Breast Cancer

SAN FRANCISCO – Patients with breast cancer who received hormone therapy were over seven times more likely to show cognitive decline as were untreated patients after controlling for other factors, based on a prospective study of 81 patients.

Further, objective results on neuropsychological testing tended to back up patients’ complaints of cognitive difficulties.

Hormone therapy may be a risk factor for cognitive deficits, and interventional studies should be designed to focus on this group of patients, Dr. Hope S. Rugo and her associates recommended in a poster presentation at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The study collected neuropsychological test results and patient reports before treatment and at several points after starting hormone therapy (22 patients), chemotherapy (14), or chemotherapy followed by hormone therapy (33), and in a control group of 12 untreated patients.

Compared with baseline results, nearly 25% of patients had cognitive decline on neuropsychological testing after 5 months. (Among treated patients, this occurred 1 month after ending chemotherapy or 5 months after starting hormone therapy.) Nearly 35% had cognitive declines at 9 months of follow-up, and 30% had cognitive declines after 18 months.

"Decline in cognitive function is common in patients receiving adjuvant therapy for early-stage breast cancer," concluded Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. "Ongoing hormone therapy appears to be a risk factor for worse cognitive function."

Other factors that did not predict cognitive decline in the multivariate analysis included age, education level, average estradiol level over time, and estimated verbal IQ at baseline.

Separate univariate conditional logistic regression analyses found that hormone therapy predicted cognitive decline with an odds ratio of 5, but chemotherapy, radiation therapy, average fatigue over time, and average depression over time were not predictive of cognitive decline at any point.

The study enrolled women aged 35-80 years with early-stage breast cancer. Those who underwent adjuvant therapy received 3-4 months of chemotherapy alone, 5 years of hormone therapy alone, or both.

A separate analysis in the same study looked at how well subjective patient reports correlated with objective measures on neuropsychological tests. Dr. Lara Heflin and her associates found significant cross-section correlations between patient-reported cognitive problems and psychological distress and fatigue.

After researchers controlled for the influence of depression and fatigue, however, significant relationships remained between patients’ perceived cognitive functioning and measurable cognitive decline from baseline (pretreatment) to the first follow-up. Patients whose scores indicated memory decline were more likely to perceive memory problems, and patients whose scores on letter fluency declined were more likely to perceive problems with verbal fluency.

"Patients who self-report cognitive problems may indeed be experiencing cognitive decline, and their self-report should not simply be attributed to fatigue or to psychological factors such as anxiety and depression," concluded Dr. Heflin, a visiting professor of psychology at New Mexico Highlands University, Las Vegas.

Patients in the study had no prior chemotherapy or central nervous system radiation and no history of major psychiatric illness, serious head injury, neurologic disease, drug or alcohol abuse, or significant medical illness. The median age was 54 years, and 78% of patients were white. Patient characteristics were similar between groups.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

The National Institutes of Health funded the study. Dr. Rugo reported having financial associations with Merck, Novartis, and Pfizer.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – Patients with breast cancer who received hormone therapy were over seven times more likely to show cognitive decline as were untreated patients after controlling for other factors, based on a prospective study of 81 patients.

Further, objective results on neuropsychological testing tended to back up patients’ complaints of cognitive difficulties.

Hormone therapy may be a risk factor for cognitive deficits, and interventional studies should be designed to focus on this group of patients, Dr. Hope S. Rugo and her associates recommended in a poster presentation at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The study collected neuropsychological test results and patient reports before treatment and at several points after starting hormone therapy (22 patients), chemotherapy (14), or chemotherapy followed by hormone therapy (33), and in a control group of 12 untreated patients.

Compared with baseline results, nearly 25% of patients had cognitive decline on neuropsychological testing after 5 months. (Among treated patients, this occurred 1 month after ending chemotherapy or 5 months after starting hormone therapy.) Nearly 35% had cognitive declines at 9 months of follow-up, and 30% had cognitive declines after 18 months.

"Decline in cognitive function is common in patients receiving adjuvant therapy for early-stage breast cancer," concluded Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. "Ongoing hormone therapy appears to be a risk factor for worse cognitive function."

Other factors that did not predict cognitive decline in the multivariate analysis included age, education level, average estradiol level over time, and estimated verbal IQ at baseline.

Separate univariate conditional logistic regression analyses found that hormone therapy predicted cognitive decline with an odds ratio of 5, but chemotherapy, radiation therapy, average fatigue over time, and average depression over time were not predictive of cognitive decline at any point.

The study enrolled women aged 35-80 years with early-stage breast cancer. Those who underwent adjuvant therapy received 3-4 months of chemotherapy alone, 5 years of hormone therapy alone, or both.

A separate analysis in the same study looked at how well subjective patient reports correlated with objective measures on neuropsychological tests. Dr. Lara Heflin and her associates found significant cross-section correlations between patient-reported cognitive problems and psychological distress and fatigue.

After researchers controlled for the influence of depression and fatigue, however, significant relationships remained between patients’ perceived cognitive functioning and measurable cognitive decline from baseline (pretreatment) to the first follow-up. Patients whose scores indicated memory decline were more likely to perceive memory problems, and patients whose scores on letter fluency declined were more likely to perceive problems with verbal fluency.

"Patients who self-report cognitive problems may indeed be experiencing cognitive decline, and their self-report should not simply be attributed to fatigue or to psychological factors such as anxiety and depression," concluded Dr. Heflin, a visiting professor of psychology at New Mexico Highlands University, Las Vegas.

Patients in the study had no prior chemotherapy or central nervous system radiation and no history of major psychiatric illness, serious head injury, neurologic disease, drug or alcohol abuse, or significant medical illness. The median age was 54 years, and 78% of patients were white. Patient characteristics were similar between groups.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

The National Institutes of Health funded the study. Dr. Rugo reported having financial associations with Merck, Novartis, and Pfizer.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – Patients with breast cancer who received hormone therapy were over seven times more likely to show cognitive decline as were untreated patients after controlling for other factors, based on a prospective study of 81 patients.

Further, objective results on neuropsychological testing tended to back up patients’ complaints of cognitive difficulties.

Hormone therapy may be a risk factor for cognitive deficits, and interventional studies should be designed to focus on this group of patients, Dr. Hope S. Rugo and her associates recommended in a poster presentation at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The study collected neuropsychological test results and patient reports before treatment and at several points after starting hormone therapy (22 patients), chemotherapy (14), or chemotherapy followed by hormone therapy (33), and in a control group of 12 untreated patients.

Compared with baseline results, nearly 25% of patients had cognitive decline on neuropsychological testing after 5 months. (Among treated patients, this occurred 1 month after ending chemotherapy or 5 months after starting hormone therapy.) Nearly 35% had cognitive declines at 9 months of follow-up, and 30% had cognitive declines after 18 months.

"Decline in cognitive function is common in patients receiving adjuvant therapy for early-stage breast cancer," concluded Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. "Ongoing hormone therapy appears to be a risk factor for worse cognitive function."

Other factors that did not predict cognitive decline in the multivariate analysis included age, education level, average estradiol level over time, and estimated verbal IQ at baseline.

Separate univariate conditional logistic regression analyses found that hormone therapy predicted cognitive decline with an odds ratio of 5, but chemotherapy, radiation therapy, average fatigue over time, and average depression over time were not predictive of cognitive decline at any point.

The study enrolled women aged 35-80 years with early-stage breast cancer. Those who underwent adjuvant therapy received 3-4 months of chemotherapy alone, 5 years of hormone therapy alone, or both.

A separate analysis in the same study looked at how well subjective patient reports correlated with objective measures on neuropsychological tests. Dr. Lara Heflin and her associates found significant cross-section correlations between patient-reported cognitive problems and psychological distress and fatigue.

After researchers controlled for the influence of depression and fatigue, however, significant relationships remained between patients’ perceived cognitive functioning and measurable cognitive decline from baseline (pretreatment) to the first follow-up. Patients whose scores indicated memory decline were more likely to perceive memory problems, and patients whose scores on letter fluency declined were more likely to perceive problems with verbal fluency.

"Patients who self-report cognitive problems may indeed be experiencing cognitive decline, and their self-report should not simply be attributed to fatigue or to psychological factors such as anxiety and depression," concluded Dr. Heflin, a visiting professor of psychology at New Mexico Highlands University, Las Vegas.

Patients in the study had no prior chemotherapy or central nervous system radiation and no history of major psychiatric illness, serious head injury, neurologic disease, drug or alcohol abuse, or significant medical illness. The median age was 54 years, and 78% of patients were white. Patient characteristics were similar between groups.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

The National Institutes of Health funded the study. Dr. Rugo reported having financial associations with Merck, Novartis, and Pfizer.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

BOSTON – Less than half of all women of child-bearing age who are diagnosed with cancer discuss with their physicians the potential effects of cancer therapy on fertility, and even fewer are referred to reproductive specialists, investigators reported at the conjoint meeting of the International Federation of Fertility Societies and the American Society for Reproductive Medicine.

A survey of 1,282 female survivors of various cancers showed that more than 50% did not have a discussion with their oncologists about the possible deleterious effects of chemotherapy or radiation on fertility, and few patients received referrals to reproductive specialists, said Penelope P. Howards, Ph.D., assistant professor of epidemiology at Emory University’s Rollins School of Public Health in Atlanta.

"In our cohort, which was women who were diagnosed between 1990 and 2009, a large proportion is not getting the message about how treatments may affect their fertility," Dr. Howards said in an interview.

The likelihood that women would have been counseled about fertility varied by the type of cancer and by the typical treatment approach. For example, nearly 70% of women with cervical cancer said they had talked about fertility with their physicians, whereas women with cancers more typically managed by surgery – such as melanoma and thyroid cancer – were the least likely to be informed about potentially compromised fertility.

Only 60% of women with uterine cancers and 42% of women with ovarian cancers were told about the effects of treatment on fertility, despite having cancers of the reproductive system. Among women with breast cancer, the most common cancer type represented in the study, only 44% said they received fertility counseling.

Women who had at least one child by the time of diagnosis were less likely to be counseled than were women with no children (42% vs. 50%, respectively), and women aged 20-24 years were less likely to be informed about potentially compromised fertility than were women in their 30s, the investigators found.

Dr. Howards speculated that oncologists may assume that younger cancer patients are less likely to need counseling because they have a longer time to recover reproductive function than women who are approaching the age of menopause. Additionally, they may observe that young women who are rendered amenorrheic by cancer treatment may eventually resume menses, and wrongly assume that a return to menstruation indicates a return to full reproductive health.

Of those women who reported having a fertility discussion, 33% said they had initiated it themselves, 44% said that their oncologists had brought it up, and 23% said someone else initiated the discussion.

Dr. Howards and her colleagues searched the Georgia Cancer Registry to identify and interview women with a first diagnosis of cancer between the ages of 20 and 35 years. The interviews included questions about their reproductive histories, whether they had discussed with a clinician how cancer therapies might affect their fertility, and whether they had received a referral to a fertility specialist.

Factors that significantly predicted which women would be less likely to be counseled about infertility included having a child at diagnosis (adjusted odds ratio, 1.7), younger age at diagnosis (aOR, 1.5), being African American vs. white (aOR, 1.2), and not receiving chemotherapy or radiation (aOR, 3.1).

Of those women who did have a fertility discussion, only 6% of those with a child and 19% of those without children were referred to a fertility specialist.

An investigator who was not involved in the study said that the problem is not limited to women.

"With regard to men who get a diagnosis of cancer, we have seen that the discussion about their fertility status is not often had prior to getting a therapy that would affect their fertility status, such as chemotherapy, radiotherapy, or surgery," said Dr. Anand Shridharani, a urologist at the Erlanger Health System in Chattanooga, Tenn.

The study was supported by a grant from the Eunice Kennedy Shriver National Institute for Child Health and Development. Dr. Howards and Dr. Shridharani reported having no relevant disclosures.

BOSTON – Less than half of all women of child-bearing age who are diagnosed with cancer discuss with their physicians the potential effects of cancer therapy on fertility, and even fewer are referred to reproductive specialists, investigators reported at the conjoint meeting of the International Federation of Fertility Societies and the American Society for Reproductive Medicine.

A survey of 1,282 female survivors of various cancers showed that more than 50% did not have a discussion with their oncologists about the possible deleterious effects of chemotherapy or radiation on fertility, and few patients received referrals to reproductive specialists, said Penelope P. Howards, Ph.D., assistant professor of epidemiology at Emory University’s Rollins School of Public Health in Atlanta.

"In our cohort, which was women who were diagnosed between 1990 and 2009, a large proportion is not getting the message about how treatments may affect their fertility," Dr. Howards said in an interview.

The likelihood that women would have been counseled about fertility varied by the type of cancer and by the typical treatment approach. For example, nearly 70% of women with cervical cancer said they had talked about fertility with their physicians, whereas women with cancers more typically managed by surgery – such as melanoma and thyroid cancer – were the least likely to be informed about potentially compromised fertility.

Only 60% of women with uterine cancers and 42% of women with ovarian cancers were told about the effects of treatment on fertility, despite having cancers of the reproductive system. Among women with breast cancer, the most common cancer type represented in the study, only 44% said they received fertility counseling.

Women who had at least one child by the time of diagnosis were less likely to be counseled than were women with no children (42% vs. 50%, respectively), and women aged 20-24 years were less likely to be informed about potentially compromised fertility than were women in their 30s, the investigators found.

Dr. Howards speculated that oncologists may assume that younger cancer patients are less likely to need counseling because they have a longer time to recover reproductive function than women who are approaching the age of menopause. Additionally, they may observe that young women who are rendered amenorrheic by cancer treatment may eventually resume menses, and wrongly assume that a return to menstruation indicates a return to full reproductive health.

Of those women who reported having a fertility discussion, 33% said they had initiated it themselves, 44% said that their oncologists had brought it up, and 23% said someone else initiated the discussion.

Dr. Howards and her colleagues searched the Georgia Cancer Registry to identify and interview women with a first diagnosis of cancer between the ages of 20 and 35 years. The interviews included questions about their reproductive histories, whether they had discussed with a clinician how cancer therapies might affect their fertility, and whether they had received a referral to a fertility specialist.

Factors that significantly predicted which women would be less likely to be counseled about infertility included having a child at diagnosis (adjusted odds ratio, 1.7), younger age at diagnosis (aOR, 1.5), being African American vs. white (aOR, 1.2), and not receiving chemotherapy or radiation (aOR, 3.1).

Of those women who did have a fertility discussion, only 6% of those with a child and 19% of those without children were referred to a fertility specialist.

An investigator who was not involved in the study said that the problem is not limited to women.

"With regard to men who get a diagnosis of cancer, we have seen that the discussion about their fertility status is not often had prior to getting a therapy that would affect their fertility status, such as chemotherapy, radiotherapy, or surgery," said Dr. Anand Shridharani, a urologist at the Erlanger Health System in Chattanooga, Tenn.

The study was supported by a grant from the Eunice Kennedy Shriver National Institute for Child Health and Development. Dr. Howards and Dr. Shridharani reported having no relevant disclosures.

BOSTON – Less than half of all women of child-bearing age who are diagnosed with cancer discuss with their physicians the potential effects of cancer therapy on fertility, and even fewer are referred to reproductive specialists, investigators reported at the conjoint meeting of the International Federation of Fertility Societies and the American Society for Reproductive Medicine.

A survey of 1,282 female survivors of various cancers showed that more than 50% did not have a discussion with their oncologists about the possible deleterious effects of chemotherapy or radiation on fertility, and few patients received referrals to reproductive specialists, said Penelope P. Howards, Ph.D., assistant professor of epidemiology at Emory University’s Rollins School of Public Health in Atlanta.

"In our cohort, which was women who were diagnosed between 1990 and 2009, a large proportion is not getting the message about how treatments may affect their fertility," Dr. Howards said in an interview.

The likelihood that women would have been counseled about fertility varied by the type of cancer and by the typical treatment approach. For example, nearly 70% of women with cervical cancer said they had talked about fertility with their physicians, whereas women with cancers more typically managed by surgery – such as melanoma and thyroid cancer – were the least likely to be informed about potentially compromised fertility.

Only 60% of women with uterine cancers and 42% of women with ovarian cancers were told about the effects of treatment on fertility, despite having cancers of the reproductive system. Among women with breast cancer, the most common cancer type represented in the study, only 44% said they received fertility counseling.

Women who had at least one child by the time of diagnosis were less likely to be counseled than were women with no children (42% vs. 50%, respectively), and women aged 20-24 years were less likely to be informed about potentially compromised fertility than were women in their 30s, the investigators found.

Dr. Howards speculated that oncologists may assume that younger cancer patients are less likely to need counseling because they have a longer time to recover reproductive function than women who are approaching the age of menopause. Additionally, they may observe that young women who are rendered amenorrheic by cancer treatment may eventually resume menses, and wrongly assume that a return to menstruation indicates a return to full reproductive health.

Of those women who reported having a fertility discussion, 33% said they had initiated it themselves, 44% said that their oncologists had brought it up, and 23% said someone else initiated the discussion.

Dr. Howards and her colleagues searched the Georgia Cancer Registry to identify and interview women with a first diagnosis of cancer between the ages of 20 and 35 years. The interviews included questions about their reproductive histories, whether they had discussed with a clinician how cancer therapies might affect their fertility, and whether they had received a referral to a fertility specialist.

Factors that significantly predicted which women would be less likely to be counseled about infertility included having a child at diagnosis (adjusted odds ratio, 1.7), younger age at diagnosis (aOR, 1.5), being African American vs. white (aOR, 1.2), and not receiving chemotherapy or radiation (aOR, 3.1).

Of those women who did have a fertility discussion, only 6% of those with a child and 19% of those without children were referred to a fertility specialist.

An investigator who was not involved in the study said that the problem is not limited to women.

"With regard to men who get a diagnosis of cancer, we have seen that the discussion about their fertility status is not often had prior to getting a therapy that would affect their fertility status, such as chemotherapy, radiotherapy, or surgery," said Dr. Anand Shridharani, a urologist at the Erlanger Health System in Chattanooga, Tenn.

The study was supported by a grant from the Eunice Kennedy Shriver National Institute for Child Health and Development. Dr. Howards and Dr. Shridharani reported having no relevant disclosures.

AMSTERDAM – Irradiating the internal mammary and medial supraclavicular lymph nodes provides a survival benefit in women with stage I-III breast cancer, independent of the number of lymph nodes involved, a randomized, phase III trial has shown.

At 10 years, internal mammary–medial supraclavicular (IM-MS) irradiation significantly increased overall survival by 1.6%, compared with no IM-MS irradiation (82.3% vs. 80.7%; hazard ratio, 0.87; P = .056), disease-free survival by 3% (72.1% vs. 69.1%; HR, 0.89; P = .044), and metastases-free survival by 3% (78% vs. 75%; HR, 0.86; P = .02).

Importantly, there was "no increased lethal toxicity," Dr. Philip Poortmans reported on behalf of the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups during a presidential session at the European Cancer Congress 2013.

Patrice Wendling/IMNG Medical Media

With irradiation, "we might be able to stop metastasis at their source," he said.

Although metastatic lymph nodes in the axilla are usually treated by surgery and/or radiation therapy, the role of regional IM-MS radiotherapy has remained controversial and is not yet the standard of care, he acknowledged. The internal mammary chain is one of the known draining routes in breast cancer, but the benefits of irradiating such a large area are unclear, and concerns exist over increased late toxicity, particularly cardiac toxicity.

The internal lymph nodes are generally not treated in the United States. Even in the Netherlands, his center is the only one to routinely radiate the internal lymph nodes in high-risk patients, said Dr. Poortmans of the Institute Verbeeten in Tilburg, the Netherlands, and president-elect of the European Society for Radiotherapy and Oncology.

More modern radiation techniques and a trio of recent publications, however, are renewing the conversation. Overall survival and cancer-specific survival were increased with internal mammary node irradiation in a large series of 1,630 node-negative breast cancer patients with inner or centrally located tumors, he observed (Radiother. Oncol. 2013 [doi:10.1016/j.radonc.2013.06.028]).

Dr. Poortmans and EORTC trial 22922/10925 investigators at 46 institutions in 13 countries evenly randomized 4,004 women with stage I, II, and III breast cancer with involved axillary lymph nodes and/or a medially located primary tumor to IM-MS radiation (50 Gy in 25 fractions) or no IM-MS irradiation. Three-fourths of women (76.2%) had breast-conserving surgery, 55.6% had axillary lymph node involvement, and axillary radiation was given to 7.8% of women with IM-MS radiation and 6.8% without.

Radiation therapy was performed with the standard fields in 34%, adapted standard fields in 44%, and individualized in 22%, Dr. Poortmans said.

After a median follow-up of 10.9 years (maximum 15.9 years), 382 (9.5% of 4,004) women in the IM-MS arm had died vs. 429 women in the no IM-MS arm (10.7% of 4,004). The causes of death were similar in both groups, including cardiovascular disease (22 deaths vs. 20 deaths) and toxicity (one in each group), although breast cancer deaths were lower with IM-MS therapy (259 vs. 310), he said.

A multivariate analysis showed that the nodal stage did not significantly influence overall survival, although there was a trend favoring IM-MS irradiation with the use of adjuvant systemic therapy, Dr. Poortmans said. Nearly all lymph-node–positive patients (99%) and 66.3% of lymph-node–negative patients received adjuvant systemic therapy.

Commenting on the results, Dr. Roberto Orecchia, director of radiation therapy at the University of Milan, European Institute of Oncology, agreed that irradiation of the internal mammary chain is "quite controversial" and said there is greater consensus about its use in more locally advanced disease with positive nodes.

Part of the problem is inconsistent trial results, he said, pointing to a lack of 10-year overall survival benefit with internal mammary chain irradiation using two-dimensional techniques in one of the three studies highlighted by Dr. Poortmans (Int. J. Radiat. Oncol. Biol. Phys. 2013;86:860-6).

He said that technique may be a problem in the EORTC study, since it started in July 1996 and closed in January 2004 and radiation techniques have evolved, but observed that the lack of toxicity was reassuring.

"In the future, we probably have to consider [improving] our capability to select the patient, not only on the basis of the location of the tumor or the positivity/negativity of the axilla, but also to implement the use of more sophisticated imaging examinations like [positron emission tomography] or scintigraphy" to identify the patients who will benefit most from internal mammary chain irradiation, Dr. Orecchia said.

The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.

pwendling@frontlinemedcom.com

AMSTERDAM – Irradiating the internal mammary and medial supraclavicular lymph nodes provides a survival benefit in women with stage I-III breast cancer, independent of the number of lymph nodes involved, a randomized, phase III trial has shown.

At 10 years, internal mammary–medial supraclavicular (IM-MS) irradiation significantly increased overall survival by 1.6%, compared with no IM-MS irradiation (82.3% vs. 80.7%; hazard ratio, 0.87; P = .056), disease-free survival by 3% (72.1% vs. 69.1%; HR, 0.89; P = .044), and metastases-free survival by 3% (78% vs. 75%; HR, 0.86; P = .02).

Importantly, there was "no increased lethal toxicity," Dr. Philip Poortmans reported on behalf of the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups during a presidential session at the European Cancer Congress 2013.

Patrice Wendling/IMNG Medical Media

With irradiation, "we might be able to stop metastasis at their source," he said.

Although metastatic lymph nodes in the axilla are usually treated by surgery and/or radiation therapy, the role of regional IM-MS radiotherapy has remained controversial and is not yet the standard of care, he acknowledged. The internal mammary chain is one of the known draining routes in breast cancer, but the benefits of irradiating such a large area are unclear, and concerns exist over increased late toxicity, particularly cardiac toxicity.

The internal lymph nodes are generally not treated in the United States. Even in the Netherlands, his center is the only one to routinely radiate the internal lymph nodes in high-risk patients, said Dr. Poortmans of the Institute Verbeeten in Tilburg, the Netherlands, and president-elect of the European Society for Radiotherapy and Oncology.

More modern radiation techniques and a trio of recent publications, however, are renewing the conversation. Overall survival and cancer-specific survival were increased with internal mammary node irradiation in a large series of 1,630 node-negative breast cancer patients with inner or centrally located tumors, he observed (Radiother. Oncol. 2013 [doi:10.1016/j.radonc.2013.06.028]).

Dr. Poortmans and EORTC trial 22922/10925 investigators at 46 institutions in 13 countries evenly randomized 4,004 women with stage I, II, and III breast cancer with involved axillary lymph nodes and/or a medially located primary tumor to IM-MS radiation (50 Gy in 25 fractions) or no IM-MS irradiation. Three-fourths of women (76.2%) had breast-conserving surgery, 55.6% had axillary lymph node involvement, and axillary radiation was given to 7.8% of women with IM-MS radiation and 6.8% without.

Radiation therapy was performed with the standard fields in 34%, adapted standard fields in 44%, and individualized in 22%, Dr. Poortmans said.

After a median follow-up of 10.9 years (maximum 15.9 years), 382 (9.5% of 4,004) women in the IM-MS arm had died vs. 429 women in the no IM-MS arm (10.7% of 4,004). The causes of death were similar in both groups, including cardiovascular disease (22 deaths vs. 20 deaths) and toxicity (one in each group), although breast cancer deaths were lower with IM-MS therapy (259 vs. 310), he said.

A multivariate analysis showed that the nodal stage did not significantly influence overall survival, although there was a trend favoring IM-MS irradiation with the use of adjuvant systemic therapy, Dr. Poortmans said. Nearly all lymph-node–positive patients (99%) and 66.3% of lymph-node–negative patients received adjuvant systemic therapy.

Commenting on the results, Dr. Roberto Orecchia, director of radiation therapy at the University of Milan, European Institute of Oncology, agreed that irradiation of the internal mammary chain is "quite controversial" and said there is greater consensus about its use in more locally advanced disease with positive nodes.

Part of the problem is inconsistent trial results, he said, pointing to a lack of 10-year overall survival benefit with internal mammary chain irradiation using two-dimensional techniques in one of the three studies highlighted by Dr. Poortmans (Int. J. Radiat. Oncol. Biol. Phys. 2013;86:860-6).

He said that technique may be a problem in the EORTC study, since it started in July 1996 and closed in January 2004 and radiation techniques have evolved, but observed that the lack of toxicity was reassuring.

"In the future, we probably have to consider [improving] our capability to select the patient, not only on the basis of the location of the tumor or the positivity/negativity of the axilla, but also to implement the use of more sophisticated imaging examinations like [positron emission tomography] or scintigraphy" to identify the patients who will benefit most from internal mammary chain irradiation, Dr. Orecchia said.

The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.

pwendling@frontlinemedcom.com

AMSTERDAM – Irradiating the internal mammary and medial supraclavicular lymph nodes provides a survival benefit in women with stage I-III breast cancer, independent of the number of lymph nodes involved, a randomized, phase III trial has shown.

At 10 years, internal mammary–medial supraclavicular (IM-MS) irradiation significantly increased overall survival by 1.6%, compared with no IM-MS irradiation (82.3% vs. 80.7%; hazard ratio, 0.87; P = .056), disease-free survival by 3% (72.1% vs. 69.1%; HR, 0.89; P = .044), and metastases-free survival by 3% (78% vs. 75%; HR, 0.86; P = .02).

Importantly, there was "no increased lethal toxicity," Dr. Philip Poortmans reported on behalf of the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups during a presidential session at the European Cancer Congress 2013.

Patrice Wendling/IMNG Medical Media

With irradiation, "we might be able to stop metastasis at their source," he said.

Although metastatic lymph nodes in the axilla are usually treated by surgery and/or radiation therapy, the role of regional IM-MS radiotherapy has remained controversial and is not yet the standard of care, he acknowledged. The internal mammary chain is one of the known draining routes in breast cancer, but the benefits of irradiating such a large area are unclear, and concerns exist over increased late toxicity, particularly cardiac toxicity.

The internal lymph nodes are generally not treated in the United States. Even in the Netherlands, his center is the only one to routinely radiate the internal lymph nodes in high-risk patients, said Dr. Poortmans of the Institute Verbeeten in Tilburg, the Netherlands, and president-elect of the European Society for Radiotherapy and Oncology.

More modern radiation techniques and a trio of recent publications, however, are renewing the conversation. Overall survival and cancer-specific survival were increased with internal mammary node irradiation in a large series of 1,630 node-negative breast cancer patients with inner or centrally located tumors, he observed (Radiother. Oncol. 2013 [doi:10.1016/j.radonc.2013.06.028]).

Dr. Poortmans and EORTC trial 22922/10925 investigators at 46 institutions in 13 countries evenly randomized 4,004 women with stage I, II, and III breast cancer with involved axillary lymph nodes and/or a medially located primary tumor to IM-MS radiation (50 Gy in 25 fractions) or no IM-MS irradiation. Three-fourths of women (76.2%) had breast-conserving surgery, 55.6% had axillary lymph node involvement, and axillary radiation was given to 7.8% of women with IM-MS radiation and 6.8% without.

Radiation therapy was performed with the standard fields in 34%, adapted standard fields in 44%, and individualized in 22%, Dr. Poortmans said.

After a median follow-up of 10.9 years (maximum 15.9 years), 382 (9.5% of 4,004) women in the IM-MS arm had died vs. 429 women in the no IM-MS arm (10.7% of 4,004). The causes of death were similar in both groups, including cardiovascular disease (22 deaths vs. 20 deaths) and toxicity (one in each group), although breast cancer deaths were lower with IM-MS therapy (259 vs. 310), he said.

A multivariate analysis showed that the nodal stage did not significantly influence overall survival, although there was a trend favoring IM-MS irradiation with the use of adjuvant systemic therapy, Dr. Poortmans said. Nearly all lymph-node–positive patients (99%) and 66.3% of lymph-node–negative patients received adjuvant systemic therapy.

Commenting on the results, Dr. Roberto Orecchia, director of radiation therapy at the University of Milan, European Institute of Oncology, agreed that irradiation of the internal mammary chain is "quite controversial" and said there is greater consensus about its use in more locally advanced disease with positive nodes.

Part of the problem is inconsistent trial results, he said, pointing to a lack of 10-year overall survival benefit with internal mammary chain irradiation using two-dimensional techniques in one of the three studies highlighted by Dr. Poortmans (Int. J. Radiat. Oncol. Biol. Phys. 2013;86:860-6).

He said that technique may be a problem in the EORTC study, since it started in July 1996 and closed in January 2004 and radiation techniques have evolved, but observed that the lack of toxicity was reassuring.

"In the future, we probably have to consider [improving] our capability to select the patient, not only on the basis of the location of the tumor or the positivity/negativity of the axilla, but also to implement the use of more sophisticated imaging examinations like [positron emission tomography] or scintigraphy" to identify the patients who will benefit most from internal mammary chain irradiation, Dr. Orecchia said.

The study was supported by grants from the National Cancer Institute. Dr. Poortmans and Dr. Orecchia reported having no financial disclosures.

pwendling@frontlinemedcom.com

Rates of contralateral prophylactic mastectomy in breast cancer are on the rise, but are clinical indications always present to justify the procedure? Dr. Todd Tuttle discusses the trend and cautions physicians to provide patients with accurate assessments of cancer risk and the procedure's actual effects on life expectancy..

Rates of contralateral prophylactic mastectomy in breast cancer are on the rise, but are clinical indications always present to justify the procedure? Dr. Todd Tuttle discusses the trend and cautions physicians to provide patients with accurate assessments of cancer risk and the procedure's actual effects on life expectancy..

Rates of contralateral prophylactic mastectomy in breast cancer are on the rise, but are clinical indications always present to justify the procedure? Dr. Todd Tuttle discusses the trend and cautions physicians to provide patients with accurate assessments of cancer risk and the procedure's actual effects on life expectancy..

LAS VEGAS – Concerns about use of a tumor necrosis factor inhibitor in a rheumatoid arthritis patient with a history of cancer are common, but the data are largely reassuring, according to Dr. Iain McInnes.

He used as an example a case involving a 56-year-old woman who had erosive RA that was anti-citrullinated peptide antibody–positive (ACPA+). The woman failed triple therapy, responded well to etanercept, and achieved clinical remission after 9 months. The patient then developed breast cancer and her TNF inhibitor was stopped, as recommended by current American College of Rheumatology guidelines.

The patient returned a year later after undergoing "the whole gamut from the oncological armamentarium," including chemotherapy, radiation therapy, and surgery.

"So what do you do? She wants her TNF blocker back – she did very well on it," said Dr. McInnes, who is Muirhead Chair of Medicine and Director of Institute of Infection, Immunity, and Inflammation at the University of Glasgow, Scotland.

Prescribe a conventional disease-modifying antirheumatic drug (DMARD)? Try a different mode of action?

What if the patient is a 56-year-old female with ACPA+ erosive RA who failed triple therapy and leflunomide; is doing poorly; has a history of breast cancer treated successfully 3 years ago by lumpectomy, radiation therapy and chemotherapy; and asks for a change in therapy?

According to the ACR guidelines, any biologic agent can be used in a patient with solid malignancy or nonmelanoma skin cancer that was treated more than 5 years ago, while rituximab should be considered in those treated for a solid malignancy within the last 5 years, those treated with nonmelanoma skin cancer within the last 5 years, those treated for skin melanoma, and those treated for lymphoproliferative malignancy.

The British Society of Rheumatology guidelines are "broadly similar but less restrictive on the use of rituximab, and less restrictive of the time duration from solid malignancy to decision making," Dr. McInnes said at Perspectives in Rheumatic Diseases 2013.

A number of studies looking at whether TNF inhibitors are associated with increased cancer risk have been published and, basically, "the more one looks at the data, the less concerned one becomes," he said.

In a large meta-analysis that included 74 randomized controlled studies, more than 15,400 patients treated with TNF inhibitors, and nearly 7,500 controls, investigators found no evidence to support or refute a link between TNF inhibitors treatment and short-term risk of all cancers except nonmelanoma skin cancer. The risk of nonmelanoma skin cancer, however, was nearly more than doubled in the treatment group (Pharmacoedpidemiol. Drug Saf. 2011;20:119-30).

A 2012 study demonstrated a very low risk of malignancy among patients on TNF inhibitors across several registries (Rheum. Dis. Clin. North Am. 2012;38:761-70).

Also, a study published earlier this year showed that, in nearly 40,000 patients with various types of rheumatic diseases, treatment with anti-TNF drugs was not associated with a short-term increase in the risk of cancer, compared with commonly used therapies for immune-mediated chronic inflammatory diseases (Arthritis Rheum. 2013;65:48-58).

Another large population-based cohort study published this year (BMJ 2013;346:f1939), showed that RA patients treated with TNF inhibitors are not at increased overall risk for cancer, but they do have a 50% increased relative risk of invasive melanoma. The increase in absolute melanoma risk is small, however, and "may not markedly shift the overall risk-benefit balance of TNF inhibitors as used in clinical practice but might do so in patients at high risk of melanoma for other reasons."

Notably, another large study published in 2011 linked data from multiple Swedish clinical registries of RA with nationwide data on hospitalization and outpatient visits for RA, showing that cancers that occur in patients taking TNF inhibitors are not characterized by any distinction, such as a later stage at presentation or worse survival.

"This is true whether you look at overall cancer or lung, colorectal, or hematologic cancers. You can reassure your patient," Dr. McInnes said.

As for RA patients with a history of prior malignancy, findings from a 2010 analysis of data from the British Society for Rheumatology Biologics Register showed that, in 117 patients on a DMARD and 177 on an anti-TNF drug, the risk of cancer was actually greater among those on a DMARD, with a rate of incident malignancy per 1,000 person-years of 25.3 in the anti-TNF patients, compared with 38.3 in the DMARD patients (Arthritis Care Res. 2010;62:755-63).

"When you look at the numbers they are, by and large, reassuring, and this is the message you should give to patients, but make decisions on an individual-patient basis," Dr. McInnes said.

Dr. McInnes disclosed that he has been a speaker, adviser, and/or investigator for Janssen, Roche, Pfizer, BMS, and Novartis. The meeting was held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

LAS VEGAS – Concerns about use of a tumor necrosis factor inhibitor in a rheumatoid arthritis patient with a history of cancer are common, but the data are largely reassuring, according to Dr. Iain McInnes.

He used as an example a case involving a 56-year-old woman who had erosive RA that was anti-citrullinated peptide antibody–positive (ACPA+). The woman failed triple therapy, responded well to etanercept, and achieved clinical remission after 9 months. The patient then developed breast cancer and her TNF inhibitor was stopped, as recommended by current American College of Rheumatology guidelines.

The patient returned a year later after undergoing "the whole gamut from the oncological armamentarium," including chemotherapy, radiation therapy, and surgery.

"So what do you do? She wants her TNF blocker back – she did very well on it," said Dr. McInnes, who is Muirhead Chair of Medicine and Director of Institute of Infection, Immunity, and Inflammation at the University of Glasgow, Scotland.

Prescribe a conventional disease-modifying antirheumatic drug (DMARD)? Try a different mode of action?

What if the patient is a 56-year-old female with ACPA+ erosive RA who failed triple therapy and leflunomide; is doing poorly; has a history of breast cancer treated successfully 3 years ago by lumpectomy, radiation therapy and chemotherapy; and asks for a change in therapy?

According to the ACR guidelines, any biologic agent can be used in a patient with solid malignancy or nonmelanoma skin cancer that was treated more than 5 years ago, while rituximab should be considered in those treated for a solid malignancy within the last 5 years, those treated with nonmelanoma skin cancer within the last 5 years, those treated for skin melanoma, and those treated for lymphoproliferative malignancy.

The British Society of Rheumatology guidelines are "broadly similar but less restrictive on the use of rituximab, and less restrictive of the time duration from solid malignancy to decision making," Dr. McInnes said at Perspectives in Rheumatic Diseases 2013.

A number of studies looking at whether TNF inhibitors are associated with increased cancer risk have been published and, basically, "the more one looks at the data, the less concerned one becomes," he said.

In a large meta-analysis that included 74 randomized controlled studies, more than 15,400 patients treated with TNF inhibitors, and nearly 7,500 controls, investigators found no evidence to support or refute a link between TNF inhibitors treatment and short-term risk of all cancers except nonmelanoma skin cancer. The risk of nonmelanoma skin cancer, however, was nearly more than doubled in the treatment group (Pharmacoedpidemiol. Drug Saf. 2011;20:119-30).

A 2012 study demonstrated a very low risk of malignancy among patients on TNF inhibitors across several registries (Rheum. Dis. Clin. North Am. 2012;38:761-70).

Also, a study published earlier this year showed that, in nearly 40,000 patients with various types of rheumatic diseases, treatment with anti-TNF drugs was not associated with a short-term increase in the risk of cancer, compared with commonly used therapies for immune-mediated chronic inflammatory diseases (Arthritis Rheum. 2013;65:48-58).

Another large population-based cohort study published this year (BMJ 2013;346:f1939), showed that RA patients treated with TNF inhibitors are not at increased overall risk for cancer, but they do have a 50% increased relative risk of invasive melanoma. The increase in absolute melanoma risk is small, however, and "may not markedly shift the overall risk-benefit balance of TNF inhibitors as used in clinical practice but might do so in patients at high risk of melanoma for other reasons."

Notably, another large study published in 2011 linked data from multiple Swedish clinical registries of RA with nationwide data on hospitalization and outpatient visits for RA, showing that cancers that occur in patients taking TNF inhibitors are not characterized by any distinction, such as a later stage at presentation or worse survival.

"This is true whether you look at overall cancer or lung, colorectal, or hematologic cancers. You can reassure your patient," Dr. McInnes said.

As for RA patients with a history of prior malignancy, findings from a 2010 analysis of data from the British Society for Rheumatology Biologics Register showed that, in 117 patients on a DMARD and 177 on an anti-TNF drug, the risk of cancer was actually greater among those on a DMARD, with a rate of incident malignancy per 1,000 person-years of 25.3 in the anti-TNF patients, compared with 38.3 in the DMARD patients (Arthritis Care Res. 2010;62:755-63).

"When you look at the numbers they are, by and large, reassuring, and this is the message you should give to patients, but make decisions on an individual-patient basis," Dr. McInnes said.

Dr. McInnes disclosed that he has been a speaker, adviser, and/or investigator for Janssen, Roche, Pfizer, BMS, and Novartis. The meeting was held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

LAS VEGAS – Concerns about use of a tumor necrosis factor inhibitor in a rheumatoid arthritis patient with a history of cancer are common, but the data are largely reassuring, according to Dr. Iain McInnes.

He used as an example a case involving a 56-year-old woman who had erosive RA that was anti-citrullinated peptide antibody–positive (ACPA+). The woman failed triple therapy, responded well to etanercept, and achieved clinical remission after 9 months. The patient then developed breast cancer and her TNF inhibitor was stopped, as recommended by current American College of Rheumatology guidelines.

The patient returned a year later after undergoing "the whole gamut from the oncological armamentarium," including chemotherapy, radiation therapy, and surgery.

"So what do you do? She wants her TNF blocker back – she did very well on it," said Dr. McInnes, who is Muirhead Chair of Medicine and Director of Institute of Infection, Immunity, and Inflammation at the University of Glasgow, Scotland.

Prescribe a conventional disease-modifying antirheumatic drug (DMARD)? Try a different mode of action?

What if the patient is a 56-year-old female with ACPA+ erosive RA who failed triple therapy and leflunomide; is doing poorly; has a history of breast cancer treated successfully 3 years ago by lumpectomy, radiation therapy and chemotherapy; and asks for a change in therapy?

According to the ACR guidelines, any biologic agent can be used in a patient with solid malignancy or nonmelanoma skin cancer that was treated more than 5 years ago, while rituximab should be considered in those treated for a solid malignancy within the last 5 years, those treated with nonmelanoma skin cancer within the last 5 years, those treated for skin melanoma, and those treated for lymphoproliferative malignancy.

The British Society of Rheumatology guidelines are "broadly similar but less restrictive on the use of rituximab, and less restrictive of the time duration from solid malignancy to decision making," Dr. McInnes said at Perspectives in Rheumatic Diseases 2013.

A number of studies looking at whether TNF inhibitors are associated with increased cancer risk have been published and, basically, "the more one looks at the data, the less concerned one becomes," he said.

In a large meta-analysis that included 74 randomized controlled studies, more than 15,400 patients treated with TNF inhibitors, and nearly 7,500 controls, investigators found no evidence to support or refute a link between TNF inhibitors treatment and short-term risk of all cancers except nonmelanoma skin cancer. The risk of nonmelanoma skin cancer, however, was nearly more than doubled in the treatment group (Pharmacoedpidemiol. Drug Saf. 2011;20:119-30).

A 2012 study demonstrated a very low risk of malignancy among patients on TNF inhibitors across several registries (Rheum. Dis. Clin. North Am. 2012;38:761-70).

Also, a study published earlier this year showed that, in nearly 40,000 patients with various types of rheumatic diseases, treatment with anti-TNF drugs was not associated with a short-term increase in the risk of cancer, compared with commonly used therapies for immune-mediated chronic inflammatory diseases (Arthritis Rheum. 2013;65:48-58).

Another large population-based cohort study published this year (BMJ 2013;346:f1939), showed that RA patients treated with TNF inhibitors are not at increased overall risk for cancer, but they do have a 50% increased relative risk of invasive melanoma. The increase in absolute melanoma risk is small, however, and "may not markedly shift the overall risk-benefit balance of TNF inhibitors as used in clinical practice but might do so in patients at high risk of melanoma for other reasons."

Notably, another large study published in 2011 linked data from multiple Swedish clinical registries of RA with nationwide data on hospitalization and outpatient visits for RA, showing that cancers that occur in patients taking TNF inhibitors are not characterized by any distinction, such as a later stage at presentation or worse survival.

"This is true whether you look at overall cancer or lung, colorectal, or hematologic cancers. You can reassure your patient," Dr. McInnes said.

As for RA patients with a history of prior malignancy, findings from a 2010 analysis of data from the British Society for Rheumatology Biologics Register showed that, in 117 patients on a DMARD and 177 on an anti-TNF drug, the risk of cancer was actually greater among those on a DMARD, with a rate of incident malignancy per 1,000 person-years of 25.3 in the anti-TNF patients, compared with 38.3 in the DMARD patients (Arthritis Care Res. 2010;62:755-63).

"When you look at the numbers they are, by and large, reassuring, and this is the message you should give to patients, but make decisions on an individual-patient basis," Dr. McInnes said.

Dr. McInnes disclosed that he has been a speaker, adviser, and/or investigator for Janssen, Roche, Pfizer, BMS, and Novartis. The meeting was held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

AMSTERDAM – Ado-trastuzumab emtansine nearly doubled the time to disease progression for women with heavily pretreated, HER2-positive metastatic breast cancer compared with physician’s choice of treatment in the open-label, phase III TH3RESA trial.

Median progression-free survival was 6.2 months with ado-trastuzumab emtansine (Kadcyla), previously known as T-DM1, and 3.3 months with a treatment of physician’s choice (hazard ratio 0.528; P less than .0001).

Courtesy European CanCer Organisation

Physician’s choice included chemotherapy and trastuzumab (Herceptin) (68.5%), lapatinib and trastuzumab (10.3%), chemotherapy and lapatinib (2.7%), and hormonal therapy and trastuzumab (1.6%).

An interim overall survival analysis also favored T-DM1 (median not reached vs. 14.9 months; HR 0.552; P = .0034), with the final analysis expected in 2015, Dr. Hans Wildiers said in a presidential session at the multidisciplinary European cancer congresses.

The data reaffirm results from the phase III EMILIA trial, demonstrating a consistent benefit with T-DM1 in previously treated human epidermal growth factor receptor 2–positive (HER2-positive) advanced breast cancer.

"In my opinion, combining EMELIA and TH3RESA, T-DM1 should become the standard of care," he added.

As previously reported, EMILIA showed a 5-month gain in overall survival with T-DM1 over capecitabine (Xeloda) plus lapatinib (Tykerb) in relapsed, metastatic breast cancer.

This led to the approval of T-DM1 in February 2013 in the United States for the treatment of HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. T-DM1 is expected to gain European Union approval by the end of the year, according to Genentech, which markets the drug.

Notably, a total of 80.4% of patients in that arm received a regimen containing trastuzumab.* Median progression-free survival (PFS) in this subgroup was significantly extended by 3 months with T-DM1 compared with physician’s choice (3.2 vs. 6.2; HR 0.558; P less than .001), said Dr. Wildiers of University Hospitals Leuven, Belgium.

Commenting on the results, invited discussant Dr. Clifford Hudis, chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York, said he is optimistic T-DM1 will deliver an overall survival advantage because prior research has shown that a small incremental improvement in PFS, measured in weeks, can lead to an improvement in months in overall survival simply by reintroducing trastuzumab (J. Clin. Oncol. 2012;30:2585-92).

"A definitive and clinically meaningful overall survival may just be what some markets need to bless this approach, but cost will be an issue," he said. "Arguably, we’re more willing to tolerate the higher cost when overall survival is improved, but even without it, I would see the toxicity advantage as worth a lot."

Patients treated with T-DM1 were less likely than were those given their physician’s choice to reduce dosage (9.4% vs. 19.6%) or stop treatment due to an adverse event (6.7% vs. 11%), Dr. Wildiers said. Grade 3 or higher adverse events were also lower with T-DM1 (32.3% vs. 43.5%).

Significantly more women also responded to T-DM1 than to their physician’s choice (31.3% vs. 8.6%; P less than .001). Further, analyses showed "a clear and consistent effect" that T-DM1 was better across all subgroups, he said.

When pressed by the audience on how T-DM1 should be used in clinical practice, Dr. Wildiers said T-DM1 should likely be reserved for the second-line setting until results are known from the ongoing MARIANNE trial. The phase III trial is evaluating T-DM1 with pertuzumab (Perjeta) versus trastuzumab plus a taxane in women with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer.

Dr. Wildiers reported serving on an advisory board for Roche. His coauthors disclosed ties with several firms, including employment with Genentech, which markets ado-trastuzumab emtansine.

pwendling@frontlinemedcom.com

*CORRECTION, 10/10/13: A previous version of this story did not clearly describe the patients who received trastuzumab in the physician's choice arm of TH3RESA.

AMSTERDAM – Ado-trastuzumab emtansine nearly doubled the time to disease progression for women with heavily pretreated, HER2-positive metastatic breast cancer compared with physician’s choice of treatment in the open-label, phase III TH3RESA trial.

Median progression-free survival was 6.2 months with ado-trastuzumab emtansine (Kadcyla), previously known as T-DM1, and 3.3 months with a treatment of physician’s choice (hazard ratio 0.528; P less than .0001).

Courtesy European CanCer Organisation

Physician’s choice included chemotherapy and trastuzumab (Herceptin) (68.5%), lapatinib and trastuzumab (10.3%), chemotherapy and lapatinib (2.7%), and hormonal therapy and trastuzumab (1.6%).

An interim overall survival analysis also favored T-DM1 (median not reached vs. 14.9 months; HR 0.552; P = .0034), with the final analysis expected in 2015, Dr. Hans Wildiers said in a presidential session at the multidisciplinary European cancer congresses.

The data reaffirm results from the phase III EMILIA trial, demonstrating a consistent benefit with T-DM1 in previously treated human epidermal growth factor receptor 2–positive (HER2-positive) advanced breast cancer.

"In my opinion, combining EMELIA and TH3RESA, T-DM1 should become the standard of care," he added.

As previously reported, EMILIA showed a 5-month gain in overall survival with T-DM1 over capecitabine (Xeloda) plus lapatinib (Tykerb) in relapsed, metastatic breast cancer.

This led to the approval of T-DM1 in February 2013 in the United States for the treatment of HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. T-DM1 is expected to gain European Union approval by the end of the year, according to Genentech, which markets the drug.

Notably, a total of 80.4% of patients in that arm received a regimen containing trastuzumab.* Median progression-free survival (PFS) in this subgroup was significantly extended by 3 months with T-DM1 compared with physician’s choice (3.2 vs. 6.2; HR 0.558; P less than .001), said Dr. Wildiers of University Hospitals Leuven, Belgium.

Commenting on the results, invited discussant Dr. Clifford Hudis, chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York, said he is optimistic T-DM1 will deliver an overall survival advantage because prior research has shown that a small incremental improvement in PFS, measured in weeks, can lead to an improvement in months in overall survival simply by reintroducing trastuzumab (J. Clin. Oncol. 2012;30:2585-92).

"A definitive and clinically meaningful overall survival may just be what some markets need to bless this approach, but cost will be an issue," he said. "Arguably, we’re more willing to tolerate the higher cost when overall survival is improved, but even without it, I would see the toxicity advantage as worth a lot."

Patients treated with T-DM1 were less likely than were those given their physician’s choice to reduce dosage (9.4% vs. 19.6%) or stop treatment due to an adverse event (6.7% vs. 11%), Dr. Wildiers said. Grade 3 or higher adverse events were also lower with T-DM1 (32.3% vs. 43.5%).

Significantly more women also responded to T-DM1 than to their physician’s choice (31.3% vs. 8.6%; P less than .001). Further, analyses showed "a clear and consistent effect" that T-DM1 was better across all subgroups, he said.

When pressed by the audience on how T-DM1 should be used in clinical practice, Dr. Wildiers said T-DM1 should likely be reserved for the second-line setting until results are known from the ongoing MARIANNE trial. The phase III trial is evaluating T-DM1 with pertuzumab (Perjeta) versus trastuzumab plus a taxane in women with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer.

Dr. Wildiers reported serving on an advisory board for Roche. His coauthors disclosed ties with several firms, including employment with Genentech, which markets ado-trastuzumab emtansine.

pwendling@frontlinemedcom.com

*CORRECTION, 10/10/13: A previous version of this story did not clearly describe the patients who received trastuzumab in the physician's choice arm of TH3RESA.

AMSTERDAM – Ado-trastuzumab emtansine nearly doubled the time to disease progression for women with heavily pretreated, HER2-positive metastatic breast cancer compared with physician’s choice of treatment in the open-label, phase III TH3RESA trial.

Median progression-free survival was 6.2 months with ado-trastuzumab emtansine (Kadcyla), previously known as T-DM1, and 3.3 months with a treatment of physician’s choice (hazard ratio 0.528; P less than .0001).

Courtesy European CanCer Organisation

Physician’s choice included chemotherapy and trastuzumab (Herceptin) (68.5%), lapatinib and trastuzumab (10.3%), chemotherapy and lapatinib (2.7%), and hormonal therapy and trastuzumab (1.6%).

An interim overall survival analysis also favored T-DM1 (median not reached vs. 14.9 months; HR 0.552; P = .0034), with the final analysis expected in 2015, Dr. Hans Wildiers said in a presidential session at the multidisciplinary European cancer congresses.

The data reaffirm results from the phase III EMILIA trial, demonstrating a consistent benefit with T-DM1 in previously treated human epidermal growth factor receptor 2–positive (HER2-positive) advanced breast cancer.

"In my opinion, combining EMELIA and TH3RESA, T-DM1 should become the standard of care," he added.

As previously reported, EMILIA showed a 5-month gain in overall survival with T-DM1 over capecitabine (Xeloda) plus lapatinib (Tykerb) in relapsed, metastatic breast cancer.

This led to the approval of T-DM1 in February 2013 in the United States for the treatment of HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. T-DM1 is expected to gain European Union approval by the end of the year, according to Genentech, which markets the drug.

Notably, a total of 80.4% of patients in that arm received a regimen containing trastuzumab.* Median progression-free survival (PFS) in this subgroup was significantly extended by 3 months with T-DM1 compared with physician’s choice (3.2 vs. 6.2; HR 0.558; P less than .001), said Dr. Wildiers of University Hospitals Leuven, Belgium.

Commenting on the results, invited discussant Dr. Clifford Hudis, chief of breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York, said he is optimistic T-DM1 will deliver an overall survival advantage because prior research has shown that a small incremental improvement in PFS, measured in weeks, can lead to an improvement in months in overall survival simply by reintroducing trastuzumab (J. Clin. Oncol. 2012;30:2585-92).

"A definitive and clinically meaningful overall survival may just be what some markets need to bless this approach, but cost will be an issue," he said. "Arguably, we’re more willing to tolerate the higher cost when overall survival is improved, but even without it, I would see the toxicity advantage as worth a lot."

Patients treated with T-DM1 were less likely than were those given their physician’s choice to reduce dosage (9.4% vs. 19.6%) or stop treatment due to an adverse event (6.7% vs. 11%), Dr. Wildiers said. Grade 3 or higher adverse events were also lower with T-DM1 (32.3% vs. 43.5%).

Significantly more women also responded to T-DM1 than to their physician’s choice (31.3% vs. 8.6%; P less than .001). Further, analyses showed "a clear and consistent effect" that T-DM1 was better across all subgroups, he said.

When pressed by the audience on how T-DM1 should be used in clinical practice, Dr. Wildiers said T-DM1 should likely be reserved for the second-line setting until results are known from the ongoing MARIANNE trial. The phase III trial is evaluating T-DM1 with pertuzumab (Perjeta) versus trastuzumab plus a taxane in women with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer.

Dr. Wildiers reported serving on an advisory board for Roche. His coauthors disclosed ties with several firms, including employment with Genentech, which markets ado-trastuzumab emtansine.

pwendling@frontlinemedcom.com

*CORRECTION, 10/10/13: A previous version of this story did not clearly describe the patients who received trastuzumab in the physician's choice arm of TH3RESA.

The false-negative rate of sentinel lymph node results was almost 13% after neoadjuvant chemotherapy, in a study of women initially presenting with biopsy-proven node-positive breast cancer, which is above the acceptable threshold, a study has shown.

Considering the threshold for a false-negative rate is 10%, "changes in approach and patient selection that result in greater sensitivity would be necessary" to support the use of sentinel lymph node (SLN) surgery "as an alternative" to axillary lymph node dissection in this population of patients with breast cancer, concluded Dr. Judy Boughey of the department of surgery, Mayo Clinic, Rochester, Minn., and her associates in the Alliance for Clinical Trials in Oncology.

The investigators also found that false-negative SLN biopsy results were significantly lower when two mapping agents were used; the false-negative rate was also significantly lower when at least three sentinel lymph nodes were sampled. The results of the study were presented at the annual clinical congress of the American Congress of Surgeons and simultaneously published online on Oct. 7, 2013, in JAMA (doi:10.1001/jama.2013.278932).

The phase II study addressed the false-negative rate of SLN biopsy after neoadjuvant chemotherapy, in women who initially presented with pathologically confirmed node-positive disease. The study enrolled 701 women from July 2009 to June 2011, at 136 institutions. The women had clinical stage T0 through T4, N1 through N2, M0 breast cancer; most (663) had cN1 disease (disease in movable axillary lymph nodes) and 38 had cN2 disease (disease in fixed or matted axillary lymph nodes). After chemotherapy was completed, the patients had surgery, involving SLN biopsy and axillary lymph node dissection.

Of the 701 women, 687 underwent both SLN biopsy and axillary lymph node dissection, 2 had only SLN biopsy, and 12 had axillary lymph node dissection only. Most of the 689 women who underwent SLN biopsy had the procedure performed with blue dye and radiolabeled colloid (79%), 116 (16.8%) had radiolabeled colloid only, and 28 (4.1%) had blue dye only.

Of the 689 women who had SLN biopsy, at least one SLN was detected in 639 (almost 93%). Among the 651 women with cN1 disease, at least one SLN was detected in 605 women (93%); and among the 38 women with cN2 disease, at least one SNL was detected in 34 (89.5%).

In 525 of the patients with cN1 disease, at least two SLNs were excised and axillary lymph node dissection was completed. There was no residual node disease found in 215 of these patients, for a nodal pathologic complete response rate of 41%.

Of the remaining 310 patients, nodal disease was found in the sentinel lymph nodes in 108 patients (20.6%), and in both axillary and sentinel nodes in 163 patients (31.1%).

Residual node disease was found in the axillary lymph nodes of only 39 (7.4%) of the patients. Therefore, the results of the SLN biopsy results were false negative in 39 of the 310 patients, for a false negative rate of 12.6%.

While the study results "suggest that surgeons cannot reliably detect all axillary lymph node metastases in patients with cN1 breast cancer following chemotherapy" with SLN procedures, "we did identify important factors influencing the likelihood of a false-negative SLN," the authors said. The false-negative rate for the SLN biopsy results was significantly decreased when both blue dye and radiolabeled colloid were used as mapping agents, and when at least three sentinel lymph nodes were biopsied.

When both blue dye and radiolabeled colloid were used, the false-negative rate was 10.8%, compared with 20.3% when only one agent was used. "Using two mapping agents with different molecule sizes and transit times is an important surgical standard that should be adhered to for SLN surgery after chemotherapy," they said, noting that after chemotherapy, "the axilla often has more fibrosis, making evaluation of lymphatic drainage and surgical dissection more challenging."

And when at least three SLNs were examined, the false negative rate was 9.1%, compared with 21.1% when two were sampled. "As the accuracy of any sampling test is dependent on the amount of material sampled, these results are not surprising," they said, noting that this has been found in other studies.

SLN is less invasive than axillary dissection and is considered a reliable way to check for axillary nodal disease in women who present with node-negative disease, but the use of SLN biopsy after neoadjuvant chemotherapy in women with cN1 disease "has been questioned," because the false-negative rate for this approach in this population has ranged from 7% to 25% in small studies, the only data available on this approach, according to the authors.

The study was supported by a grant from the National Cancer Institute to the American College of Surgeons Oncology Group (ACOSOG). The patients were in the ACOSOG Z1071 trial. Four of the authors reported having grants from the National Institutes of Health or Komen Foundation, having contracts with Galena BioPharma, or having been paid for lectures from LifeCell. The remaining 17 authors said they had no relevant financial disclosures.

emechcatie@frontlinemedcom.com

The false-negative rate of sentinel lymph node results was almost 13% after neoadjuvant chemotherapy, in a study of women initially presenting with biopsy-proven node-positive breast cancer, which is above the acceptable threshold, a study has shown.

Considering the threshold for a false-negative rate is 10%, "changes in approach and patient selection that result in greater sensitivity would be necessary" to support the use of sentinel lymph node (SLN) surgery "as an alternative" to axillary lymph node dissection in this population of patients with breast cancer, concluded Dr. Judy Boughey of the department of surgery, Mayo Clinic, Rochester, Minn., and her associates in the Alliance for Clinical Trials in Oncology.

The investigators also found that false-negative SLN biopsy results were significantly lower when two mapping agents were used; the false-negative rate was also significantly lower when at least three sentinel lymph nodes were sampled. The results of the study were presented at the annual clinical congress of the American Congress of Surgeons and simultaneously published online on Oct. 7, 2013, in JAMA (doi:10.1001/jama.2013.278932).

The phase II study addressed the false-negative rate of SLN biopsy after neoadjuvant chemotherapy, in women who initially presented with pathologically confirmed node-positive disease. The study enrolled 701 women from July 2009 to June 2011, at 136 institutions. The women had clinical stage T0 through T4, N1 through N2, M0 breast cancer; most (663) had cN1 disease (disease in movable axillary lymph nodes) and 38 had cN2 disease (disease in fixed or matted axillary lymph nodes). After chemotherapy was completed, the patients had surgery, involving SLN biopsy and axillary lymph node dissection.

Of the 701 women, 687 underwent both SLN biopsy and axillary lymph node dissection, 2 had only SLN biopsy, and 12 had axillary lymph node dissection only. Most of the 689 women who underwent SLN biopsy had the procedure performed with blue dye and radiolabeled colloid (79%), 116 (16.8%) had radiolabeled colloid only, and 28 (4.1%) had blue dye only.

Of the 689 women who had SLN biopsy, at least one SLN was detected in 639 (almost 93%). Among the 651 women with cN1 disease, at least one SLN was detected in 605 women (93%); and among the 38 women with cN2 disease, at least one SNL was detected in 34 (89.5%).

In 525 of the patients with cN1 disease, at least two SLNs were excised and axillary lymph node dissection was completed. There was no residual node disease found in 215 of these patients, for a nodal pathologic complete response rate of 41%.

Of the remaining 310 patients, nodal disease was found in the sentinel lymph nodes in 108 patients (20.6%), and in both axillary and sentinel nodes in 163 patients (31.1%).

Residual node disease was found in the axillary lymph nodes of only 39 (7.4%) of the patients. Therefore, the results of the SLN biopsy results were false negative in 39 of the 310 patients, for a false negative rate of 12.6%.

While the study results "suggest that surgeons cannot reliably detect all axillary lymph node metastases in patients with cN1 breast cancer following chemotherapy" with SLN procedures, "we did identify important factors influencing the likelihood of a false-negative SLN," the authors said. The false-negative rate for the SLN biopsy results was significantly decreased when both blue dye and radiolabeled colloid were used as mapping agents, and when at least three sentinel lymph nodes were biopsied.

When both blue dye and radiolabeled colloid were used, the false-negative rate was 10.8%, compared with 20.3% when only one agent was used. "Using two mapping agents with different molecule sizes and transit times is an important surgical standard that should be adhered to for SLN surgery after chemotherapy," they said, noting that after chemotherapy, "the axilla often has more fibrosis, making evaluation of lymphatic drainage and surgical dissection more challenging."

And when at least three SLNs were examined, the false negative rate was 9.1%, compared with 21.1% when two were sampled. "As the accuracy of any sampling test is dependent on the amount of material sampled, these results are not surprising," they said, noting that this has been found in other studies.

SLN is less invasive than axillary dissection and is considered a reliable way to check for axillary nodal disease in women who present with node-negative disease, but the use of SLN biopsy after neoadjuvant chemotherapy in women with cN1 disease "has been questioned," because the false-negative rate for this approach in this population has ranged from 7% to 25% in small studies, the only data available on this approach, according to the authors.

The study was supported by a grant from the National Cancer Institute to the American College of Surgeons Oncology Group (ACOSOG). The patients were in the ACOSOG Z1071 trial. Four of the authors reported having grants from the National Institutes of Health or Komen Foundation, having contracts with Galena BioPharma, or having been paid for lectures from LifeCell. The remaining 17 authors said they had no relevant financial disclosures.

emechcatie@frontlinemedcom.com

The false-negative rate of sentinel lymph node results was almost 13% after neoadjuvant chemotherapy, in a study of women initially presenting with biopsy-proven node-positive breast cancer, which is above the acceptable threshold, a study has shown.

Considering the threshold for a false-negative rate is 10%, "changes in approach and patient selection that result in greater sensitivity would be necessary" to support the use of sentinel lymph node (SLN) surgery "as an alternative" to axillary lymph node dissection in this population of patients with breast cancer, concluded Dr. Judy Boughey of the department of surgery, Mayo Clinic, Rochester, Minn., and her associates in the Alliance for Clinical Trials in Oncology.

The investigators also found that false-negative SLN biopsy results were significantly lower when two mapping agents were used; the false-negative rate was also significantly lower when at least three sentinel lymph nodes were sampled. The results of the study were presented at the annual clinical congress of the American Congress of Surgeons and simultaneously published online on Oct. 7, 2013, in JAMA (doi:10.1001/jama.2013.278932).

The phase II study addressed the false-negative rate of SLN biopsy after neoadjuvant chemotherapy, in women who initially presented with pathologically confirmed node-positive disease. The study enrolled 701 women from July 2009 to June 2011, at 136 institutions. The women had clinical stage T0 through T4, N1 through N2, M0 breast cancer; most (663) had cN1 disease (disease in movable axillary lymph nodes) and 38 had cN2 disease (disease in fixed or matted axillary lymph nodes). After chemotherapy was completed, the patients had surgery, involving SLN biopsy and axillary lymph node dissection.

Of the 701 women, 687 underwent both SLN biopsy and axillary lymph node dissection, 2 had only SLN biopsy, and 12 had axillary lymph node dissection only. Most of the 689 women who underwent SLN biopsy had the procedure performed with blue dye and radiolabeled colloid (79%), 116 (16.8%) had radiolabeled colloid only, and 28 (4.1%) had blue dye only.

Of the 689 women who had SLN biopsy, at least one SLN was detected in 639 (almost 93%). Among the 651 women with cN1 disease, at least one SLN was detected in 605 women (93%); and among the 38 women with cN2 disease, at least one SNL was detected in 34 (89.5%).

In 525 of the patients with cN1 disease, at least two SLNs were excised and axillary lymph node dissection was completed. There was no residual node disease found in 215 of these patients, for a nodal pathologic complete response rate of 41%.

Of the remaining 310 patients, nodal disease was found in the sentinel lymph nodes in 108 patients (20.6%), and in both axillary and sentinel nodes in 163 patients (31.1%).

Residual node disease was found in the axillary lymph nodes of only 39 (7.4%) of the patients. Therefore, the results of the SLN biopsy results were false negative in 39 of the 310 patients, for a false negative rate of 12.6%.

While the study results "suggest that surgeons cannot reliably detect all axillary lymph node metastases in patients with cN1 breast cancer following chemotherapy" with SLN procedures, "we did identify important factors influencing the likelihood of a false-negative SLN," the authors said. The false-negative rate for the SLN biopsy results was significantly decreased when both blue dye and radiolabeled colloid were used as mapping agents, and when at least three sentinel lymph nodes were biopsied.

When both blue dye and radiolabeled colloid were used, the false-negative rate was 10.8%, compared with 20.3% when only one agent was used. "Using two mapping agents with different molecule sizes and transit times is an important surgical standard that should be adhered to for SLN surgery after chemotherapy," they said, noting that after chemotherapy, "the axilla often has more fibrosis, making evaluation of lymphatic drainage and surgical dissection more challenging."

And when at least three SLNs were examined, the false negative rate was 9.1%, compared with 21.1% when two were sampled. "As the accuracy of any sampling test is dependent on the amount of material sampled, these results are not surprising," they said, noting that this has been found in other studies.

SLN is less invasive than axillary dissection and is considered a reliable way to check for axillary nodal disease in women who present with node-negative disease, but the use of SLN biopsy after neoadjuvant chemotherapy in women with cN1 disease "has been questioned," because the false-negative rate for this approach in this population has ranged from 7% to 25% in small studies, the only data available on this approach, according to the authors.

The study was supported by a grant from the National Cancer Institute to the American College of Surgeons Oncology Group (ACOSOG). The patients were in the ACOSOG Z1071 trial. Four of the authors reported having grants from the National Institutes of Health or Komen Foundation, having contracts with Galena BioPharma, or having been paid for lectures from LifeCell. The remaining 17 authors said they had no relevant financial disclosures.

emechcatie@frontlinemedcom.com

Pertuzumab is now approved by the Food and Drug Administration for the neoadjuvant treatment of breast cancer in the preoperative setting. This is the first time the agency has approved an agent to be used in this manner.

Pertuzumab, a HER2-targeted monoclonal antibody, has been approved for use in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of recurrence, metastasis, or death.

It is to be used in combination with trastuzumab and docetaxel, and "depending upon the treatment regimen used, may be followed by chemotherapy after surgery. Following surgery, patients should continue to receive trastuzumab to complete one year of treatment," the FDA announced on Sept. 30.

"We are seeing a significant shift in the treatment paradigm for early-stage breast cancer," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research, said in the FDA statement. "By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or prevent cancer recurrences."

The label includes the statement that the neoadjuvant indication is based on a demonstration of an improvement in pathological complete response (pCR) rate, and that "no data are available demonstrating improvement in event-free survival or overall survival."

Because this was an accelerated approval, full approval depends on the results of a confirmatory phase III study that has already enrolled about 4,800 women with HER2-positive breast cancer, a history of prior breast cancer surgery, and a high risk of recurrence, according to the FDA. This study, called APHINITY, is following patients for 10 years, with the first results expected in 2016.

Pertuzumab, marketed as Perjeta by Genentech, was initially approved in 2012 for advanced or late-stage HER2-positive breast cancer.

The accelerated approval is based on the pCR, defined as the absence of invasive cancer in the breast and lymph nodes, in a phase II study of 417 women with early HER2-positive breast cancer, randomized to one of four neoadjuvant treatment regimens. About 39% of those treated with pertuzumab, trastuzumab, and docetaxel achieved a pCR, vs. about 21% of those on trastuzumab and docetaxel. This study was the NEOSPHERE (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) study.

The most common adverse events associated with the treatment were alopecia, diarrhea, nausea, and neutropenia.

The approval was announced less than 3 weeks after the FDA Oncologic Drugs Advisory Committee voted 13 to 0 with one abstention to support approval. At the Sept. 12 meeting, several panelists remarked on the historical significance of the approval of the first drug for breast cancer in the neoadjuvant setting, but also emphasized the importance of the confirmatory trial, to confirm the effectiveness and to provide more data on the safety of the treatment, including effects on cardiac function.

The new approval pathway, using the pCR results, "has made Perjeta available to people with HER2-positive early breast cancer several years earlier than previously possible," Dr. Hal Barron, chief medical officer and head of global product development at Genentech, said in a statement. The company is investigating the option of submitting approval of pertuzumab in the neoadjuvant setting in other countries.

emechcatie@frontlinemedcom.com

Pertuzumab is now approved by the Food and Drug Administration for the neoadjuvant treatment of breast cancer in the preoperative setting. This is the first time the agency has approved an agent to be used in this manner.

Pertuzumab, a HER2-targeted monoclonal antibody, has been approved for use in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of recurrence, metastasis, or death.

It is to be used in combination with trastuzumab and docetaxel, and "depending upon the treatment regimen used, may be followed by chemotherapy after surgery. Following surgery, patients should continue to receive trastuzumab to complete one year of treatment," the FDA announced on Sept. 30.

"We are seeing a significant shift in the treatment paradigm for early-stage breast cancer," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research, said in the FDA statement. "By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or prevent cancer recurrences."

The label includes the statement that the neoadjuvant indication is based on a demonstration of an improvement in pathological complete response (pCR) rate, and that "no data are available demonstrating improvement in event-free survival or overall survival."

Because this was an accelerated approval, full approval depends on the results of a confirmatory phase III study that has already enrolled about 4,800 women with HER2-positive breast cancer, a history of prior breast cancer surgery, and a high risk of recurrence, according to the FDA. This study, called APHINITY, is following patients for 10 years, with the first results expected in 2016.

Pertuzumab, marketed as Perjeta by Genentech, was initially approved in 2012 for advanced or late-stage HER2-positive breast cancer.

The accelerated approval is based on the pCR, defined as the absence of invasive cancer in the breast and lymph nodes, in a phase II study of 417 women with early HER2-positive breast cancer, randomized to one of four neoadjuvant treatment regimens. About 39% of those treated with pertuzumab, trastuzumab, and docetaxel achieved a pCR, vs. about 21% of those on trastuzumab and docetaxel. This study was the NEOSPHERE (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) study.

The most common adverse events associated with the treatment were alopecia, diarrhea, nausea, and neutropenia.

The approval was announced less than 3 weeks after the FDA Oncologic Drugs Advisory Committee voted 13 to 0 with one abstention to support approval. At the Sept. 12 meeting, several panelists remarked on the historical significance of the approval of the first drug for breast cancer in the neoadjuvant setting, but also emphasized the importance of the confirmatory trial, to confirm the effectiveness and to provide more data on the safety of the treatment, including effects on cardiac function.

The new approval pathway, using the pCR results, "has made Perjeta available to people with HER2-positive early breast cancer several years earlier than previously possible," Dr. Hal Barron, chief medical officer and head of global product development at Genentech, said in a statement. The company is investigating the option of submitting approval of pertuzumab in the neoadjuvant setting in other countries.

emechcatie@frontlinemedcom.com

Pertuzumab is now approved by the Food and Drug Administration for the neoadjuvant treatment of breast cancer in the preoperative setting. This is the first time the agency has approved an agent to be used in this manner.

Pertuzumab, a HER2-targeted monoclonal antibody, has been approved for use in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of recurrence, metastasis, or death.

It is to be used in combination with trastuzumab and docetaxel, and "depending upon the treatment regimen used, may be followed by chemotherapy after surgery. Following surgery, patients should continue to receive trastuzumab to complete one year of treatment," the FDA announced on Sept. 30.

"We are seeing a significant shift in the treatment paradigm for early-stage breast cancer," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research, said in the FDA statement. "By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or prevent cancer recurrences."

The label includes the statement that the neoadjuvant indication is based on a demonstration of an improvement in pathological complete response (pCR) rate, and that "no data are available demonstrating improvement in event-free survival or overall survival."

Because this was an accelerated approval, full approval depends on the results of a confirmatory phase III study that has already enrolled about 4,800 women with HER2-positive breast cancer, a history of prior breast cancer surgery, and a high risk of recurrence, according to the FDA. This study, called APHINITY, is following patients for 10 years, with the first results expected in 2016.

Pertuzumab, marketed as Perjeta by Genentech, was initially approved in 2012 for advanced or late-stage HER2-positive breast cancer.

The accelerated approval is based on the pCR, defined as the absence of invasive cancer in the breast and lymph nodes, in a phase II study of 417 women with early HER2-positive breast cancer, randomized to one of four neoadjuvant treatment regimens. About 39% of those treated with pertuzumab, trastuzumab, and docetaxel achieved a pCR, vs. about 21% of those on trastuzumab and docetaxel. This study was the NEOSPHERE (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) study.

The most common adverse events associated with the treatment were alopecia, diarrhea, nausea, and neutropenia.

The approval was announced less than 3 weeks after the FDA Oncologic Drugs Advisory Committee voted 13 to 0 with one abstention to support approval. At the Sept. 12 meeting, several panelists remarked on the historical significance of the approval of the first drug for breast cancer in the neoadjuvant setting, but also emphasized the importance of the confirmatory trial, to confirm the effectiveness and to provide more data on the safety of the treatment, including effects on cardiac function.

The new approval pathway, using the pCR results, "has made Perjeta available to people with HER2-positive early breast cancer several years earlier than previously possible," Dr. Hal Barron, chief medical officer and head of global product development at Genentech, said in a statement. The company is investigating the option of submitting approval of pertuzumab in the neoadjuvant setting in other countries.

emechcatie@frontlinemedcom.com

SAN FRANCISCO – The distance of a breast cancer from a woman’s nipple added to the ability of nomograms to predict sentinel lymph node positivity, based on a study of data from 401 breast cancers.

The data came from 395 patients who had clinical stage T1 (85% of the cohort) or T2 tumors and underwent prebiopsy ultrasounds at the Mayo Clinic, Rochester, Minn. The investigators performed a second review of the images to measure the tumors’ distance from the nipple.

Nomograms published online by the Memorial Sloan-Kettering Cancer Center and by the University of Texas M.D. Anderson Cancer Center do a reasonably good job of discriminating which newly diagnosed breast cancer patients who have not undergone neoadjuvant therapy are likely to have positive and negative sentinel nodes. Using those two nomograms alone on the patients in the study produced an area under the curve (AUC) of 0.71 for the Memorial Sloan-Kettering nomogram and 0.74 for the M.D. Anderson nomogram. Adding a tumor-to-nipple distance of 2 cm or less improved the AUCs to 0.73 and 0.76, respectively, Dr. Miraj Shah-Khan and her coinvestigators reported.

Sentinel lymph nodes were positive in 20% of the 401 tumors; 17 of 33 tumors within 2 cm of the nipple had positive sentinel lymph nodes (52%), compared with 17% of 368 tumors farther than 2 cm from the nipple, Dr. Shah-Khan, of the Medical College of Wisconsin, Milwaukee, and her associates reported in a poster presented at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

In each subgroup of probability predicted by the nomograms, tumor-to-nipple distance helped to refine the probability of a positive node.

When the Memorial Sloan-Kettering nomogram predicted less than a 25% chance of node positivity, adding a tumor-to-nipple distance of 2 cm or less changed the probability to 35%, compared with 11% if the distance was greater than 2 cm. A probability of 25%-49% from the same nomogram changed to 62% if a tumor was within 2 cm of the nipple or 29% for tumors farther from the nipple. A probability of 50% or greater from the nomogram changed to 100% if a tumor was within 2 cm of the nipple or 32% if it was farther away.

When the M.D. Anderson nomogram predicted less than a 25% chance of node positivity, adding a tumor-to-nipple distance of 2 cm or less changed the probability to 42%, compared with 14% if the distance was greater than 2 cm. A probability of 25%-49% from the same nomogram changed to 83% if a tumor was within 2 cm of the nipple or 40% for tumors farther from the nipple. A probability of 50% or greater from the nomogram changed to 100% if a tumor was within 2 cm of the nipple or 67% if it was farther away, she reported.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

Dr. Shah-Khan reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – The distance of a breast cancer from a woman’s nipple added to the ability of nomograms to predict sentinel lymph node positivity, based on a study of data from 401 breast cancers.

The data came from 395 patients who had clinical stage T1 (85% of the cohort) or T2 tumors and underwent prebiopsy ultrasounds at the Mayo Clinic, Rochester, Minn. The investigators performed a second review of the images to measure the tumors’ distance from the nipple.

Nomograms published online by the Memorial Sloan-Kettering Cancer Center and by the University of Texas M.D. Anderson Cancer Center do a reasonably good job of discriminating which newly diagnosed breast cancer patients who have not undergone neoadjuvant therapy are likely to have positive and negative sentinel nodes. Using those two nomograms alone on the patients in the study produced an area under the curve (AUC) of 0.71 for the Memorial Sloan-Kettering nomogram and 0.74 for the M.D. Anderson nomogram. Adding a tumor-to-nipple distance of 2 cm or less improved the AUCs to 0.73 and 0.76, respectively, Dr. Miraj Shah-Khan and her coinvestigators reported.

Sentinel lymph nodes were positive in 20% of the 401 tumors; 17 of 33 tumors within 2 cm of the nipple had positive sentinel lymph nodes (52%), compared with 17% of 368 tumors farther than 2 cm from the nipple, Dr. Shah-Khan, of the Medical College of Wisconsin, Milwaukee, and her associates reported in a poster presented at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

In each subgroup of probability predicted by the nomograms, tumor-to-nipple distance helped to refine the probability of a positive node.

When the Memorial Sloan-Kettering nomogram predicted less than a 25% chance of node positivity, adding a tumor-to-nipple distance of 2 cm or less changed the probability to 35%, compared with 11% if the distance was greater than 2 cm. A probability of 25%-49% from the same nomogram changed to 62% if a tumor was within 2 cm of the nipple or 29% for tumors farther from the nipple. A probability of 50% or greater from the nomogram changed to 100% if a tumor was within 2 cm of the nipple or 32% if it was farther away.

When the M.D. Anderson nomogram predicted less than a 25% chance of node positivity, adding a tumor-to-nipple distance of 2 cm or less changed the probability to 42%, compared with 14% if the distance was greater than 2 cm. A probability of 25%-49% from the same nomogram changed to 83% if a tumor was within 2 cm of the nipple or 40% for tumors farther from the nipple. A probability of 50% or greater from the nomogram changed to 100% if a tumor was within 2 cm of the nipple or 67% if it was farther away, she reported.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

Dr. Shah-Khan reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

SAN FRANCISCO – The distance of a breast cancer from a woman’s nipple added to the ability of nomograms to predict sentinel lymph node positivity, based on a study of data from 401 breast cancers.

The data came from 395 patients who had clinical stage T1 (85% of the cohort) or T2 tumors and underwent prebiopsy ultrasounds at the Mayo Clinic, Rochester, Minn. The investigators performed a second review of the images to measure the tumors’ distance from the nipple.

Nomograms published online by the Memorial Sloan-Kettering Cancer Center and by the University of Texas M.D. Anderson Cancer Center do a reasonably good job of discriminating which newly diagnosed breast cancer patients who have not undergone neoadjuvant therapy are likely to have positive and negative sentinel nodes. Using those two nomograms alone on the patients in the study produced an area under the curve (AUC) of 0.71 for the Memorial Sloan-Kettering nomogram and 0.74 for the M.D. Anderson nomogram. Adding a tumor-to-nipple distance of 2 cm or less improved the AUCs to 0.73 and 0.76, respectively, Dr. Miraj Shah-Khan and her coinvestigators reported.

Sentinel lymph nodes were positive in 20% of the 401 tumors; 17 of 33 tumors within 2 cm of the nipple had positive sentinel lymph nodes (52%), compared with 17% of 368 tumors farther than 2 cm from the nipple, Dr. Shah-Khan, of the Medical College of Wisconsin, Milwaukee, and her associates reported in a poster presented at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

In each subgroup of probability predicted by the nomograms, tumor-to-nipple distance helped to refine the probability of a positive node.

When the Memorial Sloan-Kettering nomogram predicted less than a 25% chance of node positivity, adding a tumor-to-nipple distance of 2 cm or less changed the probability to 35%, compared with 11% if the distance was greater than 2 cm. A probability of 25%-49% from the same nomogram changed to 62% if a tumor was within 2 cm of the nipple or 29% for tumors farther from the nipple. A probability of 50% or greater from the nomogram changed to 100% if a tumor was within 2 cm of the nipple or 32% if it was farther away.

When the M.D. Anderson nomogram predicted less than a 25% chance of node positivity, adding a tumor-to-nipple distance of 2 cm or less changed the probability to 42%, compared with 14% if the distance was greater than 2 cm. A probability of 25%-49% from the same nomogram changed to 83% if a tumor was within 2 cm of the nipple or 40% for tumors farther from the nipple. A probability of 50% or greater from the nomogram changed to 100% if a tumor was within 2 cm of the nipple or 67% if it was farther away, she reported.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

Dr. Shah-Khan reported having no financial disclosures.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

AMSTERDAM – The experimental PARP inhibitor BMN 673 had impressive single-agent activity in pretreated breast and ovarian cancer patients carrying BRCA 1 and 2 mutations, based on results from a small, ongoing phase I/II trial.

The objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors) criteria was 44% for both the breast (8/18) and ovarian (11/25) cancer patients.

Patrice Wendling/IMNG Medical Media

Responses were durable in both groups at a median of about 8 months, leading to a median progression-free survival of 32.3 weeks in ovarian cancer patients and 33.1 weeks in breast cancer patients, Dr. Ramesh Ramanathan reported in a late-breaking abstract at the multidisciplinary European cancer congresses.

"There’s very little to discuss here. This is a flat-out, very successful phase 1 trial," said Dr. Peter Dubsky, a surgeon with the Medical University of Vienna, who was invited to discuss the results.

He observed that toxicity with BMN 673, described in the abstract as the most potent and specific inhibitor of poly-ADP ribose polymerase (PARP) in clinical development, was lower than would be expected from a PARP inhibitor. In addition, "responses were seen starting at 100 mcg, but the maximum tolerated dose is 10 times that," Dr. Dubsky said.

The maximum tolerated dose of 1 mg/day is being used in a newly launched, open-label, 429-patient phase III trial, said Dr. Ramanathan, medical director of the Scottsdale (Ariz.) Healthcare Research Institute. The multicenter trial is evaluating BMN 673 against the physician’s choice of capecitabine (Xeloda), eribulin (Halaven), gemcitabine (Gemzar), or vinorelbine (Navelbine) in germline BRCA-mutation patients with locally advanced or metastatic breast cancer treated with no more than two prior chemotherapy regimens for metastatic disease.

The dose-escalation portion of the phase I study involved 80 patients dosed at 25-1,100 mcg/day. The study was then expanded and included 18 patients with germline BRCA-mutant breast cancer and 28 patients with germline BRCA-mutant ovarian cancer. Patients were dosed once daily at 100 mcg and above.

The heavily pretreated expansion cohort had received a median of three prior chemotherapy regimens (range, 0-8). BRCA 1 mutations were more common in ovarian cancer patients (20/28), and BRCA 2 mutations were more frequent in the breast group (11/18). Their median age was 58 years and 42 years, respectively.

Among 25 ovarian cancer patients evaluable by RECIST, 1 patient had a complete response, 10 had partial responses, and 4 had stable disease lasting 24 weeks or more, Dr. Ramanathan reported.

Responses were seen in 17 of 22 platinum-sensitive patients. "Platinum sensitivity may be important in identifying patients sensitive to BMN 673," he said.

Cancer antigen 125 levels evaluable in 27 ovarian cancer patients dropped by more than 50% in 19 (70%) and returned to the normal range in 9.

All 18 breast cancer patients were evaluable by RECIST, with a complete response in 1, partial responses in 7, and stable disease in 5. The clinical benefit response rate (complete response, partial response, or stable disease for at least 24 weeks) was 72% (13/18).

At the 1-mg/day phase III dose, however, the RECIST response rate reached 50% (7/14), and the clinical benefit response rate, 86% (12/14), Dr. Ramanathan said.

He noted that BMN 673 was generally well tolerated, with the most common drug-related toxicities being myelosuppression, fatigue, nausea, and alopecia occurring in less than 30% of patients. In the phase I portion of the trial, thrombocytopenia was dose limiting, occurring as a grade 3 event in 14 patients (17.5%) and a grade 4 event in 1 patient (1.3%). Grade 3 anemia was seen in 12 patients (15%).

BioMarin Pharmaceuticals funded the trial. Dr. Ramanathan reported clinical research and travel support for the presentation. His coauthors reported similar relationships as well as employment with BioMarin.

pwendling@frontlinemedcom.com

AMSTERDAM – The experimental PARP inhibitor BMN 673 had impressive single-agent activity in pretreated breast and ovarian cancer patients carrying BRCA 1 and 2 mutations, based on results from a small, ongoing phase I/II trial.

The objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors) criteria was 44% for both the breast (8/18) and ovarian (11/25) cancer patients.

Patrice Wendling/IMNG Medical Media

Responses were durable in both groups at a median of about 8 months, leading to a median progression-free survival of 32.3 weeks in ovarian cancer patients and 33.1 weeks in breast cancer patients, Dr. Ramesh Ramanathan reported in a late-breaking abstract at the multidisciplinary European cancer congresses.

"There’s very little to discuss here. This is a flat-out, very successful phase 1 trial," said Dr. Peter Dubsky, a surgeon with the Medical University of Vienna, who was invited to discuss the results.

He observed that toxicity with BMN 673, described in the abstract as the most potent and specific inhibitor of poly-ADP ribose polymerase (PARP) in clinical development, was lower than would be expected from a PARP inhibitor. In addition, "responses were seen starting at 100 mcg, but the maximum tolerated dose is 10 times that," Dr. Dubsky said.

The maximum tolerated dose of 1 mg/day is being used in a newly launched, open-label, 429-patient phase III trial, said Dr. Ramanathan, medical director of the Scottsdale (Ariz.) Healthcare Research Institute. The multicenter trial is evaluating BMN 673 against the physician’s choice of capecitabine (Xeloda), eribulin (Halaven), gemcitabine (Gemzar), or vinorelbine (Navelbine) in germline BRCA-mutation patients with locally advanced or metastatic breast cancer treated with no more than two prior chemotherapy regimens for metastatic disease.

The dose-escalation portion of the phase I study involved 80 patients dosed at 25-1,100 mcg/day. The study was then expanded and included 18 patients with germline BRCA-mutant breast cancer and 28 patients with germline BRCA-mutant ovarian cancer. Patients were dosed once daily at 100 mcg and above.

The heavily pretreated expansion cohort had received a median of three prior chemotherapy regimens (range, 0-8). BRCA 1 mutations were more common in ovarian cancer patients (20/28), and BRCA 2 mutations were more frequent in the breast group (11/18). Their median age was 58 years and 42 years, respectively.

Among 25 ovarian cancer patients evaluable by RECIST, 1 patient had a complete response, 10 had partial responses, and 4 had stable disease lasting 24 weeks or more, Dr. Ramanathan reported.

Responses were seen in 17 of 22 platinum-sensitive patients. "Platinum sensitivity may be important in identifying patients sensitive to BMN 673," he said.

Cancer antigen 125 levels evaluable in 27 ovarian cancer patients dropped by more than 50% in 19 (70%) and returned to the normal range in 9.

All 18 breast cancer patients were evaluable by RECIST, with a complete response in 1, partial responses in 7, and stable disease in 5. The clinical benefit response rate (complete response, partial response, or stable disease for at least 24 weeks) was 72% (13/18).

At the 1-mg/day phase III dose, however, the RECIST response rate reached 50% (7/14), and the clinical benefit response rate, 86% (12/14), Dr. Ramanathan said.

He noted that BMN 673 was generally well tolerated, with the most common drug-related toxicities being myelosuppression, fatigue, nausea, and alopecia occurring in less than 30% of patients. In the phase I portion of the trial, thrombocytopenia was dose limiting, occurring as a grade 3 event in 14 patients (17.5%) and a grade 4 event in 1 patient (1.3%). Grade 3 anemia was seen in 12 patients (15%).

BioMarin Pharmaceuticals funded the trial. Dr. Ramanathan reported clinical research and travel support for the presentation. His coauthors reported similar relationships as well as employment with BioMarin.

pwendling@frontlinemedcom.com

AMSTERDAM – The experimental PARP inhibitor BMN 673 had impressive single-agent activity in pretreated breast and ovarian cancer patients carrying BRCA 1 and 2 mutations, based on results from a small, ongoing phase I/II trial.

The objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors) criteria was 44% for both the breast (8/18) and ovarian (11/25) cancer patients.

Patrice Wendling/IMNG Medical Media

Responses were durable in both groups at a median of about 8 months, leading to a median progression-free survival of 32.3 weeks in ovarian cancer patients and 33.1 weeks in breast cancer patients, Dr. Ramesh Ramanathan reported in a late-breaking abstract at the multidisciplinary European cancer congresses.

"There’s very little to discuss here. This is a flat-out, very successful phase 1 trial," said Dr. Peter Dubsky, a surgeon with the Medical University of Vienna, who was invited to discuss the results.

He observed that toxicity with BMN 673, described in the abstract as the most potent and specific inhibitor of poly-ADP ribose polymerase (PARP) in clinical development, was lower than would be expected from a PARP inhibitor. In addition, "responses were seen starting at 100 mcg, but the maximum tolerated dose is 10 times that," Dr. Dubsky said.

The maximum tolerated dose of 1 mg/day is being used in a newly launched, open-label, 429-patient phase III trial, said Dr. Ramanathan, medical director of the Scottsdale (Ariz.) Healthcare Research Institute. The multicenter trial is evaluating BMN 673 against the physician’s choice of capecitabine (Xeloda), eribulin (Halaven), gemcitabine (Gemzar), or vinorelbine (Navelbine) in germline BRCA-mutation patients with locally advanced or metastatic breast cancer treated with no more than two prior chemotherapy regimens for metastatic disease.

The dose-escalation portion of the phase I study involved 80 patients dosed at 25-1,100 mcg/day. The study was then expanded and included 18 patients with germline BRCA-mutant breast cancer and 28 patients with germline BRCA-mutant ovarian cancer. Patients were dosed once daily at 100 mcg and above.

The heavily pretreated expansion cohort had received a median of three prior chemotherapy regimens (range, 0-8). BRCA 1 mutations were more common in ovarian cancer patients (20/28), and BRCA 2 mutations were more frequent in the breast group (11/18). Their median age was 58 years and 42 years, respectively.

Among 25 ovarian cancer patients evaluable by RECIST, 1 patient had a complete response, 10 had partial responses, and 4 had stable disease lasting 24 weeks or more, Dr. Ramanathan reported.

Responses were seen in 17 of 22 platinum-sensitive patients. "Platinum sensitivity may be important in identifying patients sensitive to BMN 673," he said.

Cancer antigen 125 levels evaluable in 27 ovarian cancer patients dropped by more than 50% in 19 (70%) and returned to the normal range in 9.

All 18 breast cancer patients were evaluable by RECIST, with a complete response in 1, partial responses in 7, and stable disease in 5. The clinical benefit response rate (complete response, partial response, or stable disease for at least 24 weeks) was 72% (13/18).

At the 1-mg/day phase III dose, however, the RECIST response rate reached 50% (7/14), and the clinical benefit response rate, 86% (12/14), Dr. Ramanathan said.

He noted that BMN 673 was generally well tolerated, with the most common drug-related toxicities being myelosuppression, fatigue, nausea, and alopecia occurring in less than 30% of patients. In the phase I portion of the trial, thrombocytopenia was dose limiting, occurring as a grade 3 event in 14 patients (17.5%) and a grade 4 event in 1 patient (1.3%). Grade 3 anemia was seen in 12 patients (15%).

BioMarin Pharmaceuticals funded the trial. Dr. Ramanathan reported clinical research and travel support for the presentation. His coauthors reported similar relationships as well as employment with BioMarin.

pwendling@frontlinemedcom.com