Breast Cancer

SAN FRANCISCO – Tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor increase the risk of a fatal adverse event in cancer patients, but the absolute rate is still low, investigators concluded from a meta-analysis of 10 randomized trials with a total of 4,679 patients.

Trial participants given sorafenib (Nexavar), sunitinib (Sutent), or pazopanib (Votrient) were more than twice as likely to die from an adverse event as were peers given control treatment, said lead investigator Dr. Christopher J. Richards of the Beth Israel Deaconess Medical Center in Boston. Yet, the rate was still less than 2%.

"Our analysis may underestimate the true incidence of fatal adverse events, as study patients may be healthier than the general population exposed to these drugs," he noted at the Genitourinary Cancers Symposium. But that said, "all three of the study drugs have been shown in various randomized controlled trials to improve clinical outcomes compared to traditional therapies."

Discussant Dr. Thomas E. Hutson of the Baylor Sammons Cancer Center in Dallas commented, "I feel confident that everyone or almost everyone in the room today would agree with me that our current therapy benefit outweighs the risk associated with the treatment."

Moreover, even among the new targeted agents, the 1.5% rate seen with the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in the meta-analysis "compares very favorably" with the rate of 2.9% seen previously with bevacizumab (Avastin), another VEGF-targeted therapy, in a similar analysis (JAMA 2011;305:487-94).

"Targeted therapies have real toxicities, and these toxicities include a low risk of death – a risk of death not much different than other therapies used for kidney and other cancer types," Dr. Hutson asserted. "If anything, this meta-analysis shows us that close monitoring is going to be essential for optimal use of these agents."

In the study, Dr. Richards and his colleagues identified 10 randomized controlled phase II or III trials in which patients received any of three VEGFR TKIs approved by the Food and Drug Administration for cancer treatment as of February 2011: sorafenib, sunitinib, or pazopanib. The control groups were usually treated with a placebo, but in some cases with chemotherapy or immunotherapy.

The enrolled patients had a variety of malignancies: renal cell carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, breast cancer, and pancreatic neuroendocrine tumor. "All patients included in the studies had good performance status and had adequate baseline cardiac, hematologic, and renal function at the time of study entry," Dr. Richards pointed out.

In a pooled analysis, relative to control treatment, VEGFR TKI treatment was associated with a 2.23-fold increased risk of fatal adverse events (P = .02). But even so, the absolute rate of such events was just 1.5%, compared with 0.7% with the control treatment.

In stratified analyses, there was no significant difference in the relative risks across the three agents or the relative risks for renal cell carcinoma vs. other types of cancer.

The most common fatal adverse events in the trials overall (considering both control and VEGFR TKI arms) were hemorrhage (48% of the total), myocardial infarction (15%), and hepatic failure (10%). These events "occurred in both the placebo and control groups as well as study groups," Dr. Richards noted.

He acknowledged that limitations of the study included the fact that the analysis used study-level instead of patient-level data, which may have resulted in confounding, and that it did not have adequate power to detect differences between the three VEGFR TKIs, although they all have a similar mechanism of action.

The symposium was sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Richards disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor increase the risk of a fatal adverse event in cancer patients, but the absolute rate is still low, investigators concluded from a meta-analysis of 10 randomized trials with a total of 4,679 patients.

Trial participants given sorafenib (Nexavar), sunitinib (Sutent), or pazopanib (Votrient) were more than twice as likely to die from an adverse event as were peers given control treatment, said lead investigator Dr. Christopher J. Richards of the Beth Israel Deaconess Medical Center in Boston. Yet, the rate was still less than 2%.

"Our analysis may underestimate the true incidence of fatal adverse events, as study patients may be healthier than the general population exposed to these drugs," he noted at the Genitourinary Cancers Symposium. But that said, "all three of the study drugs have been shown in various randomized controlled trials to improve clinical outcomes compared to traditional therapies."

Discussant Dr. Thomas E. Hutson of the Baylor Sammons Cancer Center in Dallas commented, "I feel confident that everyone or almost everyone in the room today would agree with me that our current therapy benefit outweighs the risk associated with the treatment."

Moreover, even among the new targeted agents, the 1.5% rate seen with the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in the meta-analysis "compares very favorably" with the rate of 2.9% seen previously with bevacizumab (Avastin), another VEGF-targeted therapy, in a similar analysis (JAMA 2011;305:487-94).

"Targeted therapies have real toxicities, and these toxicities include a low risk of death – a risk of death not much different than other therapies used for kidney and other cancer types," Dr. Hutson asserted. "If anything, this meta-analysis shows us that close monitoring is going to be essential for optimal use of these agents."

In the study, Dr. Richards and his colleagues identified 10 randomized controlled phase II or III trials in which patients received any of three VEGFR TKIs approved by the Food and Drug Administration for cancer treatment as of February 2011: sorafenib, sunitinib, or pazopanib. The control groups were usually treated with a placebo, but in some cases with chemotherapy or immunotherapy.

The enrolled patients had a variety of malignancies: renal cell carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, breast cancer, and pancreatic neuroendocrine tumor. "All patients included in the studies had good performance status and had adequate baseline cardiac, hematologic, and renal function at the time of study entry," Dr. Richards pointed out.

In a pooled analysis, relative to control treatment, VEGFR TKI treatment was associated with a 2.23-fold increased risk of fatal adverse events (P = .02). But even so, the absolute rate of such events was just 1.5%, compared with 0.7% with the control treatment.

In stratified analyses, there was no significant difference in the relative risks across the three agents or the relative risks for renal cell carcinoma vs. other types of cancer.

The most common fatal adverse events in the trials overall (considering both control and VEGFR TKI arms) were hemorrhage (48% of the total), myocardial infarction (15%), and hepatic failure (10%). These events "occurred in both the placebo and control groups as well as study groups," Dr. Richards noted.

He acknowledged that limitations of the study included the fact that the analysis used study-level instead of patient-level data, which may have resulted in confounding, and that it did not have adequate power to detect differences between the three VEGFR TKIs, although they all have a similar mechanism of action.

The symposium was sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Richards disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor increase the risk of a fatal adverse event in cancer patients, but the absolute rate is still low, investigators concluded from a meta-analysis of 10 randomized trials with a total of 4,679 patients.

Trial participants given sorafenib (Nexavar), sunitinib (Sutent), or pazopanib (Votrient) were more than twice as likely to die from an adverse event as were peers given control treatment, said lead investigator Dr. Christopher J. Richards of the Beth Israel Deaconess Medical Center in Boston. Yet, the rate was still less than 2%.

"Our analysis may underestimate the true incidence of fatal adverse events, as study patients may be healthier than the general population exposed to these drugs," he noted at the Genitourinary Cancers Symposium. But that said, "all three of the study drugs have been shown in various randomized controlled trials to improve clinical outcomes compared to traditional therapies."

Discussant Dr. Thomas E. Hutson of the Baylor Sammons Cancer Center in Dallas commented, "I feel confident that everyone or almost everyone in the room today would agree with me that our current therapy benefit outweighs the risk associated with the treatment."

Moreover, even among the new targeted agents, the 1.5% rate seen with the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in the meta-analysis "compares very favorably" with the rate of 2.9% seen previously with bevacizumab (Avastin), another VEGF-targeted therapy, in a similar analysis (JAMA 2011;305:487-94).

"Targeted therapies have real toxicities, and these toxicities include a low risk of death – a risk of death not much different than other therapies used for kidney and other cancer types," Dr. Hutson asserted. "If anything, this meta-analysis shows us that close monitoring is going to be essential for optimal use of these agents."

In the study, Dr. Richards and his colleagues identified 10 randomized controlled phase II or III trials in which patients received any of three VEGFR TKIs approved by the Food and Drug Administration for cancer treatment as of February 2011: sorafenib, sunitinib, or pazopanib. The control groups were usually treated with a placebo, but in some cases with chemotherapy or immunotherapy.

The enrolled patients had a variety of malignancies: renal cell carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, breast cancer, and pancreatic neuroendocrine tumor. "All patients included in the studies had good performance status and had adequate baseline cardiac, hematologic, and renal function at the time of study entry," Dr. Richards pointed out.

In a pooled analysis, relative to control treatment, VEGFR TKI treatment was associated with a 2.23-fold increased risk of fatal adverse events (P = .02). But even so, the absolute rate of such events was just 1.5%, compared with 0.7% with the control treatment.

In stratified analyses, there was no significant difference in the relative risks across the three agents or the relative risks for renal cell carcinoma vs. other types of cancer.

The most common fatal adverse events in the trials overall (considering both control and VEGFR TKI arms) were hemorrhage (48% of the total), myocardial infarction (15%), and hepatic failure (10%). These events "occurred in both the placebo and control groups as well as study groups," Dr. Richards noted.

He acknowledged that limitations of the study included the fact that the analysis used study-level instead of patient-level data, which may have resulted in confounding, and that it did not have adequate power to detect differences between the three VEGFR TKIs, although they all have a similar mechanism of action.

The symposium was sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Richards disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

The American College of Obstetricians and Gynecologists advises that selective serotonin reuptake inhibitors, or SSRIs, can safely be used to treat hot flashes in some women with breast cancer.

And women who are able to become pregnant following breast cancer treatment can do so without increasing the risk of disease recurrence, according to the college.

The advice, published online Feb. 21 in Obstetrics and Gynecology as Practice Bulletin No. 126, is part of the college’s comprehensive new clinical guideline on the gynecological management of women who are being treated for – or who have been treated for – breast cancer (Obstet. Gynecol. 2012;119:666-82).

The guideline, which cites evidence from 166 published sources, covers such diverse issues as vasomotor symptoms; vaginal atrophy; contraception and fertility; uterine evaluation; and the treatment and prevention of bone loss in the context of current treatment regimens, which may include chemotherapy, hormonal treatments, radiation, and surgery.

"More and more women are living with breast cancer, and breast cancer treatments – particularly the hormonal therapies – have gynecological side effects," Dr. Mindy E. Goldman, lead author of the guideline, said in an interview.

"Ob.gyns. need to be aware of how these drugs work and know about any of the gynecological side effects," said Dr. Goldman, who is director of women’s cancer care for the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco.

For managing vasomotor symptoms such as hot flashes, the guideline recommends that – because hormonal therapy is generally contraindicated in women with hormone-positive breast cancer – an SSRI, an SNRI (serotonin norepinephrine reuptake inhibitor), or gabapentin be used instead. For women on tamoxifen, an SNRI is a better choice than an SSRI, because it avoids a potential interaction.

One SNRI, venlafaxine, was shown in randomized clinical trials to provide significant relief at low doses (75 mg) among women who had been treated for breast cancer. Gabapentin, an anticonvulsant used to control neuropathic pain in breast cancer patients, also helps relieve vasomotor symptoms at low doses, and may improve sleep quality. Pregabalin, a drug in the same class as gabapentin, also was seen as helpful, as was clonidine.

None of these medicines is licensed in the United States for the treatment of hot flashes.

Because chemotherapy, ovarian suppression, and aromatase inhibitors contribute to bone loss and increase fracture risk, the guideline recommends that pharmacologic therapy with bisphosphonates be considered for women who have T scores between –1.5 and –2.0, and be strongly considered for women with T scores less than –2.0, or who have a 10-year risk greater than 20% for a major fracture, or a 10-year hip fracture risk greater than 3%. Zoledronic acid was seen as a strong option among the bisphosphonates, and although raloxifene was generally well tolerated, vasomotor symptoms are among its reported adverse effects.

The guideline also recommends annual monitoring of women whose risks of bone loss significantly change as a result of treatment (for example, premenopausal women being treated with aromatase inhibitors). And vitamin D levels should be checked in women with breast cancer.

Up to 40% of women with breast cancer have severe vaginal dryness, and the topical hormonal creams, suppositories, and vaginal rings commonly used to treat vaginal dryness and atrophy have not been shown to be safe in women with breast cancer. Preference should be given to nonhormonal vaginal moisturizers, with hormonal treatments used on a short-term basis when nonhormonal options have failed. Testosterone supplementation, in patches or creams, remains without enough breast safety data to support it.

Contraceptives that are appropriate for women with breast cancer include barrier methods, the copper intrauterine device, and sterilization. Hormonal methods are contraindicated in women with breast cancer and are considered a risk even for women who have been cancer free for 5 or more years.

One exception may be the levonorgestrel-releasing intrauterine system, in which systemic absorption of levonorgestrel is minimal. However, the system has not been thoroughly studied with regard to long-term breast risk and should be considered only on a case-by-case basis, the guideline states.

Pregnancy following breast cancer treatment has not been shown to increase the risk of recurrence or mortality, according to a recent meta-analysis cited in the guideline (Eur. J. Cancer 2011;47:74-83).

But chemotherapy can compromise fertility, and 5-year use of tamoxifen may diminish a woman’s ovarian reserve before she may safely conceive. Therefore, many women of childbearing age will have difficulty becoming pregnant after treatment, and a fertility consultation at diagnosis is recommended so that advance planning can take place.

In vitro fertilization (IVF) with embryo cryopreservation is seen as a strong option for preserving the potential to have a child; however, there is concern that ovarian stimulation in IVF could cause proliferation of breast cancer cells, leading some practitioners to recommend natural cycle (nonstimulated) IVF.

It is not clear whether ovarian suppression during cancer treatment preserves fertility, according to the guideline. Tamoxifen as an ovarian stimulant has been investigated and has shown promise in treating women whose fertility has been compromised as a result of breast cancer treatment. Although the aromatase inhibitor letrozole cannot be used in premenopausal women as a breast cancer treatment, it may be used in combination with gonadotropins as a fertility agent following treatment.

Finally, routine endometrial biopsy and uterine ultrasonography are not recommended for postmenopausal women taking tamoxifen without evidence of vaginal bleeding, as ultrasound has been associated with a significant false-positive rate leading to unnecessary invasive diagnostic procedures.

However, for women on tamoxifen who experience vaginal bleeding, an endometrial evaluation – including biopsy and follow-up of possible uterine structural anomalies – is essential, the guideline states.

The members of the Committee on Practice Bulletins–Gynecology who wrote the guideline reported no relevant conflicts of interest.

The American College of Obstetricians and Gynecologists advises that selective serotonin reuptake inhibitors, or SSRIs, can safely be used to treat hot flashes in some women with breast cancer.

And women who are able to become pregnant following breast cancer treatment can do so without increasing the risk of disease recurrence, according to the college.

The advice, published online Feb. 21 in Obstetrics and Gynecology as Practice Bulletin No. 126, is part of the college’s comprehensive new clinical guideline on the gynecological management of women who are being treated for – or who have been treated for – breast cancer (Obstet. Gynecol. 2012;119:666-82).

The guideline, which cites evidence from 166 published sources, covers such diverse issues as vasomotor symptoms; vaginal atrophy; contraception and fertility; uterine evaluation; and the treatment and prevention of bone loss in the context of current treatment regimens, which may include chemotherapy, hormonal treatments, radiation, and surgery.

"More and more women are living with breast cancer, and breast cancer treatments – particularly the hormonal therapies – have gynecological side effects," Dr. Mindy E. Goldman, lead author of the guideline, said in an interview.

"Ob.gyns. need to be aware of how these drugs work and know about any of the gynecological side effects," said Dr. Goldman, who is director of women’s cancer care for the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco.

For managing vasomotor symptoms such as hot flashes, the guideline recommends that – because hormonal therapy is generally contraindicated in women with hormone-positive breast cancer – an SSRI, an SNRI (serotonin norepinephrine reuptake inhibitor), or gabapentin be used instead. For women on tamoxifen, an SNRI is a better choice than an SSRI, because it avoids a potential interaction.

One SNRI, venlafaxine, was shown in randomized clinical trials to provide significant relief at low doses (75 mg) among women who had been treated for breast cancer. Gabapentin, an anticonvulsant used to control neuropathic pain in breast cancer patients, also helps relieve vasomotor symptoms at low doses, and may improve sleep quality. Pregabalin, a drug in the same class as gabapentin, also was seen as helpful, as was clonidine.

None of these medicines is licensed in the United States for the treatment of hot flashes.

Because chemotherapy, ovarian suppression, and aromatase inhibitors contribute to bone loss and increase fracture risk, the guideline recommends that pharmacologic therapy with bisphosphonates be considered for women who have T scores between –1.5 and –2.0, and be strongly considered for women with T scores less than –2.0, or who have a 10-year risk greater than 20% for a major fracture, or a 10-year hip fracture risk greater than 3%. Zoledronic acid was seen as a strong option among the bisphosphonates, and although raloxifene was generally well tolerated, vasomotor symptoms are among its reported adverse effects.

The guideline also recommends annual monitoring of women whose risks of bone loss significantly change as a result of treatment (for example, premenopausal women being treated with aromatase inhibitors). And vitamin D levels should be checked in women with breast cancer.

Up to 40% of women with breast cancer have severe vaginal dryness, and the topical hormonal creams, suppositories, and vaginal rings commonly used to treat vaginal dryness and atrophy have not been shown to be safe in women with breast cancer. Preference should be given to nonhormonal vaginal moisturizers, with hormonal treatments used on a short-term basis when nonhormonal options have failed. Testosterone supplementation, in patches or creams, remains without enough breast safety data to support it.

Contraceptives that are appropriate for women with breast cancer include barrier methods, the copper intrauterine device, and sterilization. Hormonal methods are contraindicated in women with breast cancer and are considered a risk even for women who have been cancer free for 5 or more years.

One exception may be the levonorgestrel-releasing intrauterine system, in which systemic absorption of levonorgestrel is minimal. However, the system has not been thoroughly studied with regard to long-term breast risk and should be considered only on a case-by-case basis, the guideline states.

Pregnancy following breast cancer treatment has not been shown to increase the risk of recurrence or mortality, according to a recent meta-analysis cited in the guideline (Eur. J. Cancer 2011;47:74-83).

But chemotherapy can compromise fertility, and 5-year use of tamoxifen may diminish a woman’s ovarian reserve before she may safely conceive. Therefore, many women of childbearing age will have difficulty becoming pregnant after treatment, and a fertility consultation at diagnosis is recommended so that advance planning can take place.

In vitro fertilization (IVF) with embryo cryopreservation is seen as a strong option for preserving the potential to have a child; however, there is concern that ovarian stimulation in IVF could cause proliferation of breast cancer cells, leading some practitioners to recommend natural cycle (nonstimulated) IVF.

It is not clear whether ovarian suppression during cancer treatment preserves fertility, according to the guideline. Tamoxifen as an ovarian stimulant has been investigated and has shown promise in treating women whose fertility has been compromised as a result of breast cancer treatment. Although the aromatase inhibitor letrozole cannot be used in premenopausal women as a breast cancer treatment, it may be used in combination with gonadotropins as a fertility agent following treatment.

Finally, routine endometrial biopsy and uterine ultrasonography are not recommended for postmenopausal women taking tamoxifen without evidence of vaginal bleeding, as ultrasound has been associated with a significant false-positive rate leading to unnecessary invasive diagnostic procedures.

However, for women on tamoxifen who experience vaginal bleeding, an endometrial evaluation – including biopsy and follow-up of possible uterine structural anomalies – is essential, the guideline states.

The members of the Committee on Practice Bulletins–Gynecology who wrote the guideline reported no relevant conflicts of interest.

The American College of Obstetricians and Gynecologists advises that selective serotonin reuptake inhibitors, or SSRIs, can safely be used to treat hot flashes in some women with breast cancer.

And women who are able to become pregnant following breast cancer treatment can do so without increasing the risk of disease recurrence, according to the college.

The advice, published online Feb. 21 in Obstetrics and Gynecology as Practice Bulletin No. 126, is part of the college’s comprehensive new clinical guideline on the gynecological management of women who are being treated for – or who have been treated for – breast cancer (Obstet. Gynecol. 2012;119:666-82).

The guideline, which cites evidence from 166 published sources, covers such diverse issues as vasomotor symptoms; vaginal atrophy; contraception and fertility; uterine evaluation; and the treatment and prevention of bone loss in the context of current treatment regimens, which may include chemotherapy, hormonal treatments, radiation, and surgery.

"More and more women are living with breast cancer, and breast cancer treatments – particularly the hormonal therapies – have gynecological side effects," Dr. Mindy E. Goldman, lead author of the guideline, said in an interview.

"Ob.gyns. need to be aware of how these drugs work and know about any of the gynecological side effects," said Dr. Goldman, who is director of women’s cancer care for the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco.

For managing vasomotor symptoms such as hot flashes, the guideline recommends that – because hormonal therapy is generally contraindicated in women with hormone-positive breast cancer – an SSRI, an SNRI (serotonin norepinephrine reuptake inhibitor), or gabapentin be used instead. For women on tamoxifen, an SNRI is a better choice than an SSRI, because it avoids a potential interaction.

One SNRI, venlafaxine, was shown in randomized clinical trials to provide significant relief at low doses (75 mg) among women who had been treated for breast cancer. Gabapentin, an anticonvulsant used to control neuropathic pain in breast cancer patients, also helps relieve vasomotor symptoms at low doses, and may improve sleep quality. Pregabalin, a drug in the same class as gabapentin, also was seen as helpful, as was clonidine.

None of these medicines is licensed in the United States for the treatment of hot flashes.

Because chemotherapy, ovarian suppression, and aromatase inhibitors contribute to bone loss and increase fracture risk, the guideline recommends that pharmacologic therapy with bisphosphonates be considered for women who have T scores between –1.5 and –2.0, and be strongly considered for women with T scores less than –2.0, or who have a 10-year risk greater than 20% for a major fracture, or a 10-year hip fracture risk greater than 3%. Zoledronic acid was seen as a strong option among the bisphosphonates, and although raloxifene was generally well tolerated, vasomotor symptoms are among its reported adverse effects.

The guideline also recommends annual monitoring of women whose risks of bone loss significantly change as a result of treatment (for example, premenopausal women being treated with aromatase inhibitors). And vitamin D levels should be checked in women with breast cancer.

Up to 40% of women with breast cancer have severe vaginal dryness, and the topical hormonal creams, suppositories, and vaginal rings commonly used to treat vaginal dryness and atrophy have not been shown to be safe in women with breast cancer. Preference should be given to nonhormonal vaginal moisturizers, with hormonal treatments used on a short-term basis when nonhormonal options have failed. Testosterone supplementation, in patches or creams, remains without enough breast safety data to support it.

Contraceptives that are appropriate for women with breast cancer include barrier methods, the copper intrauterine device, and sterilization. Hormonal methods are contraindicated in women with breast cancer and are considered a risk even for women who have been cancer free for 5 or more years.

One exception may be the levonorgestrel-releasing intrauterine system, in which systemic absorption of levonorgestrel is minimal. However, the system has not been thoroughly studied with regard to long-term breast risk and should be considered only on a case-by-case basis, the guideline states.

Pregnancy following breast cancer treatment has not been shown to increase the risk of recurrence or mortality, according to a recent meta-analysis cited in the guideline (Eur. J. Cancer 2011;47:74-83).

But chemotherapy can compromise fertility, and 5-year use of tamoxifen may diminish a woman’s ovarian reserve before she may safely conceive. Therefore, many women of childbearing age will have difficulty becoming pregnant after treatment, and a fertility consultation at diagnosis is recommended so that advance planning can take place.

In vitro fertilization (IVF) with embryo cryopreservation is seen as a strong option for preserving the potential to have a child; however, there is concern that ovarian stimulation in IVF could cause proliferation of breast cancer cells, leading some practitioners to recommend natural cycle (nonstimulated) IVF.

It is not clear whether ovarian suppression during cancer treatment preserves fertility, according to the guideline. Tamoxifen as an ovarian stimulant has been investigated and has shown promise in treating women whose fertility has been compromised as a result of breast cancer treatment. Although the aromatase inhibitor letrozole cannot be used in premenopausal women as a breast cancer treatment, it may be used in combination with gonadotropins as a fertility agent following treatment.

Finally, routine endometrial biopsy and uterine ultrasonography are not recommended for postmenopausal women taking tamoxifen without evidence of vaginal bleeding, as ultrasound has been associated with a significant false-positive rate leading to unnecessary invasive diagnostic procedures.

However, for women on tamoxifen who experience vaginal bleeding, an endometrial evaluation – including biopsy and follow-up of possible uterine structural anomalies – is essential, the guideline states.

The members of the Committee on Practice Bulletins–Gynecology who wrote the guideline reported no relevant conflicts of interest.

England’s clinical and cost-effectiveness agency has said that it would not recommend lapatinib or trastuzumab with aromatase inhibitors as first-line treatments for postmenopausal women with HER2 positive metastatic breast cancer.

The new negative draft guidance follows previous negative guidance, issued in July 2011, and a subsequent appeal by Roche, the manufacturer of trastuzumab (Herceptin). While an independent panel upheld parts of Roche’s appeal in November, the National Institute for Health and Clinical Excellence nonetheless rejected both treatments once more, citing cost concerns and unclear overall survival evidence for this patient group.

In clinical trial results evaluated by NICE, lapatinib plus an aromatase inhibitor was associated with progression-free survival of 5.2 months, and trastuzumab plus an aromatase inhibitor with 2.4 months; however, NICE said that there was insufficient evidence of an overall survival gain with either treatment.

While NICE has never before issued guidance on lapatinib (Tyverb and Tykerb, GlaxoSmithKline) for any indication, trastuzumab is currently recommended by NICE for the treatment of HER2 positive gastric cancer and for two groups of women with breast cancer: those whose tumors overexpress HER2 at levels of 3+ who have not had chemotherapy for metastatic breast cancer and for whom anthracycline is inappropriate (for this group, trastuzumab is recommended in combination with paclitaxel); and those who have early-stage HER2 positive breast cancer following surgery and chemotherapy.

Lapatinib and trastuzumab combined with aromatase inhibitors are being assessed as treatments for women only when chemotherapy is deemed unsuitable.

Trastuzumab, a humanized monoclonal antibody directed against HER2, is administered as an intravenous infusion of 4 mg/kg, followed by a weekly maintenance dose of 2 mg/kg until disease progression (or an alternative schedule of 8 mg/kg followed by 3-weekly doses of 6 mg/kg). NICE estimates the cost of treatment with trastuzumab plus the aromatase inhibitor anastrozole to be between £26,000 and £27,000, depending on the dosing schedule.

Lapatinib, an oral medication, is administered in six tablets totaling 1,500 mg/day. Treatment with lapatinib plus the aromatase inhibitor letrozole is estimated at about £28,000.

NICE said that the estimated incremental cost effectiveness ratio for lapatinib plus letrozole, compared with letrozole alone, is about £74,400 per quality-adjusted life year gained. Trastuzumab plus anastrozole, compared with anastrozole alone, is estimated at £51,000 per QALY gained. Both estimates surpass NICE’s cost-effectiveness caps.

England’s clinical and cost-effectiveness agency has said that it would not recommend lapatinib or trastuzumab with aromatase inhibitors as first-line treatments for postmenopausal women with HER2 positive metastatic breast cancer.

The new negative draft guidance follows previous negative guidance, issued in July 2011, and a subsequent appeal by Roche, the manufacturer of trastuzumab (Herceptin). While an independent panel upheld parts of Roche’s appeal in November, the National Institute for Health and Clinical Excellence nonetheless rejected both treatments once more, citing cost concerns and unclear overall survival evidence for this patient group.

In clinical trial results evaluated by NICE, lapatinib plus an aromatase inhibitor was associated with progression-free survival of 5.2 months, and trastuzumab plus an aromatase inhibitor with 2.4 months; however, NICE said that there was insufficient evidence of an overall survival gain with either treatment.

While NICE has never before issued guidance on lapatinib (Tyverb and Tykerb, GlaxoSmithKline) for any indication, trastuzumab is currently recommended by NICE for the treatment of HER2 positive gastric cancer and for two groups of women with breast cancer: those whose tumors overexpress HER2 at levels of 3+ who have not had chemotherapy for metastatic breast cancer and for whom anthracycline is inappropriate (for this group, trastuzumab is recommended in combination with paclitaxel); and those who have early-stage HER2 positive breast cancer following surgery and chemotherapy.

Lapatinib and trastuzumab combined with aromatase inhibitors are being assessed as treatments for women only when chemotherapy is deemed unsuitable.

Trastuzumab, a humanized monoclonal antibody directed against HER2, is administered as an intravenous infusion of 4 mg/kg, followed by a weekly maintenance dose of 2 mg/kg until disease progression (or an alternative schedule of 8 mg/kg followed by 3-weekly doses of 6 mg/kg). NICE estimates the cost of treatment with trastuzumab plus the aromatase inhibitor anastrozole to be between £26,000 and £27,000, depending on the dosing schedule.

Lapatinib, an oral medication, is administered in six tablets totaling 1,500 mg/day. Treatment with lapatinib plus the aromatase inhibitor letrozole is estimated at about £28,000.

NICE said that the estimated incremental cost effectiveness ratio for lapatinib plus letrozole, compared with letrozole alone, is about £74,400 per quality-adjusted life year gained. Trastuzumab plus anastrozole, compared with anastrozole alone, is estimated at £51,000 per QALY gained. Both estimates surpass NICE’s cost-effectiveness caps.

England’s clinical and cost-effectiveness agency has said that it would not recommend lapatinib or trastuzumab with aromatase inhibitors as first-line treatments for postmenopausal women with HER2 positive metastatic breast cancer.

The new negative draft guidance follows previous negative guidance, issued in July 2011, and a subsequent appeal by Roche, the manufacturer of trastuzumab (Herceptin). While an independent panel upheld parts of Roche’s appeal in November, the National Institute for Health and Clinical Excellence nonetheless rejected both treatments once more, citing cost concerns and unclear overall survival evidence for this patient group.

In clinical trial results evaluated by NICE, lapatinib plus an aromatase inhibitor was associated with progression-free survival of 5.2 months, and trastuzumab plus an aromatase inhibitor with 2.4 months; however, NICE said that there was insufficient evidence of an overall survival gain with either treatment.

While NICE has never before issued guidance on lapatinib (Tyverb and Tykerb, GlaxoSmithKline) for any indication, trastuzumab is currently recommended by NICE for the treatment of HER2 positive gastric cancer and for two groups of women with breast cancer: those whose tumors overexpress HER2 at levels of 3+ who have not had chemotherapy for metastatic breast cancer and for whom anthracycline is inappropriate (for this group, trastuzumab is recommended in combination with paclitaxel); and those who have early-stage HER2 positive breast cancer following surgery and chemotherapy.

Lapatinib and trastuzumab combined with aromatase inhibitors are being assessed as treatments for women only when chemotherapy is deemed unsuitable.

Trastuzumab, a humanized monoclonal antibody directed against HER2, is administered as an intravenous infusion of 4 mg/kg, followed by a weekly maintenance dose of 2 mg/kg until disease progression (or an alternative schedule of 8 mg/kg followed by 3-weekly doses of 6 mg/kg). NICE estimates the cost of treatment with trastuzumab plus the aromatase inhibitor anastrozole to be between £26,000 and £27,000, depending on the dosing schedule.

Lapatinib, an oral medication, is administered in six tablets totaling 1,500 mg/day. Treatment with lapatinib plus the aromatase inhibitor letrozole is estimated at about £28,000.

NICE said that the estimated incremental cost effectiveness ratio for lapatinib plus letrozole, compared with letrozole alone, is about £74,400 per quality-adjusted life year gained. Trastuzumab plus anastrozole, compared with anastrozole alone, is estimated at £51,000 per QALY gained. Both estimates surpass NICE’s cost-effectiveness caps.

A prospective study has confirmed that Lynch syndrome, an inherited disorder that predisposes to many types of cancer, significantly raises the risk of both breast cancer and pancreatic cancer.

The trial is the first to "find a strong association between breast cancer and Lynch syndrome," said senior author and genetic epidemiologist Mark A. Jenkins, Ph.D., of the centre for molecular, environmental, genetic, and analytic epidemiology at the University of Melbourne.

Risk of breast cancer was fourfold higher for the Lynch syndrome patients, compared with the general population. The syndrome is known to increase the risk for a wide variety of other cancers, including colon cancer. Patients are typically advised to begin colonoscopies at an earlier age and repeat them more often than does the general population.

The new findings suggest that women with the syndrome might also benefit from enhanced breast cancer screening, but "further clarification of the risk of breast cancer for women at various ages is needed to determine the recommended age for mammography ... and to determine whether additional tests such as MRI are warranted," Dr. Jenkins said.

The researchers also found an 11-fold increase in pancreatic cancers among the Lynch syndrome patients. Although elevated risk of this cancer has long been suspected, the evidence from previous studies has been inconsistent. The results were published online Feb. 13 in the Journal of Clinical Oncology.

The autosomal dominant disorder, detected with a blood test, is caused by a mutation in one of four DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. The estimated carrier frequency in the population ranges from 1 in 360 to 1 in 3,010 individuals, depending on whether all four specific mutations, or fewer than four, are included in the calculations.

Family members without the mutation, however, do not have a greater risk for cancer, and do not need more intensive screening than does the general population – something that has been unclear until now.

The investigators followed 446 mutation carriers and 1,029 noncarrier relatives recruited from the Colon Cancer Family Registry in 1997-2010. Almost all study subjects (96%) were white, and slightly more than half were female. At recruitment, mean age ranged from 40 to 50 years for the different subgroups. The registry includes subjects from the United States, Canada, Australia, and New Zealand.

After a median follow-up of 5 years, mutation carriers had a 20-fold greater risk of colorectal cancer, a 31-fold greater risk of endometrial cancer, a 19-fold higher risk of ovarian cancer, an 11-fold greater risk of renal cancer, and a 10-fold greater risk of stomach and bladder cancers, compared with the general population. The increase in risk for breast and pancreatic cancer was 4-fold and 11-fold, respectively.

For each cancer type, the increased rate in mutation carriers was highly significant, with P values ranging from .009 to less than .001. In addition, the Lynch syndrome patients’ cancer diagnoses typically came at an earlier age than it did in the general population. (J. Clin. Oncol. 2012 Feb. 13 [doi:10.1200/JCO.2011.39.5590]).

"Estimates of site-specific cancer risks for MMR gene mutation carriers inform optimal clinical management," the researchers noted. "Screening colonoscopy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy have the potential to decrease the risk of colorectal cancer, endometrial cancer, and ovarian cancer, respectively."

"Eventually, we expect that the management of cancer risk, including the choice and timing of screening, will be able to be tailored to the specific underlying gene mutation in a person with Lynch syndrome." However, there are no data demonstrating that screening for cancers other than colorectal "is beneficial, in part due to the absence of effective screening tests," Dr. Jenkins and colleagues wrote.

The authors said that they have no relevant conflicts of interest. The study was funded by the National Cancer Institute.

A prospective study has confirmed that Lynch syndrome, an inherited disorder that predisposes to many types of cancer, significantly raises the risk of both breast cancer and pancreatic cancer.

The trial is the first to "find a strong association between breast cancer and Lynch syndrome," said senior author and genetic epidemiologist Mark A. Jenkins, Ph.D., of the centre for molecular, environmental, genetic, and analytic epidemiology at the University of Melbourne.

Risk of breast cancer was fourfold higher for the Lynch syndrome patients, compared with the general population. The syndrome is known to increase the risk for a wide variety of other cancers, including colon cancer. Patients are typically advised to begin colonoscopies at an earlier age and repeat them more often than does the general population.

The new findings suggest that women with the syndrome might also benefit from enhanced breast cancer screening, but "further clarification of the risk of breast cancer for women at various ages is needed to determine the recommended age for mammography ... and to determine whether additional tests such as MRI are warranted," Dr. Jenkins said.

The researchers also found an 11-fold increase in pancreatic cancers among the Lynch syndrome patients. Although elevated risk of this cancer has long been suspected, the evidence from previous studies has been inconsistent. The results were published online Feb. 13 in the Journal of Clinical Oncology.

The autosomal dominant disorder, detected with a blood test, is caused by a mutation in one of four DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. The estimated carrier frequency in the population ranges from 1 in 360 to 1 in 3,010 individuals, depending on whether all four specific mutations, or fewer than four, are included in the calculations.

Family members without the mutation, however, do not have a greater risk for cancer, and do not need more intensive screening than does the general population – something that has been unclear until now.

The investigators followed 446 mutation carriers and 1,029 noncarrier relatives recruited from the Colon Cancer Family Registry in 1997-2010. Almost all study subjects (96%) were white, and slightly more than half were female. At recruitment, mean age ranged from 40 to 50 years for the different subgroups. The registry includes subjects from the United States, Canada, Australia, and New Zealand.

After a median follow-up of 5 years, mutation carriers had a 20-fold greater risk of colorectal cancer, a 31-fold greater risk of endometrial cancer, a 19-fold higher risk of ovarian cancer, an 11-fold greater risk of renal cancer, and a 10-fold greater risk of stomach and bladder cancers, compared with the general population. The increase in risk for breast and pancreatic cancer was 4-fold and 11-fold, respectively.

For each cancer type, the increased rate in mutation carriers was highly significant, with P values ranging from .009 to less than .001. In addition, the Lynch syndrome patients’ cancer diagnoses typically came at an earlier age than it did in the general population. (J. Clin. Oncol. 2012 Feb. 13 [doi:10.1200/JCO.2011.39.5590]).

"Estimates of site-specific cancer risks for MMR gene mutation carriers inform optimal clinical management," the researchers noted. "Screening colonoscopy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy have the potential to decrease the risk of colorectal cancer, endometrial cancer, and ovarian cancer, respectively."

"Eventually, we expect that the management of cancer risk, including the choice and timing of screening, will be able to be tailored to the specific underlying gene mutation in a person with Lynch syndrome." However, there are no data demonstrating that screening for cancers other than colorectal "is beneficial, in part due to the absence of effective screening tests," Dr. Jenkins and colleagues wrote.

The authors said that they have no relevant conflicts of interest. The study was funded by the National Cancer Institute.

A prospective study has confirmed that Lynch syndrome, an inherited disorder that predisposes to many types of cancer, significantly raises the risk of both breast cancer and pancreatic cancer.

The trial is the first to "find a strong association between breast cancer and Lynch syndrome," said senior author and genetic epidemiologist Mark A. Jenkins, Ph.D., of the centre for molecular, environmental, genetic, and analytic epidemiology at the University of Melbourne.

Risk of breast cancer was fourfold higher for the Lynch syndrome patients, compared with the general population. The syndrome is known to increase the risk for a wide variety of other cancers, including colon cancer. Patients are typically advised to begin colonoscopies at an earlier age and repeat them more often than does the general population.

The new findings suggest that women with the syndrome might also benefit from enhanced breast cancer screening, but "further clarification of the risk of breast cancer for women at various ages is needed to determine the recommended age for mammography ... and to determine whether additional tests such as MRI are warranted," Dr. Jenkins said.

The researchers also found an 11-fold increase in pancreatic cancers among the Lynch syndrome patients. Although elevated risk of this cancer has long been suspected, the evidence from previous studies has been inconsistent. The results were published online Feb. 13 in the Journal of Clinical Oncology.

The autosomal dominant disorder, detected with a blood test, is caused by a mutation in one of four DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. The estimated carrier frequency in the population ranges from 1 in 360 to 1 in 3,010 individuals, depending on whether all four specific mutations, or fewer than four, are included in the calculations.

Family members without the mutation, however, do not have a greater risk for cancer, and do not need more intensive screening than does the general population – something that has been unclear until now.

The investigators followed 446 mutation carriers and 1,029 noncarrier relatives recruited from the Colon Cancer Family Registry in 1997-2010. Almost all study subjects (96%) were white, and slightly more than half were female. At recruitment, mean age ranged from 40 to 50 years for the different subgroups. The registry includes subjects from the United States, Canada, Australia, and New Zealand.

After a median follow-up of 5 years, mutation carriers had a 20-fold greater risk of colorectal cancer, a 31-fold greater risk of endometrial cancer, a 19-fold higher risk of ovarian cancer, an 11-fold greater risk of renal cancer, and a 10-fold greater risk of stomach and bladder cancers, compared with the general population. The increase in risk for breast and pancreatic cancer was 4-fold and 11-fold, respectively.

For each cancer type, the increased rate in mutation carriers was highly significant, with P values ranging from .009 to less than .001. In addition, the Lynch syndrome patients’ cancer diagnoses typically came at an earlier age than it did in the general population. (J. Clin. Oncol. 2012 Feb. 13 [doi:10.1200/JCO.2011.39.5590]).

"Estimates of site-specific cancer risks for MMR gene mutation carriers inform optimal clinical management," the researchers noted. "Screening colonoscopy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy have the potential to decrease the risk of colorectal cancer, endometrial cancer, and ovarian cancer, respectively."

"Eventually, we expect that the management of cancer risk, including the choice and timing of screening, will be able to be tailored to the specific underlying gene mutation in a person with Lynch syndrome." However, there are no data demonstrating that screening for cancers other than colorectal "is beneficial, in part due to the absence of effective screening tests," Dr. Jenkins and colleagues wrote.

The authors said that they have no relevant conflicts of interest. The study was funded by the National Cancer Institute.

Among postmenopausal women who have hormone receptor–positive breast cancer, increasing age correlates with a rise in disease-specific mortality, independently of tumor, treatment, and patient characteristics, according to a report in the Feb. 9 issue of JAMA.

This increased cancer-specific mortality is particularly noteworthy because it occurs against a background in which other, competing causes of mortality are also increasing as these women age, said Dr. Willemien van de Water of the departments of surgical oncology and gerontology, Leiden (the Netherlands) University Medical Center, and associates.

To assess the relationship between aging and breast-cancer-specific mortality, the investigators analyzed data from the TEAM (Tamoxifen Exemestane Adjuvant Multinational) study, a phase III, randomized, open-label trial that had no upper age limit and included subjects up to 96 years old. The TEAM study involved 9,766 women who had estrogen receptor–positive tumors, progesterone receptor–positive tumors, or both, and were treated in Belgium, the Netherlands, the United Kingdom, Ireland, the United States, Japan, Greece, Germany, and France.

Because the 5-year TEAM trial found no significant differences in outcomes between the study groups and comparable mortality from other causes, it proved ideal for this post hoc analysis of disease-specific mortality, Dr. van de Water and colleagues said.

They divided the study subjects into three age groups: younger than 65 years (5,349 women; 55% of the entire cohort), 65-74 years (3,060 women; 31% of the cohort), and 75 years and older (1,357 women; 14% of the cohort).

The cumulative incidence of death from breast cancer rose from 5.7% in the youngest group to 6.3% in the intermediate group and 8.3% in the oldest group, the investigators said (JAMA 2012;307:590-7).

"Since tumor and treatment characteristics may be associated with disease-specific mortality, multivariable analyses were performed in an attempt to adjust for unequal distributions among age categories. ... Again, disease-specific mortality increased with age," with hazard ratios of 1.25 for patients aged 65-74 years and 1.62 for those aged 75 and older, compared with women younger than 65.

"To test the robustness of the age cut points, additional analyses were performed with age as a continuous variable, which confirmed an increased risk of breast cancer death per 10-year increase in age," they said.

Because there was a tendency for older patients to have larger tumors at diagnosis than did younger patients, additional analyses were performed to adjust for any residual confounding that might be related to tumor size. The results were unchanged.

Finally, the data were adjusted to account for mortality from competing causes such as infection, trauma, dementia, and cardiovascular disease. Again, the results were not affected by study subjects’ comorbidities.

This study was not designed to assess the reasons why breast-cancer mortality rises with increasing patient age, but the researchers proposed four possible underlying mechanisms.

First, older patients may be undertreated. Several other studies have shown that older age at diagnosis correlates with greater deviation from treatment guidelines for surgery, radiotherapy, chemotherapy, and endocrine therapy, as well as with more frequent cessation of medication.

Next, older patients may be more vulnerable to treatment-related toxicities. Third, tumor biology might be more aggressive in older patients. And fourth, polypharmacy, which is more common in older patients, might cause adverse interactions with anticancer therapies, rendering them less effective, Dr. van de Water and associates said.

The study findings "underline the need for age-specific breast cancer studies in order to improve breast cancer outcome in patients of all ages," they said.

The TEAM trial was supported by Pfizer. Dr. van de Water's associates reported ties to numerous industry sources.

Among postmenopausal women who have hormone receptor–positive breast cancer, increasing age correlates with a rise in disease-specific mortality, independently of tumor, treatment, and patient characteristics, according to a report in the Feb. 9 issue of JAMA.

This increased cancer-specific mortality is particularly noteworthy because it occurs against a background in which other, competing causes of mortality are also increasing as these women age, said Dr. Willemien van de Water of the departments of surgical oncology and gerontology, Leiden (the Netherlands) University Medical Center, and associates.

To assess the relationship between aging and breast-cancer-specific mortality, the investigators analyzed data from the TEAM (Tamoxifen Exemestane Adjuvant Multinational) study, a phase III, randomized, open-label trial that had no upper age limit and included subjects up to 96 years old. The TEAM study involved 9,766 women who had estrogen receptor–positive tumors, progesterone receptor–positive tumors, or both, and were treated in Belgium, the Netherlands, the United Kingdom, Ireland, the United States, Japan, Greece, Germany, and France.

Because the 5-year TEAM trial found no significant differences in outcomes between the study groups and comparable mortality from other causes, it proved ideal for this post hoc analysis of disease-specific mortality, Dr. van de Water and colleagues said.

They divided the study subjects into three age groups: younger than 65 years (5,349 women; 55% of the entire cohort), 65-74 years (3,060 women; 31% of the cohort), and 75 years and older (1,357 women; 14% of the cohort).

The cumulative incidence of death from breast cancer rose from 5.7% in the youngest group to 6.3% in the intermediate group and 8.3% in the oldest group, the investigators said (JAMA 2012;307:590-7).

"Since tumor and treatment characteristics may be associated with disease-specific mortality, multivariable analyses were performed in an attempt to adjust for unequal distributions among age categories. ... Again, disease-specific mortality increased with age," with hazard ratios of 1.25 for patients aged 65-74 years and 1.62 for those aged 75 and older, compared with women younger than 65.

"To test the robustness of the age cut points, additional analyses were performed with age as a continuous variable, which confirmed an increased risk of breast cancer death per 10-year increase in age," they said.

Because there was a tendency for older patients to have larger tumors at diagnosis than did younger patients, additional analyses were performed to adjust for any residual confounding that might be related to tumor size. The results were unchanged.

Finally, the data were adjusted to account for mortality from competing causes such as infection, trauma, dementia, and cardiovascular disease. Again, the results were not affected by study subjects’ comorbidities.

This study was not designed to assess the reasons why breast-cancer mortality rises with increasing patient age, but the researchers proposed four possible underlying mechanisms.

First, older patients may be undertreated. Several other studies have shown that older age at diagnosis correlates with greater deviation from treatment guidelines for surgery, radiotherapy, chemotherapy, and endocrine therapy, as well as with more frequent cessation of medication.

Next, older patients may be more vulnerable to treatment-related toxicities. Third, tumor biology might be more aggressive in older patients. And fourth, polypharmacy, which is more common in older patients, might cause adverse interactions with anticancer therapies, rendering them less effective, Dr. van de Water and associates said.

The study findings "underline the need for age-specific breast cancer studies in order to improve breast cancer outcome in patients of all ages," they said.

The TEAM trial was supported by Pfizer. Dr. van de Water's associates reported ties to numerous industry sources.

Among postmenopausal women who have hormone receptor–positive breast cancer, increasing age correlates with a rise in disease-specific mortality, independently of tumor, treatment, and patient characteristics, according to a report in the Feb. 9 issue of JAMA.

This increased cancer-specific mortality is particularly noteworthy because it occurs against a background in which other, competing causes of mortality are also increasing as these women age, said Dr. Willemien van de Water of the departments of surgical oncology and gerontology, Leiden (the Netherlands) University Medical Center, and associates.

To assess the relationship between aging and breast-cancer-specific mortality, the investigators analyzed data from the TEAM (Tamoxifen Exemestane Adjuvant Multinational) study, a phase III, randomized, open-label trial that had no upper age limit and included subjects up to 96 years old. The TEAM study involved 9,766 women who had estrogen receptor–positive tumors, progesterone receptor–positive tumors, or both, and were treated in Belgium, the Netherlands, the United Kingdom, Ireland, the United States, Japan, Greece, Germany, and France.

Because the 5-year TEAM trial found no significant differences in outcomes between the study groups and comparable mortality from other causes, it proved ideal for this post hoc analysis of disease-specific mortality, Dr. van de Water and colleagues said.

They divided the study subjects into three age groups: younger than 65 years (5,349 women; 55% of the entire cohort), 65-74 years (3,060 women; 31% of the cohort), and 75 years and older (1,357 women; 14% of the cohort).

The cumulative incidence of death from breast cancer rose from 5.7% in the youngest group to 6.3% in the intermediate group and 8.3% in the oldest group, the investigators said (JAMA 2012;307:590-7).

"Since tumor and treatment characteristics may be associated with disease-specific mortality, multivariable analyses were performed in an attempt to adjust for unequal distributions among age categories. ... Again, disease-specific mortality increased with age," with hazard ratios of 1.25 for patients aged 65-74 years and 1.62 for those aged 75 and older, compared with women younger than 65.

"To test the robustness of the age cut points, additional analyses were performed with age as a continuous variable, which confirmed an increased risk of breast cancer death per 10-year increase in age," they said.

Because there was a tendency for older patients to have larger tumors at diagnosis than did younger patients, additional analyses were performed to adjust for any residual confounding that might be related to tumor size. The results were unchanged.

Finally, the data were adjusted to account for mortality from competing causes such as infection, trauma, dementia, and cardiovascular disease. Again, the results were not affected by study subjects’ comorbidities.

This study was not designed to assess the reasons why breast-cancer mortality rises with increasing patient age, but the researchers proposed four possible underlying mechanisms.

First, older patients may be undertreated. Several other studies have shown that older age at diagnosis correlates with greater deviation from treatment guidelines for surgery, radiotherapy, chemotherapy, and endocrine therapy, as well as with more frequent cessation of medication.

Next, older patients may be more vulnerable to treatment-related toxicities. Third, tumor biology might be more aggressive in older patients. And fourth, polypharmacy, which is more common in older patients, might cause adverse interactions with anticancer therapies, rendering them less effective, Dr. van de Water and associates said.

The study findings "underline the need for age-specific breast cancer studies in order to improve breast cancer outcome in patients of all ages," they said.

The TEAM trial was supported by Pfizer. Dr. van de Water's associates reported ties to numerous industry sources.

Exemestane significantly decreases bone mineral density in healthy postmenopausal women who take it to reduce their risk of breast cancer, according to a study published online Feb. 7 in The Lancet Oncology.

Two years of daily oral treatment with the steroidal aromatase inhibitor was found to worsen age-related decreases in BMD "by about three times, even in the setting of adequate calcium and vitamin D intake," said Dr. Angela M. Cheung of the University Health Network in Toronto and her associates.

Dr. Cheung and her colleagues performed a safety substudy as part of the National Cancer Institute of Canada’s Mammary Prevention Trial 3 (MAP.3), a double-blind randomized study showing that exemestane significantly reduced the development of breast cancer in high-risk women, compared with placebo. Previous studies had suggested that exemestane exerted a small protective effect and caused less bone loss than other, nonsteroidal aromatase inhibitors such as anastrozole and letrozole.

This substudy focused on the drug’s effect on bone health and involved 351 subjects with T-scores above 2.0 at the lumbar spine, total hip, and femoral neck at baseline. The women had adequate dietary intake of calcium and vitamin D but received supplements as well. This was not a large enough sample to assess fracture risk directly, so the researchers instead assessed the intermediate end points of bone density and structure.

Theirs is the first study to use high-resolution peripheral quantitative CT scanning as well as the usual dual-energy x-ray absorptiometry to examine bone. Unlike the latter method, high-resolution peripheral quantitative CT captures aspects of bone fragility, including microarchitectural, geometric, and material properties that heavily influence fracture risk, the investigators noted.

The study subjects were treated and followed at three medical centers in Canada and two in the United States; median age was 61 years. A total of 176 were randomly assigned to receive daily oral exemestane and 175 to receive placebo.

The primary end point, percent change in total volumetric BMD at the distal radius after 2 years, was significantly greater with exemestane (mean loss of 6.1%) than placebo (mean loss of 1.8%). Exemestane also decreased cortical volumetric BMD at the distal radius by 4.6%, compared with 1.9% for placebo.

The drug also decreased total volumetric BMD at the distal tibia (loss of 5.0%) and cortical volumetric BMD at the distal tibia (loss of 5.3%), compared with placebo (losses of 1.3% and 2.3%, respectively).

In addition, exemestane was associated with a loss of 7.9% in mean cortical thickness at the distal radius (compared with –1.1% with placebo) and a loss of 7.6% in cortical thickness at the distal tibia (compared with –0.7% with placebo). Exemestane also cut mean total area and mean cortical area at both sites, compared with placebo, Dr. Cheung and her associates said (Lancet Oncol. 2012 [doi:10.1016/S1470-2045(11)70389-8]).

With exemestane, more women had clinically significant areal BMD loss at the lumbar spine (45%), total hip (26%), and femoral neck (22%), compared with placebo (20%, 19%, and 6%, respectively). Moreover, 65% of women taking exemestane showed clinically significant areal BMD loss at one of these three sites, compared with only 35% of women taking placebo.

These changes in bone strength, however, were not reflected in fracture rates during this relatively short study. There were no significant differences between the two study groups in fractures deemed to be attributable to bone fragility (1 with exemestane and 3 with placebo) or in total fractures (6 with exemestane and 11 with placebo), and the difference in height reduction (2 mm for exemestane vs. 1 mm for placebo) also was not significant, the researchers noted.

More importantly, "the minor areal BMD changes detected by dual-energy x-ray absorptiometry did not reflect the underlying structural deterioration seen with high-resolution peripheral quantitative CT. Although dual x-ray absorptiometry is the current clinical gold standard for skeletal assessment of fracture risk, it does not capture bone geometry, microarchitecture, or biomechanical properties, which also contribute to fracture risk," Dr. Cheung and her colleagues noted.

Unfortunately, this CT technique is not yet available for routine clinical care, they added.

This study was limited in that it involved healthy, predominantly white women with normal BMD and adequate calcium and vitamin D intake, so the findings may not be generalizable to women with osteoporosis, women with breast cancer, or nonwhite women. Also, follow-up was only 2 years; longer follow-up (up to 5 years) is needed to assess exemestane’s long-term effects on bone, the researchers said.

Nonetheless, the findings do reinforce the importance of monitoring bone health in these patients, they said.

This substudy was supported by the Canadian Breast Cancer Research Alliance, a joint initiative between the Canadian Institutes of Health Research and the Canadian Cancer Society. The main MAP.3 study also was supported by Pfizer. Jamieson Laboratories provided calcium and vitamin D supplements and Pfizer Pharmaceuticals provided exemestane and placebo. Dr. Cheung is supported in part by a Canadian Institutes of Health Research/Institute of Gender and Health Senior Investigator Award, and the Lillian Love Chair in Women’s Health at the University of Toronto/University Health Network. One of Dr. Cheung’s associates reported ties to Pfizer and Avon Foundation. None of the other researchers reported conflicts of interest.

Exemestane significantly decreases bone mineral density in healthy postmenopausal women who take it to reduce their risk of breast cancer, according to a study published online Feb. 7 in The Lancet Oncology.

Two years of daily oral treatment with the steroidal aromatase inhibitor was found to worsen age-related decreases in BMD "by about three times, even in the setting of adequate calcium and vitamin D intake," said Dr. Angela M. Cheung of the University Health Network in Toronto and her associates.

Dr. Cheung and her colleagues performed a safety substudy as part of the National Cancer Institute of Canada’s Mammary Prevention Trial 3 (MAP.3), a double-blind randomized study showing that exemestane significantly reduced the development of breast cancer in high-risk women, compared with placebo. Previous studies had suggested that exemestane exerted a small protective effect and caused less bone loss than other, nonsteroidal aromatase inhibitors such as anastrozole and letrozole.

This substudy focused on the drug’s effect on bone health and involved 351 subjects with T-scores above 2.0 at the lumbar spine, total hip, and femoral neck at baseline. The women had adequate dietary intake of calcium and vitamin D but received supplements as well. This was not a large enough sample to assess fracture risk directly, so the researchers instead assessed the intermediate end points of bone density and structure.

Theirs is the first study to use high-resolution peripheral quantitative CT scanning as well as the usual dual-energy x-ray absorptiometry to examine bone. Unlike the latter method, high-resolution peripheral quantitative CT captures aspects of bone fragility, including microarchitectural, geometric, and material properties that heavily influence fracture risk, the investigators noted.

The study subjects were treated and followed at three medical centers in Canada and two in the United States; median age was 61 years. A total of 176 were randomly assigned to receive daily oral exemestane and 175 to receive placebo.

The primary end point, percent change in total volumetric BMD at the distal radius after 2 years, was significantly greater with exemestane (mean loss of 6.1%) than placebo (mean loss of 1.8%). Exemestane also decreased cortical volumetric BMD at the distal radius by 4.6%, compared with 1.9% for placebo.

The drug also decreased total volumetric BMD at the distal tibia (loss of 5.0%) and cortical volumetric BMD at the distal tibia (loss of 5.3%), compared with placebo (losses of 1.3% and 2.3%, respectively).

In addition, exemestane was associated with a loss of 7.9% in mean cortical thickness at the distal radius (compared with –1.1% with placebo) and a loss of 7.6% in cortical thickness at the distal tibia (compared with –0.7% with placebo). Exemestane also cut mean total area and mean cortical area at both sites, compared with placebo, Dr. Cheung and her associates said (Lancet Oncol. 2012 [doi:10.1016/S1470-2045(11)70389-8]).

With exemestane, more women had clinically significant areal BMD loss at the lumbar spine (45%), total hip (26%), and femoral neck (22%), compared with placebo (20%, 19%, and 6%, respectively). Moreover, 65% of women taking exemestane showed clinically significant areal BMD loss at one of these three sites, compared with only 35% of women taking placebo.

These changes in bone strength, however, were not reflected in fracture rates during this relatively short study. There were no significant differences between the two study groups in fractures deemed to be attributable to bone fragility (1 with exemestane and 3 with placebo) or in total fractures (6 with exemestane and 11 with placebo), and the difference in height reduction (2 mm for exemestane vs. 1 mm for placebo) also was not significant, the researchers noted.

More importantly, "the minor areal BMD changes detected by dual-energy x-ray absorptiometry did not reflect the underlying structural deterioration seen with high-resolution peripheral quantitative CT. Although dual x-ray absorptiometry is the current clinical gold standard for skeletal assessment of fracture risk, it does not capture bone geometry, microarchitecture, or biomechanical properties, which also contribute to fracture risk," Dr. Cheung and her colleagues noted.

Unfortunately, this CT technique is not yet available for routine clinical care, they added.

This study was limited in that it involved healthy, predominantly white women with normal BMD and adequate calcium and vitamin D intake, so the findings may not be generalizable to women with osteoporosis, women with breast cancer, or nonwhite women. Also, follow-up was only 2 years; longer follow-up (up to 5 years) is needed to assess exemestane’s long-term effects on bone, the researchers said.

Nonetheless, the findings do reinforce the importance of monitoring bone health in these patients, they said.

This substudy was supported by the Canadian Breast Cancer Research Alliance, a joint initiative between the Canadian Institutes of Health Research and the Canadian Cancer Society. The main MAP.3 study also was supported by Pfizer. Jamieson Laboratories provided calcium and vitamin D supplements and Pfizer Pharmaceuticals provided exemestane and placebo. Dr. Cheung is supported in part by a Canadian Institutes of Health Research/Institute of Gender and Health Senior Investigator Award, and the Lillian Love Chair in Women’s Health at the University of Toronto/University Health Network. One of Dr. Cheung’s associates reported ties to Pfizer and Avon Foundation. None of the other researchers reported conflicts of interest.

Exemestane significantly decreases bone mineral density in healthy postmenopausal women who take it to reduce their risk of breast cancer, according to a study published online Feb. 7 in The Lancet Oncology.

Two years of daily oral treatment with the steroidal aromatase inhibitor was found to worsen age-related decreases in BMD "by about three times, even in the setting of adequate calcium and vitamin D intake," said Dr. Angela M. Cheung of the University Health Network in Toronto and her associates.

Dr. Cheung and her colleagues performed a safety substudy as part of the National Cancer Institute of Canada’s Mammary Prevention Trial 3 (MAP.3), a double-blind randomized study showing that exemestane significantly reduced the development of breast cancer in high-risk women, compared with placebo. Previous studies had suggested that exemestane exerted a small protective effect and caused less bone loss than other, nonsteroidal aromatase inhibitors such as anastrozole and letrozole.

This substudy focused on the drug’s effect on bone health and involved 351 subjects with T-scores above 2.0 at the lumbar spine, total hip, and femoral neck at baseline. The women had adequate dietary intake of calcium and vitamin D but received supplements as well. This was not a large enough sample to assess fracture risk directly, so the researchers instead assessed the intermediate end points of bone density and structure.

Theirs is the first study to use high-resolution peripheral quantitative CT scanning as well as the usual dual-energy x-ray absorptiometry to examine bone. Unlike the latter method, high-resolution peripheral quantitative CT captures aspects of bone fragility, including microarchitectural, geometric, and material properties that heavily influence fracture risk, the investigators noted.

The study subjects were treated and followed at three medical centers in Canada and two in the United States; median age was 61 years. A total of 176 were randomly assigned to receive daily oral exemestane and 175 to receive placebo.

The primary end point, percent change in total volumetric BMD at the distal radius after 2 years, was significantly greater with exemestane (mean loss of 6.1%) than placebo (mean loss of 1.8%). Exemestane also decreased cortical volumetric BMD at the distal radius by 4.6%, compared with 1.9% for placebo.

The drug also decreased total volumetric BMD at the distal tibia (loss of 5.0%) and cortical volumetric BMD at the distal tibia (loss of 5.3%), compared with placebo (losses of 1.3% and 2.3%, respectively).

In addition, exemestane was associated with a loss of 7.9% in mean cortical thickness at the distal radius (compared with –1.1% with placebo) and a loss of 7.6% in cortical thickness at the distal tibia (compared with –0.7% with placebo). Exemestane also cut mean total area and mean cortical area at both sites, compared with placebo, Dr. Cheung and her associates said (Lancet Oncol. 2012 [doi:10.1016/S1470-2045(11)70389-8]).

With exemestane, more women had clinically significant areal BMD loss at the lumbar spine (45%), total hip (26%), and femoral neck (22%), compared with placebo (20%, 19%, and 6%, respectively). Moreover, 65% of women taking exemestane showed clinically significant areal BMD loss at one of these three sites, compared with only 35% of women taking placebo.

These changes in bone strength, however, were not reflected in fracture rates during this relatively short study. There were no significant differences between the two study groups in fractures deemed to be attributable to bone fragility (1 with exemestane and 3 with placebo) or in total fractures (6 with exemestane and 11 with placebo), and the difference in height reduction (2 mm for exemestane vs. 1 mm for placebo) also was not significant, the researchers noted.

More importantly, "the minor areal BMD changes detected by dual-energy x-ray absorptiometry did not reflect the underlying structural deterioration seen with high-resolution peripheral quantitative CT. Although dual x-ray absorptiometry is the current clinical gold standard for skeletal assessment of fracture risk, it does not capture bone geometry, microarchitecture, or biomechanical properties, which also contribute to fracture risk," Dr. Cheung and her colleagues noted.

Unfortunately, this CT technique is not yet available for routine clinical care, they added.

This study was limited in that it involved healthy, predominantly white women with normal BMD and adequate calcium and vitamin D intake, so the findings may not be generalizable to women with osteoporosis, women with breast cancer, or nonwhite women. Also, follow-up was only 2 years; longer follow-up (up to 5 years) is needed to assess exemestane’s long-term effects on bone, the researchers said.

Nonetheless, the findings do reinforce the importance of monitoring bone health in these patients, they said.

This substudy was supported by the Canadian Breast Cancer Research Alliance, a joint initiative between the Canadian Institutes of Health Research and the Canadian Cancer Society. The main MAP.3 study also was supported by Pfizer. Jamieson Laboratories provided calcium and vitamin D supplements and Pfizer Pharmaceuticals provided exemestane and placebo. Dr. Cheung is supported in part by a Canadian Institutes of Health Research/Institute of Gender and Health Senior Investigator Award, and the Lillian Love Chair in Women’s Health at the University of Toronto/University Health Network. One of Dr. Cheung’s associates reported ties to Pfizer and Avon Foundation. None of the other researchers reported conflicts of interest.

The anti-HER2 monoclonal antibody trastuzumab works by binding to subdomain IV of the HER2 extracellular domain, thereby blocking HER2 cleavage; stimulating antibody-dependent, cell-mediated cytotoxicity; and preventing ligand-independent, HER2- mediated mitogenic signaling. Pertuzumab is an anti- HER2 monoclonal antibody that binds to subdomain II of the HER2 extracellular domain, preventing HER2 from dimerizing with other ligand-activated HER receptors; like trastuzumab, pertuzumab also stimulates antibodydependent cell-mediated cytotoxicity. Pertuzumab’s binding at a different HER2 epitope than trastuzumab represents a complementary mechanism of action that provides more comprehensive inhibition of HER2 signaling when the two agents are used together; the combination has been shown to produce greater antitumor activity than either agent alone in HER2-positive tumor models...

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

The anti-HER2 monoclonal antibody trastuzumab works by binding to subdomain IV of the HER2 extracellular domain, thereby blocking HER2 cleavage; stimulating antibody-dependent, cell-mediated cytotoxicity; and preventing ligand-independent, HER2- mediated mitogenic signaling. Pertuzumab is an anti- HER2 monoclonal antibody that binds to subdomain II of the HER2 extracellular domain, preventing HER2 from dimerizing with other ligand-activated HER receptors; like trastuzumab, pertuzumab also stimulates antibodydependent cell-mediated cytotoxicity. Pertuzumab’s binding at a different HER2 epitope than trastuzumab represents a complementary mechanism of action that provides more comprehensive inhibition of HER2 signaling when the two agents are used together; the combination has been shown to produce greater antitumor activity than either agent alone in HER2-positive tumor models...

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

The anti-HER2 monoclonal antibody trastuzumab works by binding to subdomain IV of the HER2 extracellular domain, thereby blocking HER2 cleavage; stimulating antibody-dependent, cell-mediated cytotoxicity; and preventing ligand-independent, HER2- mediated mitogenic signaling. Pertuzumab is an anti- HER2 monoclonal antibody that binds to subdomain II of the HER2 extracellular domain, preventing HER2 from dimerizing with other ligand-activated HER receptors; like trastuzumab, pertuzumab also stimulates antibodydependent cell-mediated cytotoxicity. Pertuzumab’s binding at a different HER2 epitope than trastuzumab represents a complementary mechanism of action that provides more comprehensive inhibition of HER2 signaling when the two agents are used together; the combination has been shown to produce greater antitumor activity than either agent alone in HER2-positive tumor models...

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

Rates of re-excision after initial breast-conserving surgery for invasive breast cancer vary greatly across surgeons and across medical centers, according to a report in the Feb. 1 issue of JAMA.

These variations are only partly explained by the basic clinical and demographic factors that dictate treatment decisions, such as tumor size and patient age. The remaining reasons for the profound differences in re-excision rates remain unexplained.

Nevertheless, these variations certainly are a barrier to consistent, high-quality, cost-effective care for breast cancer. "Outcomes such as local recurrence and even overall survival could be affected by variability in initial surgical care," said Dr. Laurence E. McCahill of the Richard J. Lacks Cancer Center, Van Andel Research Institute, and department of surgery at Michigan State University, Grand Rapids, and his associates.

Noting that "currently, there are no readily identifiable quality measures that allow for meaningful comparisons of breast cancer surgical outcomes among treating surgeons and hospitals," the investigators examined re-excision rates across four geographically diverse health systems. Their chief goal was to determine whether significant variations existed, which would in turn determine whether the re-excision rate is a meaningful measure of surgical quality.

They assessed detailed data on initial and subsequent surgeries for invasive ductal carcinoma or invasive lobular carcinoma in 2,206 women who underwent an initial breast-conserving procedure for incident cancer.

Overall, 509 patients (23%) underwent re-excision of the affected breast during 5 years of follow-up. A total of 454 women had a single re-excision, 48 had two re-excisions, and 7 had three re-excisions. Approximately 9% of the study subjects (190 women) underwent total mastectomy after the initial breast-conserving surgery.

The rate of re-excision varied greatly from one surgeon to another, ranging from 0% to 70%. This implies that patients with the same clinical presentations are likely to undergo re-excision based on who is doing their procedure, not on their clinical traits, the investigators said (JAMA 2012;307:467-75).

This study was designed to determine whether such variations exist, not the reasons why they exist. But the researchers suggested that "differences in surgical training, surgeon confidence in their operative technique in localizing tumors, utilization of intraoperative assessment of margins, and surgeon’s and pathologist’s coordination of specimen orientation and margin interpretation" may all play a role.

Surprisingly, the volume of procedures a surgeon performs did not affect his or her re-excision rate in this study, so surgical experience may not play an important role in these variations, Dr. McCahill and his colleagues added.

The rate of re-excision also varied greatly from one medical center to another, ranging from 1.7% at the center with the lowest rate to 21% at the center with the highest rate. In particular, the rate of re-excision for cases with positive margins ranged from 74% to 94%. Any variation in this statistic is surprising because positive margins are known to correlate with local recurrence and are "almost always" re-excised, the researchers said.

Again, this study was not designed to determine why re-excision rates differ so greatly between medical centers, but the investigators suggested that "institutional variation in surgeon’s training, regional variation in interpretation of the required criteria for [re-excision], or both" may account, at least in part, for the variation.

The need for re-excision in patients who have negative (pathologically clear) margins at the initial surgery is controversial, because "there is no clear consensus on the appropriate distance required for a clear margin to be deemed adequate." So perhaps it should not be surprising that almost half of the re-excisions (242 of the 509) in this study were performed in patients who had negative margins, the researchers said.

One major limitation of this study was that some factors that greatly influence treatment decisions, including patient preferences, were not included in the data and so could not be factored into the analysis, they noted.

This study was funded by the National Institutes of Health under the American Recovery and Reinvestment Act. The authors reported no financial conflicts of interest.

Rates of re-excision after initial breast-conserving surgery for invasive breast cancer vary greatly across surgeons and across medical centers, according to a report in the Feb. 1 issue of JAMA.

These variations are only partly explained by the basic clinical and demographic factors that dictate treatment decisions, such as tumor size and patient age. The remaining reasons for the profound differences in re-excision rates remain unexplained.

Nevertheless, these variations certainly are a barrier to consistent, high-quality, cost-effective care for breast cancer. "Outcomes such as local recurrence and even overall survival could be affected by variability in initial surgical care," said Dr. Laurence E. McCahill of the Richard J. Lacks Cancer Center, Van Andel Research Institute, and department of surgery at Michigan State University, Grand Rapids, and his associates.

Noting that "currently, there are no readily identifiable quality measures that allow for meaningful comparisons of breast cancer surgical outcomes among treating surgeons and hospitals," the investigators examined re-excision rates across four geographically diverse health systems. Their chief goal was to determine whether significant variations existed, which would in turn determine whether the re-excision rate is a meaningful measure of surgical quality.

They assessed detailed data on initial and subsequent surgeries for invasive ductal carcinoma or invasive lobular carcinoma in 2,206 women who underwent an initial breast-conserving procedure for incident cancer.

Overall, 509 patients (23%) underwent re-excision of the affected breast during 5 years of follow-up. A total of 454 women had a single re-excision, 48 had two re-excisions, and 7 had three re-excisions. Approximately 9% of the study subjects (190 women) underwent total mastectomy after the initial breast-conserving surgery.

The rate of re-excision varied greatly from one surgeon to another, ranging from 0% to 70%. This implies that patients with the same clinical presentations are likely to undergo re-excision based on who is doing their procedure, not on their clinical traits, the investigators said (JAMA 2012;307:467-75).

This study was designed to determine whether such variations exist, not the reasons why they exist. But the researchers suggested that "differences in surgical training, surgeon confidence in their operative technique in localizing tumors, utilization of intraoperative assessment of margins, and surgeon’s and pathologist’s coordination of specimen orientation and margin interpretation" may all play a role.

Surprisingly, the volume of procedures a surgeon performs did not affect his or her re-excision rate in this study, so surgical experience may not play an important role in these variations, Dr. McCahill and his colleagues added.

The rate of re-excision also varied greatly from one medical center to another, ranging from 1.7% at the center with the lowest rate to 21% at the center with the highest rate. In particular, the rate of re-excision for cases with positive margins ranged from 74% to 94%. Any variation in this statistic is surprising because positive margins are known to correlate with local recurrence and are "almost always" re-excised, the researchers said.

Again, this study was not designed to determine why re-excision rates differ so greatly between medical centers, but the investigators suggested that "institutional variation in surgeon’s training, regional variation in interpretation of the required criteria for [re-excision], or both" may account, at least in part, for the variation.

The need for re-excision in patients who have negative (pathologically clear) margins at the initial surgery is controversial, because "there is no clear consensus on the appropriate distance required for a clear margin to be deemed adequate." So perhaps it should not be surprising that almost half of the re-excisions (242 of the 509) in this study were performed in patients who had negative margins, the researchers said.

One major limitation of this study was that some factors that greatly influence treatment decisions, including patient preferences, were not included in the data and so could not be factored into the analysis, they noted.

This study was funded by the National Institutes of Health under the American Recovery and Reinvestment Act. The authors reported no financial conflicts of interest.

Rates of re-excision after initial breast-conserving surgery for invasive breast cancer vary greatly across surgeons and across medical centers, according to a report in the Feb. 1 issue of JAMA.

These variations are only partly explained by the basic clinical and demographic factors that dictate treatment decisions, such as tumor size and patient age. The remaining reasons for the profound differences in re-excision rates remain unexplained.

Nevertheless, these variations certainly are a barrier to consistent, high-quality, cost-effective care for breast cancer. "Outcomes such as local recurrence and even overall survival could be affected by variability in initial surgical care," said Dr. Laurence E. McCahill of the Richard J. Lacks Cancer Center, Van Andel Research Institute, and department of surgery at Michigan State University, Grand Rapids, and his associates.

Noting that "currently, there are no readily identifiable quality measures that allow for meaningful comparisons of breast cancer surgical outcomes among treating surgeons and hospitals," the investigators examined re-excision rates across four geographically diverse health systems. Their chief goal was to determine whether significant variations existed, which would in turn determine whether the re-excision rate is a meaningful measure of surgical quality.

They assessed detailed data on initial and subsequent surgeries for invasive ductal carcinoma or invasive lobular carcinoma in 2,206 women who underwent an initial breast-conserving procedure for incident cancer.

Overall, 509 patients (23%) underwent re-excision of the affected breast during 5 years of follow-up. A total of 454 women had a single re-excision, 48 had two re-excisions, and 7 had three re-excisions. Approximately 9% of the study subjects (190 women) underwent total mastectomy after the initial breast-conserving surgery.

The rate of re-excision varied greatly from one surgeon to another, ranging from 0% to 70%. This implies that patients with the same clinical presentations are likely to undergo re-excision based on who is doing their procedure, not on their clinical traits, the investigators said (JAMA 2012;307:467-75).

This study was designed to determine whether such variations exist, not the reasons why they exist. But the researchers suggested that "differences in surgical training, surgeon confidence in their operative technique in localizing tumors, utilization of intraoperative assessment of margins, and surgeon’s and pathologist’s coordination of specimen orientation and margin interpretation" may all play a role.

Surprisingly, the volume of procedures a surgeon performs did not affect his or her re-excision rate in this study, so surgical experience may not play an important role in these variations, Dr. McCahill and his colleagues added.

The rate of re-excision also varied greatly from one medical center to another, ranging from 1.7% at the center with the lowest rate to 21% at the center with the highest rate. In particular, the rate of re-excision for cases with positive margins ranged from 74% to 94%. Any variation in this statistic is surprising because positive margins are known to correlate with local recurrence and are "almost always" re-excised, the researchers said.

Again, this study was not designed to determine why re-excision rates differ so greatly between medical centers, but the investigators suggested that "institutional variation in surgeon’s training, regional variation in interpretation of the required criteria for [re-excision], or both" may account, at least in part, for the variation.

The need for re-excision in patients who have negative (pathologically clear) margins at the initial surgery is controversial, because "there is no clear consensus on the appropriate distance required for a clear margin to be deemed adequate." So perhaps it should not be surprising that almost half of the re-excisions (242 of the 509) in this study were performed in patients who had negative margins, the researchers said.

One major limitation of this study was that some factors that greatly influence treatment decisions, including patient preferences, were not included in the data and so could not be factored into the analysis, they noted.

This study was funded by the National Institutes of Health under the American Recovery and Reinvestment Act. The authors reported no financial conflicts of interest.

Adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage HER2-negative breast cancer significantly improves pathological complete response, according to preliminary reports from two large randomized clinical trials.

The published results are likely to reopen debate over the recent U.S. Food and Drug Administration decision to revoke an indication for bevacizumab (Avastin) in metastatic breast cancer and the use of surrogate end points for survival in breast cancer trials.

Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial and the GeparQuinto (GBG44) trial appear in the Jan. 26 issue of The New England Journal of Medicine.

Docetaxel-Based Chemo in NSABP B-40

In NSABP B-40, 1,206 patients were enrolled between Jan. 5, 2007 and June 20, 2101 and randomly assigned to receive docetaxel (Taxotere), docetaxel plus capecitabine (Xeloda), or docetaxel plus gemcitabine (Gemzar) for four cycles. All groups received doxorubicin and cyclophosphamide for an additional four cycles, and the participants were additionally assigned to receive or not receive bevacizumab (Avastin) – an antiangiogenic monoclonal antibody against vascular endothelial growth factor (VEGF), for the first 6 of the 8 treatment cycles.

The addition of the antimetabolites capecitabine or gemcitabine had no significant effect on pathological complete response in the breast, with, respectively 29.7% and 31.8% of patients achieving that primary end point, compared with 32.7% of those receiving only docetaxel, Dr. Harry D. Bear of Virginia Commonwealth University, Richmond and his colleagues reported (N. Engl. J. Med. 2012;366:310-20).

Adding bevacizumab, however, increased the rate of pathological complete response in the breast significantly from 28.2% to 34.5%. Subgroup analysis indicated the effect was more pronounced in patients with hormone receptor–positive tumors (the rate increasing significantly from 15.1% without bevacizumab to 23.2% with bevacizumab) than in hormone receptor–negative tumors (47.1% and 51.5%, respectively), the investigators said. The benefit of bevacizumab tended to be seen more in patients with a high tumor grade.

Epirubicin-based Chemo in GeparQuinto

In the GeparQuinto trial, 1,948 patients were enrolled from November 2007 through June 2010 and randomized to receive neoadjuvant epirubicin (Ellence) and cyclophosphamide followed by docetaxel either with or without bevacizumab.

Pathological complete response occurred in 18.4% of those who received bevacizumab, compared with 14.9% of those who did not (odds ratio, 1.29), Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, Germany and his colleagues reported. (N. Engl. J. Med. 2012;366:299-309). After adjusting for age, clinical tumor and nodal stage, hormone-receptor status, tumor grade, and histologic type, the odds ratio was 1.36.

In contrast with the findings from NSABP B-40, the greatest effects of bevacizumab in GBG44 were seen in the 633 patients with triple-negative tumors (27.9% without vs. 39.3% with bevacizumab), compared with the 1,262 patients with hormone-receptor-positive tumors (7.8% and 7.7%, respectively). The test for interaction for this finding was not significant, but the study was not powered to show these differential effects, the investigators noted.

Investigators from both trials suggested that possible reasons for the divergent findings between the studies include differences in inclusion criteria and drug dosing and/or sequencing.

The NSABP B-40 investigators noted that "the increased rate of pathological complete response in patients with hormone receptor–positive tumors is encouraging, since this group tends to have low rates of pathological complete response with chemotherapy."

Bevacizumab was associated with toxic effects in both studies, including hand-foot syndrome, mucositis, hypertension, and left ventricular systolic dysfunction in NSABP B-40, and with bleeding, febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension in GBG44.

Survival Results Pending

The NSABP B-40 investigators said that the potential for bevacizumab to improve patient outcomes should be clarified when disease-free and overall survival results become available for those who underwent surgery in this study, and for those in other ongoing studies.

They also noted that "the collection of tissue samples from all our patients before treatment, a major advantage of the neoadjuvant approach, offers an opportunity to discover molecular markers that might predict a benefit from bevacizumab."

The GBG44 investigators noted that because of the short follow-up in their study, it cannot be confirmed that the observed increases in the rate of pathological complete response will translate into a survival advantage.

"However, given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effects will be sustained," they said, adding, "Long-term follow-up data are needed before this treatment option can be fully understood."

Dosing in the studies was as follows:

In NSABP B-40, docetaxel was administered intravenously at 100 mg/m² on day 1 of the cycle every 3 weeks in the docetaxel-only group, followed by four cycles of doxorubicin-cyclophosphamide at 60 mg/m² and 600 mg/m², respectively, administered intravenously every 3 weeks. Docetaxel was administered at a dose of 75 mg/m² on day 1 in the docetaxel plus capecitabine or gemcitabine groups followed by the doxorubicin-cyclophosphamide. The capecitabine dose was 825 mg/m² twice daily on days 1-14; the gemcitabine dose was 1,000 mg/m² on days 1 and 8. The bevacizumab dose was 15 mg/kg administered intravenously for the first six cycles.

In GBG44, epirubicin was administered at a dose of 90 mg/m²and cyclophosphamide was administered at a dose of 600 mg/m²– both on day 1, every 3 weeks for four cycles, followed by four cycles of docetaxel a dose of 100 mg/m² on day 1, every 3 weeks. As in NSABP B-40, bevacizumab was administered at a dose of 15 mg/kg intravenously. In this study, however, it was administered every 3 weeks starting on day 1 of the first epirubicin-cyclophosphamide cycle for 8 cycles.

NSABP B-40 was supported by grants from the National Cancer Institute, the Department of Health and Human Services, the Public Health Service, F. Hoffman-La Roche, Genentech USA, and Eli Lilly. GeparQuinto was supported by grants from Sanofi-Aventis and Roche, Germany. Detailed individual author disclosures are available with the full text of the articles at NEJM.org.

Adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage HER2-negative breast cancer significantly improves pathological complete response, according to preliminary reports from two large randomized clinical trials.

The published results are likely to reopen debate over the recent U.S. Food and Drug Administration decision to revoke an indication for bevacizumab (Avastin) in metastatic breast cancer and the use of surrogate end points for survival in breast cancer trials.

Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial and the GeparQuinto (GBG44) trial appear in the Jan. 26 issue of The New England Journal of Medicine.

Docetaxel-Based Chemo in NSABP B-40

In NSABP B-40, 1,206 patients were enrolled between Jan. 5, 2007 and June 20, 2101 and randomly assigned to receive docetaxel (Taxotere), docetaxel plus capecitabine (Xeloda), or docetaxel plus gemcitabine (Gemzar) for four cycles. All groups received doxorubicin and cyclophosphamide for an additional four cycles, and the participants were additionally assigned to receive or not receive bevacizumab (Avastin) – an antiangiogenic monoclonal antibody against vascular endothelial growth factor (VEGF), for the first 6 of the 8 treatment cycles.

The addition of the antimetabolites capecitabine or gemcitabine had no significant effect on pathological complete response in the breast, with, respectively 29.7% and 31.8% of patients achieving that primary end point, compared with 32.7% of those receiving only docetaxel, Dr. Harry D. Bear of Virginia Commonwealth University, Richmond and his colleagues reported (N. Engl. J. Med. 2012;366:310-20).

Adding bevacizumab, however, increased the rate of pathological complete response in the breast significantly from 28.2% to 34.5%. Subgroup analysis indicated the effect was more pronounced in patients with hormone receptor–positive tumors (the rate increasing significantly from 15.1% without bevacizumab to 23.2% with bevacizumab) than in hormone receptor–negative tumors (47.1% and 51.5%, respectively), the investigators said. The benefit of bevacizumab tended to be seen more in patients with a high tumor grade.

Epirubicin-based Chemo in GeparQuinto

In the GeparQuinto trial, 1,948 patients were enrolled from November 2007 through June 2010 and randomized to receive neoadjuvant epirubicin (Ellence) and cyclophosphamide followed by docetaxel either with or without bevacizumab.

Pathological complete response occurred in 18.4% of those who received bevacizumab, compared with 14.9% of those who did not (odds ratio, 1.29), Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, Germany and his colleagues reported. (N. Engl. J. Med. 2012;366:299-309). After adjusting for age, clinical tumor and nodal stage, hormone-receptor status, tumor grade, and histologic type, the odds ratio was 1.36.

In contrast with the findings from NSABP B-40, the greatest effects of bevacizumab in GBG44 were seen in the 633 patients with triple-negative tumors (27.9% without vs. 39.3% with bevacizumab), compared with the 1,262 patients with hormone-receptor-positive tumors (7.8% and 7.7%, respectively). The test for interaction for this finding was not significant, but the study was not powered to show these differential effects, the investigators noted.

Investigators from both trials suggested that possible reasons for the divergent findings between the studies include differences in inclusion criteria and drug dosing and/or sequencing.

The NSABP B-40 investigators noted that "the increased rate of pathological complete response in patients with hormone receptor–positive tumors is encouraging, since this group tends to have low rates of pathological complete response with chemotherapy."

Bevacizumab was associated with toxic effects in both studies, including hand-foot syndrome, mucositis, hypertension, and left ventricular systolic dysfunction in NSABP B-40, and with bleeding, febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension in GBG44.

Survival Results Pending

The NSABP B-40 investigators said that the potential for bevacizumab to improve patient outcomes should be clarified when disease-free and overall survival results become available for those who underwent surgery in this study, and for those in other ongoing studies.

They also noted that "the collection of tissue samples from all our patients before treatment, a major advantage of the neoadjuvant approach, offers an opportunity to discover molecular markers that might predict a benefit from bevacizumab."

The GBG44 investigators noted that because of the short follow-up in their study, it cannot be confirmed that the observed increases in the rate of pathological complete response will translate into a survival advantage.

"However, given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effects will be sustained," they said, adding, "Long-term follow-up data are needed before this treatment option can be fully understood."

Dosing in the studies was as follows:

In NSABP B-40, docetaxel was administered intravenously at 100 mg/m² on day 1 of the cycle every 3 weeks in the docetaxel-only group, followed by four cycles of doxorubicin-cyclophosphamide at 60 mg/m² and 600 mg/m², respectively, administered intravenously every 3 weeks. Docetaxel was administered at a dose of 75 mg/m² on day 1 in the docetaxel plus capecitabine or gemcitabine groups followed by the doxorubicin-cyclophosphamide. The capecitabine dose was 825 mg/m² twice daily on days 1-14; the gemcitabine dose was 1,000 mg/m² on days 1 and 8. The bevacizumab dose was 15 mg/kg administered intravenously for the first six cycles.

In GBG44, epirubicin was administered at a dose of 90 mg/m²and cyclophosphamide was administered at a dose of 600 mg/m²– both on day 1, every 3 weeks for four cycles, followed by four cycles of docetaxel a dose of 100 mg/m² on day 1, every 3 weeks. As in NSABP B-40, bevacizumab was administered at a dose of 15 mg/kg intravenously. In this study, however, it was administered every 3 weeks starting on day 1 of the first epirubicin-cyclophosphamide cycle for 8 cycles.

NSABP B-40 was supported by grants from the National Cancer Institute, the Department of Health and Human Services, the Public Health Service, F. Hoffman-La Roche, Genentech USA, and Eli Lilly. GeparQuinto was supported by grants from Sanofi-Aventis and Roche, Germany. Detailed individual author disclosures are available with the full text of the articles at NEJM.org.

Adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage HER2-negative breast cancer significantly improves pathological complete response, according to preliminary reports from two large randomized clinical trials.

The published results are likely to reopen debate over the recent U.S. Food and Drug Administration decision to revoke an indication for bevacizumab (Avastin) in metastatic breast cancer and the use of surrogate end points for survival in breast cancer trials.

Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial and the GeparQuinto (GBG44) trial appear in the Jan. 26 issue of The New England Journal of Medicine.

Docetaxel-Based Chemo in NSABP B-40

In NSABP B-40, 1,206 patients were enrolled between Jan. 5, 2007 and June 20, 2101 and randomly assigned to receive docetaxel (Taxotere), docetaxel plus capecitabine (Xeloda), or docetaxel plus gemcitabine (Gemzar) for four cycles. All groups received doxorubicin and cyclophosphamide for an additional four cycles, and the participants were additionally assigned to receive or not receive bevacizumab (Avastin) – an antiangiogenic monoclonal antibody against vascular endothelial growth factor (VEGF), for the first 6 of the 8 treatment cycles.

The addition of the antimetabolites capecitabine or gemcitabine had no significant effect on pathological complete response in the breast, with, respectively 29.7% and 31.8% of patients achieving that primary end point, compared with 32.7% of those receiving only docetaxel, Dr. Harry D. Bear of Virginia Commonwealth University, Richmond and his colleagues reported (N. Engl. J. Med. 2012;366:310-20).

Adding bevacizumab, however, increased the rate of pathological complete response in the breast significantly from 28.2% to 34.5%. Subgroup analysis indicated the effect was more pronounced in patients with hormone receptor–positive tumors (the rate increasing significantly from 15.1% without bevacizumab to 23.2% with bevacizumab) than in hormone receptor–negative tumors (47.1% and 51.5%, respectively), the investigators said. The benefit of bevacizumab tended to be seen more in patients with a high tumor grade.

Epirubicin-based Chemo in GeparQuinto

In the GeparQuinto trial, 1,948 patients were enrolled from November 2007 through June 2010 and randomized to receive neoadjuvant epirubicin (Ellence) and cyclophosphamide followed by docetaxel either with or without bevacizumab.

Pathological complete response occurred in 18.4% of those who received bevacizumab, compared with 14.9% of those who did not (odds ratio, 1.29), Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, Germany and his colleagues reported. (N. Engl. J. Med. 2012;366:299-309). After adjusting for age, clinical tumor and nodal stage, hormone-receptor status, tumor grade, and histologic type, the odds ratio was 1.36.

In contrast with the findings from NSABP B-40, the greatest effects of bevacizumab in GBG44 were seen in the 633 patients with triple-negative tumors (27.9% without vs. 39.3% with bevacizumab), compared with the 1,262 patients with hormone-receptor-positive tumors (7.8% and 7.7%, respectively). The test for interaction for this finding was not significant, but the study was not powered to show these differential effects, the investigators noted.

Investigators from both trials suggested that possible reasons for the divergent findings between the studies include differences in inclusion criteria and drug dosing and/or sequencing.

The NSABP B-40 investigators noted that "the increased rate of pathological complete response in patients with hormone receptor–positive tumors is encouraging, since this group tends to have low rates of pathological complete response with chemotherapy."

Bevacizumab was associated with toxic effects in both studies, including hand-foot syndrome, mucositis, hypertension, and left ventricular systolic dysfunction in NSABP B-40, and with bleeding, febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension in GBG44.

Survival Results Pending

The NSABP B-40 investigators said that the potential for bevacizumab to improve patient outcomes should be clarified when disease-free and overall survival results become available for those who underwent surgery in this study, and for those in other ongoing studies.

They also noted that "the collection of tissue samples from all our patients before treatment, a major advantage of the neoadjuvant approach, offers an opportunity to discover molecular markers that might predict a benefit from bevacizumab."

The GBG44 investigators noted that because of the short follow-up in their study, it cannot be confirmed that the observed increases in the rate of pathological complete response will translate into a survival advantage.

"However, given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effects will be sustained," they said, adding, "Long-term follow-up data are needed before this treatment option can be fully understood."

Dosing in the studies was as follows:

In NSABP B-40, docetaxel was administered intravenously at 100 mg/m² on day 1 of the cycle every 3 weeks in the docetaxel-only group, followed by four cycles of doxorubicin-cyclophosphamide at 60 mg/m² and 600 mg/m², respectively, administered intravenously every 3 weeks. Docetaxel was administered at a dose of 75 mg/m² on day 1 in the docetaxel plus capecitabine or gemcitabine groups followed by the doxorubicin-cyclophosphamide. The capecitabine dose was 825 mg/m² twice daily on days 1-14; the gemcitabine dose was 1,000 mg/m² on days 1 and 8. The bevacizumab dose was 15 mg/kg administered intravenously for the first six cycles.

In GBG44, epirubicin was administered at a dose of 90 mg/m²and cyclophosphamide was administered at a dose of 600 mg/m²– both on day 1, every 3 weeks for four cycles, followed by four cycles of docetaxel a dose of 100 mg/m² on day 1, every 3 weeks. As in NSABP B-40, bevacizumab was administered at a dose of 15 mg/kg intravenously. In this study, however, it was administered every 3 weeks starting on day 1 of the first epirubicin-cyclophosphamide cycle for 8 cycles.

NSABP B-40 was supported by grants from the National Cancer Institute, the Department of Health and Human Services, the Public Health Service, F. Hoffman-La Roche, Genentech USA, and Eli Lilly. GeparQuinto was supported by grants from Sanofi-Aventis and Roche, Germany. Detailed individual author disclosures are available with the full text of the articles at NEJM.org.