Breast Cancer

Many breast cancer patients would have more advanced disease at diagnosis and face harsher treatment if recently updated screening guidelines of the U.S. Preventive Services Task Force were widely adopted, suggests a retrospective cohort study of more than 5,000 women with breast cancer in Michigan.

Study results, being reported this week at a breast cancer symposium sponsored by the American Society of Clinical Oncology, show that nearly a third of the women’s cancers were detected by palpation. The guidelines do not advocate for self-exams at all and question the usefulness of clinical breast exams after age 40.

Additionally, nearly half of the cancers in women younger than 50 years were detected by mammography, while the guidelines now recommend against this practice in the 40- to 49-year age group.

Women with palpation-detected cancers had later-stage disease and were significantly more likely to undergo mastectomy and receive chemotherapy than were those with mammography-detected cancers.

"Annual screening mammograms and evaluation of palpable breast masses are important tools in breast cancer detection," second author Dr. Jamie Caughran said during a premeeting press briefing from the American Society of Clinical Oncology (ASCO).

She declined to say whether the study’s results contradict the U.S. Preventive Services Task Force (USPSTF) guidelines, as the investigators did not have adequate information on the women’s screening history.

But "we take this data to conclude that you’re better off if you can ... have your cancer detected by mammography – that you are more likely to have options and less likely to need aggressive treatment. So ... we would support the rest of the societies that continue to recommend annual screening mammography starting at age 40," she said.

Additionally, this study "highlights the still-significant number of women who present with a palpable mass that shouldn’t be overlooked by physicians even if they have a negative mammogram," pointed out Dr. Caughran, medical director of the Comprehensive Breast Center at the Lacks Cancer Center in Grand Rapids, Mich. "So it just continues to reinforce what we believe is inherently true."

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York City, commented that the appropriate age for starting screening mammography remains controversial.

"A lot of the debate and focus regarding the utility of mammography have been on overall survival and breast cancer–specific survival, and I certainly think that is the most important end point," he said, noting that the study speaks to another important end point – reduced intensity of treatment.

"As a medical oncologist or chemotherapist, I think this is a very important gain, independent of any potential survival benefit," he said. "Having less disfiguring surgery and the ability to deliver less chemotherapy based on the stage at diagnosis are for me a step forward."

This newest study will not quell the debate, according to Dr. Seidman. "Undoubtedly, this area will continue to remain an area of controversy for some," he said. "But certainly, women in this age group would be well served to know about this data."

In the study, Dr. Caughran and her colleagues analyzed data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative, identifying 5,628 women who received a diagnosis of stage 0 to III breast cancer between 2006 and 2009. Their average age was 59.4 years.

In the cohort overall, 65.5% of breast cancers were detected by mammography, 29.8% by palpation, and 4.7% by other means.

Fully 90% of the cancers detected by palpation were detected by the patient herself, although "it’s unclear if the patients ... were practicing regular breast self-examination or if these were incidental findings," noted Dr. Caughran.

When analyses were restricted to women younger than 50 years of age, 48.3% of breast cancers were detected by mammography, 46.1% by palpation, and 5.6% by other means.

Palpation-detected cancers were of later stages (P less than .0001) – two-thirds were stage II or higher – and were more often treated with mastectomy (45.8% vs. 27.1%, P less than .0001) and with chemotherapy (22.7% vs. 15.7%, P less than .0001).

Dr. Caughran and Dr. Seidman reported that they had no relevant conflicts of interest.

Many breast cancer patients would have more advanced disease at diagnosis and face harsher treatment if recently updated screening guidelines of the U.S. Preventive Services Task Force were widely adopted, suggests a retrospective cohort study of more than 5,000 women with breast cancer in Michigan.

Study results, being reported this week at a breast cancer symposium sponsored by the American Society of Clinical Oncology, show that nearly a third of the women’s cancers were detected by palpation. The guidelines do not advocate for self-exams at all and question the usefulness of clinical breast exams after age 40.

Additionally, nearly half of the cancers in women younger than 50 years were detected by mammography, while the guidelines now recommend against this practice in the 40- to 49-year age group.

Women with palpation-detected cancers had later-stage disease and were significantly more likely to undergo mastectomy and receive chemotherapy than were those with mammography-detected cancers.

"Annual screening mammograms and evaluation of palpable breast masses are important tools in breast cancer detection," second author Dr. Jamie Caughran said during a premeeting press briefing from the American Society of Clinical Oncology (ASCO).

She declined to say whether the study’s results contradict the U.S. Preventive Services Task Force (USPSTF) guidelines, as the investigators did not have adequate information on the women’s screening history.

But "we take this data to conclude that you’re better off if you can ... have your cancer detected by mammography – that you are more likely to have options and less likely to need aggressive treatment. So ... we would support the rest of the societies that continue to recommend annual screening mammography starting at age 40," she said.

Additionally, this study "highlights the still-significant number of women who present with a palpable mass that shouldn’t be overlooked by physicians even if they have a negative mammogram," pointed out Dr. Caughran, medical director of the Comprehensive Breast Center at the Lacks Cancer Center in Grand Rapids, Mich. "So it just continues to reinforce what we believe is inherently true."

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York City, commented that the appropriate age for starting screening mammography remains controversial.

"A lot of the debate and focus regarding the utility of mammography have been on overall survival and breast cancer–specific survival, and I certainly think that is the most important end point," he said, noting that the study speaks to another important end point – reduced intensity of treatment.

"As a medical oncologist or chemotherapist, I think this is a very important gain, independent of any potential survival benefit," he said. "Having less disfiguring surgery and the ability to deliver less chemotherapy based on the stage at diagnosis are for me a step forward."

This newest study will not quell the debate, according to Dr. Seidman. "Undoubtedly, this area will continue to remain an area of controversy for some," he said. "But certainly, women in this age group would be well served to know about this data."

In the study, Dr. Caughran and her colleagues analyzed data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative, identifying 5,628 women who received a diagnosis of stage 0 to III breast cancer between 2006 and 2009. Their average age was 59.4 years.

In the cohort overall, 65.5% of breast cancers were detected by mammography, 29.8% by palpation, and 4.7% by other means.

Fully 90% of the cancers detected by palpation were detected by the patient herself, although "it’s unclear if the patients ... were practicing regular breast self-examination or if these were incidental findings," noted Dr. Caughran.

When analyses were restricted to women younger than 50 years of age, 48.3% of breast cancers were detected by mammography, 46.1% by palpation, and 5.6% by other means.

Palpation-detected cancers were of later stages (P less than .0001) – two-thirds were stage II or higher – and were more often treated with mastectomy (45.8% vs. 27.1%, P less than .0001) and with chemotherapy (22.7% vs. 15.7%, P less than .0001).

Dr. Caughran and Dr. Seidman reported that they had no relevant conflicts of interest.

Many breast cancer patients would have more advanced disease at diagnosis and face harsher treatment if recently updated screening guidelines of the U.S. Preventive Services Task Force were widely adopted, suggests a retrospective cohort study of more than 5,000 women with breast cancer in Michigan.

Study results, being reported this week at a breast cancer symposium sponsored by the American Society of Clinical Oncology, show that nearly a third of the women’s cancers were detected by palpation. The guidelines do not advocate for self-exams at all and question the usefulness of clinical breast exams after age 40.

Additionally, nearly half of the cancers in women younger than 50 years were detected by mammography, while the guidelines now recommend against this practice in the 40- to 49-year age group.

Women with palpation-detected cancers had later-stage disease and were significantly more likely to undergo mastectomy and receive chemotherapy than were those with mammography-detected cancers.

"Annual screening mammograms and evaluation of palpable breast masses are important tools in breast cancer detection," second author Dr. Jamie Caughran said during a premeeting press briefing from the American Society of Clinical Oncology (ASCO).

She declined to say whether the study’s results contradict the U.S. Preventive Services Task Force (USPSTF) guidelines, as the investigators did not have adequate information on the women’s screening history.

But "we take this data to conclude that you’re better off if you can ... have your cancer detected by mammography – that you are more likely to have options and less likely to need aggressive treatment. So ... we would support the rest of the societies that continue to recommend annual screening mammography starting at age 40," she said.

Additionally, this study "highlights the still-significant number of women who present with a palpable mass that shouldn’t be overlooked by physicians even if they have a negative mammogram," pointed out Dr. Caughran, medical director of the Comprehensive Breast Center at the Lacks Cancer Center in Grand Rapids, Mich. "So it just continues to reinforce what we believe is inherently true."

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York City, commented that the appropriate age for starting screening mammography remains controversial.

"A lot of the debate and focus regarding the utility of mammography have been on overall survival and breast cancer–specific survival, and I certainly think that is the most important end point," he said, noting that the study speaks to another important end point – reduced intensity of treatment.

"As a medical oncologist or chemotherapist, I think this is a very important gain, independent of any potential survival benefit," he said. "Having less disfiguring surgery and the ability to deliver less chemotherapy based on the stage at diagnosis are for me a step forward."

This newest study will not quell the debate, according to Dr. Seidman. "Undoubtedly, this area will continue to remain an area of controversy for some," he said. "But certainly, women in this age group would be well served to know about this data."

In the study, Dr. Caughran and her colleagues analyzed data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative, identifying 5,628 women who received a diagnosis of stage 0 to III breast cancer between 2006 and 2009. Their average age was 59.4 years.

In the cohort overall, 65.5% of breast cancers were detected by mammography, 29.8% by palpation, and 4.7% by other means.

Fully 90% of the cancers detected by palpation were detected by the patient herself, although "it’s unclear if the patients ... were practicing regular breast self-examination or if these were incidental findings," noted Dr. Caughran.

When analyses were restricted to women younger than 50 years of age, 48.3% of breast cancers were detected by mammography, 46.1% by palpation, and 5.6% by other means.

Palpation-detected cancers were of later stages (P less than .0001) – two-thirds were stage II or higher – and were more often treated with mastectomy (45.8% vs. 27.1%, P less than .0001) and with chemotherapy (22.7% vs. 15.7%, P less than .0001).

Dr. Caughran and Dr. Seidman reported that they had no relevant conflicts of interest.

I enjoyed the review article by Dr. Jeannie Shen (Community Oncology, December 2010), both for her succinct summary of the indications for postmastectomy plastic surgical reconstruction and the optimal timing of the procedure. Her salient presentation contained some of the most contemporary indications for postmastectomy radiotherapy (PMRT).

Along with the points Dr. Shen mentioned as indicators for PMRT— tumor size, regional nodal involvement, presence of lymphovascular space invasion, and patient youth—I would add estrogen receptor-negative disease as another tumor factor to consider for adjuvant radiotherapy. Many series, including some of those referenced by Dr. Shen and the American Society of Clinical Oncology in the composition of its recommendations, have demonstrated that estrogen receptor-negative status represents an independent risk factor for locoregionally recurrent disease after mastectomy and that the risk is significantly reduced by PMRT.^1–7 ...

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

I enjoyed the review article by Dr. Jeannie Shen (Community Oncology, December 2010), both for her succinct summary of the indications for postmastectomy plastic surgical reconstruction and the optimal timing of the procedure. Her salient presentation contained some of the most contemporary indications for postmastectomy radiotherapy (PMRT).

Along with the points Dr. Shen mentioned as indicators for PMRT— tumor size, regional nodal involvement, presence of lymphovascular space invasion, and patient youth—I would add estrogen receptor-negative disease as another tumor factor to consider for adjuvant radiotherapy. Many series, including some of those referenced by Dr. Shen and the American Society of Clinical Oncology in the composition of its recommendations, have demonstrated that estrogen receptor-negative status represents an independent risk factor for locoregionally recurrent disease after mastectomy and that the risk is significantly reduced by PMRT.^1–7 ...

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

I enjoyed the review article by Dr. Jeannie Shen (Community Oncology, December 2010), both for her succinct summary of the indications for postmastectomy plastic surgical reconstruction and the optimal timing of the procedure. Her salient presentation contained some of the most contemporary indications for postmastectomy radiotherapy (PMRT).

Along with the points Dr. Shen mentioned as indicators for PMRT— tumor size, regional nodal involvement, presence of lymphovascular space invasion, and patient youth—I would add estrogen receptor-negative disease as another tumor factor to consider for adjuvant radiotherapy. Many series, including some of those referenced by Dr. Shen and the American Society of Clinical Oncology in the composition of its recommendations, have demonstrated that estrogen receptor-negative status represents an independent risk factor for locoregionally recurrent disease after mastectomy and that the risk is significantly reduced by PMRT.^1–7 ...

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

An independent committee of experts that develops guidance on behalf of the U.K. National Institute for Health and Clinical Excellence does not believe that fulvestrant, which can be used to delay the growth of a particular type of advanced breast cancer, represents a good use of National Health Service resources.

Draft guidance, published Aug. 22 for public comment, does not recommend fulvestrant (known commercially as Faslodex and manufactured by AstraZeneca) as an alternative to aromatase inhibitor therapy in postmenopausal women who have locally advanced or metastatic breast cancer that is estrogen-receptor positive.

In accordance with its marketing authorization, the committee’s provisional recommendation relates to the use of fulvestrant once antiestrogen treatments (such as tamoxifen) are no longer controlling the spread of the cancer. The committee has not been able to consider the clinical and cost effectiveness of fulvestrant when it is used outside of its marketing authorization (for example, after an aromatase inhibitor).

Sir Andrew Dillon, chief executive of NICE, said in a written statement that "while it is important for women with locally advanced or metastatic breast cancer to have a range of options, NICE has to ensure that the NHS provides treatments that bring benefits which are value for money.

"After analysing the evidence comparing fulvestrant’s clinical effectiveness with aromatase inhibitor therapy, our independent committee found that the estimates of overall survival and time to tumour progression were very uncertain. The Committee concluded that it had not been given any conclusive evidence that fulvestrant extends life or delays tumour progression any more than aromatase inhibitor therapy, which is currently used in the NHS."

NICE’s final guidance will determine whether the NHS is legally obliged to allocate funding for fulvestrant as an alternative to aromatase inhibitors for the treatment of locally advanced or metastatic breast cancer after antiestrogen treatment. Until NICE issues final guidance, these decisions should continue to be made locally by NHS bodies.

Those wishing to comment on NICE’s draft recommendations have until Sept. 13 to do so. NICE’s independent committee will then meet again to review the comments received. NICE expects to publish its final guidance for the NHS in January 2012.

An independent committee of experts that develops guidance on behalf of the U.K. National Institute for Health and Clinical Excellence does not believe that fulvestrant, which can be used to delay the growth of a particular type of advanced breast cancer, represents a good use of National Health Service resources.

Draft guidance, published Aug. 22 for public comment, does not recommend fulvestrant (known commercially as Faslodex and manufactured by AstraZeneca) as an alternative to aromatase inhibitor therapy in postmenopausal women who have locally advanced or metastatic breast cancer that is estrogen-receptor positive.

In accordance with its marketing authorization, the committee’s provisional recommendation relates to the use of fulvestrant once antiestrogen treatments (such as tamoxifen) are no longer controlling the spread of the cancer. The committee has not been able to consider the clinical and cost effectiveness of fulvestrant when it is used outside of its marketing authorization (for example, after an aromatase inhibitor).

Sir Andrew Dillon, chief executive of NICE, said in a written statement that "while it is important for women with locally advanced or metastatic breast cancer to have a range of options, NICE has to ensure that the NHS provides treatments that bring benefits which are value for money.

"After analysing the evidence comparing fulvestrant’s clinical effectiveness with aromatase inhibitor therapy, our independent committee found that the estimates of overall survival and time to tumour progression were very uncertain. The Committee concluded that it had not been given any conclusive evidence that fulvestrant extends life or delays tumour progression any more than aromatase inhibitor therapy, which is currently used in the NHS."

NICE’s final guidance will determine whether the NHS is legally obliged to allocate funding for fulvestrant as an alternative to aromatase inhibitors for the treatment of locally advanced or metastatic breast cancer after antiestrogen treatment. Until NICE issues final guidance, these decisions should continue to be made locally by NHS bodies.

Those wishing to comment on NICE’s draft recommendations have until Sept. 13 to do so. NICE’s independent committee will then meet again to review the comments received. NICE expects to publish its final guidance for the NHS in January 2012.

An independent committee of experts that develops guidance on behalf of the U.K. National Institute for Health and Clinical Excellence does not believe that fulvestrant, which can be used to delay the growth of a particular type of advanced breast cancer, represents a good use of National Health Service resources.

Draft guidance, published Aug. 22 for public comment, does not recommend fulvestrant (known commercially as Faslodex and manufactured by AstraZeneca) as an alternative to aromatase inhibitor therapy in postmenopausal women who have locally advanced or metastatic breast cancer that is estrogen-receptor positive.

In accordance with its marketing authorization, the committee’s provisional recommendation relates to the use of fulvestrant once antiestrogen treatments (such as tamoxifen) are no longer controlling the spread of the cancer. The committee has not been able to consider the clinical and cost effectiveness of fulvestrant when it is used outside of its marketing authorization (for example, after an aromatase inhibitor).

Sir Andrew Dillon, chief executive of NICE, said in a written statement that "while it is important for women with locally advanced or metastatic breast cancer to have a range of options, NICE has to ensure that the NHS provides treatments that bring benefits which are value for money.

"After analysing the evidence comparing fulvestrant’s clinical effectiveness with aromatase inhibitor therapy, our independent committee found that the estimates of overall survival and time to tumour progression were very uncertain. The Committee concluded that it had not been given any conclusive evidence that fulvestrant extends life or delays tumour progression any more than aromatase inhibitor therapy, which is currently used in the NHS."

NICE’s final guidance will determine whether the NHS is legally obliged to allocate funding for fulvestrant as an alternative to aromatase inhibitors for the treatment of locally advanced or metastatic breast cancer after antiestrogen treatment. Until NICE issues final guidance, these decisions should continue to be made locally by NHS bodies.

Those wishing to comment on NICE’s draft recommendations have until Sept. 13 to do so. NICE’s independent committee will then meet again to review the comments received. NICE expects to publish its final guidance for the NHS in January 2012.

To treat or not to treat? When it comes to deciding whether adjuvant chemotherapy is the appropriate management choice for patients with HER2 positive, node-negative breast cancer less than 1 cm in size, the only sure thing is that there is no sure thing, and seemingly conflicting research data exacerbates the uncertainty.

A recent study demonstrated that patients who did not receive adjuvant chemotherapy or trastuzumab for node-negative, non-metastasized HER2 positive T1a (less than or equal to 0.1 cm to 0.5 cm) or T1b (greater than 0.5 cm to 1.0 cm) tumors were at greater risk for worse recurrence-free survival and worse distant recurrence-free survival than patients with hormone-receptor–positive disease.

This was especially true for those younger than age 35 years – and also was the case in similarly staged patients with triple-negative breast cancer, according to the report from the University of Texas M.D. Anderson Cancer Center in Houston.

The authors concluded that planning systemic treatment based on disease stage alone "appears to lead to worse outcomes," and that individualized treatment plans may be better informed by taking into account aggressive biological subtypes of small, node-negative breast cancers, as well as age at diagnosis (Clin. Breast Cancer. 2011 July 15 [doi: 10.1016/j.clbc.2011.05.002]).

While the findings of this retrospective, single-institution study validate the large body of evidence suggesting that younger patients with aggressive tumor subtypes have worse outcomes when not treated with adjuvant chemotherapy or trastuzumab (Herceptin), the authors do not recommend universal treatment of this patient population.

Rather, the results provide a strong argument for the inclusion of women with small tumors that have biologically aggressive traits in prospective clinical trials "to evaluate the extent of therapeutic benefits," they wrote. Further, patient age and disease subtype "should be considered when counseling patients about treatment interventions."

No Treatment Not Worse for Some

With the absolute benefits of treatment yet to be determined, investigators also are looking closely at the risks associated with skipping adjuvant treatment.

The findings of an observational cohort study presented at the annual meeting of the American Society of Clinical Oncology (ASCO) suggest that women with early HER2 positive T1aN0M0 breast cancers can safely do so because of the low distant recurrence rate observed in this patient subgroup. A higher rate was observed in those with T1bN0M0, indicating that adjuvant systemic therapy may be more relevant in this patient population.

The study assessed outcomes among 237 women with HER2-positive T1a (116 patients) or T1b (121 patients) tumors diagnosed between 2000 and 2006, all of whom had negative nodes and no metastases. Most did not receive adjuvant chemotherapy or trastuzumab.

With a median duration of follow-up of 5.8 years, the rate of distant recurrence was 0.9% among patients with T1a tumors versus 5.8% among those with T1b, lead investigator Dr. Louis Fehrenbacher, an oncologist with Kaiser Permanente in Vallejo, Calif., reported in a poster presentation, analyzing data from the tumor registry of the Kaiser Permanente Clinical Care Program of Northern California.

The investigators chose distant recurrence-free survival as the main outcome measure, rather than the more commonly used disease-free survival rate, because they "did not want to include non-breast malignancies, contralateral malignancies, or deaths from any other cause," Dr. Fehrenbacher said. "That isn’t the real important factor in deciding to give intensive chemotherapy to these patients," he explained.

By tumor size, the rate of distant recurrence ranged from 0% to 5.8% for tumors measuring 0.1 cm to 0.9 cm, but it was 10.7% for the tumors measuring 1.0 cm. In other words, Dr. Fehrenbacher said, "the 1.0-cm tumors carried the burden of the distant recurrence risk."

Results for the actuarial distant recurrence-free interval showed a 5-year rate of 96.5% for the patients as a whole, with 99.1% and 94.0% in the T1a and T1b groups, respectively.

Overall, 25% of the study patients received chemotherapy and 8% received trastuzumab. "Most of these patients had only a smattering of chemotherapy or trastuzumab, and it didn't seem to affect outcome," Dr. Fehrenbacher commented, but he acknowledged that there may have been bias influencing who received chemotherapy. While 59% of the patients had tumors that were positive for estrogen receptors, there was little difference in recurrence rate according to estrogen receptor status, he said.

"The take-home message is, I think, the T1a’s have too low of a risk of distant invasive recurrence to justify chemotherapy or trastuzumab," Dr. Fehrenbacher said in an interview. "We need to specifically individualize the risk of the patient based on the size of their primary [tumor], because the T1a’s and T1b’s are quite different in our findings."

Dr. Lajos Pusztai, a professor in the department of breast medical oncology at M.D. Anderson, agrees with Dr. Fehrenbacher’s conclusion. "I think the findings are correct, as several other studies have also indicated a very low risk of recurrence for very small HER2-positive cancers," he said in an interview.

"It may also be important to remember that HER2 has not been considered by the ASCO biomarker review panels [to be] an important prognostic marker, but rather a predictive marker for trastuzumab therapy."

Review Warns of Cardiotoxicity

In a recent review article looking into whether the existing data supports a definitive treatment threshold for patients with T1aN0M0 or T1bN0M0 HER2-positive breast cancer, Dr. Pusztai, along with lead author Dr. Catherine M. Kelly of Waterford Regional Hospital in Waterford, Ireland and colleagues, wrote that "a blanket recommendation to treat all small HER2 positive breast cancer with trastuzumab-based therapy will almost certainly lead to clinically significant cardiotoxicity in some without any benefit in breast cancer recurrence."

Similarly, they noted, "withholding this form of adjuvant therapy from all small HER2 positive cancers will result in some otherwise avoidable breast cancer recurrence. Unfortunately, today we do not have accurate tools to identify precisely the subset of patients for whom the risks of trastuzumab outweigh the benefits."

Lacking such tools, shared medical decision making based on estimates achieved using established risk calculators and discussion of the risks with patients should be the order of the day, they said, with the decision depending upon the patients’ perspective and risk tolerance level. If trastuzumab-based treatment is an option, the authors stressed that regimens with the lowest risk of cardiotoxicity should be pursued (Ann. Oncol. 2011 Mar. 15 [doi:10.1093/annonc/mdq786]).

In the absence of randomized controlled trials to establish or refute the benefit from adjuvant trastuzumab in this patient subset, the authors called for the development of molecular predictors of prognosis within HER2 positive disease to further optimize risk/benefit estimates. The development of better prediction tools for more precise estimations of the risk of death from comorbid illnesses and the risk of cardiac death, in particular, are important, they said.

Level 1 Evidence Lacking

The lack of level 1 evidence from large, prospective trials contributes to the overall uncertainty surrounding the role of adjuvant chemotherapy in early HER2 breast cancer, according to Dr. Gabriel Hortobágyi, professor and chair of the department of Breast Medical Oncology at M.D. Anderson.

Studies examining the prognostic value of HER2 are limited by their reliance on retrospective database analyses and small cohort sized, Dr. Hortobágyi said in an interview. "I think it is critically important to perform a couple of larger trials with prospective collection of patients, HER2 checked centrally in a high-volume lab, and long enough follow-up to determine the real outcomes of these patients."

In this regard, the Southwest Oncology Group’s breast committee, chaired by Dr. Hortobágyi, is trying to activate a clinical trial for HER2 positive T1a and T1b patients comparing trastuzumab alone and in combination with lapatinib "to determine whether treatment with targeted chemotherapy would be effective enough for these patients." Additionally, he said investigators at Dana Farber Cancer Institute are completing recruitment to a single-arm trial for patients with small, HER2 positive breast cancer treated uniformly with paclitaxel and trastuzumab.

"Both trials will give us prospective data and should contribute significantly to our assessment of the real prognosis of this group of patients," he said.

In the meantime, Dr. Hortobágyi said that his group, and many others, "considers that risk of recurrence exceeding about 10% deserves adjuvant chemotherapy, and in the HER2 positive group we believe the risk exceeds, by far, that level. Therefore, we discuss trastuzumab and chemotherapy with all patients without significant comorbid conditions if they have any size-invasive, HER2 positive breast cancer."

The uncertainty regarding the role of adjuvant chemotherapy in early HER2 breast cancer touches on a "fascinating aspect of medicine: how to deal with and communicate uncertainty in diagnosis and treatment benefit," observed Dr. Pusztai.

"Medicine is a very imprecise science and the handling of imprecision is what makes it, as some would call it, an art," he said. "I suspect that what patients perceive as a ‘good’ vs. ‘not so good’ doctor often comes down to how efficiently one can make decisions under uncertainty of information and how effectively one communicates this uncertainty and the decision that is based on it."

Dr. Fehrenbacher, Dr. Pusztai, and Dr. Hortobágyi reported no relevant conflicts of interest with respect to the information presented.

Susan London contributed to this report.

To treat or not to treat? When it comes to deciding whether adjuvant chemotherapy is the appropriate management choice for patients with HER2 positive, node-negative breast cancer less than 1 cm in size, the only sure thing is that there is no sure thing, and seemingly conflicting research data exacerbates the uncertainty.

A recent study demonstrated that patients who did not receive adjuvant chemotherapy or trastuzumab for node-negative, non-metastasized HER2 positive T1a (less than or equal to 0.1 cm to 0.5 cm) or T1b (greater than 0.5 cm to 1.0 cm) tumors were at greater risk for worse recurrence-free survival and worse distant recurrence-free survival than patients with hormone-receptor–positive disease.

This was especially true for those younger than age 35 years – and also was the case in similarly staged patients with triple-negative breast cancer, according to the report from the University of Texas M.D. Anderson Cancer Center in Houston.

The authors concluded that planning systemic treatment based on disease stage alone "appears to lead to worse outcomes," and that individualized treatment plans may be better informed by taking into account aggressive biological subtypes of small, node-negative breast cancers, as well as age at diagnosis (Clin. Breast Cancer. 2011 July 15 [doi: 10.1016/j.clbc.2011.05.002]).

While the findings of this retrospective, single-institution study validate the large body of evidence suggesting that younger patients with aggressive tumor subtypes have worse outcomes when not treated with adjuvant chemotherapy or trastuzumab (Herceptin), the authors do not recommend universal treatment of this patient population.

Rather, the results provide a strong argument for the inclusion of women with small tumors that have biologically aggressive traits in prospective clinical trials "to evaluate the extent of therapeutic benefits," they wrote. Further, patient age and disease subtype "should be considered when counseling patients about treatment interventions."

No Treatment Not Worse for Some

With the absolute benefits of treatment yet to be determined, investigators also are looking closely at the risks associated with skipping adjuvant treatment.

The findings of an observational cohort study presented at the annual meeting of the American Society of Clinical Oncology (ASCO) suggest that women with early HER2 positive T1aN0M0 breast cancers can safely do so because of the low distant recurrence rate observed in this patient subgroup. A higher rate was observed in those with T1bN0M0, indicating that adjuvant systemic therapy may be more relevant in this patient population.

The study assessed outcomes among 237 women with HER2-positive T1a (116 patients) or T1b (121 patients) tumors diagnosed between 2000 and 2006, all of whom had negative nodes and no metastases. Most did not receive adjuvant chemotherapy or trastuzumab.

With a median duration of follow-up of 5.8 years, the rate of distant recurrence was 0.9% among patients with T1a tumors versus 5.8% among those with T1b, lead investigator Dr. Louis Fehrenbacher, an oncologist with Kaiser Permanente in Vallejo, Calif., reported in a poster presentation, analyzing data from the tumor registry of the Kaiser Permanente Clinical Care Program of Northern California.

The investigators chose distant recurrence-free survival as the main outcome measure, rather than the more commonly used disease-free survival rate, because they "did not want to include non-breast malignancies, contralateral malignancies, or deaths from any other cause," Dr. Fehrenbacher said. "That isn’t the real important factor in deciding to give intensive chemotherapy to these patients," he explained.

By tumor size, the rate of distant recurrence ranged from 0% to 5.8% for tumors measuring 0.1 cm to 0.9 cm, but it was 10.7% for the tumors measuring 1.0 cm. In other words, Dr. Fehrenbacher said, "the 1.0-cm tumors carried the burden of the distant recurrence risk."

Results for the actuarial distant recurrence-free interval showed a 5-year rate of 96.5% for the patients as a whole, with 99.1% and 94.0% in the T1a and T1b groups, respectively.

Overall, 25% of the study patients received chemotherapy and 8% received trastuzumab. "Most of these patients had only a smattering of chemotherapy or trastuzumab, and it didn't seem to affect outcome," Dr. Fehrenbacher commented, but he acknowledged that there may have been bias influencing who received chemotherapy. While 59% of the patients had tumors that were positive for estrogen receptors, there was little difference in recurrence rate according to estrogen receptor status, he said.

"The take-home message is, I think, the T1a’s have too low of a risk of distant invasive recurrence to justify chemotherapy or trastuzumab," Dr. Fehrenbacher said in an interview. "We need to specifically individualize the risk of the patient based on the size of their primary [tumor], because the T1a’s and T1b’s are quite different in our findings."

Dr. Lajos Pusztai, a professor in the department of breast medical oncology at M.D. Anderson, agrees with Dr. Fehrenbacher’s conclusion. "I think the findings are correct, as several other studies have also indicated a very low risk of recurrence for very small HER2-positive cancers," he said in an interview.

"It may also be important to remember that HER2 has not been considered by the ASCO biomarker review panels [to be] an important prognostic marker, but rather a predictive marker for trastuzumab therapy."

Review Warns of Cardiotoxicity

In a recent review article looking into whether the existing data supports a definitive treatment threshold for patients with T1aN0M0 or T1bN0M0 HER2-positive breast cancer, Dr. Pusztai, along with lead author Dr. Catherine M. Kelly of Waterford Regional Hospital in Waterford, Ireland and colleagues, wrote that "a blanket recommendation to treat all small HER2 positive breast cancer with trastuzumab-based therapy will almost certainly lead to clinically significant cardiotoxicity in some without any benefit in breast cancer recurrence."

Similarly, they noted, "withholding this form of adjuvant therapy from all small HER2 positive cancers will result in some otherwise avoidable breast cancer recurrence. Unfortunately, today we do not have accurate tools to identify precisely the subset of patients for whom the risks of trastuzumab outweigh the benefits."

Lacking such tools, shared medical decision making based on estimates achieved using established risk calculators and discussion of the risks with patients should be the order of the day, they said, with the decision depending upon the patients’ perspective and risk tolerance level. If trastuzumab-based treatment is an option, the authors stressed that regimens with the lowest risk of cardiotoxicity should be pursued (Ann. Oncol. 2011 Mar. 15 [doi:10.1093/annonc/mdq786]).

In the absence of randomized controlled trials to establish or refute the benefit from adjuvant trastuzumab in this patient subset, the authors called for the development of molecular predictors of prognosis within HER2 positive disease to further optimize risk/benefit estimates. The development of better prediction tools for more precise estimations of the risk of death from comorbid illnesses and the risk of cardiac death, in particular, are important, they said.

Level 1 Evidence Lacking

The lack of level 1 evidence from large, prospective trials contributes to the overall uncertainty surrounding the role of adjuvant chemotherapy in early HER2 breast cancer, according to Dr. Gabriel Hortobágyi, professor and chair of the department of Breast Medical Oncology at M.D. Anderson.

Studies examining the prognostic value of HER2 are limited by their reliance on retrospective database analyses and small cohort sized, Dr. Hortobágyi said in an interview. "I think it is critically important to perform a couple of larger trials with prospective collection of patients, HER2 checked centrally in a high-volume lab, and long enough follow-up to determine the real outcomes of these patients."

In this regard, the Southwest Oncology Group’s breast committee, chaired by Dr. Hortobágyi, is trying to activate a clinical trial for HER2 positive T1a and T1b patients comparing trastuzumab alone and in combination with lapatinib "to determine whether treatment with targeted chemotherapy would be effective enough for these patients." Additionally, he said investigators at Dana Farber Cancer Institute are completing recruitment to a single-arm trial for patients with small, HER2 positive breast cancer treated uniformly with paclitaxel and trastuzumab.

"Both trials will give us prospective data and should contribute significantly to our assessment of the real prognosis of this group of patients," he said.

In the meantime, Dr. Hortobágyi said that his group, and many others, "considers that risk of recurrence exceeding about 10% deserves adjuvant chemotherapy, and in the HER2 positive group we believe the risk exceeds, by far, that level. Therefore, we discuss trastuzumab and chemotherapy with all patients without significant comorbid conditions if they have any size-invasive, HER2 positive breast cancer."

The uncertainty regarding the role of adjuvant chemotherapy in early HER2 breast cancer touches on a "fascinating aspect of medicine: how to deal with and communicate uncertainty in diagnosis and treatment benefit," observed Dr. Pusztai.

"Medicine is a very imprecise science and the handling of imprecision is what makes it, as some would call it, an art," he said. "I suspect that what patients perceive as a ‘good’ vs. ‘not so good’ doctor often comes down to how efficiently one can make decisions under uncertainty of information and how effectively one communicates this uncertainty and the decision that is based on it."

Dr. Fehrenbacher, Dr. Pusztai, and Dr. Hortobágyi reported no relevant conflicts of interest with respect to the information presented.

Susan London contributed to this report.

To treat or not to treat? When it comes to deciding whether adjuvant chemotherapy is the appropriate management choice for patients with HER2 positive, node-negative breast cancer less than 1 cm in size, the only sure thing is that there is no sure thing, and seemingly conflicting research data exacerbates the uncertainty.

A recent study demonstrated that patients who did not receive adjuvant chemotherapy or trastuzumab for node-negative, non-metastasized HER2 positive T1a (less than or equal to 0.1 cm to 0.5 cm) or T1b (greater than 0.5 cm to 1.0 cm) tumors were at greater risk for worse recurrence-free survival and worse distant recurrence-free survival than patients with hormone-receptor–positive disease.

This was especially true for those younger than age 35 years – and also was the case in similarly staged patients with triple-negative breast cancer, according to the report from the University of Texas M.D. Anderson Cancer Center in Houston.

The authors concluded that planning systemic treatment based on disease stage alone "appears to lead to worse outcomes," and that individualized treatment plans may be better informed by taking into account aggressive biological subtypes of small, node-negative breast cancers, as well as age at diagnosis (Clin. Breast Cancer. 2011 July 15 [doi: 10.1016/j.clbc.2011.05.002]).

While the findings of this retrospective, single-institution study validate the large body of evidence suggesting that younger patients with aggressive tumor subtypes have worse outcomes when not treated with adjuvant chemotherapy or trastuzumab (Herceptin), the authors do not recommend universal treatment of this patient population.

Rather, the results provide a strong argument for the inclusion of women with small tumors that have biologically aggressive traits in prospective clinical trials "to evaluate the extent of therapeutic benefits," they wrote. Further, patient age and disease subtype "should be considered when counseling patients about treatment interventions."

No Treatment Not Worse for Some

With the absolute benefits of treatment yet to be determined, investigators also are looking closely at the risks associated with skipping adjuvant treatment.

The findings of an observational cohort study presented at the annual meeting of the American Society of Clinical Oncology (ASCO) suggest that women with early HER2 positive T1aN0M0 breast cancers can safely do so because of the low distant recurrence rate observed in this patient subgroup. A higher rate was observed in those with T1bN0M0, indicating that adjuvant systemic therapy may be more relevant in this patient population.

The study assessed outcomes among 237 women with HER2-positive T1a (116 patients) or T1b (121 patients) tumors diagnosed between 2000 and 2006, all of whom had negative nodes and no metastases. Most did not receive adjuvant chemotherapy or trastuzumab.

With a median duration of follow-up of 5.8 years, the rate of distant recurrence was 0.9% among patients with T1a tumors versus 5.8% among those with T1b, lead investigator Dr. Louis Fehrenbacher, an oncologist with Kaiser Permanente in Vallejo, Calif., reported in a poster presentation, analyzing data from the tumor registry of the Kaiser Permanente Clinical Care Program of Northern California.

The investigators chose distant recurrence-free survival as the main outcome measure, rather than the more commonly used disease-free survival rate, because they "did not want to include non-breast malignancies, contralateral malignancies, or deaths from any other cause," Dr. Fehrenbacher said. "That isn’t the real important factor in deciding to give intensive chemotherapy to these patients," he explained.

By tumor size, the rate of distant recurrence ranged from 0% to 5.8% for tumors measuring 0.1 cm to 0.9 cm, but it was 10.7% for the tumors measuring 1.0 cm. In other words, Dr. Fehrenbacher said, "the 1.0-cm tumors carried the burden of the distant recurrence risk."

Results for the actuarial distant recurrence-free interval showed a 5-year rate of 96.5% for the patients as a whole, with 99.1% and 94.0% in the T1a and T1b groups, respectively.

Overall, 25% of the study patients received chemotherapy and 8% received trastuzumab. "Most of these patients had only a smattering of chemotherapy or trastuzumab, and it didn't seem to affect outcome," Dr. Fehrenbacher commented, but he acknowledged that there may have been bias influencing who received chemotherapy. While 59% of the patients had tumors that were positive for estrogen receptors, there was little difference in recurrence rate according to estrogen receptor status, he said.

"The take-home message is, I think, the T1a’s have too low of a risk of distant invasive recurrence to justify chemotherapy or trastuzumab," Dr. Fehrenbacher said in an interview. "We need to specifically individualize the risk of the patient based on the size of their primary [tumor], because the T1a’s and T1b’s are quite different in our findings."

Dr. Lajos Pusztai, a professor in the department of breast medical oncology at M.D. Anderson, agrees with Dr. Fehrenbacher’s conclusion. "I think the findings are correct, as several other studies have also indicated a very low risk of recurrence for very small HER2-positive cancers," he said in an interview.

"It may also be important to remember that HER2 has not been considered by the ASCO biomarker review panels [to be] an important prognostic marker, but rather a predictive marker for trastuzumab therapy."

Review Warns of Cardiotoxicity

In a recent review article looking into whether the existing data supports a definitive treatment threshold for patients with T1aN0M0 or T1bN0M0 HER2-positive breast cancer, Dr. Pusztai, along with lead author Dr. Catherine M. Kelly of Waterford Regional Hospital in Waterford, Ireland and colleagues, wrote that "a blanket recommendation to treat all small HER2 positive breast cancer with trastuzumab-based therapy will almost certainly lead to clinically significant cardiotoxicity in some without any benefit in breast cancer recurrence."

Similarly, they noted, "withholding this form of adjuvant therapy from all small HER2 positive cancers will result in some otherwise avoidable breast cancer recurrence. Unfortunately, today we do not have accurate tools to identify precisely the subset of patients for whom the risks of trastuzumab outweigh the benefits."

Lacking such tools, shared medical decision making based on estimates achieved using established risk calculators and discussion of the risks with patients should be the order of the day, they said, with the decision depending upon the patients’ perspective and risk tolerance level. If trastuzumab-based treatment is an option, the authors stressed that regimens with the lowest risk of cardiotoxicity should be pursued (Ann. Oncol. 2011 Mar. 15 [doi:10.1093/annonc/mdq786]).

In the absence of randomized controlled trials to establish or refute the benefit from adjuvant trastuzumab in this patient subset, the authors called for the development of molecular predictors of prognosis within HER2 positive disease to further optimize risk/benefit estimates. The development of better prediction tools for more precise estimations of the risk of death from comorbid illnesses and the risk of cardiac death, in particular, are important, they said.

Level 1 Evidence Lacking

The lack of level 1 evidence from large, prospective trials contributes to the overall uncertainty surrounding the role of adjuvant chemotherapy in early HER2 breast cancer, according to Dr. Gabriel Hortobágyi, professor and chair of the department of Breast Medical Oncology at M.D. Anderson.

Studies examining the prognostic value of HER2 are limited by their reliance on retrospective database analyses and small cohort sized, Dr. Hortobágyi said in an interview. "I think it is critically important to perform a couple of larger trials with prospective collection of patients, HER2 checked centrally in a high-volume lab, and long enough follow-up to determine the real outcomes of these patients."

In this regard, the Southwest Oncology Group’s breast committee, chaired by Dr. Hortobágyi, is trying to activate a clinical trial for HER2 positive T1a and T1b patients comparing trastuzumab alone and in combination with lapatinib "to determine whether treatment with targeted chemotherapy would be effective enough for these patients." Additionally, he said investigators at Dana Farber Cancer Institute are completing recruitment to a single-arm trial for patients with small, HER2 positive breast cancer treated uniformly with paclitaxel and trastuzumab.

"Both trials will give us prospective data and should contribute significantly to our assessment of the real prognosis of this group of patients," he said.

In the meantime, Dr. Hortobágyi said that his group, and many others, "considers that risk of recurrence exceeding about 10% deserves adjuvant chemotherapy, and in the HER2 positive group we believe the risk exceeds, by far, that level. Therefore, we discuss trastuzumab and chemotherapy with all patients without significant comorbid conditions if they have any size-invasive, HER2 positive breast cancer."

The uncertainty regarding the role of adjuvant chemotherapy in early HER2 breast cancer touches on a "fascinating aspect of medicine: how to deal with and communicate uncertainty in diagnosis and treatment benefit," observed Dr. Pusztai.

"Medicine is a very imprecise science and the handling of imprecision is what makes it, as some would call it, an art," he said. "I suspect that what patients perceive as a ‘good’ vs. ‘not so good’ doctor often comes down to how efficiently one can make decisions under uncertainty of information and how effectively one communicates this uncertainty and the decision that is based on it."

Dr. Fehrenbacher, Dr. Pusztai, and Dr. Hortobágyi reported no relevant conflicts of interest with respect to the information presented.

Susan London contributed to this report.

Efforts to build on the effectiveness of trastuzumab with a dual blockade of the HER2 pathway continue to suggest such a strategy has the potential to enhance outcomes for HER2-positive breast cancer patients.

Genentech announced this summer that the combination of trastuzumab (Herceptin) and docetaxel (Taxotere) with the investigational agent pertuzumab (Omnitarg) met the primary end point of improved progression-free survival in the randomized, double-blind, placebo-controlled phase III CLEOPATRA trial.

A monoclonal antibody, pertuzumab prevents the HER2 receptor from pairing with other HER receptors, including HER1/EGFR, HER3, and HER4, according to Genentech. The Roche-owned company released no data, but said it expects to submit the trial results for "global regulatory approval" this year. A spokesperson said the results will be submitted at "an upcoming medical meeting,"

Trastuzumab emtansine (formerly known as trastuzumab-DM1) is also in ongoing trials, assessing it in various combinations involving trastuzumab, pertuzumab, and lapatinib (Tykerb), the last of which is a dual inhibitor of HER2 and the epidermal growth factor receptor (EGFR). Genentech is developing this experimental antibody-drug conjugate, with Immunogen. It sought accelerated approval based on a positive phase II study last summer but was rebuffed by the Food and Drug Administration on grounds that patients in the trial had not exhausted other therapies.

Since then, the combination of trastuzumab and lapatinib – both approved for HER2-positive breast cancer – was shown to boost complete response rates to 74% when combined with preoperative chemotherapy in a phase II trial reported in June at the annual meeting of the American Society of Clinical Oncology (ASCO).

The study was one of a trio of neoadjuvant trials that evaluated whether complete responses rates could be bettered by adding lapatinib to chemotherapy plus trastuzumab or by combining lapatinib and trastuzumab without chemotherapy, but with the option of endocrine therapy.

Trastuzumab, Lapatinib, and Chemotherapy

Investigators in the phase II CHER-LOB study defined pathological complete response (pCR) as the complete disappearance of invasive residual disease in the breast and axillary nodes. Among 115 evaluable women, the pCR rate increased from 25.7% with chemotherapy plus trastuzumab (arm A) and 27.8% with chemotherapy plus lapatinib (arm B) to 43.1% with the addition of lapatinib to chemotherapy plus trastuzumab (arm C).

The cardiac safety data were reassuring, with no reports of heart failure or significant loss of left ventricular function. Diarrhea, however, was a significant toxicity that caused dose reductions and treatment interruptions in the majority of patients receiving chemotherapy plus lapatinib, acknowledged Dr. Valentina Guarneri of the Modena (Italy) University Hospital. Grade 3 or higher diarrhea was reported in 36% of 39 patients in arm B and 33% of 46 patients in arm C. Permanent lapatinib discontinuation occurred in 25.6% and 13%, respectively.

Because of the high incidence of diarrhea, the protocol was amended to reduce continuous daily dosing of lapatinib from 1,500 mg to 1,250 mg in arm B and from 1,000 mg to 750 mg in arm C. After the amendment, dose reductions fell from 80% to 54% in arm B and from 55% to 34% in arm C, she said.

Chemotherapy consisted of weekly paclitaxel 80 mg/m² for 12 weeks followed by four cycles of fluorouracil 600 mg/m² plus epirubicin 75 mg/m² plus cyclophosphamide 600 mg/m² every 3 weeks (FE₇₅C). Trastuzumab 4 mg/m² was given as a loading dose, followed by 2 mg/m² every week.

A Similar Protocol but With Modifications

The second trial extended the 24-week preoperative FE₇₅C chemotherapy sequence to 26 weeks after a 2-week run-in period of anti-HER2 therapy and used weekly paclitaxel after, rather than before, FE₇₅C. Also, the daily lapatinib dose was set at 1,250 mg in arm B and increased from 750 mg-1,000 mg in arm C. Trastuzumab dosing was the same as above.

Using this protocol, pCR rates among 78 evaluable women reached 54% with chemotherapy plus trastuzumab (arm A), 45% with chemotherapy plus lapatinib (arm B), and 74% with double HER2 blockade plus chemotherapy (arm C), reported Dr. Frankie Ann Holmes with Texas Oncology in Houston.

Patients had stage II-III biopsy proven invasive HER2-positive breast cancer, whereas CHER-LOB limited enrollment to stage II-IIIA disease.

Headed in the Right Direction

Invited discussant Dr. Gunther von Minckwitz, with the German Breast Group, said that despite the small patient numbers, the pCR rates were quite impressive, especially for the study presented by Dr. Holmes, and are in range with previous trials using longer chemotherapy regimens.

The difference in pCR rates between the two studies could be explained by the small sample sizes and differences in patient characteristics. "Still the tendency is going in the same direction," he observed.

Dr. von Minckwitz urged caution in using pCR as an end point, however, particularly among patients with HER2-positive and estrogen receptor (ER)-positive disease. His own meta-analysis presented at ASCO of seven German neoadjuvant breast trials using anthracycline/taxane regimens with or without trastuzumab, showed that pCR strongly correlates with disease-free survival in higher risk groups such as ductal, HER2-positive, and ER-negative disease, but not in luminal A-like and ER-positive/HER2-positive tumors (Abstract 1028).

Lapatinib vs. Trastuzumab Sans Chemo

The third study used neoadjuvant lapatinib 1,000 mg daily plus trastuzumab at a loading dose of 4 mg/kg followed by 2 mg/kg weekly, without chemotherapy, in women with large HER2-positive tumors (median 6 cm; range 1.5-30 cm). In an effort to overcome estrogen receptor crosstalk, ER-positive patients also received letrozole (Femara), plus goserelin, if premenopausal.

A pCR, defined as no invasive cancer in the breast only, was achieved by 28% of the 64 evaluable patients – 21% of ER-positive and 40% of ER-negative patients, Dr. Jenny C. Chang reported on behalf of the Translational Breast Cancer Research Consortium (TBCRC) 006 investigators. No patient progressed during the 12 weeks of targeted therapy alone.

The secondary end point of residual disease of less than 1 cm (near pCR) was seen in 56% of ER-positive and 48% of ER-negative patients, suggesting that these patients may benefit from longer therapy, she said. In all, 62% of patients were ER positive, 62% had a tumor size greater than 5 cm, and 54% were premenopausal.

The regimen in the phase II TBCRC 006 study was very well tolerated, with only five patients discontinuing therapy and 3 reports of grade 3/4 abnormal liver function tests that completely resolved.

Further study is needed before suggesting that select patients with HER2-positive tumors may not need neoadjuvant chemotherapy, said Dr. Chang, director of the Methodist Cancer Center in Houston.

The data compare favorably with those reported at the 2010 San Antonio Breast Cancer Symposium from the phase II NEOSPHERE trial, in which 17% of patients overall, 6% of ER-positive and 29% of ER-negative patients experienced a pCR after 12 weeks of neoadjuvant trastuzumab plus the monoclonal antibody, pertuzumab, Dr. von Minckwitz observed.

New insights are expected from three upcoming neoadjuvant chemotherapy trials in HER2-positive breast cancer: Cancer and Leukemia Group B 40601, European Organization for Research and Treatment of Cancer 10054 and a National Surgical Adjuvant Breast and Bowel Project B-41.

Molecular Profiles Begin to Emerge

Dr. Holmes and her colleagues conducted a variety of molecular analyses in tumor samples from 49 patients before and after anti-HER2 therapy. She reported that their findings indicate the following:

• Baseline phosphorylated EGFR tyrosine1068 is a marker of nonresponse to lapatinib.

• Baseline activation of autophagy correlates with no pCR to all therapies.

• Baseline ratios of phosphorylated Forkhead box O to PTEN and PI3K correlate with response.

• Phosphorylated STAT5 after trastuzumab correlates with pCR.

The molecular profiles suggest that pCR tumors rely on a truncated, rudimentary social network, while resistant tumors use a far more extensive network of autophagy and stem cell–regulated pathways to evade therapy and are thus harder to kill, Dr. Holmes said.

"Despite the limitations, this exploratory analysis shows that the pathway to accelerating the cure of breast cancer is available in every oncologist’s office if she or he can network to tissue-based research trials," she said.

The CHER-LOB investigators tested tumor samples for p95HER2, which is expressed in approximately 30% of HER2-positive breast cancer patients and thought to confer resistance to trastuzumab. No significant differences were observed in all treatment arms in pCR rates based on p95HER2 expression, Dr. Guarneri said.

The p95HER2 results contradict earlier research, observed Dr. von Minckwitz. "We really have to design these biomarker studies very cautiously and the first [issue] we have to address is that we have to have sufficient numbers to study," he added.

CHER-LOB was supported by GlaxoSmithKline. Dr. Guarneri reports no conflicts. Dr. Holmes reports a consultant-advisory role with Phillips Home Monitoring and honoraria from Genentech and Novartis. Dr. Chang reports no relevant conflicts. Dr. Von Minckwitz reports honoraria from Amgen, Roche, and Sanofi-Aventis and research funding from Abraxis BioScience, Amgen, Bayer, GSK, Novartis, Pfizer, Roche, Sanofi-Aventis, and bioMérieux.

Efforts to build on the effectiveness of trastuzumab with a dual blockade of the HER2 pathway continue to suggest such a strategy has the potential to enhance outcomes for HER2-positive breast cancer patients.

Genentech announced this summer that the combination of trastuzumab (Herceptin) and docetaxel (Taxotere) with the investigational agent pertuzumab (Omnitarg) met the primary end point of improved progression-free survival in the randomized, double-blind, placebo-controlled phase III CLEOPATRA trial.

A monoclonal antibody, pertuzumab prevents the HER2 receptor from pairing with other HER receptors, including HER1/EGFR, HER3, and HER4, according to Genentech. The Roche-owned company released no data, but said it expects to submit the trial results for "global regulatory approval" this year. A spokesperson said the results will be submitted at "an upcoming medical meeting,"

Trastuzumab emtansine (formerly known as trastuzumab-DM1) is also in ongoing trials, assessing it in various combinations involving trastuzumab, pertuzumab, and lapatinib (Tykerb), the last of which is a dual inhibitor of HER2 and the epidermal growth factor receptor (EGFR). Genentech is developing this experimental antibody-drug conjugate, with Immunogen. It sought accelerated approval based on a positive phase II study last summer but was rebuffed by the Food and Drug Administration on grounds that patients in the trial had not exhausted other therapies.

Since then, the combination of trastuzumab and lapatinib – both approved for HER2-positive breast cancer – was shown to boost complete response rates to 74% when combined with preoperative chemotherapy in a phase II trial reported in June at the annual meeting of the American Society of Clinical Oncology (ASCO).

The study was one of a trio of neoadjuvant trials that evaluated whether complete responses rates could be bettered by adding lapatinib to chemotherapy plus trastuzumab or by combining lapatinib and trastuzumab without chemotherapy, but with the option of endocrine therapy.

Trastuzumab, Lapatinib, and Chemotherapy

Investigators in the phase II CHER-LOB study defined pathological complete response (pCR) as the complete disappearance of invasive residual disease in the breast and axillary nodes. Among 115 evaluable women, the pCR rate increased from 25.7% with chemotherapy plus trastuzumab (arm A) and 27.8% with chemotherapy plus lapatinib (arm B) to 43.1% with the addition of lapatinib to chemotherapy plus trastuzumab (arm C).

The cardiac safety data were reassuring, with no reports of heart failure or significant loss of left ventricular function. Diarrhea, however, was a significant toxicity that caused dose reductions and treatment interruptions in the majority of patients receiving chemotherapy plus lapatinib, acknowledged Dr. Valentina Guarneri of the Modena (Italy) University Hospital. Grade 3 or higher diarrhea was reported in 36% of 39 patients in arm B and 33% of 46 patients in arm C. Permanent lapatinib discontinuation occurred in 25.6% and 13%, respectively.

Because of the high incidence of diarrhea, the protocol was amended to reduce continuous daily dosing of lapatinib from 1,500 mg to 1,250 mg in arm B and from 1,000 mg to 750 mg in arm C. After the amendment, dose reductions fell from 80% to 54% in arm B and from 55% to 34% in arm C, she said.

Chemotherapy consisted of weekly paclitaxel 80 mg/m² for 12 weeks followed by four cycles of fluorouracil 600 mg/m² plus epirubicin 75 mg/m² plus cyclophosphamide 600 mg/m² every 3 weeks (FE₇₅C). Trastuzumab 4 mg/m² was given as a loading dose, followed by 2 mg/m² every week.

A Similar Protocol but With Modifications

The second trial extended the 24-week preoperative FE₇₅C chemotherapy sequence to 26 weeks after a 2-week run-in period of anti-HER2 therapy and used weekly paclitaxel after, rather than before, FE₇₅C. Also, the daily lapatinib dose was set at 1,250 mg in arm B and increased from 750 mg-1,000 mg in arm C. Trastuzumab dosing was the same as above.

Using this protocol, pCR rates among 78 evaluable women reached 54% with chemotherapy plus trastuzumab (arm A), 45% with chemotherapy plus lapatinib (arm B), and 74% with double HER2 blockade plus chemotherapy (arm C), reported Dr. Frankie Ann Holmes with Texas Oncology in Houston.

Patients had stage II-III biopsy proven invasive HER2-positive breast cancer, whereas CHER-LOB limited enrollment to stage II-IIIA disease.

Headed in the Right Direction

Invited discussant Dr. Gunther von Minckwitz, with the German Breast Group, said that despite the small patient numbers, the pCR rates were quite impressive, especially for the study presented by Dr. Holmes, and are in range with previous trials using longer chemotherapy regimens.

The difference in pCR rates between the two studies could be explained by the small sample sizes and differences in patient characteristics. "Still the tendency is going in the same direction," he observed.

Dr. von Minckwitz urged caution in using pCR as an end point, however, particularly among patients with HER2-positive and estrogen receptor (ER)-positive disease. His own meta-analysis presented at ASCO of seven German neoadjuvant breast trials using anthracycline/taxane regimens with or without trastuzumab, showed that pCR strongly correlates with disease-free survival in higher risk groups such as ductal, HER2-positive, and ER-negative disease, but not in luminal A-like and ER-positive/HER2-positive tumors (Abstract 1028).

Lapatinib vs. Trastuzumab Sans Chemo

The third study used neoadjuvant lapatinib 1,000 mg daily plus trastuzumab at a loading dose of 4 mg/kg followed by 2 mg/kg weekly, without chemotherapy, in women with large HER2-positive tumors (median 6 cm; range 1.5-30 cm). In an effort to overcome estrogen receptor crosstalk, ER-positive patients also received letrozole (Femara), plus goserelin, if premenopausal.

A pCR, defined as no invasive cancer in the breast only, was achieved by 28% of the 64 evaluable patients – 21% of ER-positive and 40% of ER-negative patients, Dr. Jenny C. Chang reported on behalf of the Translational Breast Cancer Research Consortium (TBCRC) 006 investigators. No patient progressed during the 12 weeks of targeted therapy alone.

The secondary end point of residual disease of less than 1 cm (near pCR) was seen in 56% of ER-positive and 48% of ER-negative patients, suggesting that these patients may benefit from longer therapy, she said. In all, 62% of patients were ER positive, 62% had a tumor size greater than 5 cm, and 54% were premenopausal.

The regimen in the phase II TBCRC 006 study was very well tolerated, with only five patients discontinuing therapy and 3 reports of grade 3/4 abnormal liver function tests that completely resolved.

Further study is needed before suggesting that select patients with HER2-positive tumors may not need neoadjuvant chemotherapy, said Dr. Chang, director of the Methodist Cancer Center in Houston.

The data compare favorably with those reported at the 2010 San Antonio Breast Cancer Symposium from the phase II NEOSPHERE trial, in which 17% of patients overall, 6% of ER-positive and 29% of ER-negative patients experienced a pCR after 12 weeks of neoadjuvant trastuzumab plus the monoclonal antibody, pertuzumab, Dr. von Minckwitz observed.

New insights are expected from three upcoming neoadjuvant chemotherapy trials in HER2-positive breast cancer: Cancer and Leukemia Group B 40601, European Organization for Research and Treatment of Cancer 10054 and a National Surgical Adjuvant Breast and Bowel Project B-41.

Molecular Profiles Begin to Emerge

Dr. Holmes and her colleagues conducted a variety of molecular analyses in tumor samples from 49 patients before and after anti-HER2 therapy. She reported that their findings indicate the following:

• Baseline phosphorylated EGFR tyrosine1068 is a marker of nonresponse to lapatinib.

• Baseline activation of autophagy correlates with no pCR to all therapies.

• Baseline ratios of phosphorylated Forkhead box O to PTEN and PI3K correlate with response.

• Phosphorylated STAT5 after trastuzumab correlates with pCR.

The molecular profiles suggest that pCR tumors rely on a truncated, rudimentary social network, while resistant tumors use a far more extensive network of autophagy and stem cell–regulated pathways to evade therapy and are thus harder to kill, Dr. Holmes said.

"Despite the limitations, this exploratory analysis shows that the pathway to accelerating the cure of breast cancer is available in every oncologist’s office if she or he can network to tissue-based research trials," she said.

The CHER-LOB investigators tested tumor samples for p95HER2, which is expressed in approximately 30% of HER2-positive breast cancer patients and thought to confer resistance to trastuzumab. No significant differences were observed in all treatment arms in pCR rates based on p95HER2 expression, Dr. Guarneri said.

The p95HER2 results contradict earlier research, observed Dr. von Minckwitz. "We really have to design these biomarker studies very cautiously and the first [issue] we have to address is that we have to have sufficient numbers to study," he added.

CHER-LOB was supported by GlaxoSmithKline. Dr. Guarneri reports no conflicts. Dr. Holmes reports a consultant-advisory role with Phillips Home Monitoring and honoraria from Genentech and Novartis. Dr. Chang reports no relevant conflicts. Dr. Von Minckwitz reports honoraria from Amgen, Roche, and Sanofi-Aventis and research funding from Abraxis BioScience, Amgen, Bayer, GSK, Novartis, Pfizer, Roche, Sanofi-Aventis, and bioMérieux.

Efforts to build on the effectiveness of trastuzumab with a dual blockade of the HER2 pathway continue to suggest such a strategy has the potential to enhance outcomes for HER2-positive breast cancer patients.

Genentech announced this summer that the combination of trastuzumab (Herceptin) and docetaxel (Taxotere) with the investigational agent pertuzumab (Omnitarg) met the primary end point of improved progression-free survival in the randomized, double-blind, placebo-controlled phase III CLEOPATRA trial.

A monoclonal antibody, pertuzumab prevents the HER2 receptor from pairing with other HER receptors, including HER1/EGFR, HER3, and HER4, according to Genentech. The Roche-owned company released no data, but said it expects to submit the trial results for "global regulatory approval" this year. A spokesperson said the results will be submitted at "an upcoming medical meeting,"

Trastuzumab emtansine (formerly known as trastuzumab-DM1) is also in ongoing trials, assessing it in various combinations involving trastuzumab, pertuzumab, and lapatinib (Tykerb), the last of which is a dual inhibitor of HER2 and the epidermal growth factor receptor (EGFR). Genentech is developing this experimental antibody-drug conjugate, with Immunogen. It sought accelerated approval based on a positive phase II study last summer but was rebuffed by the Food and Drug Administration on grounds that patients in the trial had not exhausted other therapies.

Since then, the combination of trastuzumab and lapatinib – both approved for HER2-positive breast cancer – was shown to boost complete response rates to 74% when combined with preoperative chemotherapy in a phase II trial reported in June at the annual meeting of the American Society of Clinical Oncology (ASCO).

The study was one of a trio of neoadjuvant trials that evaluated whether complete responses rates could be bettered by adding lapatinib to chemotherapy plus trastuzumab or by combining lapatinib and trastuzumab without chemotherapy, but with the option of endocrine therapy.

Trastuzumab, Lapatinib, and Chemotherapy

Investigators in the phase II CHER-LOB study defined pathological complete response (pCR) as the complete disappearance of invasive residual disease in the breast and axillary nodes. Among 115 evaluable women, the pCR rate increased from 25.7% with chemotherapy plus trastuzumab (arm A) and 27.8% with chemotherapy plus lapatinib (arm B) to 43.1% with the addition of lapatinib to chemotherapy plus trastuzumab (arm C).

The cardiac safety data were reassuring, with no reports of heart failure or significant loss of left ventricular function. Diarrhea, however, was a significant toxicity that caused dose reductions and treatment interruptions in the majority of patients receiving chemotherapy plus lapatinib, acknowledged Dr. Valentina Guarneri of the Modena (Italy) University Hospital. Grade 3 or higher diarrhea was reported in 36% of 39 patients in arm B and 33% of 46 patients in arm C. Permanent lapatinib discontinuation occurred in 25.6% and 13%, respectively.

Because of the high incidence of diarrhea, the protocol was amended to reduce continuous daily dosing of lapatinib from 1,500 mg to 1,250 mg in arm B and from 1,000 mg to 750 mg in arm C. After the amendment, dose reductions fell from 80% to 54% in arm B and from 55% to 34% in arm C, she said.

Chemotherapy consisted of weekly paclitaxel 80 mg/m² for 12 weeks followed by four cycles of fluorouracil 600 mg/m² plus epirubicin 75 mg/m² plus cyclophosphamide 600 mg/m² every 3 weeks (FE₇₅C). Trastuzumab 4 mg/m² was given as a loading dose, followed by 2 mg/m² every week.

A Similar Protocol but With Modifications

The second trial extended the 24-week preoperative FE₇₅C chemotherapy sequence to 26 weeks after a 2-week run-in period of anti-HER2 therapy and used weekly paclitaxel after, rather than before, FE₇₅C. Also, the daily lapatinib dose was set at 1,250 mg in arm B and increased from 750 mg-1,000 mg in arm C. Trastuzumab dosing was the same as above.

Using this protocol, pCR rates among 78 evaluable women reached 54% with chemotherapy plus trastuzumab (arm A), 45% with chemotherapy plus lapatinib (arm B), and 74% with double HER2 blockade plus chemotherapy (arm C), reported Dr. Frankie Ann Holmes with Texas Oncology in Houston.

Patients had stage II-III biopsy proven invasive HER2-positive breast cancer, whereas CHER-LOB limited enrollment to stage II-IIIA disease.

Headed in the Right Direction

Invited discussant Dr. Gunther von Minckwitz, with the German Breast Group, said that despite the small patient numbers, the pCR rates were quite impressive, especially for the study presented by Dr. Holmes, and are in range with previous trials using longer chemotherapy regimens.

The difference in pCR rates between the two studies could be explained by the small sample sizes and differences in patient characteristics. "Still the tendency is going in the same direction," he observed.

Dr. von Minckwitz urged caution in using pCR as an end point, however, particularly among patients with HER2-positive and estrogen receptor (ER)-positive disease. His own meta-analysis presented at ASCO of seven German neoadjuvant breast trials using anthracycline/taxane regimens with or without trastuzumab, showed that pCR strongly correlates with disease-free survival in higher risk groups such as ductal, HER2-positive, and ER-negative disease, but not in luminal A-like and ER-positive/HER2-positive tumors (Abstract 1028).

Lapatinib vs. Trastuzumab Sans Chemo

The third study used neoadjuvant lapatinib 1,000 mg daily plus trastuzumab at a loading dose of 4 mg/kg followed by 2 mg/kg weekly, without chemotherapy, in women with large HER2-positive tumors (median 6 cm; range 1.5-30 cm). In an effort to overcome estrogen receptor crosstalk, ER-positive patients also received letrozole (Femara), plus goserelin, if premenopausal.

A pCR, defined as no invasive cancer in the breast only, was achieved by 28% of the 64 evaluable patients – 21% of ER-positive and 40% of ER-negative patients, Dr. Jenny C. Chang reported on behalf of the Translational Breast Cancer Research Consortium (TBCRC) 006 investigators. No patient progressed during the 12 weeks of targeted therapy alone.

The secondary end point of residual disease of less than 1 cm (near pCR) was seen in 56% of ER-positive and 48% of ER-negative patients, suggesting that these patients may benefit from longer therapy, she said. In all, 62% of patients were ER positive, 62% had a tumor size greater than 5 cm, and 54% were premenopausal.

The regimen in the phase II TBCRC 006 study was very well tolerated, with only five patients discontinuing therapy and 3 reports of grade 3/4 abnormal liver function tests that completely resolved.

Further study is needed before suggesting that select patients with HER2-positive tumors may not need neoadjuvant chemotherapy, said Dr. Chang, director of the Methodist Cancer Center in Houston.

The data compare favorably with those reported at the 2010 San Antonio Breast Cancer Symposium from the phase II NEOSPHERE trial, in which 17% of patients overall, 6% of ER-positive and 29% of ER-negative patients experienced a pCR after 12 weeks of neoadjuvant trastuzumab plus the monoclonal antibody, pertuzumab, Dr. von Minckwitz observed.

New insights are expected from three upcoming neoadjuvant chemotherapy trials in HER2-positive breast cancer: Cancer and Leukemia Group B 40601, European Organization for Research and Treatment of Cancer 10054 and a National Surgical Adjuvant Breast and Bowel Project B-41.

Molecular Profiles Begin to Emerge

Dr. Holmes and her colleagues conducted a variety of molecular analyses in tumor samples from 49 patients before and after anti-HER2 therapy. She reported that their findings indicate the following:

• Baseline phosphorylated EGFR tyrosine1068 is a marker of nonresponse to lapatinib.

• Baseline activation of autophagy correlates with no pCR to all therapies.

• Baseline ratios of phosphorylated Forkhead box O to PTEN and PI3K correlate with response.

• Phosphorylated STAT5 after trastuzumab correlates with pCR.

The molecular profiles suggest that pCR tumors rely on a truncated, rudimentary social network, while resistant tumors use a far more extensive network of autophagy and stem cell–regulated pathways to evade therapy and are thus harder to kill, Dr. Holmes said.

"Despite the limitations, this exploratory analysis shows that the pathway to accelerating the cure of breast cancer is available in every oncologist’s office if she or he can network to tissue-based research trials," she said.

The CHER-LOB investigators tested tumor samples for p95HER2, which is expressed in approximately 30% of HER2-positive breast cancer patients and thought to confer resistance to trastuzumab. No significant differences were observed in all treatment arms in pCR rates based on p95HER2 expression, Dr. Guarneri said.

The p95HER2 results contradict earlier research, observed Dr. von Minckwitz. "We really have to design these biomarker studies very cautiously and the first [issue] we have to address is that we have to have sufficient numbers to study," he added.

CHER-LOB was supported by GlaxoSmithKline. Dr. Guarneri reports no conflicts. Dr. Holmes reports a consultant-advisory role with Phillips Home Monitoring and honoraria from Genentech and Novartis. Dr. Chang reports no relevant conflicts. Dr. Von Minckwitz reports honoraria from Amgen, Roche, and Sanofi-Aventis and research funding from Abraxis BioScience, Amgen, Bayer, GSK, Novartis, Pfizer, Roche, Sanofi-Aventis, and bioMérieux.

Adam M. Brufsky, MD, PhD
University of Pittsburgh School of Medicine, Pittsburgh, PA

Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.

Although many different agents have been used in the clinic to treat these patients, aromatase inhibitors (AIs) and antiestrogens form the two major categories of endocrine therapy in current use. These two types of agents have distinct mechanisms of action (MOAs).1 AIs reduce circulating estrogen levels by preventing the conversion of androstenedione into estrogen in peripheral tissues. 1 Antiestrogens, also referred to as ER antagonists, can be further classified into two subgroups based on their MOA: the selective ER modulators (SERMs), typified by tamoxifen, and the selective ER downregulators (SERDs), exemplified by fulvestrant (Faslodex).1

A number of randomized clinical studies have demonstrated the efficacy of tamoxifen and the AIs (anastrozole, letrozole, and exemestane) in the adjuvant2–5 and metastatic6–8 settings. Fulvestrant has demonstrated effectiveness in the metastatic setting.9–13

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

Adam M. Brufsky, MD, PhD
University of Pittsburgh School of Medicine, Pittsburgh, PA

Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.

Although many different agents have been used in the clinic to treat these patients, aromatase inhibitors (AIs) and antiestrogens form the two major categories of endocrine therapy in current use. These two types of agents have distinct mechanisms of action (MOAs).1 AIs reduce circulating estrogen levels by preventing the conversion of androstenedione into estrogen in peripheral tissues. 1 Antiestrogens, also referred to as ER antagonists, can be further classified into two subgroups based on their MOA: the selective ER modulators (SERMs), typified by tamoxifen, and the selective ER downregulators (SERDs), exemplified by fulvestrant (Faslodex).1

A number of randomized clinical studies have demonstrated the efficacy of tamoxifen and the AIs (anastrozole, letrozole, and exemestane) in the adjuvant2–5 and metastatic6–8 settings. Fulvestrant has demonstrated effectiveness in the metastatic setting.9–13

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

Adam M. Brufsky, MD, PhD
University of Pittsburgh School of Medicine, Pittsburgh, PA

Estrogen receptor (ER) signaling plays a critical role in many breast cancers. As a result, endocrine therapy is a mainstay in the treatment plan for patients with hormone receptor-positive breast cancer. Although patients with metastatic breast cancer (MBC) are often given several lines of endocrine therapy throughout the course of their disease, the optimal sequence of and exact mechanisms of resistance to endocrine therapy remain unclear. Endocrine therapies include aromatase inhibitors, selective ER modulators, and selective ER downregulators. These agents interfere with ER signaling and inhibit breast cancer growth, but their mechanisms of action (MOAs) are distinct and potential mechanisms of resistance vary. Patient-specific factors (eg, tumor characteristics, burden of disease, patient preferences, and treatment history) and the MOAs of the available agents are important considerations. This review discusses the latest understanding of ER biology, the mechanistic differences between endocrine therapies, and future directions in endocrine therapy for MBC.

Although many different agents have been used in the clinic to treat these patients, aromatase inhibitors (AIs) and antiestrogens form the two major categories of endocrine therapy in current use. These two types of agents have distinct mechanisms of action (MOAs).1 AIs reduce circulating estrogen levels by preventing the conversion of androstenedione into estrogen in peripheral tissues. 1 Antiestrogens, also referred to as ER antagonists, can be further classified into two subgroups based on their MOA: the selective ER modulators (SERMs), typified by tamoxifen, and the selective ER downregulators (SERDs), exemplified by fulvestrant (Faslodex).1

A number of randomized clinical studies have demonstrated the efficacy of tamoxifen and the AIs (anastrozole, letrozole, and exemestane) in the adjuvant2–5 and metastatic6–8 settings. Fulvestrant has demonstrated effectiveness in the metastatic setting.9–13

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

Dr. David H Henry summarizes key articles in the July issue of the journal Community Oncology. Topics include Exemestane for postmenopausal women at increased risk of breast cancer and a summary of key research from the 2011 ASCO meeting, including crizotinib for ALK+ non-small cell lung cancer and vemurafenib and ipilimumab for metastatic melanoma.

Dr. David H Henry summarizes key articles in the July issue of the journal Community Oncology. Topics include Exemestane for postmenopausal women at increased risk of breast cancer and a summary of key research from the 2011 ASCO meeting, including crizotinib for ALK+ non-small cell lung cancer and vemurafenib and ipilimumab for metastatic melanoma.

Dr. David H Henry summarizes key articles in the July issue of the journal Community Oncology. Topics include Exemestane for postmenopausal women at increased risk of breast cancer and a summary of key research from the 2011 ASCO meeting, including crizotinib for ALK+ non-small cell lung cancer and vemurafenib and ipilimumab for metastatic melanoma.

Yes – It Is Time to Consider a Paradigm Shift.

By Dr. Seema Khan

In stage IV breast cancer, local therapy is not considered important except for controlling symptoms. But recent large-scale retrospective studies tell us that, if you follow enough women long enough, you see a difference in survival related to control of local disease. These emerging data tell us it’s time to consider a paradigm shift in the treatment of stage IV breast cancer.

Researchers are finding that primary site treatment regimens are important because an intact primary tumor can serve as a continued source of new metastatic lesions. There is reason, therefore, to believe that treating these can prolong life.

First explored by Dr. Larry Norton and Joan Massagué, Ph.D., (Nature Med. 2006;12:875-8), the concept of cancer self-seeding holds that cells from the primary tumor not only travel unidirectionally to seed metastases but also return to the primary tumor, self-seeding it and helping it to grow even more.

This view incorporates the microenvironment of the primary tumor. Here, fibroblasts and other cells – particularly mesenchymal stem cells derived from bone marrow – may play a very important role, creating a reactive stroma that seems to release growth-promoting substances that increase the metastatic efficiency of the circulating cells.

Robert A. Weinberg, Ph.D., published data showing that these mesenchymal stem cells are pluripotent progenitor cells. When weakly metastatic human breast cancer cells were mixed with these stem cells, the cancer cells’ metastatic potential greatly increased. The breast cancer cells then stimulated the stem cells to secrete a chemokine which – in turn – enhanced the cancer cells’ motility and their ability to invade and metastasize (Nature 2007;449:557-63). In effect, the primary tumor acts like a filling station, giving these tumor cells more energy to go out and metastasize in different sites.

Although such studies remain animal models, I think we can say there is a basis for primary tumor therapy in the metastatic setting. A dozen or more retrospective studies of large institutional series, cancer databases, and population-based studies have examined outcomes in women treated with and without surgical resection. Data on about 30,000 women have been published, with about 50% receiving some form of primary tumor therapy. The survival benefit across them is quite consistent, with the hazard ratio of death over a given time period reduced from 30% to 50%.

These studies do demonstrate selection bias: Women treated with surgical removal were more likely to be young, white, married, with smaller tumors and a lower burden of disease, and it is possible that they would have done better anyway. Studies have also shown that better survival, even in stage IV cancer, occurs in women who have a therapeutic target (that is, hormone receptors or HER2). But there was still a significant survival benefit for surgery.

Surgical resection may also confer benefit by preventing the primary tumor in the breast from becoming a quality of-life problem. At Northwestern Memorial Hospital, Chicago, we conducted a study that showed the odds of symptomatic chest wall disease were far lower in the surgical group, compared with the nonsurgical group. In this 2008 study, we found that women with good local control– surgical or systemic - did better. Time to first progression was prolonged by 50% in the surgical group, while chest wall control was associated with a 60% improvement in overall survival, regardless of whether surgical resection was performed (Cancer 2008;113:2011-9).

So the question is, do we need a randomized trial? My unbiased answer is that we do – and I am the principal investigator of such a trial open to all U.S. and Canadian institutions (NCT01242800). The end points are survival, local control, and quality of life. In addition, the trial will provide an opportunity to answer biological questions regarding the relationship between the primary tumor and metastatic site. Only when we have samples of primary and metastatic tumors can we settle this continuing debate.

Dr. Seema Khan is the Bluhm Family Professor of Cancer Research at the Lurie Comprehensive Cancer Center, Chicago.

No – Case Selection Bias Is Behind the Survival Advantage.

By Dr. Blake Cady

It’s true that some studies show an increase in stage IV breast cancer survival after primary site resection – but this more likely reflects a bias of case selection than a true benefit of local therapy.

Any findings of positive benefit other than case selection must be biologically plausible. The suggestion that the primary tumor releases some sort of growth-promoting substance that is gone when you remove the tumor, inhibiting metastatic disease has not yet been proven in humans; nor has the proposition that continued cell shedding might further metastasis.

Decreased tumor burden has sometimes been shown to increase the usefulness of systemic therapy, but I think that, all in all, case selection simply promotes breast surgery in patients with a better prognosis.

To show improved survival, we must find causality and not simply coincidence. Findings from large case series or cancer databases are unable to provide the answer. Although registry interpretations can provide basic data, they often break down when you attempt to extract detailed data.

Sometimes a stage IV cancer is registered initially on the basis of a pulmonary or liver shadow on imaging, which later is proven not to have been metastatic disease – and the case is never amended in the registry. There are also registry misinterpretations of the type of surgery that’s been done.

We performed a matched pair analysis of stage IV breast cancer patients with and without resection of the primary tumor. This was based on the Partners Health Care Consortium cancer database, which included information on 19,464 invasive breast cancers treated between 1970 and 2002; 808 of these (4%) were recorded as stage IV. Of these, 622 were analyzed by case matching that considered age, diagnostic date, metastatic disease location, estrogen-receptor status, and systemic therapy (Ann. Surg. Oncol. 2008; 15:3384-95).

It’s absolutely true that there was a statistically significant difference in survival in the overall comparison of surgery vs. no surgery. With bone metastases only, it was still statistically significant, but with a substantially lower difference in survival. In visceral metastases, the difference became nonsignificant.

Looking at therapy sequence in those who had the same type of systemic therapy, but with chemotherapy before or after surgery, you see a suggestion that giving systemic therapy first with a clinical response, which is a favorable prognostic indication, leads to a selection bias in choosing patients for surgery.

I reviewed the 86 cases who survived 5 years with records available. In those records, 22 were actually not stage IV disease, leaving 64 with confirmed stage IV (M1) – an overall 10% 5-year survival rate. Patients who survived were significantly younger than those who did not survive, significantly more likely to have estrogen receptor-positive tumors, and significantly more likely to have bone rather than visceral metastases or oligometastatic disease – all of which are good prognostic factors.

Among the 64 5-year survivors, 25 had therapeutic breast surgery. Of these, 8 had an excellent chemotherapy response followed by breast surgery; 8 had delayed surgery following a failure of systemic therapy; 7 had an initial therapeutic and curative surgery, but staging revealed metastases because of unexpected positive nodes; and 2 had initial surgery with oligometastatic resection.

Thirty-nine patients had no therapeutic breast surgery, and, of these, 16 had an excellent response to systemic therapy; 15 had slowly progressive disease; and 8 had oligometastatic disease – a positive prognostic factor. Thus, favorable prognostic factors led to a selection of primary-site surgery, whereas poor prognostic factors mean that primary-site surgery was avoided, contradicting the assumption of its therapeutic benefit.

There were also surgical discrepancies among the 5-year survivors. The registry listed 11 as having had breast surgery, while a chart review showed that surgery was not therapeutic. Five were listed as having no breast surgery, while they had indeed undergone a therapeutic operation.

Cancer registry data are not reliable for defining stage IV disease, discriminating advanced local disease with bone involvement from true distant, imaging-confirmed metastasis, or assessing surgical procedures. Case selection bias accounts for most, if not all, of the apparent survival advantage.

Dr. Blake Cady is professor of surgery (emeritus) at Harvard Medical School, Boston, and at Brown University, Providence, R.I.

Yes – It Is Time to Consider a Paradigm Shift.

By Dr. Seema Khan

In stage IV breast cancer, local therapy is not considered important except for controlling symptoms. But recent large-scale retrospective studies tell us that, if you follow enough women long enough, you see a difference in survival related to control of local disease. These emerging data tell us it’s time to consider a paradigm shift in the treatment of stage IV breast cancer.

Researchers are finding that primary site treatment regimens are important because an intact primary tumor can serve as a continued source of new metastatic lesions. There is reason, therefore, to believe that treating these can prolong life.

First explored by Dr. Larry Norton and Joan Massagué, Ph.D., (Nature Med. 2006;12:875-8), the concept of cancer self-seeding holds that cells from the primary tumor not only travel unidirectionally to seed metastases but also return to the primary tumor, self-seeding it and helping it to grow even more.

This view incorporates the microenvironment of the primary tumor. Here, fibroblasts and other cells – particularly mesenchymal stem cells derived from bone marrow – may play a very important role, creating a reactive stroma that seems to release growth-promoting substances that increase the metastatic efficiency of the circulating cells.

Robert A. Weinberg, Ph.D., published data showing that these mesenchymal stem cells are pluripotent progenitor cells. When weakly metastatic human breast cancer cells were mixed with these stem cells, the cancer cells’ metastatic potential greatly increased. The breast cancer cells then stimulated the stem cells to secrete a chemokine which – in turn – enhanced the cancer cells’ motility and their ability to invade and metastasize (Nature 2007;449:557-63). In effect, the primary tumor acts like a filling station, giving these tumor cells more energy to go out and metastasize in different sites.

Although such studies remain animal models, I think we can say there is a basis for primary tumor therapy in the metastatic setting. A dozen or more retrospective studies of large institutional series, cancer databases, and population-based studies have examined outcomes in women treated with and without surgical resection. Data on about 30,000 women have been published, with about 50% receiving some form of primary tumor therapy. The survival benefit across them is quite consistent, with the hazard ratio of death over a given time period reduced from 30% to 50%.

These studies do demonstrate selection bias: Women treated with surgical removal were more likely to be young, white, married, with smaller tumors and a lower burden of disease, and it is possible that they would have done better anyway. Studies have also shown that better survival, even in stage IV cancer, occurs in women who have a therapeutic target (that is, hormone receptors or HER2). But there was still a significant survival benefit for surgery.

Surgical resection may also confer benefit by preventing the primary tumor in the breast from becoming a quality of-life problem. At Northwestern Memorial Hospital, Chicago, we conducted a study that showed the odds of symptomatic chest wall disease were far lower in the surgical group, compared with the nonsurgical group. In this 2008 study, we found that women with good local control– surgical or systemic - did better. Time to first progression was prolonged by 50% in the surgical group, while chest wall control was associated with a 60% improvement in overall survival, regardless of whether surgical resection was performed (Cancer 2008;113:2011-9).

So the question is, do we need a randomized trial? My unbiased answer is that we do – and I am the principal investigator of such a trial open to all U.S. and Canadian institutions (NCT01242800). The end points are survival, local control, and quality of life. In addition, the trial will provide an opportunity to answer biological questions regarding the relationship between the primary tumor and metastatic site. Only when we have samples of primary and metastatic tumors can we settle this continuing debate.

Dr. Seema Khan is the Bluhm Family Professor of Cancer Research at the Lurie Comprehensive Cancer Center, Chicago.

No – Case Selection Bias Is Behind the Survival Advantage.

By Dr. Blake Cady

It’s true that some studies show an increase in stage IV breast cancer survival after primary site resection – but this more likely reflects a bias of case selection than a true benefit of local therapy.

Any findings of positive benefit other than case selection must be biologically plausible. The suggestion that the primary tumor releases some sort of growth-promoting substance that is gone when you remove the tumor, inhibiting metastatic disease has not yet been proven in humans; nor has the proposition that continued cell shedding might further metastasis.

Decreased tumor burden has sometimes been shown to increase the usefulness of systemic therapy, but I think that, all in all, case selection simply promotes breast surgery in patients with a better prognosis.

To show improved survival, we must find causality and not simply coincidence. Findings from large case series or cancer databases are unable to provide the answer. Although registry interpretations can provide basic data, they often break down when you attempt to extract detailed data.

Sometimes a stage IV cancer is registered initially on the basis of a pulmonary or liver shadow on imaging, which later is proven not to have been metastatic disease – and the case is never amended in the registry. There are also registry misinterpretations of the type of surgery that’s been done.

We performed a matched pair analysis of stage IV breast cancer patients with and without resection of the primary tumor. This was based on the Partners Health Care Consortium cancer database, which included information on 19,464 invasive breast cancers treated between 1970 and 2002; 808 of these (4%) were recorded as stage IV. Of these, 622 were analyzed by case matching that considered age, diagnostic date, metastatic disease location, estrogen-receptor status, and systemic therapy (Ann. Surg. Oncol. 2008; 15:3384-95).

It’s absolutely true that there was a statistically significant difference in survival in the overall comparison of surgery vs. no surgery. With bone metastases only, it was still statistically significant, but with a substantially lower difference in survival. In visceral metastases, the difference became nonsignificant.

Looking at therapy sequence in those who had the same type of systemic therapy, but with chemotherapy before or after surgery, you see a suggestion that giving systemic therapy first with a clinical response, which is a favorable prognostic indication, leads to a selection bias in choosing patients for surgery.

I reviewed the 86 cases who survived 5 years with records available. In those records, 22 were actually not stage IV disease, leaving 64 with confirmed stage IV (M1) – an overall 10% 5-year survival rate. Patients who survived were significantly younger than those who did not survive, significantly more likely to have estrogen receptor-positive tumors, and significantly more likely to have bone rather than visceral metastases or oligometastatic disease – all of which are good prognostic factors.

Among the 64 5-year survivors, 25 had therapeutic breast surgery. Of these, 8 had an excellent chemotherapy response followed by breast surgery; 8 had delayed surgery following a failure of systemic therapy; 7 had an initial therapeutic and curative surgery, but staging revealed metastases because of unexpected positive nodes; and 2 had initial surgery with oligometastatic resection.

Thirty-nine patients had no therapeutic breast surgery, and, of these, 16 had an excellent response to systemic therapy; 15 had slowly progressive disease; and 8 had oligometastatic disease – a positive prognostic factor. Thus, favorable prognostic factors led to a selection of primary-site surgery, whereas poor prognostic factors mean that primary-site surgery was avoided, contradicting the assumption of its therapeutic benefit.

There were also surgical discrepancies among the 5-year survivors. The registry listed 11 as having had breast surgery, while a chart review showed that surgery was not therapeutic. Five were listed as having no breast surgery, while they had indeed undergone a therapeutic operation.

Cancer registry data are not reliable for defining stage IV disease, discriminating advanced local disease with bone involvement from true distant, imaging-confirmed metastasis, or assessing surgical procedures. Case selection bias accounts for most, if not all, of the apparent survival advantage.

Dr. Blake Cady is professor of surgery (emeritus) at Harvard Medical School, Boston, and at Brown University, Providence, R.I.

Yes – It Is Time to Consider a Paradigm Shift.

By Dr. Seema Khan

In stage IV breast cancer, local therapy is not considered important except for controlling symptoms. But recent large-scale retrospective studies tell us that, if you follow enough women long enough, you see a difference in survival related to control of local disease. These emerging data tell us it’s time to consider a paradigm shift in the treatment of stage IV breast cancer.

Researchers are finding that primary site treatment regimens are important because an intact primary tumor can serve as a continued source of new metastatic lesions. There is reason, therefore, to believe that treating these can prolong life.

First explored by Dr. Larry Norton and Joan Massagué, Ph.D., (Nature Med. 2006;12:875-8), the concept of cancer self-seeding holds that cells from the primary tumor not only travel unidirectionally to seed metastases but also return to the primary tumor, self-seeding it and helping it to grow even more.

This view incorporates the microenvironment of the primary tumor. Here, fibroblasts and other cells – particularly mesenchymal stem cells derived from bone marrow – may play a very important role, creating a reactive stroma that seems to release growth-promoting substances that increase the metastatic efficiency of the circulating cells.

Robert A. Weinberg, Ph.D., published data showing that these mesenchymal stem cells are pluripotent progenitor cells. When weakly metastatic human breast cancer cells were mixed with these stem cells, the cancer cells’ metastatic potential greatly increased. The breast cancer cells then stimulated the stem cells to secrete a chemokine which – in turn – enhanced the cancer cells’ motility and their ability to invade and metastasize (Nature 2007;449:557-63). In effect, the primary tumor acts like a filling station, giving these tumor cells more energy to go out and metastasize in different sites.

Although such studies remain animal models, I think we can say there is a basis for primary tumor therapy in the metastatic setting. A dozen or more retrospective studies of large institutional series, cancer databases, and population-based studies have examined outcomes in women treated with and without surgical resection. Data on about 30,000 women have been published, with about 50% receiving some form of primary tumor therapy. The survival benefit across them is quite consistent, with the hazard ratio of death over a given time period reduced from 30% to 50%.

These studies do demonstrate selection bias: Women treated with surgical removal were more likely to be young, white, married, with smaller tumors and a lower burden of disease, and it is possible that they would have done better anyway. Studies have also shown that better survival, even in stage IV cancer, occurs in women who have a therapeutic target (that is, hormone receptors or HER2). But there was still a significant survival benefit for surgery.

Surgical resection may also confer benefit by preventing the primary tumor in the breast from becoming a quality of-life problem. At Northwestern Memorial Hospital, Chicago, we conducted a study that showed the odds of symptomatic chest wall disease were far lower in the surgical group, compared with the nonsurgical group. In this 2008 study, we found that women with good local control– surgical or systemic - did better. Time to first progression was prolonged by 50% in the surgical group, while chest wall control was associated with a 60% improvement in overall survival, regardless of whether surgical resection was performed (Cancer 2008;113:2011-9).

So the question is, do we need a randomized trial? My unbiased answer is that we do – and I am the principal investigator of such a trial open to all U.S. and Canadian institutions (NCT01242800). The end points are survival, local control, and quality of life. In addition, the trial will provide an opportunity to answer biological questions regarding the relationship between the primary tumor and metastatic site. Only when we have samples of primary and metastatic tumors can we settle this continuing debate.

Dr. Seema Khan is the Bluhm Family Professor of Cancer Research at the Lurie Comprehensive Cancer Center, Chicago.

No – Case Selection Bias Is Behind the Survival Advantage.

By Dr. Blake Cady

It’s true that some studies show an increase in stage IV breast cancer survival after primary site resection – but this more likely reflects a bias of case selection than a true benefit of local therapy.

Any findings of positive benefit other than case selection must be biologically plausible. The suggestion that the primary tumor releases some sort of growth-promoting substance that is gone when you remove the tumor, inhibiting metastatic disease has not yet been proven in humans; nor has the proposition that continued cell shedding might further metastasis.

Decreased tumor burden has sometimes been shown to increase the usefulness of systemic therapy, but I think that, all in all, case selection simply promotes breast surgery in patients with a better prognosis.

To show improved survival, we must find causality and not simply coincidence. Findings from large case series or cancer databases are unable to provide the answer. Although registry interpretations can provide basic data, they often break down when you attempt to extract detailed data.

Sometimes a stage IV cancer is registered initially on the basis of a pulmonary or liver shadow on imaging, which later is proven not to have been metastatic disease – and the case is never amended in the registry. There are also registry misinterpretations of the type of surgery that’s been done.

We performed a matched pair analysis of stage IV breast cancer patients with and without resection of the primary tumor. This was based on the Partners Health Care Consortium cancer database, which included information on 19,464 invasive breast cancers treated between 1970 and 2002; 808 of these (4%) were recorded as stage IV. Of these, 622 were analyzed by case matching that considered age, diagnostic date, metastatic disease location, estrogen-receptor status, and systemic therapy (Ann. Surg. Oncol. 2008; 15:3384-95).

It’s absolutely true that there was a statistically significant difference in survival in the overall comparison of surgery vs. no surgery. With bone metastases only, it was still statistically significant, but with a substantially lower difference in survival. In visceral metastases, the difference became nonsignificant.

Looking at therapy sequence in those who had the same type of systemic therapy, but with chemotherapy before or after surgery, you see a suggestion that giving systemic therapy first with a clinical response, which is a favorable prognostic indication, leads to a selection bias in choosing patients for surgery.

I reviewed the 86 cases who survived 5 years with records available. In those records, 22 were actually not stage IV disease, leaving 64 with confirmed stage IV (M1) – an overall 10% 5-year survival rate. Patients who survived were significantly younger than those who did not survive, significantly more likely to have estrogen receptor-positive tumors, and significantly more likely to have bone rather than visceral metastases or oligometastatic disease – all of which are good prognostic factors.

Among the 64 5-year survivors, 25 had therapeutic breast surgery. Of these, 8 had an excellent chemotherapy response followed by breast surgery; 8 had delayed surgery following a failure of systemic therapy; 7 had an initial therapeutic and curative surgery, but staging revealed metastases because of unexpected positive nodes; and 2 had initial surgery with oligometastatic resection.

Thirty-nine patients had no therapeutic breast surgery, and, of these, 16 had an excellent response to systemic therapy; 15 had slowly progressive disease; and 8 had oligometastatic disease – a positive prognostic factor. Thus, favorable prognostic factors led to a selection of primary-site surgery, whereas poor prognostic factors mean that primary-site surgery was avoided, contradicting the assumption of its therapeutic benefit.

There were also surgical discrepancies among the 5-year survivors. The registry listed 11 as having had breast surgery, while a chart review showed that surgery was not therapeutic. Five were listed as having no breast surgery, while they had indeed undergone a therapeutic operation.

Cancer registry data are not reliable for defining stage IV disease, discriminating advanced local disease with bone involvement from true distant, imaging-confirmed metastasis, or assessing surgical procedures. Case selection bias accounts for most, if not all, of the apparent survival advantage.

Dr. Blake Cady is professor of surgery (emeritus) at Harvard Medical School, Boston, and at Brown University, Providence, R.I.

The recent bevacizumab (Avastin) hearing yielded a result that was not surprising, as the jury, or ODAC [Oncologic Drugs Advisory Committee], members were largely the reviewers who participated in last year's discussion and negative vote. Furthermore, in this era of attempting to have impartial experts by eliminating those with scientific or financial conflicts, it was unfortunate that the panel consisted of so few breast cancer specialists.

Seemingly lost in the emotion of the debate was the simple fact that the addition of bevacizumab to standard therapy reached statistically positive end points in each of the randomized, well-controlled, first-line metastatic breast cancer studies.

The results are complicated by the use of different chemotherapy combinations with Avastin. It is not logical to expect the same outcomes with each regimen. While the "magnitude of benefit" and the lack of an overall survival advantage would certainly have an effect on the prescribing patterns of medical oncologists, those factors do not seem sufficient to withdraw the labeled indication.

The safety and toxicity issues also appear overstated for an agent still approved and widely used in colon, lung, kidney, and brain cancer. The 2 days of hearings were filled with passion and emotion.

It will be interesting to see whether FDA Commissioner Dr. Margaret Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients. For example, the treatment of subsets of women with limited options, such as those with triple-negative breast cancer, could still be part of a more restricted label, as could the treatment of those women already receiving the agent.

Requiring further clinical research, including the investigation of predictive biomarkers, as the sponsor has proposed, is also a reasonable course of action while maintaining the current accelerated approval with paclitaxel. Strategies for oncology drug development, the use of the accelerated approval process, and the design of clinical trials will be greatly affected by this very important decision.

-Howard A. Burris III, M.D.

-William J. Gradishar, M.D.

-Hope S. Rugo, M.D.

Dr. Burris, editor of The Oncology Report, is chief medical officer and director of drug development at the Sarah Cannon Research Institute in Nashville. Dr. Gradishar and Dr. Rugo are associate editors of The Oncology Report. Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology and director of the Maggie Daley Center For Women's Cancer Care at the Robert H. Lurie Comprehensive Cancer Center and Northwestern University Feinberg School of Medicine in Chicago. Dr. Rugo is clinical professor of medicine and director, Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

The recent bevacizumab (Avastin) hearing yielded a result that was not surprising, as the jury, or ODAC [Oncologic Drugs Advisory Committee], members were largely the reviewers who participated in last year's discussion and negative vote. Furthermore, in this era of attempting to have impartial experts by eliminating those with scientific or financial conflicts, it was unfortunate that the panel consisted of so few breast cancer specialists.

Seemingly lost in the emotion of the debate was the simple fact that the addition of bevacizumab to standard therapy reached statistically positive end points in each of the randomized, well-controlled, first-line metastatic breast cancer studies.

The results are complicated by the use of different chemotherapy combinations with Avastin. It is not logical to expect the same outcomes with each regimen. While the "magnitude of benefit" and the lack of an overall survival advantage would certainly have an effect on the prescribing patterns of medical oncologists, those factors do not seem sufficient to withdraw the labeled indication.

The safety and toxicity issues also appear overstated for an agent still approved and widely used in colon, lung, kidney, and brain cancer. The 2 days of hearings were filled with passion and emotion.

It will be interesting to see whether FDA Commissioner Dr. Margaret Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients. For example, the treatment of subsets of women with limited options, such as those with triple-negative breast cancer, could still be part of a more restricted label, as could the treatment of those women already receiving the agent.

Requiring further clinical research, including the investigation of predictive biomarkers, as the sponsor has proposed, is also a reasonable course of action while maintaining the current accelerated approval with paclitaxel. Strategies for oncology drug development, the use of the accelerated approval process, and the design of clinical trials will be greatly affected by this very important decision.

-Howard A. Burris III, M.D.

-William J. Gradishar, M.D.

-Hope S. Rugo, M.D.

Dr. Burris, editor of The Oncology Report, is chief medical officer and director of drug development at the Sarah Cannon Research Institute in Nashville. Dr. Gradishar and Dr. Rugo are associate editors of The Oncology Report. Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology and director of the Maggie Daley Center For Women's Cancer Care at the Robert H. Lurie Comprehensive Cancer Center and Northwestern University Feinberg School of Medicine in Chicago. Dr. Rugo is clinical professor of medicine and director, Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

The recent bevacizumab (Avastin) hearing yielded a result that was not surprising, as the jury, or ODAC [Oncologic Drugs Advisory Committee], members were largely the reviewers who participated in last year's discussion and negative vote. Furthermore, in this era of attempting to have impartial experts by eliminating those with scientific or financial conflicts, it was unfortunate that the panel consisted of so few breast cancer specialists.

Seemingly lost in the emotion of the debate was the simple fact that the addition of bevacizumab to standard therapy reached statistically positive end points in each of the randomized, well-controlled, first-line metastatic breast cancer studies.

The results are complicated by the use of different chemotherapy combinations with Avastin. It is not logical to expect the same outcomes with each regimen. While the "magnitude of benefit" and the lack of an overall survival advantage would certainly have an effect on the prescribing patterns of medical oncologists, those factors do not seem sufficient to withdraw the labeled indication.

The safety and toxicity issues also appear overstated for an agent still approved and widely used in colon, lung, kidney, and brain cancer. The 2 days of hearings were filled with passion and emotion.

It will be interesting to see whether FDA Commissioner Dr. Margaret Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients. For example, the treatment of subsets of women with limited options, such as those with triple-negative breast cancer, could still be part of a more restricted label, as could the treatment of those women already receiving the agent.

Requiring further clinical research, including the investigation of predictive biomarkers, as the sponsor has proposed, is also a reasonable course of action while maintaining the current accelerated approval with paclitaxel. Strategies for oncology drug development, the use of the accelerated approval process, and the design of clinical trials will be greatly affected by this very important decision.

-Howard A. Burris III, M.D.

-William J. Gradishar, M.D.

-Hope S. Rugo, M.D.

Dr. Burris, editor of The Oncology Report, is chief medical officer and director of drug development at the Sarah Cannon Research Institute in Nashville. Dr. Gradishar and Dr. Rugo are associate editors of The Oncology Report. Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology and director of the Maggie Daley Center For Women's Cancer Care at the Robert H. Lurie Comprehensive Cancer Center and Northwestern University Feinberg School of Medicine in Chicago. Dr. Rugo is clinical professor of medicine and director, Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

In a move that should surprise no one, the National Comprehensive Cancer Network’s panel of breast cancer experts has voted 24-0-1 to stand by its endorsement of bevacizumab (Avastin) for metastatic breast cancer.

Photo credit: Flickr user Earls37a (CC)

The unanimous vote echoes the position taken by the panel at the NCCN’s annual conference earlier this year. “The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?” panel chair Dr. Robert W. Carlson of Stanford (Calif.) University said at that time.

The new endorsement is not the strongest, with an evidence designation of 2A, but the expert panel called bevacizumab in combination with paclitaxel “an appropriate therapeutic option for metastatic breast cancer.”

The panel conveyed its thinking in the following footnote:

“Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.”

The unanimity of NCCN panel’s stance – in direct opposition to the unanimity of the Food and Drug Administration’s Oncologic Drugs Advisory Committee’s 6-0 vote in favor of withdrawing Avastin’s indication for metastatic breast cancer does raise the question of how the proposed withdrawal is viewed by breast cancer experts.

But breast specialists were in short supply on the pared-down advisory committee — a reality noted in a joint comment by Dr. Howard A. Burris III, editor of The Oncology Report, and associate editors Dr. Hope S. Rugo and Dr. William J. Gradishar. In the comment, posted online in advance of print publication, the three oncologists wonder whether “FDA Commissioner [Dr. Margaret] Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients.”

The Pink Sheet, a sister publication of The Oncology Report, tallied 34 speakers in the public portion of last month’s sturm-und-drang hearing — 4 favoring withdrawal, 22 against, 1 defending the pivotal Eastern Cooperative Oncology Group E2100 study, 1 calling for better collaboration on breast biomarker research, and 6 “who generally opposed withdrawing the [metastatic breast cancer] claim but spoke primarily to express concerns about FDA approval standards and the potential impact a withdrawal decision could have on development and approval of oncology treatments in settings beyond breast cancer.”

Public comments on the proposed withdrawal were due to close today, July 28. It will be interesting to see how comments stack up after the mishmash that came in on Medicare’s deliberations over coverage for the prostate cancer drug Provenge.

Meanwhile, the dueling parties — Genentech, Inc. and the FDA’s Center for Drug Evaluation and Research — have been granted an extra week until Aug. 4 for their post-hearing submissions. Considering the current stalemate in Congress, one can only wonder whether there will be anyone at the FDA to read them.

– Jane Salodof MacNeil

In a move that should surprise no one, the National Comprehensive Cancer Network’s panel of breast cancer experts has voted 24-0-1 to stand by its endorsement of bevacizumab (Avastin) for metastatic breast cancer.

Photo credit: Flickr user Earls37a (CC)

The unanimous vote echoes the position taken by the panel at the NCCN’s annual conference earlier this year. “The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?” panel chair Dr. Robert W. Carlson of Stanford (Calif.) University said at that time.

The new endorsement is not the strongest, with an evidence designation of 2A, but the expert panel called bevacizumab in combination with paclitaxel “an appropriate therapeutic option for metastatic breast cancer.”

The panel conveyed its thinking in the following footnote:

“Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.”

The unanimity of NCCN panel’s stance – in direct opposition to the unanimity of the Food and Drug Administration’s Oncologic Drugs Advisory Committee’s 6-0 vote in favor of withdrawing Avastin’s indication for metastatic breast cancer does raise the question of how the proposed withdrawal is viewed by breast cancer experts.

But breast specialists were in short supply on the pared-down advisory committee — a reality noted in a joint comment by Dr. Howard A. Burris III, editor of The Oncology Report, and associate editors Dr. Hope S. Rugo and Dr. William J. Gradishar. In the comment, posted online in advance of print publication, the three oncologists wonder whether “FDA Commissioner [Dr. Margaret] Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients.”

The Pink Sheet, a sister publication of The Oncology Report, tallied 34 speakers in the public portion of last month’s sturm-und-drang hearing — 4 favoring withdrawal, 22 against, 1 defending the pivotal Eastern Cooperative Oncology Group E2100 study, 1 calling for better collaboration on breast biomarker research, and 6 “who generally opposed withdrawing the [metastatic breast cancer] claim but spoke primarily to express concerns about FDA approval standards and the potential impact a withdrawal decision could have on development and approval of oncology treatments in settings beyond breast cancer.”

Public comments on the proposed withdrawal were due to close today, July 28. It will be interesting to see how comments stack up after the mishmash that came in on Medicare’s deliberations over coverage for the prostate cancer drug Provenge.

Meanwhile, the dueling parties — Genentech, Inc. and the FDA’s Center for Drug Evaluation and Research — have been granted an extra week until Aug. 4 for their post-hearing submissions. Considering the current stalemate in Congress, one can only wonder whether there will be anyone at the FDA to read them.

– Jane Salodof MacNeil

In a move that should surprise no one, the National Comprehensive Cancer Network’s panel of breast cancer experts has voted 24-0-1 to stand by its endorsement of bevacizumab (Avastin) for metastatic breast cancer.

Photo credit: Flickr user Earls37a (CC)

The unanimous vote echoes the position taken by the panel at the NCCN’s annual conference earlier this year. “The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?” panel chair Dr. Robert W. Carlson of Stanford (Calif.) University said at that time.

The new endorsement is not the strongest, with an evidence designation of 2A, but the expert panel called bevacizumab in combination with paclitaxel “an appropriate therapeutic option for metastatic breast cancer.”

The panel conveyed its thinking in the following footnote:

“Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.”

The unanimity of NCCN panel’s stance – in direct opposition to the unanimity of the Food and Drug Administration’s Oncologic Drugs Advisory Committee’s 6-0 vote in favor of withdrawing Avastin’s indication for metastatic breast cancer does raise the question of how the proposed withdrawal is viewed by breast cancer experts.

But breast specialists were in short supply on the pared-down advisory committee — a reality noted in a joint comment by Dr. Howard A. Burris III, editor of The Oncology Report, and associate editors Dr. Hope S. Rugo and Dr. William J. Gradishar. In the comment, posted online in advance of print publication, the three oncologists wonder whether “FDA Commissioner [Dr. Margaret] Hamburg is able to hear through the noise and reach a compromise that will be the best for our patients.”

The Pink Sheet, a sister publication of The Oncology Report, tallied 34 speakers in the public portion of last month’s sturm-und-drang hearing — 4 favoring withdrawal, 22 against, 1 defending the pivotal Eastern Cooperative Oncology Group E2100 study, 1 calling for better collaboration on breast biomarker research, and 6 “who generally opposed withdrawing the [metastatic breast cancer] claim but spoke primarily to express concerns about FDA approval standards and the potential impact a withdrawal decision could have on development and approval of oncology treatments in settings beyond breast cancer.”

Public comments on the proposed withdrawal were due to close today, July 28. It will be interesting to see how comments stack up after the mishmash that came in on Medicare’s deliberations over coverage for the prostate cancer drug Provenge.

Meanwhile, the dueling parties — Genentech, Inc. and the FDA’s Center for Drug Evaluation and Research — have been granted an extra week until Aug. 4 for their post-hearing submissions. Considering the current stalemate in Congress, one can only wonder whether there will be anyone at the FDA to read them.

– Jane Salodof MacNeil