SABCS 2012

SAN ANTONIO – Some breast cancers categorized as HER2 negative by conventional testing harbor mutations that may still render them amenable to therapy targeting this receptor, researchers reported at the San Antonio Breast Cancer Symposium.

A team led by Dr. Ron Bose, of Washington University and the Siteman Cancer Center, St. Louis, compiled data from eight studies in which tissue from 1,499 breast cancers was sequenced.

Results showed that 25 cancers, or about 1.7%, had activating HER2 mutations. Most of these cancers did not have amplification of the HER2 gene and thus would be categorized as HER2 negative by conventional testing.

"We argue that mutation is an alternate mechanism to activate HER2 in breast cancer," he commented. "Patients with these mutations will be missed by current HER2 testing. Gene sequencing is required to identify these mutations."

The investigational tyrosine kinase inhibitor neratinib readily outperformed lapatinib (Tykerb) at inhibiting the growth of cells bearing the HER2 mutations, according to data presented at the meeting and recently published (Cancer Discov. 2012;3:1-14). The investigators are therefore planning a phase II trial of neratinib for metastatic HER2 gene amplification–negative, HER2 mutation–positive breast cancer.

"These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment," Dr. Bose maintained in a related press briefing. "If this trial is successful, we estimate that 4,000 women per year in the U.S. could benefit. Worldwide, that number could be five times as large."

He anticipates that the technological feasibility and cost of HER2 sequencing in clinical practice would be similar to those of sequencing for epidermal growth factor receptor (EGFR) mutations in lung cancer.

"Within the context of the clinical trial, we are specifically screening for HER2 mutations. But in the future, outside of a clinical trial setting, probably including HER2 in a panel of genes would be most cost effective," he elaborated. "If you compare to cost of treatment, a month of treatment with many of the chemotherapy drugs or with targeted inhibitors is in the thousands of dollars. So the cost of screening [for mutations] is much lower than that."

Dr. Kent Osborne, moderator of the press briefing and director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, characterized the research as "interesting" while adding that its usefulness may be limited at present.

"But what if these mutations occur in other cancers, now that Dr. Bose has identified them?" he said. "If you are a patient with that mutation, even though it’s pretty rare, that’s important to know for you. When we get into the era of personalized medicine, where we start doing these mutational analyses, ... there are going to be mutations that perhaps are contributing to the cancer and are pretty rare in the population, but are important for that particular patient."

"Some in the audience may remember the large trial in HER2-positive patients done by the National Surgical Adjuvant Breast and Bowel Project (NSABP). A few hundred of those patients on central review did not have HER2 amplification or overexpression, yet they seemed to have the same benefits from trastuzumab as did those [with HER2]," Dr. Osborne noted. "I guess at an incidence rate of 1% to 2%, [activating mutations don’t] explain all of those by any means, but I wonder if you could get those samples from the NSABP and screen them. They could be enriched for these mutations."

"That’s an excellent possibility," Dr. Bose replied. "We have had preliminary discussions with members of the NSABP. Now that the work is published, I think those discussions will go further."

When asked why neratinib was being used in the trial instead of trastuzumab (Herceptin), Dr. Bose said that in tissue culture, the former proved much more effective at inhibiting growth of cells harboring these mutations.

On a related note, a session attendee commented, "I am modestly concerned that you don’t have trastuzumab in your trial. And the reason is that I would expect trastuzumab to down-regulate this single-copy HER2 receptor and help neratinib. So have you done combinations of both preclinically to see whether it adds or not to neratinib?"

The investigators have done such in vitro work, Dr. Bose replied. "With trastuzumab alone, we see a partial growth suppression effect when you are looking at MCF-10A cells that bear these mutations. When we tried the combination, we did not see any benefit of adding trastuzumab on top of neratinib. But I would caution that this is with MCF-10A cells, and this is in tissue culture, where there are no immune effectors. We don’t know what the situation will be in actual patients."

Additional study results showed that all of the HER2 activating mutations were found only in the tumor and were thus somatic and not inherited, according to Dr. Bose, who disclosed having no conflicts of interest related to the research.

The mutations clustered in two areas of the HER2 gene: one area affecting the tyrosine kinase domain of the protein (seen in 68% of cases) and another area affecting the extracellular domain (seen in 20%).

Laboratory analyses indicated that the mutations were indeed being expressed at the RNA level, that those affecting the kinase domain of the protein were associated with increased kinase activity, and that the mutations spurred tumor growth in nude mice.

"The majority of these HER2 mutations are activating events that cause cancerous growth of the cells in the lab, meaning that they stimulate the function of HER2 or turn on HER2’s activity in an excessive or inappropriate manner," Dr. Bose summarized. "Thus, we feel they are highly likely to drive the growth of these human breast cancers in which they occur."

In sensitivity testing, the six cases having the L755S mutation were resistant to the tyrosine kinase inhibitor lapatinib but sensitive to neratinib, an irreversible pan-ErbB tyrosine kinase inhibitor.

In fact, neratinib showed greater effectiveness than lapatinib at inhibiting cell growth in all of the mutated tumors tested, with several hundred to several thousand times greater concentrations of lapatinib needed to achieve the same level of inhibition.

Dr. Bose disclosed having no relevant conflicts of interest.

SAN ANTONIO – Some breast cancers categorized as HER2 negative by conventional testing harbor mutations that may still render them amenable to therapy targeting this receptor, researchers reported at the San Antonio Breast Cancer Symposium.

A team led by Dr. Ron Bose, of Washington University and the Siteman Cancer Center, St. Louis, compiled data from eight studies in which tissue from 1,499 breast cancers was sequenced.

Results showed that 25 cancers, or about 1.7%, had activating HER2 mutations. Most of these cancers did not have amplification of the HER2 gene and thus would be categorized as HER2 negative by conventional testing.

"We argue that mutation is an alternate mechanism to activate HER2 in breast cancer," he commented. "Patients with these mutations will be missed by current HER2 testing. Gene sequencing is required to identify these mutations."

The investigational tyrosine kinase inhibitor neratinib readily outperformed lapatinib (Tykerb) at inhibiting the growth of cells bearing the HER2 mutations, according to data presented at the meeting and recently published (Cancer Discov. 2012;3:1-14). The investigators are therefore planning a phase II trial of neratinib for metastatic HER2 gene amplification–negative, HER2 mutation–positive breast cancer.

"These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment," Dr. Bose maintained in a related press briefing. "If this trial is successful, we estimate that 4,000 women per year in the U.S. could benefit. Worldwide, that number could be five times as large."

He anticipates that the technological feasibility and cost of HER2 sequencing in clinical practice would be similar to those of sequencing for epidermal growth factor receptor (EGFR) mutations in lung cancer.

"Within the context of the clinical trial, we are specifically screening for HER2 mutations. But in the future, outside of a clinical trial setting, probably including HER2 in a panel of genes would be most cost effective," he elaborated. "If you compare to cost of treatment, a month of treatment with many of the chemotherapy drugs or with targeted inhibitors is in the thousands of dollars. So the cost of screening [for mutations] is much lower than that."

Dr. Kent Osborne, moderator of the press briefing and director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, characterized the research as "interesting" while adding that its usefulness may be limited at present.

"But what if these mutations occur in other cancers, now that Dr. Bose has identified them?" he said. "If you are a patient with that mutation, even though it’s pretty rare, that’s important to know for you. When we get into the era of personalized medicine, where we start doing these mutational analyses, ... there are going to be mutations that perhaps are contributing to the cancer and are pretty rare in the population, but are important for that particular patient."

"Some in the audience may remember the large trial in HER2-positive patients done by the National Surgical Adjuvant Breast and Bowel Project (NSABP). A few hundred of those patients on central review did not have HER2 amplification or overexpression, yet they seemed to have the same benefits from trastuzumab as did those [with HER2]," Dr. Osborne noted. "I guess at an incidence rate of 1% to 2%, [activating mutations don’t] explain all of those by any means, but I wonder if you could get those samples from the NSABP and screen them. They could be enriched for these mutations."

"That’s an excellent possibility," Dr. Bose replied. "We have had preliminary discussions with members of the NSABP. Now that the work is published, I think those discussions will go further."

When asked why neratinib was being used in the trial instead of trastuzumab (Herceptin), Dr. Bose said that in tissue culture, the former proved much more effective at inhibiting growth of cells harboring these mutations.

On a related note, a session attendee commented, "I am modestly concerned that you don’t have trastuzumab in your trial. And the reason is that I would expect trastuzumab to down-regulate this single-copy HER2 receptor and help neratinib. So have you done combinations of both preclinically to see whether it adds or not to neratinib?"

The investigators have done such in vitro work, Dr. Bose replied. "With trastuzumab alone, we see a partial growth suppression effect when you are looking at MCF-10A cells that bear these mutations. When we tried the combination, we did not see any benefit of adding trastuzumab on top of neratinib. But I would caution that this is with MCF-10A cells, and this is in tissue culture, where there are no immune effectors. We don’t know what the situation will be in actual patients."

Additional study results showed that all of the HER2 activating mutations were found only in the tumor and were thus somatic and not inherited, according to Dr. Bose, who disclosed having no conflicts of interest related to the research.

The mutations clustered in two areas of the HER2 gene: one area affecting the tyrosine kinase domain of the protein (seen in 68% of cases) and another area affecting the extracellular domain (seen in 20%).

Laboratory analyses indicated that the mutations were indeed being expressed at the RNA level, that those affecting the kinase domain of the protein were associated with increased kinase activity, and that the mutations spurred tumor growth in nude mice.

"The majority of these HER2 mutations are activating events that cause cancerous growth of the cells in the lab, meaning that they stimulate the function of HER2 or turn on HER2’s activity in an excessive or inappropriate manner," Dr. Bose summarized. "Thus, we feel they are highly likely to drive the growth of these human breast cancers in which they occur."

In sensitivity testing, the six cases having the L755S mutation were resistant to the tyrosine kinase inhibitor lapatinib but sensitive to neratinib, an irreversible pan-ErbB tyrosine kinase inhibitor.

In fact, neratinib showed greater effectiveness than lapatinib at inhibiting cell growth in all of the mutated tumors tested, with several hundred to several thousand times greater concentrations of lapatinib needed to achieve the same level of inhibition.

Dr. Bose disclosed having no relevant conflicts of interest.

SAN ANTONIO – Some breast cancers categorized as HER2 negative by conventional testing harbor mutations that may still render them amenable to therapy targeting this receptor, researchers reported at the San Antonio Breast Cancer Symposium.

A team led by Dr. Ron Bose, of Washington University and the Siteman Cancer Center, St. Louis, compiled data from eight studies in which tissue from 1,499 breast cancers was sequenced.

Results showed that 25 cancers, or about 1.7%, had activating HER2 mutations. Most of these cancers did not have amplification of the HER2 gene and thus would be categorized as HER2 negative by conventional testing.

"We argue that mutation is an alternate mechanism to activate HER2 in breast cancer," he commented. "Patients with these mutations will be missed by current HER2 testing. Gene sequencing is required to identify these mutations."

The investigational tyrosine kinase inhibitor neratinib readily outperformed lapatinib (Tykerb) at inhibiting the growth of cells bearing the HER2 mutations, according to data presented at the meeting and recently published (Cancer Discov. 2012;3:1-14). The investigators are therefore planning a phase II trial of neratinib for metastatic HER2 gene amplification–negative, HER2 mutation–positive breast cancer.

"These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment," Dr. Bose maintained in a related press briefing. "If this trial is successful, we estimate that 4,000 women per year in the U.S. could benefit. Worldwide, that number could be five times as large."

He anticipates that the technological feasibility and cost of HER2 sequencing in clinical practice would be similar to those of sequencing for epidermal growth factor receptor (EGFR) mutations in lung cancer.

"Within the context of the clinical trial, we are specifically screening for HER2 mutations. But in the future, outside of a clinical trial setting, probably including HER2 in a panel of genes would be most cost effective," he elaborated. "If you compare to cost of treatment, a month of treatment with many of the chemotherapy drugs or with targeted inhibitors is in the thousands of dollars. So the cost of screening [for mutations] is much lower than that."

Dr. Kent Osborne, moderator of the press briefing and director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, characterized the research as "interesting" while adding that its usefulness may be limited at present.

"But what if these mutations occur in other cancers, now that Dr. Bose has identified them?" he said. "If you are a patient with that mutation, even though it’s pretty rare, that’s important to know for you. When we get into the era of personalized medicine, where we start doing these mutational analyses, ... there are going to be mutations that perhaps are contributing to the cancer and are pretty rare in the population, but are important for that particular patient."

"Some in the audience may remember the large trial in HER2-positive patients done by the National Surgical Adjuvant Breast and Bowel Project (NSABP). A few hundred of those patients on central review did not have HER2 amplification or overexpression, yet they seemed to have the same benefits from trastuzumab as did those [with HER2]," Dr. Osborne noted. "I guess at an incidence rate of 1% to 2%, [activating mutations don’t] explain all of those by any means, but I wonder if you could get those samples from the NSABP and screen them. They could be enriched for these mutations."

"That’s an excellent possibility," Dr. Bose replied. "We have had preliminary discussions with members of the NSABP. Now that the work is published, I think those discussions will go further."

When asked why neratinib was being used in the trial instead of trastuzumab (Herceptin), Dr. Bose said that in tissue culture, the former proved much more effective at inhibiting growth of cells harboring these mutations.

On a related note, a session attendee commented, "I am modestly concerned that you don’t have trastuzumab in your trial. And the reason is that I would expect trastuzumab to down-regulate this single-copy HER2 receptor and help neratinib. So have you done combinations of both preclinically to see whether it adds or not to neratinib?"

The investigators have done such in vitro work, Dr. Bose replied. "With trastuzumab alone, we see a partial growth suppression effect when you are looking at MCF-10A cells that bear these mutations. When we tried the combination, we did not see any benefit of adding trastuzumab on top of neratinib. But I would caution that this is with MCF-10A cells, and this is in tissue culture, where there are no immune effectors. We don’t know what the situation will be in actual patients."

Additional study results showed that all of the HER2 activating mutations were found only in the tumor and were thus somatic and not inherited, according to Dr. Bose, who disclosed having no conflicts of interest related to the research.

The mutations clustered in two areas of the HER2 gene: one area affecting the tyrosine kinase domain of the protein (seen in 68% of cases) and another area affecting the extracellular domain (seen in 20%).

Laboratory analyses indicated that the mutations were indeed being expressed at the RNA level, that those affecting the kinase domain of the protein were associated with increased kinase activity, and that the mutations spurred tumor growth in nude mice.

"The majority of these HER2 mutations are activating events that cause cancerous growth of the cells in the lab, meaning that they stimulate the function of HER2 or turn on HER2’s activity in an excessive or inappropriate manner," Dr. Bose summarized. "Thus, we feel they are highly likely to drive the growth of these human breast cancers in which they occur."

In sensitivity testing, the six cases having the L755S mutation were resistant to the tyrosine kinase inhibitor lapatinib but sensitive to neratinib, an irreversible pan-ErbB tyrosine kinase inhibitor.

In fact, neratinib showed greater effectiveness than lapatinib at inhibiting cell growth in all of the mutated tumors tested, with several hundred to several thousand times greater concentrations of lapatinib needed to achieve the same level of inhibition.

Dr. Bose disclosed having no relevant conflicts of interest.

SAN ANTONIO – A novel multigene signature known as the breast cancer index markedly outperformed the widely used Oncotype DX Recurrence Score and IHC4 tools in predicting late recurrences of estrogen receptor-positive/lymph node-negative breast cancer, Dr. Dennis C. Sgroi reported at the annual San Antonio Breast Cancer Symposium.

In a large clinical study, all three tools demonstrated significant prognostic value for early distant recurrences – that is, breast cancers recurring within 5 years of diagnosis. But only the breast cancer index (BCI) had sustained power for predicting distant recurrences arising during years 5-10. Both Oncotype DX and the IHC4 – a test based upon a tumor’s estrogen receptor, progesterone receptor, HER2, and Ki-67 status – lost their prognostic ability at about the 5-year mark, observed Dr. Sgroi of Massachusetts General Hospital, Boston.

More than half of all recurrences of estrogen receptor–positive early-stage breast cancer take place after 5 years of adjuvant tamoxifen or aromatase inhibitor therapy. Thus, the BCI fills a major need: a biomarker capable of identifying those estrogen receptor–positive breast cancer patients at increased risk for recurrence 5-10 years after their diagnosis.

The BCI includes the ratio of HOXB13-to-IL17BR gene expression and a five-gene molecular grade index shown to be predictive beyond tumor grade of distance metastasis. Dr. Sgroi and coinvestigators have previously established that these two biomarkers are complementary in their power to predict recurrences (Clin. Cancer Res. 2008;14:2601-8).

At the San Antonio symposium, Dr. Sgroi presented an analysis of the comparative prognostic performance of the BCI, the Oncotype DX recurrence score, and the IHC4 as applied to baseline tumor samples from 665 hormone receptor-positive participants in the randomized, multicenter TransATAC (Arimedex, Tamoxifen, Alone or Together) trial. The primary endpoint was distant recurrence.

The baseline BCI score differentiated three risk groups over the course of 10 years of follow-up in TransATAC: 58% of women fell into the low-risk group with a 4.2% risk of distant recurrence within 10 years, 25% had an intermediate score with an 18% risk, and 17% had a high score with a 30% risk.

In the first 5 years of follow-up, patients with a low- or intermediate-risk BCI had a distant recurrence risk of 1.3% and 5.6%, respectively. Thus, the BCI identified 83% of study participants as having, on average, a 5-year distant recurrence risk of less than 5%. In contrast, women with a high BCI score had a 5-year recurrence risk of 18%.

Among patients who remained disease free at 5 years, the 61% with a low baseline BCI score had a 3.5% rate of distant recurrence during years 5-10. Those with an intermediate or high BCI had a 13.4% rate.

In a multivariate analysis adjusted for the clinical treatment score – an algorithm based upon nodal status, tumor size and grade, age, and treatment (J. Clin. Oncol. 2011;29:4273-8) – the BCI, IHC4, and Oncotype DX displayed similar prognostic performance for distant recurrences in years 0-5. But the latter two tests lost their predictive capability in years 5-10.

Estrogen receptor–positive/node-negative patients have traditionally been considered at low risk. But, as shown in the TransATAC analysis, applying the BCI to primary tumor specimens from such patients enables physicians to identify two groups at the time of diagnosis: those who are at low risk for recurrence within the next 5 years and who are adequately treated with endocrine therapy alone; and a high-risk subgroup who should be considered for chemotherapy or some other additional therapy along with endocrine therapy, Dr. Sgroi concluded.

Moreover, the BCI score at diagnosis also permits identification of two distinct groups among patients remaining disease free at 5 years of follow up: those at low risk of late recurrence and who don’t need subsequent therapy; and those at roughly a threefold greater risk of late recurrence and are therefore candidates for further systemic adjuvant therapy.

"What that additional treatment should be is something we don’t know at this point. It might be extended adjuvant hormonal therapy alone or in combination with another therapeutic agent," he added.

In response to an audience question, Dr. Sgroi admitted that the exact biologic role of the genes incorporated in the BCI is "still a bit of a mystery," although it’s clear that they’re not solely involved in proliferation.

The TransATAC study was funded by AstraZeneca. Dr. Sgroi’s BCI work is supported by the National Institutes of Health, the U.S. Department of Defense, the Avon Foundation, and the Susan G. Komen for the Cure.

SAN ANTONIO – A novel multigene signature known as the breast cancer index markedly outperformed the widely used Oncotype DX Recurrence Score and IHC4 tools in predicting late recurrences of estrogen receptor-positive/lymph node-negative breast cancer, Dr. Dennis C. Sgroi reported at the annual San Antonio Breast Cancer Symposium.

In a large clinical study, all three tools demonstrated significant prognostic value for early distant recurrences – that is, breast cancers recurring within 5 years of diagnosis. But only the breast cancer index (BCI) had sustained power for predicting distant recurrences arising during years 5-10. Both Oncotype DX and the IHC4 – a test based upon a tumor’s estrogen receptor, progesterone receptor, HER2, and Ki-67 status – lost their prognostic ability at about the 5-year mark, observed Dr. Sgroi of Massachusetts General Hospital, Boston.

More than half of all recurrences of estrogen receptor–positive early-stage breast cancer take place after 5 years of adjuvant tamoxifen or aromatase inhibitor therapy. Thus, the BCI fills a major need: a biomarker capable of identifying those estrogen receptor–positive breast cancer patients at increased risk for recurrence 5-10 years after their diagnosis.

The BCI includes the ratio of HOXB13-to-IL17BR gene expression and a five-gene molecular grade index shown to be predictive beyond tumor grade of distance metastasis. Dr. Sgroi and coinvestigators have previously established that these two biomarkers are complementary in their power to predict recurrences (Clin. Cancer Res. 2008;14:2601-8).

At the San Antonio symposium, Dr. Sgroi presented an analysis of the comparative prognostic performance of the BCI, the Oncotype DX recurrence score, and the IHC4 as applied to baseline tumor samples from 665 hormone receptor-positive participants in the randomized, multicenter TransATAC (Arimedex, Tamoxifen, Alone or Together) trial. The primary endpoint was distant recurrence.

The baseline BCI score differentiated three risk groups over the course of 10 years of follow-up in TransATAC: 58% of women fell into the low-risk group with a 4.2% risk of distant recurrence within 10 years, 25% had an intermediate score with an 18% risk, and 17% had a high score with a 30% risk.

In the first 5 years of follow-up, patients with a low- or intermediate-risk BCI had a distant recurrence risk of 1.3% and 5.6%, respectively. Thus, the BCI identified 83% of study participants as having, on average, a 5-year distant recurrence risk of less than 5%. In contrast, women with a high BCI score had a 5-year recurrence risk of 18%.

Among patients who remained disease free at 5 years, the 61% with a low baseline BCI score had a 3.5% rate of distant recurrence during years 5-10. Those with an intermediate or high BCI had a 13.4% rate.

In a multivariate analysis adjusted for the clinical treatment score – an algorithm based upon nodal status, tumor size and grade, age, and treatment (J. Clin. Oncol. 2011;29:4273-8) – the BCI, IHC4, and Oncotype DX displayed similar prognostic performance for distant recurrences in years 0-5. But the latter two tests lost their predictive capability in years 5-10.

Estrogen receptor–positive/node-negative patients have traditionally been considered at low risk. But, as shown in the TransATAC analysis, applying the BCI to primary tumor specimens from such patients enables physicians to identify two groups at the time of diagnosis: those who are at low risk for recurrence within the next 5 years and who are adequately treated with endocrine therapy alone; and a high-risk subgroup who should be considered for chemotherapy or some other additional therapy along with endocrine therapy, Dr. Sgroi concluded.

Moreover, the BCI score at diagnosis also permits identification of two distinct groups among patients remaining disease free at 5 years of follow up: those at low risk of late recurrence and who don’t need subsequent therapy; and those at roughly a threefold greater risk of late recurrence and are therefore candidates for further systemic adjuvant therapy.

"What that additional treatment should be is something we don’t know at this point. It might be extended adjuvant hormonal therapy alone or in combination with another therapeutic agent," he added.

In response to an audience question, Dr. Sgroi admitted that the exact biologic role of the genes incorporated in the BCI is "still a bit of a mystery," although it’s clear that they’re not solely involved in proliferation.

The TransATAC study was funded by AstraZeneca. Dr. Sgroi’s BCI work is supported by the National Institutes of Health, the U.S. Department of Defense, the Avon Foundation, and the Susan G. Komen for the Cure.

SAN ANTONIO – A novel multigene signature known as the breast cancer index markedly outperformed the widely used Oncotype DX Recurrence Score and IHC4 tools in predicting late recurrences of estrogen receptor-positive/lymph node-negative breast cancer, Dr. Dennis C. Sgroi reported at the annual San Antonio Breast Cancer Symposium.

In a large clinical study, all three tools demonstrated significant prognostic value for early distant recurrences – that is, breast cancers recurring within 5 years of diagnosis. But only the breast cancer index (BCI) had sustained power for predicting distant recurrences arising during years 5-10. Both Oncotype DX and the IHC4 – a test based upon a tumor’s estrogen receptor, progesterone receptor, HER2, and Ki-67 status – lost their prognostic ability at about the 5-year mark, observed Dr. Sgroi of Massachusetts General Hospital, Boston.

More than half of all recurrences of estrogen receptor–positive early-stage breast cancer take place after 5 years of adjuvant tamoxifen or aromatase inhibitor therapy. Thus, the BCI fills a major need: a biomarker capable of identifying those estrogen receptor–positive breast cancer patients at increased risk for recurrence 5-10 years after their diagnosis.

The BCI includes the ratio of HOXB13-to-IL17BR gene expression and a five-gene molecular grade index shown to be predictive beyond tumor grade of distance metastasis. Dr. Sgroi and coinvestigators have previously established that these two biomarkers are complementary in their power to predict recurrences (Clin. Cancer Res. 2008;14:2601-8).

At the San Antonio symposium, Dr. Sgroi presented an analysis of the comparative prognostic performance of the BCI, the Oncotype DX recurrence score, and the IHC4 as applied to baseline tumor samples from 665 hormone receptor-positive participants in the randomized, multicenter TransATAC (Arimedex, Tamoxifen, Alone or Together) trial. The primary endpoint was distant recurrence.

The baseline BCI score differentiated three risk groups over the course of 10 years of follow-up in TransATAC: 58% of women fell into the low-risk group with a 4.2% risk of distant recurrence within 10 years, 25% had an intermediate score with an 18% risk, and 17% had a high score with a 30% risk.

In the first 5 years of follow-up, patients with a low- or intermediate-risk BCI had a distant recurrence risk of 1.3% and 5.6%, respectively. Thus, the BCI identified 83% of study participants as having, on average, a 5-year distant recurrence risk of less than 5%. In contrast, women with a high BCI score had a 5-year recurrence risk of 18%.

Among patients who remained disease free at 5 years, the 61% with a low baseline BCI score had a 3.5% rate of distant recurrence during years 5-10. Those with an intermediate or high BCI had a 13.4% rate.

In a multivariate analysis adjusted for the clinical treatment score – an algorithm based upon nodal status, tumor size and grade, age, and treatment (J. Clin. Oncol. 2011;29:4273-8) – the BCI, IHC4, and Oncotype DX displayed similar prognostic performance for distant recurrences in years 0-5. But the latter two tests lost their predictive capability in years 5-10.

Estrogen receptor–positive/node-negative patients have traditionally been considered at low risk. But, as shown in the TransATAC analysis, applying the BCI to primary tumor specimens from such patients enables physicians to identify two groups at the time of diagnosis: those who are at low risk for recurrence within the next 5 years and who are adequately treated with endocrine therapy alone; and a high-risk subgroup who should be considered for chemotherapy or some other additional therapy along with endocrine therapy, Dr. Sgroi concluded.

Moreover, the BCI score at diagnosis also permits identification of two distinct groups among patients remaining disease free at 5 years of follow up: those at low risk of late recurrence and who don’t need subsequent therapy; and those at roughly a threefold greater risk of late recurrence and are therefore candidates for further systemic adjuvant therapy.

"What that additional treatment should be is something we don’t know at this point. It might be extended adjuvant hormonal therapy alone or in combination with another therapeutic agent," he added.

In response to an audience question, Dr. Sgroi admitted that the exact biologic role of the genes incorporated in the BCI is "still a bit of a mystery," although it’s clear that they’re not solely involved in proliferation.

The TransATAC study was funded by AstraZeneca. Dr. Sgroi’s BCI work is supported by the National Institutes of Health, the U.S. Department of Defense, the Avon Foundation, and the Susan G. Komen for the Cure.

SAN ANTONIO – A variety of biomarkers failed to improve on the results of tumor HER2 status for predicting the benefits of therapy targeting HER2 signaling, based on an analysis of data from the CLEOPATRA trial.

In the trial, 808 patients with metastatic HER2-positive disease were given trastuzumab (Herceptin) and docetaxel (Taxotere) and evenly randomized to either pertuzumab (Perjeta) or placebo.

The main results, previously reported, showed that pertuzumab was significantly superior to placebo in terms of progression-free survival and overall survival.

In the new analysis, reported at the San Antonio Breast Cancer Symposium, a variety of protocol-predefined biomarkers of HER2 signaling in tumor tissue and in serum did not identify any patient subgroups that did better or worse on pertuzumab.

"Our analysis confirms that HER2 is the only marker for selecting patients for HER2-targeted therapy. This was despite a comprehensive exploration of a broad panel of candidate biomarkers," commented lead investigator Dr. Jose Baselga of the Memorial Sloan-Kettering Cancer Center in New York. "It is also consistent with the TRYPHAENA and NeoSphere studies, also presented here in San Antonio."

Discussing study limitations, Dr. Baselga said that "the lack of a HER2-naive treatment control arm may have resulted in the absence of a signal for other biomarkers in CLEOPATRA."

In additional findings, mutation of the gene for the catalytic subunit alpha of PI3 kinase (PIK3CA) in the tumor was associated with a poorer prognosis in the trial population as a whole. Patients whose tumors had the alternate, wildtype form of the gene were about one-fourth less likely to experience cancer progression or death.

"Mutations in PI3 kinase were not associated with resistance to pertuzumab, as patients derived similar additional benefit independent of PI3 kinase mutational status. However, the PI3 kinase mutational status may identify patients with poorer prognosis and particular unmet medical needs," Dr. Baselga commented. Prior studies have similarly shown mutant PI3 kinase to be associated with resistance to lapatinib (Tykerb), another HER2-targeted therapy and with a poorer prognosis after trastuzumab therapy.

"Clinical trials of HER2-targeted molecules in combination with PI3 kinase pathway–targeted agents may therefore be justified based on our findings," he added.

It would be interesting to see how a subset of untreated HER2-positive tumors behave as a function of PI3 kinase mutational status, Dr. Baselga said. "I think that will be what we need to know."

In the new analysis, the investigators evaluated a dozen biomarkers lying on the HER2 signaling pathway for both predictive and prognostic value. "From the cell surface down, we analyzed ligands, receptor tyrosine kinases, soluble HER2, and key intracellular pathway markers," Dr. Baselga explained. For most, they defined high and low levels as above- and below-median values, respectively.

In analyses of the predictive value of the biomarkers, the improvement in progression-free survival with pertuzumab relative to placebo was similar for patients having high versus low levels of all the biomarkers studied.

But in analyses of the prognostic value of the biomarkers in both trial arms pooled, patients had better progression-free survival if they had low serum levels of soluble HER2 (hazard ratio, 1.23; P = .04); in terms of ligands and receptor tyrosine kinases, if they had high levels of HER2 mRNA (0.77; P = .008) and HER3 mRNA (0.81; P = .03), and a high HER2 modified histoscore (0.83; P = .05); and in terms of tumor intracellular pathway markers, if they had mutation of the PIK3CA gene (0.83 for wild type; P = .0001).

The last "was by far our strongest prognostic marker," Dr. Baselga commented. Further analysis showed median progression-free survival was better with pertuzumab in both the mutant PIK3CA group (12.5 vs. 8.6 months) and in the wildtype PIK3CA group (21.8 vs. 13.8 months).

"Patients who harbor PI3 kinase mutations have clearly a worse prognosis. The treatment benefit, however, is maintained...the risk reduction is similar for mutants, for wild type, and for the whole study population," he noted.

In a final, longitudinal analysis to determine if serum biomarkers were early indicators of disease progression, levels of the biomarkers at baseline, week 9, and the time of disease progression showed no correlation with disease progression and did not differ between treatment arms.

Dr. Baselga disclosed that he is a consultant for Roche/Genentech and Sanofi. The trial was sponsored by Genentech.

SAN ANTONIO – A variety of biomarkers failed to improve on the results of tumor HER2 status for predicting the benefits of therapy targeting HER2 signaling, based on an analysis of data from the CLEOPATRA trial.

In the trial, 808 patients with metastatic HER2-positive disease were given trastuzumab (Herceptin) and docetaxel (Taxotere) and evenly randomized to either pertuzumab (Perjeta) or placebo.

The main results, previously reported, showed that pertuzumab was significantly superior to placebo in terms of progression-free survival and overall survival.

In the new analysis, reported at the San Antonio Breast Cancer Symposium, a variety of protocol-predefined biomarkers of HER2 signaling in tumor tissue and in serum did not identify any patient subgroups that did better or worse on pertuzumab.

"Our analysis confirms that HER2 is the only marker for selecting patients for HER2-targeted therapy. This was despite a comprehensive exploration of a broad panel of candidate biomarkers," commented lead investigator Dr. Jose Baselga of the Memorial Sloan-Kettering Cancer Center in New York. "It is also consistent with the TRYPHAENA and NeoSphere studies, also presented here in San Antonio."

Discussing study limitations, Dr. Baselga said that "the lack of a HER2-naive treatment control arm may have resulted in the absence of a signal for other biomarkers in CLEOPATRA."

In additional findings, mutation of the gene for the catalytic subunit alpha of PI3 kinase (PIK3CA) in the tumor was associated with a poorer prognosis in the trial population as a whole. Patients whose tumors had the alternate, wildtype form of the gene were about one-fourth less likely to experience cancer progression or death.

"Mutations in PI3 kinase were not associated with resistance to pertuzumab, as patients derived similar additional benefit independent of PI3 kinase mutational status. However, the PI3 kinase mutational status may identify patients with poorer prognosis and particular unmet medical needs," Dr. Baselga commented. Prior studies have similarly shown mutant PI3 kinase to be associated with resistance to lapatinib (Tykerb), another HER2-targeted therapy and with a poorer prognosis after trastuzumab therapy.

"Clinical trials of HER2-targeted molecules in combination with PI3 kinase pathway–targeted agents may therefore be justified based on our findings," he added.

It would be interesting to see how a subset of untreated HER2-positive tumors behave as a function of PI3 kinase mutational status, Dr. Baselga said. "I think that will be what we need to know."

In the new analysis, the investigators evaluated a dozen biomarkers lying on the HER2 signaling pathway for both predictive and prognostic value. "From the cell surface down, we analyzed ligands, receptor tyrosine kinases, soluble HER2, and key intracellular pathway markers," Dr. Baselga explained. For most, they defined high and low levels as above- and below-median values, respectively.

In analyses of the predictive value of the biomarkers, the improvement in progression-free survival with pertuzumab relative to placebo was similar for patients having high versus low levels of all the biomarkers studied.

But in analyses of the prognostic value of the biomarkers in both trial arms pooled, patients had better progression-free survival if they had low serum levels of soluble HER2 (hazard ratio, 1.23; P = .04); in terms of ligands and receptor tyrosine kinases, if they had high levels of HER2 mRNA (0.77; P = .008) and HER3 mRNA (0.81; P = .03), and a high HER2 modified histoscore (0.83; P = .05); and in terms of tumor intracellular pathway markers, if they had mutation of the PIK3CA gene (0.83 for wild type; P = .0001).

The last "was by far our strongest prognostic marker," Dr. Baselga commented. Further analysis showed median progression-free survival was better with pertuzumab in both the mutant PIK3CA group (12.5 vs. 8.6 months) and in the wildtype PIK3CA group (21.8 vs. 13.8 months).

"Patients who harbor PI3 kinase mutations have clearly a worse prognosis. The treatment benefit, however, is maintained...the risk reduction is similar for mutants, for wild type, and for the whole study population," he noted.

In a final, longitudinal analysis to determine if serum biomarkers were early indicators of disease progression, levels of the biomarkers at baseline, week 9, and the time of disease progression showed no correlation with disease progression and did not differ between treatment arms.

Dr. Baselga disclosed that he is a consultant for Roche/Genentech and Sanofi. The trial was sponsored by Genentech.

SAN ANTONIO – A variety of biomarkers failed to improve on the results of tumor HER2 status for predicting the benefits of therapy targeting HER2 signaling, based on an analysis of data from the CLEOPATRA trial.

In the trial, 808 patients with metastatic HER2-positive disease were given trastuzumab (Herceptin) and docetaxel (Taxotere) and evenly randomized to either pertuzumab (Perjeta) or placebo.

The main results, previously reported, showed that pertuzumab was significantly superior to placebo in terms of progression-free survival and overall survival.

In the new analysis, reported at the San Antonio Breast Cancer Symposium, a variety of protocol-predefined biomarkers of HER2 signaling in tumor tissue and in serum did not identify any patient subgroups that did better or worse on pertuzumab.

"Our analysis confirms that HER2 is the only marker for selecting patients for HER2-targeted therapy. This was despite a comprehensive exploration of a broad panel of candidate biomarkers," commented lead investigator Dr. Jose Baselga of the Memorial Sloan-Kettering Cancer Center in New York. "It is also consistent with the TRYPHAENA and NeoSphere studies, also presented here in San Antonio."

Discussing study limitations, Dr. Baselga said that "the lack of a HER2-naive treatment control arm may have resulted in the absence of a signal for other biomarkers in CLEOPATRA."

In additional findings, mutation of the gene for the catalytic subunit alpha of PI3 kinase (PIK3CA) in the tumor was associated with a poorer prognosis in the trial population as a whole. Patients whose tumors had the alternate, wildtype form of the gene were about one-fourth less likely to experience cancer progression or death.

"Mutations in PI3 kinase were not associated with resistance to pertuzumab, as patients derived similar additional benefit independent of PI3 kinase mutational status. However, the PI3 kinase mutational status may identify patients with poorer prognosis and particular unmet medical needs," Dr. Baselga commented. Prior studies have similarly shown mutant PI3 kinase to be associated with resistance to lapatinib (Tykerb), another HER2-targeted therapy and with a poorer prognosis after trastuzumab therapy.

"Clinical trials of HER2-targeted molecules in combination with PI3 kinase pathway–targeted agents may therefore be justified based on our findings," he added.

It would be interesting to see how a subset of untreated HER2-positive tumors behave as a function of PI3 kinase mutational status, Dr. Baselga said. "I think that will be what we need to know."

In the new analysis, the investigators evaluated a dozen biomarkers lying on the HER2 signaling pathway for both predictive and prognostic value. "From the cell surface down, we analyzed ligands, receptor tyrosine kinases, soluble HER2, and key intracellular pathway markers," Dr. Baselga explained. For most, they defined high and low levels as above- and below-median values, respectively.

In analyses of the predictive value of the biomarkers, the improvement in progression-free survival with pertuzumab relative to placebo was similar for patients having high versus low levels of all the biomarkers studied.

But in analyses of the prognostic value of the biomarkers in both trial arms pooled, patients had better progression-free survival if they had low serum levels of soluble HER2 (hazard ratio, 1.23; P = .04); in terms of ligands and receptor tyrosine kinases, if they had high levels of HER2 mRNA (0.77; P = .008) and HER3 mRNA (0.81; P = .03), and a high HER2 modified histoscore (0.83; P = .05); and in terms of tumor intracellular pathway markers, if they had mutation of the PIK3CA gene (0.83 for wild type; P = .0001).

The last "was by far our strongest prognostic marker," Dr. Baselga commented. Further analysis showed median progression-free survival was better with pertuzumab in both the mutant PIK3CA group (12.5 vs. 8.6 months) and in the wildtype PIK3CA group (21.8 vs. 13.8 months).

"Patients who harbor PI3 kinase mutations have clearly a worse prognosis. The treatment benefit, however, is maintained...the risk reduction is similar for mutants, for wild type, and for the whole study population," he noted.

In a final, longitudinal analysis to determine if serum biomarkers were early indicators of disease progression, levels of the biomarkers at baseline, week 9, and the time of disease progression showed no correlation with disease progression and did not differ between treatment arms.

Dr. Baselga disclosed that he is a consultant for Roche/Genentech and Sanofi. The trial was sponsored by Genentech.

SAN ANTONIO – The results of a sentinel node biopsy performed after neoadjuvant chemotherapy for breast cancer are often unreliable, new data suggest.

Researchers with the German SENTINA trial prospectively analyzed the impact of the timing of sentinel lymph node (SLN) biopsy on the accuracy and feasibility of the procedure in 1,737 patients with early breast cancer who received neoadjuvant chemotherapy.

Patients with initial clinically node-negative disease (cN0) underwent SLN biopsy before chemotherapy. If biopsy results were positive, they underwent biopsy along with an axillary dissection after chemotherapy. Patients with clinically node-positive disease (cN1) underwent chemotherapy followed by SLN biopsy plus axillary dissection if they had a downstaging to clinically node-negative disease.

The SLN biopsy procedure was standardized according to interdisciplinary consensus (Cancer 2005;103:451-61); radiocolloid tracer with lymphoscintigraphy was mandatory for identifying sentinel nodes, whereas blue dye was optional.

Study results showed that the false-negative rate was 51.6% in patients with cN0 disease who had an initial SLN biopsy showing nodal involvement and therefore went on to have another SLN biopsy after the chemotherapy.

SLN biopsy had a false-negative rate of 14.2% when performed after the neoadjuvant chemotherapy in patients with initial cN1 disease who had downstaging to cN0 disease, lead author Dr. Thorsten Kuehn reported at the San Antonio Breast Cancer Symposium.

This rate was up to twice as high as that seen historically in patients instead having the SLN biopsy at the time of primary surgery, which has been on the order of 7%-10%.

"The SLN biopsy as a diagnostic procedure is not a reliable tool in patients who convert on neoadjuvant chemotherapy from cN1 to cN0 compared to SLN biopsy in primary surgery," he said.

Within this downstaged group, data showed that the odds of a false-negative result were reduced by half when patients had more than one sentinel node examined.

"It strikes me that your conclusion should have been, if you take two or more sentinel nodes, this is a safe procedure," one attendee noted during a discussion session. "But if you take less than that, it’s not safe. Is that true?"

The study biopsies were adequate in that all patients had lymphoscintigraphy, contended Dr. Kuehn, who is head of the breast center and chief of the gynecology and obstetrics clinic at Klinikum Esslingen in Germany. "I don’t think you necessarily always have two sentinel nodes – you may have one sentinel node. And every institution or every surgeon had to prove that the sentinel nodes that were shown on lymphoscintigraphy had to be removed."

Another attendee wondered about the extent of residual axillary disease in the patients having false-positive SLN results.

"As a radiation oncologist, I am seeing a lot of patients who have had sentinel node biopsies done after neoadjuvant chemotherapy without an axillary dissection, and I’m being asked to irradiate the patient, which makes me uncomfortable because I don’t know what the volume of disease left is," he explained. "Do you have a sense of what the volume of disease is – micrometastases, macrometastases, number of nodes – in the patients with false-negative sentinel nodes, and do you also have a sense of what that volume is in the axillary dissection specimen outside the true-positive sentinel nodes?"

"We don’t have information on the size of the metastases. We have information on the number of involved non–sentinel nodes, and these numbers are from 1 to 11," Dr. Kuehn replied.

"What we want to say is SLN biopsy is a diagnostic tool, and this tool is worse after previous treatment. I can say I work with this tool, but it is not a good diagnostic tool," he added.

In the study, SLN detection rates, a measure of feasibility, also differed significantly across groups. Surgeons were able to detect these nodes in 99% of all SLN biopsies performed before any treatment, but in only 80% of those performed after a downstaging of disease with the neoadjuvant chemotherapy and in only 61% of the repeated SLN biopsies. The pattern of nodal uptake of the radiocolloid tracer mirrored these findings.

"Previous local and systemic treatment significantly impairs the tracer uptake and the detection rate," concluded Dr. Kuehn, who disclosed no conflicts of interest related to the research.

In a multivariate analysis in the downstaged group, none of a variety of tumor characteristics significantly predicted the ability to detect an SLN.

SAN ANTONIO – The results of a sentinel node biopsy performed after neoadjuvant chemotherapy for breast cancer are often unreliable, new data suggest.

Researchers with the German SENTINA trial prospectively analyzed the impact of the timing of sentinel lymph node (SLN) biopsy on the accuracy and feasibility of the procedure in 1,737 patients with early breast cancer who received neoadjuvant chemotherapy.

Patients with initial clinically node-negative disease (cN0) underwent SLN biopsy before chemotherapy. If biopsy results were positive, they underwent biopsy along with an axillary dissection after chemotherapy. Patients with clinically node-positive disease (cN1) underwent chemotherapy followed by SLN biopsy plus axillary dissection if they had a downstaging to clinically node-negative disease.

The SLN biopsy procedure was standardized according to interdisciplinary consensus (Cancer 2005;103:451-61); radiocolloid tracer with lymphoscintigraphy was mandatory for identifying sentinel nodes, whereas blue dye was optional.

Study results showed that the false-negative rate was 51.6% in patients with cN0 disease who had an initial SLN biopsy showing nodal involvement and therefore went on to have another SLN biopsy after the chemotherapy.

SLN biopsy had a false-negative rate of 14.2% when performed after the neoadjuvant chemotherapy in patients with initial cN1 disease who had downstaging to cN0 disease, lead author Dr. Thorsten Kuehn reported at the San Antonio Breast Cancer Symposium.

This rate was up to twice as high as that seen historically in patients instead having the SLN biopsy at the time of primary surgery, which has been on the order of 7%-10%.

"The SLN biopsy as a diagnostic procedure is not a reliable tool in patients who convert on neoadjuvant chemotherapy from cN1 to cN0 compared to SLN biopsy in primary surgery," he said.

Within this downstaged group, data showed that the odds of a false-negative result were reduced by half when patients had more than one sentinel node examined.

"It strikes me that your conclusion should have been, if you take two or more sentinel nodes, this is a safe procedure," one attendee noted during a discussion session. "But if you take less than that, it’s not safe. Is that true?"

The study biopsies were adequate in that all patients had lymphoscintigraphy, contended Dr. Kuehn, who is head of the breast center and chief of the gynecology and obstetrics clinic at Klinikum Esslingen in Germany. "I don’t think you necessarily always have two sentinel nodes – you may have one sentinel node. And every institution or every surgeon had to prove that the sentinel nodes that were shown on lymphoscintigraphy had to be removed."

Another attendee wondered about the extent of residual axillary disease in the patients having false-positive SLN results.

"As a radiation oncologist, I am seeing a lot of patients who have had sentinel node biopsies done after neoadjuvant chemotherapy without an axillary dissection, and I’m being asked to irradiate the patient, which makes me uncomfortable because I don’t know what the volume of disease left is," he explained. "Do you have a sense of what the volume of disease is – micrometastases, macrometastases, number of nodes – in the patients with false-negative sentinel nodes, and do you also have a sense of what that volume is in the axillary dissection specimen outside the true-positive sentinel nodes?"

"We don’t have information on the size of the metastases. We have information on the number of involved non–sentinel nodes, and these numbers are from 1 to 11," Dr. Kuehn replied.

"What we want to say is SLN biopsy is a diagnostic tool, and this tool is worse after previous treatment. I can say I work with this tool, but it is not a good diagnostic tool," he added.

In the study, SLN detection rates, a measure of feasibility, also differed significantly across groups. Surgeons were able to detect these nodes in 99% of all SLN biopsies performed before any treatment, but in only 80% of those performed after a downstaging of disease with the neoadjuvant chemotherapy and in only 61% of the repeated SLN biopsies. The pattern of nodal uptake of the radiocolloid tracer mirrored these findings.

"Previous local and systemic treatment significantly impairs the tracer uptake and the detection rate," concluded Dr. Kuehn, who disclosed no conflicts of interest related to the research.

In a multivariate analysis in the downstaged group, none of a variety of tumor characteristics significantly predicted the ability to detect an SLN.

SAN ANTONIO – The results of a sentinel node biopsy performed after neoadjuvant chemotherapy for breast cancer are often unreliable, new data suggest.

Researchers with the German SENTINA trial prospectively analyzed the impact of the timing of sentinel lymph node (SLN) biopsy on the accuracy and feasibility of the procedure in 1,737 patients with early breast cancer who received neoadjuvant chemotherapy.

Patients with initial clinically node-negative disease (cN0) underwent SLN biopsy before chemotherapy. If biopsy results were positive, they underwent biopsy along with an axillary dissection after chemotherapy. Patients with clinically node-positive disease (cN1) underwent chemotherapy followed by SLN biopsy plus axillary dissection if they had a downstaging to clinically node-negative disease.

The SLN biopsy procedure was standardized according to interdisciplinary consensus (Cancer 2005;103:451-61); radiocolloid tracer with lymphoscintigraphy was mandatory for identifying sentinel nodes, whereas blue dye was optional.

Study results showed that the false-negative rate was 51.6% in patients with cN0 disease who had an initial SLN biopsy showing nodal involvement and therefore went on to have another SLN biopsy after the chemotherapy.

SLN biopsy had a false-negative rate of 14.2% when performed after the neoadjuvant chemotherapy in patients with initial cN1 disease who had downstaging to cN0 disease, lead author Dr. Thorsten Kuehn reported at the San Antonio Breast Cancer Symposium.

This rate was up to twice as high as that seen historically in patients instead having the SLN biopsy at the time of primary surgery, which has been on the order of 7%-10%.

"The SLN biopsy as a diagnostic procedure is not a reliable tool in patients who convert on neoadjuvant chemotherapy from cN1 to cN0 compared to SLN biopsy in primary surgery," he said.

Within this downstaged group, data showed that the odds of a false-negative result were reduced by half when patients had more than one sentinel node examined.

"It strikes me that your conclusion should have been, if you take two or more sentinel nodes, this is a safe procedure," one attendee noted during a discussion session. "But if you take less than that, it’s not safe. Is that true?"

The study biopsies were adequate in that all patients had lymphoscintigraphy, contended Dr. Kuehn, who is head of the breast center and chief of the gynecology and obstetrics clinic at Klinikum Esslingen in Germany. "I don’t think you necessarily always have two sentinel nodes – you may have one sentinel node. And every institution or every surgeon had to prove that the sentinel nodes that were shown on lymphoscintigraphy had to be removed."

Another attendee wondered about the extent of residual axillary disease in the patients having false-positive SLN results.

"As a radiation oncologist, I am seeing a lot of patients who have had sentinel node biopsies done after neoadjuvant chemotherapy without an axillary dissection, and I’m being asked to irradiate the patient, which makes me uncomfortable because I don’t know what the volume of disease left is," he explained. "Do you have a sense of what the volume of disease is – micrometastases, macrometastases, number of nodes – in the patients with false-negative sentinel nodes, and do you also have a sense of what that volume is in the axillary dissection specimen outside the true-positive sentinel nodes?"

"We don’t have information on the size of the metastases. We have information on the number of involved non–sentinel nodes, and these numbers are from 1 to 11," Dr. Kuehn replied.

"What we want to say is SLN biopsy is a diagnostic tool, and this tool is worse after previous treatment. I can say I work with this tool, but it is not a good diagnostic tool," he added.

In the study, SLN detection rates, a measure of feasibility, also differed significantly across groups. Surgeons were able to detect these nodes in 99% of all SLN biopsies performed before any treatment, but in only 80% of those performed after a downstaging of disease with the neoadjuvant chemotherapy and in only 61% of the repeated SLN biopsies. The pattern of nodal uptake of the radiocolloid tracer mirrored these findings.

"Previous local and systemic treatment significantly impairs the tracer uptake and the detection rate," concluded Dr. Kuehn, who disclosed no conflicts of interest related to the research.

In a multivariate analysis in the downstaged group, none of a variety of tumor characteristics significantly predicted the ability to detect an SLN.

SAN ANTONIO – Immunohistochemical expression of the proliferation marker Ki67 in a pretreatment biopsy of breast cancer is valid as both a positive predictive marker and a negative prognostic marker of response to neoadjuvant therapy, said Dr. Carsten Denkert, senior pathologist and head of the translational cancer research group at the Institute of Pathology, Charité University Hospital, Berlin.

The findings are based on an analysis of data from the GeparTrio trial of the German Breast Group.

Among the eight molecular subtypes of breast cancer (hormone receptor positive/negative, HER2 positive/negative, and four subtypes created by combining these features), Ki67 was a positive predictive marker in six subtypes and a negative prognostic marker in the three hormone receptor–positive subtypes, Dr. Denkert said at the San Antonio Breast Cancer Symposium.

Across cutpoints for Ki67 positivity ranging from 10% to 45%, women with Ki67-positive tumors were significantly more likely to have a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they also had significantly poorer disease-free and overall survival.

The analysis was unable to identify an optimal cutpoint for positivity, but the "results provide an explanation for the very different cutpoint results in various previous clinical studies," he said. As Ki67 is a continuous marker that measures tumor proliferation, cutpoints can be defined by the scientific community.

In the GeparTrio trial, the 1,166 patients all had tumors measuring at least 2 cm, underwent a core biopsy, received two cycles of neoadjuvant chemotherapy, underwent ultrasound assessment of response, and then received additional cycles of chemotherapy tailored to that response.

The research team led by Dr. Denkert performed immunohistochemical staining for Ki67 in the pretreatment core biopsy using the MIB-1 antibody and systematically assessed 94 cutpoints for Ki67 positivity between 0% and 100% for their association with outcomes.

Results showed that 93 of the cutpoints were significantly associated with pCR, 48 were significantly associated with disease-free survival, and 58 were significantly associated with overall survival. "So it is very difficult to decide which one is the optimal cutpoint," Dr. Denkert commented.

For further analyses, patients were split into three equal groups according to Ki67 cutpoint: low (less than or equal to 15%), intermediate (15.1%-35%), and high (greater than 35%).

In a multivariate analysis, these three groups differed significantly with respect to pCR rate (P less than .0005), median disease-free survival (P = .012), and median overall survival (P = .013).

In a discussion after the presentation, Dr. Steven Vogl of the Montefiore Medical Center, New York, referenced earlier reports from the same trial. "Getting a partial response for some of the hormone receptor–positive tumors was good in terms of prognosis, even though a pCR wasn’t achieved. Did you look at Ki67 in the non-pCR patients and see if that gave you any information as to their prognosis? That is, Ki67 at the time of the final surgical procedure."

"In fact, this was one of the aims of the large Ki67 program that we did on the core biopsies and also on the surgical tissues," Dr. Denkert replied. "So far, we have not yet been able to define Ki67 as a parameter for the effect observed with the hormone receptor–positive tumors in the GeparTrio trial. Very likely, we have to combine this parameter with other parameters, and we are currently working on this."

Although the 12th St. Gallen International Breast Cancer Conference (2011) Expert Panel has proposed that Ki67 may be able to differentiate between the luminal A and luminal B molecular subtypes of breast cancer (Ann. Oncol. 2011;22:1736-47), the optimal cutpoint of the percentage of positive cells for defining a tumor to be Ki67 positive is still debated, he noted.

Dr. Denkert disclosed that he receives research/grant support from Siemens Medical Solutions and Sividon Diagnostics; that he is a consultant for Celgene, Amgen, and Sividon Diagnostics; and that he is a shareholder in Sividon Diagnostics.

SAN ANTONIO – Immunohistochemical expression of the proliferation marker Ki67 in a pretreatment biopsy of breast cancer is valid as both a positive predictive marker and a negative prognostic marker of response to neoadjuvant therapy, said Dr. Carsten Denkert, senior pathologist and head of the translational cancer research group at the Institute of Pathology, Charité University Hospital, Berlin.

The findings are based on an analysis of data from the GeparTrio trial of the German Breast Group.

Among the eight molecular subtypes of breast cancer (hormone receptor positive/negative, HER2 positive/negative, and four subtypes created by combining these features), Ki67 was a positive predictive marker in six subtypes and a negative prognostic marker in the three hormone receptor–positive subtypes, Dr. Denkert said at the San Antonio Breast Cancer Symposium.

Across cutpoints for Ki67 positivity ranging from 10% to 45%, women with Ki67-positive tumors were significantly more likely to have a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they also had significantly poorer disease-free and overall survival.

The analysis was unable to identify an optimal cutpoint for positivity, but the "results provide an explanation for the very different cutpoint results in various previous clinical studies," he said. As Ki67 is a continuous marker that measures tumor proliferation, cutpoints can be defined by the scientific community.

In the GeparTrio trial, the 1,166 patients all had tumors measuring at least 2 cm, underwent a core biopsy, received two cycles of neoadjuvant chemotherapy, underwent ultrasound assessment of response, and then received additional cycles of chemotherapy tailored to that response.

The research team led by Dr. Denkert performed immunohistochemical staining for Ki67 in the pretreatment core biopsy using the MIB-1 antibody and systematically assessed 94 cutpoints for Ki67 positivity between 0% and 100% for their association with outcomes.

Results showed that 93 of the cutpoints were significantly associated with pCR, 48 were significantly associated with disease-free survival, and 58 were significantly associated with overall survival. "So it is very difficult to decide which one is the optimal cutpoint," Dr. Denkert commented.

For further analyses, patients were split into three equal groups according to Ki67 cutpoint: low (less than or equal to 15%), intermediate (15.1%-35%), and high (greater than 35%).

In a multivariate analysis, these three groups differed significantly with respect to pCR rate (P less than .0005), median disease-free survival (P = .012), and median overall survival (P = .013).

In a discussion after the presentation, Dr. Steven Vogl of the Montefiore Medical Center, New York, referenced earlier reports from the same trial. "Getting a partial response for some of the hormone receptor–positive tumors was good in terms of prognosis, even though a pCR wasn’t achieved. Did you look at Ki67 in the non-pCR patients and see if that gave you any information as to their prognosis? That is, Ki67 at the time of the final surgical procedure."

"In fact, this was one of the aims of the large Ki67 program that we did on the core biopsies and also on the surgical tissues," Dr. Denkert replied. "So far, we have not yet been able to define Ki67 as a parameter for the effect observed with the hormone receptor–positive tumors in the GeparTrio trial. Very likely, we have to combine this parameter with other parameters, and we are currently working on this."

Although the 12th St. Gallen International Breast Cancer Conference (2011) Expert Panel has proposed that Ki67 may be able to differentiate between the luminal A and luminal B molecular subtypes of breast cancer (Ann. Oncol. 2011;22:1736-47), the optimal cutpoint of the percentage of positive cells for defining a tumor to be Ki67 positive is still debated, he noted.

Dr. Denkert disclosed that he receives research/grant support from Siemens Medical Solutions and Sividon Diagnostics; that he is a consultant for Celgene, Amgen, and Sividon Diagnostics; and that he is a shareholder in Sividon Diagnostics.

SAN ANTONIO – Immunohistochemical expression of the proliferation marker Ki67 in a pretreatment biopsy of breast cancer is valid as both a positive predictive marker and a negative prognostic marker of response to neoadjuvant therapy, said Dr. Carsten Denkert, senior pathologist and head of the translational cancer research group at the Institute of Pathology, Charité University Hospital, Berlin.

The findings are based on an analysis of data from the GeparTrio trial of the German Breast Group.

Among the eight molecular subtypes of breast cancer (hormone receptor positive/negative, HER2 positive/negative, and four subtypes created by combining these features), Ki67 was a positive predictive marker in six subtypes and a negative prognostic marker in the three hormone receptor–positive subtypes, Dr. Denkert said at the San Antonio Breast Cancer Symposium.

Across cutpoints for Ki67 positivity ranging from 10% to 45%, women with Ki67-positive tumors were significantly more likely to have a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they also had significantly poorer disease-free and overall survival.

The analysis was unable to identify an optimal cutpoint for positivity, but the "results provide an explanation for the very different cutpoint results in various previous clinical studies," he said. As Ki67 is a continuous marker that measures tumor proliferation, cutpoints can be defined by the scientific community.

In the GeparTrio trial, the 1,166 patients all had tumors measuring at least 2 cm, underwent a core biopsy, received two cycles of neoadjuvant chemotherapy, underwent ultrasound assessment of response, and then received additional cycles of chemotherapy tailored to that response.

The research team led by Dr. Denkert performed immunohistochemical staining for Ki67 in the pretreatment core biopsy using the MIB-1 antibody and systematically assessed 94 cutpoints for Ki67 positivity between 0% and 100% for their association with outcomes.

Results showed that 93 of the cutpoints were significantly associated with pCR, 48 were significantly associated with disease-free survival, and 58 were significantly associated with overall survival. "So it is very difficult to decide which one is the optimal cutpoint," Dr. Denkert commented.

For further analyses, patients were split into three equal groups according to Ki67 cutpoint: low (less than or equal to 15%), intermediate (15.1%-35%), and high (greater than 35%).

In a multivariate analysis, these three groups differed significantly with respect to pCR rate (P less than .0005), median disease-free survival (P = .012), and median overall survival (P = .013).

In a discussion after the presentation, Dr. Steven Vogl of the Montefiore Medical Center, New York, referenced earlier reports from the same trial. "Getting a partial response for some of the hormone receptor–positive tumors was good in terms of prognosis, even though a pCR wasn’t achieved. Did you look at Ki67 in the non-pCR patients and see if that gave you any information as to their prognosis? That is, Ki67 at the time of the final surgical procedure."

"In fact, this was one of the aims of the large Ki67 program that we did on the core biopsies and also on the surgical tissues," Dr. Denkert replied. "So far, we have not yet been able to define Ki67 as a parameter for the effect observed with the hormone receptor–positive tumors in the GeparTrio trial. Very likely, we have to combine this parameter with other parameters, and we are currently working on this."

Although the 12th St. Gallen International Breast Cancer Conference (2011) Expert Panel has proposed that Ki67 may be able to differentiate between the luminal A and luminal B molecular subtypes of breast cancer (Ann. Oncol. 2011;22:1736-47), the optimal cutpoint of the percentage of positive cells for defining a tumor to be Ki67 positive is still debated, he noted.

Dr. Denkert disclosed that he receives research/grant support from Siemens Medical Solutions and Sividon Diagnostics; that he is a consultant for Celgene, Amgen, and Sividon Diagnostics; and that he is a shareholder in Sividon Diagnostics.

SAN ANTONIO – Metabolic syndrome is a potent independent risk factor for breast cancer recurrence in patients who are otherwise at low risk, based on a widely used 21-gene recurrence score assay.

This novel finding in an observational study underscores how much is riding on the outcome of ongoing randomized clinical trials of metformin and aggressive lifestyle modification through weight loss and exercise for secondary prevention of breast cancer, Dr. Arti Lakhani reported at the annual San Antonio Breast Cancer Symposium. If those interventions ultimately prove effective in reducing the risk of breast cancer recurrence, their success may in part be attributed to their ability to reduce the prevalence of metabolic syndrome.

Dr. Lakhani, of Loyola University Medical Center in Maywood, Ill., presented a single-center study of 322 consecutive women newly diagnosed in 2006-2011 with estrogen receptor–positive/lymph node–negative early-stage breast cancer. All patients’ tumors were analyzed using the Oncotype DX assay, which is used to estimate the risk of recurrence based on the expression of 21 genes.

Of the 322 patients, 89 (27%) met World Health Organization criteria for metabolic syndrome. So far, breast cancer has recurred in 21 patients; 13 (62%) of them had metabolic syndrome.

In a multivariate analysis, patients with a low-risk Oncotype DX score of 0-17 had a 24-fold greater risk of recurrence if they had metabolic syndrome. In intermediate-risk patients having a score of 18-30, metabolic syndrome was independently associated with a fourfold increased risk of recurrence. In patients with higher scores, metabolic syndrome didn’t significantly add to the predictive value of the test result, said Dr. Lakhani.

The impact of metabolic syndrome on recurrence score was independent of tumor grade, size, HER2/neu status, and Ki67, as well as patient age and menopausal status.

During a discussion after the presentation, one physician remarked that if the findings are confirmed in an independent data set with larger numbers, he would feel compelled to recommend chemotherapy in all patients with hormone receptor–positive/lymph node–negative breast cancer and metabolic syndrome.

Another oncologist observed that breast cancer treatment seems to inherently promote metabolic syndrome, with its pear-shaped body habitus. "If my breast cancer patients don’t have metabolic syndrome before they start treatment, they often seem to afterwards."

Dr. Lakhani reported having no financial conflicts.

[email protected]

SAN ANTONIO – Metabolic syndrome is a potent independent risk factor for breast cancer recurrence in patients who are otherwise at low risk, based on a widely used 21-gene recurrence score assay.

This novel finding in an observational study underscores how much is riding on the outcome of ongoing randomized clinical trials of metformin and aggressive lifestyle modification through weight loss and exercise for secondary prevention of breast cancer, Dr. Arti Lakhani reported at the annual San Antonio Breast Cancer Symposium. If those interventions ultimately prove effective in reducing the risk of breast cancer recurrence, their success may in part be attributed to their ability to reduce the prevalence of metabolic syndrome.

Dr. Lakhani, of Loyola University Medical Center in Maywood, Ill., presented a single-center study of 322 consecutive women newly diagnosed in 2006-2011 with estrogen receptor–positive/lymph node–negative early-stage breast cancer. All patients’ tumors were analyzed using the Oncotype DX assay, which is used to estimate the risk of recurrence based on the expression of 21 genes.

Of the 322 patients, 89 (27%) met World Health Organization criteria for metabolic syndrome. So far, breast cancer has recurred in 21 patients; 13 (62%) of them had metabolic syndrome.

In a multivariate analysis, patients with a low-risk Oncotype DX score of 0-17 had a 24-fold greater risk of recurrence if they had metabolic syndrome. In intermediate-risk patients having a score of 18-30, metabolic syndrome was independently associated with a fourfold increased risk of recurrence. In patients with higher scores, metabolic syndrome didn’t significantly add to the predictive value of the test result, said Dr. Lakhani.

The impact of metabolic syndrome on recurrence score was independent of tumor grade, size, HER2/neu status, and Ki67, as well as patient age and menopausal status.

During a discussion after the presentation, one physician remarked that if the findings are confirmed in an independent data set with larger numbers, he would feel compelled to recommend chemotherapy in all patients with hormone receptor–positive/lymph node–negative breast cancer and metabolic syndrome.

Another oncologist observed that breast cancer treatment seems to inherently promote metabolic syndrome, with its pear-shaped body habitus. "If my breast cancer patients don’t have metabolic syndrome before they start treatment, they often seem to afterwards."

Dr. Lakhani reported having no financial conflicts.

[email protected]

SAN ANTONIO – Metabolic syndrome is a potent independent risk factor for breast cancer recurrence in patients who are otherwise at low risk, based on a widely used 21-gene recurrence score assay.

This novel finding in an observational study underscores how much is riding on the outcome of ongoing randomized clinical trials of metformin and aggressive lifestyle modification through weight loss and exercise for secondary prevention of breast cancer, Dr. Arti Lakhani reported at the annual San Antonio Breast Cancer Symposium. If those interventions ultimately prove effective in reducing the risk of breast cancer recurrence, their success may in part be attributed to their ability to reduce the prevalence of metabolic syndrome.

Dr. Lakhani, of Loyola University Medical Center in Maywood, Ill., presented a single-center study of 322 consecutive women newly diagnosed in 2006-2011 with estrogen receptor–positive/lymph node–negative early-stage breast cancer. All patients’ tumors were analyzed using the Oncotype DX assay, which is used to estimate the risk of recurrence based on the expression of 21 genes.

Of the 322 patients, 89 (27%) met World Health Organization criteria for metabolic syndrome. So far, breast cancer has recurred in 21 patients; 13 (62%) of them had metabolic syndrome.

In a multivariate analysis, patients with a low-risk Oncotype DX score of 0-17 had a 24-fold greater risk of recurrence if they had metabolic syndrome. In intermediate-risk patients having a score of 18-30, metabolic syndrome was independently associated with a fourfold increased risk of recurrence. In patients with higher scores, metabolic syndrome didn’t significantly add to the predictive value of the test result, said Dr. Lakhani.

The impact of metabolic syndrome on recurrence score was independent of tumor grade, size, HER2/neu status, and Ki67, as well as patient age and menopausal status.

During a discussion after the presentation, one physician remarked that if the findings are confirmed in an independent data set with larger numbers, he would feel compelled to recommend chemotherapy in all patients with hormone receptor–positive/lymph node–negative breast cancer and metabolic syndrome.

Another oncologist observed that breast cancer treatment seems to inherently promote metabolic syndrome, with its pear-shaped body habitus. "If my breast cancer patients don’t have metabolic syndrome before they start treatment, they often seem to afterwards."

Dr. Lakhani reported having no financial conflicts.

[email protected]

SAN ANTONIO – Breast cancer outcomes haven’t improved to nearly the same impressive extent in older women as in younger women, according to Dr. Hyman B. Muss.

The reasons for this age-related disparity in breast cancer–specific survival include the increased level of comorbidities in the elderly, the underrepresentation of geriatric patients in major clinical trials, and oncologists’ limited geriatric training, he said in his Susan G. Komen for the Cure Brinker Award Lecture for Scientific Distinction in Clinical Research.

While the benefits of chemotherapy are similar in seniors and younger patients, the risks of serious toxicity are greater with age, he noted. Here’s where a pretreatment geriatric assessment to identify clinical predictors of morbidity and mortality can be enormously helpful, said Dr. Muss, professor of medicine and director of the geriatric oncology program at the University of North Carolina, Chapel Hill.

A growing body of data speaks to the importance of determining comorbidities to offer optimal treatment to elderly breast cancer patients. In a soon-to-be-published update of the Cancer and Leukemia Group 9343 trial of more than 600 elderly women with early breast cancer, for example, 51% of participants were still alive at the 12-year follow up. Of those who died, just 3% died of breast cancer; the other 46% died from other causes.

"If an elderly breast cancer patient in your office has high blood pressure or a blood sugar of 300 mg/dL, that’s almost more important than whether or not she gets radiation ... is cancer the patient’s major illness or is it something else, like diabetes or cardiac disease? The key thing we should be thinking of is not ‘How old are you?’ but ‘What’s your life expectancy?’ " he said.

Online tools can aid in those evaluations, including Adjuvant! Online (www.adjuvantonline.com). This tool allows one to factor comorbid conditions into clinical decisions about adjuvant therapy in women with early breast cancer. Also helpful is ePrognosis (www.eprognosis.org), which provides several scales to estimate an older community-dwelling individual’s life expectancy without breast cancer. The ePrognosis tool "can help you make a better decision about how aggressively to treat breast cancer. Some of my colleagues are doing this now in the office. It just takes a few minutes and is very user friendly," Dr. Muss said.

He said he is particularly impressed with a predictive tool developed by Dr. Arti Hurria and coworkers at the City of Hope Comprehensive Cancer Center in Duarte, Calif. This tool incorporates a brief geriatric assessment along with several laboratory test results and patient, tumor, and planned chemotherapy characteristics. The results generate a score that’s predictive of grade 3-5 chemotherapy toxicity. This predictive model performed well when tested in 500 older patients with a variety of cancers in a multicenter, prospective study conducted by the Cancer and Aging Research Group (J. Clin. Oncol. 2011;29:3457-65).

The physician’s portion of this brief geriatric assessment takes about 10 minutes and consists of three items: the Timed Up & Go test, a measure of functional status; the Blessed Orientation-Memory-Concentration test, a screen for cognitive function; and the Karnofksy performance status (KPS), a performance status measure commonly used in oncology.

The patient self-report part of the assessment takes 20-30 minutes and consists of validated scales measuring comorbidity, functional status, psychological state, social support, nutrition, and medications.

"If you’re as efficient as I am in the clinic, patients have a lot of time to do this before they see you," Dr. Muss quipped.

Scores of 0-25 are possible on this brief geriatric assessment. In the 500-patient multicenter validation study, grade 3-5 chemotherapy toxicity occurred in 53% of study participants. The incidence was 30% among patients with a score of 0-5, 52% in those with a score of 6-9, 77% with a score of 10 or 11, and 89% with a score of 12-19.

Among the significant predictive variables in this study, five stood out: one or more falls in the past 6 months; hearing impairment; difficulty in walking one block; decreased social activity; and need for assistance in taking medications.

"I’ve read hundreds of history and physical exam reports and I never see those data in there," Dr. Muss observed.

Because many oncologists now rely largely upon the KPS in an effort to predict chemotherapy toxicity, the investigators compared its performance to that of the structured brief geriatric assessment. The KPS paled in comparison.

"We pride ourselves in oncology on our judgment of performance status, but the KPS was just about worthless in predicting this. I think this brief geriatric assessment tool has made a real difference," the oncologist commented.

Indeed, pretreatment brief geriatric assessments are now being incorporated into many ongoing oncology clinical trials applying a new and badly needed focus on elderly patients with a variety of cancers, he added.

Geriatric assessments done in real time in the office "might help you identify certain problems in your patients and intervene before you get them on adjuvant chemotherapy or radiation therapy," Dr. Muss explained.

For example, identifying an elderly patient who is predisposed to falling might generate a referral to physical therapy for balance training prior to adjuvant therapy. That could improve quality of life and functional status and might even extend survival. This prospect is going to be tested in a planned randomized trial with standard care in the control group.

Also under active study are a variety of biomarkers that might predict chemotherapy toxicity and functional loss. Dr. Muss and coworkers are focusing on p16INK4A, also known as cyclin-dependent kinase inhibitor 2A or multiple tumor suppressor 1. Levels of this protein increase dramatically with tissue aging.

"As cells accumulate this protein due to increased gene expression, they become senescent. (That finding applies to) all our cells, from our blood cells to our T cells to our glomerular cells. So this is a wonderful marker of aging and we want to see if it’s an independent predictor of toxicity and functional loss. We’re doing those studies now," he said.

Dr. Muss reported that he serves as a consultant to Pfizer and Eisai.

[email protected]

SAN ANTONIO – Breast cancer outcomes haven’t improved to nearly the same impressive extent in older women as in younger women, according to Dr. Hyman B. Muss.

The reasons for this age-related disparity in breast cancer–specific survival include the increased level of comorbidities in the elderly, the underrepresentation of geriatric patients in major clinical trials, and oncologists’ limited geriatric training, he said in his Susan G. Komen for the Cure Brinker Award Lecture for Scientific Distinction in Clinical Research.

While the benefits of chemotherapy are similar in seniors and younger patients, the risks of serious toxicity are greater with age, he noted. Here’s where a pretreatment geriatric assessment to identify clinical predictors of morbidity and mortality can be enormously helpful, said Dr. Muss, professor of medicine and director of the geriatric oncology program at the University of North Carolina, Chapel Hill.

A growing body of data speaks to the importance of determining comorbidities to offer optimal treatment to elderly breast cancer patients. In a soon-to-be-published update of the Cancer and Leukemia Group 9343 trial of more than 600 elderly women with early breast cancer, for example, 51% of participants were still alive at the 12-year follow up. Of those who died, just 3% died of breast cancer; the other 46% died from other causes.

"If an elderly breast cancer patient in your office has high blood pressure or a blood sugar of 300 mg/dL, that’s almost more important than whether or not she gets radiation ... is cancer the patient’s major illness or is it something else, like diabetes or cardiac disease? The key thing we should be thinking of is not ‘How old are you?’ but ‘What’s your life expectancy?’ " he said.

Online tools can aid in those evaluations, including Adjuvant! Online (www.adjuvantonline.com). This tool allows one to factor comorbid conditions into clinical decisions about adjuvant therapy in women with early breast cancer. Also helpful is ePrognosis (www.eprognosis.org), which provides several scales to estimate an older community-dwelling individual’s life expectancy without breast cancer. The ePrognosis tool "can help you make a better decision about how aggressively to treat breast cancer. Some of my colleagues are doing this now in the office. It just takes a few minutes and is very user friendly," Dr. Muss said.

He said he is particularly impressed with a predictive tool developed by Dr. Arti Hurria and coworkers at the City of Hope Comprehensive Cancer Center in Duarte, Calif. This tool incorporates a brief geriatric assessment along with several laboratory test results and patient, tumor, and planned chemotherapy characteristics. The results generate a score that’s predictive of grade 3-5 chemotherapy toxicity. This predictive model performed well when tested in 500 older patients with a variety of cancers in a multicenter, prospective study conducted by the Cancer and Aging Research Group (J. Clin. Oncol. 2011;29:3457-65).

The physician’s portion of this brief geriatric assessment takes about 10 minutes and consists of three items: the Timed Up & Go test, a measure of functional status; the Blessed Orientation-Memory-Concentration test, a screen for cognitive function; and the Karnofksy performance status (KPS), a performance status measure commonly used in oncology.

The patient self-report part of the assessment takes 20-30 minutes and consists of validated scales measuring comorbidity, functional status, psychological state, social support, nutrition, and medications.

"If you’re as efficient as I am in the clinic, patients have a lot of time to do this before they see you," Dr. Muss quipped.

Scores of 0-25 are possible on this brief geriatric assessment. In the 500-patient multicenter validation study, grade 3-5 chemotherapy toxicity occurred in 53% of study participants. The incidence was 30% among patients with a score of 0-5, 52% in those with a score of 6-9, 77% with a score of 10 or 11, and 89% with a score of 12-19.

Among the significant predictive variables in this study, five stood out: one or more falls in the past 6 months; hearing impairment; difficulty in walking one block; decreased social activity; and need for assistance in taking medications.

"I’ve read hundreds of history and physical exam reports and I never see those data in there," Dr. Muss observed.

Because many oncologists now rely largely upon the KPS in an effort to predict chemotherapy toxicity, the investigators compared its performance to that of the structured brief geriatric assessment. The KPS paled in comparison.

"We pride ourselves in oncology on our judgment of performance status, but the KPS was just about worthless in predicting this. I think this brief geriatric assessment tool has made a real difference," the oncologist commented.

Indeed, pretreatment brief geriatric assessments are now being incorporated into many ongoing oncology clinical trials applying a new and badly needed focus on elderly patients with a variety of cancers, he added.

Geriatric assessments done in real time in the office "might help you identify certain problems in your patients and intervene before you get them on adjuvant chemotherapy or radiation therapy," Dr. Muss explained.

For example, identifying an elderly patient who is predisposed to falling might generate a referral to physical therapy for balance training prior to adjuvant therapy. That could improve quality of life and functional status and might even extend survival. This prospect is going to be tested in a planned randomized trial with standard care in the control group.

Also under active study are a variety of biomarkers that might predict chemotherapy toxicity and functional loss. Dr. Muss and coworkers are focusing on p16INK4A, also known as cyclin-dependent kinase inhibitor 2A or multiple tumor suppressor 1. Levels of this protein increase dramatically with tissue aging.

"As cells accumulate this protein due to increased gene expression, they become senescent. (That finding applies to) all our cells, from our blood cells to our T cells to our glomerular cells. So this is a wonderful marker of aging and we want to see if it’s an independent predictor of toxicity and functional loss. We’re doing those studies now," he said.

Dr. Muss reported that he serves as a consultant to Pfizer and Eisai.

[email protected]

SAN ANTONIO – Breast cancer outcomes haven’t improved to nearly the same impressive extent in older women as in younger women, according to Dr. Hyman B. Muss.

The reasons for this age-related disparity in breast cancer–specific survival include the increased level of comorbidities in the elderly, the underrepresentation of geriatric patients in major clinical trials, and oncologists’ limited geriatric training, he said in his Susan G. Komen for the Cure Brinker Award Lecture for Scientific Distinction in Clinical Research.

While the benefits of chemotherapy are similar in seniors and younger patients, the risks of serious toxicity are greater with age, he noted. Here’s where a pretreatment geriatric assessment to identify clinical predictors of morbidity and mortality can be enormously helpful, said Dr. Muss, professor of medicine and director of the geriatric oncology program at the University of North Carolina, Chapel Hill.

A growing body of data speaks to the importance of determining comorbidities to offer optimal treatment to elderly breast cancer patients. In a soon-to-be-published update of the Cancer and Leukemia Group 9343 trial of more than 600 elderly women with early breast cancer, for example, 51% of participants were still alive at the 12-year follow up. Of those who died, just 3% died of breast cancer; the other 46% died from other causes.

"If an elderly breast cancer patient in your office has high blood pressure or a blood sugar of 300 mg/dL, that’s almost more important than whether or not she gets radiation ... is cancer the patient’s major illness or is it something else, like diabetes or cardiac disease? The key thing we should be thinking of is not ‘How old are you?’ but ‘What’s your life expectancy?’ " he said.

Online tools can aid in those evaluations, including Adjuvant! Online (www.adjuvantonline.com). This tool allows one to factor comorbid conditions into clinical decisions about adjuvant therapy in women with early breast cancer. Also helpful is ePrognosis (www.eprognosis.org), which provides several scales to estimate an older community-dwelling individual’s life expectancy without breast cancer. The ePrognosis tool "can help you make a better decision about how aggressively to treat breast cancer. Some of my colleagues are doing this now in the office. It just takes a few minutes and is very user friendly," Dr. Muss said.

He said he is particularly impressed with a predictive tool developed by Dr. Arti Hurria and coworkers at the City of Hope Comprehensive Cancer Center in Duarte, Calif. This tool incorporates a brief geriatric assessment along with several laboratory test results and patient, tumor, and planned chemotherapy characteristics. The results generate a score that’s predictive of grade 3-5 chemotherapy toxicity. This predictive model performed well when tested in 500 older patients with a variety of cancers in a multicenter, prospective study conducted by the Cancer and Aging Research Group (J. Clin. Oncol. 2011;29:3457-65).

The physician’s portion of this brief geriatric assessment takes about 10 minutes and consists of three items: the Timed Up & Go test, a measure of functional status; the Blessed Orientation-Memory-Concentration test, a screen for cognitive function; and the Karnofksy performance status (KPS), a performance status measure commonly used in oncology.

The patient self-report part of the assessment takes 20-30 minutes and consists of validated scales measuring comorbidity, functional status, psychological state, social support, nutrition, and medications.

"If you’re as efficient as I am in the clinic, patients have a lot of time to do this before they see you," Dr. Muss quipped.

Scores of 0-25 are possible on this brief geriatric assessment. In the 500-patient multicenter validation study, grade 3-5 chemotherapy toxicity occurred in 53% of study participants. The incidence was 30% among patients with a score of 0-5, 52% in those with a score of 6-9, 77% with a score of 10 or 11, and 89% with a score of 12-19.

Among the significant predictive variables in this study, five stood out: one or more falls in the past 6 months; hearing impairment; difficulty in walking one block; decreased social activity; and need for assistance in taking medications.

"I’ve read hundreds of history and physical exam reports and I never see those data in there," Dr. Muss observed.

Because many oncologists now rely largely upon the KPS in an effort to predict chemotherapy toxicity, the investigators compared its performance to that of the structured brief geriatric assessment. The KPS paled in comparison.

"We pride ourselves in oncology on our judgment of performance status, but the KPS was just about worthless in predicting this. I think this brief geriatric assessment tool has made a real difference," the oncologist commented.

Indeed, pretreatment brief geriatric assessments are now being incorporated into many ongoing oncology clinical trials applying a new and badly needed focus on elderly patients with a variety of cancers, he added.

Geriatric assessments done in real time in the office "might help you identify certain problems in your patients and intervene before you get them on adjuvant chemotherapy or radiation therapy," Dr. Muss explained.

For example, identifying an elderly patient who is predisposed to falling might generate a referral to physical therapy for balance training prior to adjuvant therapy. That could improve quality of life and functional status and might even extend survival. This prospect is going to be tested in a planned randomized trial with standard care in the control group.

Also under active study are a variety of biomarkers that might predict chemotherapy toxicity and functional loss. Dr. Muss and coworkers are focusing on p16INK4A, also known as cyclin-dependent kinase inhibitor 2A or multiple tumor suppressor 1. Levels of this protein increase dramatically with tissue aging.

"As cells accumulate this protein due to increased gene expression, they become senescent. (That finding applies to) all our cells, from our blood cells to our T cells to our glomerular cells. So this is a wonderful marker of aging and we want to see if it’s an independent predictor of toxicity and functional loss. We’re doing those studies now," he said.

Dr. Muss reported that he serves as a consultant to Pfizer and Eisai.

[email protected]

SAN ANTONIO – Researchers have taken a first stride toward the goal of developing a gene test that predicts a breast cancer patient’s likelihood of a favorable clinical outcome in response to adjuvant trastuzumab.

A massive gene expression profiling analysis of baseline pretreatment tumor specimens obtained from 372 breast cancer patients identified 32 genes that correlated strongly with 5-year relapse-free survival, each with a P value less than .001, Dr. Edith A. Perez reported at the San Antonio Breast Cancer Symposium.

The ideal thing would be to find a gene that, if highly expressed, predicts for benefit or not of Herceptin [trastuzumab]. We are on our way to developing a predictive test that can define the right treatment for individual patients, and that is very exciting," declared Dr. Perez, deputy director at large of the Mayo Clinic Comprehensive Cancer Center and director of the breast cancer translational genomics program at the Mayo Clinic in Jacksonville, Fla.

In all, 27 of the genes were associated with good outcome, while the other 5 correlated with poor outcome. The major functional categories these genes are involved in have been identified: cell receptor signaling, chromatin structure and transcription, control of cell death, cell cycle, Wnt/beta-catenin signaling, and lipid signaling. It’s not yet known whether these 32 genes are expressed in the epithelial or the stromal component of the tumors, and it will be challenging to figure that out, she said.

All 372 specimens in this analysis came from women randomized to adjuvant chemotherapy plus concurrent trastuzumab in the previously reported North Central Cancer Treatment Group N9831 trial. The N9831 trial was one of the pivotal studies that led to adjuvant trastuzumab plus chemotherapy becoming established as the standard of care in treating HER2-positive breast cancer

Dr. Perez and her coinvestigators have also just completed a gene expression profiling analysis of baseline tumor samples from an additional 910 women in the N9831 trial who were randomized to either chemotherapy alone or chemotherapy followed sequentially by trastuzumab. The plan is to identify similarities and differences in the patterns of gene expression in the chemotherapy-only and the two chemotherapy-plus-trastuzumab groups in order to home in more specifically on genes associated with the outcome of trastuzumab therapy. Those data weren’t ready for presentation at the symposium.

The study used the DNA-mediated DASL (annealing, extension, selection, and ligation) assay marketed by Illumina to scrutinize the activity of more than 29,000 genes in tumor specimens from 1,262 N9831 trial participants.

In addition, Dr. Perez and her coworkers are collaborating with other investigators around the world who also conducted adjuvant trastuzumab trials with collections of tumor samples, including the HERA (Herceptin Adjuvant) and FinHer studies, in order to carry out a validation study.

Discussant Dr. Dennis C. Sgroi called this work tremendously exciting. He noted that trastuzumab is a very expensive drug, and roughly 25% of treated patients relapse within 5 years. Trastuzumab also carries a risk of cardiotoxicity, and he was intrigued by Dr. Perez’ suggestion that the investigators believe they may have identified baseline tumor gene activity signatures predisposing to symptomatic cardiomyopathy and transient asymptomatic drops in left ventricular ejection fraction.

A noteworthy aspect of this study is that many of the 32 predictive genomic markers that were identified function in domains other than proliferation. Genes that figure in proliferation are the predominant drivers of the prognostic performance of Genomic Health’s Oncotype DX and all the other molecular biomarker assays developed to date. So the work of Dr. Perez and her coinvestigators is definitely next-generation in the molecular profiling arena, said Dr. Sgroi of Massachusetts General Hospital, Boston.

This study was funded by the National Cancer Institute, the Breast Cancer Research Foundation, and the 26.2 with Donna Foundation. Dr. Perez reported no financial conflicts.

SAN ANTONIO – Researchers have taken a first stride toward the goal of developing a gene test that predicts a breast cancer patient’s likelihood of a favorable clinical outcome in response to adjuvant trastuzumab.

A massive gene expression profiling analysis of baseline pretreatment tumor specimens obtained from 372 breast cancer patients identified 32 genes that correlated strongly with 5-year relapse-free survival, each with a P value less than .001, Dr. Edith A. Perez reported at the San Antonio Breast Cancer Symposium.

The ideal thing would be to find a gene that, if highly expressed, predicts for benefit or not of Herceptin [trastuzumab]. We are on our way to developing a predictive test that can define the right treatment for individual patients, and that is very exciting," declared Dr. Perez, deputy director at large of the Mayo Clinic Comprehensive Cancer Center and director of the breast cancer translational genomics program at the Mayo Clinic in Jacksonville, Fla.

In all, 27 of the genes were associated with good outcome, while the other 5 correlated with poor outcome. The major functional categories these genes are involved in have been identified: cell receptor signaling, chromatin structure and transcription, control of cell death, cell cycle, Wnt/beta-catenin signaling, and lipid signaling. It’s not yet known whether these 32 genes are expressed in the epithelial or the stromal component of the tumors, and it will be challenging to figure that out, she said.

All 372 specimens in this analysis came from women randomized to adjuvant chemotherapy plus concurrent trastuzumab in the previously reported North Central Cancer Treatment Group N9831 trial. The N9831 trial was one of the pivotal studies that led to adjuvant trastuzumab plus chemotherapy becoming established as the standard of care in treating HER2-positive breast cancer

Dr. Perez and her coinvestigators have also just completed a gene expression profiling analysis of baseline tumor samples from an additional 910 women in the N9831 trial who were randomized to either chemotherapy alone or chemotherapy followed sequentially by trastuzumab. The plan is to identify similarities and differences in the patterns of gene expression in the chemotherapy-only and the two chemotherapy-plus-trastuzumab groups in order to home in more specifically on genes associated with the outcome of trastuzumab therapy. Those data weren’t ready for presentation at the symposium.

The study used the DNA-mediated DASL (annealing, extension, selection, and ligation) assay marketed by Illumina to scrutinize the activity of more than 29,000 genes in tumor specimens from 1,262 N9831 trial participants.

In addition, Dr. Perez and her coworkers are collaborating with other investigators around the world who also conducted adjuvant trastuzumab trials with collections of tumor samples, including the HERA (Herceptin Adjuvant) and FinHer studies, in order to carry out a validation study.

Discussant Dr. Dennis C. Sgroi called this work tremendously exciting. He noted that trastuzumab is a very expensive drug, and roughly 25% of treated patients relapse within 5 years. Trastuzumab also carries a risk of cardiotoxicity, and he was intrigued by Dr. Perez’ suggestion that the investigators believe they may have identified baseline tumor gene activity signatures predisposing to symptomatic cardiomyopathy and transient asymptomatic drops in left ventricular ejection fraction.

A noteworthy aspect of this study is that many of the 32 predictive genomic markers that were identified function in domains other than proliferation. Genes that figure in proliferation are the predominant drivers of the prognostic performance of Genomic Health’s Oncotype DX and all the other molecular biomarker assays developed to date. So the work of Dr. Perez and her coinvestigators is definitely next-generation in the molecular profiling arena, said Dr. Sgroi of Massachusetts General Hospital, Boston.

This study was funded by the National Cancer Institute, the Breast Cancer Research Foundation, and the 26.2 with Donna Foundation. Dr. Perez reported no financial conflicts.

SAN ANTONIO – Researchers have taken a first stride toward the goal of developing a gene test that predicts a breast cancer patient’s likelihood of a favorable clinical outcome in response to adjuvant trastuzumab.

A massive gene expression profiling analysis of baseline pretreatment tumor specimens obtained from 372 breast cancer patients identified 32 genes that correlated strongly with 5-year relapse-free survival, each with a P value less than .001, Dr. Edith A. Perez reported at the San Antonio Breast Cancer Symposium.

The ideal thing would be to find a gene that, if highly expressed, predicts for benefit or not of Herceptin [trastuzumab]. We are on our way to developing a predictive test that can define the right treatment for individual patients, and that is very exciting," declared Dr. Perez, deputy director at large of the Mayo Clinic Comprehensive Cancer Center and director of the breast cancer translational genomics program at the Mayo Clinic in Jacksonville, Fla.

In all, 27 of the genes were associated with good outcome, while the other 5 correlated with poor outcome. The major functional categories these genes are involved in have been identified: cell receptor signaling, chromatin structure and transcription, control of cell death, cell cycle, Wnt/beta-catenin signaling, and lipid signaling. It’s not yet known whether these 32 genes are expressed in the epithelial or the stromal component of the tumors, and it will be challenging to figure that out, she said.

All 372 specimens in this analysis came from women randomized to adjuvant chemotherapy plus concurrent trastuzumab in the previously reported North Central Cancer Treatment Group N9831 trial. The N9831 trial was one of the pivotal studies that led to adjuvant trastuzumab plus chemotherapy becoming established as the standard of care in treating HER2-positive breast cancer

Dr. Perez and her coinvestigators have also just completed a gene expression profiling analysis of baseline tumor samples from an additional 910 women in the N9831 trial who were randomized to either chemotherapy alone or chemotherapy followed sequentially by trastuzumab. The plan is to identify similarities and differences in the patterns of gene expression in the chemotherapy-only and the two chemotherapy-plus-trastuzumab groups in order to home in more specifically on genes associated with the outcome of trastuzumab therapy. Those data weren’t ready for presentation at the symposium.

The study used the DNA-mediated DASL (annealing, extension, selection, and ligation) assay marketed by Illumina to scrutinize the activity of more than 29,000 genes in tumor specimens from 1,262 N9831 trial participants.

In addition, Dr. Perez and her coworkers are collaborating with other investigators around the world who also conducted adjuvant trastuzumab trials with collections of tumor samples, including the HERA (Herceptin Adjuvant) and FinHer studies, in order to carry out a validation study.

Discussant Dr. Dennis C. Sgroi called this work tremendously exciting. He noted that trastuzumab is a very expensive drug, and roughly 25% of treated patients relapse within 5 years. Trastuzumab also carries a risk of cardiotoxicity, and he was intrigued by Dr. Perez’ suggestion that the investigators believe they may have identified baseline tumor gene activity signatures predisposing to symptomatic cardiomyopathy and transient asymptomatic drops in left ventricular ejection fraction.

A noteworthy aspect of this study is that many of the 32 predictive genomic markers that were identified function in domains other than proliferation. Genes that figure in proliferation are the predominant drivers of the prognostic performance of Genomic Health’s Oncotype DX and all the other molecular biomarker assays developed to date. So the work of Dr. Perez and her coinvestigators is definitely next-generation in the molecular profiling arena, said Dr. Sgroi of Massachusetts General Hospital, Boston.

This study was funded by the National Cancer Institute, the Breast Cancer Research Foundation, and the 26.2 with Donna Foundation. Dr. Perez reported no financial conflicts.

SAN ANTONIO – Diabetes is independently associated with a 27% increased risk of breast cancer, but this elevated risk is confined to postmenopausal type 2 diabetic patients, a large meta-analysis has shown.

The meta-analysis, which included 40 published studies and 56,111 women with breast cancer, found no association between risk of the malignancy and circulating serum insulin level, insulin growth factor–1 level, fasting blood glucose level, or C-peptide concentration.

These findings suggest that the hyperinsulinemic theory of the pathogenesis of breast cancer may need to be reevaluated in order to account for the increased risk being confined to postmenopausal patients and unrelated to indices of metabolic control, Dr. Peter Boyle said at the annual San Antonio Breast Cancer Symposium.

The key risk factors for breast cancer that emerged from the meta-analysis were adiposity and lack of physical activity. Both are also well established as risk factors for diabetes.

Based on the findings from this meta-analysis, efforts to avoid overweight and increase physical activity should form the basis of a common public health strategy simultaneously aimed at preventing diabetes and breast cancer, according to Dr. Boyle of the International Prevention Research Institute in Lyon, France.

High levels of physical activity, whether occupational or recreational, were independently associated with a 17% reduction in the relative risk of being diagnosed with breast cancer in premenopausal women and a 12% decrease in the postmenopausal population.

The relationship between adiposity and breast cancer was less straightforward. Premenopausal women who were overweight or obese had a significantly lower breast cancer risk than did leaner women, while breast cancer risk was increased in adipose postmenopausal women. More specifically, a 5-U increase in body mass index – equivalent to an extra 14.5 kg in a woman 1.7 m tall – was associated with an 11% increased risk of breast cancer in postmenopausal women but a 10% reduction in risk in premenopausal women.

Dr. Boyle and coworkers also presented a related meta-analysis looking at breast cancer risk in women using insulin glargine (Lantus). The study was prompted by recent evidence linking pioglitazone to a possible increase in bladder cancer, liraglutide and pancreatic cancer, insulin use and lung cancer, and exenatide and pancreatic cancer.

This meta-analysis included 18 epidemiologic studies published within the past 3 years. Collectively the studies involved 4,080 cases of breast cancer in 903,675 patients followed for 2.7 million person-years.

The meta-analysis demonstrated no increase in breast cancer risk in insulin glargine users, compared with users of other insulins. Indeed, the risk of all forms of cancer was 9% lower in insulin glargine users, a statistically significant reduction. This was driven by a 14% reduction in the relative risk of colorectal cancer.

Another reassuring finding was that breast cancer risk did not increase with longer use of insulin glargine, as would be expected if a causal relationship existed, he added.

Both meta-analyses were funded by Sanofi-Aventis, which markets glargine. Dr. Boyle reported having no relevant financial conflicts, although several of his coinvestigators have served on advisory boards for Sanofi-Aventis and other insulin manufacturers.

SAN ANTONIO – Diabetes is independently associated with a 27% increased risk of breast cancer, but this elevated risk is confined to postmenopausal type 2 diabetic patients, a large meta-analysis has shown.

The meta-analysis, which included 40 published studies and 56,111 women with breast cancer, found no association between risk of the malignancy and circulating serum insulin level, insulin growth factor–1 level, fasting blood glucose level, or C-peptide concentration.

These findings suggest that the hyperinsulinemic theory of the pathogenesis of breast cancer may need to be reevaluated in order to account for the increased risk being confined to postmenopausal patients and unrelated to indices of metabolic control, Dr. Peter Boyle said at the annual San Antonio Breast Cancer Symposium.

The key risk factors for breast cancer that emerged from the meta-analysis were adiposity and lack of physical activity. Both are also well established as risk factors for diabetes.

Based on the findings from this meta-analysis, efforts to avoid overweight and increase physical activity should form the basis of a common public health strategy simultaneously aimed at preventing diabetes and breast cancer, according to Dr. Boyle of the International Prevention Research Institute in Lyon, France.

High levels of physical activity, whether occupational or recreational, were independently associated with a 17% reduction in the relative risk of being diagnosed with breast cancer in premenopausal women and a 12% decrease in the postmenopausal population.

The relationship between adiposity and breast cancer was less straightforward. Premenopausal women who were overweight or obese had a significantly lower breast cancer risk than did leaner women, while breast cancer risk was increased in adipose postmenopausal women. More specifically, a 5-U increase in body mass index – equivalent to an extra 14.5 kg in a woman 1.7 m tall – was associated with an 11% increased risk of breast cancer in postmenopausal women but a 10% reduction in risk in premenopausal women.

Dr. Boyle and coworkers also presented a related meta-analysis looking at breast cancer risk in women using insulin glargine (Lantus). The study was prompted by recent evidence linking pioglitazone to a possible increase in bladder cancer, liraglutide and pancreatic cancer, insulin use and lung cancer, and exenatide and pancreatic cancer.

This meta-analysis included 18 epidemiologic studies published within the past 3 years. Collectively the studies involved 4,080 cases of breast cancer in 903,675 patients followed for 2.7 million person-years.

The meta-analysis demonstrated no increase in breast cancer risk in insulin glargine users, compared with users of other insulins. Indeed, the risk of all forms of cancer was 9% lower in insulin glargine users, a statistically significant reduction. This was driven by a 14% reduction in the relative risk of colorectal cancer.

Another reassuring finding was that breast cancer risk did not increase with longer use of insulin glargine, as would be expected if a causal relationship existed, he added.

Both meta-analyses were funded by Sanofi-Aventis, which markets glargine. Dr. Boyle reported having no relevant financial conflicts, although several of his coinvestigators have served on advisory boards for Sanofi-Aventis and other insulin manufacturers.

SAN ANTONIO – Diabetes is independently associated with a 27% increased risk of breast cancer, but this elevated risk is confined to postmenopausal type 2 diabetic patients, a large meta-analysis has shown.

The meta-analysis, which included 40 published studies and 56,111 women with breast cancer, found no association between risk of the malignancy and circulating serum insulin level, insulin growth factor–1 level, fasting blood glucose level, or C-peptide concentration.

These findings suggest that the hyperinsulinemic theory of the pathogenesis of breast cancer may need to be reevaluated in order to account for the increased risk being confined to postmenopausal patients and unrelated to indices of metabolic control, Dr. Peter Boyle said at the annual San Antonio Breast Cancer Symposium.

The key risk factors for breast cancer that emerged from the meta-analysis were adiposity and lack of physical activity. Both are also well established as risk factors for diabetes.

Based on the findings from this meta-analysis, efforts to avoid overweight and increase physical activity should form the basis of a common public health strategy simultaneously aimed at preventing diabetes and breast cancer, according to Dr. Boyle of the International Prevention Research Institute in Lyon, France.

High levels of physical activity, whether occupational or recreational, were independently associated with a 17% reduction in the relative risk of being diagnosed with breast cancer in premenopausal women and a 12% decrease in the postmenopausal population.

The relationship between adiposity and breast cancer was less straightforward. Premenopausal women who were overweight or obese had a significantly lower breast cancer risk than did leaner women, while breast cancer risk was increased in adipose postmenopausal women. More specifically, a 5-U increase in body mass index – equivalent to an extra 14.5 kg in a woman 1.7 m tall – was associated with an 11% increased risk of breast cancer in postmenopausal women but a 10% reduction in risk in premenopausal women.

Dr. Boyle and coworkers also presented a related meta-analysis looking at breast cancer risk in women using insulin glargine (Lantus). The study was prompted by recent evidence linking pioglitazone to a possible increase in bladder cancer, liraglutide and pancreatic cancer, insulin use and lung cancer, and exenatide and pancreatic cancer.

This meta-analysis included 18 epidemiologic studies published within the past 3 years. Collectively the studies involved 4,080 cases of breast cancer in 903,675 patients followed for 2.7 million person-years.

The meta-analysis demonstrated no increase in breast cancer risk in insulin glargine users, compared with users of other insulins. Indeed, the risk of all forms of cancer was 9% lower in insulin glargine users, a statistically significant reduction. This was driven by a 14% reduction in the relative risk of colorectal cancer.

Another reassuring finding was that breast cancer risk did not increase with longer use of insulin glargine, as would be expected if a causal relationship existed, he added.

Both meta-analyses were funded by Sanofi-Aventis, which markets glargine. Dr. Boyle reported having no relevant financial conflicts, although several of his coinvestigators have served on advisory boards for Sanofi-Aventis and other insulin manufacturers.