume allergy, a type IV allergy, was related inversely to brain cancer incidence (Am. J. Epidemiol. 2007;166:941-50).

The positive association between contact allergy and bladder cancer (OR, 1.44) was more likely related to accumulations of chemical metabolites of type IV allergens in the bladder than to an effect on NKT cells or another immune response, the investigators said.

They cautioned that the relationships between type IV reactions and cancers were "uncertain and not necessarily the result of causality," and that future analyses would have to adjust for social class and smoking, as the latter can increase the risk of developing nickel contact allergies and several types of cancer.

Also, they wrote, "studies focusing on specific chemical exposures are required to further our understanding of the role of contact allergies in the development of cancer." However, if the relationships are in fact etiologic, the findings have "implications for understanding how contact allergy can affect cancer development and vice versa," they said.

Dr. Engkilde and his coauthors received research support from Aage Bang’s Foundation and the Capital Region’s Research Foundation, and disclosed no competing interests.

Patients with a history of contact allergies may be less likely to develop nonmelanoma skin cancer, brain cancer, and breast cancer, a study has shown.

In research published online July 11 in BMJ Open (doi:10.1136/bmjopen-2011-000084), investigators conversely found diagnoses of bladder cancer more likely in people with a history of contact allergies.

Any protective effects could possibly be explained by the stimulation of natural killer T (NKT) cells through contact allergic reactions, the observational study’s lead author, Kaare Engkilde, Ph.D., of the national allergy research center at Copenhagen University Hospital, said in an interview. "You would probably think that [contact allergy] could lead to skin cancer, but that is not what we found," Dr. Engkilde said.

Contact allergic reactions are delayed reactions caused by chemicals small enough to penetrate the skin – triggers can include perfumes, hair dyes, cobalt, nickel, and formaldehyde. Animal studies have shown that contact allergens have the ability to increase the number of NKT cells, at least temporarily, Dr. Engkilde said.

For their research, Dr. Engkilde and his colleagues used a database of 16,922 Danish patients patch tested for type IV allergies between 1984 and 2008. Of these, 6,065 (35.8%) had at least one positive reaction (26.1% of men, 41.4% of women). Linkage with the Danish Cancer Registry showed 3,200, or 18.9%, of dermatitis patients had a benign tumor, a malignant cancer diagnosis, or both, and 1,207 (37.7%) of these patients had had a positive patch test reaction.

Dr. Engkilde and his colleagues looked specifically at 15 types of cancers, all of which affected at least 40 people in the study population.

The investigators found an inverse association between diagnosed contact allergy and nonmelanoma skin cancer (OR, 0.82) along with breast cancer (OR, 0.80) among both men and women. Dr. Engkilde and his colleagues also noted an inverse trend for brain cancer among women with contact allergies, though the P value was above.05 (OR, 0.36).

The findings related to nonmelanoma skin cancers were on some level expected, Dr. Engkilde said; however, the researchers said they were surprised not to see any protective effect against melanomas.

Dr. Engkilde said his group had no hypothesis for the inverse breast cancer finding, but noted that an earlier study had found that self-reported perfume allergy, a type IV allergy, was related inversely to brain cancer incidence (Am. J. Epidemiol. 2007;166:941-50).

The positive association between contact allergy and bladder cancer (OR, 1.44) was more likely related to accumulations of chemical metabolites of type IV allergens in the bladder than to an effect on NKT cells or another immune response, the investigators said.

They cautioned that the relationships between type IV reactions and cancers were "uncertain and not necessarily the result of causality," and that future analyses would have to adjust for social class and smoking, as the latter can increase the risk of developing nickel contact allergies and several types of cancer.

Also, they wrote, "studies focusing on specific chemical exposures are required to further our understanding of the role of contact allergies in the development of cancer." However, if the relationships are in fact etiologic, the findings have "implications for understanding how contact allergy can affect cancer development and vice versa," they said.

Dr. Engkilde and his coauthors received research support from Aage Bang’s Foundation and the Capital Region’s Research Foundation, and disclosed no competing interests.

CHICAGO – Circulating tumor necrosis factor appears to play a role in the cognitive dysfunction called "chemo brain" that some women experience after receiving chemotherapy as part of their primary treatment for newly diagnosed breast cancer.

Preliminary data on 93 women in a prospective observational cohort study show that women who underwent chemotherapy had higher levels of circulating tumor necrosis factor (TNF) than did similar women who had not received chemotherapy as part of their primary treatment.

The chemotherapy group also started the study with worse quality of life and poorer cognitive function, compared with patients who did not have chemotherapy before enrolling in the study. None of the women had started endocrine therapy at that point.

"These effects are specific to TNF and were not associated with other biomarkers of inflammation studied," Dr. Patricia A. Ganz reported at the annual meeting of the American Society of Clinical Oncology.

TNF may, therefore, represent a biologic target for pharmacologic therapy, as well as a biomarker that could help identify patients at increased risk for so-called "chemo brain," cognitive complaints during adjuvant chemotherapy that can persist for years afterward in up to 25% of breast cancer survivors, according to Dr. Ganz, director of prevention and control research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

The study is thought to be among the first to comprehensively examine the relationship between inflammatory markers and cognitive changes in breast cancer patients, she said. It was suggested in part by a study of doxorubicin exposure in an animal model, which found systemic increases in the proinflammatory cytokine TNF-alpha. This cytokine is able to cross the blood-brain barrier and accumulate in the central nervous system (Neurobiol. Dis. July 2006;23:127-39).

The current study enrolled 191 women within 3 months of completion of primary therapy (surgery, radiation, and/or chemotherapy), and prior to initiating endocrine therapy for recently diagnosed breast cancer. All women underwent comprehensive assessments at baseline, 6 months, and 12 months after enrollment. A subset of 16 women also participated in a PET scan substudy and had brain scans at baseline and 12 months later.

The longitudinal data reported by Dr. Ganz was based on the first 93 women with complete cytokine assessments: 49 women who received chemotherapy and 44 women who did not have chemotherapy as part of their primary treatment. Similar proportions of both groups had undergone mastectomy (28% overall) and radiotherapy (76% overall) during primary treatment; 72% of the total population went on to receive endocrine therapy. The women had a mean age of 51 years and were enrolled an average of 7 months after diagnosis of breast cancer.

At baseline, the postchemotherapy group reported significantly poorer quality of life and functioning on several standardized measures, including the SF36 physical and mental component summary scales, sleep, fatigue, and depression.

Self-reported measures of cognitive complaints, including the multidimensional Patients Assessment of Own Functioning Inventory, also suggested that they had greater memory impairments. A significant correlation was found between the memory subscale score in the chemotherapy group (correlation with log r = 0.33, P = .05).

Fasting blood specimens were tested for four inflammatory markers: interleukin-1 receptor antagonist, interleukin-6, C-reactive protein, and soluble TNF receptor type II (sTNFRII), which provides a stable assessment of TNF-alpha activity.

Only sTNFRII was significantly increased in the chemotherapy-treated group (2,492.5 pg/mL vs. 2,115.6 pg/mL in the other patients, P = .007). Over the course of the year, it decreased to the point where the difference between groups was no longer significant.

In the 16 patients with complete PET scan data, soluble TNF receptor level at baseline was negatively correlated with metabolic activity in the inferior frontal gyrus in chemotherapy-treated patients (P = .04). Patients with higher levels of TNF receptor had lower levels of metabolic activity. This also improved over 12 months.

Finally, genetic analysis suggests that the GG allele of the TNF-alpha 308 single nucleotide polymorphism was associated with more cognitive complaints. It may enhance the patient’s vulnerability to cognitive complaints and cognitive dysfunction.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) said, "The strengths of this study include its prospective longitudinal design as well as the examination of potential biological mechanisms, including inflammation, genetic polymorphisms, and cerebral function."

She described examination of biomarkers and mechanisms as important in supportive care research, and expressed optimism that this type of research has only just begun.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Ganz and Dr. Mustian said they had no relevant relationships.

CHICAGO – Circulating tumor necrosis factor appears to play a role in the cognitive dysfunction called "chemo brain" that some women experience after receiving chemotherapy as part of their primary treatment for newly diagnosed breast cancer.

Preliminary data on 93 women in a prospective observational cohort study show that women who underwent chemotherapy had higher levels of circulating tumor necrosis factor (TNF) than did similar women who had not received chemotherapy as part of their primary treatment.

The chemotherapy group also started the study with worse quality of life and poorer cognitive function, compared with patients who did not have chemotherapy before enrolling in the study. None of the women had started endocrine therapy at that point.

"These effects are specific to TNF and were not associated with other biomarkers of inflammation studied," Dr. Patricia A. Ganz reported at the annual meeting of the American Society of Clinical Oncology.

TNF may, therefore, represent a biologic target for pharmacologic therapy, as well as a biomarker that could help identify patients at increased risk for so-called "chemo brain," cognitive complaints during adjuvant chemotherapy that can persist for years afterward in up to 25% of breast cancer survivors, according to Dr. Ganz, director of prevention and control research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

The study is thought to be among the first to comprehensively examine the relationship between inflammatory markers and cognitive changes in breast cancer patients, she said. It was suggested in part by a study of doxorubicin exposure in an animal model, which found systemic increases in the proinflammatory cytokine TNF-alpha. This cytokine is able to cross the blood-brain barrier and accumulate in the central nervous system (Neurobiol. Dis. July 2006;23:127-39).

The current study enrolled 191 women within 3 months of completion of primary therapy (surgery, radiation, and/or chemotherapy), and prior to initiating endocrine therapy for recently diagnosed breast cancer. All women underwent comprehensive assessments at baseline, 6 months, and 12 months after enrollment. A subset of 16 women also participated in a PET scan substudy and had brain scans at baseline and 12 months later.

The longitudinal data reported by Dr. Ganz was based on the first 93 women with complete cytokine assessments: 49 women who received chemotherapy and 44 women who did not have chemotherapy as part of their primary treatment. Similar proportions of both groups had undergone mastectomy (28% overall) and radiotherapy (76% overall) during primary treatment; 72% of the total population went on to receive endocrine therapy. The women had a mean age of 51 years and were enrolled an average of 7 months after diagnosis of breast cancer.

At baseline, the postchemotherapy group reported significantly poorer quality of life and functioning on several standardized measures, including the SF36 physical and mental component summary scales, sleep, fatigue, and depression.

Self-reported measures of cognitive complaints, including the multidimensional Patients Assessment of Own Functioning Inventory, also suggested that they had greater memory impairments. A significant correlation was found between the memory subscale score in the chemotherapy group (correlation with log r = 0.33, P = .05).

Fasting blood specimens were tested for four inflammatory markers: interleukin-1 receptor antagonist, interleukin-6, C-reactive protein, and soluble TNF receptor type II (sTNFRII), which provides a stable assessment of TNF-alpha activity.

Only sTNFRII was significantly increased in the chemotherapy-treated group (2,492.5 pg/mL vs. 2,115.6 pg/mL in the other patients, P = .007). Over the course of the year, it decreased to the point where the difference between groups was no longer significant.

In the 16 patients with complete PET scan data, soluble TNF receptor level at baseline was negatively correlated with metabolic activity in the inferior frontal gyrus in chemotherapy-treated patients (P = .04). Patients with higher levels of TNF receptor had lower levels of metabolic activity. This also improved over 12 months.

Finally, genetic analysis suggests that the GG allele of the TNF-alpha 308 single nucleotide polymorphism was associated with more cognitive complaints. It may enhance the patient’s vulnerability to cognitive complaints and cognitive dysfunction.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) said, "The strengths of this study include its prospective longitudinal design as well as the examination of potential biological mechanisms, including inflammation, genetic polymorphisms, and cerebral function."

She described examination of biomarkers and mechanisms as important in supportive care research, and expressed optimism that this type of research has only just begun.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Ganz and Dr. Mustian said they had no relevant relationships.

CHICAGO – Circulating tumor necrosis factor appears to play a role in the cognitive dysfunction called "chemo brain" that some women experience after receiving chemotherapy as part of their primary treatment for newly diagnosed breast cancer.

Preliminary data on 93 women in a prospective observational cohort study show that women who underwent chemotherapy had higher levels of circulating tumor necrosis factor (TNF) than did similar women who had not received chemotherapy as part of their primary treatment.

The chemotherapy group also started the study with worse quality of life and poorer cognitive function, compared with patients who did not have chemotherapy before enrolling in the study. None of the women had started endocrine therapy at that point.

"These effects are specific to TNF and were not associated with other biomarkers of inflammation studied," Dr. Patricia A. Ganz reported at the annual meeting of the American Society of Clinical Oncology.

TNF may, therefore, represent a biologic target for pharmacologic therapy, as well as a biomarker that could help identify patients at increased risk for so-called "chemo brain," cognitive complaints during adjuvant chemotherapy that can persist for years afterward in up to 25% of breast cancer survivors, according to Dr. Ganz, director of prevention and control research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

The study is thought to be among the first to comprehensively examine the relationship between inflammatory markers and cognitive changes in breast cancer patients, she said. It was suggested in part by a study of doxorubicin exposure in an animal model, which found systemic increases in the proinflammatory cytokine TNF-alpha. This cytokine is able to cross the blood-brain barrier and accumulate in the central nervous system (Neurobiol. Dis. July 2006;23:127-39).

The current study enrolled 191 women within 3 months of completion of primary therapy (surgery, radiation, and/or chemotherapy), and prior to initiating endocrine therapy for recently diagnosed breast cancer. All women underwent comprehensive assessments at baseline, 6 months, and 12 months after enrollment. A subset of 16 women also participated in a PET scan substudy and had brain scans at baseline and 12 months later.

The longitudinal data reported by Dr. Ganz was based on the first 93 women with complete cytokine assessments: 49 women who received chemotherapy and 44 women who did not have chemotherapy as part of their primary treatment. Similar proportions of both groups had undergone mastectomy (28% overall) and radiotherapy (76% overall) during primary treatment; 72% of the total population went on to receive endocrine therapy. The women had a mean age of 51 years and were enrolled an average of 7 months after diagnosis of breast cancer.

At baseline, the postchemotherapy group reported significantly poorer quality of life and functioning on several standardized measures, including the SF36 physical and mental component summary scales, sleep, fatigue, and depression.

Self-reported measures of cognitive complaints, including the multidimensional Patients Assessment of Own Functioning Inventory, also suggested that they had greater memory impairments. A significant correlation was found between the memory subscale score in the chemotherapy group (correlation with log r = 0.33, P = .05).

Fasting blood specimens were tested for four inflammatory markers: interleukin-1 receptor antagonist, interleukin-6, C-reactive protein, and soluble TNF receptor type II (sTNFRII), which provides a stable assessment of TNF-alpha activity.

Only sTNFRII was significantly increased in the chemotherapy-treated group (2,492.5 pg/mL vs. 2,115.6 pg/mL in the other patients, P = .007). Over the course of the year, it decreased to the point where the difference between groups was no longer significant.

In the 16 patients with complete PET scan data, soluble TNF receptor level at baseline was negatively correlated with metabolic activity in the inferior frontal gyrus in chemotherapy-treated patients (P = .04). Patients with higher levels of TNF receptor had lower levels of metabolic activity. This also improved over 12 months.

Finally, genetic analysis suggests that the GG allele of the TNF-alpha 308 single nucleotide polymorphism was associated with more cognitive complaints. It may enhance the patient’s vulnerability to cognitive complaints and cognitive dysfunction.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) said, "The strengths of this study include its prospective longitudinal design as well as the examination of potential biological mechanisms, including inflammation, genetic polymorphisms, and cerebral function."

She described examination of biomarkers and mechanisms as important in supportive care research, and expressed optimism that this type of research has only just begun.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Ganz and Dr. Mustian said they had no relevant relationships.

CHICAGO – The bone loss associated with aromatase inhibitors was significantly slowed with increasing supplements of vitamin D in a prospective cohort study of 156 postmenopausal women.

"The bone loss was less, the higher your vitamin D level was maintained," said session chair Dr. Thomas J. Smith of Massey Cancer Center of Virginia Commonwealth University. "This is one of the first intervention studies," he said. "And the results are pretty striking."

Dr. Sonia Servitja of Hospital del Mar in Barcelona, and colleagues, assessed the association between 25-hydroxy-vitamin D (25(OH)D) concentrations and bone loss at baseline, after 3 months of supplementation, and after 1 year, in patients receiving aromatase inhibitor therapy for early-stage breast cancer.

The 156 women in the prospective cohort had hormone-positive breast cancer and had initiated aromatase inhibitors from January 2006 to June 2009.

All patients received daily oral calcium (1 g) and vitamin D3 (800 IU). Patients with a baseline level of 25(OH)D less than 30 ng/mL received additional oral vitamin D3. The women were a mean age of 62 years with a mean age of menopause onset of 50 years.

The magnitude of the bone-loss prevention correlated with incremental increases in 25(OH)D concentrations.

Each 10-ng/mL increase in 25(OH)D concentration at 3 months appeared to be associated with a 0.55% decrease in bone loss, which was almost a third of the average bone loss experienced by these patients, according to the study findings, presented as a poster at the annual meeting of the American Society of Clinical Oncology.

The findings suggest that vitamin D supplementation at doses higher than the standard of 400 to 800 IU/day might be useful to minimize bone loss in women starting out on aromatase inhibitors and who are not eligible for bisphosphonate therapy according to current guidelines.

Patients who achieved 25(OH)D concentrations greater than or equal to 40 ng/mL at 3 months experienced significantly reduced bone loss. In addition, 25(OH)D increases at 3 months were protective for relative bone loss (adjusted beta for each quintile 1.01%, P value less than .001).

Dr. Servitja disclosed no relevant relationships. Dr. Smith disclosed research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – The bone loss associated with aromatase inhibitors was significantly slowed with increasing supplements of vitamin D in a prospective cohort study of 156 postmenopausal women.

"The bone loss was less, the higher your vitamin D level was maintained," said session chair Dr. Thomas J. Smith of Massey Cancer Center of Virginia Commonwealth University. "This is one of the first intervention studies," he said. "And the results are pretty striking."

Dr. Sonia Servitja of Hospital del Mar in Barcelona, and colleagues, assessed the association between 25-hydroxy-vitamin D (25(OH)D) concentrations and bone loss at baseline, after 3 months of supplementation, and after 1 year, in patients receiving aromatase inhibitor therapy for early-stage breast cancer.

The 156 women in the prospective cohort had hormone-positive breast cancer and had initiated aromatase inhibitors from January 2006 to June 2009.

All patients received daily oral calcium (1 g) and vitamin D3 (800 IU). Patients with a baseline level of 25(OH)D less than 30 ng/mL received additional oral vitamin D3. The women were a mean age of 62 years with a mean age of menopause onset of 50 years.

The magnitude of the bone-loss prevention correlated with incremental increases in 25(OH)D concentrations.

Each 10-ng/mL increase in 25(OH)D concentration at 3 months appeared to be associated with a 0.55% decrease in bone loss, which was almost a third of the average bone loss experienced by these patients, according to the study findings, presented as a poster at the annual meeting of the American Society of Clinical Oncology.

The findings suggest that vitamin D supplementation at doses higher than the standard of 400 to 800 IU/day might be useful to minimize bone loss in women starting out on aromatase inhibitors and who are not eligible for bisphosphonate therapy according to current guidelines.

Patients who achieved 25(OH)D concentrations greater than or equal to 40 ng/mL at 3 months experienced significantly reduced bone loss. In addition, 25(OH)D increases at 3 months were protective for relative bone loss (adjusted beta for each quintile 1.01%, P value less than .001).

Dr. Servitja disclosed no relevant relationships. Dr. Smith disclosed research funding from the American Cancer Society and the National Cancer Institute.

CHICAGO – The bone loss associated with aromatase inhibitors was significantly slowed with increasing supplements of vitamin D in a prospective cohort study of 156 postmenopausal women.

"The bone loss was less, the higher your vitamin D level was maintained," said session chair Dr. Thomas J. Smith of Massey Cancer Center of Virginia Commonwealth University. "This is one of the first intervention studies," he said. "And the results are pretty striking."

Dr. Sonia Servitja of Hospital del Mar in Barcelona, and colleagues, assessed the association between 25-hydroxy-vitamin D (25(OH)D) concentrations and bone loss at baseline, after 3 months of supplementation, and after 1 year, in patients receiving aromatase inhibitor therapy for early-stage breast cancer.

The 156 women in the prospective cohort had hormone-positive breast cancer and had initiated aromatase inhibitors from January 2006 to June 2009.

All patients received daily oral calcium (1 g) and vitamin D3 (800 IU). Patients with a baseline level of 25(OH)D less than 30 ng/mL received additional oral vitamin D3. The women were a mean age of 62 years with a mean age of menopause onset of 50 years.

The magnitude of the bone-loss prevention correlated with incremental increases in 25(OH)D concentrations.

Each 10-ng/mL increase in 25(OH)D concentration at 3 months appeared to be associated with a 0.55% decrease in bone loss, which was almost a third of the average bone loss experienced by these patients, according to the study findings, presented as a poster at the annual meeting of the American Society of Clinical Oncology.

The findings suggest that vitamin D supplementation at doses higher than the standard of 400 to 800 IU/day might be useful to minimize bone loss in women starting out on aromatase inhibitors and who are not eligible for bisphosphonate therapy according to current guidelines.

Patients who achieved 25(OH)D concentrations greater than or equal to 40 ng/mL at 3 months experienced significantly reduced bone loss. In addition, 25(OH)D increases at 3 months were protective for relative bone loss (adjusted beta for each quintile 1.01%, P value less than .001).

Dr. Servitja disclosed no relevant relationships. Dr. Smith disclosed research funding from the American Cancer Society and the National Cancer Institute.

Report prepared by Matt Stenger

The selective estrogen-receptor modulators tamoxifen and raloxifene (Evista) are available for chemoprevention of breast cancer in women at increased risk of disease but are rarely used due to fears of serious adverse effects; there is an increased risk of endometrial cancer with tamoxifen and an increased risk of thromboembolism with both agents. The aromatase inhibitor exemestane (Aromasin) was recently shown to reduce the risk of invasive cancer in women at moderate risk, with no serious toxic effects and minimal changes in quality of life (QOL).1

In a double-blind trial, 4,560 postmenopausal women aged 35 years or older who were at moderate risk of breast cancer were randomized to receive exemestane (25 mg/day; n = 2,285) or placebo (n = 2,275).1 Patients had to have at least one of the following risk factors: age ≥ 60 years, Gail 5-year risk score (chance in 100 of developing invasive breast cancer) > 1.66%, prior atypical ductal hyperplasia (ADH) or lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS) treated with mastectomy. The primary endpoint of the trial was incidence of invasive breast cancer, with the trial being designed to detect a 65% relative reduction in risk with exemestane. The trial was event-driven, with patients continuing to receive study treatment for a planned maximum duration of 5 years or until occurrence of a breast event, neoplastic disease, cardiovascular event, or unacceptable toxicity.

The two study groups were well matched for baseline characteristics and risk factors. The median age was 62.5 years in the exemestane group vs 62.4 years in the placebo group, with 67.6% vs 69.1% being ≥ 60 years of age. The median body mass index values were 27.9 vs 28.1 kg/m2. The Gail model score was > 1.66% in 40.7% vs 39.8%; 48.8% vs 49.5% were aged ≥ 60 years (as a risk factor); 8.1% vs 8.3% had ADH, ALH, or LCIS on biopsy; and 2.5% vs 2.5% had DCIS treated with mastectomy. The median Gail score was 2.3% in both groups, with 57.8% vs 57.1% having a score > 2.0%. Prior use of menopausal hormone therapy; bone mineral density; history of clinical fracture; cardiovascular risk factors; and use of bisphosphonates, lipid-lowering drugs, and cardiovascular drugs were similar in the two groups. At the time of the clinical data cutoff, 33% of women randomized to receive exemestane and 29% of those randomized to receive placebo were no longer taking the study medication. About 5% in each group had completed treatment. The primary reason for discontinuation of treatment was toxicity, which resulted in discontinuation in 15.4% of exemestane recipients and 10.8% of placebo recipients (P < 0.0001). Patient refusal of treatment resulted in discontinuation in 6.9% vs 6.0% (P = not significant).

At a median follow-up of 35 months, invasive breast cancer had occurred in 11 exemestane recipients and 32 placebo recipients, representing a significant 65% reduction in annual incidence with exemestane(0.19% vs 0.55%; hazard ratio [HR], 0.35; P = 0.002; Figure 1). Exemestane was also associated with a lower incidence in the combined endpoint of invasive breast cancer or DCIS (20 vs 44 cases), with a significant 53% reduction in annual incidence (0.35% vs 0.77%; HR, 0.47; P = 0.004). Fewer cases of DCIS (9 vs 14) and the combined endpoint of ADH, ALH, or LCIS (4 vs 11 cases) occurred in the exemestane group, although the reduction in annual incidence of these outcomes did not reach statistical significance (0.16% vs 0.24%; HR, 0.65; P = 0.31 for DCIS; 0.07% vs 0.20%; HR, 0.36; P = 0.08 for ADH, ALH, or LCIS). Exemestane appeared to demonstrate consistent superiority over placebo in the subgroups included in the planned subgroup analysis (Figure 1). The number needed to treat to prevent 1 case of invasive breast cancer with exemestane was 94 over 3 years and 26 over 5 years (although few women had completed 5 years of therapy at data cutoff).

Adverse events of any grade were slightly more common with exemestane (88% vs 85%; P = 0.003). By grade, 21% vs 25% were grade 1; 42% vs 39% were grade 2; 24% vs 19% were grade 3; and 1% vs 1% were grade 4. Table 1 shows the incidence of adverse events that occurred in 5% or more of women, with a difference between groups of 1% or more, and the incidence of toxicities specified as secondary endpoints. Although there were statistically significant differences between groups for some adverse events, the absolute percentage differences were usually small. Menopausal symptoms were frequent and somewhat more common with exemestane. The most frequent adverse events were hot flashes (40% vs 32%; P < 0.001) and joint pain (30% vs 27%; P = 0.04); arthritis was also more common with exemestane (11% vs 9%; P = 0.01). There were no differences between groups in clinical fracture rates, new diagnoses of osteoporosis, new prescriptions for bisphosphonates, cardiovascular events, or rates of other cancers or time to detection of other cancers. There were 19 deaths in each group, with causes consisting of breast cancer in 1 exemestane recipient vs 0 placebo recipients, other cancers in 10 patients vs 12 patients, cardiovascular causes in 5 vs 4, and other causes in 3 vs 3. None of the deaths was considered treatment-related.

Health-related and menopausespecific QOL were assessed by the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and the Menopause-Specific QOL questionnaire. When distributions of worsened, stable, and improved scores were compared, no differences in health-related QOL between groups were found. Women taking exemestane had an overall 7% worsened menopause-related QOL compared with those taking placebo.

Reference
1. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.

COMMENTARY

An aromatase inhibitor for breast cancer prevention: a promising option with barriers to resolve

D. Lawrence Wickerham, MD, Drexel University College of Medicine, Philadelphia, PA

The first results of the National Cancer Institute of Canada Clinical Trials Group (NCIC–CTG) MAP-3 trial, a randomized doubleblind placebo-controlled study of the aromatase inhibitor (AI) exemestane, was presented at the June 2011 meeting of the American Society of Oncology1 and was published in the New England Journal of Medicine.2 They represent good news for postmenopausal women at increased risk for developing breast cancer.

With a median follow-up of 35 months, the exemestane-treated women had a 65% (0.19% vs 0.55%; hazard ratio, 0.35; 95% confidence interval, 0.18 to 0.70; P = 0.002) reduction in the incidence of invasive breast cancer. A total of 4,560 postmenopausal women from the United States, Canada, Spain, and France entered this study between 2004 and 2010. All the women were at increased risk, which was determined based on age 60 years or older, prior breast biopsy showing atypical hyperplasia or lobular carcinoma in situ (LCIS), prior ductal carcinoma in situ (DCIS) treated by mastectomy, or a Gail model risk score of greater than 1.66% of developing breast cancer over the next 5 years.

Concerns and barriers amid the good news
Although I have heard my colleagues express some concerns about the trial results, I find most of their issues to be relatively minor. The median follow-up is only about 3 years, and relatively few of the trial participants have completed 5 years of therapy. However, the results are highly statistically significant and are in keeping with the data in adjuvant therapy trials, where the AIs appear to have a durable benefit in reducing new primary cancers of the opposite breast. At the time of analysis, only 43 invasive breast cancers had been diagnosed— 11 in the exemestane-treated group and 32 in the placebo group.

With the estimated reduction in invasive breast cancer of 65%, again estimated from treatment trials and compared with an untreated control, it takes relatively few events to confirm the reduction in invasive breast cancer, which was the primary endpoint. The women were carefully followed and had annual mammograms. The cancers that did occur in both groups were small, early-stage tumors, making a survival benefit almost impossible to document; however, the study was not designed to demonstrate such a finding.

In addition, the treatment assignments were unblinded, the women were informed of their current treatment, and the placebo group was offered the opportunity to cross over to exemestane. These actions make follow-up analyses less meaningful, but the study officials should be applauded for this approach. Although individuals enter trials such as MAP- 3 with the hope that it will benefit them, they understand that if new information concerning their care options becomes available, they will be informed.

There will be barriers to the routine use of exemestane for risk reduction. First, it has not yet been approved for this use by the US Food and Drug Administration, so insurance coverage may not apply. The drug is scheduled to become available generically in the near future, but it currently costs $300-plus per month.

Second, AIs reduce estrogen levels in postmenopausal women to almost zero; that is an effective way to treat and now prevent breast cancer. However, AIs are associated with potential side effects and toxicities, which can be a barrier to their use. Use of AIs can reduce bone density and may result in bone fractures. In MAP-3, bone density measures were obtained at study entry but not routinely during the trial. During treatment, reports of a diagnosis of osteoporosis were balanced in both groups, and fracture rates were similar. Here, the short follow-up and patient selection may have been factors. With prolonged use of AIs, the bone loss can be cumulative. The development of osteoporosis in women who start with normal bone density is low, but for women who already have lowbone mass, other prevention options may be a better first choice. Following AI-treated women with periodic bone density studies and the use of bisphosphonates to blunt the bone impact is an additional approach but further adds to the cost of treatment.

Third, the biggest problem with exemestane may be that to obtain the 65% risk reduction, the drug must be taken on a daily basis. Among the most common side effects of the AIs are troubling arthralgias and myalgias; these problems are the most common reason for women discontinuing AIs during the treatment of breast cancer, and in MAP-3, almost one-third of the exemestane-treated women had stopped taking their medication. That fact does not impact the trial results, which achieved the risk reduction despite the drop-offs, but for those women who stop their medication early, it is unlikely they will achieve substantial risk reduction. In addition, medication adherence within trials is often better than in the real world, due to patients volunteering and being committed to the trial plus the trial investigators monitoring and encouraging adherence. Similar adherence rates can be achieved outside research studies, but they require effort and reinforcement at each follow-up visit.

Patients with DCIS
Participants with a history of DCIS treated by mastectomy were eligible for MAP-3 and appear to have a risk reduction benefit similar in magnitude to other trial participants. However, it would be premature to begin to use exemestane in the adjuvant treatment of patients with receptor-positive DCIS. That step should await the results of two adjuvant AI trials in DCIS that have completed accrual—IBIS II (International Breast Cancer Intervention Study) and NSABP (National Surgical Adjuvant Breast and Bowel Project) B-35—both of which compare anastrozole with tamoxifen in patients with receptor-positive DCIS treated by lumpectomy. Exemestane did reduce the number of cases of DCIS that were diagnosed, although that reduction did not reach statistical significance. However, given the overall sample size and the median follow-up, the lack of significance is not surprising and is unlikely to be clinically important.

Overall, the MAP-3 results are impressive and demonstrate that exemestane should be included with tamoxifen and raloxifene as an effective option for breast cancer prevention.

References
1. Goss PE, Ingle JN, Ales-Martinez J, et al. Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—a randomized, placebo-controlled clinical trial. J Clin Oncol 2011;29:LBA504.
2. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.

WHAT'S NEW, WHAT'S IMPORTANT
Jame Abraham, MD, Editor

Breast cancer is the most common cancer in women. The National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 studies both showed that selective inhibition of estrogen receptors with such drugs as tamoxifen or raloxifene (Evista) can decrease the incidence of breast cancer by about 50% in women who are at high risk of developing breast cancer based on the Gail risk model. Several studies in postmenopausal patients have shown that aromatase inhibitors are effective agents for the treatment of breast cancer when used in the metastatic, neoadjuvant, or adjuvant setting. The study by Paul Goss and colleagues described here has shown, for the first time, that exemestane, a steroidal aromatize inhibitor, can decrease the incidence of breast cancer by 65% in high-risk, postmenopausal patients.

So what do we tell our patients? In postmenopausal women who are at high risk of developing breast cancer, per the Gail risk criteria, we now have three drugs available: tamoxifen, raloxifene, and exemestane. When we consider any preventive intervention, we need to look at both the risk and the benefit expected. Because the median followup in the Goss study was only 3 years, the long-term side effects of exemestane are not well established in this setting.

Report prepared by Matt Stenger

The selective estrogen-receptor modulators tamoxifen and raloxifene (Evista) are available for chemoprevention of breast cancer in women at increased risk of disease but are rarely used due to fears of serious adverse effects; there is an increased risk of endometrial cancer with tamoxifen and an increased risk of thromboembolism with both agents. The aromatase inhibitor exemestane (Aromasin) was recently shown to reduce the risk of invasive cancer in women at moderate risk, with no serious toxic effects and minimal changes in quality of life (QOL).1

In a double-blind trial, 4,560 postmenopausal women aged 35 years or older who were at moderate risk of breast cancer were randomized to receive exemestane (25 mg/day; n = 2,285) or placebo (n = 2,275).1 Patients had to have at least one of the following risk factors: age ≥ 60 years, Gail 5-year risk score (chance in 100 of developing invasive breast cancer) > 1.66%, prior atypical ductal hyperplasia (ADH) or lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS) treated with mastectomy. The primary endpoint of the trial was incidence of invasive breast cancer, with the trial being designed to detect a 65% relative reduction in risk with exemestane. The trial was event-driven, with patients continuing to receive study treatment for a planned maximum duration of 5 years or until occurrence of a breast event, neoplastic disease, cardiovascular event, or unacceptable toxicity.

The two study groups were well matched for baseline characteristics and risk factors. The median age was 62.5 years in the exemestane group vs 62.4 years in the placebo group, with 67.6% vs 69.1% being ≥ 60 years of age. The median body mass index values were 27.9 vs 28.1 kg/m2. The Gail model score was > 1.66% in 40.7% vs 39.8%; 48.8% vs 49.5% were aged ≥ 60 years (as a risk factor); 8.1% vs 8.3% had ADH, ALH, or LCIS on biopsy; and 2.5% vs 2.5% had DCIS treated with mastectomy. The median Gail score was 2.3% in both groups, with 57.8% vs 57.1% having a score > 2.0%. Prior use of menopausal hormone therapy; bone mineral density; history of clinical fracture; cardiovascular risk factors; and use of bisphosphonates, lipid-lowering drugs, and cardiovascular drugs were similar in the two groups. At the time of the clinical data cutoff, 33% of women randomized to receive exemestane and 29% of those randomized to receive placebo were no longer taking the study medication. About 5% in each group had completed treatment. The primary reason for discontinuation of treatment was toxicity, which resulted in discontinuation in 15.4% of exemestane recipients and 10.8% of placebo recipients (P < 0.0001). Patient refusal of treatment resulted in discontinuation in 6.9% vs 6.0% (P = not significant).

At a median follow-up of 35 months, invasive breast cancer had occurred in 11 exemestane recipients and 32 placebo recipients, representing a significant 65% reduction in annual incidence with exemestane(0.19% vs 0.55%; hazard ratio [HR], 0.35; P = 0.002; Figure 1). Exemestane was also associated with a lower incidence in the combined endpoint of invasive breast cancer or DCIS (20 vs 44 cases), with a significant 53% reduction in annual incidence (0.35% vs 0.77%; HR, 0.47; P = 0.004). Fewer cases of DCIS (9 vs 14) and the combined endpoint of ADH, ALH, or LCIS (4 vs 11 cases) occurred in the exemestane group, although the reduction in annual incidence of these outcomes did not reach statistical significance (0.16% vs 0.24%; HR, 0.65; P = 0.31 for DCIS; 0.07% vs 0.20%; HR, 0.36; P = 0.08 for ADH, ALH, or LCIS). Exemestane appeared to demonstrate consistent superiority over placebo in the subgroups included in the planned subgroup analysis (Figure 1). The number needed to treat to prevent 1 case of invasive breast cancer with exemestane was 94 over 3 years and 26 over 5 years (although few women had completed 5 years of therapy at data cutoff).

Adverse events of any grade were slightly more common with exemestane (88% vs 85%; P = 0.003). By grade, 21% vs 25% were grade 1; 42% vs 39% were grade 2; 24% vs 19% were grade 3; and 1% vs 1% were grade 4. Table 1 shows the incidence of adverse events that occurred in 5% or more of women, with a difference between groups of 1% or more, and the incidence of toxicities specified as secondary endpoints. Although there were statistically significant differences between groups for some adverse events, the absolute percentage differences were usually small. Menopausal symptoms were frequent and somewhat more common with exemestane. The most frequent adverse events were hot flashes (40% vs 32%; P < 0.001) and joint pain (30% vs 27%; P = 0.04); arthritis was also more common with exemestane (11% vs 9%; P = 0.01). There were no differences between groups in clinical fracture rates, new diagnoses of osteoporosis, new prescriptions for bisphosphonates, cardiovascular events, or rates of other cancers or time to detection of other cancers. There were 19 deaths in each group, with causes consisting of breast cancer in 1 exemestane recipient vs 0 placebo recipients, other cancers in 10 patients vs 12 patients, cardiovascular causes in 5 vs 4, and other causes in 3 vs 3. None of the deaths was considered treatment-related.

Health-related and menopausespecific QOL were assessed by the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and the Menopause-Specific QOL questionnaire. When distributions of worsened, stable, and improved scores were compared, no differences in health-related QOL between groups were found. Women taking exemestane had an overall 7% worsened menopause-related QOL compared with those taking placebo.

Reference
1. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.

COMMENTARY

An aromatase inhibitor for breast cancer prevention: a promising option with barriers to resolve

D. Lawrence Wickerham, MD, Drexel University College of Medicine, Philadelphia, PA

The first results of the National Cancer Institute of Canada Clinical Trials Group (NCIC–CTG) MAP-3 trial, a randomized doubleblind placebo-controlled study of the aromatase inhibitor (AI) exemestane, was presented at the June 2011 meeting of the American Society of Oncology1 and was published in the New England Journal of Medicine.2 They represent good news for postmenopausal women at increased risk for developing breast cancer.

With a median follow-up of 35 months, the exemestane-treated women had a 65% (0.19% vs 0.55%; hazard ratio, 0.35; 95% confidence interval, 0.18 to 0.70; P = 0.002) reduction in the incidence of invasive breast cancer. A total of 4,560 postmenopausal women from the United States, Canada, Spain, and France entered this study between 2004 and 2010. All the women were at increased risk, which was determined based on age 60 years or older, prior breast biopsy showing atypical hyperplasia or lobular carcinoma in situ (LCIS), prior ductal carcinoma in situ (DCIS) treated by mastectomy, or a Gail model risk score of greater than 1.66% of developing breast cancer over the next 5 years.

Concerns and barriers amid the good news
Although I have heard my colleagues express some concerns about the trial results, I find most of their issues to be relatively minor. The median follow-up is only about 3 years, and relatively few of the trial participants have completed 5 years of therapy. However, the results are highly statistically significant and are in keeping with the data in adjuvant therapy trials, where the AIs appear to have a durable benefit in reducing new primary cancers of the opposite breast. At the time of analysis, only 43 invasive breast cancers had been diagnosed— 11 in the exemestane-treated group and 32 in the placebo group.

With the estimated reduction in invasive breast cancer of 65%, again estimated from treatment trials and compared with an untreated control, it takes relatively few events to confirm the reduction in invasive breast cancer, which was the primary endpoint. The women were carefully followed and had annual mammograms. The cancers that did occur in both groups were small, early-stage tumors, making a survival benefit almost impossible to document; however, the study was not designed to demonstrate such a finding.

In addition, the treatment assignments were unblinded, the women were informed of their current treatment, and the placebo group was offered the opportunity to cross over to exemestane. These actions make follow-up analyses less meaningful, but the study officials should be applauded for this approach. Although individuals enter trials such as MAP- 3 with the hope that it will benefit them, they understand that if new information concerning their care options becomes available, they will be informed.

There will be barriers to the routine use of exemestane for risk reduction. First, it has not yet been approved for this use by the US Food and Drug Administration, so insurance coverage may not apply. The drug is scheduled to become available generically in the near future, but it currently costs $300-plus per month.

Second, AIs reduce estrogen levels in postmenopausal women to almost zero; that is an effective way to treat and now prevent breast cancer. However, AIs are associated with potential side effects and toxicities, which can be a barrier to their use. Use of AIs can reduce bone density and may result in bone fractures. In MAP-3, bone density measures were obtained at study entry but not routinely during the trial. During treatment, reports of a diagnosis of osteoporosis were balanced in both groups, and fracture rates were similar. Here, the short follow-up and patient selection may have been factors. With prolonged use of AIs, the bone loss can be cumulative. The development of osteoporosis in women who start with normal bone density is low, but for women who already have lowbone mass, other prevention options may be a better first choice. Following AI-treated women with periodic bone density studies and the use of bisphosphonates to blunt the bone impact is an additional approach but further adds to the cost of treatment.

Third, the biggest problem with exemestane may be that to obtain the 65% risk reduction, the drug must be taken on a daily basis. Among the most common side effects of the AIs are troubling arthralgias and myalgias; these problems are the most common reason for women discontinuing AIs during the treatment of breast cancer, and in MAP-3, almost one-third of the exemestane-treated women had stopped taking their medication. That fact does not impact the trial results, which achieved the risk reduction despite the drop-offs, but for those women who stop their medication early, it is unlikely they will achieve substantial risk reduction. In addition, medication adherence within trials is often better than in the real world, due to patients volunteering and being committed to the trial plus the trial investigators monitoring and encouraging adherence. Similar adherence rates can be achieved outside research studies, but they require effort and reinforcement at each follow-up visit.

Patients with DCIS
Participants with a history of DCIS treated by mastectomy were eligible for MAP-3 and appear to have a risk reduction benefit similar in magnitude to other trial participants. However, it would be premature to begin to use exemestane in the adjuvant treatment of patients with receptor-positive DCIS. That step should await the results of two adjuvant AI trials in DCIS that have completed accrual—IBIS II (International Breast Cancer Intervention Study) and NSABP (National Surgical Adjuvant Breast and Bowel Project) B-35—both of which compare anastrozole with tamoxifen in patients with receptor-positive DCIS treated by lumpectomy. Exemestane did reduce the number of cases of DCIS that were diagnosed, although that reduction did not reach statistical significance. However, given the overall sample size and the median follow-up, the lack of significance is not surprising and is unlikely to be clinically important.

Overall, the MAP-3 results are impressive and demonstrate that exemestane should be included with tamoxifen and raloxifene as an effective option for breast cancer prevention.

References
1. Goss PE, Ingle JN, Ales-Martinez J, et al. Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—a randomized, placebo-controlled clinical trial. J Clin Oncol 2011;29:LBA504.
2. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.

WHAT'S NEW, WHAT'S IMPORTANT
Jame Abraham, MD, Editor

Breast cancer is the most common cancer in women. The National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 studies both showed that selective inhibition of estrogen receptors with such drugs as tamoxifen or raloxifene (Evista) can decrease the incidence of breast cancer by about 50% in women who are at high risk of developing breast cancer based on the Gail risk model. Several studies in postmenopausal patients have shown that aromatase inhibitors are effective agents for the treatment of breast cancer when used in the metastatic, neoadjuvant, or adjuvant setting. The study by Paul Goss and colleagues described here has shown, for the first time, that exemestane, a steroidal aromatize inhibitor, can decrease the incidence of breast cancer by 65% in high-risk, postmenopausal patients.

So what do we tell our patients? In postmenopausal women who are at high risk of developing breast cancer, per the Gail risk criteria, we now have three drugs available: tamoxifen, raloxifene, and exemestane. When we consider any preventive intervention, we need to look at both the risk and the benefit expected. Because the median followup in the Goss study was only 3 years, the long-term side effects of exemestane are not well established in this setting.

Report prepared by Matt Stenger

The selective estrogen-receptor modulators tamoxifen and raloxifene (Evista) are available for chemoprevention of breast cancer in women at increased risk of disease but are rarely used due to fears of serious adverse effects; there is an increased risk of endometrial cancer with tamoxifen and an increased risk of thromboembolism with both agents. The aromatase inhibitor exemestane (Aromasin) was recently shown to reduce the risk of invasive cancer in women at moderate risk, with no serious toxic effects and minimal changes in quality of life (QOL).1

In a double-blind trial, 4,560 postmenopausal women aged 35 years or older who were at moderate risk of breast cancer were randomized to receive exemestane (25 mg/day; n = 2,285) or placebo (n = 2,275).1 Patients had to have at least one of the following risk factors: age ≥ 60 years, Gail 5-year risk score (chance in 100 of developing invasive breast cancer) > 1.66%, prior atypical ductal hyperplasia (ADH) or lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS) treated with mastectomy. The primary endpoint of the trial was incidence of invasive breast cancer, with the trial being designed to detect a 65% relative reduction in risk with exemestane. The trial was event-driven, with patients continuing to receive study treatment for a planned maximum duration of 5 years or until occurrence of a breast event, neoplastic disease, cardiovascular event, or unacceptable toxicity.

The two study groups were well matched for baseline characteristics and risk factors. The median age was 62.5 years in the exemestane group vs 62.4 years in the placebo group, with 67.6% vs 69.1% being ≥ 60 years of age. The median body mass index values were 27.9 vs 28.1 kg/m2. The Gail model score was > 1.66% in 40.7% vs 39.8%; 48.8% vs 49.5% were aged ≥ 60 years (as a risk factor); 8.1% vs 8.3% had ADH, ALH, or LCIS on biopsy; and 2.5% vs 2.5% had DCIS treated with mastectomy. The median Gail score was 2.3% in both groups, with 57.8% vs 57.1% having a score > 2.0%. Prior use of menopausal hormone therapy; bone mineral density; history of clinical fracture; cardiovascular risk factors; and use of bisphosphonates, lipid-lowering drugs, and cardiovascular drugs were similar in the two groups. At the time of the clinical data cutoff, 33% of women randomized to receive exemestane and 29% of those randomized to receive placebo were no longer taking the study medication. About 5% in each group had completed treatment. The primary reason for discontinuation of treatment was toxicity, which resulted in discontinuation in 15.4% of exemestane recipients and 10.8% of placebo recipients (P < 0.0001). Patient refusal of treatment resulted in discontinuation in 6.9% vs 6.0% (P = not significant).

At a median follow-up of 35 months, invasive breast cancer had occurred in 11 exemestane recipients and 32 placebo recipients, representing a significant 65% reduction in annual incidence with exemestane(0.19% vs 0.55%; hazard ratio [HR], 0.35; P = 0.002; Figure 1). Exemestane was also associated with a lower incidence in the combined endpoint of invasive breast cancer or DCIS (20 vs 44 cases), with a significant 53% reduction in annual incidence (0.35% vs 0.77%; HR, 0.47; P = 0.004). Fewer cases of DCIS (9 vs 14) and the combined endpoint of ADH, ALH, or LCIS (4 vs 11 cases) occurred in the exemestane group, although the reduction in annual incidence of these outcomes did not reach statistical significance (0.16% vs 0.24%; HR, 0.65; P = 0.31 for DCIS; 0.07% vs 0.20%; HR, 0.36; P = 0.08 for ADH, ALH, or LCIS). Exemestane appeared to demonstrate consistent superiority over placebo in the subgroups included in the planned subgroup analysis (Figure 1). The number needed to treat to prevent 1 case of invasive breast cancer with exemestane was 94 over 3 years and 26 over 5 years (although few women had completed 5 years of therapy at data cutoff).

Adverse events of any grade were slightly more common with exemestane (88% vs 85%; P = 0.003). By grade, 21% vs 25% were grade 1; 42% vs 39% were grade 2; 24% vs 19% were grade 3; and 1% vs 1% were grade 4. Table 1 shows the incidence of adverse events that occurred in 5% or more of women, with a difference between groups of 1% or more, and the incidence of toxicities specified as secondary endpoints. Although there were statistically significant differences between groups for some adverse events, the absolute percentage differences were usually small. Menopausal symptoms were frequent and somewhat more common with exemestane. The most frequent adverse events were hot flashes (40% vs 32%; P < 0.001) and joint pain (30% vs 27%; P = 0.04); arthritis was also more common with exemestane (11% vs 9%; P = 0.01). There were no differences between groups in clinical fracture rates, new diagnoses of osteoporosis, new prescriptions for bisphosphonates, cardiovascular events, or rates of other cancers or time to detection of other cancers. There were 19 deaths in each group, with causes consisting of breast cancer in 1 exemestane recipient vs 0 placebo recipients, other cancers in 10 patients vs 12 patients, cardiovascular causes in 5 vs 4, and other causes in 3 vs 3. None of the deaths was considered treatment-related.

Health-related and menopausespecific QOL were assessed by the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and the Menopause-Specific QOL questionnaire. When distributions of worsened, stable, and improved scores were compared, no differences in health-related QOL between groups were found. Women taking exemestane had an overall 7% worsened menopause-related QOL compared with those taking placebo.

Reference
1. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.

COMMENTARY

An aromatase inhibitor for breast cancer prevention: a promising option with barriers to resolve

D. Lawrence Wickerham, MD, Drexel University College of Medicine, Philadelphia, PA

The first results of the National Cancer Institute of Canada Clinical Trials Group (NCIC–CTG) MAP-3 trial, a randomized doubleblind placebo-controlled study of the aromatase inhibitor (AI) exemestane, was presented at the June 2011 meeting of the American Society of Oncology1 and was published in the New England Journal of Medicine.2 They represent good news for postmenopausal women at increased risk for developing breast cancer.

With a median follow-up of 35 months, the exemestane-treated women had a 65% (0.19% vs 0.55%; hazard ratio, 0.35; 95% confidence interval, 0.18 to 0.70; P = 0.002) reduction in the incidence of invasive breast cancer. A total of 4,560 postmenopausal women from the United States, Canada, Spain, and France entered this study between 2004 and 2010. All the women were at increased risk, which was determined based on age 60 years or older, prior breast biopsy showing atypical hyperplasia or lobular carcinoma in situ (LCIS), prior ductal carcinoma in situ (DCIS) treated by mastectomy, or a Gail model risk score of greater than 1.66% of developing breast cancer over the next 5 years.

Concerns and barriers amid the good news
Although I have heard my colleagues express some concerns about the trial results, I find most of their issues to be relatively minor. The median follow-up is only about 3 years, and relatively few of the trial participants have completed 5 years of therapy. However, the results are highly statistically significant and are in keeping with the data in adjuvant therapy trials, where the AIs appear to have a durable benefit in reducing new primary cancers of the opposite breast. At the time of analysis, only 43 invasive breast cancers had been diagnosed— 11 in the exemestane-treated group and 32 in the placebo group.

With the estimated reduction in invasive breast cancer of 65%, again estimated from treatment trials and compared with an untreated control, it takes relatively few events to confirm the reduction in invasive breast cancer, which was the primary endpoint. The women were carefully followed and had annual mammograms. The cancers that did occur in both groups were small, early-stage tumors, making a survival benefit almost impossible to document; however, the study was not designed to demonstrate such a finding.

In addition, the treatment assignments were unblinded, the women were informed of their current treatment, and the placebo group was offered the opportunity to cross over to exemestane. These actions make follow-up analyses less meaningful, but the study officials should be applauded for this approach. Although individuals enter trials such as MAP- 3 with the hope that it will benefit them, they understand that if new information concerning their care options becomes available, they will be informed.

There will be barriers to the routine use of exemestane for risk reduction. First, it has not yet been approved for this use by the US Food and Drug Administration, so insurance coverage may not apply. The drug is scheduled to become available generically in the near future, but it currently costs $300-plus per month.

Second, AIs reduce estrogen levels in postmenopausal women to almost zero; that is an effective way to treat and now prevent breast cancer. However, AIs are associated with potential side effects and toxicities, which can be a barrier to their use. Use of AIs can reduce bone density and may result in bone fractures. In MAP-3, bone density measures were obtained at study entry but not routinely during the trial. During treatment, reports of a diagnosis of osteoporosis were balanced in both groups, and fracture rates were similar. Here, the short follow-up and patient selection may have been factors. With prolonged use of AIs, the bone loss can be cumulative. The development of osteoporosis in women who start with normal bone density is low, but for women who already have lowbone mass, other prevention options may be a better first choice. Following AI-treated women with periodic bone density studies and the use of bisphosphonates to blunt the bone impact is an additional approach but further adds to the cost of treatment.

Third, the biggest problem with exemestane may be that to obtain the 65% risk reduction, the drug must be taken on a daily basis. Among the most common side effects of the AIs are troubling arthralgias and myalgias; these problems are the most common reason for women discontinuing AIs during the treatment of breast cancer, and in MAP-3, almost one-third of the exemestane-treated women had stopped taking their medication. That fact does not impact the trial results, which achieved the risk reduction despite the drop-offs, but for those women who stop their medication early, it is unlikely they will achieve substantial risk reduction. In addition, medication adherence within trials is often better than in the real world, due to patients volunteering and being committed to the trial plus the trial investigators monitoring and encouraging adherence. Similar adherence rates can be achieved outside research studies, but they require effort and reinforcement at each follow-up visit.

Patients with DCIS
Participants with a history of DCIS treated by mastectomy were eligible for MAP-3 and appear to have a risk reduction benefit similar in magnitude to other trial participants. However, it would be premature to begin to use exemestane in the adjuvant treatment of patients with receptor-positive DCIS. That step should await the results of two adjuvant AI trials in DCIS that have completed accrual—IBIS II (International Breast Cancer Intervention Study) and NSABP (National Surgical Adjuvant Breast and Bowel Project) B-35—both of which compare anastrozole with tamoxifen in patients with receptor-positive DCIS treated by lumpectomy. Exemestane did reduce the number of cases of DCIS that were diagnosed, although that reduction did not reach statistical significance. However, given the overall sample size and the median follow-up, the lack of significance is not surprising and is unlikely to be clinically important.

Overall, the MAP-3 results are impressive and demonstrate that exemestane should be included with tamoxifen and raloxifene as an effective option for breast cancer prevention.

References
1. Goss PE, Ingle JN, Ales-Martinez J, et al. Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—a randomized, placebo-controlled clinical trial. J Clin Oncol 2011;29:LBA504.
2. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.

WHAT'S NEW, WHAT'S IMPORTANT
Jame Abraham, MD, Editor

Breast cancer is the most common cancer in women. The National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 studies both showed that selective inhibition of estrogen receptors with such drugs as tamoxifen or raloxifene (Evista) can decrease the incidence of breast cancer by about 50% in women who are at high risk of developing breast cancer based on the Gail risk model. Several studies in postmenopausal patients have shown that aromatase inhibitors are effective agents for the treatment of breast cancer when used in the metastatic, neoadjuvant, or adjuvant setting. The study by Paul Goss and colleagues described here has shown, for the first time, that exemestane, a steroidal aromatize inhibitor, can decrease the incidence of breast cancer by 65% in high-risk, postmenopausal patients.

So what do we tell our patients? In postmenopausal women who are at high risk of developing breast cancer, per the Gail risk criteria, we now have three drugs available: tamoxifen, raloxifene, and exemestane. When we consider any preventive intervention, we need to look at both the risk and the benefit expected. Because the median followup in the Goss study was only 3 years, the long-term side effects of exemestane are not well established in this setting.

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.

Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.

Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.

The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.

“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.

Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.

And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.

With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.

Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.

Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.

The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.

But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.

None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.

At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.

The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.

The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.

But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.

Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.

Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.

The company issued a statement after the meeting expressing its disappointment and avowing that it remains “ready to collaborate with the FDA to find a solution that is in the best interest of patients who need Avastin.”

On the second day of the Avastin hearing at the Food and Drug Administration, Genentech officials took the podium and in a two-hour session argued why Avastin should be approved for metastatic breast cancer.

On the second day of the Avastin hearing at the Food and Drug Administration, Genentech officials took the podium and in a two-hour session argued why Avastin should be approved for metastatic breast cancer.

On the second day of the Avastin hearing at the Food and Drug Administration, Genentech officials took the podium and in a two-hour session argued why Avastin should be approved for metastatic breast cancer.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The second day of the Avastin hearing at the Food and Drug Administration has started. Following the FDA's presentation yesterday, representatives for Genentech will argue why the drug should be approved for breast cancer treatment. Following a question-and-answer session, the FDA's independent advisory board will announce its vote this afternoon.

Naseem S. Miller and Elizabeth Mechcatie contributed to this report.

The second day of the Avastin hearing at the Food and Drug Administration has started. Following the FDA's presentation yesterday, representatives for Genentech will argue why the drug should be approved for breast cancer treatment. Following a question-and-answer session, the FDA's independent advisory board will announce its vote this afternoon.

Naseem S. Miller and Elizabeth Mechcatie contributed to this report.

The second day of the Avastin hearing at the Food and Drug Administration has started. Following the FDA's presentation yesterday, representatives for Genentech will argue why the drug should be approved for breast cancer treatment. Following a question-and-answer session, the FDA's independent advisory board will announce its vote this afternoon.

Naseem S. Miller and Elizabeth Mechcatie contributed to this report.

The first day of the Food and Drug Administration’s hearing on Avastin (bevacizumab) came to an end with a question-and-answer session between FDA officials and representatives from Genentech, the maker of the drug.

Earlier in the day, the Center for Drug Evaluation and Research (CDER) presented its position and stood by its proposal to withdraw approval for the breast cancer indication for Avastin.

The first day of the Food and Drug Administration’s hearing on Avastin (bevacizumab) came to an end with a question-and-answer session between FDA officials and representatives from Genentech, the maker of the drug.

Earlier in the day, the Center for Drug Evaluation and Research (CDER) presented its position and stood by its proposal to withdraw approval for the breast cancer indication for Avastin.

The first day of the Food and Drug Administration’s hearing on Avastin (bevacizumab) came to an end with a question-and-answer session between FDA officials and representatives from Genentech, the maker of the drug.

Earlier in the day, the Center for Drug Evaluation and Research (CDER) presented its position and stood by its proposal to withdraw approval for the breast cancer indication for Avastin.

During a two-day meeting at the Food and Drug Administration offices outside of Washington, Genentech will provide evidence to support the company’s contention that the metastatic breast cancer approval of bevacizumab, in combination with paclitaxel, should not be withdrawn.

In December, the FDA proposed that the accelerated approval for this indication be pulled after two studies failed to show the magnitude of benefit on progression-free survival seen in an earlier study. Moreover, none of the trials showed an improvement in overall survival. 

In an unprecedented move, Genentech appealed the decision, and the FDA granted the company the hearing.

During a two-day meeting at the Food and Drug Administration offices outside of Washington, Genentech will provide evidence to support the company’s contention that the metastatic breast cancer approval of bevacizumab, in combination with paclitaxel, should not be withdrawn.

In December, the FDA proposed that the accelerated approval for this indication be pulled after two studies failed to show the magnitude of benefit on progression-free survival seen in an earlier study. Moreover, none of the trials showed an improvement in overall survival. 

In an unprecedented move, Genentech appealed the decision, and the FDA granted the company the hearing.

During a two-day meeting at the Food and Drug Administration offices outside of Washington, Genentech will provide evidence to support the company’s contention that the metastatic breast cancer approval of bevacizumab, in combination with paclitaxel, should not be withdrawn.

In December, the FDA proposed that the accelerated approval for this indication be pulled after two studies failed to show the magnitude of benefit on progression-free survival seen in an earlier study. Moreover, none of the trials showed an improvement in overall survival. 

In an unprecedented move, Genentech appealed the decision, and the FDA granted the company the hearing.